The FDA has required the manufacturer of Plavix, an antiplatelet drug used in addition to aspirin to prevent cardiovascular events in high-risk patients,1 to add a boxed warning to the package insert about the risk of a poor response to the drug in patients with genetic polymorphisms of the cytochrome P450 enzyme CYP2C19. Clopidogrel is a prodrug and CYP2C19 is mainly responsible for its bioactivation. The Medical Letter reported last year that several studies have found higher rates of cardiovascular events, including stent thrombosis, in patients with these polymorphisms taking clopidogrel.2

At least one genetic polymorphism leading to poor metabolism of clopidogrel has been reported to occur in 15% of Caucasians, 17% of African Americans and 30% of Asians.3 Since many patients take clopidogrel to protect against life-threatening events, and some continue to do so for extended periods of time, it might be worthwhile to test for these polymorphisms. Such tests, requiring small amounts of blood or saliva, are commercially available from clinical laboratories. More directly, patients who are taking clopidogrel could have platelet aggregation assays to determine whether the drug is being activated.

However, the best course of action for patients who prove to be poor metabolizers of clopidogrel is not clear. They could be treated with higher doses of clopidogrel, but the doses that would be safe and effective in such patients have not been established. Alternatively, they could be treated with prasugrel (Effient), a similar antiplatelet drug that does not require CYP2C19 for activation, instead of clopidogrel, but prasugrel has a greater effect on platelets and may cause more bleeding.4

1. Antiplatelet and anticoagulant drugs. Treat Guidel Med Lett 2008; 6:29.
2. PPI interactions with clopidogrel revisited. Med Lett Drugs Ther 2009; 51:13.
3. Z Desta et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41:913.
4. Prasugrel (Effient) vs. clopidogrel (Plavix). Med Lett Drugs Ther 2009; 51:69.

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Everolimus (Afinitor – Novartis) and pazopanib (Votrient – GlaxoSmithKline), two oral multikinase inhibitors, have been approved by the FDA for treatment of advanced renal cell carcinoma. Sunitinib (Sutent) and sorafenib (Nexavar), two other oral multikinase inhibitors, and temsirolimus (Torisel), an IV multikinase inhibitor, were approved earlier for the same indication.

The FDA has approved the marketing of fenofibric acid (Trilipix - Abbott) to reduce triglycerides and increase HDL-C in patients with mixed dyslipidemia on optimal doses of a HMG-CoA reductase inhibitor (statin) who have, or have risk factors for, coronary heart disease. It is the first fibrate approved by the FDA specifically for combined use with a statin. Trilipix is also approved as monotherapy for hypertriglyceridemia, hypercholesterolemia and low HDL-C. The patent for Tricor, Abbott's older formulation of fenofibrate, will expire in 2011.

Ciclesonide (Omnaris - Sepracor/Nycomed), a once daily corticosteroid nasal spray, is now available for treatment of seasonal allergic rhinitis (SAR) in adults and children ≥6 years old and for perennial allergic rhinitis (PAR) in those ≥12 years old. An orally inhaled formulation of ciclesonide (Alvesco) was recently approved by the FDA for maintenance treatment of asthma, and will be reviewed in a future issue of The Medical Letter

Colesevelam (Welchol - Daiichi Sankyo - Med Lett Drugs Ther 2000; 42:102), a bile-acid sequestrant used to lower LDL cholesterol, has been approved by the FDA as an adjunct to diet and exercise in the treatment of type 2 diabetes. In unpublished studies summarized in the package insert, patients with type 2 diabetes taking metformin (Glucophage, and others), a sulfonylurea or insulin (each as either monotherapy or in combination with other anti-diabetic agents) were given colesevelam 3800 mg per day or placebo; colesevelam significantly reduced glycosylated hemoglobin (A1c) by about 0.5% more than placebo in all three trials. The mechanism is unclear.

Colesevelam can cause constipation, nausea and dyspepsia, increase serum triglyceride concentrations, and interfere with absorption of other oral drugs. One month's treatment with Welchol obtained from drugstore.com would cost about $200. Medical Letter consultants are not enthusiastic about prescribing it for this indication.

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Information about empirical treatment of bacterial infections, emerging trends in antimicrobial resistance, new drugs and new data about older drugs continue to become available. Usual pathogens and empiric treatment for some common types of infections are summarized in the text and a table listing the drugs of choice and alternatives for each pathogen begins on page 40. The recommendations made here are based on the results of susceptibility studies, clinical trials and the opinions of Medical Letter consultants.

Sexual complaints related to desire, arousal, orgasm and pain are common in women. No drugs are approved by the FDA for any of these indications, but many are used off-label.