Rifamixin for the Prevention of Traveler’s Diarrhea?
Pharmacology Watch

Rifamixin, a nonabsorbed oral antibiotic, is effective for preventing traveler's diarrhea, according to new research. The study was done in 210 US students traveling to Guadalajara, Mexico. They were randomized to receive rifamixin 200 mg once a day, 200 mg twice daily, 200 mg 3 times a day, or placebo for 2 weeks. Rifamixin effectively prevented traveler’s diarrhea for all doses. Overall, traveler’s diarrhea developed in 14.74% of participants taking rifamixin and 53.70% of those taking placebo (rate ratio 0.27 [95% CI, 0.17 to 0.43]). All doses of rifamixin were superior to placebo in preventing diarrhea. In test subjects who did not report traveler’s diarrhea, rifamixin significantly reduced the occurrence of mild diarrhea (P = .02) and moderate and severe intestinal problems, including pain and cramps (P = .009) and excessive gas (P = .02). Adverse reactions with rifamixin were comparable to placebo, and minimal change in coliform flora was found during rifamixin therapy. The authors conclude that rifamixin effectively prevents traveler’s diarrhea in Mexico, with minimal changes in fecal flora. They also suggest that further studies should be performed to evaluate whether the drug is effective in preventing diarrhea in other areas of the world where E. coli is not the major pathogen, and whether rifamixin is effective in preventing postinfectious irritable bowel syndrome (Ann Int Med. 2005;142:805-812). The accompanying editorial suggests that rifamixin may not be appropriate for prophylaxis of all travelers, but rather selected patients at risk, and that rapid and judicious treatment of diarrhea is best recommended for most travelers (Ann Int Med. 2005;142:861-862). Rifamixin is currently only approved for the treatment of travelers diarrhea caused by E. coli. The drug is manufactured by Salix pharmaceuticals and marketed under the trade name Xifaxan.

Erectile Dysfunction and Visual Disturbance

Sildenafil (Viagra), Pfizer's blockbuster erectile dysfunction drug, has been implicated along with tadalafil (Cialis) and vardenafil (Levitra) in causing a relatively uncommon form of visual disturbance known as nonarteritic anterior ischemic optic neuropathy (NAION). The first reports of the relationship were published in March of this year. An ophthalmologist at the University of Minnesota noticed 7 patients in his practice who developed NAION within 36 hours after taking sildenafil (J Neuroophthalmol. 2005;25:9-13). Since that time, the FDA has received a total of 38 reported cases associated with sildenafil, 4 with tadalafil, and 1 with vardenafil. Pfizer is countering that review of 103 clinical trials involving over 13,000 patients. They say they found no reports of NAION and that there is no evidence that NAION occurs more frequently in men taking sildenafil than in men of similar age and health who did not take the drug. And while it is true that the risk factors for erectile dysfunction and NAION are similar and include hypertension and diabetes, the FDA may still require labeling changes for all 3 drugs, listing NAION as a possible risk. NAION results in loss of vision in parts of the visual field that are usually permanent. The FDA is continuing to evaluate the situation, and notes that there is no direct evidence relating erectile dysfunction drugs to NAION, but warns that patients who notice visual changes after taking one of these medications should report it to their physician immediately.

Mixed News on Statins

Good news and bad news about statins. First the good. It appears that statins are associated with a significant reduction in the risk of colorectal cancer. A population-based, case-control study from northern Israel of 1953 patients with colorectal cancer and 2015 matched controls, reviewed whether use of a statin between 1998 and 2004 reduced the risk of colorectal cancer. In comparison to patients who did not use statins, statin use was associated with a significantly reduced relative risk of colorectal cancer (odds ratio, 0.50; 95% CI, 0.40-0.63). This relationship remained significant after adjustment for aspirin use, NSAID use, physical activity, hypercholesterolemia, family history of colorectal cancer, ethnic group, and diet (odds ratio 0.53; 95% CI, 0.38-0.74) resulted in a 47% relative reduction in the risk of colorectal cancer. The authors admit that the absolute risk reduction is likely to be small, and further studies are needed (N Engl J Med. 2005;352:2184-2192). An accompanying editorial suggests it is too early to recommend statins as chemoprotective agents against cancer, but notes there is biologic plausibility to their use in this role. There is also the suggestion that statins may target many diseases of aging including osteoporosis and dementia, as well as cardiovascular disease by similar mechanisms (N Engl J Med. 2005;352:2238-2239).

Bad news for rosuvastatin (Crestor), AstraZeneca's high-potency statin. The drug has been under scrutiny after related reports of high rates of toxicity in premarketing and some postmarketing studies, compared with other statins. The drug has been a favorite target of the watchdog group Public Citizen, which has petitioned the FDA to withdraw rosuvastatin from the market. Now a report in the May 23rd online version of Circulation confirms a higher level of adverse events associated with the drug. Researchers from Tufts University reviewed all rosuvastatin related adverse events reported to the FDA in the drug's first year of marketing. Higher rates of rhabdomyolysis, proteinuria, nephropathy, and renal failure were seen with rosuvastatin, when compared with atorvastatin (P < 0.001) , simvastatin (P < 0.001), and pravastatin (P < 0.001). Adverse events generally occurred early in the course of treatment and at recommended doses. The authors conclude that there are safety concerns associated with rosuvastain, and that healthcare providers should consider other statins as first-line therapy.

FDA Actions

Pegasys, Roche's pegylated interferon, has been approved for the treatment of chronic hepatitis B infections, including both HBeAg-positive and HBeAg-negative disease. The drug was previously approved for the treatment of chronic hepatitis C.

Infliximab (Remicade) is approved for the treatment of psoriatic arthritis affecting at least 5 joints. The biologic agent is a monoclonal antibody that targets tumor necrosis factor alpha. It is also approved for ankylosing spondylitis, Crohn's disease, and rheumatoid arthritis.

Pfizer has received approval to market sildenafil citrate for the treatment of pulmonary arterial hypertension. Sildenfil, which is the active ingredient in Viagra, will be marketed under the trade name Revatio, in a 20 mg tablet that looks different from Viagra tablets to avoid confusion. Sildenafil as Revatio is dosed 3 times a day.

The FDA has approved an extended-release form of dexmethylphenidate for the treatment of attention deficit, hyperactivity disorder. The once daily formulation is approved for adults, adolescents, and children. It will be marketed as Focalin XR by Novartis Pharmaceuticals.

Canadian drug maker Depomed has received approval to market a once a day form of metformin for the treatment of type 2 diabetes. Glumetza will be marketed in 500 and 1000 mg doses. The formulation employs the company’s Gastric Retention technology that slows transit and controls drug delivery.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: leslie.hamlin@thomson.com.