Do Not Use! The Flu Drug Zanamivir (RELENZA) Revisited

Editor’s Note: We are reprinting our first review of zanamivir (RELENZA) that appeared in the November 1999 issue of Worst Pills, Best Pills News. Over the past two years no credible evidence has been published that would alter our view that this drug lacks meaningful therapeutic value in the treatment of influenza. In fact, as additional information became available about the questionable effectiveness of this drug (see the February 2000 issue of Worst Pills, Best Pills News) and it was required to have stronger warnings about serious respiratory adverse effects (see the September 2000 issue of Worst Pills, Best Pills News) our negative opinion of zanamivir was strengthened.

The Food and Drug Administration (FDA) approved Glaxo Wellcome’s zanamivir (RELENZA) for the treatment of type A and type B influenza in late July 1999. Earlier in the year the FDA’s Antiviral Drug Advisory Committee of 17 outside experts reviewed zanamivir and voted 13 to 4 not to recommend it for approval because of insufficient evidence that it is, in fact, effective for treating flu. One committee member remarked during the meeting ”... there isn’t sufficient efficacy to warrant [my] recommending this drug for my family or myself.”

Zanamivir will be on pharmacy shelves by the time you read this—just in time for the flu season. It must be administered within the first 48 hours after the onset of flu symptoms and is administered as a dry powder through an oral inhalation device. The dose is two inhalations twice daily for five days. The cost for the five-day course of treatment at a Washington DC chain pharmacy is $52.99.

Little information is available about the effectiveness of zanamivir, other than what Glaxo Wellcome has chosen to make available. Of course, this is almost always the good news. Drug companies control nearly all the information about a new drug, from results of the first injection into a laboratory animal to the contacting and promotion to doctors and pharmacists—and now through direct-to-consumer advertising of prescription drugs.

Only one study has been published evaluating zanamivir’s effectiveness against flu compared to an inactive dummy drug or placebo. This study appeared in the December 12, 1998 issue of The Lancet and was funded by Glaxo Wellcome. It involved 455 patients 12 years of age and older with flu-like symptoms of 36 hours duration or less who lived in Australia, New Zealand, or South Africa. The patients either inhaled zanamivir or placebo twice daily for five days and recorded their symptoms on diary cards for nine days after treatment.

This study found that compared to placebo, zanamivir relieved symptoms a median of 1.5 days earlier in patients with confirmed flu and in those with fever at the start of the study. High risk patients receiving zanamivir were reported to have their symptoms alleviated a median of 2.5 days earlier, fewer had complications, and fewer had to take antibiotics compared to the placebo group. The authors of this study concluded, “Our findings need to be confirmed in future studies because of the small number of patients [in the study].”

We obtained the transcript of the February 1999 meeting of the FDA’s Antiviral Drugs Advisory Committee at which zanamivir was reviewed; the minutes of this meeting, and two FDA memos posted on the Agency’s web site at the end of August revealed much more about zanamivir. On examination of these documents a different picture of the drug’s effectiveness—or, more to the point, its lack of effectiveness—emerges. These documents are available on the FDA’s web site at www.fda.gov/ohrms/dockets/ac/cder99t.htm#Antiviral and www.fda.gov/cder/news/relenza/default.htm.

Glaxo Wellcome had submitted three major placebo-controlled clinical trials to the FDA, conducted in North America, Europe and the Southern Hemisphere, in support of zanamivir’s approval. The Southern Hemisphere study was the one published in the 1998 Lancet issue and neither the North American nor the European trial had been published at this time. The North American trial involved 777 patients and was almost as large as the other two studies combined. Zanamivir was tested against placebo in 356 patients in the European study and in 455 patients in the Southern Hemisphere study.

In the North American trial, the difference between the median time to alleviation of major influenza-like symptoms was one day, a difference that is not statistically significant. Similarly, a trial to determine the optimal dose of zanamivir conducted in North America found a small, non-statistically significant, difference of 0.75 day in symptom alleviation between the drug and placebo-treatment groups. The European trial, the smallest of the three submitted to the FDA, found a 2.5 day difference in alleviation of symptoms.

The FDA has been unable to determine the reason for the difference in results between the North American trial and the others.

In all three trials, the time to alleviation of major flu-like symptoms was the primary endpoint used to assess the effectiveness of zanamivir. However, some patients reported influenza-like symptoms after this primary endpoint was reached. The FDA statistical reviewer presented an analysis at the zanamivir Advisory Committee meeting using mean days without alleviation of symptoms as an endpoint. This was done to take into account symptoms experienced after the symptom-improvement endpoint was reached. Under this analysis, the North American trial showed an improvement of 0.3 day (7.5 days for placebo vs. 7.2 days for zanamivir), the Southern Hemisphere trial showed a reduction of 1.1 days and the European trial demonstrated an improvement of 1.8 days (8.7 days vs. 6.9 days).

The director of the Division of Antiviral Drug Products, the FDA division responsible for the review of zanamivir, wrote in a July 26, 1999 memo that “Overall, the totality of the data provides evidence that treatment with zanamivir confers a modest reduction in time to alleviation of influenza symptoms.” She went on to say that the modest treatment benefit was “... approximately one-day on average ....” Her estimate of a one-day difference with zanamivir versus no treatment is the same as the difference found in the North American trial that was not statistically significant. We are at a loss to understand the basis for the approval of zanamivir.

