NISOLDIPINE: 52 Adverse Event Reports & Safety Profile

DESCRIPTION Nisoldipine is an extended-release tablet dosage form of the dihydropyridine calcium channel blocker nisoldipine. Nisoldipine is (±)-Isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-( o -nitrophenyl)-3,5-pyridinedicarboxylate, C 20 H 24 N 2 O 6 , and has the structural formula: Nisoldipine is a yellow crystalline powder, practically insoluble in water, but soluble in acetone, ethanol and methanol. It has a molecular weight of 388.4. Nisoldipine extended-release tablets are film-coated monolithic tablets containing a hydrogel which provides for the controlled release of the drug. Nisoldipine extended-release tablets contain either 8.5 mg, 17 mg, 25.5 mg or 34 mg of nisoldipine for once-a-day oral administration. Inactive ingredients include: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide and triacetin. In addition, the following product specific coloring agents are used: The 8.5 mg tablets also contain FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

The

17 mg tablets also contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

The

25.5 mg tablets also contain red iron oxide and yellow iron oxide.

The

34 mg tablets also contain FD&C Yellow No. 6 Aluminum Lake.

Nisoldipine Structural

Formula

INDICATIONS AND USAGE Nisoldipine extended-release tablets are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents.

DOSAGE AND ADMINISTRATION The dosage of nisoldipine extended-release tablets must be adjusted to each patient’s needs. Therapy usually should be initiated with 17 mg orally once daily, then increased by 8.5 mg per week or longer intervals, to attain adequate control of blood pressure. Usual maintenance dosage is 17 mg to 34 mg once daily. Blood pressure response increases over the 8.5 mg to 34 mg daily dose range but adverse event rates also increase. Doses beyond 34 mg once daily are not recommended. Nisoldipine extended-release tablets have been used safely with diuretics, ACE inhibitors, and beta-blocking agents. Patients over age 65, or patients with impaired liver function, are expected to develop higher plasma concentrations of nisoldipine. Their blood pressure should be monitored closely during any dosage adjustment. A starting dose not exceeding 8.5 mg daily is recommended in these patient groups. Nisoldipine extended-release tablets should be administered orally once daily. Nisoldipine extended-release tablets should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit products should be avoided before and after dosing. Nisoldipine extended-release tablets are an extended release dosage form and tablets should be swallowed whole, not bitten, divided or crushed.

CONTRAINDICATIONS Nisoldipine extended-release tablets are contraindicated in patients with known hypersensitivity to dihydropyridine calcium channel blockers.

ADVERSE REACTIONS More than 6000 patients world-wide have received nisoldipine in clinical trials for the treatment of hypertension, either as the immediate release or the nisoldipine extended-release formulation. Of about 1500 patients who received nisoldipine extended-release tablets in hypertension studies, about 55% were exposed for at least 2 months and about one-third were exposed for over 6 months, the great majority at doses equivalent to 17 mg and above. Nisoldipine extended-release tablets are generally well-tolerated. In the U.S. clinical trials of nisoldipine extended-release tablets in hypertension, 10.9% of the 921 nisoldipine extended-release tablets patients discontinued treatment due to adverse events compared with 2.9% of 280 placebo patients. The frequency of discontinuations due to adverse experiences was related to dose, with a 5.4% and 10.9% discontinuation rate at the lowest and highest daily dose, respectively. The most frequently occurring adverse experiences with nisoldipine extended-release tablets are those related to its vasodilator properties; these are generally mild and only occasionally lead to patient withdrawal from treatment. The table below, from U.S. placebo-controlled parallel dose response trials of nisoldipine extended-release tablets using doses across the clinical dosage range in patients with hypertension, lists all of the adverse events, regardless of the causal relationship to nisoldipine extended-release tablets, for which the overall incidence on nisoldipine extended-release tablets was both > 1% and greater with nisoldipine extended-release tablets than with placebo.

Adverse Event

Nisoldipine (%) (n = 663) Placebo (%) (n = 280)

Peripheral Edema

22 10 Headache 22 15 Dizziness 5 4 Pharyngitis 5 4 Vasodilation 4 2 Sinusitis 3 2 Palpitation 3 1 Chest Pain 2 1 Nausea 2 1 Rash 2 1 Only peripheral edema and possibly dizziness appear to be dose related.

