rosuvastatin (Rx)

>10%

Myalgia (3-13%)

1-10%

Arthralgia (10%)

Pharyngitis (9%)

Headache (3.1-8.5%)

Myalgia (7.6%)

Nausea (2.4-6.3%)

Asthenia (0.9-6.3%)

Constipation (2.1-4.7%)

Dizziness (4%)

Arthralgia (3.8%)

CPK increased (3%)

Diabetes mellitus (2.8%)

Abdominal pain (2%)

ALT increased (2%)

Flulike illness (2%)

UTI (2%)

<1%

Jaundice

Myopathy

Rhabdomyolysis

Postmarketing Reports

Arthralgia

Peripheral neuropathy

Depression and sleep disorders (including insomnia and nightmares)

Fatal and nonfatal hepatic failure, hepatitis, jaundice

Thrombocytopenia

Gynecomastia

Interstitial lung disease

Immune-mediated necrotizing myopathy

Cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion)

Contraindications

Hypersensitivity

Active liver disease (including unexplained persistent elevations of LFTs)

Pregnancy, lactation

Cautions

Nonserious and reversible cognitive adverse effects may occur

Increased blood glucose and glycosylated hemoglobin (HbA1c) levels reported with statin intake; in some instances, these increases may exceed the threshold for the diagnosis of diabetes mellitus

Use caution in patients who consume large amounts of ethanol or have a history of liver disease

Interrupt therapy if serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment

Increases in AST or ALT reported with HMG-CoA reductase inhibitors; monitor liver enzymes before initiating and if signs or symptoms of liver injury occur

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria reported with HMG-CoA reductase inhibitors; may occur at any dose level, but are increased at the highest dose (40 mg); caution in patients with predisposing factors for myopathy (eg, age ≥65 years, inadequately treated hypothyroidism, renal impairment)

Discontinue treatment if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected; temporarily withhold in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (eg, sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures)

Pharmacokinetic studies demonstrated an ~2-fold elevation in median exposure (AUC and peak plasma concentrations) in Asian subjects when compared with a white control group

Hematuria and proteinuria reported without decrease in renal function; consider dosage reduction if unexplained hematuria and proteinuria persists

Rule out secondary causes of hyperlipidemia prior to 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

Drug interactions overview

• Exercise caution when anticoagulants coadministered with rosuvastatin because of its potentiation of effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR; monitor INR at baseline and frequently during concomitant therapy
• Cyclosporine and gemfibrozil increased rosuvastatin exposure and may result in increased risk of myopathy
• Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure and may increase risk of myopathy
• Risk of skeletal muscle effects may be enhanced when used in combination with lipid-modifying doses (≥1 g/day) of niacin; use with caution when administered with rosuvastatin
• Because the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, use with caution
• Cases of myopathy, including rhabdomyolysis, reported with HMG-CoA reductase inhibitors when coadministered with colchicine
• Also see Dosage Modifications

Pregnancy

Contraindicated

Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly synthesis of other biologically active substances derived from cholesterol (eg, cell membranes), rosuvastatin may cause fetal harm when administered to pregnant women

Lactation

Contraindicated

Limited data indicate that rosuvastatin is present in human milk; because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin treatment should not breastfeed their infants

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: 20%

Peak plasma time: 3-5 hr

Distribution

Vd: 134 L

Protein bound: 88%

Metabolism

Metabolism: ~10% by hepatic CYP2C9

Metabolites: N-desmethyl, lactone

Elimination

Half-Life, Elimination: 19 hr

Excretion: Feces (90%)

Pharmacogenomics

Hepatic influx and efflux transporters (single-nucleotide polymorphisms [SNPs] within the solute carrier organic anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion transporter polypeptide 1B1 (OATP1B1) influx transporter)

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%); decrease dose by 50% in people of Asian descent

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)

Oral Administration

Take with or without food

Tablets: Swallow whole

Capsules

• Swallow whole; do not crush or chew

• For patients who have difficulty swallowing capsules

  • May open capsule and carefully empty granules onto 1 tsp of applesauce; swallow immediately, without chewing
  • Do not store mixture for future use
  • If not used in its entirety, discard remaining contents immediately

Nasogastric Tube Administration

Open capsule and empty granules into a 60-mL catheter-tipped syringe and add 40 mL of water

Shake syringe vigorously for 15 seconds; granules may start dissolving which is acceptable

Attach syringe to a nasogastric tube (≥16-French) and deliver contents of syringe through nasogastric tube

After administering granules, flush nasogastric tube with 20 mL of additional water

Use immediately after preparation and do not store for future use

If not used in its entirety, discard remaining contents immediately

Use with any other liquids is not recommended

Storage

Capsules and tablets: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

Protect from moisture