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Summary of Symptoms

Drowsiness
Allopurinol may cause drowsiness.
Captopril may cause drowsiness.
Clonidine may cause drowsiness.
Gemfibrozil may cause drowsiness.
Hydrochlorothiazide may cause drowsiness.
Verapamil may cause drowsiness.
Captopril and naproxen in combination may cause a symptom that is related to drowsiness
Captopril and allopurinol in combination may cause a symptom that is related to drowsiness
Simvastatin may cause symptoms that are related to drowsiness
Niacin may cause a symptom that is related to drowsiness
Naproxen may cause symptoms that are related to drowsiness
Levothyroxine may cause symptoms that are related to drowsiness
HydrALAZINE may cause a symptom that is related to drowsiness
Erectile dysfunction
Simvastatin may cause erectile dysfunction.
Verapamil may cause symptoms that are related to erectile dysfunction
Niacin may cause a symptom that is related to erectile dysfunction
HydrALAZINE may cause a symptom that is related to erectile dysfunction
Gemfibrozil may cause symptoms that are related to erectile dysfunction
Clonidine may cause symptoms that are related to erectile dysfunction
Genital problems
Simvastatin may cause a symptom that is related to genital problems
Gemfibrozil may cause a symptom that is related to genital problems
Gout-like arthritis
Captopril and allopurinol in combination may cause a symptom that is related to gout-like arthritis
Verapamil may cause a symptom that is related to gout-like arthritis
Simvastatin may cause symptoms that are related to gout-like arthritis
Naproxen may cause a symptom that is related to gout-like arthritis
Hydrochlorothiazide may cause symptoms that are related to gout-like arthritis
HydrALAZINE may cause symptoms that are related to gout-like arthritis
Gemfibrozil may cause symptoms that are related to gout-like arthritis
Clonidine may cause symptoms that are related to gout-like arthritis
Captopril may cause symptoms that are related to gout-like arthritis
Allopurinol may cause symptoms that are related to gout-like arthritis
Hearing loss
Levothyroxine and simvastatin in combination may cause a symptom that is related to hearing loss
Naproxen may cause a symptom that is related to hearing loss
Levothyroxine may cause symptoms that are related to hearing loss
Heart disease due to high blood pressure
Naproxen and hydrochlorothiazide in combination may cause a symptom that is related to heart disease due to high blood pressure
Verapamil may cause a symptom that is related to heart disease due to high blood pressure
Naproxen may cause a symptom that is related to heart disease due to high blood pressure
Levothyroxine may cause a symptom that is related to heart disease due to high blood pressure
Hydrochlorothiazide may cause a symptom that is related to heart disease due to high blood pressure
HydrALAZINE may cause symptoms that are related to heart disease due to high blood pressure
Clonidine may cause a symptom that is related to heart disease due to high blood pressure
Captopril may cause a symptom that is related to heart disease due to high blood pressure
Numbness or tingling
HydrALAZINE may cause numbness or tingling (common).
Gemfibrozil may cause numbness or tingling.
Hydrochlorothiazide may cause numbness or tingling.
Simvastatin may cause numbness or tingling.
Verapamil may cause numbness or tingling in less than 1% of people.
Allopurinol may cause numbness or tingling (first sign that a side effect is occuring).
Niacin may cause numbness or tingling (rare).
Naproxen may cause a symptom that is related to numbness or tingling
Clonidine may cause symptoms that are related to numbness or tingling
Captopril may cause symptoms that are related to numbness or tingling
Ringing in the ears
Naproxen may cause ringing in the ears.
Verapamil may cause ringing in the ears.
HydrALAZINE may cause a symptom that is related to ringing in the ears
Clonidine may cause a symptom that is related to ringing in the ears
Swelling of the hands or feet
HydrALAZINE may cause swelling of the hands or feet (uncommon).
Naproxen and hydrochlorothiazide in combination may cause a symptom that is related to swelling of the hands or feet
Verapamil may cause symptoms that are related to swelling of the hands or feet
Simvastatin may cause symptoms that are related to swelling of the hands or feet
Niacin may cause symptoms that are related to swelling of the hands or feet
Naproxen may cause symptoms that are related to swelling of the hands or feet
Gemfibrozil may cause symptoms that are related to swelling of the hands or feet
Clonidine may cause symptoms that are related to swelling of the hands or feet
Captopril may cause symptoms that are related to swelling of the hands or feet
Allopurinol may cause a symptom that is related to swelling of the hands or feet
Acetaminophen may cause a symptom that is related to swelling of the hands or feet
Throbbing headache
Verapamil may cause symptoms that are related to throbbing headache
Simvastatin may cause symptoms that are related to throbbing headache
Niacin may cause a symptom that is related to throbbing headache
Naproxen may cause symptoms that are related to throbbing headache
Levothyroxine may cause a symptom that is related to throbbing headache
Hydrochlorothiazide may cause a symptom that is related to throbbing headache
HydrALAZINE may cause symptoms that are related to throbbing headache
Gemfibrozil may cause a symptom that is related to throbbing headache
Clonidine may cause symptoms that are related to throbbing headache
Captopril may cause a symptom that is related to throbbing headache
Allopurinol may cause symptoms that are related to throbbing headache

       
 
Drowsiness
Allopurinol may cause drowsiness.

This drug may also cause the following symptoms that are related to drowsiness:

  • Kidney failure (common)
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Note: Original Source for Medical Professionals
Allopurinol should be discontinued at the first sign of skin rash or any other signs or symptoms suggestive of a hypersensitivity reaction. In some instances, a skin rash may be followed by more severe adverse reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, rarely, death. Renal dysfunction increases the risk of allopurinol hypersensitivity.

Because allopurinol has been associated with drowsiness, patients should be cautious when engaging in activities where alertness is mandatory.

Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN during allopurinol therapy. Although the mechanism responsible for this has not been determined, patients with impaired renal function should be carefully monitored during the early stages of allopurinol use and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. Renal failure in association with allopurinol use has been reported among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunction increased after allopurinol therapy was started. Renal failure is frequently observed with the use of allopurinol therapy. Albuminemia has been observed in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. Patients with decreased renal function require lower doses of allopurinol therapy than those with normal renal function. Periodic monitoring of renal function is recommended during the course of therapy.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using allopurinol and call your doctor at once if you have any of these serious side effects: the first sign of any skin rash, no matter how mild; pain or bleeding when you urinate; urinating less than usual or not at all; fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; bruising, severe tingling, numbness, pain, muscle weakness; easy bruising or bleeding, unusual weakness; fever, chills, body aches, flu symptoms; jaundice (yellowing of the skin or eyes); or seizure (convulsions). Less serious side effects may include: nausea, vomiting, diarrhea; dizziness or drowsiness; increased sweating; or joint pain. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

 
       
 
Drowsiness
Captopril may cause drowsiness.

This drug may also cause the following symptoms that are related to drowsiness:

  • Insomnia and other sleep problems
  • Mania (rare)
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Note: Original Source for Medical Professionals
Get emergency medical help if you have any of these signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: feeling light-headed, fainting; urinating more or less than usual, or not at all; fever, chills, body aches, flu symptoms; pale skin, easy bruising or bleeding; fast, pounding, or uneven heartbeats; chest pain; or swelling, rapid weight gain. Less serious side effects may include: cough; loss of taste sensation, loss of appetite; dizziness, drowsiness, headache; sleep problems (insomnia); dry mouth, sores in the mouth or on the lips; nausea, diarrhea, constipation; or mild skin itching or rash. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Psychiatric side effects have rarely included mania.

 
       
 
Drowsiness
Clonidine may cause drowsiness.

This drug may also cause the following symptoms that are related to drowsiness:

  • Decreased alertness/consciousness. This symptom may occur with a history of spinal cord defects
  • Decreased blood flow to the brain
  • Insomnia and other sleep problems
  • Encephalopathy (rare). This symptom may occur when the drug is stopped or dose is decreased
  • Stroke (rare). This symptom may occur when the drug is stopped or dose is decreased
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Note: Original Source for Medical Professionals
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: fast or pounding heartbeats; a very slow heart rate (fewer than 60 beats per minute); feeling short of breath, even with mild exertion; swelling, rapid weight gain; confusion, hallucinations; fever, pale skin; urinating less than usual or not at all; or feeling like you might pass out. Less serious side effects may include: feeling dizzy, drowsy, tired, or nervous; dry mouth; dry or burning eyes, blurred vision; headache, muscle or joint pain; nausea, vomiting, constipation, loss of appetite; sleep problems (insomnia); urinating more at night; mild skin rash or itching; or decreased sex drive, impotence. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Nervous system side effects have included drowsiness (28%), dizziness (9%). Patients with decreased autoregulation of cerebral blood flow appear to be at increased risk for clonidine-induced cerebral hypoperfusion if blood pressure is lowered too much or too quickly. This may be important in some elderly patients. Confusion (13.2%) and hallucinations (5.3%) have been reported with epidural usage. Dose-dependent sedative effects, memory impairment, and reduced cognitive performance have been reported in subjects receiving intravenous clonidine.

A study of 13 patients who had pre- and post-clonidine cerebral blood flow (CBF) measured by nuclear scanning revealed that patients with an initially high pretreatment CBF tended to demonstrate decreased CBF after clonidine therapy. Patients with traumatic spinal cord injury receiving clonidine may experience a delayed-onset of sedation regardless of the route of administration (i.e., intrathecal, intramuscular).

Epidural administration is contraindicated in patients receiving anticoagulant therapy, patients with bleeding diathesis, and in the presence of an injection site infection.

Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine can result in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of clonidine transdermal therapy can be reversed by administration of oral clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine transdermal therapy.

REFERENCE +

  1. Is clonidine an effective smoking cessation therapy? Gourlay SG, Benowitz NL Drugs 1995;50:197-207.
  2. A dose-response study of orally administered clonidine as premedication in the elderly - evaluating hemodynamic safety. Filos KS, Patroni O, Goudas LC, Bosas O, Kassaras A, Gartaganis S Anesth Analg 1993;77:1185-92.
  3. Cerebral blood flow during the acute therapy of severe hypertension with oral clonidine. Greene CS, Gretler DD, Cervenka K, et al Am J Emerg Med 1990;8:293-6.
  4. Product Information. Duraclon Injection (clonidine) Anonymous Roxane Laboratories Inc, Columbus, OH. PROD;
  5. Sedation caused by clonidine in patients with spinal cord injury. Malinovsky JM, Malinge M, Lepage JY, Pinaud M Br J Anaesth 2003;90:742-745.
  6. CNS side effects of centrally-active antihypertensive agents: a prospective, placebo-controlled study of sleep, mood state, and cognitive and sexual function in hypertensive males. Kostis JB, Rosen RC, Holzer BC, et al Psychopharmacology (Berl) 1990;102:163-70.
  7. Epidural clonidine analgesia for intractable cancer pain. Eisenach JC, Dupen S, Dubois M, Miguel R, Allin D, Bryce D, Burger GA, Chamberlain D, Docherty R, Evans G, Finnegan R, Hantler Pain 1995;61:391-9.
  8. Rebound phenomena in Tourette's syndrome after abrupt withdrawal of clonidine: behavioral, cardiovascular, and neurochemical effects. Leckman JF, Ort S, Caruso KA, et al Arch Gen Psychiatry 1986;43:1168-76.
  9. Sedative, analgesic and cognitive effects of clonidine infusions in humans. Hall JE, Uhrich TD, Ebert TJ Br J Anaesth 2001;86:5-11.
  10. Safety aspects of long-term antihypertensive therapy (10 years) with clonidine. Ferder L, Inserra F, Medina F J Cardiovasc Pharmacol 1987;10:s104-8.
 
       
 
Drowsiness
Gemfibrozil may cause drowsiness.

This drug may also cause the following symptoms that are related to drowsiness:

  • Drug withdrawal symptoms
  • Kidney failure
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Note: Original Source for Medical Professionals
Concurrent administration of gemfibrozil with cerivastatin is contraindicated due to the increased risk of myopathy and rhabdomyolysis. Gemfibrozil is considered contraindicated in patients with a history of gallbladder disease. Gemfibrozil decreases bile acid and increases cholesterol secretion thus increasing the lithogenicity of the bile and promoting gallstone formation. Gemfibrozil is contraindicated for use in patients with clinically significant renal or hepatic dysfunction, including patients with primary biliary cirrhosis or persistent hepatic abnormalities.

Periodic determination of serum lipids should be obtained, and the drug withdrawn if lipid response is inadequate after three months of treatment.

Nervous system side effects of gemfibrozil include dizziness, somnolence, headache, vertigo, hyperesthesia, paresthesias, taste perversion, and confusion.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: sharp pain in your upper stomach (especially after eating); jaundice (yellowing of your skin or eyes); blurred vision, eye pain, or seeing halos around lights; or pain or burning when you urinate. Less serious side effects may include: heartburn, upset stomach; nausea, vomiting, diarrhea, constipation, stomach pain; dizziness, spinning sensation; drowsiness, tired feeling; unusual or unpleasant taste in your mouth; cough or cold symptoms; numbness or tingly feeling; joint or muscle pain; mild skin rash; or blurred vision. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Musculoskeletal side effects of gemfibrozil include arthralgia, myopathy, myalgia, polyarthritis, and rhabdomyolysis. Myositis induced compartment syndrome is reported in one patient.

Gemfibrozil has been associated with severe myopathy and rhabdomyolysis. This is accompanied by elevations in creatine kinase, myoglobinuria, and proteinuria, as well as renal failure. Elevations in creatine kinase are more marked when gemfibrozil has been combined with another agent which is also capable of causing myopathy (i.e., HMG CoA reductase inhibitors, niacin). One review noted a case report with a creatine kinase level of 148,000 units/mL in a 79-year-old woman taking both gemfibrozil and lovastatin. Additional studies have confirmed that the combination of gemfibrozil and a HMG CoA reductase inhibitor increases the incidence and severity of myotoxicity. Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and, if elevated, gemfibrozil should be discontinued. Gemfibrozil is associated with a higher incidence of myotoxicity (i.e., rhabdomyolysis) than fenofibrate when used in combination with any HMG CoA reductase inhibitor (statin). Fenofibrate is primarily metabolized by glucuronidation, whereas gemfibrozil undergoes extensive oxidative metabolism which results in higher plasma levels of statins. This pharmacokinetic difference may account for the differences in the rates of myotoxicity.

Renal side effects of gemfibrozil include acute renal failure associated with myositis and rhabdomyolysis.

Gemfibrozil is reported to cause rhabdomyolysis and subsequent renal failure. In one review, all patients in whom outcome was reported either significantly improved or completely recovered.

REFERENCE +

  1. Product Information. Lopid (gemfibrozil). Anonymous Parke-Davis, Morris Plains, NJ. PROD;
  2. Polymyositis exacerbated by gemfibrozil . Fusella J, Strosberg JM J Rheumatol 1990;17:572-3.
  3. Gemfibrozil-induced headache . Alvarez-Sabin J, Codina A, Rodriguez C, Laporte JR Lancet 1988;2:1246.
  4. Gemfibrozil-induced headache . Arellano F, de Cos MA, Valiente R, Quiros C Lancet 1988;1:705.
 
       
 
Drowsiness
Hydrochlorothiazide may cause drowsiness.

This drug may also cause the following symptoms that are related to drowsiness:

  • Brain dysfunction
  • Coma that occurs with advanced liver disease. This symptom may occur with a history of severe liver disease or severely abnormal liver blood tests
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Note: Original Source for Medical Professionals
Hydrochlorothiazide is contraindicated in patients with anuria.

Caution is recommended in patients with hepatic dysfunction or progressive hepatic disease. Thiazides can precipitate hepatic coma in patients with severe liver disease.

Nervous system side effects including cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction. At least one case of cognitive and neurologic impairment (i.e., confusion, somnolence, feeling dazed) has been reported. Symptoms immediately resolved following discontinuation of hydrochlorothiazide.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as: dry mouth, thirst, nausea, vomiting; feeling weak, drowsy, restless, or light-headed; fast or uneven heartbeat; muscle pain or weakness; numbness or tingly feeling; a red, blistering, peeling skin rash; or nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes). Less serious side effects may include: diarrhea; mild stomach pain; constipation; or blurred vision. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

REFERENCE +

  1. Life-threatening reaction to thiazides. Gould L, Reddy CV, Zen B, Singh BK N Y State J Med 1980;80:1975-6.
  2. Cognitive and neurologic impairment with hydrochlorothiazide. Daugherty KK, Subramanian J Am J Health Syst Pharm 2005;62:2630-3.
  3. Comparison of the efficacy and metabolic effects of nicardipine and hydrochlorothiazide in hypertensive black men and women. Weir MR, Wright JT, Jr Ferdinand KC, Cook CA, Champion D, Wong S, Jenkins PA, Kong BW J Hum Hypertens 1993;7:141-7.
 
       
 
Drowsiness
Verapamil may cause drowsiness.

This drug may also cause the following symptoms that are related to drowsiness:

  • Lethargy in less than 3.2% of people
  • Insomnia and other sleep problems in less than 1.4% of people
  • Increased pressure inside the head. This symptom may occur with a history of increased risk of tumors/cancers
  • Kidney failure
  • Stroke
  • Brain dysfunction (rare)
  • Kidney failure that continues to worsen over time (rare)
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Note: Original Source for Medical Professionals
Nervous system side effects have included headache (up to 12.1%), dizziness (up to 4.7%), lethargy (up to 3.2%), fatigue (up to 4.5%), sleep disturbances (up to 1.4%), paresthesia (up to 1%), and rare neurologic complaints (including paresthesias, sleeping problems, and tremors; less than 1%). Dizziness (1.2%), headache (1.2%), sleepiness, vertigo, and rare cases of seizures during injection have been reported with intravenous verapamil. Rare cases of muscle fasciculations in patients with underlying neuromuscular diseases, stroke associated with verapamil-induced hypotension, exacerbation of myasthenia gravis, and myoclonic dystonia have been reported. Cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, paresthesia, shakiness, somnolence, syncope, and tinnitus have been reported during open trials/postmarketing experience.

Verapamil is contraindicated in hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock, in sick sinus syndrome or second- or third-degree AV block in patients without a functioning artificial ventricular pacemaker, and in patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). In addition, oral verapamil is contraindicated in severe left ventricular dysfunction and intravenous verapamil is contraindicated in severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy), in patients receiving intravenous beta-adrenergic blocking drugs, and in ventricular tachycardia. Intravenous verapamil is contraindicated within a few hours of administration of intravenous beta-adrenergic blocking agents since both may depress myocardial contractility and AV conduction. Intravenous verapamil is contraindicated in patients with wide complex ventricular tachycardia (QRS less than 0.12 sec) due to the risk of marked hemodynamic deterioration and ventricular fibrillation.

Significant hepatic and renal failure should not increase the effects of a single intravenous dose of verapamil but may prolong its duration. Repeated injections of intravenous verapamil in patients with significant hepatic and renal failure may lead to accumulation and an excessive pharmacologic effect of the drug. In general, multiple doses should be avoided in such patients. If repeated injections are essential, blood pressure and PR interval should be closely monitored and smaller repeat doses are recommended.

Increased intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction has been reported with intravenous verapamil. Caution and appropriate monitoring are recommended.

Renal side effects have included rare cases of oliguria and worsened renal function in patients with preexisting chronic renal failure.

Rare cases of hypertensive patients with chronic renal failure who developed acute oliguric renal failure after receiving verapamil have been reported. These patients also developed symptomatic hypotension associated with slow cardiac arrhythmias.

REFERENCE +

  1. Product Information. Covera-HS (verapamil). Anonymous Searle, Skokie, IL. PROD;
  2. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
  3. Case report: sustained-release verapamil overdose causing stroke: an unusual complication. Shah AR, Passalacqua BR Am J Med Sci 1992;304:357-9.
  4. Verapamil and acute dystonia. Pina MA, Ara JR, Remirez A, Castiella J J Clin Pharm Ther 1998;23:79-80.
  5. Long-term safety and efficacy of immediate-release and sustained-release oral verapamil in systemic hypertension. Frishman WH, Eisen G, Charlap S, Strom JA J Clin Hypertens 1987;3:605-9.
  6. Delirium induced by verapamil. Jacobsen FM, Sack DA, James SP Am J Psychiatry 1987;144:248.
  7. Fasciculations due to verapamil in a patient with neuropathy. Thomke F, Vogt T, Roder R, Hopf HC J Neurol 1990;237:448-9.
  8. Verapamil and myoclonic dystonia. Hicks CB, Abraham K Ann Intern Med 1985;103:154.
  9. Antihypertensive efficacy of sustained-release verapamil. Zachariah PK, Sheps SG, Oshrain C, et al J Clin Hypertens 1987;3:536-46.
  10. Verapamil-induced parkinsonism. Padrell MD, Navarro M, Faura CC, Horga JF Am J Med 1995;99:436.
  11. Verapamil toxicity: treatment with hemoperfusion. Rosansky SJ Ann Intern Med 1991;114:340-1.
  12. Adverse effect of verapamil in myasthenia gravis: an additional comment. Reverte M Muscle Nerve 1993;16:879-81.
  13. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  14. Treatment of mild hypertension with low once-daily doses of a sustained-release capsule formulation of verapamil. Davis PJ, Fagan TC, Topmiller MJ, Levine JH, Ferdinand KC J Clin Pharmacol 1995;35:52-8.
  15. Verapamil in the long-term treatment of angina pectoris. Raftos J Med J Aust 1980;07/26/80:78-80.
  16. Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. McTavish D, Sorkin EM Drugs 1989;38:19-76.
 
       
 
Drowsiness
Captopril and naproxen in combination may cause the following symptom that is related to drowsiness:
  • Kidney failure
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Monitor blood pressure carefully if you are using both of these medications. Using these medications together may decrease the blood pressure-lowering effectiveness of the ACE inhibitor blood pressure medications and lead to increased blood pressure. Monitor blood pressure carefully if you are using both of these medications.

Long-term use of anti-inflammatory drug/s increases the chances of developing side effects. Long-term use of anti-inflammatory drug/s increases the chances of developing kidney inflammation, interstitial nephritis, acute tubular necrosis, kidney failure, nephrotic syndrome, abnormal kidney blood test - elevated "creatinine", renal papillary necrosis, abnormal kidney blood test - elevated "bun" or kidney damage. This drug combination of can affect kidney function.

Dose adjustments may be necessary. Blood pressure should be monitored regularly when this drug combination is taken for long periods of time. People should be observed more closely around the time that the anti-inflammatory drug/s is started or stopped, or when the dose is changed. Blood tests for kidney function should be monitored regularly in individuals who take both of these medications.
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Note: Original Source for Medical Professionals
MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effects of ACE inhibitors. The proposed mechanism is NSAID-induced inhibition of renal prostaglandin synthesis, which results in unopposed pressor activity producing hypertension. In addition, NSAIDs can cause fluid retention, which also affects blood pressure. Some NSAIDs may also alter the pharmacokinetics of certain ACE inhibitors. For example, oxaprozin has been shown to reduce the systemic exposure (AUC) of enalapril and its active metabolite, enalaprilat.

MONITOR: Concomitant use of NSAIDs and ACE inhibitors may increase the risk of renal impairment, particularly in volume-depleted patients. Chronic use of NSAIDs alone may be associated with renal toxicities, including elevations in serum creatinine and BUN, tubular necrosis, glomerulitis, renal papillary necrosis, acute interstitial nephritis, nephrotic syndrome, and renal failure. Additionally, in patients with prerenal conditions whose renal perfusion may be dependent on the function of prostaglandins, NSAIDs may precipitate overt renal decompensation via a dose-related inhibition of prostaglandin synthesis. ACE inhibitors can further worsen renal function by blocking the effect of angiotensin II-mediated efferent arteriolar vasoconstriction, thereby decreasing glomerular filtration.

MANAGEMENT: Patients receiving ACE inhibitors who require prolonged (greater than 1 week) concomitant therapy with an NSAID should have blood pressure monitored more closely following initiation, discontinuation, or change of dosage of the NSAID. Renal function should also be evaluated periodically during prolonged coadministration. The interaction is not expected to occur with low doses (e.g., low-dose aspirin) or intermittent short-term administration of NSAIDs.

REFERENCE +

  1. Effect of propranolol and indomethacin on the depressor action of captopril in patients with essential hypertension. Seto S, Aoi W, Iwami K, et al Clin Exp Hypertens 1987;9:623-7.
  2. Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. Moore TJ, Crantz FR, Hollenberg NK Hypertension 1981;3:168-73.
  3. Interaction of captopril and ibuprofen on glomerular and tubular function in humans. Allon M, Pasque CB, Rodriguez M Am J Physiol 1990;259:f233-8.
  4. Influence of non-steroidal anti-inflammatory drugs on renal function and 24h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients. Polonia J, Boaventura I, Gama G, Camoes I, Bernardo F, Andrade P, Nunes JP, Brandao F, Cerqueiragomes M J Hypertens 1995;13:925-31.
  5. Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril. Townend JN, Doran J, Lote CJ, Davies MK Br Heart J 1995;73:434-41.
  6. Product Information. Celebrex (celecoxib). Anonymous Searle, Chicago, IL. PROD;
  7. Indomethacin-enalapril interaction: an alert. Ahmad S South Med J 1991;84:411-2.
  8. Acute hypotensive effect of captopril in man modified by prostaglandin synthesis inhibition. Silberbauer K, Stanek B, Templ H Br J Clin Pharmacol 1982;14:s87-93.
  9. Product Information. Toradol (ketorolac). Anonymous Syntex Laboratories Inc, Palo Alto, CA. PROD;
  10. Hemodynamic and humoral interactions between perindopril and indomethacin in essential hypertensive subjects. Abdel-Haq B, Magagna A, Favilla S, Salvetti A J Cardiovasc Pharmacol 1991;18:s33-6.
  11. Interaction of indomethacin with felodipine and enalapril. Morgan T, Anderson A J Hypertens 1993;11:S338-9.
  12. Product Information. Daypro (oxaprozin). Anonymous Searle, Skokie, IL. PROD;
  13. Ibuprofen interferes with the efficacy of antihypertensive drugs: a randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen. Radack KL, Deck CC, Bloomfield SS Ann Intern Med 1987;107:628-35.
 
       
 
Drowsiness
Captopril and allopurinol in combination may cause the following symptom that is related to drowsiness:
  • Lethargy
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Patients who are taking captopril (captopril) and allopurinol (allopurinol) should be followed closely for signs of infection. Caution is advised if captopril (captopril) and allopurinol (allopurinol) are used together. People who are taking this drug combination should be followed closely. Serious side effects can occur with this drug combination. Cases of fatalities in individuals taking this drug combination have been reported in the medical literature. The following side effects have been mentioned in a case report: fast pulse/rapid heart rate that originates in the sinus node, nausea, hives, gout, breathing problems - tightening of the airways, significant decrease in blood pressure, generalized itching, thickening chest secretions, severe chest pain or bluish tone to fingers/toes due to lack of circulation. Some patients may experience the following side effects with the first dose of the enalapril: fast pulse/rapid heart rate that originates in the sinus node, nausea, hives, gout, breathing problems - tightening of the airways, significant decrease in blood pressure, generalized itching, thickening chest secretions, severe chest pain or bluish tone to fingers/toes due to lack of circulation. This medication combination may cause severe breathing problems due to closure of the airways.

Notify your physician if you develop: joint pain, lethargy, body pain, swelling of the tongue, skin rash, hives, sore throat/throat irritation, shortness of breath, swelling of the face, fever, tightness in the throat, infection, shaking chills, muscle pain/soreness, flu or cold-like symptoms or swelling of the lips.
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MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE) inhibitors has been associated with a risk of severe hypersensitivity reactions, neutropenia, agranulocytosis, and serious infections. The mechanism of interaction is unknown, but impaired renal function may be a predisposing factor. Case reports, albeit rare, have mostly involved captopril. Fever, myalgia, arthralgia, exfoliative dermatitis, and Stevens-Johnson syndrome (including one fatality) have been reported, with the latter occurring 3 to 5 weeks after initiation of allopurinol. In an isolated case involving enalapril, a man who had been receiving enalapril without incident developed generalized pruritus, urticaria, severe chest pain, severe nausea, peripheral cyanosis, hypotension, sinus tachycardia, and mild bronchospasm approximately 20 minutes after the first dose of allopurinol 100 mg prescribed for acute gout. Serial electrocardiograms and cardiac enzyme studies revealed evidence of acute myocardial infarction. Following recovery, the patient continued to take enalapril uneventfully without allopurinol. No pharmacokinetic interactions have been reported between allopurinol and ACE inhibitors. In a study of 12 healthy volunteers, allopurinol had no significant effect on the bioavailability of captopril.

MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor, particularly in the elderly and patients with renal impairment. Periodic monitoring of white blood cell counts is recommended. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop dyspnea; throat constriction; swelling of the face, lips, or tongue; urticaria; rash; fever; arthralgia; or myalgia. Patients should also contact their physician if they notice signs of infection or experience fever, chills, sore throat, lethargy, body aches, or other flu-like symptoms.

REFERENCE +

  1. Fatal Stevens-Johnson syndrome in a patient on captopril and allopurinol. Pennell DJ, Nunan TO, O'Doherty MJ, Croft DN Lancet 1984;1:463.
  2. Product Information. Zyloprim capsules (allopurinol). Anonymous Glaxo Wellcome, Research Triangle Park, NC. PROD;
  3. EPARs. European Union Public Assessment Reports. Available from: URL: http://www.emea.eu.int/htms/human/epar/a.htm. EMEA. European Medicines Agency [1995-2007];
  4. Fever, myalgia, and arthralgia in a patient on captopril and allopurinol. Samanta A, Burden AC Lancet 1984;1:679.
  5. Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases. Duchin KL, McKinstry DN, Cohen AI, Migdalof BH Clin Pharmacokinet 1988;14:241-59.
  6. Allopurinol and enalapril: drug induced anaphylactic coronary spasm and acute myocardial infarction. Ahmad S Chest 1995;108:586.
 
