Ezetimibe and Simvastatin (Page 5 of 9)

8.2 Lactation

Risk Summary
There is no information about the presence of ezetimibe or simvastatin in human breast milk, the effects of the drug on the breastfed infant or the effect of the drug on milk production. However, it has been shown that other statins pass into human milk. Statins, including ezetimibe and simvastatin tablets, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breast fed 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 ezetimibe and simvastatin tablets [see Use in Specific Populations (8.2) and Clinical Pharmacology (12.1)].
Data
Animal Data
Ezetimibe was present in the milk of lactating rats. The pup to maternal plasma ratio for total ezetimibe was 0.5 on lactation day 12.

8.4 Pediatric Use

The safety and effectiveness of ezetimibe in combination with a statin 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 ezetimibe and simvastatin tablets for this indication is based on a double-blind, placebo-controlled clinical trial in 248 pediatric patients (142 males and 106 postmenarchal females) 10 years of age and older with HeFH [see Clinical Studies (14)]. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the adolescent males or females, or on menstrual cycle length in females.

The safety and effectiveness of ezetimibe and simvastatin tablets have not been established in pediatric patients younger than 10 years of age with HeFH, or in pediatric patients with other types of hyperlipidemia.

8.5 Geriatric Use

Advanced age (≥65 years) is a risk factor for ezetimibe and simvastatin tablets-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving ezetimibe and simvastatin tablets for the increased risk of myopathy [see Warnings and Precautions (5.1)].
Of the 10,189 patients who received ezetimibe and simvastatin tablets in clinical studies, 3242 (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.

8.6 Renal Impairment

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Doses of ezetimibe and simvastatin tablets exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].
In the SHARP trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2 , and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of trial 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 tablets 10/20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years.

8.7 Hepatic Impairment

Ezetimibe and simvastatin tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis. [See Contraindications ( 4) and Warnings and Precautions (5.3).]

8.8 Chinese Patients

In a clinical trial 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 trial the incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe and 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 ezetimibe and simvastatin tablets with lipid-modifying doses of niacin-containing products (≥1 g/day niacin) is not recommended in Chinese patients [see Warnings and Precautions ( 5.1) and Drug Interactions ( 7.1)].

10 OVERDOSAGE

No specific antidotes for ezetimibe and simvastatin tablets are known. In the event of an overdose with ezetimibe and simvastatin tablets, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for overdosage management recommendations.

11 DESCRIPTION

Ezetimibe and Simvastatin Tablets contain ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, an HMG-CoA reductase inhibitor.

The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The molecular formula is C24 H21 F2 NO3 and its molecular weight is 409.44 g/mol.

Ezetimibe is a white, crystalline powder that is freely soluble in ethanol, methanol and acetone and practically insoluble in water. Its structural formula is:

ezetimibe-structure
(click image for full-size original)

Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S -[1α,3α,7α,8α(2S* ,4S*),-8aβ]]. The molecular formula of simvastatin is C25 H38 O5 and its molecular weight is 418.57 g/mol.

Simvastatin is a white to off-white, nonhygroscopic powder that is freely soluble in chloroform, methanol and alcohol, sparingly soluble in propylene glycol, very slightly soluble in hexane and practically insoluble in water. Its structural formula is:

simva-structure
(click image for full-size original)

Ezetimibe and Simvastatin Tablets are available for oral use as tablets containing 10 mg of ezetimibe, and 10 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/10 mg), 20 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/20 mg), 40 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/40 mg), or 80 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/80 mg). Each tablet contains the following inactive ingredients: butylated hydroxyanisole, citric acid monohydrate, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propyl gallate, and sodium lauryl sulfate.

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