Ezetimibe and Simvastatin (Page 6 of 11)

8.5 Geriatric Use

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. Since advanced age (≥65 years) is a predisposing factor for myopathy, Ezetimibe and Simvastatin Tablets 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 Tablets 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).]

8.6 Renal Impairment

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 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 Tablets 10/20 mg (n=4650) or placebo (n=4620) 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 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 (2.5), Adverse Reactions (6.1), and Clinical Studies (14.3).]

8.7 Hepatic Impairment

Ezetimibe and Simvastatin Tablets are contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminases. [See Contraindications (4) and Warnings and Precautions (5.3).]

8.8 Chinese Patients

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=7367) compared with 0.24% for Chinese patients (n=5468). 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 patients appropriately. Coadministration of Ezetimibe and Simvastatin Tablets 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)].

10 OVERDOSAGE

Ezetimibe and Simvastatin Tablets

No specific treatment of overdosage with Ezetimibe and Simvastatin Tablets can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed.

Ezetimibe

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, was generally well tolerated.

A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.

Simvastatin

Significant lethality was observed in mice after a single oral dose of 9 g/m². No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/ m² , respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.

A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.

The dialyzability of simvastatin and its metabolites in man is not known at present.

11 DESCRIPTION

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

The chemical name of ezetimibe, USP is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C₂₄ H₂₁ F₂ NO₃ and its molecular weight is 409.43.

Ezetimibe, USP is a white to off white, crystalline powder, hygroscopic that is soluble in methanol. Its structural formula is:

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

Simvastatin, USP is a white to off-white powder that is freely soluble in chloroform, methanol and alcohol. Sparingly soluble in Propylene glycol, very slightly soluble in Hexane. Practically insoluble in water. Its structural formula is:

Ezetimibe and Simvastatin Tablets is available for oral use as tablets containing 10 mg of ezetimibe, USP, and 10 mg of simvastatin, USP (Ezetimibe and Simvastatin Tablets 10/10), 20 mg of simvastatin, USP (Ezetimibe and Simvastatin Tablets 10/20), 40 mg of simvastatin, USP (Ezetimibe and Simvastatin Tablets 10/40), or 80 mg of simvastatin, USP (Ezetimibe and Simvastatin Tablets 10/80). Each tablet contains the following inactive ingredients: Lactose Monohydrate, Microcrystalline Cellulose, Croscarmellose Sodium, Sodium Lauryl Sulfate, Hypromellose, Citric Acid Monohydrate, Propyl Gallate, Butylated Hydroxy Anisole and Magnesium Stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ezetimibe and Simvastatin Tablets

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and Simvastatin Tablets contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe and Simvastatin Tablets reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.

Ezetimibe

Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production.

Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins [see Clinical Studies (14)].

Simvastatin

Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces very-low-density lipoproteins (VLDL) and TG and increases HDL-C.