COLLEGE PARK, MD. — Clinical trial data indicate that the antibiotic telavancin is safe and effective for treating complicated skin and skin structure infections, including those caused by methicillin-resistant Staphylococcus aureus, the majority of a federal advisory panel agreed.
The Food and Drug Administration's anti-infective drugs advisory committee voted 21–5 regarding the safety and efficacy of telavancin. Those voting in favor said that while they were concerned about nephrotoxicity, QT prolongation, and possible teratogenic effects associated with the drug, they believed these risks were manageable.
The panel voted 18–5, with 3 abstentions, that there could be clinical situations in which the benefits of telavancin in pregnant women would outweigh its risks. All but one panelist agreed that a risk management strategy was needed to prevent unintended use in pregnant women or in women of childbearing potential.
Telavancin was teratogenic in animal studies, which found it was associated with limb malformations in three animal species, but there are no human data available. The FDA's analysis concluded that these findings “strongly” support that these effects are drug-related.
Theravance Inc., the drug's manufacturer, has developed a risk management plan designed to minimize pregnancy exposures, the risk of nephrotoxicity, and the risk related to QT prolongation, and has proposed that the drug not be used during pregnancy unless the benefit to the patient outweighs the potential risks to the fetus.
The plan also includes recommendations to adjust the dose based on creatinine clearance and avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.
Those voting no on the safety and efficacy question cited concerns about the association of the drug with more than one toxicity, “Safety concerns in multiple systems, not just one, complicate risk management,” said the acting panel chair, Dr. L. Barth Reller, professor of medicine and pathology at Duke University, Durham, N.C.
The proposed indication for is for the treatment of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, the Streptococcus anginosus group, and Enterococcus faecalis.
For approval, the company submitted the results of two double-blind, randomized phase III noninferiority studies of almost 1,800 adults with cSSSI caused by gram-positive bacteria, enrolled from 2005 to 2006. (Half of the 1,320 patients with microbiologic confirmation of pathogens at baseline had MRSA.) Patients were treated with telavancin (10 mg/kg IV once daily) or vancomycin (1 g IV every 12 hours).
FDA and company analyses of different outcome measures indicated that in both studies treatment with telavancin for 7–14 days was as effective as treatment with vancomycin. Efficacy against MRSA infections was slightly better among those treated with telavancin, but the difference was not significant.
Telavancin was associated with common adverse events that were mostly mild or moderate. The rate of renal adverse events among those on telavancin was 3.4%, compared with 1.2% among those on vancomycin; the rate of severe renal adverse events also was higher among those on telavancin (1.2% vs. 0.4%, respectively). Renal events were associated with comorbidities such as heart failure or kidney disease at baseline, according to Theravance.
The company is recommending that serum creatinine be monitored during treatment and that the potential risks of the drug be weighed against the benefits in patients with moderate or severe renal impairment or conditions that predispose them to kidney dysfunction.
Cardiac-related severe adverse events were similar among those on telavancin and vancomycin (11% in both groups). There were four patients on telavancin and six on vancomycin who had a fatal cardiac event; in two cases in the telavancin group, the investigator considered that the deaths were possibly related to the drug, according to the FDA.
In October 2007, the FDA issued an approvable letter for telavancin, which indicated the agency's preparedness to approve the product after the outstanding questions specified in the letter are resolved.