NDC 0378-2099 Nisoldipine

Nisoldipine

NDC Product Code 0378-2099

NDC CODE: 0378-2099

Proprietary Name: Nisoldipine What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Nisoldipine What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Nisoldipine is used with or without other medications to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Nisoldipine is called a calcium channel blocker. It works by relaxing blood vessels so blood can flow more easily.

Product Characteristics

Color(s):
BROWN (C48332 - BEIGE)
YELLOW (C48330)
ORANGE (C48331 - LIGHT ORANGE)
ORANGE (C48331)
Shape: ROUND (C48348)
Size(s):
10 MM
Imprint(s):
M;NE;8
M;NE;17
M;NE;25
M;NE;34
Score: 1

NDC Code Structure

  • 0378 - Mylan Pharmaceuticals Inc.

NDC 0378-2099-01

Package Description: 100 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE, PLASTIC

NDC Product Information

Nisoldipine with NDC 0378-2099 is a a human prescription drug product labeled by Mylan Pharmaceuticals Inc.. The generic name of Nisoldipine is nisoldipine. The product's dosage form is tablet, film coated, extended release and is administered via oral form.

Labeler Name: Mylan Pharmaceuticals Inc.

Dosage Form: Tablet, Film Coated, Extended Release - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer; the tablet is formulated in such manner as to make the contained medicament available over an extended period of time following ingestion.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Nisoldipine Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • NISOLDIPINE 34 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • HYDROXYPROPYL CELLULOSE (1200000 MW) (UNII: RFW2ET671P)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • POLYDEXTROSE (UNII: VH2XOU12IE)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIACETIN (UNII: XHX3C3X673)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • HYDROXYPROPYL CELLULOSE (1200000 MW) (UNII: RFW2ET671P)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • POLYDEXTROSE (UNII: VH2XOU12IE)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIACETIN (UNII: XHX3C3X673)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • HYDROXYPROPYL CELLULOSE (1200000 MW) (UNII: RFW2ET671P)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • POLYDEXTROSE (UNII: VH2XOU12IE)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIACETIN (UNII: XHX3C3X673)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • HYDROXYPROPYL CELLULOSE (1200000 MW) (UNII: RFW2ET671P)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • POLYDEXTROSE (UNII: VH2XOU12IE)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIACETIN (UNII: XHX3C3X673)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Dihydropyridine Calcium Channel Blocker - [EPC] (Established Pharmacologic Class)
  • Dihydropyridines - [CS]
  • Calcium Channel Antagonists - [MoA] (Mechanism of Action)
  • Decreased Blood Pressure - [PE] (Physiologic Effect)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Mylan Pharmaceuticals Inc.
Labeler Code: 0378
FDA Application Number: ANDA091001 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-28-2011 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Nisoldipine

Nisoldipine is pronounced as (nye' sole di peen)

Why is nisoldipine medication prescribed?
Nisoldipine is used to treat high blood pressure. Nisoldipine is in a class of medications called calcium channel blockers. It works by relaxing your blood vessels so you...
[Read More]

* Please review the disclaimer below.

Nisoldipine Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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-(o-nitrophenyl)-3,5-pyridinedicarboxylate, C20H24N2O6, 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, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide and triacetin. In addition, the following product specific coloring agents are used:The 8.5 mg tablets also contain FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake. The 17 mg tablets also contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake. The 25.5 mg tablets also contain red iron oxide and yellow iron oxide. The 34 mg tablets also contain FD&C Yellow No. 6 Aluminum Lake.

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.

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 (Cmax) 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 P450 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 P450 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 Cmax 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.

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 (Cmax 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.

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 TabletsDoses bioequivalent to:(mg/day)8.5 mg17 mg25.5 mg34 mg8.5 mg to 34 mgtitratedSystolic811111415Diastolic35778In 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.

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.

Contraindications

Nisoldipine extended-release tablets are contraindicated in patients with known hypersensitivity to dihydropyridine calcium channel blockers.

Increased Angina And/Or Myocardial Infarction In Patients With Coronary Artery Disease

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration and/or severity of angina, or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been established. In controlled studies of nisoldipine extended-release tablets in patients with angina this was seen about 1.5% of the time in patients given nisoldipine, compared with 0.9% in patients given placebo.

