Yael Waknine

April 26, 2010

April 26, 2010 — The US Food and Drug Administration (FDA) approved in March safety labeling revisions for a fixed-dose combination tablet containing the calcium channel blocker amlodipine and the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor (statin) atorvastatin (Caduet; Pfizer, Inc).

The revisions address atorvastatin drug interactions that increase the risk for myopathy, atorvastatin-related liver dysfunction, nonfatal hemorrhagic stroke after a recent stroke or transient ischemic attack, and atorvastatin-associated pregnancy risks.

Amlodipine is indicated for the treatment of hypertension, chronic stable angina, confirmed or suspected vasospastic angina (Prinzmetal's or variant angina), and reduction in the risk for coronary revascularization procedures in patients with angiographically documented coronary artery disease.

Atorvastatin is indicated as an adjunct to diet and other nonpharmacologic measures as lipid-reduction therapy to prevent cardiovascular disease in patients with or without clinically evident coronary heart disease and in those with type 2 diabetes mellitus, and for the treatment of heterozygous hyperlipidemia, hypertriglyceridemia, primary dysbetalipoproteinemia, and homozygous familial hypercholesterolemia.

The fixed-dose combination of amlodipine/atorvastatin is indicated for patients in whom treatment with both drugs is appropriate.

Atorvastatin Component Drug Interactions Increase the Risk for Myopathy

As with other statin drugs, atorvastatin is linked to an exposure-related risk for myopathy that presents as muscle pain, tenderness, or weakness, and with elevated creatine kinase levels greater than 10 times the upper limit of normal. Myopathy may also take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have been reported.

Because atorvastatin is a substrate for the cytochrome P450 isoenzyme 3A4, concomitant use of cytochrome P450 isoenzyme inhibitors (eg, clarithromycin, itraconazole, and HIV protease inhibitors) can lead to increased plasma concentrations of atorvastatin and the attendant risk for myopathy. The extent of this effect is dependent on the variability of cytochrome P450 isoenzyme 3A4 inhibition.

Healthcare professionals considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, clarithromycin, a combination of ritonavir with saquinavir or lopinavir, immunosuppressive drugs, azole antifungals, or lipid-modifying doses of niacin are advised to carefully weigh the potential benefits and risks of therapy. Lower starting and maintenance doses of atorvastatin may be required.

The dose of atorvastatin should not exceed 10 mg daily when taking cyclosporine, and caution is advised with doses higher than 20 mg daily when receiving treatment with clarithromycin, itraconazole, or HIV protease inhibitors (ritonavir/saquinavir or ritonavir/lopinavir).

Patients should be carefully monitored for signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during upward dosage titration of either drug.

Treatment should be temporarily withheld or discontinued in any patient who presents with an acute, serious condition suggestive of myopathy or having a risk factor for renal failure secondary to rhabdomyolysis, such as severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; and uncontrolled seizures.

Atorvastatin Component Linked to Risk for Liver Dysfunction

Like other statin drugs, atorvastatin has been linked to a risk for biochemical liver function abnormalities. Persistent elevations in serum transaminases (> 3 times the upper limit of normal on ≥ 2 occasions) have occurred with an overall frequency of 0.7% in clinical trials, increasing in a dose-dependent fashion from 0.2% in patients receiving 10 or 20 mg daily, to 0.6% in those receiving 40 mg daily, and 2.3% among those receiving 80 mg daily.

In most cases, these increases were not associated with jaundice or other clinical signs or symptoms of liver dysfunction. Transaminase levels returned to or near pretreatment levels without sequelae on dose reduction, drug interruption, or discontinuation of treatment.

The FDA advises that liver function tests be performed before and 12 weeks after both initiation of therapy and dose increases, and periodically thereafter. Patients in whom increased transaminase levels develop should be monitored until the abnormalities resolve; persistent increases greater than 3 times the upper limit of normal require dose reduction or discontinuation of therapy.

Atorvastatin should not be used in patients with active liver disease or unexplained, persistent elevations in transaminase levels.

Additional Warnings and Precautions

The FDA has added a section to the prescribing information for amlodipine/atorvastatin tablets to advise of the potential increased risk for hemorrhagic stroke in atorvastatin-treated patients with a recent history of stroke or transient ischemic attack.

Data from a post hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study (n = 4731) showed that use of 80-mg atorvastatin daily was linked to an increased incidence of hemorrhagic stroke relative to placebo in patients without coronary heart disease but who had a stroke or transient ischemic attack within the preceding 6 months (2.3% vs 1.4%; hazard ratio, 1.68; 95% confidence interval, 1.09 - 2.59; P = .0168). This increase was driven by a significant increase in nonfatal vs fatal events (1.6% vs 0.7%).

The FDA also warned that atorvastatin is contraindicated in women who are or may become pregnant. It should only be used in women of childbearing age who are highly unlikely to conceive and have been apprised of potential risks to the fetus. Treatment should be immediately discontinued if pregnancy occurs.

The agency notes that serum cholesterol and triglyceride levels normally increase during pregnancy and that cholesterol and its derivatives are essential for fetal development. Because atherosclerosis is a chronic process, discontinuation of lipid-lowering agents during pregnancy should have little impact on the outcome of long-term treatment of primary hypercholesterolemia.

Because of the potential for atorvastatin secretion into breast milk and the attendant risk for serious adverse events in nursing infants, women taking amlodipine/atorvastatin therapy should not breast-feed their infants.