Michael R. Page, PharmD, RPh
Liptruzet (ezetimibe/atorvastatin) is FDA approved for improving levels of several markers of dyslipidemia.
On May 5, 2013, the FDA approved Liptruzet, a combination tablet of ezetimibe/atorvastatin at 4 different doses of atorvastatin (10, 20, 40, or 80 mg) combined with a 10-mg dose of ezetimibe.1
The combination of these 2 medications is indicated for improvement of levels of several markers of dyslipidemia, including total cholesterol, low-density lipoprotein (LDL-C), apolipoprotein B, and triglycerides, for patients with genetically and nongenetically determined types of dyslipidemia. However, ezetimibe/atorvastatin has not been evaluated in Fredrickson types I, III, IV, and V dyslipidemias.2
Pharmacology and Pharmacokinetics
Atorvastatin inhibits an enzyme called HMG-CoA reductase
that mediates an important step in the synthesis of cholesterol. Working through a different mechanism, ezetimibe reduces cholesterol absorption in the intestinal brush border by inhibiting a cholesterol and phytosterol transporter.2
Atorvastatin reaches peak plasma levels within 1 to 2 hours, and the half-life of atorvastatin and its active metabolites in the body ranges from 20 to 30 hours. Due to the long half-life of atorvastatin and its active metabolites, steady-state levels occur after about a week of treatment. The blood plasma half-life of ezetimibe and its active metabolite is about 22 hours.2
Dosage and Administration
Patients taking ezetimibe and atorvastatin may take a single, intact tablet of the medication at a regular time each day, either with or without food. Total exposure to atorvastatin may increase in patients older than 65 years and in patients with impaired liver function. Although renal disease does not change the disposition of atorvastatin, patients with severe kidney disease (creatinine clearance [CrCl] of 30 mL/min or lower) have an approximately 50% greater level of total ezetimibe exposure than patients with normal kidney function.2
In a 12-week study, 628 patients received a combination tablet of ezetimibe and atorvastatin. Investigators adjusted the dose based on each patient’s need for LDL lowering. Pooling all patient data, investigators found that patients experienced an average of a 55% reduction in LDL-C from baseline, significantly greater than the 44% reduction observed with atorvastatin alone. Investigators also found a reduction in triglyceride levels of 33% from baseline with ezetimibe/atorvastatin, significantly greater than the 24% reduction observed with atorvastatin alone. Reductions in LDL-C ranged from 53% with the lowest dose to 61% with the highest dose of ezetimibe/atorvastatin.2
Warnings and Precautions
Taking ezetimibe and atorvastatin with grapefruit juice may lead to an increased level of atorvastatin and an increase in the risk of rhabdomyolysis. Drugs that inhibit cytochrome P450 (CYP) 3A4 (eg, protease inhibitors, cyclosporine, clarithromycin, itraconazole) should be avoided, or administered with a reduced dose of ezetimibe/atorvastatin in accordance with the package insert. Use with medications such as fibrates, niacin, and colchicine may increase the risk of rhabdomyolysis. Patients should be aware of muscle pain, especially muscle pain associated with fever, and prescribers should monitor increases in liver enzyme levels and increases in the creatinine phosphokinase level.2
Treatment with ezetimibe/atorvastatin may increase levels of digoxin, norethindrone, and ethinyl estradiol. Conversely, cholestyramine may reduce exposure to ezetimibe/atorvastatin. Drugs that both induce and inhibit CYP 3A4, such as rifampin and efavirenz, should be taken at the same time as atorvastatin/ezetimibe to minimize rifampin- or efavirenz-mediated CYP 3A4 induction, which decreases the atorvastatin level.2
Atorvastatin is a pregnancy category X drug, meaning that the risks of treatment always outweigh the benefits. Women who are breast-feeding should not take atorvastatin/ezetimibe.2
Atorvastatin may increase glycosylated hemoglobin (A1C) and fasting serum glucose levels. Cognitive impairment has been documented as an adverse event of statins, but symptoms may develop with variable onset (days to years) and generally reverse within a median of 3 weeks of discontinuation of therapy.2
Myalgia, abdominal pain, and increased levels of hepatic enzymes were the most common causes of discontinuation of treatment in clinical trials, with discontinuation due to each occurring at a rate of less than 1%. Other adverse events included musculoskeletal pain and arthralgia.2
Michael R. Page earned his PharmD from the Ernest Mario School of Pharmacy at Rutgers University. He has worked as a community pharmacist at CVS Pharmacy and is currently clinical editor in clinical and scientific affairs at
FDA. Liptruzet NDA approval. www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/200153Orig1s000ltr.pdf. Accessed July 2013.
Liptruzet (ezetimibe and atorvastatin) [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2013.