Paper
It's time medicine stopped burying its mistakes.
Published Apr 1, 2000 · J. Clough, R. Macklis, D. Nadzam
Cleveland Clinic journal of medicine
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Abstract
U.S. Pharmaceuticals Itiurmaccutica) KoundUiblc MemberA m e r i c a n Hear t f m A s s o c i a t i o n ® ^ ^ Brief Summary NORVASC® (amlodipine besylate) Tablets For Oral Use CONTRAINDICATIONS: NORVASC is contraindicated in patients with known sensitivity to amlodipine. WARNINGS: Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly Ihose with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated. PRECAUTIONS: General: Since the vasodilation induced by NORVASC is gradual in onset, acute hypotension has rarely been reported after oral administration of NORVASC. Nonetheless, caution should be exercised when administering NORVASC as with any other peripheral vasodilator particularly in patients wi th severe aortic stenosis. Use in Patients with Congestive Heart Failure: In general, calcium channel blockers should be used wi th caution in patients with heart failure. NORVASC (5-10 mg per day) has been studied in a placebo-control led trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as def ined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). NORVASC has been compared to placebo in four 8-12 week studies of patients with NYHA Class l l / l l l heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF. Beta-Blocker Withdrawal: NORVASC is not a beta-blocker and therefore gives no protect ion against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of the beta-blocker. Patients with Hepatic Failure: Since NORVASC is extensively metabolized by the liver and the plasma elimination halflife (t !i) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering NORVASC to patients with severe hepatic impairment. Drug Interactions: In vitro data in human plasma indicate that NORVASC has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin). Special studies have indicated that the co-administration of NORVASC with digoxin d id not change serum digoxin levels or digoxin renal c learance in normal volunteers; that coadministration with cimetidine d id not alter the pharmacokinetics of amlodipine; and that co-administration with warfarin d id not change the warfarin prothrombin response time. In clinical trials, NORVASC has been safely administered with thiazide diuretics, beta-blockers, angiotensin convert ing enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal antiinflammatory drugs, antibiotics, and oral hypoglycemic drugs. Drug/Laboratory Test Interactions: None known. Carcinogenesis, Mutagenesis, Impairment of Fertility: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5,1.25, and 2.5 mg /kg /day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended cl inical dose of 10 mg on a m g / m 2 basis), was c lose to the maximum tolerated dose for mice but not for rats. Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels. There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg /kg /day (8 t imes* the maximum recommended human dose of 10 mg on a m g / m ? basis). Pregnancy Category C: No evidence of teratogenicity or other embryo/ feta l toxicity was found when pregnant rats or rabbits were treated orally with up to 10 m g / k g amlodipine (respectively 8 t imes* and 23 t imes* the maximum recommended human dose of 10 m g on a mg /m 2 basis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats administered 10 mg/kg amlodipine for 14 days before mating and throughout mat ing and gestation. Amlodipine has been shown to prolong both the gestation per iod and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should b e used dur ing pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while NORVASC is administered. Pediatric Use: Safety and effectiveness of NORVASC in children have not been established. ADVERSE REACTIONS: NORVASC has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with NORVASC was well-tolerated at doses up to 10 m g daily. Most adverse reactions reported dur ing therapy with NORVASC were of mild or moderate severity. In controlled clinical trials directly compar ing NORVASC (N =1730) in doses up to 10 mg to p lacebo (N=1250), discontinuation of NORVASC due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of s ide effects which occurred in a dose related manner are as follows: edema (1.8% at 2.5 mg, 3.0% at 5.0 mg, and 10.8% at 10.0 mg, compared with 0 .6% placebo); dizziness (1.1% at 2.5 mg, 3.4% at 5.0 mg, and 3.4% at 10.0 mg, compared with 1.5% placebo); f lushing (0.7% at 2.5 mg, 1.4% at 5.0 mg, and 2.6% at 10.0 mg, compared with 0.0% placebo); and palpitation (0.7% at 2.5 mg, 1.4% at 5.0 mg, and 4.5% at 10.0 mg, compared with 0.6% placebo). Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo-controlfed clinical trials include the following: headache (7.3%, compared with 7.8% placebo); fatigue (4.5%, compared with 2.8% placebo); nausea (2.9%, compared with 1.9% placebo); abdominal pain (1.6%, compared with 0 .3% placebo); and somnolence (1.4%, compared with 0.6% placebo). For several adverse exper iences that appear to be drug and dose related, there was a greater inc idence in women than men associated with amlodipine treatment as follows: edema (5.6% in men, 14.6% in women, compared with a placebo incidence in men of 1.4% and 5.1% in women); f lushing (1.5% in men, 4.5% in women, compared with a placebo incidence of 0 .3% in men and 0.9% in women); palpitations (1.4% in men, 3.3% in women, compared with a placebo incidence of 0 .9% in men and 0.9% in women); and somnolence (1.3% in men, 1.6% in women, compared with a placebo incidence of 0 .8% in men and 0.3% in women). The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under condit ions of open trials or marketing exper ience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension; central and peripheral nervous system: hypoesthesia, paresthesia, tremor, vertigo; gastrointestinal: anorexia, constipation, dyspeps ia , * * dysphagia, diarrhea, flatulence, vomiting, gingival hyperplasia; general: asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain; musculo-skeletal system: arthralgia, arthrosis, muscle c ramps , * * myalgia; psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization; respiratory system: dyspnea, * * epistaxis; skin and appendages: pruri tus,** rash , * * rash erythematous, rash maculopapular; special senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus; urinary system: micturition frequency, micturition disorder, nocturia; autonomic nervous system: dry mouth, sweating increased; metabolic and nutritional: thirst; hemopoietic: purpura. The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, co ld and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be dist inguished from medicat ions or concurrent disease states such as myocardial infarction and angina. NORVASC therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total tr iglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, creatinine or liver function tests. NORVASC has been used safely in patients with chronic obstruct ive pulmonary disease, well compensated congestive heart failure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles. OVERDOSAGE: Single oral doses of 40 m g / k g and 100 m g / k g in mice and rats, respectively, caused deaths. A single oral dose of 4 m g / k g or higher in dogs caused a marked peripheral vasodilation
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