Nisoldipine

INDICATIONS AND USAGE Nisoldipine extended-release tablets are indicated for the treatment of hypertension. It 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 to 34 mg once daily. Blood pressure response increases over the 8.5 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 EXPERIENCES More than 6,000 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 1,500 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. Only peripheral edema and possibly dizziness appear to be dose related. 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 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 thinkin …

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 H2 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.

Mechanism of Action Nisoldipine is a member of the dihydropyridine class of calcium channel antagonists (calcium ion antagonists or slow channel blockers) that inhibit the transmembrane influx of calcium into vascular smooth muscle and cardiac muscle. It reversibly competes with other dihydropyridines for binding to the calcium channel. Because the contractile process of vascular smooth muscle is dependent upon the movement of extracellular calcium into the muscle through specific ion channels, inhibition of the calcium channel results in dilation of the arterioles. In vitro studies show that the effects of nisoldipine on contractile processes are selective, with greater potency on vascular smooth muscle than on cardiac muscle. Although, like other dihydropyridine calcium channel blockers, nisoldipine has negative inotropic effects in vitro , studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those that affect cardiac contractility. The effect of nisoldipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance. While nisoldipine, like other dihydropyridines, exhibits a mild diuretic effect, most of the antihypertensive activity is attributed to its effect on peripheral vascular resistance.

DESCRIPTION Nisoldipine is an extended release tablet dosage form of the dihydropyridine calcium channel blocker nisoldipine. Nisoldipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, methyl 2-methylpropyl ester, C 20 H 24 N 2 O 6 , and has the structural formula: Nisoldipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 388.4. Nisoldipine tablets comprise three layers: a top barrier layer, a middle layer containing nisoldipine, and a bottom barrier layer. The erodible barrier layers and the hydrogel middle layer provide for the controlled release of the drug. Nisoldipine tablets contain either 8.5, 17, or 34 mg of nisoldipine for once-a-day oral administration. Inactive ingredients in the formulation include: Hypromellose, hypromellose phthalate, lactose, glyceryl behenate, povidone, magnesium stearate, silicon dioxide, methacrylic acid copolymer, and sodium lauryl sulfate. Inactive ingredients in the film coating include: polydextrose, titanium dioxide, hypromellose, polyethylene glycol, iron oxide, and carnauba wax. Additionally, the 17 mg formulation contains FD&C Yellow #5. chem

OVERDOSAGE There is no experience with nisoldipine overdosage. Generally, overdosage with other dihydropyridines leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents and fluids. Clearance of nisoldipine would be expected to be slowed in patients with impaired liver function. Since nisoldipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial.

HOW SUPPLIED Nisoldipine Extended-Release Tablets are supplied as 8.5 mg, yellow film coated round tablets, debossed with “ ” and “133” on one side and plain on the other side. NDC 23155-976-01, bottles of 100 tablets with child-resistant closure. Nisoldipine Extended-Release Tablets are supplied as 17 mg, yellow film coated round tablets, debossed with “ ” and “134” on one side and plain on the other side. NDC 23155-977-01, bottles of 100 tablets with child-resistant closure. Protect from light and moisture. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure. Keep out of the reach of children. Rx only Manufactured by: Yichang Humanwell Oral Solid Dosage Plant Yichang, Hubei, China 443001 Manufactured for: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) Revised: 04/2026 UPI1080-16-01 ink logo