Hypotension

Because nisoldipine, like other vasodilators, decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nisoldipine extended-release tablets is recommended. Close observation is especially important for patients already taking medications that are known to lower blood pressure. Although in most patients the hypotensive effect of nisoldipine extended-release tablets is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment.

Congestive Heart Failure

Although acute hemodynamic studies of nisoldipine in patients with NYHA Class II to IV heart failure have not demonstrated negative inotropic effects, safety of nisoldipine extended-release tablets in patients with heart failure has not been established. Caution therefore should be exercised when 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).

Information For Patients

Nisoldipine is an extended release tablet and should be swallowed whole. Tablets should not be chewed, divided or crushed. Nisoldipine extended-release tablets should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit juice, which has been shown to increase significantly the bioavailability of nisoldipine and other dihydropyridine type calcium channel blockers, should not be taken with nisoldipine extended-release tablets.

Laboratory Tests

Nisoldipine extended-release tablets are not known to interfere with the interpretation of laboratory tests.

Drug Interactions

A 30% to 45% increase in AUC and Cmax 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.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 mg/kg/day and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose [MRHD] on a mg/m2 basis, 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/m2 basis) 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/m2 basis), 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 in vivo mouse micronucleus test and in vitro 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/m2 basis) nisoldipine had no effect on fertility.

Pregnancy Category C

Nisoldipine was neither teratogenic nor fetotoxic at doses that were not maternally toxic. Nisoldipine was fetotoxic but not teratogenic in rats and rabbits at doses resulting in maternal toxicity (reduced maternal body weight gain). In pregnant rats, increased fetal resorption (postimplantation loss) was observed at 100 mg/kg/day and decreased fetal weight was observed at both 30 mg/kg/day and 100 mg/kg/day. These doses are, respectively, about 5 and 16 times the MRHD when compared on a mg/m2 basis. In pregnant rabbits, decreased fetal and placental weights were observed at a dose of 30 mg/kg/day, about 10 times the MRHD when compared on a mg/m2 basis. In a study in which pregnant monkeys (both treated and control) had high rates of abortion and mortality, the only surviving fetus from a group exposed to a maternal dose of 100 mg nisoldipine/kg/day (about 30 times the MRHD when compared on a mg/m2 basis) presented with forelimb and vertebral abnormalities not previously seen in control monkeys of the same strain. There are no adequate and well controlled studies in pregnant women. Nisoldipine extended-release tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether nisoldipine is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made to discontinue nursing, or to discontinue nisoldipine extended-release tablets, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of nisoldipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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 EventNisoldipine (%)(n = 663)Placebo (%)(n = 280)Peripheral Edema2210Headache2215Dizziness54Pharyngitis54Vasodilation42Sinusitis32Palpitation31Chest Pain21Nausea21Rash21Only peripheral edema and possibly dizziness appear to be dose related.   Adverse EventNisoldipine Extended-Release Tablets, Dose Bioequivalent to:Placebo8.5 mg17 mg25.5 mg34 mg(Rates in %)n = 280n = 30n = 170n = 105n = 139Peripheral Edema107152027Dizziness47334   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.

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.

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.

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 M on one side of the tablet and NE over 8 on the other side. They are available as follows:NDC 0378-2096-01bottles of 100 tabletsThe 17 mg tablets are yellow, film-coated, round, unscored tablets debossed with M on one side of the tablet and NE over 17 on the other side. They are available as follows:NDC 0378-2097-01bottles of 100 tabletsThe 25.5 mg tablets are light orange, film-coated, round, unscored tablets debossed with M on one side of the tablet and NE over 25 on the other side. They are available as follows:NDC 0378-2098-01 bottles of 100 tabletsThe 34 mg tablets are orange, film-coated, round, unscored tablets debossed with M on one side of the tablet and NE over 34 on the other side. They are available as follows:NDC 0378-2099-01 bottles of 100 tabletsStore at 20° 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.Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.Revised: 6/2017NISOER:R2

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