Adverse Event Nisoldipine

Extended-Release Tablets, Dose Bioequivalent to: Placebo 8.5 mg 17 mg 25.5 mg 34 mg (Rates in %) n = 280 n = 30 n = 170 n = 105 n = 139 Peripheral Edema 10 7 15 20 27 Dizziness 4 7 3 3 4 The common adverse events occurred at about the same rate in men as in women, and at a similar rate in patients over age 65 as in those under that age, except that headache was much less common in older patients. Except for peripheral edema and vasodilation, which were more common in whites, adverse event rates were similar in blacks and whites. The following adverse events occurred in ≤ 1% of all patients treated for hypertension in U.S. and foreign clinical trials, or with unspecified incidence in other studies. Although a causal relationship of nisoldipine extended-release tablets to these events cannot be established, they are listed to alert the physician to a possible relationship with nisoldipine extended-release tablets treatment. Body as a Whole: cellulitis, chills, facial edema, fever, flu syndrome, malaise Cardiovascular: atrial fibrillation, cerebrovascular accident, congestive heart failure, first degree AV block, hypertension, hypotension, jugular venous distension, migraine, myocardial infarction, postural hypotension, ventricular extrasystoles, supraventricular tachycardia, syncope, systolic ejection murmur, T wave abnormalities on ECG (flattening, inversion, nonspecific changes), venous insufficiency Digestive: abnormal liver function tests, anorexia, colitis, diarrhea, dry mouth, dyspepsia, dysphagia, flatulence, gastritis, gastrointestinal hemorrhage, gingival hyperplasia, glossitis, hepatomegaly, increased appetite, melena, mouth ulceration Endocrine: diabetes mellitus, thyroiditis Hemic and Lymphatic: anemia, ecchymoses, leukopenia, petechiae Metabolic and Nutritional: gout, hypokalemia, increased serum creatine kinase, increased nonprotein nitrogen, weight gain, weight loss Musculoskeletal: arthralgia, arthritis, leg cramps, myalgia, myasthenia, myositis, tenosynovitis Nervous: abnormal dreams, abnormal thinking and confusion, amnesia, anxiety, ataxia, cerebral ischemia, decreased libido, depression, hypesthesia, hypertonia, insomnia, nervousness, paresthesia, somnolence, tremor, vertigo Respiratory: asthma, dyspnea, end inspiratory wheeze and fine rales, epistaxis, increased cough, laryngitis, pharyngitis, pleural effusion, rhinitis, sinusitis Skin and Appendages: acne, alopecia, dry skin, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, maculopapular rash, pruritus, pustular rash, skin discoloration, skin ulcer, sweating, urticaria Special Senses: abnormal vision, amblyopia, blepharitis, conjunctivitis, ear pain, glaucoma, itchy eyes, keratoconjunctivitis, otitis media, retinal detachment, tinnitus, watery eyes, taste disturbance, temporary unilateral loss of vision, vitreous floater Urogenital: dysuria, hematuria, impotence, nocturia, urinary frequency, increased BUN and serum creatinine, vaginal hemorrhage, vaginitis The following postmarketing event has been reported very rarely in patients receiving nisoldipine extended-release tablets: systemic hypersensitivity reaction, which may include one or more of the following; angioedema, shortness of breath, tachycardia, chest tightness, hypotension, and rash. A definite causal relationship with nisoldipine extended-release tablets has not been established. An unusual event observed with immediate release nisoldipine but not observed with nisoldipine extended-release tablets was one case of photosensitivity. Gynecomastia has been associated with the use of calcium channel blockers.

WARNINGS Increased Angina and/or Myocardial Infarction in Patients with Coronary Artery Disease Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed 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 established. In controlled studies of nisoldipine extended-release tablets in patients with angina this was seen about 1.5% of the time in patients given nisoldipine, compared with 0.9% in patients given placebo.

PRECAUTIONS General Hypotension Because nisoldipine, like other vasodilators, decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nisoldipine extended-release tablets is recommended. Close observation is especially important for patients already taking medications that are known to lower blood pressure. Although in most patients the hypotensive effect of nisoldipine extended-release tablets is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment.

Congestive Heart Failure

Although acute hemodynamic studies of nisoldipine in patients with NYHA Class II to IV heart failure have not demonstrated negative inotropic effects, safety of nisoldipine extended-release tablets in patients with heart failure has not been established. Caution therefore should be exercised when using nisoldipine extended-release tablets in patients with heart failure or compromised ventricular function, particularly in combination with a beta-blocker. Patients with Hepatic Impairment Because nisoldipine is extensively metabolized by the liver and, in patients with cirrhosis, it reaches blood concentrations about 5 times those in normals, nisoldipine extended-release tablets should be administered cautiously in patients with severe hepatic dysfunction (see DOSAGE AND ADMINISTRATION ). Information for Patients Nisoldipine is an extended release tablet and should be swallowed whole. Tablets should not be chewed, divided or crushed. Nisoldipine extended-release tablets should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit juice, which has been shown to increase significantly the bioavailability of nisoldipine and other dihydropyridine type calcium channel blockers, should not be taken with nisoldipine extended-release tablets.

