hen 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 ).

y. 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.

ith 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.

at 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. 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. special populations renal dysfunction because renal elimination is not an important pathway, bioavailability and pharmacokinetics of nisoldipine extended-release tablets were not significantly different in patients with various degrees of renal impairment. dosing adjustments in patients with mild to moderate renal impairment are not necessary. geriatric elderly patients have been found to have 2- to 3-fold higher plasma concentrations (c max and auc) than young subjects. this should be reflected in more cautious dosing (see dosage and administration ). hepatic insufficiency in patients with liver cirrhosis given a dose bioequivalent to 8.5 mg nisoldipine extended-release tablets, plasma concentrations of the parent compound were 4 to 5 times higher than those in healthy young subjects. lower starting and maintenance doses should be used in cirrhotic patients (see dosage and administration ). gender and race the effect of gender or race on the pharmacokinetics of nisoldipine has not been investigated. disease states hypertension does not significantly alter the pharmacokinetics of nisoldipine. pharmacodynamics hemodynamic effects administration of a single dose of nisoldipine leads to decreased systemic vascular resistance and blood pressure with a transient increase in heart rate. the change in heart rate is greater with immediate release nisoldipine preparations. the effect on blood pressure is directly related to the initial degree of elevation above normal. chronic administration of nisoldipine results in a sustained decrease in vascular resistance and small increases in stroke index and left ventricular ejection fraction. a study of the immediate release formulation showed no effect of nisoldipine on the renin-angiotensin-aldosterone system or on plasma norepinephrine concentration in normals. changes in blood pressure in hypertensive patients given nisoldipine extended-release tablets were dose related over the clinical dosage range. nisoldipine does not appear to have significant negative inotropic activity in intact animals or humans, and did not lead to worsening of clinical heart failure in three small studies of patients with asymptomatic and symptomatic left ventricular dysfunction. there is little information, however, in patients with severe congestive heart failure, and all calcium channel blockers should be used with caution in any patient with heart failure. electrophysiologic effects nisoldipine has no clinically important chronotropic effects. except for mild shortening of sinus cycle, sa conduction time and ah intervals, single oral doses up to 20 mg of immediate release nisoldipine did not significantly change other conduction parameters. similar electrophysiologic effects were seen with single iv doses, which could be blunted in patients pre-treated with beta-blockers. dose and plasma level related flattening or inversion of t-waves have been observed in a few small studies. such reports were concentrated in patients receiving rapidly increased high doses in one study; the phenomenon has not been a cause of safety concern in large clinical trials. clinical studies in hypertension the antihypertensive efficacy of nisoldipine extended-release tablets was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with nisoldipine extended-release tablets as monotherapy and about 300 with placebo; 4 of the 5 studies compared 2 or 3 fixed doses while the fifth allowed titration from doses bioequivalent to 8.5 mg to 34 mg. once daily administration of nisoldipine extended-release tablets 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: mean supine trough systolic and diastolic blood pressure changes (mm hg) nisoldipine extended-release tablets doses bioequivalent to: (mg/day) 8.5 mg 17 mg 25.5 mg 34 mg 8.5 mg to 34 mg titrated systolic 8 11 11 14 15 diastolic 3 5 7 7 8 in patients receiving atenolol, supine blood pressure reductions with nisoldipine extended-release tablets at doses bioequivalent to 17 mg and 34 mg once daily were 12/6 and 19/8 mm hg, respectively. the sustained antihypertensive effect of nisoldipine extended-release tablets 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 mg to 25.5 mg nisoldipine extended-release tablets without incident (excessive effects on blood pressure or heart rate). the fifth study started patients on lower doses of nisoldipine extended-release tablets. patient race and gender did not influence the blood pressure lowering effect of nisoldipine extended-release tablets. 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 extended-release tablets in patients treated for up to one year.

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.

� to 25°c (68° to 77°f). [see usp controlled room temperature.] protect from light and moisture. dispense in a tight, light-resistant container as defined in the usp using a child-resistant closure. manufactured for: mylan pharmaceuticals inc. morgantown, wv 26505 u.s.a. manufactured by: mylan laboratories limited hyderabad — 500 096, india revised: 9/2020 mxi:nisoer:r1 75077325