pitavastatin (Rx)

1-10%

Back pain (1.4-3.9%)

Constipation (1.5-3.6%)

Diarrhea (1.5-2.6%)

Myalgia (1.9-3.1%)

Pain in extremity (0.6-2.3%)

Postmarketing Reports

Gastrointestinal disorders: Abdominal discomfort, abdominal pain, dyspepsia, nausea

General disorders: Asthenia, fatigue, malaise, dizziness

Hepatobiliary disorders: Hepatitis, jaundice, fatal and nonfatal hepatic failure

Immune system disorders: Immune-mediated necrotizing myopathy-associated with statin use; angioedema

Metabolism and nutrition disorders: Increases in HbA1c, fasting serum glucose levels

Musculoskeletal and connective tissue disorders: Muscle spasms, myopathy, rhabdomyolysis

Nervous system disorders: Hypoesthesia, peripheral neuropathy

Psychiatric disorders: Insomnia, depression; rare reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use; cognitive impairment was generally nonserious, and reversible upon discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks)

Reproductive system and breast disorders: Erectile dysfunction

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease

Contraindications

Hypersensitivity to drug or excipients

Active liver disease or persistent unexplained elevations of hepatic transaminases

Pregnancy

Breastfeeding

Concurrent use with cyclosporine

Cautions

Increased HbA1c and fasting serum glucose levels reported with statins; optimize lifestyle measures, including regular exercise, maintaining healthy body weight, and making healthy food choices

Hepatic dysfunction

• Increased serum transaminases reported; typically, elevations are transient and either resolved or improved on continued therapy or after briefly interrupting therapy
• There have been rare postmarketing reports of fatal and nonfatal hepatic failure in patients taking statins
• Consuming substantial quantities of alcohol and/or a history of liver disease may increase risk
• Assess liver transaminases before initiating and thereafter, when clinically indicated
• Contraindicated with active liver disease including unexplained persistent elevations in hepatic transaminase levels
• Promptly discontinue if serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs

Myopathy

• Myopathy (muscle pain, tenderness, or weakness with creatine kinase [CK] >10 x ULN) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria) reported with statins; rare fatalities have occurred as a result of rhabdomyolysis
• Myopathy risk factors include: age ≥65 yr, uncontrolled hypothyroidism, renal impairment, coadministration of drugs that decrease statin clearance or add to myopathy risk
• Pitavastatin doses >4 mg/day were associated with increased risk for severe myopathy in clinical trials

• Steps to prevent or reduce myopathy/rhabdomyolysis risk

  • See Drug Interaction Overview or Drug Interaction Checker for drugs that are contraindicated (eg, cyclosporine), not recommended (eg, gemfibrozil), require pitavastatin dosage modification (eg, erythromycin, rifampin), and other drugs that may increase myopathy or rhabdomyolysis risk
  • Discontinue if markedly elevated CK levels occur or myopathy is diagnosed or suspected; muscle symptoms and CK increases may resolve following discontinuation
  • Temporarily discontinue in patients experiencing an 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; uncontrolled epilepsy)
  • Inform patients of risk when starting or increasing dose
  • Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever

• 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

Drug interaction overview

• Contraindicated: Coadministration with cyclosporine
• Not recommended: Coadministration with gemfibrozil
• Dosage modifications for pitavastatin: Coadministration with erythromycin or rifampin
• The following drugs may also increase myopathy and/or rhabdomyolysis risk if coadministered: Lipid-modifying dosages of niacin (>1 g/day), fibrates, and colchicine

Pregnancy

Contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy during pregnancy; therapy should be discontinued as soon as pregnancy is recognized

May cause fetal harm when administered to a pregnant woman; advise females of reproductive potential to use effective contraception during therapy

Lactation

Contraindicated during breastfeeding; there is no available information on effects of drug on breastfed infant or effects of drug on milk production; however, another drug in this class passes into human milk; because of potential for serious adverse reactions in a breastfed infant, advise patients 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: 51%

Peak plasma time: 1 hr

Onset: 2-4 weeks

Distribution

Protein binding: >99%

Metabolism

Metabolism: Hepatic via UGT1A3 and UGT2B7; minimally through CYP2C9 and OATP1B1

Elimination

Half-life: 12 hr

Excretion: 79% feces; 15% 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 more 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 16.9-fold higher in CC homozygotes compared with TT homozygotes

Genetic testing laboratories

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