       
 
Drowsiness
Simvastatin may cause the following symptoms that are related to drowsiness:
  • Insomnia and other sleep problems.
  • Kidney failure (rare)
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Psychiatric side effects have included depression, suicidal thoughts, delusions, paranoia, and agitation; causality is unknown. In one uncontrolled study of simvastatin, psychiatric side effects were the second most frequent complaint. Other psychiatric side effects of HMG-CoA reductase inhibitors have included decreased libido, anxiety, insomnia, and nightmares.

Musculoskeletal side effects of simvastatin have included elevations in creatine kinase, myopathy, dermatomyositis, and rhabdomyolysis. Other musculoskeletal side effects reported with HMG-CoA reductase inhibitors have included arthralgia, myalgia, tendon rupture, and dermatomyositis. In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.

HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria, and renal failure. Concomitant use with gemfibrozil (fibric acid derivatives), niacin, cyclosporine, erythromycin (macrolides) or azole antifungals may increase the incidence and severity of musculoskeletal side effects. Other variables associated with an increased risk of statin-induced myopathy include, advanced age, small body stature, female gender, renal and/or hepatic dysfunction, perioperative periods, hypothyroidism, diabetes mellitus, and alcoholism. Milder forms of myotoxicity (i.e., myalgia) are commonly reported and occur in approximately 5% to 7% of patients taking a statin drug. Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if elevated, simvastatin should be discontinued. The value of regular monitoring of creatine kinase is not known. In some studies, elevations in creatine kinase occurred in up to 5.2% of patients on simvastatin. In most cases, these elevations were mild, transient, and not associated with clinical symptoms. At least six cases of simvastatin-induced rhabdomyolysis associated with concomitant use of a macrolide antibiotic (i.e., erythromycin, clarithromycin) have been reported. In all cases the patients had been receiving simvastatin routinely (40 to 80 mg/day) prior to short-term (7 to 10 days) macrolide therapy. The proposed mechanism of interaction is inhibition of CYP450 3A4 metabolism and/or P-glycoprotein transport of simvastatin. Symptoms included myalgia, muscle weakness, elevated serum creatine kinase levels, and in some patients elevated liver transaminase levels. A rare case of simvastatin-induced bilateral leg compartment syndrome and myonecrosis developed in a patient with hypothyroidism after one month of therapy with simvastatin. Following withdrawal of simvastatin and emergency fasciotomies the patient recovered.

REFERENCE +

  1. Product Information. Zocor (simvastatin). Anonymous Merck & Co, Inc, West Point, PA. PROD;
  2. Simvastatin in severe primary hypercholesterolemia: efficacy, safety, and tolerability in 595 patients over 18 weeks. The Principal Investigators. Simons LA Clin Cardiol 1993;16:317-22.
  3. Depressive symptoms and cholesterol-lowering drugs. Duits N, Bos FM Lancet 1993;341:114.
  4. Simvastatin causes changes in affective processes in elderly volunteers. Morales K, Wittink M, Datto C, et al. J Am Geriatr Soc 2006;54:70-6.
 
       
 
Drowsiness
Niacin may cause the following symptom that is related to drowsiness:
  • Insomnia and other sleep problems (rare)
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Nervous system side effects have included rare reports of paresthesias, nervousness, dizziness, headache, fatigue, and insomnia.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: feeling light-headed, fainting; fast, pounding, or uneven heart beats; feeling short of breath; swelling; jaundice (yellowing of your skin or eyes); or muscle pain, tenderness, or weakness with fever or flu symptoms and dark colored urine. If you are diabetic, tell your doctor about any changes in your blood sugar levels. Less serious side effects of niacin include: mild dizziness; warmth, redness, or tingly feeling under your skin; itching, dry skin; sweating or chills; nausea, diarrhea, belching, gas; muscle pain, leg cramps; or sleep problems (insomnia). This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

REFERENCE +

  1. Approaches to the management of hypercholesterolaemia. Florkowski CM, Cramb R J Clin Pharm Ther 1992;17:81-9.
  2. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. McKenney JM, Proctor JD, Harris S, Chinchili VM JAMA 1994;271:672-7.
  3. New approaches to cholesterol lowering: efficacy and safety. Knopp RH Hosp Pract (Off Ed) 1988;23 Suppl 1:22-30.
  4. Efficacy and safety of one-year treatment with slow-release nicotinic acid. Monitoring of drug concentration in serum. ChojnowskaJezierska J, AdamskaDyniewska H Int J Clin Pharmacol Ther 1998;36:326-32.
  5. Hepatotoxicity associated with sustained-release niacin. Dalton TA, Berry RS Am J Med 1992;93:102-4.
  6. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH, Tun P, Zupkis RV, Greguski RA Arch Intern Med 1994;154:1586-95.
  7. Choice of cholesterol-lowering drugs. Anonymous Med Lett Drugs Ther 1991;33:1-4.
  8. Clinical trial experience with extended-release niacin (Niaspan): Dose-escalation study. Goldberg AC Am J Cardiol 1998;82:u35-8.
  9. Choice of cholesterol-lowing drugs. Anonymous Med Lett Drugs Ther 1993;35:19-22.
  10. Continuous axillary brachial plexus blockade following intra-arterial injection of nicotinic acid. Dyson A, Henderson AM Anaesth Intensive Care 1987;15:462-5.
  11. Niacin revisited. A randomized, controlled trial of wax-matrix sustained-release niacin in hypercholesterolemia. Keenan JM, Fontaine PL, Wenz JB, Myers S, Huang ZQ, Ripsin CM Arch Intern Med 1991;151:1424-32.
  12. Adverse effects of sustained-release niacin. Knapp TR, Middleton RK DICP 1991;25:253-4.
  13. Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia. Davignon J, Roederer G, Montigny M, Hayden MR, Tan MH, Connelly PW, Hegele R, McPherson R, Lupien PJ, Gagne C, et al Am J Cardiol 1994;73:339-45.
  14. The prevalence of side effects with regular and sustained-release nicotinic acid. Gibbons LW, Gonzalez V, Gordon N, Grundy S Am J Med 1995;99:378-85.
  15. Product Information. Niaspan ER (niacin). Anonymous Allscripts Healthcare Solutions, Libertyville, IL.
  16. Niacin or niacinamide? Nicotinic acid or nicotinamide? What is the difference?. Ranchoff RE, Tomecki KJ J Am Acad Dermatol 1986;15:116-7.
  17. Niacin maculopathy. Millay RH, Klein ML, Illingworth DR Ophthalmology 1988;95:930-6.
  18. Efficacy and safety of an extended-release niacin (Niaspan): A long-term study. Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA, Brusco OA, Brody J Am J Cardiol 1998;82:u74-81.
  19. Niacin maculopathy. Jampol LM Ophthalmology 1988;95:1704-5.
 
       
 
Drowsiness
Naproxen may cause the following symptoms that are related to drowsiness:
  • Insomnia and other sleep problems.
  • Kidney failure. This symptom may occur in adults
  • Stroke caused by blockage of the arteries that supply blood to the brain. This symptom can lead to fatalities in severe cases
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Nervous system side effects have included inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, and cognitive dysfunction.

Hypersensitivity side effects have been reported rarely. These may result in an erythematous or urticarial rash, angioedema, and bronchospasm, especially in patients with aspirin-sensitive asthma. Anaphylactoid reactions have been reported as well. Hypersensitivity has been implicated in cases of renal failure, pneumonitis, and colitis.

Renal side effects have included the development of mild renal insufficiency, nephrotic syndrome (with or without renal failure), acute renal failure due to tubulointerstitial nephritis, papillary necrosis, and acute tubular necrosis. Hypersensitivity may play a role in some cases of renal failure.

A 52-year-old male developed cutaneous necrotizing vasculitis, renal failure, and nephrotic syndrome following administration of naproxen 250 mg every 12 hours and dicloxacillin 250 mg every six hours for three days for the treatment of a blunt injury to the leg. Renal pathology was suggestive of a hypersensitivity angiitis. Symptoms resolved following discontinuation of naproxen. Naproxen may impair the ability of the kidney to cope with low renal blood flow states due to inhibition of prostaglandin-dependent afferent arteriolar vasodilation. Renal function may be further compromised in patients with heart failure, hypovolemia, cirrhosis, nephrotic syndrome, or hypoalbuminemia. Additional risk factors for naproxen-induced renal insufficiency are advanced age and concomitant use of diuretics. A case-control study suggested that patients who consumed 5000 or more pills containing NSAIDs during their lifetime may be at increased risk of end-stage renal disease. Patients with reduced renal function may be at increased risk for renal side effects.

NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

Because of the potential to cause gastrointestinal bleeding, renal failure, high blood pressure, and heart failure, naproxen meets the Beers criteria as a medication that is potentially inappropriate for use in older adults.

REFERENCE +

  1. Product Information. Anaprox (naproxen). Anonymous Roche Laboratories, Nutley, NJ. PROD;
  2. Product Information. Naprosyn (naproxen). Anonymous Syntex Laboratories Inc, Palo Alto, CA. PROD;
  3. Naproxen up to date: a review of its pharmacological properties and therapeutic efficacy and use in rheumatic diseases and pain states. Brogden RN, Heel RC, Speight TM, Avery GS Drugs 1979;18:241-77.
  4. Naproxen: a reappraisal of its pharmacology, and therapeutic use in rheumatic diseases and pain states. Todd PA, Clissold SP Drugs 1990;40:91-137.
  5. Aseptic meningitis associated with naproxen. Sylvia LM, Forlenza SW, Brocavich JM Drug Intell Clin Pharm 1988;22:399-401.
  6. Naproxen-associated nightmares. Bakht FR, Miller LG South Med J 1991;84:1271-3.
  7. Naproxen-induced recurrent aseptic meningitis. Weksler BB, Lehany AM DICP 1991;25:1183-4.
  8. Comparative toxicity of non-steroidal anti-inflammatory agents. Singh G, Ramey DR, Morfeld D, Fries JF Pharmacol Ther 1994;62:175-91.
 
       
 
Drowsiness
Levothyroxine may cause the following symptoms that are related to drowsiness:
  • Coma caused by severely low thyroid hormone level (single case).
  • Insomnia and other sleep problems
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Levothyroxine is usually well tolerated. Side effects associated with levothyroxine therapy typically resulted from therapeutic overdosage and included the signs and symptoms of hyperthyroidism. Weight loss, increased appetite, insomnia, anxiety, heat intolerance, diarrhea or increase in bowel frequency, palpitations, hypertension, tachycardia, angina, and menstrual irregularities may be reported. Given the long half-life of levothyroxine, such effects may not be present for several weeks after therapy initiation or dosage increases.

Stop using levothyroxine and get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: headache; sleep problems (insomnia); nervous or irritable feeling; fever, hot flashes, sweating; changes in your menstrual periods; appetite changes, weight changes; Less serious side effects may include mild hair loss. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Cardiovascular side effects have included symptoms of palpitations, hypertension, tachycardia, and angina which may be exacerbated in patients with underlying cardiovascular disorders. Ischemic heart disease and significant effects on cardiac function including an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function have been reported in clinical trials.

Cardiac function was evaluated in twenty patients requiring TSH suppression for either thyroid goiter or following thyroidectomy and radioactive iodine therapy for thyroid cancer and in twenty age- and sex-matched controls. TSH suppression was associated with an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function. The clinical significance of these changes remains to be determined. A 38-year-old female experienced with severe hypothyroidism experienced myxedema coma and cardiac ischemia coincident with levothyroxine therapy. After 3 months of levothyroxine therapy (initial dose: 12.5 mcg/d; maintenance dose: 125 mcg/d), all abnormal laboratory values associated with hypothyroidism returned to normal. However, three weeks after initiating treatment, the patient reported intermittent chest pains during the course of treatment, and a coronary artery angiogram revealed diffuse stenosis of all 3 branches. She underwent coronary artery bypass grafting, with subsequent improvement in coronary perfusion.

REFERENCE +

  1. Product Information. Synthroid (levothyroxine). Anonymous Abbott Pharmaceutical, Abbott Park, IL. PROD;
  2. Levothyroxine treatment and occurrence of fracture of the hip. Sheppard MC, Holder R, Franklyn JA Arch Intern Med 2002;162:338-43.
 
       
 
Drowsiness
HydrALAZINE may cause the following symptom that is related to drowsiness:
  • Lethargy (most common side effect)
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Immunologic side effects including the development of a lupus-like syndrome has been reported. It is more likely in patients who receive 400 mg or more of hydralazine per day, in female patients, or in patients who are slow acetylators. Of patients who receive less than 200 mg or 400 mg or more per day of hydralazine, 40% and 50%, respectively, develop a positive ANA titer, and up to 6% and 14%, respectively, develop a lupus-like syndrome. The lupus syndrome may present as arthralgias (most common), myalgias, lethargy, malaise, a typical erythematous rash, weight loss, or dyspnea, but may be found incidentally in asymptomatic patients by urinalysis (proteinuria, hematuria), blood chemistry (elevated ESR, antinuclear antibody), or chest X-ray (interstitial lung disease, rare). Hypocomplementemia is an extremely rare finding in hydralazine-induced lupus. Alternative therapy is recommended for patients who develop the clinical appearance of a lupus syndrome, sustained rises in the antinuclear antibody titer, or the presence of LE cells. The syndrome is reversible, but may take months to years to resolve.

REFERENCE +

  1. Focal glumerulonephritis in the course of hydralazine-induced lupus syndrome. Naparstek Y, Kopolovic J, Tur-Kaspa R, Rubinger D Arthritis Rheum 1984;27:822-5.
  2. The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Cameron HA, Ramsay LE Br Med J 1984;289:410-12.
  3. Immune complex glomerulonephritis in hydralazine-induced SLE. Shapiro KS, Pinn VW, Harrington JT, Levey AS Am J Kidney Dis 1984;3:270-4.
  4. Bullous systemic lupus erythematosus. Fleming MG, Bergfeld WF, Tomecki KJ, et al Int J Dermatol 1989;28:321-6.
  5. Hydralazine-associated glomerulonephritis. Bjorck S, Svalander C, Westberg G Acta Med Scand 1985;218:261-9.
  6. Immune responses to hydralazine and nuclear antigens in hydralazine-induced lupus erythematosus. Hahn BH, Sharp GC, Irvin WS, et al Ann Intern Med 1972;76:365-74.
  7. Hydralazine-induced lupus: yet another autoantibody! triplex-DNA stabilization by hydralazine and the presence of anti-(triplex DNA) antibodies in patients treated with hydralazine - comment. Pirmohamed M Hum Exp Toxicol 1996;15:361-2.
  8. Hydralazine induced lupus and sweet's syndrome: report and review of the literature. Ramsey-Goldman R, Franz T, Solano FX, Medsger TA J Rheumatol 1990;17:682-4.
  9. Hydralazine. Koch-Weser J N Engl J Med 1976;295:320-3.
  10. Pericardial tamponade: a major presenting manifestation of hydralazine-induced lupus syndrome. Carey RM, Coleman M, Feder A Am J Med 1973;54:84-7.
  11. Hydralazine lung. Bass BH Thorax 1981;36:695-6.
  12. Hydrallazine-induced Sjogren's syndrome. Darwaza A, Lamey P-J, Connell JM Int J Oral Maxillofac Surg 1988;17:92-3.
  13. Hydrallazine-induced cutaneous vasculitis. Bernstein RM, Egerton-Vernon J, Webster J Br Med J 1980;280:156-7.
  14. Southwestern internal medicine conference: drug-induced lupus: clinical spectrum and pathogenesis. Cush JJ, Goldings EA Am J Med Sci 1985;290:36-45.
  15. Transient monoclonal gammopathy in hydralazine-induced lupus erythematosus. Freestone S, Ramsay LE Br Med J 1982;285:1536-7.
  16. Hydralazine-induced lupus: is there a toxic metabolic pathway? Timbrell JA, Facchini V, Harland SJ, Mansilla-Tinoco R Eur J Clin Pharmacol 1984;27:555-9.
  17. Disease and acetylation polymorphism. Lunde PK, Frislid K, Hansteen V Clin Pharmacokinet 1977;2:182-97.
  18. Neutrophilic dermatosis (Sweet's Syndrome). Sequeira W, Polisky RB, Alrenga DP Am J Med 1986;81:558-60.
  19. Fatal hydralazine-induced systemic lupus erythematosus. Sturman SG, Kumararatne D, Beevers DG Lancet 1988;12/03/88:1304.
  20. Hydralazine and lupus nephritis. Ihle BU, Whitworth JA, Dowling JP, Kincaid-Smith P Clin Nephrol 1984;22:230-8.
  21. Hydralazine-induced lupoid syndrome. Blumenkrantz N, Christiansen AH, Ullman S, Asboe-Hansen G Acta Med Scand 1974;195:443-9.
  22. Drug-induced lupus caused by very-low-dose hydralazine. Innes A, Rennie JA, Cato GR Br J Rheumatol 1986;25:225-31.
  23. Late toxicity to hydralazine resembling systemic lupus erythematosus or rheumatoid arthritis. Perry HM Am J Med 1973;54:58-72.
  24. Side-effects in long-term treatment with hydralazine. Widgren B, Berglund G, Andersson OK Acta Med Scand 1986;714:193-6.
  25. Cutaneous manifestations of hydrallazine toxicity. Brooks AP, Paulley JW Br Med J 1980;02/16/80:482.
  26. Clinopathologic conference: renal failure, dyspnea and anemia in a 57 year old woman. Ludmerer KM, Kissane JM Am J Med 1981;71:876-86.
  27. Hydralazine-induced necrotising vasculitis. Peacock A, Weatherall D Br Med J 1981;282:1121-2.
  28. Hypocomplementemia in hydralazine-associated systemic lupus erythematosus. Weinstein J Am J Med 1978;65:553-6.
  29. Hydrallazine-induced necrotising vasculitis. Finlay AY, Statham B, Knight AG Br Med J 1981;282:1703-4.
  30. Hydralazine-associated glomerulonephritis. Kincaid-Smith P, Whitworth JA Lancet 1983;2:348.
 
       
 
       
 
Erectile dysfunction (problems with erections)
Simvastatin may cause erectile dysfunction.

This drug may also cause the following symptoms that are related to erectile dysfunction:

  • Decreased sex drive
  • Impotence (tended to improve when drug was stopped)
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Genitourinary side effects of HMG-CoA reductase inhibitors have included erectile dysfunction, impotence, and testicular pain.

Halkin, et al report a case in which use of both lovastatin and pravastatin on different occasions in the same patient led to reversible impotence. The impotence resolved within 2 weeks after discontinuation of the HMG-CoA reductase inhibitor.

Psychiatric side effects have included depression, suicidal thoughts, delusions, paranoia, and agitation; causality is unknown. In one uncontrolled study of simvastatin, psychiatric side effects were the second most frequent complaint. Other psychiatric side effects of HMG-CoA reductase inhibitors have included decreased libido, anxiety, insomnia, and nightmares.

REFERENCE +

  1. HMG-CoA reductase inhibitor-induced impotence. Halkin A, Lossos IS, Mevorach D Ann Pharmacother 1996;30:192.
  2. Product Information. Zocor (simvastatin). Anonymous Merck & Co, Inc, West Point, PA. PROD;
  3. Probable Statin-Induced Testicular Pain (January). Linnebur SA, Hiatt WH Ann Pharmacother 2007;
 
       
 
Erectile dysfunction (problems with erections)
Verapamil may cause the following symptoms that are related to erectile dysfunction:
  • Decreased sex drive (rare).
  • Impotence (rare)
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Genitourinary side effects have included rare cases of sexual impotence and loss of libido among males. Gynecomastia, galactorrhea/hyperprolactinemia, impotence, increased urination, and spotty menstruation have been reported during open trials/postmarketing experience.

After the onset of impotence, one patient elected to discontinue verapamil. His impotence resolved upon drug discontinuation, and recurred upon rechallenge.

REFERENCE +

  1. Treatment of mild hypertension with low once-daily doses of a sustained-release capsule formulation of verapamil. Davis PJ, Fagan TC, Topmiller MJ, Levine JH, Ferdinand KC J Clin Pharmacol 1995;35:52-8.
  2. Impotence during therapy with verapamil. King BD, Pitchon R, Stern EH, et al Arch Intern Med 1983;143:1248-9.
  3. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  4. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
 
       
 
Erectile dysfunction (problems with erections)
Niacin may cause the following symptom that is related to erectile dysfunction:
  • Problems involving sexual drive/performance
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Genitourinary complaints of decreased sexual function have been reported in up to 3% and 22% of male patients who have taken unmodified and timed release niacin, respectively.

REFERENCE +

  1. Product Information. Niaspan ER (niacin). Anonymous Allscripts Healthcare Solutions, Libertyville, IL.
  2. New approaches to cholesterol lowering: efficacy and safety. Knopp RH Hosp Pract (Off Ed) 1988;23 Suppl 1:22-30.
 
       
 
Erectile dysfunction (problems with erections)
HydrALAZINE may cause the following symptom that is related to erectile dysfunction:
  • Impotence (at least 2 case(s))
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Genitourinary side effects including impotence in male patients have been reported rarely.

At least two cases of male impotence associated with hydralazine are reported. The mechanism is unclear. There was no evidence of a neuropathy in either case.

REFERENCE +

  1. Impotence during antihypertensive treatment. Keidan H Can Med Assoc J 1976;114:874.
 
       
 
Erectile dysfunction (problems with erections)
Gemfibrozil may cause the following symptoms that are related to erectile dysfunction:
  • Decreased sex drive.
  • Impotence
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Genitourinary side effects of gemfibrozil include impotence and decreased male fertility.

Psychiatric side effects of gemfibrozil include decreased libido and depression.

REFERENCE +

  1. Gemfibrozil-induced impotence. Bain SC, Lemon M, Jones AF Lancet 1990;336:1389.
  2. Sexual dysfunction after gemfibrozil. Bharani A Br Med J 1992;305:693.
  3. Product Information. Lopid (gemfibrozil). Anonymous Parke-Davis, Morris Plains, NJ. PROD;
 
       
 
Erectile dysfunction (problems with erections)
Clonidine may cause the following symptoms that are related to erectile dysfunction:
  • Decreased sex drive.
  • Impotence in 24% of people. This symptom may occur in males
  • Delayed ejaculation. This symptom may occur in females
  • Retrograde ejaculation. This symptom may occur in females
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Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: fast or pounding heartbeats; a very slow heart rate (fewer than 60 beats per minute); feeling short of breath, even with mild exertion; swelling, rapid weight gain; confusion, hallucinations; fever, pale skin; urinating less than usual or not at all; or feeling like you might pass out. Less serious side effects may include: feeling dizzy, drowsy, tired, or nervous; dry mouth; dry or burning eyes, blurred vision; headache, muscle or joint pain; nausea, vomiting, constipation, loss of appetite; sleep problems (insomnia); urinating more at night; mild skin rash or itching; or decreased sex drive, impotence. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Genitourinary side effects have included impotence in male patients (24%), retrograde and delayed ejaculation, and an inability to achieve orgasm in female patients.

 
       
 
       
 
Genital problems
Simvastatin may cause the following symptom that is related to genital problems:
  • Testicle pain
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Genitourinary side effects of HMG-CoA reductase inhibitors have included erectile dysfunction, impotence, and testicular pain.

REFERENCE +

  1. HMG-CoA reductase inhibitor-induced impotence. Halkin A, Lossos IS, Mevorach D Ann Pharmacother 1996;30:192.
  2. Product Information. Zocor (simvastatin). Anonymous Merck & Co, Inc, West Point, PA. PROD;
  3. Probable Statin-Induced Testicular Pain (January). Linnebur SA, Hiatt WH Ann Pharmacother 2007;
 
       
 
Genital problems
Gemfibrozil may cause the following symptom that is related to genital problems:
  • Leydig cell tumors
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Note: Original Source for Medical Professionals
Many lipid-lowering drugs have been associated with tumor growth in rodents. Gemfibrozil has been specifically associated with liver tumors and Leydig cell tumors. Long-term clinical trials are needed to define the risk of cancer in humans.

REFERENCE +

  1. Carcinogenicity of lipid-lowering drugs. Newman TB, Hulley SB JAMA 1996;275:55-60.
 
       
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Captopril and allopurinol in combination may cause the following symptom that is related to gout-like arthritis:
  • Stevens-Johnson syndrome
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Patients who are taking captopril (captopril) and allopurinol (allopurinol) should be followed closely for signs of infection. Caution is advised if captopril (captopril) and allopurinol (allopurinol) are used together. People who are taking this drug combination should be followed closely. Serious side effects can occur with this drug combination. Cases of fatalities in individuals taking this drug combination have been reported in the medical literature. The following side effects have been mentioned in a case report: fast pulse/rapid heart rate that originates in the sinus node, nausea, hives, gout, breathing problems - tightening of the airways, significant decrease in blood pressure, generalized itching, thickening chest secretions, severe chest pain or bluish tone to fingers/toes due to lack of circulation. Some patients may experience the following side effects with the first dose of the enalapril: fast pulse/rapid heart rate that originates in the sinus node, nausea, hives, gout, breathing problems - tightening of the airways, significant decrease in blood pressure, generalized itching, thickening chest secretions, severe chest pain or bluish tone to fingers/toes due to lack of circulation. This medication combination may cause severe breathing problems due to closure of the airways.

Notify your physician if you develop: joint pain, lethargy, body pain, swelling of the tongue, skin rash, hives, sore throat/throat irritation, shortness of breath, swelling of the face, fever, tightness in the throat, infection, shaking chills, muscle pain/soreness, flu or cold-like symptoms or swelling of the lips.
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MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE) inhibitors has been associated with a risk of severe hypersensitivity reactions, neutropenia, agranulocytosis, and serious infections. The mechanism of interaction is unknown, but impaired renal function may be a predisposing factor. Case reports, albeit rare, have mostly involved captopril. Fever, myalgia, arthralgia, exfoliative dermatitis, and Stevens-Johnson syndrome (including one fatality) have been reported, with the latter occurring 3 to 5 weeks after initiation of allopurinol. In an isolated case involving enalapril, a man who had been receiving enalapril without incident developed generalized pruritus, urticaria, severe chest pain, severe nausea, peripheral cyanosis, hypotension, sinus tachycardia, and mild bronchospasm approximately 20 minutes after the first dose of allopurinol 100 mg prescribed for acute gout. Serial electrocardiograms and cardiac enzyme studies revealed evidence of acute myocardial infarction. Following recovery, the patient continued to take enalapril uneventfully without allopurinol. No pharmacokinetic interactions have been reported between allopurinol and ACE inhibitors. In a study of 12 healthy volunteers, allopurinol had no significant effect on the bioavailability of captopril.

MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor, particularly in the elderly and patients with renal impairment. Periodic monitoring of white blood cell counts is recommended. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop dyspnea; throat constriction; swelling of the face, lips, or tongue; urticaria; rash; fever; arthralgia; or myalgia. Patients should also contact their physician if they notice signs of infection or experience fever, chills, sore throat, lethargy, body aches, or other flu-like symptoms.

REFERENCE +

  1. Fatal Stevens-Johnson syndrome in a patient on captopril and allopurinol. Pennell DJ, Nunan TO, O'Doherty MJ, Croft DN Lancet 1984;1:463.
  2. Product Information. Zyloprim capsules (allopurinol). Anonymous Glaxo Wellcome, Research Triangle Park, NC. PROD;
  3. EPARs. European Union Public Assessment Reports. Available from: URL: http://www.emea.eu.int/htms/human/epar/a.htm. EMEA. European Medicines Agency [1995-2007];
  4. Fever, myalgia, and arthralgia in a patient on captopril and allopurinol. Samanta A, Burden AC Lancet 1984;1:679.
  5. Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases. Duchin KL, McKinstry DN, Cohen AI, Migdalof BH Clin Pharmacokinet 1988;14:241-59.
  6. Allopurinol and enalapril: drug induced anaphylactic coronary spasm and acute myocardial infarction. Ahmad S Chest 1995;108:586.
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Verapamil may cause the following symptom that is related to gout-like arthritis:
  • Stevens-Johnson syndrome
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Note: Original Source for Medical Professionals
Dermatologic side effects have included rash (up to 1.4%). Diaphoresis has been reported with intravenous verapamil. Arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, and erythema multiforme have been reported during open trials/postmarketing experience.

REFERENCE +

  1. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
  2. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  3. Product Information. Covera-HS (verapamil). Anonymous Searle, Skokie, IL. PROD;
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Simvastatin may cause the following symptoms that are related to gout-like arthritis:
  • Compartment syndrome (rare).
  • Stevens-Johnson syndrome
  • Lupus-like illness (single case). Reported with similar types of drugs
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Note: Original Source for Medical Professionals
Dermatologic side effects reported with HMG-CoA reductase inhibitors have included eczematous, pruritic rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, purpura, and alopecia. These effects may be manifestations of a hypersensitivity.

Immunologic side effects of simvastatin have included a case of lupus-like syndrome which has been reported with other HMG-CoA reductase inhibitors. Other immunologic side effects reported with HMG-CoA reductase inhibitors have included positive ANA, ESR increase, polymyalgia rheumatica, and vasculitis.

Musculoskeletal side effects of simvastatin have included elevations in creatine kinase, myopathy, dermatomyositis, and rhabdomyolysis. Other musculoskeletal side effects reported with HMG-CoA reductase inhibitors have included arthralgia, myalgia, tendon rupture, and dermatomyositis. In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.

HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria, and renal failure. Concomitant use with gemfibrozil (fibric acid derivatives), niacin, cyclosporine, erythromycin (macrolides) or azole antifungals may increase the incidence and severity of musculoskeletal side effects. Other variables associated with an increased risk of statin-induced myopathy include, advanced age, small body stature, female gender, renal and/or hepatic dysfunction, perioperative periods, hypothyroidism, diabetes mellitus, and alcoholism. Milder forms of myotoxicity (i.e., myalgia) are commonly reported and occur in approximately 5% to 7% of patients taking a statin drug. Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if elevated, simvastatin should be discontinued. The value of regular monitoring of creatine kinase is not known. In some studies, elevations in creatine kinase occurred in up to 5.2% of patients on simvastatin. In most cases, these elevations were mild, transient, and not associated with clinical symptoms. At least six cases of simvastatin-induced rhabdomyolysis associated with concomitant use of a macrolide antibiotic (i.e., erythromycin, clarithromycin) have been reported. In all cases the patients had been receiving simvastatin routinely (40 to 80 mg/day) prior to short-term (7 to 10 days) macrolide therapy. The proposed mechanism of interaction is inhibition of CYP450 3A4 metabolism and/or P-glycoprotein transport of simvastatin. Symptoms included myalgia, muscle weakness, elevated serum creatine kinase levels, and in some patients elevated liver transaminase levels. A rare case of simvastatin-induced bilateral leg compartment syndrome and myonecrosis developed in a patient with hypothyroidism after one month of therapy with simvastatin. Following withdrawal of simvastatin and emergency fasciotomies the patient recovered.

REFERENCE +

  1. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the scandinavian simvastatin survival study. Pedersen TR, Berg K, Cook TJ, Faergeman O, Haghfelt T, Kjekshus J, Miettinen T, Musliner TA, Olsson AG, Pyorala K, Thorgeirsso Arch Intern Med 1996;156:2085-92.
  2. Musculoskeletal manifestations during simvastatin therapy. McDonagh J, Winocour P, Walker DJ Br J Rheumatol 1993;32:647-8.
  3. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. Vanpuijenbroek EP, Dubufvereijken PWG, Spooren PFMJ, Vandoormaal JJ J Intern Med 1996;240:403-4.
  4. Simvastatin-associated dermatomyositis. Khattak FH, Morris IM, Branford WA Br J Rheumatol 1994;33:199.
  5. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. Graham DJ, Staffa JA, Shatin D, et al. JAMA 2004;292:2585-90.
  6. Rhadbdomyolysis after coronary artery bypass grafting in a patient receiving simvastatin. Alvarez JM, Rawdanowiz TJ, Goldstein J J Thorac Cardiovasc Surg 1998;116:654-5.
  7. Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem. Peces R, Pobes A Nephron 2001;89:117-8.
  8. Can statins cause chronic low-grade myopathy? Grundy SM Ann Intern Med 2002;137:617-8.
  9. Eosinophilic fasciitis and simvastatin. ChoquetKastylevsky G, Kanitakis J, Dumas V, Descotes J, Faure M, Claudy A Arch Intern Med 2001;161:1456-7.
  10. Simvastatin - a reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia. Plosker GL, Mctavish D Drugs 1995;50:334-63.
  11. Statins and osteoporosis: a clinical review. Gonyeau MJ Pharmacotherapy 2005;25:228-43.
  12. Statin-induced myopathy: the two faces of Janus. Arora R, Liebo M, Maldonado F J Cardiovasc Pharmacol Ther 2006;11:105-12.
  13. Long-term clinical tolerance of lovastatin and simvastatin. Bilheimer DW Cardiology 1990;77:58-65.
  14. Summaries for patients. Muscle abnormalities in four patients taking statins to treat unfavorable cholesterol levels. Ann Intern Med 2002;137:I45.
  15. Muscular side effects of statins. Sinzinger H, Wolfram R, Peskar BA J Cardiovasc Pharmacol 2002;40:163-71.
  16. Simvastatin increases serum osteocalcin concentration in patients treated for hypercholesterolaemia. Chan MH, Mak TW, Chiu RW, Chow CC, Chan IH, Lam CW J Clin Endocrinol Metab 2001;86:4556-9.
  17. Simvastatin-induced bilateral leg compartment syndrome and myonecrosis associated with hypothyroidism. Ramdass MJ, Singh G, Andrews B Postgrad Med J 2007;83:152-3.
  18. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. van Puijenbroek EP, Du Buf-Vereijken PW, Spooren PF, van Doormaal JJ J Intern Med 1996;240:403-4.
  19. Product Information. Zocor (simvastatin). Anonymous Merck & Co, Inc, West Point, PA. PROD;
  20. Rhabdomyolysis after concomitant use of cyclosporine, simvastatin, gemfibrozil, and itraconazole. Maxa JL, Melton LB, Ogu CC, Sills MN, Limanni A Ann Pharmacother 2002;36:820-3.
  21. Statins unmasking a mitochondrial myopathy: a case report and proposed mechanism of disease. Diaczok BJ, Shali R South Med J 2003;96:318-20.
  22. Simvastatin: the clinical profile. Walker JF Am J Med 1989;87:s44-6.
  23. Rhabdomyolysis from Simvastatin triggered by infection and muscle exertion. Finsterer J, Zuntner G South Med J 2005;98:827-9.
  24. Simvastatin-induced rhabdomyolysis followed by a MELAS syndrome. Chariot P, Abadia R, Agnus D, Danan C, Charpentier C, Gherardi RK Am J Med 1993;94:109-10.
  25. Fatal rhabdomyolysis caused by lipid-lowering therapy. Federman DG, Hussain F, Walters AB South Med J 2001;94:1023-6.
  26. HMG-CoA reductase inhibitors and the risk of fractures. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H JAMA 2000;283:3205-10.
  27. Simvastatin-associated rhabdomyolysis after coadministration of macrolide antibiotics in two patients. Molden E, Andersson KS Pharmacotherapy 2007;27:603-7.
  28. Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and simvastatin in prostate cancer. Itakura H, Vaughn D, Haller DG, O'Dwyer PJ J Urol 2003;169:613.
  29. Simvastatin in severe primary hypercholesterolemia: efficacy, safety, and tolerability in 595 patients over 18 weeks. The Principal Investigators. Simons LA Clin Cardiol 1993;16:317-22.
  30. FDA adverse event reports on statin-associated rhabdomyolysis. Omar MA, Wilson JP Ann Pharmacother 2002;36:288-95.
  31. Fatal rhabdomyolysis associated with simvastatin in a renal transplant patient. Weise WJ, Possidente CJ Am J Med 2000;108:351-2.
  32. Statin-induced myositis: a commonly encountered or rare side effect? Mukhtar RY, Reckless JP Curr Opin Lipidol 2005;16:640-7.
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Naproxen may cause the following symptom that is related to gout-like arthritis:
  • Stevens-Johnson syndrome (rare)
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Note: Original Source for Medical Professionals
Dermatologic side effects have included pruritus (3% to 9%), ecchymoses (3% to 9%), purpura, rash, and photosensitivity. Rare cases of pseudoporphyria cutanea tarda, toxic epidermal necrolysis, generalized bullous fixed drug eruption, erythema multiforme, and Stevens-Johnson syndrome have also been reported. Skin eruptions have been reported in patients receiving the controlled release formulation of naproxen.

REFERENCE +

  1. Possible naproxen-induced relapse of subacute cutaneous lupus erythematosus. Parodi A, Rivara G, Guarrera M JAMA 1992;268:51-2.
  2. Comparative toxicity of non-steroidal anti-inflammatory agents. Singh G, Ramey DR, Morfeld D, Fries JF Pharmacol Ther 1994;62:175-91.
  3. Medication toxicity among patients with ankylosing spondylitis. Ward MM, Kuzis S Arthritis Rheum 2002;47:234-41.
  4. Pseudoporphyria due to naproxen. Howard AM, Dowling J, Varigos G Lancet 1985;04/06/85:819-20.
  5. Pseudoporphyria due to naproxen. Farr PM, Diffey BL, Pierach CA Lancet 1985;05/18/85:1166-7.
  6. Peculiar unilateral fixed drug eruption of the breast. Li H, Wiederkehr M, Rao BK, et al. Int J Dermatol 2002;41:96-8.
  7. Naproxen-induced generalized bullous fixed drug eruption. Leivo T, Heikkila H Br J Dermatol 2004;151:232.
  8. Naproxen photosensitization demonstrated by challenge. Shelley WB, Elpern DJ, Shelley ED Cutis 1986;38:169-70.
  9. Naproxen-induced pseudoporphyria. Judd LE, Henderson DW, Hill DC Arch Dermatol 1986;122:451-4.
  10. Naproxen up to date: a review of its pharmacological properties and therapeutic efficacy and use in rheumatic diseases and pain states. Brogden RN, Heel RC, Speight TM, Avery GS Drugs 1979;18:241-77.
  11. Bullous photosensativity to naproxen: pseudoporphyria. Suarez SM, Cohen PR, DeLeo VA Arthritis Rheum 1990;33:903-8.
  12. Product Information. Naprosyn (naproxen). Anonymous Syntex Laboratories Inc, Palo Alto, CA. PROD;
  13. Naproxen-induced pseudoporphyria in patients with juvenile rheumatoid arthritis. Lang BA, Finlayson LA J Pediatr 1994;124:639-42.
  14. Pseudoporphyria and propionic acid non-steroidal anti-inflammatory drugs. Meggitt SJ, Farr PM Br J Dermatol 1999;141:591-2.
  15. Naproxen: a reappraisal of its pharmacology, and therapeutic use in rheumatic diseases and pain states. Todd PA, Clissold SP Drugs 1990;40:91-137.
  16. Product Information. Anaprox (naproxen). Anonymous Roche Laboratories, Nutley, NJ. PROD;
  17. Long-term followup of naproxen-induced pseudoporphyria in juvenile rheumatoid arthritis. Mehta S, Lang B Arthritis Rheum 1999;42:2252-4.
  18. Specific site involvement in fixed drug eruption. Ozkaya-Bayazit E J Am Acad Dermatol 2003;49:1003-7.
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Hydrochlorothiazide may cause the following symptoms that are related to gout-like arthritis:
  • Gout (in some patients).
  • Lupus erythematosis
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Note: Original Source for Medical Professionals
Hydrochlorothiazide is contraindicated in patients with anuria.

Hyperuricamia or precipitation of gout may occur in some patients.

There are reports of exacerbation or activation of systemic lupus erythematosus.

Dermatologic reactions include case reports of erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus is associated with HCTZ.

A 67-year-old woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion and personality changes associated with a new positive ANA and anti-nRNP, and a skin biopsy consistent with lupus erythematosus while taking hydrochlorothiazide (HCTZ), levothyroxine, and amitriptyline. The eruption resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.

 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
HydrALAZINE may cause the following symptoms that are related to gout-like arthritis:
  • Abnormal blood test - positive "rheumatoid factor".
  • Lupus erythematosis in less than 20% of people. This symptom may occur with doses of 400 milligram(s)
  • Lupus-like illness in 14% of people. This symptom may occur with doses between 200 and 400 milligram(s) per day
  • Joint swelling
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The incidence of hydralazine-induced systemic lupus erythematosus (SLE) is estimated at 5.4% for patients receiving 100 mg daily, 10.4% for those receiving 200 mg daily, and 10% to 20% for those receiving 400 mg or more daily. It should be noted that hydralazine-induced SLE has occurred at doses as low as 50 mg daily. Risk factors associated with development of hydralazine-induced SLE include slow acetylator status, HLA-DRw4 phenotype, female gender, high daily dose, therapy longer than 3 months, and a family history of autoimmune disease. Black patients appear to develop hydralazine-induced SLE less frequently than other populations. Musculoskeletal symptoms appear to be the most common clinical manifestation of hydralazine-induced SLE; however, it appears that any organ system can be involved. Laboratory findings that may aid in the diagnosis of hydralazine-induced SLE include antinuclear antibody (ANA), lupus erythematosus cells, rheumatoid factor, and antihistone antibodies.

Immunologic side effects including the development of a lupus-like syndrome has been reported. It is more likely in patients who receive 400 mg or more of hydralazine per day, in female patients, or in patients who are slow acetylators. Of patients who receive less than 200 mg or 400 mg or more per day of hydralazine, 40% and 50%, respectively, develop a positive ANA titer, and up to 6% and 14%, respectively, develop a lupus-like syndrome. The lupus syndrome may present as arthralgias (most common), myalgias, lethargy, malaise, a typical erythematous rash, weight loss, or dyspnea, but may be found incidentally in asymptomatic patients by urinalysis (proteinuria, hematuria), blood chemistry (elevated ESR, antinuclear antibody), or chest X-ray (interstitial lung disease, rare). Hypocomplementemia is an extremely rare finding in hydralazine-induced lupus. Alternative therapy is recommended for patients who develop the clinical appearance of a lupus syndrome, sustained rises in the antinuclear antibody titer, or the presence of LE cells. The syndrome is reversible, but may take months to years to resolve.

Because up to 20% of patients who receive 400 mg per day or more develop a systemic lupus erythematosus syndrome, some experts recommend checking a patient's acetylator status before giving higher doses. Up to 70% of "resistant" patients are fast acetylators, in whom the dose can be relatively safely increased. Data suggest that hydralazine lupus may represent a unique hypersensitivity reaction in which antibodies to native DNA occur. These antibodies are believed to account for the clinical similarities between hydralazine-induced lupus and systemic lupus erythematosus.

Hydralazine is contraindicated in patients with coronary artery disease or stenotic mitral valvular rheumatic heart disease.

Hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients, hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residual effects have been detected many years later.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: fast or pounding heartbeats; swelling in your face, stomach, hands, or feet; numbness, burning, pain, or tingly feeling; feeling like you might pass out; confusion, unusual thoughts or behavior; pale skin, easy bruising; painful or difficult urination; dark-colored urine; urinating less than usual or not at all; or joint pain or swelling with fever, chest pain, weakness or tired feeling. Less serious side effects may include: nausea, vomiting, loss of appetite; diarrhea, constipation; headache; dizziness; anxiety; muscle or joint pain; runny or stuffy nose; or mild itching or skin rash. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Dermatologic manifestations of the hydralazine-induced lupus-like syndrome include cutaneous vasculitis. A generalized, pruritic rash without evidence of lupus has been associated with hydralazine. Rare cases of Sweet's syndrome (neutrophilic dermatosis) have been associated with hydralazine.

Hematologic abnormalities have been associated with the hydralazine-induced lupus-like syndrome. Anemia may be caused by one of at least four hydralazine-associated problems; hemolysis, the formation of a circulating anticoagulant, thrombocytopenia, and vasculitis. Rare cases of leukopenia and agranulocytosis have been reported.

REFERENCE +

  1. Hydralazine-induced lupus: maintaining vigilance with increased use in patients with heart failure. Finks SW, Finks AL, Self TH South Med J 2006;99:18-22.
  2. Fulminating hydralazine-induced lupus pneumonitis. Birnbaum B, Sidhu GS, Smith RL, Pillinger MH, Tagoe CE Arthritis Rheum 2006;55:501-506.
  3. Hydralazine-induced lupus. Singh S South Med J 2006;99:6-7.
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Gemfibrozil may cause the following symptoms that are related to gout-like arthritis:
  • Compartment syndrome (single case).
  • Polyarthritis
  • Gout of the shoulder joint (single case)
  • Lupus-like illness (uncertainty exists about relationship between drug and side effect)
  • Raynaud’s phenomenon (rare)
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Immunologic effects of gemfibrozil include a Lupus-like syndrome and positive antinuclear antibody tests; causality is not established.

Musculoskeletal side effects of gemfibrozil include arthralgia, myopathy, myalgia, polyarthritis, and rhabdomyolysis. Myositis induced compartment syndrome is reported in one patient.

Metabolic side effects of gemfibrozil include a case report of gout of the acromioclavicular joint.

Cardiovascular side effects of gemfibrozil include rare cases of atrial fibrillation, vasculitis, and Raynaud's phenomenon.

REFERENCE +

  1. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. Pierce LR, Wysowski DK, Gross TP JAMA 1990;264:71-5.
  2. Rhabdomyolysis and acute renal failure in a heart transplant recipient treated with hypolipemiants. Dealava E, Sola JJ, Lozano MD, Pardomindan FJ Nephron 1994;66:242-3.
  3. Rhabdomyolysis and acute renal failure associated with gemfibrozil therapy. Gorriz JL, Sancho A, Lopezmartin JM, Alcoy E, Catalan C, Pallardo LM Nephron 1996;74:437-8.
  4. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Jones PH, Davidson MH Am J Cardiol 2005;95:120-2.
  5. Risk of adverse events with fibrates. Alsheikh-Ali AA, Kuvin JT, Karas RH Am J Cardiol 2004;94:935-8.
  6. Rhabdomyolysis and renal failure associated with gemfibrozil monotherapy. Layne RD, Sehbai AS, Stark LJ Ann Pharmacother 2004;38:232-4.
  7. Acute compartment syndrome: an unusual presentation of gemfibrozil induced myositis. Chow LT, Chow WH Med J Aust 1993;158:48-9.
  8. Skeletal muscle metabolism before and after gemfibrozil treatment in dialysed patients with chronic renal failure. Thompson CH, Irish A, Kemp GJ, Taylor DJ, Radda GK Clin Nephrol 1996;45:386-9.
  9. Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil. Alexandridis G, Pappas GA, Elisaf MS Am J Med 2000;109:261-2.
  10. Rhabdomyolysis and acute renal failure associated with gemfibrozil therapy Gorriz JL, Sancho A, Lopez-Martin JM, Alcoy E, Catalan C, Pallardo LM Nephron 1996;74:437-8.
  11. Vasculitis, Raynaud's phenomenon and polyarthritis associated with gemfibrozil therapy. Smith GW, Hurst NP Br J Rheumatol 1993;32:84-5.
  12. The role of cholesterol-lowering agents in drug-induced rhabdomyolysis and polymyositis . Goldman JA, Fishman AB, Lee JE, Johnson RJ Arthritis Rheum 1989;32:358-9.
  13. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. van Puijenbroek EP, Du Buf-Vereijken PW, Spooren PF, van Doormaal JJ J Intern Med 1996;240:403-4.
  14. Spondylitis-like and symmetric polyarthralgia associated with gemfibrozil therapy. Hammoudeh M, Siam AR, Khanjar I Br J Rheumatol 1995;34:692-3.
  15. Product Information. Lopid (gemfibrozil). Anonymous Parke-Davis, Morris Plains, NJ. PROD;
  16. Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy. Pogson GW, Kindred LH, Carper BG Am J Cardiol 1999;83:1146.
  17. Long-term safety of pravastatin-gemfibrozil therapy in mixed hyperlipidemia. Iliadis EA, Rosenson RS Clin Cardiol 1999;22:25-8.
  18. Cerivastatin and gemfibrozil-associated rhabdomyolysis. Bruno-Joyce J, Dugas JM, MacCausland OE Ann Pharmacother 2001;35:1016-9.
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Clonidine may cause the following symptoms that are related to gout-like arthritis:
  • Carpal tunnel syndrome.
  • Immune complex disease
  • Raynaud’s phenomenon
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Immunologic side effects have rarely been reported and include one case of immune-complex disease.

A 46-year-old woman developed forearm edema, mild thenar atrophy, and skin hypopigmentation within three months after beginning clonidine for perimenopausal flushing. Electromyelography was consistent with carpal tunnel syndrome. At surgical decompression, a skin biopsy revealed changes consistent with immune-complex disease. The patient's signs and symptoms abated after physical therapy and discontinuation of clonidine.

Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days. Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages. Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

REFERENCE +

  1. Clonidine-induced immune complex disease. Petersen HH, Hansen M, Albrectsen JM Acta Derm Venereol 1989;69:519-20.
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Captopril may cause the following symptoms that are related to gout-like arthritis:
  • Henoch-Schonlein purpura (rare).
  • Serum sickness
  • Lupus erythematosis (rare)
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Immunologic side effects have rarely included lymphadenopathy, systemic lupus erythematosus, and Henoch-Schonlein Purpura. Serum sickness-like illness has been reported.

A 53-year-old man with diabetes mellitus, hypertension, and heart failure developed arthralgias, fever, and malaise associated with bilateral pleural effusions, elevated liver function tests, a pericardial rub, and elevated C-reactive protein. After other causes of systemic lupus erythematosus were ruled out, captopril was stopped, and these signs and symptoms resolved. In a study of 78 patients who were treated with captopril for 11 months, 13 developed a positive antinuclear antibody titer. Only one of the 13, however, developed a serum sickness-like illness.

Dermatologic side effects have included psoriasiform rashes, pemphigus-like lesions, angioedema of the face and mucous membranes, pityriasis-like eruptions, alopecia, exfoliative dermatitis, photosensitivity, bullous or lichenoid eruptions, and erythematous eruptions. Rarely, worsened Kaposi's sarcoma lesions, oncolysis, pemphigus vulgaris, and Henoch-Schonlein Purpura have been reported. A case of toxic epidermal necrolysis has also been reported.

REFERENCE +

  1. Kaposi's sarcoma in a patient with rheumatoid arthritis possible responsibility of captopril in the development of lesions. Larbre JP, Nicolas JF, Collet P, et al J Rheumatol 1991;18:476-7.
  2. Pemphigus vulgaris induced by captopril. Butt A, Burge SM Br J Dermatol 1995;132:315-6.
  3. Captopril: an update of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure. Brogden RN, Todd PA, Sorkin EM Drugs 1988;36:540-600.
  4. Captopril-induced skin eruptions. Luderer JR, Lookingbill DP, Schneck DW, et al J Clin Pharmacol 1982;22:151-9.
  5. Possible captopril-induced toxic epidermal necrolysis. Alkurtass DA, Al-Jazairi AS Ann Pharmacother 2003;37:380-3.
  6. Severe cutaneous reactions to captopril. Goodfield MJ, Millard LG Br Med J 1985;290:1111.
  7. Severe side-effects of captopril in advanced chronic kidney insufficiency. Beroniade V Proc Eur Dial Transplant Assoc 1983;20:530-7.
  8. Psoriasis related to angiotensin-converting enzyme inhibitors. Wolf R, Tamir A, Brenner S Dermatologica 1990;181:51-3.
  9. Angiotensin converting enzyme inhibitors in hypertension: potential problems. Antonios TFT, Macgregor GA J Hypertens 1995;13 Suppl:s11-6.
  10. Captopril-triggered linear IgA bullous dermatosis. Friedman IS, Rudikoff D, Phelps RG, Sapadin AN Int J Dermatol 1998;37:608-12.
  11. Safety and efficacy of chronic therapy with captopril in hypertensive patients: an update. Waeber B, Gavras I, Brunner HR, Gavras H J Clin Pharmacol 1981;21:508-16.
  12. Antinuclear and antinative DNA antibodies during captopril treatment. Kallenberg CG, Hoorntje SJ, Smit AJ, et al Acta Med Scand 1982;211:297-300.
  13. Captopril-induced pemphigus. Parfrey PS, Clement M, Vandenburg MJ, Wright P Br Med J 1980;281:194.
  14. Captopril. Vidt DG, Bravo EL, Fouad FM N Engl J Med 1982;306:214-9.
  15. Captopril-induced toxic epidermal necrolysis and agranulocytosis successfully treated with colony-stimulating factor. Winfred RI, Nanda S, Horvath G, Elnicki M South Med J 1999;92:918-20.
  16. Captopril-induced lupus. Bertin P, Kamdem J, Bonnet C, Arnaud M, Treves R Clin Exp Rheumatol 1993;11:695.
  17. Henoch-schoenlein purpura and angiotensin-converting enzyme inhibitors. Neumann J, Andrassy K, Waltersack I, Berg PA Nephron 1994;67:117.
  18. Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapril. The Quality-of-Life Hypertension Study Group. Testa MA, Anderson RB, Nackley JF, Hollenberg NK N Engl J Med 1993;328:907-13.
  19. Captopril-induced lichenoid eruption. Phillips WG, Vaughanjones S, Jenkins R, Breathnach SM Clin Exp Dermatol 1994;19:317-20.
  20. A long-term follow-up of patients with essential hypertension treated with captopril. Ohman P, Aurell M, Asplund J, et al Acta Med Scand 1984;216:53-6.
  21. Subepidermal bullous eruption induced by captopril. Fitzgerald DA Clin Exp Dermatol 1993;18:196-7.
  22. Randomized controlled trial of oral captopril, of oral isosorbide mononitrate and of intravenous magnesium sulphate started early in acute myocardial infarction - safety and haemodynamic effects. Flather M, Pipilis A, Collins R, Budaj A, Hargreaves A, Kolettis T, Jacob A, Millane T, Fitzgerald L, Cedro K, Cybulski J, Dancy Eur Heart J 1994;15:608-19.
  23. Effectiveness and safety of captopril (tensiomin) in patients with hypertension. Torok E, Biro V, Wagner M, et al Acta Physiol Hung 1988;72:51-65.
  24. Adverse effects of the angiotensin-converting enzyme inhibitors. Alderman CP Ann Pharmacother 1996;30:55-61.
  25. The captopril-induced eruption: a possible mechanism, cutaneous kinin potentiation. Wilkin JK, Hammond JJ, Kirkendall WM Arch Dermatol 1980;116:902-5.
  26. Fatal Stevens-Johnson syndrome in a patient on captopril and allopurinol. Pennell DJ, Nunan TO, O'Doherty MJ, Croft DN Lancet 1984;1:463.
  27. Captopril-induced eruptions . Clement MI Arch Dermatol 1981;117:525-6.
  28. Acute renal failure, hemolytic anemia and skin rash associated with captopril therapy. Luderer JR, Schoolwerth AC, Sinicrope R, et al Am J Med 1981;71:493-6.
  29. Kaposi's sarcoma associated with captopril . Puppin D Jr, Rybojad M, de la Chapelle C, Morel P Lancet 1990;336:1251-2.
  30. Captopril-associated lymphadenopathy. Aberg H, Morlin C, Frithz G Br Med J 1981;283:1297-8.
  31. Captopril and systemic lupus erythematosus syndrome. Sieber C, Grimm E, Follath F Br Med J 1990;301:669.
  32. Alopecia associated with captopril treatment . Leaker B, Whitworth JA Aust N Z J Med 1984;14:866.
  33. A long-term follow-up of patients with essential hypertension treated with captopril. Ohman P, Aurell M, Asplund J, et al Acta Med Scand 1984;216:53-6.
  34. Captopril and onycholysis . Borders JV Ann Intern Med 1986;105:305-6.
  35. Captopril induced lupus. Ratliff NB 3rd J Rheumatol 2002;29:1807-8.
  36. Cutaneous reaction to captopril with positive patch test and lack of cross-sensitivity to enalapril and benazepril. LluchBernal M, Novalbos A, Umpierrez A, Figueredo E, Bombin C, Sastre J Contact Dermatitis 1998;39:316-7.
  37. Exfoliative dermatitis from captopril. Solinger AM Cutis 1982;29:473-4.
  38. Henoch-schoenlein purpura and angiotensin-converting enzyme inhibitors. Neumann J, Andrassy K, Waltersack I, Berg PA Nephron 1994;67:117.
 
       
 
Gout-like arthritis (resembles the arthritis/joint inflammation caused by gout)
Allopurinol may cause the following symptoms that are related to gout-like arthritis:
  • Gout.
  • Stevens-Johnson syndrome (rare)
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Musculoskeletal side effects have included acute attacks of gout.

Allopurinol should be discontinued at the first sign of skin rash or any other signs or symptoms suggestive of a hypersensitivity reaction. In some instances, a skin rash may be followed by more severe adverse reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, rarely, death. Renal dysfunction increases the risk of allopurinol hypersensitivity.

An increase in acute attacks of gout have been observed during the early stages of use of allopurinol, even when normal or subnormal serum uric acid levels have been reached. Accordingly, maintenance doses of colchicine generally should be given prophylactically when allopurinol therapy is started. The administration of colchicine or anti-inflammatory agents may be necessary to suppress gouty attacks in some instances. The gout attacks usually become shorter and less severe after several months of treatment. The mobilization of urates from tissue deposits which lead to fluctuations in the serum uric acid levels may be a possible explanation for these attacks. Even with adequate allopurinol treatment, it may require several months to deplete the uric acid pool adequately to achieve control of the acute attacks.

Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN during allopurinol therapy. Although the mechanism responsible for this has not been determined, patients with impaired renal function should be carefully monitored during the early stages of allopurinol use and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. Renal failure in association with allopurinol use has been reported among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunction increased after allopurinol therapy was started. Renal failure is frequently observed with the use of allopurinol therapy. Albuminemia has been observed in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. Patients with decreased renal function require lower doses of allopurinol therapy than those with normal renal function. Periodic monitoring of renal function is recommended during the course of therapy.

Dermatologic side effects have included skin rash, pruritus, and alopecia. Severe skin reactions have rarely included exfoliative dermatitis, vesicular bullous eruptions, and erythema multiforme.

Allopurinol-induced rash may be followed by more severe hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, nephrotoxicity, and hepatotoxicity. Such hypersensitivity syndromes have been fatal in some cases. The incidence of skin rash may be increased in patients with renal dysfunction.

Hypersensitivity side effects have included hypersensitivity maculopapular rash (1% to 3%). Rash, eosinophilia, and fever have been reported in 0.3% of patients. Rare, but potentially fatal, reactions have included arthralgias, hepatitis, acute interstitial nephritis, vasculitis, and severe skin reactions. Stevens-Johnson syndrome, toxic epidermal necrolysis, and toxic pustuloderma have been reported rarely. At least 3 cases of allopurinol hypersensitivity syndrome have also been reported.

 
       
 
       
 
Hearing loss
Levothyroxine and simvastatin in combination may cause the following symptom that is related to hearing loss:
  • Underactive thyroid gland
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The following side effects have been mentioned in a case report: underactive thyroid gland or increased tsh levels. No special actions appear to be necessary when taking these drugs at recommended doses. This drug interaction appears to be rare. The dose of levothyroxine (levothyroxine) may need to be adjusted if an interaction is suspected. The dose of hormone may need to be adjusted if an interaction is suspected. These side effects have only occured in a few individuals.
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Rarely, lovastatin and simvastatin have been reported to reduce the pharmacologic effects of thyroid hormone. The exact mechanism of interaction is unknown. In isolated case reports, patients stabilized on levothyroxine developed symptoms of hypothyroidism and/or elevated thyroid-stimulating hormone (TSH) levels following the addition of lovastatin or simvastatin. Discontinuation of the statin led to resolution of symptoms and normalization of TSH levels. In one case, the patient was subsequently prescribed pravastatin without any adverse effects on his thyroid status. No particular intervention should be necessary when lovastatin or simvastatin is prescribed to patients receiving thyroid hormone therapy, since the interaction appears to be extremely rare. However, thyroid hormone dosage may need to be adjusted if an interaction is suspected. Alternatively, a switch to a statin with a different metabolic profile such as fluvastatin, pravastatin, or rosuvastatin may help.

