Simvastatin (Page 5 of 8)

8.6 Renal Impairment

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 to 29 mL/min), the recommended starting dosage is simvastatin 5 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].

8.7 Hepatic Impairment

Simvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].

8.8 Chinese Patients

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)].

10 OVERDOSAGE

No specific antidotes for simvastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations.

11 DESCRIPTION

Simvastatin is a prodrug of 3-hydoroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that is derived synthetically from a fermentation product of Aspergillus terreus.
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 molecular formula of simvastatin is C25 H38 O5 and its molecular weight is 418.57. Its structural formula is:

Chemical Structure

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

Simvastatin tablets USP are available for oral administration in strength of 5 mg, 10 mg, 20 mg, 40 mg or 80 mg. Each tablet contains following inactive ingredients: ascorbic acid, lactose monohydrate, microcrystalline cellulose, pregelatinized starch (maize), hydroxypropyl cellulose, hypromellose, titanium dioxide, talc, citric acid monohydrate, isopropyl alcohol, magnesium stearate and butylated hydroxyanisole. Simvastatin 5 mg also contains ferric oxide yellow, simvastatin 10 mg and simvastatin 20 mg also contains ferric oxide red and ferric oxide yellow, simvastatin 40 mg and simvastatin 80 mg also contains ferric oxide red.

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 acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

12.2 Pharmacodynamics

Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of simvastatin is usually achieved by 4 weeks and is maintained after that.

12.3 Pharmacokinetics

Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid. Pharmacokinetics (PK) of simvastatin and its metabolites was originally characterized using inhibition of HMG-CoA reductase activity following base hydrolysis of plasma samples, as specific bioanalytical methods were not available. Inhibition of the enzyme activity (equivalent to the level of total inhibitors) represented the combination of activities in plasma following administration of simvastatin from both active (simvastatin acid and its metabolites) and latent forms (simvastatin and its metabolites) after conversion to the active forms in the presence of base.

Absorption

Following an oral dose of 14 C-labeled simvastatin, 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 simvastatin to the general circulation is low (<5%). PK, assessed as area under the concentrations of total inhibitors – time curve, was apparently linear with doses up to 120 mg.

Effect of Food

The plasma profile of total inhibitors concentration was not affected when simvastatin was administered with low fat meal.

Distribution

Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins.

Elimination

Metabolism

Simvastatin is metabolized by CYP3A4. The major active metabolites of simvastatin present in human plasma are simvastatin acid 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.

Excretion

Following an oral dose of 14 C-labeled simvastatin, 13% of the dose was excreted in urine and 60% in feces.

Specific Populations

Geriatric Patients

In a study including 16 geriatric patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of total inhibitors was increased approximately 45% compared with 18 patients between 18 to 30 years of age [see Use in Specific Populations (8.5)].

Drug Interaction Studies

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of inhibitors of the transport protein OATP1B1 and/or CYP3A4 may lead to increased exposure of simvastatin acid. 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 [see Drug Interactions (7)].

Table 4 displays the effect of coadministered drugs or grapefruit juice on simvastatin systemic exposure [see Drug Interactions (7)].

Table 4: 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
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.
Telithromycin 200 mg QD for 4 days 80 mg simvastatin acid simvastatin 128.9 155.3
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 days200 mg (oral suspension) QD for 13 days 40 mg40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.310.38.510.6 9.29.49.511.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.851.35 2.180.91
Grapefruit Juice§ (high dose) 200 mL of double-strength TID 60 mg single dose simvastatin acid simvastatin 716
Grapefruit Juice§ (low dose) 8 oz (about 237 mL) of single-strength# 20 mg single dose simvastatin acid simvastatin 1.31.9
Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg onDay 10 simvastatin acid simvastatin 2.32.5 2.42.1
Diltiazem 120 mg BID for 10 days 80 mg onDay 10 simvastatin acid simvastatin 2.69 3.10 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 acid simvastatin 1.963.90 2.143.75
Amiodarone 400 mg QD for 3 days 40 mg onDay 3 simvastatin acid simvastatin 1.75 1.76 1.721.79
Amlodipine 10 mg QD x 10 days 80 mg onDay 10 simvastatin acid simvastatin 1.58 1.77 1.561.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.281.75
Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.72 1.62
Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.41.7
Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 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 active inhibitor 0.79 0.79 ↓ from33.6 to 21.1 ng·eq/mL↓ from7 to 4.7 ng·eq/mL

Simvastatin’s Effect on the Pharmacokinetics of Other Drugs

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. Simvastatin is not an inhibitor of CYP3A4 and 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 [see Drug Interactions (7.2)].

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