Get your patient on Nisoldipine - Nisoldipine tablet, Film Coated, Extended Release (Nisoldipine)

Nisoldipine is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

The dosage of Nisoldipine 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 - 34 mg daily dose range but adverse event rates also increase. Doses beyond 34 mg once daily are not recommended. Nisoldipine has 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 tablets should be administered orally once daily. Nisoldipine 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 is an extended release dosage form and tablets should be swallowed whole, not bitten, divided or crushed.

Nisoldipine is contraindicated in patients with known hypersensitivity to dihydropyridine calcium channel blockers.

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 1,500 patients who received Nisoldipine 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 is generally well-tolerated. In the U.S. clinical trials of Nisoldipine in hypertension, 10.9% of the 921 Nisoldipine 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 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 using doses across the clinical dosage range in patients with hypertension, lists all of the adverse events, regardless of the causal relationship to Nisoldipine, for which the overall incidence on Nisoldipine was both >1% and greater with Nisoldipine than with placebo.

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 to these events cannot be established, they are listed to alert the physician to a possible relationship with Nisoldipine 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: 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 has not been established. An unusual event observed with immediate release nisoldipine but not observed with Nisoldipine was one case of photosensitivity. Gynecomastia has been associated with the use of calcium channel blockers.

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 - 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 with any known inducer or inhibitor of CYP3A4 should be avoided in general.

Coadministration of phenytoin with a dose bioequivalent to 34 mg Nisoldipine tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of Nisoldipine 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 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.

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.

The antihypertensive efficacy of Nisoldipine was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with Nisoldipine as monotherapy and about 300 with placebo; 4 of the five studies compared 2 or 3 fixed doses while the fifth allowed titration from doses bioequivalent to 8.5 - 34 mg. Once daily administration of Nisoldipine produced sustained reductions in systolic and diastolic blood pressures over the 24 hour dosing interval in both supine and standing positions. The mean placebo-subtracted reductions in supine systolic and diastolic blood pressure at trough, 24 hours post-dose, in these studies, are shown below. Changes in standing blood pressure were similar:

In patients receiving atenolol, supine blood pressure reductions with Nisoldipine at doses bioequivalent to 17 and 34 mg once daily were 12/6 and 19/8 mm Hg, respectively. The sustained antihypertensive effect of Nisoldipine was demonstrated by 24 hour blood pressure monitoring and examination of peak and trough effects. The trough/peak ratios ranged from 70 to 100% for diastolic and systolic blood pressure. The mean change in heart rate in these studies was less than one beat per minute. In 4 of the 5 studies, patients received initial doses bioequivalent to 17-25.5 mg Nisoldipine without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of Nisoldipine.

Patient race and gender did not influence the blood pressure lowering effect of Nisoldipine. Despite the higher plasma concentration of nisoldipine in the elderly, there was no consistent difference in their blood pressure response except that the lowest clinical dose was somewhat more effective than in non-elderly patients. No postural effect on blood pressure was apparent and there was no evidence of tolerance to the antihypertensive effect of Nisoldipine in patients treated for up to one year.

Nisoldipine extended release tablets are supplied as 8.5 mg and 17 mg round film coated tablets and 34 mg elliptic film coated tablets. The different strengths can be identified as follows:

Nisoldipine Tablets are supplied in bottles of 100:

Protect from light and moisture. Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant containers.

Rx only

Manufactured for:
Prasco Laboratories
Mason, OH 45040 USA

Rev 10/2021

362168

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.