atorvastatin (Rx)

>10%

Diarrhea (5-14%)

Nasopharyngitis (4-13%)

Arthralgia (4-12%)

1-10%

Insomnia (1-5%)

Urinary tract infection (4-8%)

Nausea (4-7%)

Dyspepsia (3-6%)

Increased transaminases (2-3%)

Muscle spasms (2-5%)

Musculoskeletal pain (2-5%)

Myalgia (3-8%)

Limb pain (3-8%)

Pharyngolaryngeal pain (1-4%)

Frequency Not Defined

Angina

Syncope

Dyspnea

Myopathy

Anaphylaxis

Stevens-Johnson syndrome

Myositis

Contraindications

Hypersensitivity to atorvastatin

Active liver disease or unexplained transaminase elevation

Pregnancy, lactation

Cautions

Nonserious and reversible cognitive side effects may occur

Increased blood sugar and glycosylated hemoglobin (HbA1c) levels reported with statin intake

Heavy alcohol use, renal failure, history of liver disease

Fatal and nonfatal hepatic failure reported (rare)

Myopathy and rhabdomyolysis

• Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher dosage
• Therapy may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria); rare fatalities have occurred as a result of rhabdomyolysis with statin use
• Risk of myopathy: Increased by coadministration with fibrates, cyclosporine, macrolides, inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (eg, breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis; concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir not recommended
• Cases of myopathy/rhabdomyolysis reported with atorvastatin coadministered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir; consider if benefit of use of these products outweighs increased risk of myopathy and rhabdomyolysis
• Atorvastatin dosage modifications recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications
• Withhold or discontinue treatment in any patient developing myopathy, renal failure, or transaminase levels >3x ULN
• Temporary therapy discontinuation recommended for patients with acute surgical or medical conditions, elective major surgery, or serious condition suggestive of a myopathy or risk factor predisposing to development of renal failure secondary to rhabdomyolysis
• Discontinue therapy if markedly elevated CK levels occur or myopathy is diagnosed or suspected
• Use caution in hepatic impairment, recent stroke
• CYP3A4 substrate; avoid grapefruit products and caution with other CYP3A4 inhibitors; concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice not recommended
• Muscle symptoms and CK increases may resolve if atorvastatin is discontinued; temporarily discontinue therapy in patients experiencing acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (eg, sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy)
• Secondary causes of hyperlipidemia should be ruled out before initiating therapy

Immune-mediated necrotizing myopathy

• 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
• Additional neuromuscular and serologic testing may be necessary
• Treatment with immunosuppressive agents may be required
• 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

Contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy; because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, therapy may cause fetal harm when administered to a pregnant woman; discontinue therapy as soon as pregnancy is recognized; limited published data are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage

Contraception

• Advise females of reproductive potential to use effective contraception during treatment

Lactation

Use is contraindicated during breastfeeding; there is no available information on effects of drug on breastfed infant or on milk production.; not known whether atorvastatin is present in human milk; it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk; because of potential for serious adverse reactions in breastfed infant, advise women that breastfeeding is not recommended during treatment

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 rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase

Absorption

Bioavailability: 14% (parent drug)

Onset: 3-5 days

Duration: 48-72 hr

Peak serum time: 1-2 hr

Maximum effect: 2 weeks

Distribution

Protein bound: 98%

Vd: 381 L

Metabolism

Via hepatic P450 enzyme CYP3A4

Metabolites: Ortho- and parahydroxylated derivatives and beta-oxidation product (inactive)

Elimination

Half-life: 14 hr

Dialyzable: No (HD)

Excretion: Mainly via bile; urine (2%)

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 reduce transport into the liver, the main site of statin metabolism and elimination

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, 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 16.9-fold higher in CC homozygotes than in TT homozygotes

Genetic testing laboratories

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