REFERENCE +

  1. Interaction between simvastatin and L-thyroxine. Kisch E, Segall HS Ann Intern Med 2005;143:547.
  2. Drug interaction between thyroxine and lovastatin. Demke DM N Engl J Med 1989;321:1341-2.
 
       
 
Hearing loss
Naproxen may cause the following symptom that is related to hearing loss:
  • Hearing problems
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Other side effects have included tinnitus, altered hearing, vertigo, visual disturbances, and keratopathy. Increased thirst has been reported in patients receiving the controlled release naproxen.

REFERENCE +

  1. Product Information. Naprosyn (naproxen). Anonymous Syntex Laboratories Inc, Palo Alto, CA. PROD;
  2. Product Information. Anaprox (naproxen). Anonymous Roche Laboratories, Nutley, NJ. PROD;
  3. Naproxen-associated sudden sensorineural hearing loss. McKinnon BJ, Lassen LF Milit Med 1998;163:792-3.
  4. Keratopathy associated with the use of naproxen. Szmyd L, Perry HD Am J Ophthalmol 1985;99:598.
 
       
 
Hearing loss
Levothyroxine may cause the following symptoms that are related to hearing loss:
  • Coma caused by severely low thyroid hormone level (single case).
  • Underactive thyroid gland
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Thyroid hormones are not appropriate treatment for obesity or to aid in weight loss. Treatment of obesity in euthyroid patients with replacement dosages of thyroid hormones is ineffective. Serious or life-threatening toxicity may occur when thyroid hormones are given in larger doses, especially when given concomitantly with sympathomimetic amines used for their anorectic effects.

Levothyroxine is contraindicated in patients with untreated thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is also contraindicated in patients with uncorrected adrenal insufficiency. Increased requirements for adrenocortical hormone by tissue could precipitate an acute adrenal crisis. In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly elderly patients or those with underlying cardiovascular disease, levothyroxine is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating over thyrotoxicosis. If the serum TSH level is not suppressed, levothyroxine should be used cautiously in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism. Unless associated with hypothyroidism, thyroid hormone is not appropriate treatment of male or female infertility.

Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.

Cardiovascular side effects have included symptoms of palpitations, hypertension, tachycardia, and angina which may be exacerbated in patients with underlying cardiovascular disorders. Ischemic heart disease and significant effects on cardiac function including an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function have been reported in clinical trials.

Cardiac function was evaluated in twenty patients requiring TSH suppression for either thyroid goiter or following thyroidectomy and radioactive iodine therapy for thyroid cancer and in twenty age- and sex-matched controls. TSH suppression was associated with an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function. The clinical significance of these changes remains to be determined. A 38-year-old female experienced with severe hypothyroidism experienced myxedema coma and cardiac ischemia coincident with levothyroxine therapy. After 3 months of levothyroxine therapy (initial dose: 12.5 mcg/d; maintenance dose: 125 mcg/d), all abnormal laboratory values associated with hypothyroidism returned to normal. However, three weeks after initiating treatment, the patient reported intermittent chest pains during the course of treatment, and a coronary artery angiogram revealed diffuse stenosis of all 3 branches. She underwent coronary artery bypass grafting, with subsequent improvement in coronary perfusion.

REFERENCE +

  1. Product Information. Synthroid (levothyroxine). Anonymous Abbott Pharmaceutical, Abbott Park, IL. PROD;
  2. Levothyroxine treatment and occurrence of fracture of the hip. Sheppard MC, Holder R, Franklyn JA Arch Intern Med 2002;162:338-43.
 
       
 
       
 
Heart disease due to high blood pressure
Naproxen and hydrochlorothiazide in combination may cause the following symptom that is related to heart disease due to high blood pressure:
  • High blood pressure
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This drug combination of can affect kidney function. The combination of naproxen (naproxen) and hydrochlorothiazide (hydrochlorothiazide) can cause low blood pressure. Monitor blood pressure carefully if you are using both of these medications. Contact your physician if you develop symptoms of heart failure including: shortness of breath, swelling in the ankles/legs, fatigue, lack of energy, loss of appetite, or nausea. The risk of the following side effects may be increased: congestive heart failure. The risk of developing (or worsening) congestive heart failure/weakened heart is increased in patients taking these medications. One published article suggested that the chance of developing congestive heart failure may be increased by using this drug combination people age 55 or older, 9.3 or older, 1,000 or older, 23.3 or older. The risk of developing (or worsening) congestive heart failure/weakened heart is increased in patients taking these medications people age 55 or older, 9.3 or older, 1,000 or older, 23.3 or older. Taking these two drugs together can increase the blood levels of a substance called "potassium". Check with your physician immediately for any signs of increased potassium including weakness, lack of energy, irregular heartbeat, confusion, or tingling or a feeling of heaviness in the arms or legs.

Drink lots of fluids and avoid becoming dehydrated while taking this medication combination. Follow kidney function closely with regular blood tests when taking this drug combination. Kidney function may be evaluated with certain blood tests including a "BUN" and "creatinine".
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MONITOR: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics may adversely affect renal function due to NSAID inhibition of the renal synthesis of prostaglandins that help maintain renal perfusion in dehydrated states. The risk may be increased in patients on dietary sodium restriction. At the same time, hypotensive effect of the diuretics may be reduced because inhibition of prostaglandins can lead to unopposed pressor activity and, consequently, elevation in blood pressure. Natriuretic and diuretic effects may also be reduced, as NSAIDs have been reported to cause sodium and water retention, which may account for the increased risk of congestive heart failure associated with the combination. One study showed an increase in the incidence density of congestive heart failure (in patients over 55 years of age) from 9.3 per 1,000 person-years in patients on diuretics to 23.3 per 1,000 person-years in patients on both diuretic and NSAID therapy. NSAIDs may also increase the risk of hyperkalemia associated with potassium-sparing diuretics.

MANAGEMENT: In patients receiving both diuretic and NSAID therapy, management consists of avoiding dehydration and carefully monitoring the patient's renal function and blood pressure. If renal insufficiency or hyperkalemia develops, both drugs should be discontinued until the condition is corrected.

REFERENCE +

  1. Influence of meloxicam on furosemide pharmacokinetics and pharmacodynamics in healthy volunteers. Muller FO, Schall R, Devaal AC, Groenewoud G, Hundt HKL, Middle MV Eur J Clin Pharmacol 1995;48:247-51.
  2. Interaction of indomethacin with furosemide. Poe TE, Scott RB, Keith JF Jr J Fam Pract 1983;16:610-6.
  3. Interaction of triamterene-hydrochlorothiazide (T-H) and ibuprofen (I). Gehr T, Sica DA, Steigler BW, Marshall C Clin Pharmacol Ther 1990;47:200.
  4. Indomethacin- and Moduretic--induced hyperkalemia. Mor R, Pitlik S, Rosenfeld JB Isr J Med Sci 1983;19:535-7.
  5. Aldosterone antagonists in the treatment of heart failure. Marcy TR, Ripley TL Am J Health Syst Pharm 2006;63:49-58.
  6. Anuric renal failure precipitated by indomethacin and triamterene. Weinberg MS, Quigg RJ, Salant DJ, Bernard DB Nephron 1985;40:216-8.
  7. Reversible acute renal failure from combined triamterene and indomethacin. Favre L, Glasson P, Vallotton MB Ann Intern Med 1982;96:317-20.
  8. Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin. Watkins J, Abbot EC, Hensby CN, Webster J, Dollery CT Br Med J 1980;281:702-5.
  9. The effect of nonsteroidal agents (NSAIDs) on the pharmacokinetics and pharmacodynamics of metolazone. Ripley EB, Gehr TW, Wallace H, Wade J, Kish C, Sica DA Int J Clin Pharmacol Ther 1994;32:12-8.
  10. Interaction studies with bumetanide and furosemide: effects of probenecid and of indomethacin on response to bumetanide in man. Brater DC, Fox WR, Chennavasin P J Clin Pharmacol 1981;21:647-53.
  11. The effects of naproxen and sulindac on renal function and their interaction with hydrochlorothiazide and piretanide in man. Dixey JJ, Noormohamed FH, Lant AF, Brewerton DA Br J Clin Pharmacol 1987;23:55-63.
  12. Bumetanide-induced diuresis and natriuresis: effect of prostaglandin synthetase inhibition. Kaufman J, Hamburger R, Matheson J, Flamenbaum W J Clin Pharmacol 1981;21:663-7.
  13. Drug interactions and consequences of sodium restriction. Bennett WM Am J Clin Nutr 1997;65:S678-81.
  14. Drug interactions with diuretics. Leary WP, Reyes AJ S Afr Med J 1984;65:455-61.
  15. Attenuation of furosemide's diuretic effect by indomethacin: pharmacokinetic evaluation. Smith DE, Brater DC, Lin ET, Benet LZ J Pharmacokinet Biopharm 1979;7:265-74.
  16. The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons. Gurwitz JH, Everitt DE, Monane M, et al J Gerontol A Biol Sci Med Sci 1996;51:m74-9.
  17. Acute intrinsic renal failure induced by indomethacin. McCarthy JT, Torres VE, Romero JC, et al Mayo Clin Proc 1982;57:289-96.
  18. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Heerdink ER, Leufkens HG, Herings RM, Ottervanger JP, Stricker BH, Bakker A Arch Intern Med 1998;158:1108-12.
  19. Influence of indomethacin on the natriuretic and renin-stimulating effect of bumetanide in essential hypertension. Pedrinelli R, Magagna A, Arzilli F, et al Clin Pharmacol Ther 1980;28:722-31.
  20. Clinically important interactions of nonsteroidal antiinflammatory drugs with other medications. Furst DE J Rheumatol Suppl 1988;17:58-62.
  21. Indomethacin-bumetanide interaction: an alert. Ahmad S Am J Cardiol 1984;54:246-7.
  22. Drug-induced hyperkalemia: old culprits and new offenders. Perazella MA Am J Med 2000;109:307-14.
  23. Interaction of diuretics and non-steroidal anti-inflammatory drugs in man. Favre L, Glasson P, Riondel A, Vallotton MB Clin Sci 1983;64:407-15.
  24. Product Information. HydroDIURIL (hydrochlorothiazide). Anonymous Merck & Co, Inc, West Point, PA. PROD;
  25. A comparative study of the action of frusemide and methyclothiazide on renin release by rat kidney slices and the interaction with indomethacin. Desaulles E, Schwartz J Br J Pharmacol 1979;65:193-6.
  26. Interaction between diuretics and indomethacin. Allan SG, Knox J, Kerr F Br Med J 1981;283:1611.
 
       
 
Heart disease due to high blood pressure
Verapamil may cause the following symptom that is related to heart disease due to high blood pressure:
  • High blood pressure
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Cardiovascular side effects have included hypotension (up to 2.5%), new or worsened congestive heart failure (CHF) or pulmonary edema (negative inotropism; 1.8%), bradycardia (heart rate less than 50/minute; 1.4%), atrioventricular (AV) block (first-degree; up to 1.7%), AV block (total first-, second-, and third-degree; 1.2%), AV block (second- and third-degree; 0.8%), and postural hypotension (up to 0.4%). Symptomatic hypotension (1.5%), bradycardia (1.2%), and severe tachycardia (1%) have been reported with intravenous verapamil. In studies related to control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rate less than 50/minute at rest (15%) and asymptomatic hypotension (5%) were reported. Dizziness, hypotension, peripheral edema, and headache are not uncommon and are related to vasodilation of vascular smooth muscle. Verapamil may accelerate conduction of anomalous AV conduction tissue, as in the Wolff-Parkinson-White syndrome, which can result in worsened tachycardia, including malignant ventricular tachyarrhythmias or accelerated junctional tachycardia. Because of this potentially fatal side effect, verapamil is not recommended in patients with atrial fibrillation and premature ventricular depolarizations. Angina pectoris, AV block (second- and third-degree), atrioventricular dissociation, CHF, pulmonary edema, abnormal ECG, chest pain, claudication, hypertension, myocardial infarction, palpitations, and purpura (vasculitis) have been reported during open trials/postmarketing experience.

REFERENCE +

  1. Verapamil hydrochloride: pharmacological properties and role in cardiovascular therapeutics. Baky SH, Singh BN Pharmacotherapy 1982;2:328-50.
  2. Cardiogenic shock associated with verapamil in a patient with liver cirrhosis. Stehle G, Buss J, Eibach J, et al Lancet 1990;336:1079.
  3. Effects of verapamil on supraventricular tachycardia in patients with overt and concealed wolff-parkinson-white syndrome. Hame A, Peter T, Platt M, Mandel WJ Am Heart J 1981;101:600-12.
  4. Precipitation of cardiac arrest by verapamil in patients with Wolff-Parkinson-White syndrome. McGovern B, Garan H, Ruskin JN Ann Intern Med 1986;104:791-4.
  5. Pharmacokinetics of verapamil in patients with renal failure. Mooy J, Schols M, Baak MV, et al Eur J Clin Pharmacol 1985;28:405-10.
  6. Incidence of adverse events during treatment with verapamil for suspected acute myocardial infarction. Arstall MA, Beltrame JF, Mohan P, Wuttke RD, Esterman AJ, Horowitz JD Am J Cardiol 1992;70:1611-2.
  7. Efficacy and safety of verapamil in patients with angina pectoris after 1 year of continuous, high-dose therapy. Weiner DA, McCabe CH, Cutler SS, et al Am J Cardiol 1983;51:1251-5.
  8. Verapamil-induced acute right heart failure. Shimoni A, Maorkendler Y, Neuman Y Am Heart J 1996;132:193-4.
  9. Accelerated junctional rhythms during oral verapamil therapy. Schwartz JB, Jeang M, Raizner AE, et al Am Heart J 1984;107:440-3.
  10. Case report: sustained-release verapamil overdose causing stroke: an unusual complication. Shah AR, Passalacqua BR Am J Med Sci 1992;304:357-9.
  11. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
  12. Fatal ventricular fibrillation following verapamil in Wolff-Parkinson-White syndrome with atrial fibrillation. Jacob AS, Nielsen DH, Gianelly RE Ann Emerg Med 1985;14:159-60.
  13. Electrocardiological profile and proarrhythmic effects of quinidine, verapamil and their combination: a mapping study. Dhein S, Schott M, Gottwald E, Klaus W Naunyn Schmiedebergs Arch Pharmacol 1995;352:94-101.
  14. Asystole after verapamil. Benaim ME Br Med J 1972;04/15/72:169-70.
  15. Age and severe adverse drug reactions caused by nifedipine and verapamil. Pahor M, Manto A, Pedone C, Carosella L, Guralnik JM, Carbonin P J Clin Epidemiol 1996;49:921-8.
  16. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  17. Effectiveness and safety of oral verapamil to control exercise-induced tachycardia in patients with atrial fibrillation receiving digitalis. Panidis IP, Morganroth J, Baessler C Am J Cardiol 1983;52:1197-201.
  18. Emergency treatment of acute sustained tachyarrhythmias. Obel IWP S Afr Med J 1995;85:745-6.
  19. Long-term safety and efficacy of immediate-release and sustained-release oral verapamil in systemic hypertension. Frishman WH, Eisen G, Charlap S, Strom JA J Clin Hypertens 1987;3:605-9.
  20. Product Information. Covera-HS (verapamil). Anonymous Searle, Skokie, IL. PROD;
  21. Acute toxic effects of sustained-release verapamil in chronic renal failure. Pritza DR, Bierman MH, Hammeke MD Arch Intern Med 1991;151:2081-4.
  22. R-verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate. Ahmed JH, Godden J, Meredith PA, Elliott HL Br J Clin Pharmacol 1993;36:93-8.
  23. The paradoxical adverse effect of verapamil for treating clinical paroxysmal supraventricular tachycardia. Saikawa T, Inoue K, Ohmura I, et al Jpn Heart J 1987;28:107-13.
  24. Verapamil-induced polymorphous ventricular tachycardia. Winters SL, Schweitzer P, Kupersmith J, Gomes JA J Am Coll Cardiol 1985;6:257-9.
  25. Verapamil in the long-term treatment of angina pectoris. Raftos J Med J Aust 1980;07/26/80:78-80.
  26. Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. McTavish D, Sorkin EM Drugs 1989;38:19-76.
  27. Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Pollak A, Falk RH Chest 1993;104:618-20.
  28. Comparison of verapamil and captopril in elderly hypertensive subjects: results of a randomized, double-blind, crossover study. Bursztyn M, Ghanem J, Kobrin I, Fidel J, Ben-Ishay D J Cardiovasc Pharmacol 1993;21:84-8.
  29. Verapamil in atrial fibrillation: the expected, the unexpected, and the unknown. Schwartz JB Am Heart J 1983;106:173-6.
  30. Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism. Echizen H, Vogelgesang B, Eichelbaum M Clin Pharmacol Ther 1985;38:71-6.
 
       
 
Heart disease due to high blood pressure
Naproxen may cause the following symptom that is related to heart disease due to high blood pressure:
  • High blood pressure
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NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

NSAIDs, including naproxen, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. NSAIDs, including naproxen, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

 
       
 
Heart disease due to high blood pressure
Levothyroxine may cause the following symptom that is related to heart disease due to high blood pressure:
  • High blood pressure
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Levothyroxine is usually well tolerated. Side effects associated with levothyroxine therapy typically resulted from therapeutic overdosage and included the signs and symptoms of hyperthyroidism. Weight loss, increased appetite, insomnia, anxiety, heat intolerance, diarrhea or increase in bowel frequency, palpitations, hypertension, tachycardia, angina, and menstrual irregularities may be reported. Given the long half-life of levothyroxine, such effects may not be present for several weeks after therapy initiation or dosage increases.

Cardiovascular side effects have included symptoms of palpitations, hypertension, tachycardia, and angina which may be exacerbated in patients with underlying cardiovascular disorders. Ischemic heart disease and significant effects on cardiac function including an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function have been reported in clinical trials.

REFERENCE +

  1. Product Information. Synthroid (levothyroxine). Anonymous Abbott Pharmaceutical, Abbott Park, IL. PROD;
  2. Levothyroxine treatment and occurrence of fracture of the hip. Sheppard MC, Holder R, Franklyn JA Arch Intern Med 2002;162:338-43.
 
       
 
Heart disease due to high blood pressure
Hydrochlorothiazide may cause the following symptom that is related to heart disease due to high blood pressure:
  • High blood pressure (can occur as long as 18 months after starting/treatment with hydrochlorothiazide)
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Immunologic side effects are rare, and include case reports of allergic vasculitis and hemolytic anemia. There are numerous case reports of patients developing a rash histologically identical to subacute cutaneous lupus following HCTZ administration.

There are rare case reports of hydrochlorothiazide-induced immune hemolytic anemia. The following illustrates a fatal case: A 53-year-old man with hypertension developed nausea, vomiting, diarrhea, and progressive anorexia and weakness associated with scleral icterus, anemia with spherocytosis, dark red urine with proteinuria, bilirubinuria, hemoglobinuria, and elevated lactic dehydrogenase levels 18 months after beginning hydrochlorothiazide and methyldopa. Haptoglobin was less than 50 mg per dl. Direct and indirect Coombs tests were positive. The patient died suddenly; autopsy revealed no obvious cause of death, left ventricular hypertrophy, and mild coronary atherosclerosis.

REFERENCE +

  1. Can hydrochlorothiazide cause lupus? Rich MW, Eckman JM J Rheumatol 1995;22:1001.
  2. Acute immune intravascular hemolysis due to hydrochlorothiazide. Garratty G, Houston M, Petz LD, Webb M Am J Clin Pathol 1981;76:73-8.
  3. Thiazide diuretics induce cutaneous lupus-like adverse reaction. Brown CW, Deng JS J Toxicol Clin Toxicol 1995;33:729-33.
  4. Fatal intravascular immune hemolysis induced by hydrochlorothiazide. Beck ML, Cline JF, Hardman JT, Racela LS, Davis JW Am J Clin Pathol 1984;81:791-4.
  5. Allergic vasculitis induced by hydrochlorothiazide: confirmation by mast cell degranulation test. Grunwald MH, Halevy S, Livni E Isr J Med Sci 1989;25:572-4.
  6. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA Ann Intern Med 1985;103:49-51.
  7. Characterization of antibody and selection of alternative drug therapy in hydrochlorothiazide-induced immune hemolytic anemia. Shirey RS, Bartholomew J, Bell W, Pollack B, Kickler TS, Ness PM Transfusion 1988;28:70-2.
  8. Thiazides: A cause of necrotising vasculitis? Bjornberg A, Gisslen H Lancet 1965;2:982-3.
 
       
 
Heart disease due to high blood pressure
HydrALAZINE may cause the following symptoms that are related to heart disease due to high blood pressure:
  • Pulmonary hypertension. This symptom may occur with a history of chronic obstructive pulmonary disease
  • Rapidly progressive glomerulonephritis (single study)
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Cardiovascular side effects are related to the vasodilatory properties of hydralazine. Reflex tachycardia is commonly observed. Palpitations, flushing, edema, or chest pain have been reported in less than 5% of patients. The use of hydralazine in patients with severe chronic heart failure has been associated with ischemia, including episodes of myocardial infarction. In patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD), hydralazine may increase pulmonary artery hypertension, especially during periods of hypoxia. The use of hydralazine in these patients may, on rare occasions, result in profound hypotension, tachycardia, and even death. Rare cases of bradycardia or cardiac tamponade (associated with hydralazine-induced lupus) have been reported. Hydralazine does not have a deleterious effect on the lipid profile, and, in fact, has been shown to decrease total and LDL cholesterol.

Provocation of ischemia in patients with compromised left ventricular systolic dysfunction may be due to the inability of hydralazine to decrease preload, or left ventricular filling pressures. The mechanism of increased pulmonary hypertension in patients with PH or COPD is a decrease of systemic vascular resistance accompanied by an increase in cardiac output without a fall in the pulmonary vascular resistance. In case reports and small series of patients, the use of hydralazine in such patients resulted in palpitations, chest tightness, unchanged pulmonary vascular resistance, increased pulmonary artery pressure, decreased systemic vascular resistance, and increased heart rate and cardiac output. For this reason, if hydralazine must be used, many experts recommend hemodynamic monitoring during hydralazine therapy in such patients.

Renal side effects are common in idiopathic systemic lupus erythematosus; however, immune complex glomerulonephritis is rare in drug-induced lupus. Rare cases of rapidly progressive and focal glomerulonephritis associated with the hydralazine-induced lupus syndrome are often accompanied by anemia, a positive anti-DNA antibody titer, and a positive ANA titer.

In one study, rapidly progressive glomerulonephritis (RPGN) is described in 4 of 444 patients, all of whom were men who were treated for 5 to 11 years with daily doses of 100 to 250 mg. In three of the four cases, biopsy revealed a focal and segmental glomerular necrosis with crescents and positive immunofluorescence. The antinuclear antibody titer became positive in three. Renal function improved in all but one after the withdrawal of hydralazine and institution of corticosteroid therapy. A number of other cases of RPGN are reported. It appears to be far more common in patients who are slow acetylators.

REFERENCE +

  1. An adverse reaction with hydralazine: a case study. Wehner RJ, Romanauskas VS AANA J 1981;June:274-5.
  2. Provocation of myocardial ischemic events during initiation of vasodilator therapy for severe chronic heart failure. Packer M, Meller J, Medina N, et al Am J Cardiol 1981;48:939-46.
  3. Evaluation of once daily hydralazine in inadequately controlled hypertension. Danielson M, Kjellberg J, Ohman P, Wernersson B Acta Med Scand 1983;214:373-80.
  4. Multiple episodes of angioedema associated with lisinopril, an ACE inhibitor. Frontera Y, Piecuch JF J Am Dent Assoc 1995;126:217-20.
  5. Detrimental effects of hydralazine in patients with chronic air-flow obstruction and pulmonary hypertension. Tuxen DV, Powles AC, Mathur PN, et al Am Rev Respir Dis 1984;129:388-95.
  6. Effects of hydralazine on hemodynamics, ventilation, and gas exchange in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Keller CA, Shepard JW, Chun DS, et al Am Rev Respir Dis 1984;129:606-11.
  7. Cardiac tamponade in hydrallazine-induced systemic lupus erythematosus. Aylward PE, Tonkin AM Aust N Z J Med 1982;12:546.
  8. Hydralazine-induced tachycardia and sodium retention in heart failure: hemodynamic and symptomatic correlation by prazosin therapy. Laslett LJ, DeMaria AN, Amsterdam EA, Mason DT Arch Intern Med 1978;138:819-20.
  9. Deleterious effects of hydralazine in patients with pulmonary hypertension. Packer M, Greenberg B, Massie B, Dash H N Engl J Med 1982;306:1326-31.
  10. Hydralazine. Koch-Weser J N Engl J Med 1976;295:320-3.
  11. Pericardial tamponade: a major presenting manifestation of hydralazine-induced lupus syndrome. Carey RM, Coleman M, Feder A Am J Med 1973;54:84-7.
  12. Efficacy and safety comparison of nitrendipine and hydralazine as antihypertensive monotherapy. Fagan TC, Sternleib C, Vlachakis N, et al J Cardiovasc Pharmacol 1984;6:s1109-13.
  13. Efficacy and tolerability of hydralazine, in conventional and slow-release preparations, during long-term treatment of primary hypertension. Lins L-E, Berglund J, Eliasson K, Wernersson B Clin Ther 1983;5:251-9.
  14. Fatal small-bowel necrosis and pulmonary hypertension in sickle cell disease. Hammond TG, Mosesson MW Arch Intern Med 1989;149:447-8.
  15. Plasma lipid profiles and antihypertensive agents: effects of lisinopril, enalapril, nitrendipine, hydralazine, and hydrochlorothiazide. Williams LL, Lopez LM, Thorman AD, et al Drug Intell Clin Pharm 1988;22:546-50.
  16. Persistent reversal of severe systemic hypertension after prolonged toxic reaction to hydralazine. Miller AJ, Abrams DL, Kaplan BM Cardiology 1975;60:251-6.
  17. Fetal premature atrial contractions associated with hydralazine. Lodeiro JG, Feinstein SJ, Lodeiro SB Am J Obstet Gynecol 1989;160:105-7.
  18. Adverse effect of hydralazine in patients with primary pulmonary hypertension. Kronzon I, Cohen M, Winer HE JAMA 1982;247:3112-4.
 
       
 
Heart disease due to high blood pressure
Clonidine may cause the following symptom that is related to heart disease due to high blood pressure:
  • High blood pressure (can occur as long as 6 weeks after starting/treatment with clonidine)
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Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days. Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages. Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

A case of sinus arrest associated with clonidine has been reported. A 65-year-old man with diabetes, hypertension and unexplained syncope developed more frequent syncope and dizziness associated with documented episodes of sinus arrest during the first week of clonidine therapy. The patient had no hypoglycemia or orthostatic changes. The syncope and dizziness resolved upon discontinuation of clonidine; continuous electrocardiographic monitoring revealed a gradual and complete disappearance of sinus pauses. Junctional bradycardia and AV heart block have also been reported. Ventricular tachycardia (VT) relatively refractory to lidocaine, but responsive to intravenous phentolamine, has been associated with clonidine withdrawal (case report). The authors believe that the VT was probably produced by humoral or neural stimulation of unregulated myocardial alpha-adrenergic receptors. Transdermal clonidine has been implicated with hypertension in a quadriplegic patient with a C4 spinal lesion. The proposed mechanism is predominance of clonidine's peripheral alpha-1 adrenergic effects due to the patient's autonomic dysfunction, resulting in vasoconstriction and hypertension. Sinus bradycardia or other supraventricular bradyarrhythmias are more likely in patients with underlying renal dysfunction. In one case report, severe hypotension occurred during separation from cardiopulmonary bypass in a patient given intrathecal clonidine. The patient responded to volume expansion and use of vasoconstrictors.

Endocrinologic side effects have been limited to rare cases of gynecomastia, hyperprolactinemia, or hyperglycemia.

A 68-year-old black man with hypertension, status post unilateral nephrectomy, was incidentally found to have 4+ proteinuria, 1+ glycosuria, new elevated blood glucose levels, and between 1.8 and 5.4 grams of protein per 24-hour urine collection within 6 weeks after starting clonidine. The signs and symptoms of diabetes and the nephrotic syndrome disappeared within five months after discontinuation of clonidine. Because of his solitary kidney, a renal biopsy was not performed.

