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.
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.
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 simvastatin tablets 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 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)] .
|Coadministered Drug or Grapefruit Juice||Dosing of Coadministered Drug or Grapefruit Juice||Dosing of Simvastatin||Geometric Mean Ratio (Ratio * with / without co-administered drug) No Effect = 1.00|
|AUC C max||C max|
|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||15 5.3|
|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|| |
|Posaconazole||100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days||40 mg 40 mg||simvastatin acid simvastatin simvastatin acid simvastatin||7.3 10.3 8.5 10.6||9.2 9.4 9.5 11.4|
|Gemfibrozil||600 mg BID for 3 days||40 mg||simvastatin acid ‡simvastatin|| |
|Avoid grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]|
Grapefruit Juice §
|200 mL of double-strength TID ¶||60 mg single dose||simvastatin acid simvastatin||7 16|
Grapefruit Juice §
|8 oz (about 237mL) of single-strength #||20 mg single dose||simvastatin acid simvastatin||1.3 1.9|
|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 to 7 then 240 mg BID on Days 8 to 10||80 mg on Day 10||simvastatin acid simvastatin||2.3 2.5||2.4 2.1|
|Diltiazem||120 mg BID for 10 days||80 mg on Day 10||simvastatin acid
|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
|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 acid
|Amlodipine||10 mg QD x 10 days||80 mg on Day 10||simvastatin acid
|Ranolazine SR||1000 mg BID for 7 days||80 mg on Day 1 and Days 6 to 9||simvastatin acid
|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 acid simvastatin||1.7 2||1.6 2|
|Lomitapide||10 mg QD for 7 days||20 mg single dose||simvastatin acid simvastatin||1.4 1.6||1.4 1.7|
|No dosing adjustments required for the following:|
|Fenofibrate||160 mg QD X 14 days||80 mg QD on Days 8 to 14||simvastatin acid simvastatin||0.64 0.89||0.89 0.83|
|Niacin extended-release||2 g single dose||20 mg single dose||simvastatin acid simvastatin||1.6 1.4||1.84 1.08|
|Propranolol||80 mg single dose||80 mg single dose|| |
|0.79 0.79||from 33.6 to 21.1 ng·eq/mL ↓ 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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