More Side Effects of Fluoroquinolones Coming to Light
In this issue: New side effects of fluoroquinolones; probiotics and antibiotic-related diarrhea; prostate cancer risk and 5-ARIs; and FDA actions.
New study finds dysglycemia risk
Fluoroquinolones, such as levofloxacin, ciprofloxacin, and moxifloxacin, are useful broad-spectrum antibiotics, but they have been associated with tendinopathy, including tendon rupture and QT interval prolongation. Now, two new potential side effects are coming to light. In a new study from Taiwan, more than 78,000 diabetic patients who received fluoroquinolones were monitored for dysglycemia, including hyperglycemia and hypoglycemia. The study looked at users of levofloxacin, ciprofloxacin and moxifloxacin, cephalosporins, and macrolides. The absolute risk of hyperglycemia was 6.9 per 1000 for moxifloxacin and 1.6 for macrolides. The risk for hypoglycemia was 10.0 for moxifloxacin and 3.7 for macrolides. The adjusted odds ratios for hyperglycemia compared to macrolides were: moxifloxacin 2.48 (95% confidence interval [CI], 1.50-4.12), levofloxacin 1.75 (95% CI, 1.12-2.73), and ciprofloxacin 1.87 (95% CI, 1.20-2.93). For hypoglycemia, the adjusted odds ratios were moxifloxacin 2.13 (95% CI, 1.44-3.14), levofloxacin 1.79 (95% CI, 1.33-2.42), and ciprofloxacin 1.46 (95% CI, 1.07-2.00). The risk of hypoglycemia associated with moxifloxacin was even higher if patients were taking insulin. The authors suggest that fluoroquinolones, especially moxifloxacin, are associated with severe dysglycemia in diabetic patients and that clinicians should "prescribe quinolones cautiously" in diabetic patients (Clin Infect Dis published online August 14, 2013. DOI: 10.1093cid/cit439). In related news, the FDA is requiring labeling changes for fluoroquinolones regarding the risk of neuropathy. The FDA Drug Safety Communication states that "serious nerve damage potentially caused by fluoroquinolones may occur soon after these drugs are taken and may be permanent." The warning is for both oral and parenteral forms of the drugs, but not topicals. The FDA recommends that if a patient develops symptoms of peripheral neuropathy associated with a fluoroquinolone, the drug should be stopped immediately and the patient should be switched to a non-fluoroquinolone antibiotic. Further information can be found at the FDA’s website at www.fda.gov/Safety/MedWatch. n
Probiotics and antibiotic-related diarrhea
Probiotics may not prevent antibiotic-associated diarrhea (AAD), including Clostridium difficile infections. That was the finding of a randomized, double-blind, placebo-controlled trial in nearly 3000 inpatients aged ≥ 65 years who were exposed to one or more oral or parenteral antibiotics. Patients were randomized to a multistrain preparation of lactobacilli and bifidobacteria or placebo for 21 days. The rate of AAD was 10.8% in the probiotic group and 10.4% in the placebo group (P = 0.71). C. difficile was uncommon and occurred in 0.8% of the probiotic group and 1.2% of the placebo group (P = 0.35). The authors state that "we identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in the prevention of AAD or CDD." (Lancet published online August 8, 2013. doi: 10.1016/S0140-6736(13)61218-0). An accompanying editorial wonders if this study can tip the balance of probiotic evidence, as it was a rigorously performed study vs previous small studies showing a positive effect. But, the current study used only two types of non-pathogenic bacteria (doi: 10.1016/S0140-6736(13)61571-8). Still, the cost effectiveness of routine probiotic use must be questioned based on this study. n
Prostate cancer risk and 5-ARIs
The debate regarding 5-alpha reductase inhibitors (finasteride [Proscar] and dutasteride [Avodart]) and the risk of prostate cancer continues. Despite good evidence that the drugs reduce the overall risk of prostate cancer, there is also evidence that the drugs may increase the risk of high-grade prostate cancers (Gleason score 7-10). This was a finding of the Prostate Cancer Prevention Trial (PCPT) that was published in 2003. That finding was recently questioned in a study published in the British Medical Journal that found no risk of higher-grade prostate cancers (BMJ 2013;346:f3406, reported in the August Pharmacology Watch). Now, 10 years after the PCPT was originally published as an 8-year study, the 18-year follow-up has been published in the New England Journal of Medicine. Of the nearly 19,000 men who underwent randomization in the PCPT, prostate cancer was diagnosed in 10.5% of the finasteride group and 14.9% of the placebo group, a 30% reduction in the rate of prostate cancer (relative risk 0.70; 95% CI, 0.65-0.76; P < 0.001). But all of the reduction was in lower-grade prostate cancers. There was a slightly higher rate of high-grade cancer in the finasteride group (3.5% vs 3.0%, P = 0.05), but there was no difference in overall mortality. There was also no increase in mortality in men diagnosed with high-grade prostate cancer. The authors conclude that finasteride reduced the risk of prostate cancer by about one-third, and although high-grade cancer was more common in the finasteride group, there was no difference in overall mortality or survival after the diagnosis of prostate cancer (N Engl J Med 2013;369:603-610). Dutasteride was also studied in the REDUCE trial and similarly found lower rates of low-grade prostate cancers but increased rates of higher-grade cancers (N Engl J Med 2010;362:1192-1202). Some have argued that the higher rate of high-grade cancers is due to higher surveillance and "detection bias," but regardless of the cause, it is reassuring to know that there is no higher risk of mortality, at least in the PCPT. The FDA changed the labeling to both finasteride and dutasteride in 2011 regarding the increased risk of high-grade prostate cancers. n
FDA actions
The FDA has issued a Drug Safety Communication regarding a case of progressive multifocal leukoencephalopathy (PML) in a patient who was taking fingolimod (Gilenya) for the treatment of multiple sclerosis. This is the first reported case of PML associated with fingolimod in patients who had not previously taken natalizumab (Tysabri). The patient, who lives in Europe, had been on the drug for about 8 months and had previously taken interferon beta-1a, azathioprine, and steroids. Novartis, the manufacturer of fingolimod, indicated it is possible that the patient had PML prior to starting the drug. PML is a rare neurologic disease caused by latent infection with the JC virus. It has been associated with immunosuppressive drugs, including natalizumab.
The FDA has approved a new topical agent to treat facial redness in adults with rosacea. Brimonidine, an alpha-2 agonist, is currently used as an ophthalmic preparation for treating glaucoma. The drug constricts dilated facial blood vessels for up to 12 hours. It is approved in a 0.33% topical gel that is applied once daily. Patients with depression, coronary artery disease, Raynaud’s, or other conditions that may be exacerbated by an alpha agonist should use the drug with caution. Brimonidine gel is marketed by Galderma as Mirvaso.
The FDA has approved dolutegravir, a new once-daily HIV integrase inhibitor. It is the third integrase inhibitor on the market after raltegravir and elvitegravir. The drug is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infections in adults and children ≥ 12 years of age weighing at least 40 kg. It may be used in treatment-naïve patients or treatment-experienced patients, including those who have previously taken an integrase inhibitor. Approval was based on four trials in more than 2500 patients that showed efficacy in combination with other antiretrovirals. A fifth trial showed efficacy in HIV-infected children as young as 12 who had not taken an integrase inhibitor. Dolutegravir is marketed by ViiV Healthcare as Tivicay. n
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