ZOCOR (Page 5 of 8)


2
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.

8.3 Nursing Mothers

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)].

8.4 Pediatric Use

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. 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. [See Dosage and Administration (2.5), Adverse Reactions (6.1), Clinical Studies (14.2).] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1)]. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.

8.5 Geriatric Use

Of the 2,423 patients who received ZOCOR in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received ZOCOR, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. 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, ZOCOR should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3).]

A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and ZOCOR significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65-69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1)]. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.

Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, ZOCOR 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

Caution should be exercised when ZOCOR is administered to patients with severe renal impairment. [See Dosage and Administration (2.6).]

8.7 Hepatic Impairment

ZOCOR is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Warnings and Precautions (5.2)].

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/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 ZOCOR 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

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 ZOCOR have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present.

11 DESCRIPTION

ZOCOR (simvastatin) is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.

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,7β,8β(2S *,4S *),-8aβ]]. The empirical formula of simvastatin is C25 H38 O5 and its molecular weight is 418.57. Its structural formula is:

Chemical Structure

Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Tablets ZOCOR for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin and the following inactive ingredients: ascorbic acid, citric acid, hydroxypropyl cellulose, hypromellose, iron oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, talc, and titanium dioxide. Butylated hydroxyanisole is added as a preservative.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 VLDL and TG and increases HDL-C.

12.2 Pharmacodynamics

Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

12.3 Pharmacokinetics

Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin.

Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%).

Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.

The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.

In a study including 16 elderly patients between 70 and 78 years of age who received ZOCOR 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients [see Use in Specific Populations (8.5)].

Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.

The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

Table 3: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio(Ratio * with / without coadministered drug)No Effect = 1.00
AUC Cmax
*
Results based on a chemical assay except results with propranolol as indicated.
Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
Simvastatin acid refers to the β-hydroxyacid of simvastatin.
§
The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
#
Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.
Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]
Telithromycin 200 mg QD for 4 days 80 mg simvastatin acid simvastatin 12 8.9 155.3
Nelfinavir 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid simvastatin 6 6.2
Itraconazole 200 mg QD for 4 days 80 mg simvastatin acid simvastatin 13.113.1
Posaconazole 100 mg (oral suspension) QD for 13 days 40 mg simvastatin acidsimvastatin 7.310.3 9.29.4
200 mg (oral suspension) QD for 13 days 40 mg simvastatin acidsimvastatin 8.510.6 9.511.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acidsimvastatin 2.851.35 2.180.91
Avoid grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]
Grapefruit Juice §(high dose) 200 mL of double-strength TID 60 mg single dose simvastatin acidsimvastatin 716
Grapefruit Juice §(low dose) 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acidsimvastatin 1.31.9
Avoid taking with >10 mg simvastatin , based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Verapamil SR 240 mg QD Days 1-7 then 240 mg BID on Days 8-10 80 mg on Day 10 simvastatin acidsimvastatin 2.32.5 2.42.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acidsimvastatin 2.693.10 2.692.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acidsimvastatin 1.963.90 2.143.75
Avoid taking with >20 mg simvastatin , based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acidsimvastatin 1.751.76 1.721.79
Amlodipine 10 mg QD × 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.581.77 1.561.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6-9 simvastatin acidsimvastatin 2.261.86 2.281.75
Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity) , based on clinical experience
Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acidsimvastatin 1.72 1.62
Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acidsimvastatin 1.41.6 1.41.7
No dosing adjustments required for the following:
Fenofibrate 160 mg QD × 14 days 80 mg QD on Days 8-14 simvastatin acidsimvastatin 0.640.89 0.890.83
Niacin extended-release 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.61.4 1.841.08
Propranolol 80 mg single dose 80 mg single dose total inhibitor 0.79 ↓ from 33.6 to 21.1 ng∙eq/mL
active inhibitor 0.79 ↓ from 7.0 to 4.7 ng∙eq/mL

In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.

Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.

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