REFERENCE +

  1. Plasma catecholamines and autonomic nervous system function in patients with early renal insufficiency and hypertension: effect of clonidine. Levitan D, Massry SG, Romoff M, Campese VM Nephron 1984;36:24-9.
  2. Rebound hypertension during initiation of transdermal clonidine. Stewart M, Burris JF Drug Intell Clin Pharm 1988;22:573-4.
  3. Clonidine-Induced Gynecomastia and Hyperprolactinemia in a 6-Year-Old Child. Mendhekar DN J Clin Psychiatry 2005;66:1616-1617.
  4. Clonidine and sudden death. Maloney MJ, Schwam SJ Pediatrics 1995;96:1176-7.
  5. Clonidine raises blood pressure in severe idiopathic orthostatic hypotension. Robertson D, Goldberg MR, Hollister AS, et al Am J Med 1983;74:193-200.
  6. Safety aspects of long-term antihypertensive therapy (10 years) with clonidine. Ferder L, Inserra F, Medina F J Cardiovasc Pharmacol 1987;10:s104-8.
  7. Preoperative clonidine withdrawal syndrome. Bruce D, Croley T, Lee J Anesthesiology 1979;51:90-2.
  8. Clonidine, a new antihypertensive drug. Pettinger WA N Engl J Med 1975;293:1179-80.
  9. Evaluation of clonidine hydrochloride (catapres): a new antihypertensive agent. Kosman ME JAMA 1975;233:174-6.
  10. Clonidine-induced bradycardia. Golusinski LL, Blount BW J Fam Pract 1995;41:399-401.
  11. Intrathecal clonidine and severe hypotension after cardiopulmonary bypass. Puskas F, Camporesi EM, O'Leary CE, Hauser M, Nasrallah FV Anesth Analg 2003;97:1251-3.
  12. Clonidine-induced hyperglycemia in a young diabetic girl. Mimouni-Bloch A, Mimouni M Ann Pharmacother 1993;27:980.
  13. Severe hypotension associated with concurrent clonidine and antipsychotic medication. Fruncillo RJ, Gibbons WJ, Vlasses PH, Ferguson RK Am J Psychiatry 1985;142:274.
  14. Withdrawal of antihypertensive therapy. Strauss F, Franklin S, Lewin A, Maxwell M JAMA 1977;238:1734-36.
  15. A dose-response study of orally administered clonidine as premedication in the elderly - evaluating hemodynamic safety. Filos KS, Patroni O, Goudas LC, Bosas O, Kassaras A, Gartaganis S Anesth Analg 1993;77:1185-92.
  16. Risk factors for severe bradycardia during oral clonidine therapy for hypertension. Byrd BF, Collins HW, Primm RK Arch Intern Med 1988;148:729-33.
  17. Sinus arrest associated with clonidine therapy. Schwartz E, Friedman E, Mouallem M, Farfel Z Clin Cardiol 1988;11:53-4.
  18. Paradoxical hypertension from clonidine . Young E, Levey BA, Shapiro AP Ann Intern Med 1984;101:282-3.
  19. Symptomatic hypotension following the clonidine suppression test for pheochromocytoma. Given BD, Taylor T, Lilly LS, Dzau VJ Arch Intern Med 1983;143:2195-6.
  20. Clonidine-induced hypertension in a patient with a spinal lesion. Backo AL, Clause SL, Triller DM, Gibbs KA Ann Pharmacother 2002;36:1396-8.
  21. Abrupt cessation of clonidine administration: a prospective study. Whitsett TL, Chrysant SG, Dillard BL, Anton AH Am J Cardiol 1978;41:1285-90.
  22. Epidural clonidine analgesia for intractable cancer pain. Eisenach JC, Dupen S, Dubois M, Miguel R, Allin D, Bryce D, Burger GA, Chamberlain D, Docherty R, Evans G, Finnegan R, Hantler Pain 1995;61:391-9.
  23. Is clonidine an effective smoking cessation therapy? Gourlay SG, Benowitz NL Drugs 1995;50:197-207.
  24. Product Information. Duraclon Injection (clonidine) Anonymous Roxane Laboratories Inc, Columbus, OH. PROD;
  25. The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine. van Zwieten PA, Thoolen MJ, Timmermans PB Hypertension 1984;6:28-33.
 
       
 
Heart disease due to high blood pressure
Captopril may cause the following symptom that is related to heart disease due to high blood pressure:
  • High blood pressure (can occur as long as a few hours after starting/treatment with the drug)
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Note: Original Source for Medical Professionals
Dermatologic side effects have included psoriasiform rashes, pemphigus-like lesions, angioedema of the face and mucous membranes, pityriasis-like eruptions, alopecia, exfoliative dermatitis, photosensitivity, bullous or lichenoid eruptions, and erythematous eruptions. Rarely, worsened Kaposi's sarcoma lesions, oncolysis, pemphigus vulgaris, and Henoch-Schonlein Purpura have been reported. A case of toxic epidermal necrolysis has also been reported.

A 70-year-old, heterosexual, HIV-negative man with hypertension developed Kaposi's sarcoma (KS) during captopril therapy. The lesions completely resolved within three months after discontinuation of captopril. In another case, a 70-year-old woman with seropositive rheumatoid arthritis and hypertension developed KS within eight months after starting captopril therapy. A full work-up, including HIV antibody testing, was negative. The lesions did not resolve, but became flat, brown, and non-indurated within 15 days after captopril was stopped. A 47-year-old male was given captopril for hypertension and developed an erythematous eruption on both cheeks within a few hours following the first dose. Positive reactions were obtained during patch testing for captopril at a later time.

Immunologic side effects have rarely included lymphadenopathy, systemic lupus erythematosus, and Henoch-Schonlein Purpura. Serum sickness-like illness has been reported.

A 53-year-old man with diabetes mellitus, hypertension, and heart failure developed arthralgias, fever, and malaise associated with bilateral pleural effusions, elevated liver function tests, a pericardial rub, and elevated C-reactive protein. After other causes of systemic lupus erythematosus were ruled out, captopril was stopped, and these signs and symptoms resolved. In a study of 78 patients who were treated with captopril for 11 months, 13 developed a positive antinuclear antibody titer. Only one of the 13, however, developed a serum sickness-like illness.

REFERENCE +

  1. Kaposi's sarcoma in a patient with rheumatoid arthritis possible responsibility of captopril in the development of lesions. Larbre JP, Nicolas JF, Collet P, et al J Rheumatol 1991;18:476-7.
  2. Pemphigus vulgaris induced by captopril. Butt A, Burge SM Br J Dermatol 1995;132:315-6.
  3. Captopril: an update of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure. Brogden RN, Todd PA, Sorkin EM Drugs 1988;36:540-600.
  4. Captopril-induced skin eruptions. Luderer JR, Lookingbill DP, Schneck DW, et al J Clin Pharmacol 1982;22:151-9.
  5. Possible captopril-induced toxic epidermal necrolysis. Alkurtass DA, Al-Jazairi AS Ann Pharmacother 2003;37:380-3.
  6. Severe cutaneous reactions to captopril. Goodfield MJ, Millard LG Br Med J 1985;290:1111.
  7. Severe side-effects of captopril in advanced chronic kidney insufficiency. Beroniade V Proc Eur Dial Transplant Assoc 1983;20:530-7.
  8. Psoriasis related to angiotensin-converting enzyme inhibitors. Wolf R, Tamir A, Brenner S Dermatologica 1990;181:51-3.
  9. Angiotensin converting enzyme inhibitors in hypertension: potential problems. Antonios TFT, Macgregor GA J Hypertens 1995;13 Suppl:s11-6.
  10. Captopril-triggered linear IgA bullous dermatosis. Friedman IS, Rudikoff D, Phelps RG, Sapadin AN Int J Dermatol 1998;37:608-12.
  11. Safety and efficacy of chronic therapy with captopril in hypertensive patients: an update. Waeber B, Gavras I, Brunner HR, Gavras H J Clin Pharmacol 1981;21:508-16.
  12. Antinuclear and antinative DNA antibodies during captopril treatment. Kallenberg CG, Hoorntje SJ, Smit AJ, et al Acta Med Scand 1982;211:297-300.
  13. Captopril-induced pemphigus. Parfrey PS, Clement M, Vandenburg MJ, Wright P Br Med J 1980;281:194.
  14. Captopril. Vidt DG, Bravo EL, Fouad FM N Engl J Med 1982;306:214-9.
  15. Captopril-induced toxic epidermal necrolysis and agranulocytosis successfully treated with colony-stimulating factor. Winfred RI, Nanda S, Horvath G, Elnicki M South Med J 1999;92:918-20.
  16. Captopril-induced lupus. Bertin P, Kamdem J, Bonnet C, Arnaud M, Treves R Clin Exp Rheumatol 1993;11:695.
  17. Henoch-schoenlein purpura and angiotensin-converting enzyme inhibitors. Neumann J, Andrassy K, Waltersack I, Berg PA Nephron 1994;67:117.
  18. Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapril. The Quality-of-Life Hypertension Study Group. Testa MA, Anderson RB, Nackley JF, Hollenberg NK N Engl J Med 1993;328:907-13.
  19. Captopril-induced lichenoid eruption. Phillips WG, Vaughanjones S, Jenkins R, Breathnach SM Clin Exp Dermatol 1994;19:317-20.
  20. A long-term follow-up of patients with essential hypertension treated with captopril. Ohman P, Aurell M, Asplund J, et al Acta Med Scand 1984;216:53-6.
  21. Subepidermal bullous eruption induced by captopril. Fitzgerald DA Clin Exp Dermatol 1993;18:196-7.
  22. Randomized controlled trial of oral captopril, of oral isosorbide mononitrate and of intravenous magnesium sulphate started early in acute myocardial infarction - safety and haemodynamic effects. Flather M, Pipilis A, Collins R, Budaj A, Hargreaves A, Kolettis T, Jacob A, Millane T, Fitzgerald L, Cedro K, Cybulski J, Dancy Eur Heart J 1994;15:608-19.
  23. Effectiveness and safety of captopril (tensiomin) in patients with hypertension. Torok E, Biro V, Wagner M, et al Acta Physiol Hung 1988;72:51-65.
  24. Adverse effects of the angiotensin-converting enzyme inhibitors. Alderman CP Ann Pharmacother 1996;30:55-61.
  25. The captopril-induced eruption: a possible mechanism, cutaneous kinin potentiation. Wilkin JK, Hammond JJ, Kirkendall WM Arch Dermatol 1980;116:902-5.
  26. Fatal Stevens-Johnson syndrome in a patient on captopril and allopurinol. Pennell DJ, Nunan TO, O'Doherty MJ, Croft DN Lancet 1984;1:463.
  27. Captopril-induced eruptions . Clement MI Arch Dermatol 1981;117:525-6.
  28. Acute renal failure, hemolytic anemia and skin rash associated with captopril therapy. Luderer JR, Schoolwerth AC, Sinicrope R, et al Am J Med 1981;71:493-6.
  29. Kaposi's sarcoma associated with captopril . Puppin D Jr, Rybojad M, de la Chapelle C, Morel P Lancet 1990;336:1251-2.
  30. Captopril-associated lymphadenopathy. Aberg H, Morlin C, Frithz G Br Med J 1981;283:1297-8.
  31. Captopril and systemic lupus erythematosus syndrome. Sieber C, Grimm E, Follath F Br Med J 1990;301:669.
  32. Alopecia associated with captopril treatment . Leaker B, Whitworth JA Aust N Z J Med 1984;14:866.
  33. A long-term follow-up of patients with essential hypertension treated with captopril. Ohman P, Aurell M, Asplund J, et al Acta Med Scand 1984;216:53-6.
  34. Captopril and onycholysis . Borders JV Ann Intern Med 1986;105:305-6.
  35. Captopril induced lupus. Ratliff NB 3rd J Rheumatol 2002;29:1807-8.
  36. Cutaneous reaction to captopril with positive patch test and lack of cross-sensitivity to enalapril and benazepril. LluchBernal M, Novalbos A, Umpierrez A, Figueredo E, Bombin C, Sastre J Contact Dermatitis 1998;39:316-7.
  37. Exfoliative dermatitis from captopril. Solinger AM Cutis 1982;29:473-4.
  38. Henoch-schoenlein purpura and angiotensin-converting enzyme inhibitors. Neumann J, Andrassy K, Waltersack I, Berg PA Nephron 1994;67:117.
 
       
 
       
 
Numbness or tingling ("pins and needles")
HydrALAZINE may cause numbness or tingling (common).

This drug may also cause the following symptoms that are related to numbness or tingling:

  • Nerve damage (common)
  • Numbness/tingling in hands/feet (common)
  • Numbness/tingling in the arms or legs (common)
  • Numbness
  • Peripheral neuropathy
  • Vasculitis
  • Burning, prickling, tickling or tingling (uncommon)
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Nervous system side effects including peripheral neuropathy is dose-related and is more common in slow acetylators. The neuropathy usually first presents as paresthesias, numbness, and tingling in the extremities. It is probably the result of pyridoxine deficiency, perhaps because formation of a pyridoxal-hydralazine complex inactivates the coenzyme, and can, therefore, be treated by administration of pyridoxine. Headache or dizziness have been reported in approximately 5% of patients.

A 61-year-old man with hypertension developed ataxia, numbness, and lower extremity weakness approximately six months after beginning hydralazine (up to 300 mg per day) and reserpine therapy. The neuropathy partially resolved after reduction of the hydralazine dosage to 60 mg daily. A complete evaluation revealed that this man was a slow acetylator of hydralazine.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: fast or pounding heartbeats; swelling in your face, stomach, hands, or feet; numbness, burning, pain, or tingly feeling; feeling like you might pass out; confusion, unusual thoughts or behavior; pale skin, easy bruising; painful or difficult urination; dark-colored urine; urinating less than usual or not at all; or joint pain or swelling with fever, chest pain, weakness or tired feeling. Less serious side effects may include: nausea, vomiting, loss of appetite; diarrhea, constipation; headache; dizziness; anxiety; muscle or joint pain; runny or stuffy nose; or mild itching or skin rash. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Hematologic abnormalities have been associated with the hydralazine-induced lupus-like syndrome. Anemia may be caused by one of at least four hydralazine-associated problems; hemolysis, the formation of a circulating anticoagulant, thrombocytopenia, and vasculitis. Rare cases of leukopenia and agranulocytosis have been reported.

A 71-year-old man with hypertension developed anorexia, weight loss, petechiae, and a microcytic anemia during therapy with hydralazine and oxprenolol. Evaluation for iron deficiency, hemolysis, or marrow depression was negative. The patient was found to have fecal blood loss, anti-DNA antibodies, decreased complement levels, a normal upper GI series, and biopsy-proven vasculitis. The syndrome resolved within two weeks after discontinuation of hydralazine.

REFERENCE +

  1. Hydralazine. Koch-Weser J N Engl J Med 1976;295:320-3.
  2. Efficacy and tolerability of hydralazine, in conventional and slow-release preparations, during long-term treatment of primary hypertension. Lins L-E, Berglund J, Eliasson K, Wernersson B Clin Ther 1983;5:251-9.
  3. Efficacy and safety comparison of nitrendipine and hydralazine as antihypertensive monotherapy. Fagan TC, Sternleib C, Vlachakis N, et al J Cardiovasc Pharmacol 1984;6:s1109-13.
  4. Hydralazine-induced peripheral neuropathy seen in a Japanese slow acetylator patient. Tsujimoto G, Horai Y, Ishizaki T, Itoh K Br J Clin Pharmacol 1981;11:622-5.
  5. Evaluation of once daily hydralazine in inadequately controlled hypertension. Danielson M, Kjellberg J, Ohman P, Wernersson B Acta Med Scand 1983;214:373-80.
 
       
 
Numbness or tingling ("pins and needles")
Gemfibrozil may cause numbness or tingling.

This drug may also cause the following symptoms that are related to numbness or tingling:

  • Burning, prickling, tickling or tingling
  • Vasculitis (rare)
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Nervous system side effects of gemfibrozil include dizziness, somnolence, headache, vertigo, hyperesthesia, paresthesias, taste perversion, and confusion.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: sharp pain in your upper stomach (especially after eating); jaundice (yellowing of your skin or eyes); blurred vision, eye pain, or seeing halos around lights; or pain or burning when you urinate. Less serious side effects may include: heartburn, upset stomach; nausea, vomiting, diarrhea, constipation, stomach pain; dizziness, spinning sensation; drowsiness, tired feeling; unusual or unpleasant taste in your mouth; cough or cold symptoms; numbness or tingly feeling; joint or muscle pain; mild skin rash; or blurred vision. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Cardiovascular side effects of gemfibrozil include rare cases of atrial fibrillation, vasculitis, and Raynaud's phenomenon.

REFERENCE +

  1. Product Information. Lopid (gemfibrozil). Anonymous Parke-Davis, Morris Plains, NJ. PROD;
  2. Polymyositis exacerbated by gemfibrozil . Fusella J, Strosberg JM J Rheumatol 1990;17:572-3.
  3. Gemfibrozil-induced headache . Alvarez-Sabin J, Codina A, Rodriguez C, Laporte JR Lancet 1988;2:1246.
  4. Gemfibrozil-induced headache . Arellano F, de Cos MA, Valiente R, Quiros C Lancet 1988;1:705.
 
       
 
Numbness or tingling ("pins and needles")
Hydrochlorothiazide may cause numbness or tingling.
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Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as: dry mouth, thirst, nausea, vomiting; feeling weak, drowsy, restless, or light-headed; fast or uneven heartbeat; muscle pain or weakness; numbness or tingly feeling; a red, blistering, peeling skin rash; or nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes). Less serious side effects may include: diarrhea; mild stomach pain; constipation; or blurred vision. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

 
       
 
Numbness or tingling ("pins and needles")
Simvastatin may cause numbness or tingling.

This drug may also cause the following symptoms that are related to numbness or tingling:

  • Burning, prickling, tickling or tingling
  • Conditions affecting peripheral nerves
  • Peripheral neuropathy
  • Vasculitis
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Nervous system side effects have included headache (6.5%) and cognitive impairment. Other nervous system side effects reported with HMG-CoA reductase inhibitors have included cranial nerve dysfunction, tremor, vertigo, memory loss, paresthesias, peripheral neuropathy, and peripheral nerve palsy.

Immunologic side effects of simvastatin have included a case of lupus-like syndrome which has been reported with other HMG-CoA reductase inhibitors. Other immunologic side effects reported with HMG-CoA reductase inhibitors have included positive ANA, ESR increase, polymyalgia rheumatica, and vasculitis.

REFERENCE +

  1. Simvastatin-induced decline in cognition. Padala KP, Padala PR, Potter JF Ann Pharmacother 2006;40:1880-3.
  2. Statins and risk of polyneuropathy: a case-control study. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH Neurology 2002;58:1333-7.
  3. Product Information. Zocor (simvastatin). Anonymous Merck & Co, Inc, West Point, PA. PROD;
  4. Simvastatin-associated memory loss. Orsi A, Sherman O, Woldeselassie Pharmacotherapy 2001;21:767-9.
  5. Simvastatin - a reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia. Plosker GL, Mctavish D Drugs 1995;50:334-63.
  6. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB Am J Med 2004;117:823-9.
  7. Atorvastatin may cause nightmares. Gregoor PJ BMJ 2006;332:950.
  8. Short-term memory loss associated with rosuvastatin. Galatti L, Polimeni G, Salvo F, Romani M, Sessa A, Spina E Pharmacotherapy 2006;26:1190-2.
  9. Peripheral neuropathy associated with simvastatin. Phan T, Mcleod JG, Pollard JD, Peiris O, Rohan A, Halpern JP J Neurol Neurosurg Psychiatry 1995;58:625-8.
  10. Simvastatin causes changes in affective processes in elderly volunteers. Morales K, Wittink M, Datto C, et al. J Am Geriatr Soc 2006;54:70-6.
  11. Simvastatin: the clinical profile. Walker JF Am J Med 1989;87:s44-6.
 
       
 
Numbness or tingling ("pins and needles")
Verapamil may cause numbness or tingling in less than 1% of people.

This drug may also cause the following symptoms that are related to numbness or tingling:

  • Burning, prickling, tickling or tingling in less than 1% of people
  • Skin tingling
  • Stroke
  • Vasculitis
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Musculoskeletal side effects have included myalgia (up to 1.1%) and bizarre perceptual symptoms most closely described as cold extremities. Muscle fatigue has been reported with intravenous verapamil. Arthralgia (with rash) and muscle cramps have been reported during open trials/postmarketing experience.

Three case reports have been found by one practitioner. In each case, unusual symptoms of cold extremities and paresthesias without objective evidence of a neuromuscular or cardiac etiology were described. The symptoms resolved upon discontinuation and, in each case, recurred upon drug rechallenge.

Nervous system side effects have included headache (up to 12.1%), dizziness (up to 4.7%), lethargy (up to 3.2%), fatigue (up to 4.5%), sleep disturbances (up to 1.4%), paresthesia (up to 1%), and rare neurologic complaints (including paresthesias, sleeping problems, and tremors; less than 1%). Dizziness (1.2%), headache (1.2%), sleepiness, vertigo, and rare cases of seizures during injection have been reported with intravenous verapamil. Rare cases of muscle fasciculations in patients with underlying neuromuscular diseases, stroke associated with verapamil-induced hypotension, exacerbation of myasthenia gravis, and myoclonic dystonia have been reported. Cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, paresthesia, shakiness, somnolence, syncope, and tinnitus have been reported during open trials/postmarketing experience.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: fast or slow heartbeats; feeling like you might pass out; fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; feeling short of breath, even with mild exertion; swelling, rapid weight gain; or nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes). Less serious side effects may include: constipation, nausea; skin rash or itching; dizziness, headache, tired feeling; or warmth, itching, redness, or tingly feeling under your skin. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Cardiovascular side effects have included hypotension (up to 2.5%), new or worsened congestive heart failure (CHF) or pulmonary edema (negative inotropism; 1.8%), bradycardia (heart rate less than 50/minute; 1.4%), atrioventricular (AV) block (first-degree; up to 1.7%), AV block (total first-, second-, and third-degree; 1.2%), AV block (second- and third-degree; 0.8%), and postural hypotension (up to 0.4%). Symptomatic hypotension (1.5%), bradycardia (1.2%), and severe tachycardia (1%) have been reported with intravenous verapamil. In studies related to control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rate less than 50/minute at rest (15%) and asymptomatic hypotension (5%) were reported. Dizziness, hypotension, peripheral edema, and headache are not uncommon and are related to vasodilation of vascular smooth muscle. Verapamil may accelerate conduction of anomalous AV conduction tissue, as in the Wolff-Parkinson-White syndrome, which can result in worsened tachycardia, including malignant ventricular tachyarrhythmias or accelerated junctional tachycardia. Because of this potentially fatal side effect, verapamil is not recommended in patients with atrial fibrillation and premature ventricular depolarizations. Angina pectoris, AV block (second- and third-degree), atrioventricular dissociation, CHF, pulmonary edema, abnormal ECG, chest pain, claudication, hypertension, myocardial infarction, palpitations, and purpura (vasculitis) have been reported during open trials/postmarketing experience.

REFERENCE +

  1. Product Information. Covera-HS (verapamil). Anonymous Searle, Skokie, IL. PROD;
  2. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
  3. Case report: sustained-release verapamil overdose causing stroke: an unusual complication. Shah AR, Passalacqua BR Am J Med Sci 1992;304:357-9.
  4. Bizarre perceptual disorder of extremities in patients taking verapamil. Kumana CR, Mahon WA Lancet 1981;06/13/81:1324-5.
  5. Verapamil and acute dystonia. Pina MA, Ara JR, Remirez A, Castiella J J Clin Pharm Ther 1998;23:79-80.
  6. Long-term safety and efficacy of immediate-release and sustained-release oral verapamil in systemic hypertension. Frishman WH, Eisen G, Charlap S, Strom JA J Clin Hypertens 1987;3:605-9.
  7. Delirium induced by verapamil. Jacobsen FM, Sack DA, James SP Am J Psychiatry 1987;144:248.
  8. Fasciculations due to verapamil in a patient with neuropathy. Thomke F, Vogt T, Roder R, Hopf HC J Neurol 1990;237:448-9.
  9. Verapamil and myoclonic dystonia. Hicks CB, Abraham K Ann Intern Med 1985;103:154.
  10. Antihypertensive efficacy of sustained-release verapamil. Zachariah PK, Sheps SG, Oshrain C, et al J Clin Hypertens 1987;3:536-46.
  11. Verapamil-induced parkinsonism. Padrell MD, Navarro M, Faura CC, Horga JF Am J Med 1995;99:436.
  12. Verapamil toxicity: treatment with hemoperfusion. Rosansky SJ Ann Intern Med 1991;114:340-1.
  13. Adverse effect of verapamil in myasthenia gravis: an additional comment. Reverte M Muscle Nerve 1993;16:879-81.
  14. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  15. Treatment of mild hypertension with low once-daily doses of a sustained-release capsule formulation of verapamil. Davis PJ, Fagan TC, Topmiller MJ, Levine JH, Ferdinand KC J Clin Pharmacol 1995;35:52-8.
  16. Verapamil in the long-term treatment of angina pectoris. Raftos J Med J Aust 1980;07/26/80:78-80.
  17. Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. McTavish D, Sorkin EM Drugs 1989;38:19-76.
 
       
 
Numbness or tingling ("pins and needles")
Allopurinol may cause numbness or tingling (first sign that a side effect is occuring).

This drug may also cause the following symptoms that are related to numbness or tingling:

  • Vasculitis (at least 1 case(s))
  • Peripheral neuropathy (very rare)
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Nervous system side effects have been reported extremely rarely and included case reports of peripheral neuropathy, catatonia, and cerebral vasculitis associated with allopurinol hypersensitivity. At least two cases of allopurinol-induced aseptic meningitis have also been reported.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using allopurinol and call your doctor at once if you have any of these serious side effects: the first sign of any skin rash, no matter how mild; pain or bleeding when you urinate; urinating less than usual or not at all; fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; bruising, severe tingling, numbness, pain, muscle weakness; easy bruising or bleeding, unusual weakness; fever, chills, body aches, flu symptoms; jaundice (yellowing of the skin or eyes); or seizure (convulsions). Less serious side effects may include: nausea, vomiting, diarrhea; dizziness or drowsiness; increased sweating; or joint pain. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Dermatologic side effects have included skin rash, pruritus, and alopecia. Severe skin reactions have rarely included exfoliative dermatitis, vesicular bullous eruptions, and erythema multiforme.

Allopurinol-induced rash may be followed by more severe hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, nephrotoxicity, and hepatotoxicity. Such hypersensitivity syndromes have been fatal in some cases. The incidence of skin rash may be increased in patients with renal dysfunction.

Hypersensitivity side effects have included hypersensitivity maculopapular rash (1% to 3%). Rash, eosinophilia, and fever have been reported in 0.3% of patients. Rare, but potentially fatal, reactions have included arthralgias, hepatitis, acute interstitial nephritis, vasculitis, and severe skin reactions. Stevens-Johnson syndrome, toxic epidermal necrolysis, and toxic pustuloderma have been reported rarely. At least 3 cases of allopurinol hypersensitivity syndrome have also been reported.

Immunologic side effects have included at least one case of ANCA-positive vasculitis.

Antineutrophil cytoplasmic antibodies (ANCA) against human neutrophil elastase as well as against myeloperoxidase were documented in a 47-year-old man who developed vasculitis during allopurinol therapy for gout. Clinical improvement and decline in antibodies were noted upon discontinuation of allopurinol.

Renal side effects have included crystalluria and stone formation as well as elevations in blood urea nitrogen. Acute interstitial nephritis due to hypersensitivity and granulomatous nephritis have also been reported.

Studies of patients with allopurinol-induced crystalluria and nephrolithiasis have revealed both urate and allopurinol/oxypurinol (allopurinol metabolite) calculi. Biopsies in cases of suspected allopurinol-associated acute renal failure have revealed vasculitis, interstitial nephritis, and rare cases of granulomatous nephritis.

Allopurinol should be discontinued at the first sign of skin rash or any other signs or symptoms suggestive of a hypersensitivity reaction. In some instances, a skin rash may be followed by more severe adverse reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, rarely, death. Renal dysfunction increases the risk of allopurinol hypersensitivity.

 
       
 
Numbness or tingling ("pins and needles")
Niacin may cause numbness or tingling (rare).

This drug may also cause the following symptoms that are related to numbness or tingling:

  • Skin tingling
  • Burning, prickling, tickling or tingling (rare)
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Nervous system side effects have included rare reports of paresthesias, nervousness, dizziness, headache, fatigue, and insomnia.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: feeling light-headed, fainting; fast, pounding, or uneven heart beats; feeling short of breath; swelling; jaundice (yellowing of your skin or eyes); or muscle pain, tenderness, or weakness with fever or flu symptoms and dark colored urine. If you are diabetic, tell your doctor about any changes in your blood sugar levels. Less serious side effects of niacin include: mild dizziness; warmth, redness, or tingly feeling under your skin; itching, dry skin; sweating or chills; nausea, diarrhea, belching, gas; muscle pain, leg cramps; or sleep problems (insomnia). This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

REFERENCE +

  1. Approaches to the management of hypercholesterolaemia. Florkowski CM, Cramb R J Clin Pharm Ther 1992;17:81-9.
  2. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. McKenney JM, Proctor JD, Harris S, Chinchili VM JAMA 1994;271:672-7.
  3. New approaches to cholesterol lowering: efficacy and safety. Knopp RH Hosp Pract (Off Ed) 1988;23 Suppl 1:22-30.
  4. Efficacy and safety of one-year treatment with slow-release nicotinic acid. Monitoring of drug concentration in serum. ChojnowskaJezierska J, AdamskaDyniewska H Int J Clin Pharmacol Ther 1998;36:326-32.
  5. Hepatotoxicity associated with sustained-release niacin. Dalton TA, Berry RS Am J Med 1992;93:102-4.
  6. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH, Tun P, Zupkis RV, Greguski RA Arch Intern Med 1994;154:1586-95.
  7. Choice of cholesterol-lowering drugs. Anonymous Med Lett Drugs Ther 1991;33:1-4.
  8. Clinical trial experience with extended-release niacin (Niaspan): Dose-escalation study. Goldberg AC Am J Cardiol 1998;82:u35-8.
  9. Choice of cholesterol-lowing drugs. Anonymous Med Lett Drugs Ther 1993;35:19-22.
  10. Continuous axillary brachial plexus blockade following intra-arterial injection of nicotinic acid. Dyson A, Henderson AM Anaesth Intensive Care 1987;15:462-5.
  11. Niacin revisited. A randomized, controlled trial of wax-matrix sustained-release niacin in hypercholesterolemia. Keenan JM, Fontaine PL, Wenz JB, Myers S, Huang ZQ, Ripsin CM Arch Intern Med 1991;151:1424-32.
  12. Adverse effects of sustained-release niacin. Knapp TR, Middleton RK DICP 1991;25:253-4.
  13. Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia. Davignon J, Roederer G, Montigny M, Hayden MR, Tan MH, Connelly PW, Hegele R, McPherson R, Lupien PJ, Gagne C, et al Am J Cardiol 1994;73:339-45.
  14. The prevalence of side effects with regular and sustained-release nicotinic acid. Gibbons LW, Gonzalez V, Gordon N, Grundy S Am J Med 1995;99:378-85.
  15. Product Information. Niaspan ER (niacin). Anonymous Allscripts Healthcare Solutions, Libertyville, IL.
  16. Niacin or niacinamide? Nicotinic acid or nicotinamide? What is the difference?. Ranchoff RE, Tomecki KJ J Am Acad Dermatol 1986;15:116-7.
  17. Niacin maculopathy. Millay RH, Klein ML, Illingworth DR Ophthalmology 1988;95:930-6.
  18. Efficacy and safety of an extended-release niacin (Niaspan): A long-term study. Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA, Brusco OA, Brody J Am J Cardiol 1998;82:u74-81.
  19. Niacin maculopathy. Jampol LM Ophthalmology 1988;95:1704-5.
 
