atorvastatin/ezetimibe (Discontinued)

Brand and Other Names:Liptruzet
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

Product discontinued

atorvastatin/ezetimibe

tablet

  • 10mg/10mg
  • 20mg/10mg
  • 40mg/10mg
  • 80mg/10mg
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Primary Hyperlipidemia

June 4, 2015: Product discontinued

Indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia

Typical starting dose: 10 mg/10 mg PO qDay

Starting dose in patients requiring larger LDL-C reduction (ie, >55%): 40 mg/10 mg PO qDay

After initiation and/or upon dose titration, check lipid levels and adjust dose as accordingly

Homozygous Familial Hypercholesterolemia

Indicated for reducing elevated total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable

40 mg/10 mg or 80 mg/10 mg PO qDay

Dosage Modifications

Coadministration with other drugs

  • Bile acid sequestrant: Administer atorvastatin/ezetimibe >2 hr before or >4 hr after administering bile acid sequestrant
  • Cyclosporine, tipranavir plus ritonavir, telaprevir, gemfibrozil: Avoid coadministration with atorvastatin (increased risk of rhabdomyolysis, see Cautions)
  • Lopinavir plus ritonavir: Use lowest dose of atorvastatin necessary
  • Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir: Do not exceed atorvastatin dose of 20 mg/day
  • Nelfinavir, boceprevir: Do not exceed atorvastatin dose of 40 mg/day

Dosing Considerations

No incremental benefit of atorvastatin/ezetimibe on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin alone has been established

Has not been studied in Fredrickson type I, III, IV, and V dyslipidemias

Administration

May take with or without food at any time of the day

Swallow tablet whole, do not chew, crush, dissolve, or split

Safety and efficacy not established

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Interactions

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            Adverse Effects

            1-10%

            Increased ALT (5%)

            Increased AST (4%)

            Musculoskeletal pain (4%)

            Abdominal pain (3%)

            Nausea (3%)

            Arthralgias (3%)

            Muscle weakness (2%)

            Dizziness (2%)

            Hyperkalemia (2%)

            Hot flushes (2%)

            Coughing (2%)

            Bronchitis (2%)

            Sinusitis (2%)

            Postmarketing Reports

            Blood and lymphatic system disorders: Thrombocytopenia

            Nervous system disorders: Headache; paresthesia; peripheral neuropathy, cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion)

            Gastrointestinal disorders: Pancreatitis

            Skin and subcutaneous tissue disorders: Angioedema; bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis); rash; urticaria

            Musculoskeletal and connective tissue disorders: Myopathy/rhabdomyolysis, immune-mediated necrotizing myopathy

            Injury, poisoning and procedural complications: Tendon rupture

            Immune system disorders: Anaphylaxis; hypersensitivity reactions

            Hepatobiliary disorders: Hepatitis; cholelithiasis; cholecystitis; fatal and nonfatal hepatic failure

            Psychiatric disorders: Depression

            Laboratory abnormalities: Elevated CPK

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            Warnings

            Contraindications

            Hypersensitivity

            Active liver disease or unexplained elevated transaminases

            Women who are pregnant or may become pregnant

            Breast feeding women

            Cautions

            Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria reported; coadministration with cyclosporine and strong CYP3A4 inhibitors increases this risk

            Myopathies, including rare reports of immune-mediated necrotizing myopathy have occurred; temporarily withhold or discontinue if acute, serious symptoms suggestive of myopathy occur

            May increase liver enzymes levels; measure levels before initiating and repeat as clinically indicated; if serious liver injury, hyperbilirubinemia, or jaundice occurs, interrupt therapy and permanently discontinue if alternate etiology is not found

            Increased HbA1c and fasting serum glucose levels reported

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            Pregnancy & Lactation

            Pregnancy Category: X

            Lactation: Because of the potential for adverse reactions in nursing infants, women taking this drug should not breast feed. Contraindicated in breastfeeding women.

            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.

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            Pharmacology

            Mechanism of Action

            Atorvastatin: HMG-CoA reductase inhibitor, inhibits rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase

            Ezetimibe: Inhibits intestinal absorption of cholesterol at brush border

            Absorption

            Atorvastatin

            • Bioavailability: rapidly absorbed
            • Onset: 24-72 hr
            • Duration: 48-72 hr
            • Maximum effect: 2 wk
            • Peak plasma time: 1-2 hr

            Ezetimibe

            • Bioavailability: 35-60%
            • Peak plasma time: 4-12 hr (parent drug); 1-2 hr (metabolite)
            • Peak plasma concentration: 3.4-5.5 ng/mL (parent drug); 45-71 ng/mL (metabolite)

            Distribution

            Protein bound: >98% (atorvastatin); >90% (ezetimibe)

            Vd: 381 L (atorvastatin)

            Metabolism

            Atorvastatin

            • Metabolism: via hepatic P450 enzyme CYP3A4
            • Metabolite: ortho- & parahydroxylated derivatives & beta-oxidation product (inactive)

            Ezetimibe

            • Metabolized in small intestine and liver by glucuronide conjugation
            • Metabolites: ezetimibe-glucuronide (80-90%)

            Elimination

            Atorvastatin

            • Half-Life: 14 hr
            • Excretion: mainly via bile; urine: 2%
            • Dialyzable: HD: no

            Ezetimibe

            • Half-Life: 22 hr
            • Excretion: 78% feces; 11% urine

            Pharmacogenomics

            SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of atorvastatin 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

            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, 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)
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