EZETIMIBE AND SIMVASTATIN tablet

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

EZETIMIBE (UNII: EOR26LQQ24) (EZETIMIBE - UNII:EOR26LQQ24), SIMVASTATIN (UNII: AGG2FN16EV) (SIMVASTATIN - UNII:AGG2FN16EV)

Available from:

AvKARE

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Ezetimibe and simvastatin tablets have not been studied in Fredrickson type I, III, IV, and V dyslipidemias. Ezetimibe and simvastatin tablets are contraindicated in the following conditions: - Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions (5.1)] . - Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.1)] . - Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)] . - Active liver disease or unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.3)] . - Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin may cause fetal harm when administered to a pregnant woman. 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 hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe and simvastatin use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. E zetimibe and simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ezetimibe and simvastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)] . - Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require ezetimibe and simvastatin treatment should not breastfeed their infants [see Use in Specific Populations (8.3)] . Pregnancy Category X. [See Contraindications (4)]. E zetimibe and simvastatin Ezetimibe and simvastatin is contraindicated in women who are or may become pregnant. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of ezetimibe and simvastatin use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero . Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins, such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin may cause fetal harm when administered to a pregnant woman. If ezetimibe and simvastatin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential, who require ezetimibe and simvastatin treatment for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of ezetimibe and simvastatin should be considered. If pregnancy occurs, ezetimibe and simvastatin should be immediately discontinued. Ezetimibe In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1,000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1,000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1,000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe co-administered with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in co-administration therapy compared to monotherapy. Simvastatin Simvastatin was not teratogenic in rats or rabbits at doses (25 mg/kg/day, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m 2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice. There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review 1 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally-related statin, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.                                         1 Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology , 10(6):439-446, 1996. It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4)] . In rat studies, exposure to ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe or simvastatin are excreted into human breast milk. Because a small amount of another drug in the same class as simvastatin is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women who are nursing should not take ezetimibe and simvastatin [see Contraindications (4)] . The effects of ezetimibe co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multiracial) with HeFH were randomized to receive either ezetimibe co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161 mg/dL to 351 mg/dL) in the ezetimibe co-administered with simvastatin group compared to 219 mg/dL (range: 149 mg/dL to 336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6. Table 3: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Co-administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia Total-C LDL-C Apo B Non-HDL-C TG * HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% -2% +0.1% 95% Confidence Interval (-15%, -9%) (-18%, -12%) (-15%, -9%) (-17%, -11%) (-9, +4) (-3, +3) * For triglycerides, median % change from baseline. From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the ezetimibe co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group. During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 X ULN) occurred in four (3%) individuals in the ezetimibe co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 X ULN) occurred in two (2%) individuals in the ezetimibe co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. Co-administration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, ezetimibe and simvastatin has not been studied in patients younger than 10 years of age or in pre-menarchal girls. Ezetimibe Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide) there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available. Simvastatin The pharmacokinetics of simvastatin has not been studied in the pediatric population. Of the 10,189 patients who received ezetimibe and simvastatin in clinical studies, 3,242 (32%) were 65 and older (this included 844 (8%) who were 75 and older). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, ezetimibe and simvastatin should be prescribed with caution in the elderly [see Clinical Pharmacology (12.3)] . Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, ezetimibe and simvastatin should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age [see  Warnings and Precautions (5.1)  and Clinical Pharmacology (12.3) ] . In the SHARP trial of 9,270 patients with moderate to severe renal impairment (6,247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m 2 , and 3,023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe and simvastatin 10/20 mg (n=4,650) or placebo (n=4,620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of ezetimibe and simvastatin exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment [see  Dosage and Administration (2.5),  Adverse Reactions (6.1),  and Clinical Studies (14.3)] . Ezetimibe and simvastatin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminases [see Contraindications (4)  and Warnings and Precautions (5.3)] . In a clinical trial in which patients at high risk of cardiovascular disease 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=7,367) compared with 0.24% for Chinese patients (n=5,468). The incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe and simvastatin 10/40 mg/day co-administered with extended-release niacin 2 g/day was 1.24%. Chinese patients may be at higher risk for myopathy, monitor patients appropriately. Co-administration of ezetimibe and simvastatin with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products is not recommended in Chinese patients [see Warnings and Precautions (5.1), Drug Interactions (7.4)] .

Product summary:

Ezetimibe and simvastatin tablets, 10/10 mg , are supplied as white to off-white, capsule shaped tablets, debossed with “AA 70” on one side and plain on the other side. They are available as follows: Bottles of 1,000: NDC 42291-078-10 Ezetimibe and simvastatin tablets, 10/20 mg , are supplied as white to off-white, capsule shaped tablets, debossed with “AA 71” on one side and plain on the other side. They are available as follows: Bottles of 1,000: NDC 42291-079-10 Ezetimibe and simvastatin tablets, 10/40 mg , are supplied as white to off-white, capsule shaped tablets, debossed with “AA 72” on one side and plain on the other side. They are available as follows: Bottles of 1,000: NDC 42291-080-10 Ezetimibe and simvastatin tablets, 10/80 mg , are supplied as white to off-white, capsule shaped tablets, debossed with “AA 73” on one side and plain on the other side. They are available as follows: Bottles of 500: NDC 42291-081-50 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed. For more information, go to www.avkare.com or call 1-855-361-3993.

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

EZETIMIBE AND SIMVASTATIN- EZETIMIBE AND SIMVASTATIN TABLET
AVKARE
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HIGHLIGHTS OF PRESCRIBING INFORMATION
EZETIMIBE AND SIMVASTATIN TABLETS, FOR ORAL USE
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
EZETIMIBE AND
SIMVASTATIN TABLETS SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING
INFORMATION FOR EZETIMIBE
AND SIMVASTATIN TABLETS.
INITIAL U.S. APPROVAL: 2004
INDICATIONS AND USAGE
Ezetimibe and simvastatin tablets, which contains a cholesterol
absorption inhibitor and an HMG-CoA
reductase inhibitor (statin), is indicated as adjunctive therapy to
diet to:
reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to
increase HDL-C in patients with
primary (heterozygous familial and non-familial) hyperlipidemia or
mixed hyperlipidemia. ( 1.1)
reduce elevated total-C and LDL-C in patients with homozygous familial
hypercholesterolemia (HoFH),
as an adjunct to other lipid-lowering treatments. ( 1.2)
Limitations of Use ( 1.3)
No incremental benefit of ezetimibe and simvastatin tablets on
cardiovascular morbidity and mortality
over and above that demonstrated for simvastatin has been established.
Ezetimibe and simvastatin tablets have not been studied in Fredrickson
Type I, III, IV, and V
dyslipidemias.
DOSAGE AND ADMINISTRATION
Dose range is 10/10 mg/day to 10/40 mg/day. ( 2.1)
Recommended usual starting dose is 10/10 or 10/20 mg/day. ( 2.1)
Due to the increased risk of myopathy, including rhabdomyolysis, use
of the 10/80-mg dose of
ezetimibe and simvastatin tablets should be restricted to patients who
have been taking ezetimibe and
simvastatin tablets 10/80 mg chronically (e.g., for 12 months or more)
without evidence of muscle
toxicity. ( 2.2)
Patients who are currently tolerating the 10/80-mg dose of ezetimibe
and simvastatin tablets who need
to be initiated on an interacting drug that is contraindicated or is
associated with a dose cap for
simvastatin should be switched to an alternative statin or
statin-based regimen with less potential for
the drug-drug interaction. ( 2.2)
Due to the