Upon completion of this activity, participants will be able to:
1. Describe the risks associated with long-term use of celecoxib and other nonsteroidal anti-inflammatory drugs.
2. Identify a drug interaction between indinavir sulfate and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins).
3. Explain the appropriate use of isoniazid, pyrazinamide, and rifampin tablets in patients with impaired liver function.
Authors and Disclosures
Yael Waknine
Disclosure: Yael Waknine has disclosed no relevant financial relationships.
Laurie Barclay, MD
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.
This activity is part of an ongoing CME/CE initiative to provide information on labeling changes reported by the FDA. Activities of this nature will be posted on Medscape on a weekly basis.
March 12, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to provide new information regarding the increased risk for cardiovascular events in patients receiving long-term celecoxib therapy, warn of drug interactions between indinavir sulfate and statins, and advise of the need to monitor liver function in certain patients receiving treatment with rifampin as part of a tuberculosis regimen.
Long-Term Celecoxib (Celebrex) Use Linked to Increased Risk for Cardiovascular Events
On December 31, 2008, the FDA approved safety labeling revisions for celecoxib capsules (Celebrex; Pfizer, Inc) to include new study data regarding the risk for cardiovascular (CV) thrombotic adverse events in patients receiving long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDS).
The warning was based on results of the Adenoma Prevention with Celecoxib trial in 2035 patients, showing that use of 400 mg of celecoxib twice daily was linked to a 3.4-fold increase in the composite risk for CV death, myocardial infarction (MI), and stroke, relative to placebo (95% confidence interval [CI], 1.4 - 8.5). In patients receiving 200 mg of celecoxib twice daily, the hazard ratio was 2.8 (95% CI, 1.0 - 6.4).
Cumulative rates for this composite endpoint during 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, vs 0.9% (6/679 subjects) with placebo treatment; dose-related increases in both treatment groups were driven by a substantial increase in the rate of MI.
Clinical trials of up to 3 years' duration have supported these findings, linking several cyclooxgenase 2 (COX-2) selective and nonselective NSAIDs to an increased risk for serious and potentially fatal CV thrombotic events, MI, and stroke. According to the FDA, all NSAIDs may have similar risks that increase with dose, duration of use, and the presence of existing CV disease and/or related risk factors.
Clinicians are advised to remain alert for the development of CV events, even in the absence of previous symptoms. The FDA notes that there is no consistent evidence that concurrent use of low-dose aspirin mitigates the risk for thrombotic events, and concomitant use of both drugs does increase the risk for serious gastrointestinal tract adverse events.
An increased incidence of MI and stroke has also been observed in 2 large, controlled clinical trials of COX-2 selective NSAIDs for pain relief after coronary artery bypass graft surgery; use of NSAIDs is therefore contraindicated in this setting.
As with all NSAIDs, use of celecoxib can lead to the onset of new hypertension or worsening of preexisting disease, of which either may contribute to an increased incidence of CV events. Because patient response to thiazides or loop diuretics may be impaired, close monitoring of blood pressure is recommended.
Fluid retention and edema have also been observed in some patients taking NSAIDs, and they should therefore be prescribed with caution in patients with fluid retention, hypertension, or heart failure.
Celecoxib is a COX-2 inhibitor NSAID indicated for the relief of signs and symptoms associated with osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis; the management of acute pain in adults and the treatment of primary dysmenorrhea; and as adjunct therapy for familial adenomatous polyposis.
Indinavir Sulfate (Crixivan) Increases the Risk for Statin-Related Adverse Events
On December 10, 2008, the FDA approved safety labeling revisions for indinavir sulfate tablets (Crixivan; Merck and Co, Inc) to warn of drug interactions with 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA) inhibitors.
HMG-CoA inhibitors, also known as statins, are linked to an exposure-related risk for myopathy that presents as muscle pain, tenderness, or weakness, 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 statins are substrates for the cytochrome P450 isoenzyme 3A4 (CYP3A4), concomitant use of CYP3A4 inhibitors (eg, indinavir and other protease inhibitors) can increase plasma concentrations and the attendant risk for myopathy. The extent of this effect is dependent on the variability of CYP3A4 inhibition.
Concomitant use of indinavir with lovastatin or simvastatin is not recommended by the FDA, and interactions with pravastatin and fluvastatin have not been studied. Patients taking indinavir should therefore receive the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, and only if no alternatives to statin therapy are available.
Indinavir is a protease inhibitor indicated in combination with antiretroviral agents for the treatment of HIV infection.
Atorvastatin, rosuvastatin, and other statin drugs are indicated for the treatment of dyslipidemia to reduce the risk for coronary and cardiovascular events.
Rifampin Component of Rifater Linked to Risk for Liver Dysfunction
On December 18, 2008, the FDA approved safety labeling revisions for isoniazid, pyrazinamide, and rifampin tablets (Rifater; sanofi-aventis US, LLC) to provide updated information regarding the rifampin-related risk for liver dysfunction.
Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Caution and strict monitoring are therefore advised, with serial evaluation of serum glutamic pyruvic transaminase and serum glutamic oxaloacetic transaminase levels at baseline and at 2- to 4-week intervals during treatment. Discontinuation of therapy is indicated for patients in whom signs of hepatocellular damage develop.
The FDA notes that although metabolic competition between rifampin and bilirubin levels can cause hyperbilirubinemia during the initial course of therapy, an isolated report showing a moderate increase in bilirubin and/or transaminase levels is not, in itself, an indication for interrupting treatment. This decision should be reserved until tests have been repeated and results are considered in conjunction with the patient's clinical condition.
Isoniazid, pyrazinamide, and rifampin tablets are indicated in the initial 2-month phase of the short-course treatment of pulmonary tuberculosis.
Topic: [INFO] FDA Safety Changes: Celebrex, Crixivan, Rifater (Read 1133 times)