Nisoldipine

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.

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.

Pharmacokinetics and Metabolism Nisoldipine pharmacokinetics are independent of the dose across the clinical dosage range of 17 mg to 51 mg, with plasma concentrations proportional to dose. Nisoldipine accumulation, during multiple dosing, is predictable from a single dose. Nisoldipine is relatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces. The absolute bioavailability of nisoldipine is about 5%. Nisoldipine’s low bioavailability is due, in part, to pre-systemic metabolism in the gut wall, and this metabolism decreases from the proximal to the distal parts of the intestine. A pronounced food-effect is observed when nisoldipine extended-release tablets are administered with a high-fat meal resulting in an increased peak concentration (C max ) of up to 245%. Total exposure (AUC) is decreased by 25%. As a result, nisoldipine extended-release tablets should be taken on an empty stomach (1 hour before or 2 hours after a meal). Maximal plasma concentrations of nisoldipine are reached at 9.2 ± 5.1 hours. The terminal elimination half-life (reflecting post absorption clearance of nisoldipine) ranges from 13.7 ± 4.3 hours. After oral administration, the concentration of (+)-nisoldipine, the active enantiomer, is about 6 times higher than the inactive (-)-nisoldipine enantiomer. The plasma protein binding of nisoldipine is very high, with less than 1% unbound over the plasma concentration range of 100 ng/mL to 10 mcg/mL. Nisoldipine is highly metabolized; 5 major urinary metabolites have been identified. Although 60% to 80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine. The major biotransformation pathway appears to be the hydroxylation of the isobutyl ester. A hydroxylated derivative of the side chain, present in plasma at concentrations approximately equal to the parent compound, appears to be the only active metabolite, and has about 10% of the activity of the parent compound. Cytochrome P 450 enzymes are believed to play a major role in the metabolism of nisoldipine. The particular isoenzyme system responsible for its metabolism has not been identified, but other dihydropyridines are metabolized by cytochrome P 450 IIIA4. Nisoldipine should not be administered with grapefruit juice, as this has been shown, in a study of 12 subjects, to interfere with nisoldipine metabolism, resulting in a mean increase in C max of about 3-fold (ranging up to about 7-fold) and AUC of almost 2-fold (ranging up to about 5-fold). A similar phenomenon has been seen with several other dihydropyridine calcium channel blockers.