FDA Approves Zanamivir

By William T. Elliott, MD, FACP

The fda has approved glaxo wellcome’s zanamivir (relenza), an inhaled antiviral for the treatment of influenza A and B. Zanamivir is a neuraminidase inhibitor that works to prevent viral dissemination within lung tissue. The drug is delivered via a hand-held, breath-activated device called a Diskhaler. The delivery system was a concern of the FDA because adequate instruction is required for proper use. Relenza needs to be started within two days of symptoms to be effective, and needs to be continued twice a day for five days. The drug should be available by autumn, before the beginning of flu season in this country.

TAP pharmaceuticals has submitted a new drug application to the FDA for apomorphine for the treatment of erectile dysfunction. Originally used as a treatment for Parkinson’s disease, apomorphine was found to cause erections through both CNS and local mechanisms. The drug, which may be used concomittantly with sildenafil, will be tested in 2 mg, 3 mg, and 4 mg sublingual tablet doses. Higher doses have been found to be effective in early clinical trials. The trade name has already been chosen—"Uprima."

Cytokine tumor necrosis factor (TNF) seems to be associated with numerous deleterious actions from joint inflammation in rheumatoid arthritis to organ failure in septic shock. Now it appears that TNF may even play a role in left ventricular dysfunction in congestive heart failure. After a single infusion of etanercept, an anti-TNF drug, TNF levels remained depressed for two weeks, ejection fractions were improved, as was exercise tolerance and quality-of-life measures compared to placebo injections (Circulation 1999;99:3224-3226). Etanercept recieved approval in January for the treatment of rheumatoid arthritis under the name Enbrel (Immunex Corp) (See Feb 1999 PTDA).

Two vaccines are effective when given in more patient-friendly intervals. SmithKline Beecham’s Lyme disease vaccine (LYMErix) was approved at a schedule of 0,1, and 12 months, thus, it was a full year before maximum protection is achieved. A recent study randomized 800 healthy volunteers to the standard regimen or a shorter schedule of 0, 1, and 6 months. No difference in levels of protective antibodies was noted in the two groups suggesting that the shorter regimen is effective (Clin Infect Dis 1999;28:1260-1264). In contradistinction, The hepatitis B vaccine was recently found to be effective in a longer than standard dosing interval. Hepatitis B vaccine is given at 0, 1, and 6 months. This schedule generally requires extra visits, especially to pediatric clinics, where visits are usually yearly. A recent study compared the efficacy of the standard regimen to three annual injections of the vaccine. No difference was found in the efficacy of the two regimens suggesting that children can receive their injections at three yearly physicals (Pediatrics 1999;103:1243-1247).

The FDA has approved the second thiazolidinedione in three months for the treatment of type 2 diabetes. Following on the heels of SmithKline Beecham’s rosiglitazone (Avandia) which was approved in May, Takeda and Lilly are launching pioglitazone (Actos). Both drugs are similar to troglitazone (Rezulin), which has recently been linked to more than 40 cases of liver failure. Pioglitazone is approved for monotherapy, or for use in combination with metformin, sulfonylureas, or insulin. Like rosiglitazone, pioglitazone was not associated with hepatoxicity, but also like rosiglitazone, the FDA is recommending periodic liver function testing while on the drug, at baseline, then every two months for the first year, and periodically thereafter.

The febrile neutropenic patient represents a challenge to all but the most experienced infectious disease or onc- ology specialists. Now a study supports a more conservative approach for treating these patients, including the use of oral antibiotics (N Eng J Med 1999;341:305-311). One hundred and sixteen febrile chemotherapy patients with average neutrophil counts of 81 were randomized to treatment with intravenous ceftazidime or oral therapy with ciprofloxacin plus amoxicillin-clavulanate. All patients were considered "low-risk" in that they had no other underlying conditions and the neutropenia was expected to last no more than 10 days. All patients were hospitalized until fever and neutropenia resolved. Treatment was successful (no need for treatment modification) in 71% of the oral therapy group vs. 67% of the IV treatment group. The authors conclude that empiric oral therapy with ciprofloxacin and amoxicillin-clavulanate is safe in this group of patients. A second study in the same issue looked at the same oral combination vs. intravenous therapy with ceftriaxone plus amikacin in hospitalized patients (N Engl J Med 1999;341:312-318). Again, oral therapy proved as efficacious as intravenous therapy. An accompanying editorial cautions that these findings cannot be extrapolated to treating such patients as outpatients, but many centers are already doing so.

The second "morning after pill" has been approved by the FDA. Women’s Capital Corp.’s levonorgestrel (Plan B) is a progestin-only pill to prevent pregnancy after a contraceptive accident or unprotected sex. The product comes in a kit with two levonorgestrel tablets, the first to be taken within 72 hours of unprotected sex, and the second 12 hours later. Efficacy is increased if it is started as soon as possible. Overall rate of pregnancy is decreased from approximately 8% to 1% when taken as directed. The progestin-only regimen is touted as having less side effects, especially nausea, than other morning after regimens containing an estrogen/progestin combination.

Johnson & Johnson will seek approval for a contraceptive patch for women. The patch, which contains ethinyl estradiol and norgestimate, is worn for one week, obviating the need to remember to take a daily pill.

Merck is attempting to take its popular muscle relaxant cyclobenzaprine (Flexeril) over the counter. Ironically, initial concerns on the FDA’s part were less about the safety of the drug than about its efficacy. They cited a lack of evidence that muscle relaxants work. Ten million prescriptions were written for Flexeril last year.

The FDA website has published a copy of the "Dear Doctor" letter from Abbott regarding pemoline (Cylert), their CNS stimulant used for treating attention deficit hyperactivity disorder (ADHD). Because of the risk of hepatotoxicity, the company is now recommending a signed consent prior to initiating therapy and liver function tests every two weeks throughout the duration of therapy. The drug is no longer recommended as first-line therapy for this indication.

For anyone who has been involved with managed care, pharmacy benefits, or formulary management, the federal government’s first real look at these issues must seem ironic. As budget surpluses swell, President Clinton has made adding a drug benefit to Medicare a high priority. But Congress has had a rude awakening as cost estimates have swelled to upwards of $90 billion per year by 2008. Various proposals and bills have been tempered by the reality of soaring drug costs and difficult treatment choices. Pharmaceutical corporate boardrooms are, no doubt, sweating out the eventual outcome amidst words and phrases such as "price controls," "guaranteed discounts," "PBM based system," and "formulary." Meanwhile congressional aides are studiously listening to the same buzz words that the industry unsuccessfully approached managed care with in the early 1990’s—phrases such as "pharmacoeconomics" and "outcomes-based research."