Drug reference

Simvastatin

Statin · Lipid-lowering agent

StatinLipid-lowering agent

CDSCO approvedSchedule H

EXCRETION

—

not curated

INTERACTIONS

12 major

incl. contraindicated

PREGNANCY

—

not curated

Top interactionssee all 12 →

CobicistatContraindicatedDatabaseKimi deep-research + Cla
CyclosporineContraindicatedDatabaseDDInter
DarunavirContraindicatedDatabaseKimi deep-research + Cla · p948
GemfibrozilContraindicatedDatabaseKimi deep-research + Cla · p949

Mechanism

Simvastatin is an inactive lactone prodrug that is converted in the liver to its active β-hydroxy acid form, which competitively inhibits HMG-CoA reductase (Ki ~1 nM, approximately 1000-fold more potent than the natural substrate). This reduces hepatic cholesterol synthesis, upregulating LDL receptor expression and lowering circulating LDL cholesterol by 25-45%. Unlike pravastatin, simvastatin is highly lipophilic and extensively metabolized by CYP3A4, creating significant drug interaction risk with CYP3A4 inhibitors that has led to rhabdomyolysis cases with concurrent cyclosporine, gemfibrozil, or high-dose azole antifungals.

Indications

Secondary prevention of cardiovascular disease (CVD)Familial hypercholesterolaemia (as first-line therapy, dose titrated to achieve >50% reduction in LDL-cholesterol concentration from baseline)Severe hypercholesterolaemia with high risk of cardiovascular complications (for 80 mg dose, if lower doses have not achieved treatment goals and benefits outweigh risks)HypercholesterolemiaReduction of LDL-C levelsTreat dyslipidemias, especially elevated LDL-CChildren aged 11 years and older with heterozygous FHPrimary hyperlipidaemias with raised LDL and total CH levels, with or without raised TG levels (Type IIa, IIb, V)Secondary hypercholesterolaemia (e.g., in diabetes, nephrotic syndrome)Raised HDL-CH (when low)

Dosing

Adult: By mouth: 10 mg (low-intensity), 20 mg (medium-intensity), 40 mg (medium-intensity), 80 mg (high-intensity) daily. The 80 mg dose is generally avoided due to myopathy risk, unless patients are stable on it for at least one year or have severe hypercholesterolaemia and high cardiovascular risk and have not achieved goals on lower doses, provided benefits outweigh risks.…
Max dose: 80 mg daily (with restrictions and cautions)

Pharmacokinetics

Half-life

About 12 h

Bioavailability

≤5%

Protein binding

>95%

Metabolism

Primarily by CYPs 3A4 and 3A5 (administered as inactive lactone, transformed in liver to active β-hydroxy acid)

Excretion

Negligible

Contraindications

High-dose (80 mg) simvastatin generally avoided due to risk of myopathy, unless patient has been stable on this regimen for at least one year.
Contra-indications to statins (for patients with primary heterozygous familial hypercholesterolaemia where ezetimibe may be considered)
Pregnancy
Active liver disease
Concomitant use with cyclosporine
Concomitant use with HIV protease inhibitors
Concomitant use with erythromycin

Side effects

Common

MyalgiaMuscle sorenessWeaknessGastrointestinal complaintsHeadacheRashes (uncommon)Sleep disturbances (uncommon)Muscle aches (10%)

Serious

Myopathy (especially with high-dose 80 mg, or in combination with a fibrate)
Rhabdomyolysis (increased risk when combined with a fibrate)
Myopathy
Rhabdomyolysis
Hepatotoxicity
Rise in serum transaminase
Liver damage (rare)
Myopathy (rare, < 1 per 1000)
Rhabdomyolysis (fatalities on record)

Drug interactions

Cobicistat

Contraindicated

Database

CYP3A inhibition

Contraindicated; use pravastatin/low-dose alternative

Source: Kimi deep-research + Cla

Cyclosporine

Contraindicated

Database

Increased risk of myopathy and rhabdomyolysis.

Consider using pravastatin, fluvastatin, or rosuvastatin, as they are not extensively metabolized by CYP3A4. Carefully weigh the benefits against the risk of myopathy. For simvastatin, coadministration is contraindicated.

Source: DDInter

Darunavir

Contraindicated

Database

Ritonavir CYP3A4 inhibition

Contraindicated

Source: Kimi deep-research + Cla · p948

Gemfibrozil

Contraindicated

Database

OATP1B1/CYP inhibition → severe myopathy/rhabdomyolysis

Contraindicated; avoid all statin–gemfibrozil combinations where possible (prefer fenofibrate)

Source: Kimi deep-research + Cla · p949

Itraconazole

Contraindicated

Database

Itraconazole potently inhibits CYP3A4-mediated metabolism of simvastatin and lovastatin (but NOT pravastatin or rosuvastatin), resulting in markedly increased statin plasma concentrations and high risk of rhabdomyolysis, myopathy, and acute kidney injury.

CONTRAINDICATED. Discontinue simvastatin/lovastatin before starting itraconazole. If statin therapy is essential, switch to pravastatin or rosuvastatin (minimally metabolized by CYP3A4) and monitor CK levels.

Source: Kimi deep-research + Cla · p948

Letermovir

Contraindicated

Database

Marked OATP1B/CYP3A4 inhibition

Contraindicated in that combination

Source: Kimi deep-research + Cla

Nirmatrelvir

Contraindicated

Database

Ritonavir CYP3A4 inhibition

Withhold statin during and 5 days after course