lovastatin (Rx)

>10%

CPK elevation (11%)

1-10%

Flatulence (4-5%)

Abdominal pain (2-3%)

Constipation (2-3%)

Diarrhea (2-3%)

Myalgia (2-3%)

Nausea (2-3%)

Dyspepsia (1-2%)

Weakness (1-2%)

Blurred vision (0.8-1%)

Rash (0.8-1%)

Muscle cramps (0.6-1%)

Dizziness (0.5-1%)

<1%

Dermatomyositis

Increased LFTs

Hepatotoxicity

Myopathy

Rhabdomyolysis

Postmarketing Reports

Interstitial lung disease

Contraindications

Hypersensitivity to lovastatin or other components

Active liver disease, or unexplained elevated transaminases

Pregnancy, lactation

Concomitant administration with strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, cobicistat, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodone)

Cautions

Nonserious and reversible cognitive side effects may occur

Avoid coadministration with cyclosporine or gemfibrozil; caution with other fibrates or lipid-lowering doses of niacin (≥1 g/day) because of increased risk for myopathy

Use caution in heavy alcohol use, history of liver disease, or renal failure

Obtain baseline liver enzyme tests before initiating and then periodically thereafter

Increases in HbA1c and fasting serum glucose levels reported

HMG-CoA reductase inhibitor shown to reduce plasma testosterone response to HCG; effects of HMG-CoA reductase inhibitors on male fertility not studied in adequate numbers of male patients

Effects of therapy, if any, on pituitary-gonadal axis in premenopausal women are unknown; patients who develop clinical evidence of endocrine dysfunction should be evaluated appropriately

Use caution if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease levels or activity of endogenous steroid hormones

Risk of myopathy increased by coadministration of CYP3A4 inhibitors or other drugs that cause myopathy

Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria

• Increased risk can occur at any dose level, but increases in dose-dependent manner
• Predisposing factors for myopathy include advanced age (≥65 years), female gender, renal impairment, and inadequately treated hypothyroidism
• Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported with statin use
• IMNM is characterized by muscle biopsy showing necrotizing myopathy without significant inflammation improvement with immunosuppressive agents, proximal muscle weakness, and elevated serum creatine kinase, which persist despite discontinuation of statin treatment
• Treatment with immunosuppressive agents may be required
• Advice all patients starting therapy or whose dose is being increased, about the risk of myopathy, including rhabdomyolysis
• Patients should report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing therapy; additional neuromuscular and serologic testing may be necessary
• Therapy should be discontinued immediately if myopathy is diagnosed or suspected
• Discontinue therapy if markedly elevated creatine kinase (CK) levels occur or if myopathy diagnosed or suspected
• Therapy should be temporarily withheld in any patient experiencing an acute or serious condition predisposing to development of renal failure secondary to rhabdomyolysis, eg, sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy
• Consider risk of IMNM carefully prior to initiation of a different statin
• If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM

Pregnancy category: X

Lactation: Contraindicated; unsafe

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

HMG-CoA reductase inhibitor; inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase

Absorption

Bioavailability: 5% (Mevacor)

Onset: 3 d (Mevacor)

Duration: 4-6 wk (Mevacor)

Max effect: 4-6 wk (Mevacor)

Peak plasma time: 2-4 hr; 14 hr (ext-rel Altoprev)

Peak plasma concentration: 7.8 ng/mL; 5.5 ng/mL (ext-rel Altoprev)

AUC: 45 ng.hr/mL; 77 ng.hr/mL (ext-rel Altoprev)

Distribution

Protein bound: 95% (Mevacor)

Metabolism

Extensive first pass in liver; activation to beta-hydroxyacid by nonenzymatic/nonspecific hydrolysis; major CYP3A4 substrate

Metabolite: Beta-hydroxyacid derivative (active) and others

Elimination

Half-life: 1.1-1.7 hr (Mevacor)

Excretion (Mevacor): Feces (83%), urine (10% urine)

Pharmacogenomics

SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes

This polymorphism is proposed to reduced transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations

SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with those that are more lipophilic (eg, atorvastatin, pravastatin, simvastatin)

Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism

SLCO1B1 CC genotype is most common in Caucasians and Asians (15%)

Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and is 16.9-fold higher in CC homozygotes compared with TT homozygotes

Genetic testing laboratories

• Optivia Biotechnology, Inc (http://optiviabio.com)