       
 
Numbness or tingling ("pins and needles")
Naproxen may cause the following symptom that is related to numbness or tingling:
  • Stroke caused by blockage of the arteries that supply blood to the brain
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NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

 
       
 
Numbness or tingling ("pins and needles")
Clonidine may cause the following symptoms that are related to numbness or tingling:
  • Autonomic neuropathy.
  • Stroke (rare). This symptom may occur when the drug is stopped or dose is decreased
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Note: Original Source for Medical Professionals
Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days. Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages. Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

A case of sinus arrest associated with clonidine has been reported. A 65-year-old man with diabetes, hypertension and unexplained syncope developed more frequent syncope and dizziness associated with documented episodes of sinus arrest during the first week of clonidine therapy. The patient had no hypoglycemia or orthostatic changes. The syncope and dizziness resolved upon discontinuation of clonidine; continuous electrocardiographic monitoring revealed a gradual and complete disappearance of sinus pauses. Junctional bradycardia and AV heart block have also been reported. Ventricular tachycardia (VT) relatively refractory to lidocaine, but responsive to intravenous phentolamine, has been associated with clonidine withdrawal (case report). The authors believe that the VT was probably produced by humoral or neural stimulation of unregulated myocardial alpha-adrenergic receptors. Transdermal clonidine has been implicated with hypertension in a quadriplegic patient with a C4 spinal lesion. The proposed mechanism is predominance of clonidine's peripheral alpha-1 adrenergic effects due to the patient's autonomic dysfunction, resulting in vasoconstriction and hypertension. Sinus bradycardia or other supraventricular bradyarrhythmias are more likely in patients with underlying renal dysfunction. In one case report, severe hypotension occurred during separation from cardiopulmonary bypass in a patient given intrathecal clonidine. The patient responded to volume expansion and use of vasoconstrictors.

Epidural administration is contraindicated in patients receiving anticoagulant therapy, patients with bleeding diathesis, and in the presence of an injection site infection.

Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine can result in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of clonidine transdermal therapy can be reversed by administration of oral clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine transdermal therapy.

REFERENCE +

  1. Plasma catecholamines and autonomic nervous system function in patients with early renal insufficiency and hypertension: effect of clonidine. Levitan D, Massry SG, Romoff M, Campese VM Nephron 1984;36:24-9.
  2. Rebound hypertension during initiation of transdermal clonidine. Stewart M, Burris JF Drug Intell Clin Pharm 1988;22:573-4.
  3. Clonidine and sudden death. Maloney MJ, Schwam SJ Pediatrics 1995;96:1176-7.
  4. Clonidine raises blood pressure in severe idiopathic orthostatic hypotension. Robertson D, Goldberg MR, Hollister AS, et al Am J Med 1983;74:193-200.
  5. Safety aspects of long-term antihypertensive therapy (10 years) with clonidine. Ferder L, Inserra F, Medina F J Cardiovasc Pharmacol 1987;10:s104-8.
  6. Preoperative clonidine withdrawal syndrome. Bruce D, Croley T, Lee J Anesthesiology 1979;51:90-2.
  7. Clonidine, a new antihypertensive drug. Pettinger WA N Engl J Med 1975;293:1179-80.
  8. Evaluation of clonidine hydrochloride (catapres): a new antihypertensive agent. Kosman ME JAMA 1975;233:174-6.
  9. Clonidine-induced bradycardia. Golusinski LL, Blount BW J Fam Pract 1995;41:399-401.
  10. Intrathecal clonidine and severe hypotension after cardiopulmonary bypass. Puskas F, Camporesi EM, O'Leary CE, Hauser M, Nasrallah FV Anesth Analg 2003;97:1251-3.
  11. Severe hypotension associated with concurrent clonidine and antipsychotic medication. Fruncillo RJ, Gibbons WJ, Vlasses PH, Ferguson RK Am J Psychiatry 1985;142:274.
  12. Withdrawal of antihypertensive therapy. Strauss F, Franklin S, Lewin A, Maxwell M JAMA 1977;238:1734-36.
  13. A dose-response study of orally administered clonidine as premedication in the elderly - evaluating hemodynamic safety. Filos KS, Patroni O, Goudas LC, Bosas O, Kassaras A, Gartaganis S Anesth Analg 1993;77:1185-92.
  14. Risk factors for severe bradycardia during oral clonidine therapy for hypertension. Byrd BF, Collins HW, Primm RK Arch Intern Med 1988;148:729-33.
  15. Sinus arrest associated with clonidine therapy. Schwartz E, Friedman E, Mouallem M, Farfel Z Clin Cardiol 1988;11:53-4.
  16. Paradoxical hypertension from clonidine . Young E, Levey BA, Shapiro AP Ann Intern Med 1984;101:282-3.
  17. Symptomatic hypotension following the clonidine suppression test for pheochromocytoma. Given BD, Taylor T, Lilly LS, Dzau VJ Arch Intern Med 1983;143:2195-6.
  18. Clonidine-induced hypertension in a patient with a spinal lesion. Backo AL, Clause SL, Triller DM, Gibbs KA Ann Pharmacother 2002;36:1396-8.
  19. Abrupt cessation of clonidine administration: a prospective study. Whitsett TL, Chrysant SG, Dillard BL, Anton AH Am J Cardiol 1978;41:1285-90.
  20. Epidural clonidine analgesia for intractable cancer pain. Eisenach JC, Dupen S, Dubois M, Miguel R, Allin D, Bryce D, Burger GA, Chamberlain D, Docherty R, Evans G, Finnegan R, Hantler Pain 1995;61:391-9.
  21. Is clonidine an effective smoking cessation therapy? Gourlay SG, Benowitz NL Drugs 1995;50:197-207.
  22. Product Information. Duraclon Injection (clonidine) Anonymous Roxane Laboratories Inc, Columbus, OH. PROD;
  23. The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine. van Zwieten PA, Thoolen MJ, Timmermans PB Hypertension 1984;6:28-33.
 
       
 
Numbness or tingling ("pins and needles")
Captopril may cause the following symptoms that are related to numbness or tingling:
  • Guillain-Barre syndrome.
  • Nerve damage
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Nervous system side effects have included dysgeusia (0.3% to 4.0%) and headache (up to 4%). Cases of Guillain-Barre neuropathy and parkinsonism have been reported.

A 57-year-old man with hypertension and moderate alcohol use developed a sensorimotor loss associated with a cerebral spinal fluid pleocytosis three months after starting captopril therapy. A complete work-up was otherwise unremarkable. The patient eventually required mechanical ventilation, at which time captopril was discontinued. The syndrome resolved completely over the next six weeks. Nerve conduction velocity and electromyography findings were consistent with a demyelinating neuropathy of the Guillain-Barre type. A 75-year-old man with hypertension and heart failure developed a shuffling gait, resting tremors, mask face, and cogwheel rigidity several days after beginning captopril therapy. A full work-up was unremarkable. The parkinsonian symptoms resolved after captopril was discontinued.

REFERENCE +

  1. Comparison of the safety and efficacy of delapril with captopril in outpatients with congestive heart failure. Fuchs W Am J Cardiol 1995;75:f29-36.
  2. Adverse effects of the angiotensin-converting enzyme inhibitors. Alderman CP Ann Pharmacother 1996;30:55-61.
  3. Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapril. The Quality-of-Life Hypertension Study Group. Testa MA, Anderson RB, Nackley JF, Hollenberg NK N Engl J Med 1993;328:907-13.
  4. Parkinsonism induced by captopril . Sandyk R Clin Neuropharmacol 1985;8:197-8.
  5. Guillain-Barre neuropathy during treatment with captopril. Chakraborty TK, Ruddell WS Postgrad Med J 1987;63:221-2.
  6. Captopril-induced taste disturbance. Boyd I Lancet 1993;342:304.
  7. A long-term follow-up of patients with essential hypertension treated with captopril. Ohman P, Aurell M, Asplund J, et al Acta Med Scand 1984;216:53-6.
  8. Randomized controlled trial of oral captopril, of oral isosorbide mononitrate and of intravenous magnesium sulphate started early in acute myocardial infarction - safety and haemodynamic effects. Flather M, Pipilis A, Collins R, Budaj A, Hargreaves A, Kolettis T, Jacob A, Millane T, Fitzgerald L, Cedro K, Cybulski J, Dancy Eur Heart J 1994;15:608-19.
  9. Comparison of the efficacy and safety of quinapril vs. captopril in treatment of moderate to severe hypertension. Schnaper HW Angiology 1989;40:389-95.
  10. Captopril-induced dysgeusia. Zazgornik J, Kaiser W, Biesenbach G Lancet 1993;341:1542.
  11. Angiotensin converting enzyme inhibitors in hypertension: potential problems. Antonios TFT, Macgregor GA J Hypertens 1995;13 Suppl:s11-6.
  12. Neurological dysfunction in two patients receiving captopril and cimetidine . Atkinson AB, Brown JJ, Lever AF, et al Lancet 1980;2:36-7.
  13. Captopril: an update of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure. Brogden RN, Todd PA, Sorkin EM Drugs 1988;36:540-600.
  14. Safety and efficacy of chronic therapy with captopril in hypertensive patients: an update. Waeber B, Gavras I, Brunner HR, Gavras H J Clin Pharmacol 1981;21:508-16.
  15. Efficacy, safety, and quality-of-life assessment of captopril antihypertensive therapy in clinical practice. Schoenberger JA, Testa M, Ross AD, et al Arch Intern Med 1990;150:301-6.
  16. Captopril and central nervous system effects . Rapoport S, Zyman P Ann Intern Med 1983;98:1023.
 
       
 
       
 
Ringing in the ears
Naproxen may cause ringing in the ears.
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Note: Original Source for Medical Professionals
Other side effects have included tinnitus, altered hearing, vertigo, visual disturbances, and keratopathy. Increased thirst has been reported in patients receiving the controlled release naproxen.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking naproxen and seek medical attention or call your doctor at once if you have any of these serious side effects: chest pain, weakness, shortness of breath, slurred speech, problems with vision or balance; black, bloody, or tarry stools; coughing up blood or vomit that looks like coffee grounds; swelling or rapid weight gain; urinating less than usual or not at all; nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; bruising, severe tingling, numbness, pain, muscle weakness; or fever, headache, neck stiffness, chills, increased sensitivity to light, purple spots on the skin, and/or seizure (convulsions). Less serious side effects may include: upset stomach, mild heartburn or stomach pain, diarrhea, constipation; bloating, gas; dizziness, headache, nervousness; skin itching or rash; blurred vision; or ringing in your ears. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

REFERENCE +

  1. Product Information. Naprosyn (naproxen). Anonymous Syntex Laboratories Inc, Palo Alto, CA. PROD;
  2. Product Information. Anaprox (naproxen). Anonymous Roche Laboratories, Nutley, NJ. PROD;
  3. Naproxen-associated sudden sensorineural hearing loss. McKinnon BJ, Lassen LF Milit Med 1998;163:792-3.
  4. Keratopathy associated with the use of naproxen. Szmyd L, Perry HD Am J Ophthalmol 1985;99:598.
 
       
 
Ringing in the ears
Verapamil may cause ringing in the ears.
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Note: Original Source for Medical Professionals
Nervous system side effects have included headache (up to 12.1%), dizziness (up to 4.7%), lethargy (up to 3.2%), fatigue (up to 4.5%), sleep disturbances (up to 1.4%), paresthesia (up to 1%), and rare neurologic complaints (including paresthesias, sleeping problems, and tremors; less than 1%). Dizziness (1.2%), headache (1.2%), sleepiness, vertigo, and rare cases of seizures during injection have been reported with intravenous verapamil. Rare cases of muscle fasciculations in patients with underlying neuromuscular diseases, stroke associated with verapamil-induced hypotension, exacerbation of myasthenia gravis, and myoclonic dystonia have been reported. Cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, paresthesia, shakiness, somnolence, syncope, and tinnitus have been reported during open trials/postmarketing experience.

REFERENCE +

  1. Product Information. Covera-HS (verapamil). Anonymous Searle, Skokie, IL. PROD;
  2. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
  3. Case report: sustained-release verapamil overdose causing stroke: an unusual complication. Shah AR, Passalacqua BR Am J Med Sci 1992;304:357-9.
  4. Verapamil and acute dystonia. Pina MA, Ara JR, Remirez A, Castiella J J Clin Pharm Ther 1998;23:79-80.
  5. Long-term safety and efficacy of immediate-release and sustained-release oral verapamil in systemic hypertension. Frishman WH, Eisen G, Charlap S, Strom JA J Clin Hypertens 1987;3:605-9.
  6. Delirium induced by verapamil. Jacobsen FM, Sack DA, James SP Am J Psychiatry 1987;144:248.
  7. Fasciculations due to verapamil in a patient with neuropathy. Thomke F, Vogt T, Roder R, Hopf HC J Neurol 1990;237:448-9.
  8. Verapamil and myoclonic dystonia. Hicks CB, Abraham K Ann Intern Med 1985;103:154.
  9. Antihypertensive efficacy of sustained-release verapamil. Zachariah PK, Sheps SG, Oshrain C, et al J Clin Hypertens 1987;3:536-46.
  10. Verapamil-induced parkinsonism. Padrell MD, Navarro M, Faura CC, Horga JF Am J Med 1995;99:436.
  11. Verapamil toxicity: treatment with hemoperfusion. Rosansky SJ Ann Intern Med 1991;114:340-1.
  12. Adverse effect of verapamil in myasthenia gravis: an additional comment. Reverte M Muscle Nerve 1993;16:879-81.
  13. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  14. Treatment of mild hypertension with low once-daily doses of a sustained-release capsule formulation of verapamil. Davis PJ, Fagan TC, Topmiller MJ, Levine JH, Ferdinand KC J Clin Pharmacol 1995;35:52-8.
  15. Verapamil in the long-term treatment of angina pectoris. Raftos J Med J Aust 1980;07/26/80:78-80.
  16. Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. McTavish D, Sorkin EM Drugs 1989;38:19-76.
 
       
 
Ringing in the ears
HydrALAZINE may cause the following symptom that is related to ringing in the ears:
  • Throbbing/pounding heartbeat (uncommon)
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Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: fast or pounding heartbeats; swelling in your face, stomach, hands, or feet; numbness, burning, pain, or tingly feeling; feeling like you might pass out; confusion, unusual thoughts or behavior; pale skin, easy bruising; painful or difficult urination; dark-colored urine; urinating less than usual or not at all; or joint pain or swelling with fever, chest pain, weakness or tired feeling. Less serious side effects may include: nausea, vomiting, loss of appetite; diarrhea, constipation; headache; dizziness; anxiety; muscle or joint pain; runny or stuffy nose; or mild itching or skin rash. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

 
       
 
Ringing in the ears
Clonidine may cause the following symptom that is related to ringing in the ears:
  • Throbbing/pounding heartbeat
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Note: Original Source for Medical Professionals
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: fast or pounding heartbeats; a very slow heart rate (fewer than 60 beats per minute); feeling short of breath, even with mild exertion; swelling, rapid weight gain; confusion, hallucinations; fever, pale skin; urinating less than usual or not at all; or feeling like you might pass out. Less serious side effects may include: feeling dizzy, drowsy, tired, or nervous; dry mouth; dry or burning eyes, blurred vision; headache, muscle or joint pain; nausea, vomiting, constipation, loss of appetite; sleep problems (insomnia); urinating more at night; mild skin rash or itching; or decreased sex drive, impotence. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

 
       
 
       
 
Swelling of the hands or feet
HydrALAZINE may cause swelling of the hands or feet (uncommon).

This drug may also cause the following symptoms that are related to swelling of the hands or feet:

  • Rapidly progressive glomerulonephritis (single study)
  • Glomerulonephritis (rare)
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Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: fast or pounding heartbeats; swelling in your face, stomach, hands, or feet; numbness, burning, pain, or tingly feeling; feeling like you might pass out; confusion, unusual thoughts or behavior; pale skin, easy bruising; painful or difficult urination; dark-colored urine; urinating less than usual or not at all; or joint pain or swelling with fever, chest pain, weakness or tired feeling. Less serious side effects may include: nausea, vomiting, loss of appetite; diarrhea, constipation; headache; dizziness; anxiety; muscle or joint pain; runny or stuffy nose; or mild itching or skin rash. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Renal side effects are common in idiopathic systemic lupus erythematosus; however, immune complex glomerulonephritis is rare in drug-induced lupus. Rare cases of rapidly progressive and focal glomerulonephritis associated with the hydralazine-induced lupus syndrome are often accompanied by anemia, a positive anti-DNA antibody titer, and a positive ANA titer.

In one study, rapidly progressive glomerulonephritis (RPGN) is described in 4 of 444 patients, all of whom were men who were treated for 5 to 11 years with daily doses of 100 to 250 mg. In three of the four cases, biopsy revealed a focal and segmental glomerular necrosis with crescents and positive immunofluorescence. The antinuclear antibody titer became positive in three. Renal function improved in all but one after the withdrawal of hydralazine and institution of corticosteroid therapy. A number of other cases of RPGN are reported. It appears to be far more common in patients who are slow acetylators.

Hydralazine is contraindicated in patients with coronary artery disease or stenotic mitral valvular rheumatic heart disease.

Hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients, hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residual effects have been detected many years later.

 
       
 
Swelling of the hands or feet
Naproxen and hydrochlorothiazide in combination may cause the following symptom that is related to swelling of the hands or feet:
  • Congestive heart failure
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This drug combination of can affect kidney function. The combination of naproxen (naproxen) and hydrochlorothiazide (hydrochlorothiazide) can cause low blood pressure. Monitor blood pressure carefully if you are using both of these medications. Contact your physician if you develop symptoms of heart failure including: shortness of breath, swelling in the ankles/legs, fatigue, lack of energy, loss of appetite, or nausea. The risk of the following side effects may be increased: congestive heart failure. The risk of developing (or worsening) congestive heart failure/weakened heart is increased in patients taking these medications. One published article suggested that the chance of developing congestive heart failure may be increased by using this drug combination people age 55 or older, 9.3 or older, 1,000 or older, 23.3 or older. The risk of developing (or worsening) congestive heart failure/weakened heart is increased in patients taking these medications people age 55 or older, 9.3 or older, 1,000 or older, 23.3 or older. Taking these two drugs together can increase the blood levels of a substance called "potassium". Check with your physician immediately for any signs of increased potassium including weakness, lack of energy, irregular heartbeat, confusion, or tingling or a feeling of heaviness in the arms or legs.

Drink lots of fluids and avoid becoming dehydrated while taking this medication combination. Follow kidney function closely with regular blood tests when taking this drug combination. Kidney function may be evaluated with certain blood tests including a "BUN" and "creatinine".
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MONITOR: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics may adversely affect renal function due to NSAID inhibition of the renal synthesis of prostaglandins that help maintain renal perfusion in dehydrated states. The risk may be increased in patients on dietary sodium restriction. At the same time, hypotensive effect of the diuretics may be reduced because inhibition of prostaglandins can lead to unopposed pressor activity and, consequently, elevation in blood pressure. Natriuretic and diuretic effects may also be reduced, as NSAIDs have been reported to cause sodium and water retention, which may account for the increased risk of congestive heart failure associated with the combination. One study showed an increase in the incidence density of congestive heart failure (in patients over 55 years of age) from 9.3 per 1,000 person-years in patients on diuretics to 23.3 per 1,000 person-years in patients on both diuretic and NSAID therapy. NSAIDs may also increase the risk of hyperkalemia associated with potassium-sparing diuretics.

MANAGEMENT: In patients receiving both diuretic and NSAID therapy, management consists of avoiding dehydration and carefully monitoring the patient's renal function and blood pressure. If renal insufficiency or hyperkalemia develops, both drugs should be discontinued until the condition is corrected.

REFERENCE +

  1. Influence of meloxicam on furosemide pharmacokinetics and pharmacodynamics in healthy volunteers. Muller FO, Schall R, Devaal AC, Groenewoud G, Hundt HKL, Middle MV Eur J Clin Pharmacol 1995;48:247-51.
  2. Interaction of indomethacin with furosemide. Poe TE, Scott RB, Keith JF Jr J Fam Pract 1983;16:610-6.
  3. Interaction of triamterene-hydrochlorothiazide (T-H) and ibuprofen (I). Gehr T, Sica DA, Steigler BW, Marshall C Clin Pharmacol Ther 1990;47:200.
  4. Indomethacin- and Moduretic--induced hyperkalemia. Mor R, Pitlik S, Rosenfeld JB Isr J Med Sci 1983;19:535-7.
  5. Aldosterone antagonists in the treatment of heart failure. Marcy TR, Ripley TL Am J Health Syst Pharm 2006;63:49-58.
  6. Anuric renal failure precipitated by indomethacin and triamterene. Weinberg MS, Quigg RJ, Salant DJ, Bernard DB Nephron 1985;40:216-8.
  7. Reversible acute renal failure from combined triamterene and indomethacin. Favre L, Glasson P, Vallotton MB Ann Intern Med 1982;96:317-20.
  8. Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin. Watkins J, Abbot EC, Hensby CN, Webster J, Dollery CT Br Med J 1980;281:702-5.
  9. The effect of nonsteroidal agents (NSAIDs) on the pharmacokinetics and pharmacodynamics of metolazone. Ripley EB, Gehr TW, Wallace H, Wade J, Kish C, Sica DA Int J Clin Pharmacol Ther 1994;32:12-8.
  10. Interaction studies with bumetanide and furosemide: effects of probenecid and of indomethacin on response to bumetanide in man. Brater DC, Fox WR, Chennavasin P J Clin Pharmacol 1981;21:647-53.
  11. The effects of naproxen and sulindac on renal function and their interaction with hydrochlorothiazide and piretanide in man. Dixey JJ, Noormohamed FH, Lant AF, Brewerton DA Br J Clin Pharmacol 1987;23:55-63.
  12. Bumetanide-induced diuresis and natriuresis: effect of prostaglandin synthetase inhibition. Kaufman J, Hamburger R, Matheson J, Flamenbaum W J Clin Pharmacol 1981;21:663-7.
  13. Drug interactions and consequences of sodium restriction. Bennett WM Am J Clin Nutr 1997;65:S678-81.
  14. Drug interactions with diuretics. Leary WP, Reyes AJ S Afr Med J 1984;65:455-61.
  15. Attenuation of furosemide's diuretic effect by indomethacin: pharmacokinetic evaluation. Smith DE, Brater DC, Lin ET, Benet LZ J Pharmacokinet Biopharm 1979;7:265-74.
  16. The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons. Gurwitz JH, Everitt DE, Monane M, et al J Gerontol A Biol Sci Med Sci 1996;51:m74-9.
  17. Acute intrinsic renal failure induced by indomethacin. McCarthy JT, Torres VE, Romero JC, et al Mayo Clin Proc 1982;57:289-96.
  18. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Heerdink ER, Leufkens HG, Herings RM, Ottervanger JP, Stricker BH, Bakker A Arch Intern Med 1998;158:1108-12.
  19. Influence of indomethacin on the natriuretic and renin-stimulating effect of bumetanide in essential hypertension. Pedrinelli R, Magagna A, Arzilli F, et al Clin Pharmacol Ther 1980;28:722-31.
  20. Clinically important interactions of nonsteroidal antiinflammatory drugs with other medications. Furst DE J Rheumatol Suppl 1988;17:58-62.
  21. Indomethacin-bumetanide interaction: an alert. Ahmad S Am J Cardiol 1984;54:246-7.
  22. Drug-induced hyperkalemia: old culprits and new offenders. Perazella MA Am J Med 2000;109:307-14.
  23. Interaction of diuretics and non-steroidal anti-inflammatory drugs in man. Favre L, Glasson P, Riondel A, Vallotton MB Clin Sci 1983;64:407-15.
  24. Product Information. HydroDIURIL (hydrochlorothiazide). Anonymous Merck & Co, Inc, West Point, PA. PROD;
  25. A comparative study of the action of frusemide and methyclothiazide on renin release by rat kidney slices and the interaction with indomethacin. Desaulles E, Schwartz J Br J Pharmacol 1979;65:193-6.
  26. Interaction between diuretics and indomethacin. Allan SG, Knox J, Kerr F Br Med J 1981;283:1611.
 
       
 
Swelling of the hands or feet
Verapamil may cause the following symptoms that are related to swelling of the hands or feet:
  • Congestive heart failure. This symptom may occur with a history of heart failure/weakened heart
  • Swelling of the legs or arms in less than 3.7% of people
  • Swollen ankles in less than 1.4% of people
  • Irregular heartbeat - atrial fibrillation
  • Worsening of congestive heart failure
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Other side effects have included flu syndrome (up to 3.7%), peripheral edema (up to 3.7%), edema (up to 3%), pain (up to 2.4%), fatigue (1.7%), accidental injury (up to 1.5%), ankle edema (up to 1.4%), and flushing (up to 0.8%). Asthenia has been reported during open trials/postmarketing experience.

Cardiovascular side effects have included hypotension (up to 2.5%), new or worsened congestive heart failure (CHF) or pulmonary edema (negative inotropism; 1.8%), bradycardia (heart rate less than 50/minute; 1.4%), atrioventricular (AV) block (first-degree; up to 1.7%), AV block (total first-, second-, and third-degree; 1.2%), AV block (second- and third-degree; 0.8%), and postural hypotension (up to 0.4%). Symptomatic hypotension (1.5%), bradycardia (1.2%), and severe tachycardia (1%) have been reported with intravenous verapamil. In studies related to control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rate less than 50/minute at rest (15%) and asymptomatic hypotension (5%) were reported. Dizziness, hypotension, peripheral edema, and headache are not uncommon and are related to vasodilation of vascular smooth muscle. Verapamil may accelerate conduction of anomalous AV conduction tissue, as in the Wolff-Parkinson-White syndrome, which can result in worsened tachycardia, including malignant ventricular tachyarrhythmias or accelerated junctional tachycardia. Because of this potentially fatal side effect, verapamil is not recommended in patients with atrial fibrillation and premature ventricular depolarizations. Angina pectoris, AV block (second- and third-degree), atrioventricular dissociation, CHF, pulmonary edema, abnormal ECG, chest pain, claudication, hypertension, myocardial infarction, palpitations, and purpura (vasculitis) have been reported during open trials/postmarketing experience.

CHF or pulmonary edema may be particularly important in patients with poor left ventricular function. Various conduction disturbances have been reported with verapamil therapy, including bradycardia, AV block, first-, second-, third-degree heart block, and left bundle branch block. One study of patients with the Wolff-Parkinson-White syndrome (WPW) has shown that patients with a history of WPW complicated by atrial fibrillation and a history of reciprocating tachycardias with rapid conduction over an accessory pathway during atrial fibrillation are more susceptible to ventricular fibrillation after verapamil than those without a history of a rapid ventricular response. A small series of patients with WPW complicated by atrial fibrillation and a rapid ventricular response who developed cardiac arrest within 1 to 10 minutes after receiving intravenous verapamil has been reported. The mechanism by which verapamil may enhance the ventricular rate response to atrial fibrillation is not known. Verapamil may directly shorten the refractory period of the accessory pathway or cause reflex tachycardia indirectly by causing peripheral vasodilation.

Verapamil is contraindicated in hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock, in sick sinus syndrome or second- or third-degree AV block in patients without a functioning artificial ventricular pacemaker, and in patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). In addition, oral verapamil is contraindicated in severe left ventricular dysfunction and intravenous verapamil is contraindicated in severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy), in patients receiving intravenous beta-adrenergic blocking drugs, and in ventricular tachycardia. Intravenous verapamil is contraindicated within a few hours of administration of intravenous beta-adrenergic blocking agents since both may depress myocardial contractility and AV conduction. Intravenous verapamil is contraindicated in patients with wide complex ventricular tachycardia (QRS less than 0.12 sec) due to the risk of marked hemodynamic deterioration and ventricular fibrillation.

Verapamil has a negative inotropic effect, which in most patients is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4954 patients primarily with immediate release verapamil, 1.8% developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%) or moderate to severe symptoms of heart failure and in patients with any degree of ventricular dysfunction if they are receiving beta-blockers. Patients with milder ventricular dysfunction should, if possible, be controlled with digitalis and/or diuretics prior to initiation of verapamil.

