You should be seeing a good deal of demand for two new antiviral treatments for influenza; GlaxoWellcome’s Relenza and Roche’s Tamiflu recently were approved by the FDA. Unfortunately, the demand may not reflect the value of either of these new antivirals. At best, both drugs provide about a 1-day reduction in influenza symptom duration.

Relenza (zanamivir for inhalation)

Despite a 14-3 vote against approval by its Antiviral Drug Products Advisory Committee, (http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3496t1.rtf ) the FDA recently approved the New Drug Application by GlaxoWellcome for Relenza (zanamivir for inhalation) for influenza treatment. Relenza is a selective inhibitor of neuraminidase in vitro. Neuraminidase inhibition theoretically interrupts the spread of the influenza virus in the respiratory tract. Relenza is indicated in the management of uncomplicated influenza in adults and adolescents 12 years and older who have been symptomatic no more than 2 days.

The differences of opinion between the members of the Advisory Committee and the FDA stem from data presented by GlaxoWellcome for three clinical trials: one conducted in the United States and Canada, one in Europe and one in the Southern Hemisphere. The primary endpoint for all three trials was the time to alleviation of flu-like symptoms. The three trials enrolled 1588 subjects, with 1164 having culture confirmed influenza (89% influenza A, 11% influenza B). The effectiveness of Relenza was inconsistent across the three trials, with the largest of the three, the North American trial, demonstrating no treatment effect. Both of the foreign trials demonstrated a modest treatment effect (2.5 days in the European trial and 1.5 days in the Southern Hemisphere trial according to GlaxoWellcome; 1.8 days and 1.1 days, respectively, according to the FDA statistician). The Advisory Committee was concerned with the lack of demonstrated efficacy in the North American trial, the need for additional information concerning high-risk patients with preexisting pulmonary disease and the recurrence of symptoms following treatment. The Committee raised concerns about the safety of Relenza in patients with asthma and chronic obstructive pulmonary disease. Preliminary data suggest that patients with pre-existing airway disease may experience decreases in FEV₁ coincident with inhalation of the powder. The FDA approval of Relenza came at some cost. GlaxoWellcome has agreed to a fairly extensive commitment to Phase IV data collection. We will likely know more about the effectiveness of Relenza by this time next year.

With the influenza season about to descend upon us, GlaxoWellcome has embarked on a major direct-to-consumer advertising barrage. Remember, Relenza was no better than placebo in the North American clinical trial. The Average Wholesale Price (AWP) for a five-day supply of Relenza is $44.40. The cost of the influenza vaccine is about $3.00.

Tamiflu (oseltamivir)

The FDA approval of Tamiflu was based on the results of two double-blind trials conducted in 1997-8 in the United States and internationally. The transcript of the advisory committee meeting is not yet available. However, the Division Director’s Memorandum on the New Drug Application is (FDA Link) Unless otherwise specified, the following comments are based on the Division Director’s Memorandum.

Clinical trials for Tamiflu (oseltamivir) enrolled 1358 patients with suspected influenza, with 849 having a virally confirmed diagnosis. The two trials (WV15671 and WV15670) each demonstrated a 1.3 day reduction in median time until improvement in symptoms. Symptom improvement was defined as the time when 7 major symptoms were either absent or mild. Unlike Relenza, Tamiflu appears have a consistent demonstration of effect in reducing duration of symptoms. Like Relenza, however, the effect is modest at best. A five-day regimen of Tamiflu costs $53.00 at Average Wholesale Price (AWP). There are a couple of important provisos, however. Tamiflu demonstrated a reduction in duration of symptoms in otherwise healthy adults. There are insufficient data at present concerning the efficacy of Tamiflu in high-risk patient populations. It should also be noted that experience with Tamiflu in influenza B is limited, with only 3% of the patients enrolled in the clinical trials having documented influenza B infection. According to the CDC, the majority of isolates in this year’s influenza season to date are influenza A. (http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/mm4845a3.htm)

The results of two randomized studies to test the effectiveness of Tamiflu in the prevention of influenza have recently been published (http://www.nejm.org/content/1999/0341/0018/1336.asp). The studies demonstrated a 72-74% effectiveness rate in prevention in a routine risk population when administered either once or twice daily for 6 weeks. The cost at AWP for these regimens is $222.60-$445.20 when given once or twice daily, respectively. As mentioned earlier, the cost of a "flu shot" is about $3.00.

Based on a review of the available literature, the Drug Therapy Committee has recommended that neither Relenza nor Tamiflu be available at the MGH. Neither will be available from the inpatient and outpatient pharmacies of the MGH. Clinicians are reminded of the efficacy of both rimantadine and amantadine in reducing symptom duration and in prophylaxis (http://aepo-xdv-www.epo.cdc.gov/wonder/prevguid/m0052500/m0052500.htm). Until such time as additional comparative data are made available, Relenza and Tamiflu should not be considered in high-risk patients.