Nisoldipine Information
Nisoldipine () 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-(-nitrophenyl)-3,5-pyridinedicarboxylate, CHNO, 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 and sodium lauryl sulfate. In addition, the following product specific coloring agents are used:
8.5 mg - FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, hypromellose, polydextrose, polyethylene glycol, titanium dioxide and triacetin.
17 mg - D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, hypromellose, polydextrose, polyethylene glycol, titanium dioxide and triacetin.
25.5 mg - hypromellose, polydextrose, polyethylene glycol, red iron oxide, titanium dioxide, triacetin and yellow iron oxide.
34 mg - FD&C Yellow No. 6, hypromellose, polydextrose, polyethylene glycol, titanium dioxide and triacetin.
Nisoldipine () Clinical Pharmacology
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. 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. 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.
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 is administered with a high-fat meal resulting in an increased peak concentration (C) of up to 245%. Total exposure (AUC) is decreased by 25%. As a result, Nisoldipine () extended-release should be taken on an empty stomach (one hour before or 2 hours after a meal).
Maximal plasma concentrations of Nisoldipine () are reached 9.2 ± 5.1 hours after dosing. 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; five 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 Penzymes 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 PIIIA4. 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 Cof 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.
The antihypertensive efficacy of Nisoldipine () extended-release was studied in five double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with Nisoldipine () extended-release 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 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 () extended-release 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 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 without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of Nisoldipine () extended-release.
Patient race and gender did not influence the blood pressure lowering effect of Nisoldipine () extended-release. 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 in patients treated for up to one year.
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.
Nisoldipine () Contraindications
Nisoldipine () extended-release tablets are contraindicated in patients with known hypersensitivity to dihydropyridine calcium channel blockers.
Nisoldipine () Precautions
Dietary administration of Nisoldipine () to male and female rats for up to 24 months (mean doses up to 82 and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose {MRHD} on a mg/mbasis, 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/mbasis) 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/mbasis), 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 mouse micronucleus test and 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/mbasis) Nisoldipine () had no effect on fertility.
Nisoldipine () Adverse Reactions
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 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 is generally well tolerated. In the U.S. clinical trials of Nisoldipine () extended-release in hypertension, 10.9% of the 921 Nisoldipine () extended-release 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 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 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, for which the overall incidence on Nisoldipine () extended-release was both > 1% and greater with Nisoldipine () extended-release 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 () extended-release to these events cannot be established, they are listed to alert the physician to a possible relationship with Nisoldipine () extended-release treatment.
The following post-marketing event has been reported very rarely in patients receiving Nisoldipine () extended-release: 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 has not been established. An unusual event observed with immediate-release Nisoldipine () but not observed with Nisoldipine () extended-release was one case of photosensitivity. Gynecomastia has been associated with the use of calcium channel blockers.
Nisoldipine () 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.
Nisoldipine () 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 (one 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.
Nisoldipine () How Supplied
Nisoldipine () Extended-release Tablets are available containing 8.5 mg, 17 mg, 25.5 mg or 34 mg of Nisoldipine () .
The 8.5 mg tablets are beige, film-coated, round, unscored tablets debossed with on one side of the tablet andoveron the other side. They are available as follows:
NDC 0378-2096-01bottles of 100 tablets
NDC 0378-2096-05bottles of 500 tablets
The 17 mg tablets are yellow, film-coated, round, unscored tablets debossed with on one side of the tablet andoveron the other side. They are available as follows:
NDC 0378-2097-01bottles of 100 tablets
NDC 0378-2097-05bottles of 500 tablets
The 25.5 mg tablets are light orange, film-coated, round, unscored tablets debossed with on one side of the tablet and over on the other side. They are available as follows:
NDC 0378-2098-01 bottles of 100 tablets
NDC 0378-2098-05 bottles of 500 tablets
The 34 mg tablets are orange, film-coated, round, unscored tablets debossed with on one side of the tablet andoveron the other side. They are available as follows:
NDC 0378-2099-01 bottles of 100 tablets
NDC 0378-2099-05 bottles of 500 tablets
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Mylan Pharmaceuticals Inc. Morgantown, WV 26505
JANUARY 2010NISOER:R1
Nisoldipine ()
Nisoldipine ()
Nisoldipine ()
Nisoldipine ()