Laboratory Tests

Nisoldipine extended-release tablets are not known to interfere with the interpretation of laboratory tests.

Drug

Interactions A 30% to 45% increase in AUC and C max of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily.

Ranitidine

150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15% to 20%). No pharmacodynamic effects of either histamine H 2 receptor antagonist were observed. CYP3A4 Inhibitors and Inducers Nisoldipine is substrate of CYP3A4 and coadministration of nisoldipine extended-release tablets with any known inducer or inhibitor of CYP3A4 should be avoided in general. Coadministration of phenytoin with a dose bioequivalent to 34 mg nisoldipine extended-release tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of nisoldipine extended-release tablets with phenytoin should be avoided and alternative antihypertensive therapy should be considered. Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and not significant. Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine. The blood pressure effect of nisoldipine extended-release tablets tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy. Quinidine at 648 mg bid decreased the bioavailability (AUC) of nisoldipine by 26%, but not the peak concentration. Immediate release nisoldipine increased plasma quinidine concentrations by about 20%. This interaction was not accompanied by ECG changes and its clinical significance is not known. No significant interactions were found between nisoldipine and warfarin or digoxin. Carcinogenesis, Mutagenesis, Impairment of Fertility Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 mg/kg/day and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose [MRHD] on a mg/m 2 basis, respectively) and female mice for up to 21 months (mean doses of up to 217 mg/kg/day, 20 times the MRHD on a mg/m 2 basis) revealed no evidence of tumorigenic effect of nisoldipine. In male mice receiving a mean dose of 163 mg nisoldipine/kg/day (16 times the MRHD of 60 mg/day on a mg/m 2 basis), an increased frequency of stomach papilloma, but still within the historical range, was observed. No evidence of stomach neoplasia was observed at lower doses (up to 58 mg/kg/day). Nisoldipine was negative when tested in a battery of genotoxicity assays including the Ames test and the CHO/HGRPT assay for mutagenicity and the in vivo mouse micronucleus test and in vitro CHO cell test for clastogenicity. When administered to male and female rats at doses of up to 30 mg/kg/day (about 5 times the MRHD on a mg/m 2 basis) nisoldipine had no effect on fertility.

Pregnancy

Category C Nisoldipine was neither teratogenic nor fetotoxic at doses that were not maternally toxic. Nisoldipine was fetotoxic but not teratogenic in rats and rabbits at doses resulting in maternal toxicity (reduced maternal body weight gain). In pregnant rats, increased fetal resorption (postimplantation loss) was observed at 100 mg/kg/day and decreased fetal weight was observed at both 30 mg/kg/day and 100 mg/kg/day. These doses are, respectively, about 5 and 16 times the MRHD when compared on a mg/m 2 basis. In pregnant rabbits, decreased fetal and placental weights were observed at a dose of 30 mg/kg/day, about 10 times the MRHD when compared on a mg/m 2 basis. In a study in which pregnant monkeys (both treated and control) had high rates of abortion and mortality, the only surviving fetus from a group exposed to a maternal dose of 100 mg nisoldipine/kg/day (about 30 times the MRHD when compared on a mg/m 2 basis) presented with forelimb and vertebral abnormalities not previously seen in control monkeys of the same strain. There are no adequate and well controlled studies in pregnant women. Nisoldipine extended-release tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing

Mothers It is not known whether nisoldipine is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made to discontinue nursing, or to discontinue nisoldipine extended-release tablets, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of nisoldipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Drug Interactions A 30% to 45% increase in AUC and C max of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily.

Ranitidine

150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15% to 20%). No pharmacodynamic effects of either histamine H 2 receptor antagonist were observed. CYP3A4 Inhibitors and Inducers Nisoldipine is substrate of CYP3A4 and coadministration of nisoldipine extended-release tablets with any known inducer or inhibitor of CYP3A4 should be avoided in general. Coadministration of phenytoin with a dose bioequivalent to 34 mg nisoldipine extended-release tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of nisoldipine extended-release tablets with phenytoin should be avoided and alternative antihypertensive therapy should be considered. Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and not significant. Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine. The blood pressure effect of nisoldipine extended-release tablets tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy. Quinidine at 648 mg bid decreased the bioavailability (AUC) of nisoldipine by 26%, but not the peak concentration. Immediate release nisoldipine increased plasma quinidine concentrations by about 20%. This interaction was not accompanied by ECG changes and its clinical significance is not known. No significant interactions were found between nisoldipine and warfarin or digoxin.