WHO Issues Global Alert on Antiviral Use

Pharmacology Watch

In this issue: WHO recommendations for antiviral use for H1N1 flu; antibiotic use trends for acute respiratory tract infection; denosumab clears FDA Expert Panel; FDA Actions.

Antiviral Recommendations for H1N1

The World Health Organization (WHO) has issued a global alert and response regarding the use of antivirals for pandemic H1N1 flu, reiterating that antivirals should be used to prevent severe illness and death in children and adults. The neuraminidase inhibitor oseltamivir (Tamiflu®) is recommended for patients who initially present with severe illness or whose condition begins to deteriorate. H1N1 remains sensitive to the neuraminidase inhibitors such as oseltamivir despite isolated reports of resistance earlier this year. The WHO recommends that clinicians in communities where the virus is circulating widely assume that patients with flu-like symptoms have H1N1 and not wait for laboratory confirmation. Most patients with pandemic flu experience typical flu symptoms and recover within a week. These patients do not need antivirals. But in patients with severe illness, studies have shown that early treatment, within the first 48 hours, is associated with better clinical outcomes. WHO also states that if oseltamivir is unavailable zanamivir (Relenza®) may be used in its place. This recommendation applies to all patient groups including children and pregnant women. The WHO statement comes in response to an article in the British Medical Journal suggesting neuraminidase inhibitors provide minimal benefit for children with seasonal influenza and have little effect on asthmatic exacerbations or use of antibiotics (Shun-Shin M, et al. BMJ 2009;339:b3172).

Antibiotic Use Declines Overall, While Use of Broad-Spectrum Increases

Physicians are prescribing fewer antibiotics for acute respiratory tract infections (ARTIs), but if an antibiotic is used, it is more likely to be a broad-spectrum drug. Using data from 1995 to 2006, antibiotic trends were reviewed from a national database for ARTIs, which included otitis media (OM). Children younger than age 5 were seen less frequently for ARTI than in the past, and they were less likely to be prescribed an antibiotic (36% reduction; 95% confidence interval [CI], 26%-45%). Among children age 5 or older, ARTI visit rates remained stable but antibiotic prescription rates decreased by 18% (95% CI, 6%-29%). Excluding otitis media, antibiotic prescription rates decreased by 41% among all age groups. Prescription rates for a penicillin, cephalosporins, and sulfonamide/tetracycline decreased while the rate of prescriptions for azithromycin increased, making it the most commonly prescribed macrolide for ARTI and OM. Among adults, quinolone prescriptions also increased. The authors conclude that overall antibiotic prescription rates for ARTI decreased in the last 10 years; however, prescription rates for broad-spectrum antibiotics increased significantly (Grijalva CG, et al. JAMA 2009;302:758-766). This study points out the success of multiple campaigns to decrease antibiotic use for ARTIs, which are primarily caused by viruses. However the increasing use of broad-spectrum antibiotics is concerning.

Denosumab Receives Conditional Approval from FDA Expert Panel

Denosumab is a new human monoclonal antibody that suppresses osteoclast function and thus inhibits bone resorption. It is being evaluated by the FDA for treatment of osteoporosis in men and women, and although it has not yet been approved, a recent FDA Expert Panel has given conditional approval paving the way for full FDA approval this fall. Two recently published, industry-sponsored studies suggest the drug is effective in 2 different populations. In the first study, more than 1400 men receiving androgen-deprivation therapy for nonmetastatic prostate cancer were randomly assigned to receive denosumab 60 mg SQ every 6 months or placebo for 2 years. The primary endpoint was change in bone mineral density (BMD) at the lumbar spine, with secondary endpoints of change in BMD in the hip as well as fracture incidence. At 24 months, BMD increased in the lumbar spine with denosumab (5.6% increase vs 1% decrease for placebo; P < 0.001). BMD was also increased in the total hip, femoral neck, and distal radius, and the effect was maintained for 36 months. New fracture rate was also decreased with treatment (1.5% vs 3.9% with placebo; P = 0.006). Rates of adverse events were similar in both groups (Smith MR, et al. N Engl J Med 2009;361:745-755).

In the second study, 7868 postmenopausal women with low BMD were randomized to denosumab 60 mg SQ every 6 months or placebo for 36 months. The primary endpoint was new vertebral fractures. Denosumab was associated with a reduction in vertebral fractures (2.3% vs 7.2% placebo; P < 0.001), a reduction in hip fractures (0.7% vs 1.2% placebo; P = 0.04), and a smaller reduction in nonvertebral fractures. There was no increase in risk of cancer, infection, cardiovascular disease, delayed fracture healing, hypocalcemia, or osteonecrosis of the jaw in this study (Cummings SR, et al. N Engl J Med 2009;361:756-765).

These last findings are important because the FDA's Expert Panel expressed concerns about infection and cancer data in giving a recommendation to approve denosumab when the FDA votes on the drug in October. If approved, which seem likely, denosumab will be marketed by Amgen under the trade name Prolia™.

FDA Actions

The FDA is requiring new boxed warnings on TNF-blockers regarding the risk of lymphoma and other malignancies in children and adolescents who have received the drugs. The new labeling will include warnings regarding cases of leukemia in adults, adolescents, and children, as well as new onset psoriasis. The labeling will also include a revised Medication Guide to reflect the safety information. Products subject to the new boxed warning are infliximab (Remicade®), etanercept (Enbrel®), adalimumab (Humira®), and the recently approved agents certolizumab pegol (Cimzia®) and golimumab (Simponi™). These TNF-blockers are used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, Crohn's disease, and ankylosing spondylitis. The warning is based on reports of nearly 50 cases of various cancers associated with the drugs, of which half were lymphomas.

The FDA has approved a new dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes. Bristol-Myers Squibb and AstraZeneca's saxagliptin (Onglyza™) is the second DPP inhibitor approved after sitagliptin (Januvia®). It is the first drug approved since the FDA changed its standards for diabetes drug approvals, requiring evidence of cardiovascular safety. While saxigliptin has not shown evidence of higher rates of cardiovascular disease, the FDA is requiring post-marketing studies to specifically look at cardiovascular safety in high-risk populations. Saxigliptin is dosed once daily and is approved as monotherapy or in combination with metformin, sulfonylureas, or thiazolidinediones.

The FDA has announced that it is reviewing adverse event reports of liver injury in patients taking the weight-loss drug orlistat, marketed as the prescription drug Xenical® and over the counter as Alli®. The agency has received 32 reports of serious liver injury in patients taking the drug in the last 10 years. Of these, 6 resulted in liver failure. Almost all of the reports are from outside the United States. The FDA is not recommending patients discontinue the drug, but is suggesting that those who have used orlistat should consult a health care professional if they develop jaundice, fever, fatigue, brown urine, or other symptoms of liver injury.

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) 262-5468. E-mail: paula.cousins@ahcmedia.com.