Drug Profile

Zanamivir (RELENZA) is a drug used to treat uncomplicated flu infections in people who have had symptoms of the flu for no longer than two days. The drug is also approved for post-exposure prevention of influenza in adults and pediatric patients 5 years of age and older. However, there are no data on the effectiveness of prevention in a household setting when initiated more than 1.5 days after the onset of signs or symptoms in the index case. But a 2006  Cochrane review concluded that for prevention of influenza, “compared to placebo, NIs [drugs such as Relenza or Tamiflu] have no [significant] effect against influenza-like illnesses.” 

The same Cochrane Collaboration review concluded that "Because of their low effectiveness, NIs should not be used in routine seasonal influenza control. In a serious epidemic or pandemic, NIs should be used with other public health measures."[1]

The drug has not been shown to be very effective for treatment of influenza. No matter how small the risk of side effects with a minimally effective or ineffective drug, those risks always outweigh the lack of a significant benefit. This is the case with zanamivir.

Expert drug reviewers were unimpressed with the drug and recommended against its approval for treatment of influenza.

In February 1999, the drug was reviewed by the Food and Drug Administration’s (FDA), Antiviral Drug Advisory Committee. The FDA asked the committee of 17 outside experts was asked by the FDA: “Does the information presented by the applicant [manufacturer Glaxo Wellcome] support the safety and effectiveness of zanamivir for treatment of influenza?” The committee voted 13 to 4 that it did not.[2] One committee member remarked during the meeting: “There isn’t sufficient efficacy to warrant me recommending this drug [zanamivir] for my family or myself.”[2]

Despite this vote, the FDA approved zanamivir in July 1999. At the time the drug was approved for marketing, only one clinical trial comparing the drug to a placebo had been published showing a statistical benefit for zanamivir. According to the company’s interpretation, the study showed that zanamivir shortened the time to alleviation of flu symptoms by a median of 1.5 days compared to a placebo.[3]

The FDA statistical reviewer for the drug concluded his evaluation by saying, “Zanamivir has not been shown to be effective in this country [the United States] for the treatment of influenza, and in my opinion therefore should not be approved.”[4]

When Public Citizen obtained the FDA’s reviews of zanamivir through the Freedom of Information Act, we found that, in fact, two additional studies had been submitted to the FDA by Glaxo Wellcome, not just one. The largest of the trials submitted by Glaxo Wellcome, and one of the two not yet published, is of most interest. Conducted in North America, this trial showed that the median difference in improvement between zanamivir and placebo was one day, a difference that is not statistically significant.

The third and smallest trial, conducted in the European Union, found the largest treatment effect between zanamivir and placebo: 2.5 days, a difference that is statistically significant. But the European Union study had problems. It was originally designed to enroll about 500 volunteer subjects but could only manage 356. Most study centers enrolled small numbers of subjects and the estimates of treatment effect varied markedly among centers. Surprisingly, it was found that in subjects who did not have confirmed flu, there was a shorter median time to alleviation of symptoms with zanamivir than with the placebo, and it was unclear whether this was due to chance, to false-negative flu diagnoses, or to some other reason.

In their review of zanamivir, the editors of the independent French drug bulletin Prescrire International found that:[5]

1. Zanamivir shortens the duration of symptoms of suspected influenza by only about a day.
2. Zanamivir has not been shown to reduce antibiotic prescribing, or the incidence of complications necessitating hospitalization.
3. Zanamivir has no proven efficacy in preventing the spread of influenza by a treated patient.
4. Zanamivir inhalation can induce bronchospasm.

Regulatory actions surrounding zanamivir

2000: In January 2000, the FDA issued a public health advisory that included a warning about prescribing zanamivir to patients with underlying asthma or chronic obstructive pulmonary disease (COPD).[6] The agency had received several reports of deterioration of respiratory function following the use of zanamivir in patients with underlying asthma or COPD.

The professional product labeling for zanamivir now carries the following warning:

BRONCHOSPASM AND DECLINE IN LUNG FUNCTION HAVE BEEN REPORTED IN SOME PATIENTS RECEIVING RELENZA. MANY BUT NOT ALL OF THESE PATIENTS HAD UNDERLYING AIRWAYS DISEASE SUCH AS ASTHMA OR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BECAUSE OF THE RISK OF SERIOUS ADVERSE EVENTS AND BECAUSE EFFICACY HAS NOT BEEN DEMONSTRATED IN THIS POPULATION, RELENZA IS NOT GENERALLY RECOMMENDED FOR TREATMENT OF PATIENTS WITH UNDERLYING AIRWAYS DISEASE. SOME PATIENTS WITH SERIOUS ADVERSE EVENTS DURING TREATMENT WITH RELENZA HAVE HAD FATAL OUTCOMES, ALTHOUGH CAUSALITY WAS DIFFICULT TO ASSESS.

RELENZA SHOULD BE DISCONTINUED IN ANY PATIENT WHO DEVELOPS BRONCHOSPASM OR DECLINE IN RESPIRATORY FUNCTION; IMMEDIATE TREATMENT AND HOSPITALIZATION MAY BE REQUIRED.

2008: In 2008 the FDA and GlaxoSmithKline issued an advisory warning regarding delirium and abnormal behaviour leading to injury in patients taking zanamivir. Most of these reports were from Japan and occurred primarily among pediatric patients. Symptoms often had an abrupt onset and rapid resolution.[7]

The current labeling for zanimivir states that: “Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptom occur, the risks and benefits of continuing treatment should be evaluated for each patient.”