Zucapsaicin Cream 0.075% (Civamide) has had its NDA filed with the FDA for treatment of the signs and symptoms of knee osteoarthritis.19 The PDUFA date is anticipated to be in the second half of 2011; the drug will likely get a standard FDA review. Zucapsaicin is a synthetically synthesized transient receptor potential vanilloid-1 receptor modulator that selectively reduces the action of the type-C pain fibers. Zucapsaicin initiates the release of neuropeptides, substance P, and calcitonin-gene related peptide, leading to reduced pain transmission and inflammation. The most common reactions in clinical trials were burning and stinging at the site of application. Zucapsaicin has also been submitted for approval in the European Union and Canada.
Safety
The FDA has updated labelling information for colchicine (Colcrys) related to combined use with protease inhibitors to treat HIV.20 The label change was prompted by results of clinical trials noting serious drug interactions between it and HIV protease inhibitors as well as some antihypertensive agents and antibiotics. The updated label notes a dose adjustment in patients taking protease inhibitors or combinations of HIV medications such as fosamprenavir calcium (Lexiva) and ritonavir. Patients who use these agents together need to follow new dosing guidelines. In addition, colchicine is now contraindicated in patients with hepatic or renal failure that also receive protease inhibitors.
Danish registry data noted that diclofenac had the highest relative risk of heart attack or stroke among nonsteroidal antiinflammatory drugs (NSAIDs) in healthy adults.21,22 Data from more than 1 million users of NSAIDs from 1997 through 2005 were analyzed. The two NSAIDs with the greatest increased risk of cardiovascular events were diclofenac and rofecoxib. Lead investigator Emil Fosbøl, MB, noted that diclofenac has a “high COX-2 inhibiting selectivity” making it similar to rofecoxib, a COX-2 inhibitor no longer on the market. Cardiovascular events were evaluated for celecoxib, diclofenac, ibuprofen, naproxen, and rofecoxib. Results were inconclusive for celecoxib. Naproxen had the least cardiovascular risk. Other findings included a 29% increase in relative risk of fatal or nonfatal stroke with ibuprofen and a 66% increase in the risk of cardiovascular death with rofecoxib. The main limitation of the study was that it was observational.
The FDA has updated the boxed warning for leflunomide (Arava) related to the risk of severe liver injury and how to avoid it in RA patients receiving the agent.23 This decision was based on the FDA’s review of adverse event reports between August 2002 and May 2009 that identified 49 cases of severe liver injury, including 14 cases of fatal liver failure. During this review, the greatest risk for liver injury was seen in patients receiving other potential hepatotoxins and in patients with preexisting liver disease. Information added to the boxed warning also states that leflunomide should not be used in patients with preexisting liver disease or those with elevated liver enzymes (alanine aminotransferase [ALT] levels greater than two times the upper limit of normal). Additional recommendations include monitoring liver enzymes at least monthly for three months after starting treatment and at least quarterly thereafter, and stopping leflunomide treatment if the ALT rises to greater than two times the upper limit of normal and beginning cholestyramine to expedite removal of leflunomide from the body. Another recommendation is performing weekly ALT measurements until the level is within the normal range.