When the value, or the therapeutic role, of a new drug is uncertain there are those who will suggest that it should be reserved for use in high-risk patients. This was done in an editorial published in the September 11, 1999, British Medical Journal, and it is bad advice. The FDA documents we obtained indicated that evidence for zanamivir’s effectiveness in high-risk patients is lacking. A total of 217 patients out of the 1,588 enrolled in the three major trials were defined as high risk. This relatively small group included patients older than 65 or those with a variety of respiratory, cardiovascular and other medical conditions. Non-statistically significant differences in favor of zanamivir treatment were found in the Southern Hemisphere and European studies and a non-statistically significant difference of 0.25 day in favor of placebo was found in the North American study.

Concern about the safety of zanamivir in high-risk patients was also raised during the Advisory Committee meeting. Preliminary safety information from an ongoing study in patients with asthma or chronic obstructive pulmonary disease (COPD) suggest that some patients with these diseases may experience a worsening in lung function when zanamivir is used. Because of possible risks to patients with underlying respiratory disease when zanamivir is used the following warning is given in the drug’s professional product labeling or package insert:

Patients with Underlying Respiratory Disease: Safety and efficacy have not been demonstrated in patients with underlying chronic pulmonary disease. In particular, this product has not been shown to be effective, and may carry risk, in patients with severe or decompensated chronic obstructive pulmonary disease or asthma. Bronchospasm was documented following administration of zanamivir in 1 of 13 patients with mild or moderate asthma (but without acute influenza-like illness) in a phase 1 study. In interim results from an ongoing treatment study in patients with acute influenza-like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, more patients on zanamivir than on placebo experienced greater than 20% decline in FEV1 or peak expiratory flow rate [these are tests of lung function]. Some patients with underlying respiratory disease may experience bronchospasm and/or decline in lung function when treated with zanamivir. Any patient who develops bronchospasm or decline in lung function should stop the drug. Patients with underlying respiratory disease should be instructed to have a fast-acting inhaled bronchodilator available when treated with zanamivir.

Zanamivir has no effect on the viruses that cause the common cold and differentiating between a cold and the flu can be difficult. Typical influenza illness is characterized by abrupt onset of fever, muscle ache, sore throat, and nonproductive cough. Unlike other common respiratory illnesses, influenza can cause severe malaise lasting several days. More severe illness and complications can result if either influenza pneumonia or secondary bacterial pneumonia occurs. In the three major studies, flu could not be confirmed in about 30 percent of the patients.

It would be unfortunate if zanamivir is thought of as a substitute for not getting a yearly flu shot, particularly for those at high risk of complications from the flu. The Centers for Disease Control and Prevention (CDC), the agency that sets national immunization guidelines, published recommendations April 30, 1999 for the upcoming flu season. The CDC strongly recommends influenza vaccine for any one aged six months or over who, because of age or underlying medical condition, is at increased risk for complications of influenza. Groups at increased risk of influenza complications include:

• Persons 65 years of age or older;
• Residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions;
• Adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including children with asthma;
• Adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), kidney dysfunction, disorders of hemoglobin in the blood such as sickle cell disease, or immunosuppression (including that caused by medications);
• Children and teenagers (aged 6 months–18 years) who are receiving long-term aspirin therapy and therefore might be at risk for developing Reye’s syndrome after influenza;
• Women who will be in the second or third trimester of pregnancy during the influenza season.

The optimal time for receiving an influenza vaccination for persons in high-risk groups is usually the period from October through mid-November. In the U.S., influenza activity generally peaks between late December and early March.

Zanamivir has a competitor waiting in the wings, oseltamivir (TAMIFLU), a drug being developed by Roche Pharmaceuticals of Nutley NJ that is expected to be approved by the FDA soon. There is even less information available about this drug than about zanamivir. In the 4,222 medical journals indexed by the National Library of Medicine, only a single article about oseltamivir exists and even that study is not a study of oseltamivir use in humans. The article was written by employees of Gilead Sciences of Foster City, CA, the company that licensed os-eltamivir to Roche.

Competition breeds battles for market share and The Wall Street Journal is predicting a hot one between Glaxo Wellcome and Roche for the flu drug market. An unprecedented effort is expected by commercial companies to track flu outbreaks as they pop up around the country. Glaxo Wellcome and Roche will then swoop in close behind, deploying SWAT teams of salespeople targeting doctors and launching a blitzkrieg of radio, TV and print ads telling communities that the flu is around—and so is a new medicine to treat it. The aim is to generate between the two companies possibly $1 billion in new revenue, a health care cost without benefit, by next spring.

Drug companies control too much of what is known about their new drugs and they use this to their advantage in promoting and selling their products. This can be detrimental to the public’s health and the economic well-being of the health care system. The public should have access to the complete FDA reviews at or before Advisory Committee meetings. This would allow, for example, the news media to depict a more balanced view of new drugs, rather than the image the industry orchestrates by selectively withholding research results as long as possible.

The FDA reviews are not generally made available to the public until sometime after a drug is approved. In the case of zanamivir, it was approved July 27, 1999 and at the time this article went to press the complete FDA reviews of the drug’s safety and effectiveness still had not been placed in the public domain. This has given Glaxo Wellcome at least two months to etch zanamivir as a “breakthrough” into the public consciousness because there is no balancing information from the FDA that tells the whole story.

What You Can Do

If you are in one of the high-risk groups defined by the CDC (listed above), a yearly influenza vaccination is a safe and effective way of preventing flu and does not carry the potential for adverse effects that zanamivir does in those with pre-existing respiratory problems.

If you have a high fever (greater than 101^oF or 38.3^o C) accompanied by shaking chills and are coughing up thick phlegm, or if coughing or breathing deeply causes sharp chest pain, you may have pneumonia, and should consult your doctor for diagnosis and appropriate treatment.