REFERENCE +

  1. Verapamil hydrochloride: pharmacological properties and role in cardiovascular therapeutics. Baky SH, Singh BN Pharmacotherapy 1982;2:328-50.
  2. Cardiogenic shock associated with verapamil in a patient with liver cirrhosis. Stehle G, Buss J, Eibach J, et al Lancet 1990;336:1079.
  3. Effects of verapamil on supraventricular tachycardia in patients with overt and concealed wolff-parkinson-white syndrome. Hame A, Peter T, Platt M, Mandel WJ Am Heart J 1981;101:600-12.
  4. Precipitation of cardiac arrest by verapamil in patients with Wolff-Parkinson-White syndrome. McGovern B, Garan H, Ruskin JN Ann Intern Med 1986;104:791-4.
  5. Pharmacokinetics of verapamil in patients with renal failure. Mooy J, Schols M, Baak MV, et al Eur J Clin Pharmacol 1985;28:405-10.
  6. Incidence of adverse events during treatment with verapamil for suspected acute myocardial infarction. Arstall MA, Beltrame JF, Mohan P, Wuttke RD, Esterman AJ, Horowitz JD Am J Cardiol 1992;70:1611-2.
  7. Efficacy and safety of verapamil in patients with angina pectoris after 1 year of continuous, high-dose therapy. Weiner DA, McCabe CH, Cutler SS, et al Am J Cardiol 1983;51:1251-5.
  8. Verapamil-induced acute right heart failure. Shimoni A, Maorkendler Y, Neuman Y Am Heart J 1996;132:193-4.
  9. Accelerated junctional rhythms during oral verapamil therapy. Schwartz JB, Jeang M, Raizner AE, et al Am Heart J 1984;107:440-3.
  10. Case report: sustained-release verapamil overdose causing stroke: an unusual complication. Shah AR, Passalacqua BR Am J Med Sci 1992;304:357-9.
  11. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
  12. Fatal ventricular fibrillation following verapamil in Wolff-Parkinson-White syndrome with atrial fibrillation. Jacob AS, Nielsen DH, Gianelly RE Ann Emerg Med 1985;14:159-60.
  13. Electrocardiological profile and proarrhythmic effects of quinidine, verapamil and their combination: a mapping study. Dhein S, Schott M, Gottwald E, Klaus W Naunyn Schmiedebergs Arch Pharmacol 1995;352:94-101.
  14. Asystole after verapamil. Benaim ME Br Med J 1972;04/15/72:169-70.
  15. Age and severe adverse drug reactions caused by nifedipine and verapamil. Pahor M, Manto A, Pedone C, Carosella L, Guralnik JM, Carbonin P J Clin Epidemiol 1996;49:921-8.
  16. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  17. Effectiveness and safety of oral verapamil to control exercise-induced tachycardia in patients with atrial fibrillation receiving digitalis. Panidis IP, Morganroth J, Baessler C Am J Cardiol 1983;52:1197-201.
  18. Emergency treatment of acute sustained tachyarrhythmias. Obel IWP S Afr Med J 1995;85:745-6.
  19. Long-term safety and efficacy of immediate-release and sustained-release oral verapamil in systemic hypertension. Frishman WH, Eisen G, Charlap S, Strom JA J Clin Hypertens 1987;3:605-9.
  20. Product Information. Covera-HS (verapamil). Anonymous Searle, Skokie, IL. PROD;
  21. Acute toxic effects of sustained-release verapamil in chronic renal failure. Pritza DR, Bierman MH, Hammeke MD Arch Intern Med 1991;151:2081-4.
  22. R-verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate. Ahmed JH, Godden J, Meredith PA, Elliott HL Br J Clin Pharmacol 1993;36:93-8.
  23. The paradoxical adverse effect of verapamil for treating clinical paroxysmal supraventricular tachycardia. Saikawa T, Inoue K, Ohmura I, et al Jpn Heart J 1987;28:107-13.
  24. Verapamil-induced polymorphous ventricular tachycardia. Winters SL, Schweitzer P, Kupersmith J, Gomes JA J Am Coll Cardiol 1985;6:257-9.
  25. Verapamil in the long-term treatment of angina pectoris. Raftos J Med J Aust 1980;07/26/80:78-80.
  26. Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. McTavish D, Sorkin EM Drugs 1989;38:19-76.
  27. Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Pollak A, Falk RH Chest 1993;104:618-20.
  28. Comparison of verapamil and captopril in elderly hypertensive subjects: results of a randomized, double-blind, crossover study. Bursztyn M, Ghanem J, Kobrin I, Fidel J, Ben-Ishay D J Cardiovasc Pharmacol 1993;21:84-8.
  29. Verapamil in atrial fibrillation: the expected, the unexpected, and the unknown. Schwartz JB Am Heart J 1983;106:173-6.
  30. Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism. Echizen H, Vogelgesang B, Eichelbaum M Clin Pharmacol Ther 1985;38:71-6.
 
       
 
Swelling of the hands or feet
Simvastatin may cause the following symptoms that are related to swelling of the hands or feet:
  • Angioedema (rare).
  • Compartment syndrome (rare)
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Hypersensitivity reactions are reported rarely with HMG-CoA reductase inhibitors and include anaphylaxis, angioedema, urticaria, fever, chills, flushing, malaise, and dyspnea.

Musculoskeletal side effects of simvastatin have included elevations in creatine kinase, myopathy, dermatomyositis, and rhabdomyolysis. Other musculoskeletal side effects reported with HMG-CoA reductase inhibitors have included arthralgia, myalgia, tendon rupture, and dermatomyositis. In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.

HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria, and renal failure. Concomitant use with gemfibrozil (fibric acid derivatives), niacin, cyclosporine, erythromycin (macrolides) or azole antifungals may increase the incidence and severity of musculoskeletal side effects. Other variables associated with an increased risk of statin-induced myopathy include, advanced age, small body stature, female gender, renal and/or hepatic dysfunction, perioperative periods, hypothyroidism, diabetes mellitus, and alcoholism. Milder forms of myotoxicity (i.e., myalgia) are commonly reported and occur in approximately 5% to 7% of patients taking a statin drug. Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if elevated, simvastatin should be discontinued. The value of regular monitoring of creatine kinase is not known. In some studies, elevations in creatine kinase occurred in up to 5.2% of patients on simvastatin. In most cases, these elevations were mild, transient, and not associated with clinical symptoms. At least six cases of simvastatin-induced rhabdomyolysis associated with concomitant use of a macrolide antibiotic (i.e., erythromycin, clarithromycin) have been reported. In all cases the patients had been receiving simvastatin routinely (40 to 80 mg/day) prior to short-term (7 to 10 days) macrolide therapy. The proposed mechanism of interaction is inhibition of CYP450 3A4 metabolism and/or P-glycoprotein transport of simvastatin. Symptoms included myalgia, muscle weakness, elevated serum creatine kinase levels, and in some patients elevated liver transaminase levels. A rare case of simvastatin-induced bilateral leg compartment syndrome and myonecrosis developed in a patient with hypothyroidism after one month of therapy with simvastatin. Following withdrawal of simvastatin and emergency fasciotomies the patient recovered.

REFERENCE +

  1. Eosinophilic fasciitis and simvastatin. ChoquetKastylevsky G, Kanitakis J, Dumas V, Descotes J, Faure M, Claudy A Arch Intern Med 2001;161:1456-7.
  2. Product Information. Zocor (simvastatin). Anonymous Merck & Co, Inc, West Point, PA. PROD;
 
       
 
Swelling of the hands or feet
Niacin may cause the following symptoms that are related to swelling of the hands or feet:
  • Irregular heartbeat - atrial fibrillation .
  • Swelling of the legs or arms
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Hypersensitivity effects associated with niacin have included rash, generalized edema, facial edema, and peripheral edema.

Cardiovascular side effects generally have been rare. Transient tachycardia, palpitations, atrial fibrillation, orthostasis, syncope, hypotension, and dizziness have been reported. The Coronary Drug Project (1975) reported a significant increase in cardiac arrhythmias associated with the use of niacin; some experts consider preexisting arrhythmias or angina pectoris contraindications to its use. Niacin has been shown to increase plasma homocysteine levels. Homocysteine is an independent risk factor for arterial occlusive disease. Clinical implications of these increases and the influence of folic acid supplementation as a means to decrease homocysteine levels remain to be determined.

REFERENCE +

  1. Efficacy and safety of an extended-release niacin (Niaspan): A long-term study. Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA, Brusco OA, Brody J Am J Cardiol 1998;82:u74-81.
  2. Niacin. Darby WJ, McNutt KW, Todhunter EN Nutr Rev 1975;33:289-97.
  3. Unstable myocardial ischemia after the initiation of niacin therapy. Pasternak RC, Kolman BS Am J Cardiol 1991;67:904-6.
  4. Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia. Davignon J, Roederer G, Montigny M, Hayden MR, Tan MH, Connelly PW, Hegele R, McPherson R, Lupien PJ, Gagne C, et al Am J Cardiol 1994;73:339-45.
  5. Clofibrate and niacin in coronary heart disease. Coronary Drug Project JAMA 1975;231:360-81.
  6. The pharmacology and therapeutics of lipid-lowering drugs. Hunninghake DB Am Pharm 1987;ns27:s18-25.
  7. Nicotinic acid: a review of its clinical use in the treatment of lipid disorders. Figge HL, Figge J, Souney PF, Mutnick AH, Sacks F Pharmacotherapy 1988;8:287-94.
  8. The prevalence of side effects with regular and sustained-release nicotinic acid. Gibbons LW, Gonzalez V, Gordon N, Grundy S Am J Med 1995;99:378-85.
  9. Use of niacin as a drug. DiPalma JR, Thayer WS Annu Rev Nutr 1991;11:169-87.
  10. Reducing cardiac deaths with hypolipidemic drugs. Naito HK Postgrad Med 1987;82:102-12.
  11. Drugs affecting triglycerides. Capurso A Cardiology 1991;78:218-25.
  12. Niacin and myocardial metabolism. Anonymous Nutr Rev 1973;31:80-1.
  13. Product Information. Niaspan ER (niacin). Anonymous Allscripts Healthcare Solutions, Libertyville, IL.
  14. Niacin or niacinamide? Nicotinic acid or nicotinamide? What is the difference?. Ranchoff RE, Tomecki KJ J Am Acad Dermatol 1986;15:116-7.
  15. Efficacy and safety of controlled-release niacin in dyslipoproteinemic veterans. Gray DR, Morgan T, Chretien SD, Kashyap ML Ann Intern Med 1994;121:252-8.
 
       
 
Swelling of the hands or feet
Naproxen may cause the following symptoms that are related to swelling of the hands or feet:
  • Angioedema. Especially in people with allergic reaction to drugs
  • Swelling of the legs or arms in 3% to 9% of people
  • Fixed drug eruption (rare)
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NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

Patients with a hypersensitivity (angioedema, bronchospasm, urticaria, or rhinitis) to aspirin or other nonsteroidal anti-inflammatory agents (NSAIDs) may be cross sensitive to naproxen. Patients with the "triad" of asthma, nasal polyps, and aspirin or other NSAID hypersensitivity are at particular risk, and should consult their health care professional before taking products containing naprosyn. Both types of reactions have the potential of being fatal. The use of naproxen is considered contraindicated in these patients.

Naproxen is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Patients with a hypersensitivity (angioedema, bronchospasm, urticaria, or rhinitis) to aspirin or other NSAIDs may be cross sensitive to naproxen. Patients with the "triad" of asthma, nasal polyps, and aspirin or other NSAID hypersensitivity are at particular risk. Both types of reactions have the potential of being fatal. The use of naproxen is considered contraindicated in these patients.

Peripheral edema has been observed in some patients receiving naproxen. Sodium containing naproxen tablets (approximately 1 mEq/250 mg naproxen) and suspension (39 mg (1.5 mEq) per each 125 mg of naproxen) should be used with caution in patients with fluid restriction, hypertension, or heart failure.

Hypersensitivity side effects have been reported rarely. These may result in an erythematous or urticarial rash, angioedema, and bronchospasm, especially in patients with aspirin-sensitive asthma. Anaphylactoid reactions have been reported as well. Hypersensitivity has been implicated in cases of renal failure, pneumonitis, and colitis.

Cardiovascular side effects have included peripheral edema (3% to 9%) and palpitations (3%). Blood pressure may be elevated by naproxen, which may have clinical relevance in patients with comorbid illnesses. Dyspnea has been reported in patients receiving controlled release naproxen. An increased risk of cardiovascular events has been observed in preliminary study results from a clinical trial conducted by the National Institute of Aging evaluating the use of NSAIDs in patients at risk of developing Alzheimer's disease.

Dermatologic side effects have included pruritus (3% to 9%), ecchymoses (3% to 9%), purpura, rash, and photosensitivity. Rare cases of pseudoporphyria cutanea tarda, toxic epidermal necrolysis, generalized bullous fixed drug eruption, erythema multiforme, and Stevens-Johnson syndrome have also been reported. Skin eruptions have been reported in patients receiving the controlled release formulation of naproxen.

REFERENCE +

  1. Naproxen and pneumonitis. Londino AV, Wolf GL, Calabro JJ, Perrone SJ JAMA 1984;252:1853.
  2. Different risks for NSAID-induced anaphylaxis. van Puijenbroek EP, Egberts AC, Meyboom RH, Leufkens HG Ann Pharmacother 2002;36:24-9.
  3. Naproxen-induced anaphylaxis - a case report. Ross JE Am J Forensic Med Pathol 1994;15:180-1.
  4. Pulmonary infiltrates associated with naproxen. Buscaglia AJ, Cowden FE, Brill H JAMA 1984;251:65-6.
  5. Product Information. Anaprox (naproxen). Anonymous Roche Laboratories, Nutley, NJ. PROD;
  6. Pulmonary infiltrates and eosinophilia associated with naproxen. Sheehan NJ Br J Rheumatol 1985;24:302-5.
  7. Pulmonary eosinophilia associated with naproxen therapy. Flint KC, Johnson NM J R Soc Med 1987;80:120-1.
  8. Acute eosinophilic colitis and hypersensitivity reaction associated with naproxen therapy. Bridges AJ, Marshall JB, Diaz-Arias AA Am J Med 1990;89:526-7.
  9. Gold-naproxen pneumonitis. McFadden RG, Fraher LJ, Thompson JM Chest 1989;96:216-8.
  10. Product Information. Naprosyn (naproxen). Anonymous Syntex Laboratories Inc, Palo Alto, CA. PROD;
  11. Dyspnea and periorbital edema following an increase in naproxen dose. Briscoedwyer L, Etzel JV Ann Pharmacother 1994;28:1110.
  12. Severe asthma after naproxen. Lewis RV Lancet 1987;05/30/87:1270.
  13. Severe asthma induced by naproxen: a case report and review of the literature. Salberg DJ, Simon MR Ann Allergy 1980;45:372-5.
  14. Hypersensitivity angiitis associated with naproxen. Singhal PC, Faulkner M, Venkatesan J, Molho L Ann Allergy 1989;63:107-9.
  15. Pulmonary oedema, jaundice and renal impairment with naproxen. Reeve PA, Moshiri M, Bell GD Br J Rheumatol 1987;26:70-1.
 
       
 
Swelling of the hands or feet
Gemfibrozil may cause the following symptoms that are related to swelling of the hands or feet:
  • Angioedema (rare).
  • Compartment syndrome (single case)
  • Irregular heartbeat - atrial fibrillation (rare)
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Hypersensitivity reactions are reported rarely with gemfibrozil and include urticaria, angioedema, laryngeal edema, and anaphylaxis. In addition, at least one case of eosinophilic gastroenteritis associated with gemfibrozil use has been reported.

Cardiovascular side effects of gemfibrozil include rare cases of atrial fibrillation, vasculitis, and Raynaud's phenomenon.

Musculoskeletal side effects of gemfibrozil include arthralgia, myopathy, myalgia, polyarthritis, and rhabdomyolysis. Myositis induced compartment syndrome is reported in one patient.

REFERENCE +

  1. Allergic reaction to gemfibrozil manifesting as eosinophilic gastroenteritis. Lee JY, Medellin MV, Tumpkin C South Med J 2000;93:807-8.
  2. Product Information. Lopid (gemfibrozil). Anonymous Parke-Davis, Morris Plains, NJ. PROD;
 
       
 
Swelling of the hands or feet
Clonidine may cause the following symptoms that are related to swelling of the hands or feet:
  • Angioedema.
  • Congestive heart failure
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Dermatologic reactions have been reported in 10% to 38% of patients who use transdermal clonidine. These reactions include psoriasis exacerbations, local dermatitis and/or pigmentation, alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria.

Epidural administration is contraindicated in patients receiving anticoagulant therapy, patients with bleeding diathesis, and in the presence of an injection site infection.

Patients who develop an allergic reaction to the transdermal therapy may also elicit an allergic reaction from the oral formulation is substituted (i.e., generalized rash, urticaria, or angioedema).

Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days. Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages. Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

REFERENCE +

  1. Allergic contact dermatitis with transdermal clonidine . Boekhorst JC Lancet 1983;2:1031-2.
  2. Transdermal clonidine: an association with recurrent herpes simplex and hyperpigmentation . Wiser TH, Kazakis AM, LaCivita CL J Am Acad Dermatol 1987;17:143-4.
  3. Allergic skin reactions to transdermal clonidine . Anonymous Lancet 1983;2:850-1.
  4. Allergic contact dermatitis from a clonidine transdermal delivery system. Corazza M, Mantovani L, Virgili A, Strumia R Contact Dermatitis 1995;32:246.
  5. Skin reactions to long-term transdermal clonidine . Dick JB, Northridge DB, Lawson AA Lancet 1987;1:516.
  6. Skin depigmentation related to transdermal clonidine therapy. Doe N, Seth S, Hebert LA Arch Intern Med 1995;155:2129.
  7. Hydrocortisone cream in clonidine patch dermatitis. Tom GR Ann Pharmacother 1994;28:889-90.
  8. Exacerbation of psoriasis during clonidine therapy . Wilkin J Arch Dermatol 1981;117:4.
 
       
 
Swelling of the hands or feet
Captopril may cause the following symptoms that are related to swelling of the hands or feet:
  • Angioedema. Increased risk in Black/African Americans compared to non-blacks
  • Congestive heart failure
  • Membranous nephropathy (rare)
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Cardiovascular side effects have included hypotension (1% to 25%), dizziness (1% to 5%), myocardial infarction (less than 1%), palpitations (less than 1%), angina pectoris (less than 1%), and angioedema (less than 0.1%).

Angiotensin converting enzyme (ACE) inhibitor use during pregnancy can cause injury and even death to the developing fetus. When used during the second and third trimesters of pregnancy, ACE inhibitors have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Exposure to ACE inhibitors during the first trimester of pregnancy has been associated with prematurity, intrauterine growth retardation, patent ductus arteriosus, other structural cardiac malformations, and neurological malformations. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. If no alternative to ACE inhibitor therapy is available, patients should be made aware of the risks to their fetuses and the intra-amniotic environment should be evaluated by serial ultrasound examinations. If oligohydramnios develops, captopril should be discontinued unless it is considered life-saving for the mother. Depending on the week of pregnancy, contraction stress testing, a non-stress test, or biophysical profiling may be appropriate. Oligohydramnios may not show until after the fetus has suffered irreversible injury.

Anaphylactoid reactions have occurred in patients receiving ACE inhibitor therapy during desensitization treatment with hymenoptera venom, and in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In controlled trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients.

Immunologic side effects have rarely included lymphadenopathy, systemic lupus erythematosus, and Henoch-Schonlein Purpura. Serum sickness-like illness has been reported.

A 53-year-old man with diabetes mellitus, hypertension, and heart failure developed arthralgias, fever, and malaise associated with bilateral pleural effusions, elevated liver function tests, a pericardial rub, and elevated C-reactive protein. After other causes of systemic lupus erythematosus were ruled out, captopril was stopped, and these signs and symptoms resolved. In a study of 78 patients who were treated with captopril for 11 months, 13 developed a positive antinuclear antibody titer. Only one of the 13, however, developed a serum sickness-like illness.

Renal side effects have included renal insufficiency (less than 3%) and proteinuria (1%). Allergic nephritis, membranous glomerulonephritis, and nephrotic syndrome have been reported rarely.

Risk factors for the development of captopril-induced renal insufficiency are hypovolemia, hypotension, hyponatremia, concomitant use of other potentially nephrotoxic medications, and renal artery stenosis. Proteinuria associated with captopril therapy is more likely in patients with renal insufficiency. Captopril-induced hypotension may cause decreased renal blood flow and glomerular filtration in some patients. In addition, captopril may cause an interstitial nephritis (usually associated with rash, eosinophilia, fever, and azotemia), or a membranous glomerulopathy. The histological findings of membranous glomerulonephritis in some patients who have proteinuria suggest the possibility of an immune-complex glomerulopathy. These findings are similar to other cases of drug-induced glomerulopathy.

 
       
 
Swelling of the hands or feet
Allopurinol may cause the following symptom that is related to swelling of the hands or feet:
  • Glomerulonephritis
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Allopurinol should be discontinued at the first sign of skin rash or any other signs or symptoms suggestive of a hypersensitivity reaction. In some instances, a skin rash may be followed by more severe adverse reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, rarely, death. Renal dysfunction increases the risk of allopurinol hypersensitivity.

Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN during allopurinol therapy. Although the mechanism responsible for this has not been determined, patients with impaired renal function should be carefully monitored during the early stages of allopurinol use and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. Renal failure in association with allopurinol use has been reported among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunction increased after allopurinol therapy was started. Renal failure is frequently observed with the use of allopurinol therapy. Albuminemia has been observed in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. Patients with decreased renal function require lower doses of allopurinol therapy than those with normal renal function. Periodic monitoring of renal function is recommended during the course of therapy.

 
       
 
Swelling of the hands or feet
Acetaminophen may cause the following symptom that is related to swelling of the hands or feet:
  • Fixed drug eruption (rare)
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Hypersensitivity side effects including anaphylaxis and fixed drug eruptions have been reported rarely in association with acetaminophen use.

REFERENCE +

  1. Paracetamol anaphylaxis. Leung R, Plomley R, Czarny D Clin Exp Allergy 1992;22:831-3.
  2. Toxic epidermal necrolysis associated with acetaminophen ingestion. Halevi A, BenAmitai D, Garty BZ Ann Pharmacother 2000;34:32-4.
  3. Fixed drug eruption induced by acetaminophen in a 12-year-old girl. Kawada A, Hiruma M, Noguchi H, Ishibashi A Int J Dermatol 1996;35:148-9.
  4. Acetaminophen hypersensitivity and other analgesics. Kalyoncu AF Ann Allergy 1994;72:285.
  5. Nearly fatal episodes of hypotension, flushing, and dyspnea in a 47- year-old woman. Doan T, Greenberger PA Ann Allergy 1993;70:439-44.
  6. Acetaminophen hypersensitivity and other analgesics - response. Doan T Ann Allergy 1994;72:285.
  7. Anaphylactic shock induced by paracetamol. Van Diem L, Grilliat JP Eur J Clin Pharmacol 1990;38:389-90.
  8. Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma. Settipane RA, Stevenson DD J Allergy Clin Immunol 1989;84:26-33.
 
       
 
       
 
Throbbing headache
Verapamil may cause the following symptoms that are related to throbbing headache:
  • Headache in less than 12.1% of people.
  • Sinusitis in less than 3% of people
  • Stroke
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Nervous system side effects have included headache (up to 12.1%), dizziness (up to 4.7%), lethargy (up to 3.2%), fatigue (up to 4.5%), sleep disturbances (up to 1.4%), paresthesia (up to 1%), and rare neurologic complaints (including paresthesias, sleeping problems, and tremors; less than 1%). Dizziness (1.2%), headache (1.2%), sleepiness, vertigo, and rare cases of seizures during injection have been reported with intravenous verapamil. Rare cases of muscle fasciculations in patients with underlying neuromuscular diseases, stroke associated with verapamil-induced hypotension, exacerbation of myasthenia gravis, and myoclonic dystonia have been reported. Cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, paresthesia, shakiness, somnolence, syncope, and tinnitus have been reported during open trials/postmarketing experience.

Respiratory side effects have included upper respiratory infection (up to 5.4%), pharyngitis (up to 3%), sinusitis (up to 3%), rhinitis (up to 2.7%), and dyspnea (up to 1.4%). Extremely rare cases of respiratory arrest have been associated with the use of intravenous verapamil. The mechanism is unknown. An acute asthma attack associated with sustained-release verapamil has been reported. Dyspnea has also been reported during open trials/postmarketing experience.

Cardiovascular side effects have included hypotension (up to 2.5%), new or worsened congestive heart failure (CHF) or pulmonary edema (negative inotropism; 1.8%), bradycardia (heart rate less than 50/minute; 1.4%), atrioventricular (AV) block (first-degree; up to 1.7%), AV block (total first-, second-, and third-degree; 1.2%), AV block (second- and third-degree; 0.8%), and postural hypotension (up to 0.4%). Symptomatic hypotension (1.5%), bradycardia (1.2%), and severe tachycardia (1%) have been reported with intravenous verapamil. In studies related to control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rate less than 50/minute at rest (15%) and asymptomatic hypotension (5%) were reported. Dizziness, hypotension, peripheral edema, and headache are not uncommon and are related to vasodilation of vascular smooth muscle. Verapamil may accelerate conduction of anomalous AV conduction tissue, as in the Wolff-Parkinson-White syndrome, which can result in worsened tachycardia, including malignant ventricular tachyarrhythmias or accelerated junctional tachycardia. Because of this potentially fatal side effect, verapamil is not recommended in patients with atrial fibrillation and premature ventricular depolarizations. Angina pectoris, AV block (second- and third-degree), atrioventricular dissociation, CHF, pulmonary edema, abnormal ECG, chest pain, claudication, hypertension, myocardial infarction, palpitations, and purpura (vasculitis) have been reported during open trials/postmarketing experience.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: fast or slow heartbeats; feeling like you might pass out; fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; feeling short of breath, even with mild exertion; swelling, rapid weight gain; or nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes). Less serious side effects may include: constipation, nausea; skin rash or itching; dizziness, headache, tired feeling; or warmth, itching, redness, or tingly feeling under your skin. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

REFERENCE +

  1. Verapamil hydrochloride: pharmacological properties and role in cardiovascular therapeutics. Baky SH, Singh BN Pharmacotherapy 1982;2:328-50.
  2. Cardiogenic shock associated with verapamil in a patient with liver cirrhosis. Stehle G, Buss J, Eibach J, et al Lancet 1990;336:1079.
  3. Effects of verapamil on supraventricular tachycardia in patients with overt and concealed wolff-parkinson-white syndrome. Hame A, Peter T, Platt M, Mandel WJ Am Heart J 1981;101:600-12.
  4. Precipitation of cardiac arrest by verapamil in patients with Wolff-Parkinson-White syndrome. McGovern B, Garan H, Ruskin JN Ann Intern Med 1986;104:791-4.
  5. Pharmacokinetics of verapamil in patients with renal failure. Mooy J, Schols M, Baak MV, et al Eur J Clin Pharmacol 1985;28:405-10.
  6. Product Information. Covera-HS (verapamil). Anonymous Searle, Skokie, IL. PROD;
  7. Incidence of adverse events during treatment with verapamil for suspected acute myocardial infarction. Arstall MA, Beltrame JF, Mohan P, Wuttke RD, Esterman AJ, Horowitz JD Am J Cardiol 1992;70:1611-2.
  8. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
  9. Efficacy and safety of verapamil in patients with angina pectoris after 1 year of continuous, high-dose therapy. Weiner DA, McCabe CH, Cutler SS, et al Am J Cardiol 1983;51:1251-5.
  10. Case report: sustained-release verapamil overdose causing stroke: an unusual complication. Shah AR, Passalacqua BR Am J Med Sci 1992;304:357-9.
  11. Verapamil-induced acute right heart failure. Shimoni A, Maorkendler Y, Neuman Y Am Heart J 1996;132:193-4.
  12. Verapamil and acute dystonia. Pina MA, Ara JR, Remirez A, Castiella J J Clin Pharm Ther 1998;23:79-80.
  13. Long-term safety and efficacy of immediate-release and sustained-release oral verapamil in systemic hypertension. Frishman WH, Eisen G, Charlap S, Strom JA J Clin Hypertens 1987;3:605-9.
  14. Delirium induced by verapamil. Jacobsen FM, Sack DA, James SP Am J Psychiatry 1987;144:248.
  15. Fasciculations due to verapamil in a patient with neuropathy. Thomke F, Vogt T, Roder R, Hopf HC J Neurol 1990;237:448-9.
  16. Verapamil and myoclonic dystonia. Hicks CB, Abraham K Ann Intern Med 1985;103:154.
  17. Accelerated junctional rhythms during oral verapamil therapy. Schwartz JB, Jeang M, Raizner AE, et al Am Heart J 1984;107:440-3.
  18. Case report: sustained-release verapamil overdose causing stroke: an unusual complication. Shah AR, Passalacqua BR Am J Med Sci 1992;304:357-9.
  19. Product Information. Verelan PM (verapamil). Anonymous Schwarz Pharma, Mequon, WI.
  20. Fatal ventricular fibrillation following verapamil in Wolff-Parkinson-White syndrome with atrial fibrillation. Jacob AS, Nielsen DH, Gianelly RE Ann Emerg Med 1985;14:159-60.
  21. Electrocardiological profile and proarrhythmic effects of quinidine, verapamil and their combination: a mapping study. Dhein S, Schott M, Gottwald E, Klaus W Naunyn Schmiedebergs Arch Pharmacol 1995;352:94-101.
  22. Asystole after verapamil. Benaim ME Br Med J 1972;04/15/72:169-70.
  23. Antihypertensive efficacy of sustained-release verapamil. Zachariah PK, Sheps SG, Oshrain C, et al J Clin Hypertens 1987;3:536-46.
  24. Verapamil-induced parkinsonism. Padrell MD, Navarro M, Faura CC, Horga JF Am J Med 1995;99:436.
  25. Age and severe adverse drug reactions caused by nifedipine and verapamil. Pahor M, Manto A, Pedone C, Carosella L, Guralnik JM, Carbonin P J Clin Epidemiol 1996;49:921-8.
  26. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  27. Effectiveness and safety of oral verapamil to control exercise-induced tachycardia in patients with atrial fibrillation receiving digitalis. Panidis IP, Morganroth J, Baessler C Am J Cardiol 1983;52:1197-201.
  28. Verapamil toxicity: treatment with hemoperfusion. Rosansky SJ Ann Intern Med 1991;114:340-1.
  29. Emergency treatment of acute sustained tachyarrhythmias. Obel IWP S Afr Med J 1995;85:745-6.
  30. Long-term safety and efficacy of immediate-release and sustained-release oral verapamil in systemic hypertension. Frishman WH, Eisen G, Charlap S, Strom JA J Clin Hypertens 1987;3:605-9.
  31. Adverse effect of verapamil in myasthenia gravis: an additional comment. Reverte M Muscle Nerve 1993;16:879-81.
  32. Product Information. Covera-HS (verapamil). Anonymous Searle, Skokie, IL. PROD;
  33. Acute toxic effects of sustained-release verapamil in chronic renal failure. Pritza DR, Bierman MH, Hammeke MD Arch Intern Med 1991;151:2081-4.
  34. R-verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate. Ahmed JH, Godden J, Meredith PA, Elliott HL Br J Clin Pharmacol 1993;36:93-8.
  35. Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease. Brogden RN, Benfield P Drugs 1996;51:792-819.
  36. Treatment of mild hypertension with low once-daily doses of a sustained-release capsule formulation of verapamil. Davis PJ, Fagan TC, Topmiller MJ, Levine JH, Ferdinand KC J Clin Pharmacol 1995;35:52-8.
  37. The paradoxical adverse effect of verapamil for treating clinical paroxysmal supraventricular tachycardia. Saikawa T, Inoue K, Ohmura I, et al Jpn Heart J 1987;28:107-13.
  38. Verapamil-induced polymorphous ventricular tachycardia. Winters SL, Schweitzer P, Kupersmith J, Gomes JA J Am Coll Cardiol 1985;6:257-9.
  39. Verapamil in the long-term treatment of angina pectoris. Raftos J Med J Aust 1980;07/26/80:78-80.
  40. Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. McTavish D, Sorkin EM Drugs 1989;38:19-76.
  41. Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Pollak A, Falk RH Chest 1993;104:618-20.
  42. Comparison of verapamil and captopril in elderly hypertensive subjects: results of a randomized, double-blind, crossover study. Bursztyn M, Ghanem J, Kobrin I, Fidel J, Ben-Ishay D J Cardiovasc Pharmacol 1993;21:84-8.
  43. Verapamil in the long-term treatment of angina pectoris. Raftos J Med J Aust 1980;07/26/80:78-80.
  44. Verapamil in atrial fibrillation: the expected, the unexpected, and the unknown. Schwartz JB Am Heart J 1983;106:173-6.
  45. Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. McTavish D, Sorkin EM Drugs 1989;38:19-76.
  46. Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism. Echizen H, Vogelgesang B, Eichelbaum M Clin Pharmacol Ther 1985;38:71-6.
 
