SIMVASTATIN tablet, film coated

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

SIMVASTATIN (UNII: AGG2FN16EV) (SIMVASTATIN - UNII:AGG2FN16EV)

Available from:

Lupin Pharmaceuticals, Inc.

INN (International Name):

SIMVASTATIN

Composition:

SIMVASTATIN 5 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Simvastatin tablets USP are indicated: - To reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. - As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). - In adults with primary hyperlipidemia. - In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). - As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). - As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. - Primary dysbetalipoproteinemia. - Hypertriglyceridemia. Simvastatin is contraindicated in the following conditions: - Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) [see DRUG INTERACTIONS (7.1)]. - Concomitant use of cyclosporine, danazol or gemfibrozil [see DRUG INTERACTIONS (7.1)]. - Acute liver failure or decompensated cirrhosis [see WARNINGS AND PRECAUTIONS (5.3)] - Hypersensitivity to simvastatin or any excipients in simvastatin tablets USP. Hypersensitivity reactions, including anaphylaxis, angioedema and Stevens-Johnson syndrome, have been reported [see ADVERSE REACTIONS (6.2)] Risk Summary Discontinue simvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Simvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, simvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see CLINICAL PHARMACOLOGY (12.1)] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with simvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m2 ) (see DATA) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data: A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data: Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6-17 and to pregnant rabbits from gestation days 6-18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits. Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested. Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta. Risk Summary There is no information about the presence of simvastatin in human or animal milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Statins, including simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with simvastatin [see USE IN SPECIFIC POPULATIONS (8.1), CLINICAL PHARMACOLOGY (12.1)]. The safety and effectiveness of simvastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of simvastatin for this indication is based on a double-blind, placebo-controlled clinical study in 175 pediatric patients (99 boys and 76 girls at least 1 year post-menarche) 10 years of age and older with HeFH. In this limited controlled study, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls. The safety and effectiveness of simvastatin have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH). Of the total number of simvastatin-treated patients in clinical studies 1,021 (23%) patients, 5,366 (52%) patients, and 363 (15%) patients were ≥65 years old, respectively. In Study HPS, 615 (6%) patients were ≥75 years old [see CLINICAL STUDIES (14)] . In a clinical study of patients treated with simvastatin 80 mg daily, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. A pharmacokinetic study with simvastatin use showed the mean plasma level of total inhibitors to be approximately 45% higher in geriatric patients between 70-78 years of age compared with patients between 18-30 years of age [see CLINICAL PHARMACOLOGY (12.3)] . Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment (CLcr 15 – 29 mL/min), the recommended starting dosage is simvastatin 5 mg once daily [see DOSAGE AND ADMINISTRATION (2.4), WARNINGS AND PRECAUTIONS (5.1)] . Simvastatin is not available in a 5 mg strength. Use another simvastatin product to initiate dosing in such patients. Simvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.3)] . In a clinical study in which patients at high risk of CVD were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). In this study, the incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe/simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1.24%. Chinese patients may be at higher risk for myopathy, monitor these patients appropriately. Coadministration of simvastatin with lipid-modifying doses of niacin-containing products (≥1 g/day niacin) is not recommended in Chinese patients [see WARNINGS AND PRECAUTIONS (5.1), DRUG INTERACTIONS (7.1)].

Product summary:

Simvastatin Tablets USP, 5 mg are tan colored, round, biconvex, film-coated tablets, debossed with 'LL' on one side and 'C01' on the other side. They are supplied as follows: NDC 68180-482-06                Bottles of 30* NDC 68180-482-09                Bottles of 90* NDC 68180-482-03                Bottles of 1000* Simvastatin Tablets USP, 10 mg are peach colored, oval shaped, biconvex, film-coated tablets, debossed with 'LL' on one side and 'C02' on the other side. They are supplied as follows: NDC 68180-478-01                Bottles of 30 NDC 68180-478-02                Bottles of 90 NDC 68180-478-03                Bottles of 1000 Simvastatin Tablets USP, 20 mg are tan colored, oval shaped, biconvex, film-coated tablets, debossed with 'LL' on one side and 'C03' on the other side. They are supplied as follows: NDC 68180-479-01                Bottles of 30 NDC 68180-479-02                Bottles of 90 NDC 68180-479-03                Bottles of 1000 Simvastatin Tablets USP, 40 mg are brick red colored, round shaped, biconvex, film-coated tablets, debossed with 'LL' on one side and 'C04' on the other side. They are supplied as follows: NDC 68180-464-06                Bottles of 30 NDC 68180-464-09                Bottles of 90 NDC 68180-464-03                Bottles of 1000 Simvastatin Tablets USP, 80 mg are brick red colored, capsule shaped, biconvex, film-coated tablets, debossed with 'LL' on one side and 'C05' on the other side. They are supplied as follows: NDC 68180-465-06                Bottles of 30 NDC 68180-465-09                Bottles of 90 NDC 68180-465-03                Bottles of 1000 *The 5 mg strength of Simvastatin Tablets USP is no longer being marketed. Storage Store between 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Preserve in tight container as defined in USP.

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

SIMVASTATIN- SIMVASTATIN TABLET, FILM COATED
LUPIN PHARMACEUTICALS, INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
SIMVASTATIN TABLETS
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
SIMVASTATIN TABLETS.
SIMVASTATIN TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 1991
INDICATIONS AND USAGE
Simvastatin tablets USP are an HMG-CoA reductase inhibitor indicated:
(1)
To reduce the risk of total mortality by reducing risk of coronary
heart disease death, non-fatal
myocardial infarction and stroke, and the need for coronary and
non-coronary revascularization
procedures in adults with established coronary heart disease,
cerebrovascular disease, peripheral
vascular disease, and/or diabetes, who are at high risk of coronary
heart disease events.
As an adjunct to diet to reduce low-density lipoprotein cholesterol
(LDL-C):
In adults with primary hyperlipidemia.
In adults and pediatric patients aged 10 years and older with
heterozygous familial
hypercholesterolemia (HeFH).
As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in
adults with homozygous familial
hypercholesterolemia (HoFH).
As an adjunct to diet for the treatment of adults with:
Primary dysbetalipoproteinemia.
Hypertriglyceridemia.
DOSAGE AND ADMINISTRATION
_Important Dosage and Administration Information_: (1)
Take simvastatin tablets USP orally once daily in the evening.
Maximum recommended dosage is simvastatin tablets USP 40 mg once
daily. An 80 mg daily
dosage of simvastatin tablets USP is restricted to patients who have
been taking simvastatin tablets
USP 80 mg daily chronically (e.g., for 12 months or more) without
evidence of muscle toxicity.
For patients that require a high-intensity statin or are unable to
achieve their LDL-C goal receiving
simvastatin tablets USP 40 mg daily, prescribe alternative LDL-C
lowering treatment.
Assess LDL-C when clinically appropriate, as early as 4 weeks after
initiating, and adjust the dosage
if necessary.
_Adults_: Recommended