       
 
Throbbing headache
Simvastatin may cause the following symptoms that are related to throbbing headache:
  • Headache in 6.5% of people.
  • Polymyalgia rheumatica
  • Vaccination reaction when given in combination with other vaccines
  • Pompe’s disease (single case)
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Nervous system side effects have included headache (6.5%) and cognitive impairment. Other nervous system side effects reported with HMG-CoA reductase inhibitors have included cranial nerve dysfunction, tremor, vertigo, memory loss, paresthesias, peripheral neuropathy, and peripheral nerve palsy.

Simvastatin is contraindicated in patients with active liver disease or with unexplained elevations in liver function tests. Simvastatin is a prodrug which must first be metabolized by hepatic microsomal enzymes to active compounds. In patients with active liver disease, simvastatin efficacy may be reduced. In addition, simvastatin is associated with elevations in liver function tests. Safety in patients with active liver disease or with unexplained elevations in liver function tests is unknown.

Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been associated with simvastatin and other HMG-CoA reductase inhibitors. Simvastatin should be used cautiously, if at all, in patients who are at risk of developing renal failure from rhabdomyolysis (for example, patients with severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, and uncontrolled seizures). The risk of myopathy/rhabdomyolysis is dose related and is increased by concomitant use of simvastatin with potent Inhibitors of CYP450 3A4 as well as cyclosporine or danazol, particularly with higher doses of simvastatin. Use of simvastatin concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, amiodarone, verapamil, niacin (doses greater than or equal to 1 gram/day), or large quantities of grapefruit juice (greater than 1 quart daily) should be avoided. Predisposing factors include advanced age (greater than or equal to 65), uncontrolled hypothyroidism, and renal impairment. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine, danazol, or gemfibrozil. The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The benefits of the use of simvastatin in patients receiving cyclosporine or danazol should be carefully weighed against the risks of these combinations. The combined use of simvastatin with gemfibrozil should be avoided unless the benefits are likely to outweigh the risks of the combination.

Immunologic side effects of simvastatin have included a case of lupus-like syndrome which has been reported with other HMG-CoA reductase inhibitors. Other immunologic side effects reported with HMG-CoA reductase inhibitors have included positive ANA, ESR increase, polymyalgia rheumatica, and vasculitis.

Endocrine side effects of HMG-CoA reductase inhibitors have included hypospermia, gynecomastia, and thyroid function abnormalities. In addition, acid maltase deficiency (the genetic disorder also referred to as Pompe's Disease) has been revealed following simvastatin therapy in at least one presymptomatic patient.

REFERENCE +

  1. Simvastatin-induced decline in cognition. Padala KP, Padala PR, Potter JF Ann Pharmacother 2006;40:1880-3.
  2. Statins and risk of polyneuropathy: a case-control study. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH Neurology 2002;58:1333-7.
  3. Product Information. Zocor (simvastatin). Anonymous Merck & Co, Inc, West Point, PA. PROD;
  4. Simvastatin-associated memory loss. Orsi A, Sherman O, Woldeselassie Pharmacotherapy 2001;21:767-9.
  5. Simvastatin - a reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia. Plosker GL, Mctavish D Drugs 1995;50:334-63.
  6. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB Am J Med 2004;117:823-9.
  7. Atorvastatin may cause nightmares. Gregoor PJ BMJ 2006;332:950.
  8. Short-term memory loss associated with rosuvastatin. Galatti L, Polimeni G, Salvo F, Romani M, Sessa A, Spina E Pharmacotherapy 2006;26:1190-2.
  9. Peripheral neuropathy associated with simvastatin. Phan T, Mcleod JG, Pollard JD, Peiris O, Rohan A, Halpern JP J Neurol Neurosurg Psychiatry 1995;58:625-8.
  10. Simvastatin causes changes in affective processes in elderly volunteers. Morales K, Wittink M, Datto C, et al. J Am Geriatr Soc 2006;54:70-6.
  11. Simvastatin: the clinical profile. Walker JF Am J Med 1989;87:s44-6.
 
       
 
Throbbing headache
Niacin may cause the following symptom that is related to throbbing headache:
  • Headache (rare)
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Nervous system side effects have included rare reports of paresthesias, nervousness, dizziness, headache, fatigue, and insomnia.

REFERENCE +

  1. Approaches to the management of hypercholesterolaemia. Florkowski CM, Cramb R J Clin Pharm Ther 1992;17:81-9.
  2. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. McKenney JM, Proctor JD, Harris S, Chinchili VM JAMA 1994;271:672-7.
  3. New approaches to cholesterol lowering: efficacy and safety. Knopp RH Hosp Pract (Off Ed) 1988;23 Suppl 1:22-30.
  4. Efficacy and safety of one-year treatment with slow-release nicotinic acid. Monitoring of drug concentration in serum. ChojnowskaJezierska J, AdamskaDyniewska H Int J Clin Pharmacol Ther 1998;36:326-32.
  5. Hepatotoxicity associated with sustained-release niacin. Dalton TA, Berry RS Am J Med 1992;93:102-4.
  6. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH, Tun P, Zupkis RV, Greguski RA Arch Intern Med 1994;154:1586-95.
  7. Choice of cholesterol-lowering drugs. Anonymous Med Lett Drugs Ther 1991;33:1-4.
  8. Clinical trial experience with extended-release niacin (Niaspan): Dose-escalation study. Goldberg AC Am J Cardiol 1998;82:u35-8.
  9. Choice of cholesterol-lowing drugs. Anonymous Med Lett Drugs Ther 1993;35:19-22.
  10. Continuous axillary brachial plexus blockade following intra-arterial injection of nicotinic acid. Dyson A, Henderson AM Anaesth Intensive Care 1987;15:462-5.
  11. Niacin revisited. A randomized, controlled trial of wax-matrix sustained-release niacin in hypercholesterolemia. Keenan JM, Fontaine PL, Wenz JB, Myers S, Huang ZQ, Ripsin CM Arch Intern Med 1991;151:1424-32.
  12. Adverse effects of sustained-release niacin. Knapp TR, Middleton RK DICP 1991;25:253-4.
  13. Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia. Davignon J, Roederer G, Montigny M, Hayden MR, Tan MH, Connelly PW, Hegele R, McPherson R, Lupien PJ, Gagne C, et al Am J Cardiol 1994;73:339-45.
  14. The prevalence of side effects with regular and sustained-release nicotinic acid. Gibbons LW, Gonzalez V, Gordon N, Grundy S Am J Med 1995;99:378-85.
  15. Product Information. Niaspan ER (niacin). Anonymous Allscripts Healthcare Solutions, Libertyville, IL.
  16. Niacin or niacinamide? Nicotinic acid or nicotinamide? What is the difference?. Ranchoff RE, Tomecki KJ J Am Acad Dermatol 1986;15:116-7.
  17. Niacin maculopathy. Millay RH, Klein ML, Illingworth DR Ophthalmology 1988;95:930-6.
  18. Efficacy and safety of an extended-release niacin (Niaspan): A long-term study. Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA, Brusco OA, Brody J Am J Cardiol 1998;82:u74-81.
  19. Niacin maculopathy. Jampol LM Ophthalmology 1988;95:1704-5.
 
       
 
Throbbing headache
Naproxen may cause the following symptoms that are related to throbbing headache:
  • Aseptic meningitis.
  • Headache
  • Stroke caused by blockage of the arteries that supply blood to the brain. This symptom can lead to fatalities in severe cases
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Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking naproxen and seek medical attention or call your doctor at once if you have any of these serious side effects: chest pain, weakness, shortness of breath, slurred speech, problems with vision or balance; black, bloody, or tarry stools; coughing up blood or vomit that looks like coffee grounds; swelling or rapid weight gain; urinating less than usual or not at all; nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; bruising, severe tingling, numbness, pain, muscle weakness; or fever, headache, neck stiffness, chills, increased sensitivity to light, purple spots on the skin, and/or seizure (convulsions). Less serious side effects may include: upset stomach, mild heartburn or stomach pain, diarrhea, constipation; bloating, gas; dizziness, headache, nervousness; skin itching or rash; blurred vision; or ringing in your ears. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Nervous system side effects have included inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, and cognitive dysfunction.

NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

REFERENCE +

  1. Product Information. Anaprox (naproxen). Anonymous Roche Laboratories, Nutley, NJ. PROD;
  2. Product Information. Naprosyn (naproxen). Anonymous Syntex Laboratories Inc, Palo Alto, CA. PROD;
  3. Naproxen up to date: a review of its pharmacological properties and therapeutic efficacy and use in rheumatic diseases and pain states. Brogden RN, Heel RC, Speight TM, Avery GS Drugs 1979;18:241-77.
  4. Naproxen: a reappraisal of its pharmacology, and therapeutic use in rheumatic diseases and pain states. Todd PA, Clissold SP Drugs 1990;40:91-137.
  5. Aseptic meningitis associated with naproxen. Sylvia LM, Forlenza SW, Brocavich JM Drug Intell Clin Pharm 1988;22:399-401.
  6. Naproxen-associated nightmares. Bakht FR, Miller LG South Med J 1991;84:1271-3.
  7. Naproxen-induced recurrent aseptic meningitis. Weksler BB, Lehany AM DICP 1991;25:1183-4.
  8. Comparative toxicity of non-steroidal anti-inflammatory agents. Singh G, Ramey DR, Morfeld D, Fries JF Pharmacol Ther 1994;62:175-91.
 
       
 
Throbbing headache
Levothyroxine may cause the following symptom that is related to throbbing headache:
  • Headache
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Stop using levothyroxine and get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: headache; sleep problems (insomnia); nervous or irritable feeling; fever, hot flashes, sweating; changes in your menstrual periods; appetite changes, weight changes; Less serious side effects may include mild hair loss. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

 
       
 
Throbbing headache
Hydrochlorothiazide may cause the following symptom that is related to throbbing headache:
  • Headache (single case)
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Dermatologic reactions include case reports of erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus is associated with HCTZ.

A 67-year-old woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion and personality changes associated with a new positive ANA and anti-nRNP, and a skin biopsy consistent with lupus erythematosus while taking hydrochlorothiazide (HCTZ), levothyroxine, and amitriptyline. The eruption resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.

REFERENCE +

  1. Thiazide diuretic therapy and chronic photosensitivity. Robinson HN, Morison WL, Hood AF Arch Dermatol 1985;121:522-4.
  2. Can hydrochlorothiazide cause lupus? Rich MW, Eckman JM J Rheumatol 1995;22:1001.
  3. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA Ann Intern Med 1985;103:49-51.
  4. Subacute cutaneous lupus erythematosus-like eruption caused by hydrochlorothiazide. Parodi A, Romagnoli M, Rebora A Photodermatol 1989;6:100-2.
  5. Thiazides: A cause of necrotising vasculitis? Bjornberg A, Gisslen H Lancet 1965;2:982-3.
  6. Hydrochlorothiazide-induced lupus erythematosus: a new variant? Goodrich AL, Kohn SR J Am Acad Dermatol 1993;28:1001-2.
  7. Erythema annulare centrifugum caused by hydrochlorothiazide-induced interstitial nephritis. Goette DK, Beatrice E Int J Dermatol 1988;27:129-30.
  8. Thiazide diuretics induce cutaneous lupus-like adverse reaction. Brown CW, Deng JS J Toxicol Clin Toxicol 1995;33:729-33.
  9. Phototoxic potential of thiazide diuretics in normal subjects. Diffey BL, Langtry J Arch Dermatol 1989;125:1355-8.
 
       
 
Throbbing headache
HydrALAZINE may cause the following symptoms that are related to throbbing headache:
  • Glomerulonephritis (rare).
  • Headache in 5% of people
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Nervous system side effects including peripheral neuropathy is dose-related and is more common in slow acetylators. The neuropathy usually first presents as paresthesias, numbness, and tingling in the extremities. It is probably the result of pyridoxine deficiency, perhaps because formation of a pyridoxal-hydralazine complex inactivates the coenzyme, and can, therefore, be treated by administration of pyridoxine. Headache or dizziness have been reported in approximately 5% of patients.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as: fast or pounding heartbeats; swelling in your face, stomach, hands, or feet; numbness, burning, pain, or tingly feeling; feeling like you might pass out; confusion, unusual thoughts or behavior; pale skin, easy bruising; painful or difficult urination; dark-colored urine; urinating less than usual or not at all; or joint pain or swelling with fever, chest pain, weakness or tired feeling. Less serious side effects may include: nausea, vomiting, loss of appetite; diarrhea, constipation; headache; dizziness; anxiety; muscle or joint pain; runny or stuffy nose; or mild itching or skin rash. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Renal side effects are common in idiopathic systemic lupus erythematosus; however, immune complex glomerulonephritis is rare in drug-induced lupus. Rare cases of rapidly progressive and focal glomerulonephritis associated with the hydralazine-induced lupus syndrome are often accompanied by anemia, a positive anti-DNA antibody titer, and a positive ANA titer.

Hydralazine is contraindicated in patients with coronary artery disease or stenotic mitral valvular rheumatic heart disease.

Hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients, hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residual effects have been detected many years later.

REFERENCE +

  1. Hydralazine and lupus nephritis. Ihle BU, Whitworth JA, Dowling JP, Kincaid-Smith P Clin Nephrol 1984;22:230-8.
  2. Side-effects in long-term treatment with hydralazine. Widgren B, Berglund G, Andersson OK Acta Med Scand 1986;714:193-6.
  3. Clinopathologic conference: renal failure, dyspnea and anemia in a 57 year old woman. Ludmerer KM, Kissane JM Am J Med 1981;71:876-86.
  4. Hydralazine-associated glomerulonephritis. Bjorck S, Svalander C, Westberg G Acta Med Scand 1985;218:261-9.
  5. Drug-induced lupus caused by very-low-dose hydralazine. Innes A, Rennie JA, Cato GR Br J Rheumatol 1986;25:225-31.
  6. Focal glumerulonephritis in the course of hydralazine-induced lupus syndrome. Naparstek Y, Kopolovic J, Tur-Kaspa R, Rubinger D Arthritis Rheum 1984;27:822-5.
  7. Immune complex glomerulonephritis in hydralazine-induced SLE. Shapiro KS, Pinn VW, Harrington JT, Levey AS Am J Kidney Dis 1984;3:270-4.
  8. Hydralazine-associated glomerulonephritis. Kincaid-Smith P, Whitworth JA Lancet 1983;2:348.
 
       
 
Throbbing headache
Gemfibrozil may cause the following symptom that is related to throbbing headache:
  • Headache
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Nervous system side effects of gemfibrozil include dizziness, somnolence, headache, vertigo, hyperesthesia, paresthesias, taste perversion, and confusion.

REFERENCE +

  1. Product Information. Lopid (gemfibrozil). Anonymous Parke-Davis, Morris Plains, NJ. PROD;
  2. Polymyositis exacerbated by gemfibrozil . Fusella J, Strosberg JM J Rheumatol 1990;17:572-3.
  3. Gemfibrozil-induced headache . Alvarez-Sabin J, Codina A, Rodriguez C, Laporte JR Lancet 1988;2:1246.
  4. Gemfibrozil-induced headache . Arellano F, de Cos MA, Valiente R, Quiros C Lancet 1988;1:705.
 
       
 
Throbbing headache
Clonidine may cause the following symptoms that are related to throbbing headache:
  • Headache.
  • Stroke (rare). This symptom may occur when the drug is stopped or dose is decreased
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Epidural administration is contraindicated in patients receiving anticoagulant therapy, patients with bleeding diathesis, and in the presence of an injection site infection.

Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine can result in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of clonidine transdermal therapy can be reversed by administration of oral clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine transdermal therapy.

Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days. Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages. Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: fast or pounding heartbeats; a very slow heart rate (fewer than 60 beats per minute); feeling short of breath, even with mild exertion; swelling, rapid weight gain; confusion, hallucinations; fever, pale skin; urinating less than usual or not at all; or feeling like you might pass out. Less serious side effects may include: feeling dizzy, drowsy, tired, or nervous; dry mouth; dry or burning eyes, blurred vision; headache, muscle or joint pain; nausea, vomiting, constipation, loss of appetite; sleep problems (insomnia); urinating more at night; mild skin rash or itching; or decreased sex drive, impotence. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

REFERENCE +

  1. Plasma catecholamines and autonomic nervous system function in patients with early renal insufficiency and hypertension: effect of clonidine. Levitan D, Massry SG, Romoff M, Campese VM Nephron 1984;36:24-9.
  2. Rebound hypertension during initiation of transdermal clonidine. Stewart M, Burris JF Drug Intell Clin Pharm 1988;22:573-4.
  3. Clonidine and sudden death. Maloney MJ, Schwam SJ Pediatrics 1995;96:1176-7.
  4. Clonidine raises blood pressure in severe idiopathic orthostatic hypotension. Robertson D, Goldberg MR, Hollister AS, et al Am J Med 1983;74:193-200.
  5. Safety aspects of long-term antihypertensive therapy (10 years) with clonidine. Ferder L, Inserra F, Medina F J Cardiovasc Pharmacol 1987;10:s104-8.
  6. Preoperative clonidine withdrawal syndrome. Bruce D, Croley T, Lee J Anesthesiology 1979;51:90-2.
  7. Clonidine, a new antihypertensive drug. Pettinger WA N Engl J Med 1975;293:1179-80.
  8. Evaluation of clonidine hydrochloride (catapres): a new antihypertensive agent. Kosman ME JAMA 1975;233:174-6.
  9. Clonidine-induced bradycardia. Golusinski LL, Blount BW J Fam Pract 1995;41:399-401.
  10. Intrathecal clonidine and severe hypotension after cardiopulmonary bypass. Puskas F, Camporesi EM, O'Leary CE, Hauser M, Nasrallah FV Anesth Analg 2003;97:1251-3.
  11. Severe hypotension associated with concurrent clonidine and antipsychotic medication. Fruncillo RJ, Gibbons WJ, Vlasses PH, Ferguson RK Am J Psychiatry 1985;142:274.
  12. Withdrawal of antihypertensive therapy. Strauss F, Franklin S, Lewin A, Maxwell M JAMA 1977;238:1734-36.
  13. A dose-response study of orally administered clonidine as premedication in the elderly - evaluating hemodynamic safety. Filos KS, Patroni O, Goudas LC, Bosas O, Kassaras A, Gartaganis S Anesth Analg 1993;77:1185-92.
  14. Risk factors for severe bradycardia during oral clonidine therapy for hypertension. Byrd BF, Collins HW, Primm RK Arch Intern Med 1988;148:729-33.
  15. Sinus arrest associated with clonidine therapy. Schwartz E, Friedman E, Mouallem M, Farfel Z Clin Cardiol 1988;11:53-4.
  16. Paradoxical hypertension from clonidine . Young E, Levey BA, Shapiro AP Ann Intern Med 1984;101:282-3.
  17. Symptomatic hypotension following the clonidine suppression test for pheochromocytoma. Given BD, Taylor T, Lilly LS, Dzau VJ Arch Intern Med 1983;143:2195-6.
  18. Clonidine-induced hypertension in a patient with a spinal lesion. Backo AL, Clause SL, Triller DM, Gibbs KA Ann Pharmacother 2002;36:1396-8.
  19. Abrupt cessation of clonidine administration: a prospective study. Whitsett TL, Chrysant SG, Dillard BL, Anton AH Am J Cardiol 1978;41:1285-90.
  20. Epidural clonidine analgesia for intractable cancer pain. Eisenach JC, Dupen S, Dubois M, Miguel R, Allin D, Bryce D, Burger GA, Chamberlain D, Docherty R, Evans G, Finnegan R, Hantler Pain 1995;61:391-9.
  21. Is clonidine an effective smoking cessation therapy? Gourlay SG, Benowitz NL Drugs 1995;50:197-207.
  22. Product Information. Duraclon Injection (clonidine) Anonymous Roxane Laboratories Inc, Columbus, OH. PROD;
  23. The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine. van Zwieten PA, Thoolen MJ, Timmermans PB Hypertension 1984;6:28-33.
 
       
 
Throbbing headache
Captopril may cause the following symptom that is related to throbbing headache:
  • Headache in less than 4% of people
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Note: Original Source for Medical Professionals
Nervous system side effects have included dysgeusia (0.3% to 4.0%) and headache (up to 4%). Cases of Guillain-Barre neuropathy and parkinsonism have been reported.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects: feeling light-headed, fainting; urinating more or less than usual, or not at all; fever, chills, body aches, flu symptoms; pale skin, easy bruising or bleeding; fast, pounding, or uneven heartbeats; chest pain; or swelling, rapid weight gain. Less serious side effects may include: cough; loss of taste sensation, loss of appetite; dizziness, drowsiness, headache; sleep problems (insomnia); dry mouth, sores in the mouth or on the lips; nausea, diarrhea, constipation; or mild skin itching or rash. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

REFERENCE +

  1. Comparison of the safety and efficacy of delapril with captopril in outpatients with congestive heart failure. Fuchs W Am J Cardiol 1995;75:f29-36.
  2. Adverse effects of the angiotensin-converting enzyme inhibitors. Alderman CP Ann Pharmacother 1996;30:55-61.
  3. Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapril. The Quality-of-Life Hypertension Study Group. Testa MA, Anderson RB, Nackley JF, Hollenberg NK N Engl J Med 1993;328:907-13.
  4. Parkinsonism induced by captopril . Sandyk R Clin Neuropharmacol 1985;8:197-8.
  5. Guillain-Barre neuropathy during treatment with captopril. Chakraborty TK, Ruddell WS Postgrad Med J 1987;63:221-2.
  6. Captopril-induced taste disturbance. Boyd I Lancet 1993;342:304.
  7. A long-term follow-up of patients with essential hypertension treated with captopril. Ohman P, Aurell M, Asplund J, et al Acta Med Scand 1984;216:53-6.
  8. Randomized controlled trial of oral captopril, of oral isosorbide mononitrate and of intravenous magnesium sulphate started early in acute myocardial infarction - safety and haemodynamic effects. Flather M, Pipilis A, Collins R, Budaj A, Hargreaves A, Kolettis T, Jacob A, Millane T, Fitzgerald L, Cedro K, Cybulski J, Dancy Eur Heart J 1994;15:608-19.
  9. Comparison of the efficacy and safety of quinapril vs. captopril in treatment of moderate to severe hypertension. Schnaper HW Angiology 1989;40:389-95.
  10. Captopril-induced dysgeusia. Zazgornik J, Kaiser W, Biesenbach G Lancet 1993;341:1542.
  11. Angiotensin converting enzyme inhibitors in hypertension: potential problems. Antonios TFT, Macgregor GA J Hypertens 1995;13 Suppl:s11-6.
  12. Neurological dysfunction in two patients receiving captopril and cimetidine . Atkinson AB, Brown JJ, Lever AF, et al Lancet 1980;2:36-7.
  13. Captopril: an update of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure. Brogden RN, Todd PA, Sorkin EM Drugs 1988;36:540-600.
  14. Safety and efficacy of chronic therapy with captopril in hypertensive patients: an update. Waeber B, Gavras I, Brunner HR, Gavras H J Clin Pharmacol 1981;21:508-16.
  15. Efficacy, safety, and quality-of-life assessment of captopril antihypertensive therapy in clinical practice. Schoenberger JA, Testa M, Ross AD, et al Arch Intern Med 1990;150:301-6.
  16. Captopril and central nervous system effects . Rapoport S, Zyman P Ann Intern Med 1983;98:1023.
 
       
 
Throbbing headache
Allopurinol may cause the following symptoms that are related to throbbing headache:
  • Aseptic meningitis (tended to improve when drug was stopped). Especially in people with high fever
  • Glomerulonephritis
  • Headache (first sign that a side effect is occuring)
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Note: Original Source for Medical Professionals
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using allopurinol and call your doctor at once if you have any of these serious side effects: the first sign of any skin rash, no matter how mild; pain or bleeding when you urinate; urinating less than usual or not at all; fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; bruising, severe tingling, numbness, pain, muscle weakness; easy bruising or bleeding, unusual weakness; fever, chills, body aches, flu symptoms; jaundice (yellowing of the skin or eyes); or seizure (convulsions). Less serious side effects may include: nausea, vomiting, diarrhea; dizziness or drowsiness; increased sweating; or joint pain. This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Nervous system side effects have been reported extremely rarely and included case reports of peripheral neuropathy, catatonia, and cerebral vasculitis associated with allopurinol hypersensitivity. At least two cases of allopurinol-induced aseptic meningitis have also been reported.

Allopurinol-induced aseptic meningitis has been reported in two isolated cases where 60-year-old Caucasian men developed high fevers soon after taking an initial dose of 300 mg allopurinol, and when rechallenged, with quick improvement after allopurinol was stopped. There is a case report of a patient with no history of psychiatric disease whose allopurinol-associated catatonia, rash, and fever responded to steroids.

Allopurinol should be discontinued at the first sign of skin rash or any other signs or symptoms suggestive of a hypersensitivity reaction. In some instances, a skin rash may be followed by more severe adverse reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, rarely, death. Renal dysfunction increases the risk of allopurinol hypersensitivity.

Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN during allopurinol therapy. Although the mechanism responsible for this has not been determined, patients with impaired renal function should be carefully monitored during the early stages of allopurinol use and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. Renal failure in association with allopurinol use has been reported among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunction increased after allopurinol therapy was started. Renal failure is frequently observed with the use of allopurinol therapy. Albuminemia has been observed in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. Patients with decreased renal function require lower doses of allopurinol therapy than those with normal renal function. Periodic monitoring of renal function is recommended during the course of therapy.

REFERENCE +

  1. Cerebral vasculitis following allopurinol treatment. Rothwell PM, Grant R Postgrad Med J 1996;72:119-20.
  2. Acute adverse reactions attributed to allopurinol in hospitalized patients. McInnes GT, Lawson DH, Jick H Ann Rheum Dis 1981;40:245-9.
  3. Allopurinol induced meningitis. Duchene DA, Smith CP, Goldfarb AA J Urol 2000;164:2028.
  4. Regression of allopurinol-induced peripheral neuropathy after drug withdrawal. Azulay JP, Blin O, Valentin P, Abegg P, Pellissier JF, Serratrice G Eur Neurol 1993;33:193-4.
  5. Suspected allopurinol-induced aseptic meningitis. Greenberg LE, Nguyen T, Miller SM Pharmacotherapy 2001;21:1007-9.
  6. Catatonia in the allopurinol hypersensitivity syndrome. Collins CE, Thomas DJB, Gumpel JM Br Med J 1991;302:970.
 
       
 
 
NOTE: Just because a drug or combination of drugs can cause a symptom does not mean it is actually causing your symptom. Symptoms can be caused by medical conditions as well. Make sure that your physician is aware of any symptoms you are experiencing so he/she can work with you to determine the cause. Please DO NOT STOP MEDICATIONS without first consulting a physician since doing so could be hazardous to your health.
DISCLAIMER: Please note that the information DoubleCheckMD.com provides is intended to help individuals to work with their medical professionals and is for educational purposes only. It does not constitute medical or healthcare advice and serves to supplement, not substitute for, the expertise and judgment of a healthcare professional. In all cases individuals should consult with a physician before taking any action based on DoubleCheckMD feedback including, but not limited to ceasing taking any drug, changing diet or commencing or discontinuing any course of treatment. The information provided by DoubleCheckMD.com is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that the use of a particular drug is safe, appropriate or effective.


 
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