Letter Expressing Concern with Recommendations on Zanamivir (Relenza)
November 22, 2000
Professor Sir Michael Rawlins
Chair, National Institute for Clinical Excellence
Dear Dr. Rawlins:
We are extremely concerned that the recent recommendations concerning the influenza drug zanamivir (Relenza) by the National Institute for Clinical Excellence (NICE), of which you are the Chair, will jeopardize the health of many people in the United Kingdom. NICE has recommended that the drug may be used in people with asthma or chronic obstructive lung disease, people for whom the United States Food and Drug Administration (FDA) has said the drug is " not generally recommended because of the risk of serious adverse events...." We urge that you seriously consider reversing this potentially dangerous recommendation you have made.
The group that you have correctly defined as being at special risk from the complications of influenza also appear to be those at special risk of the adverse effects of zanamivir. This population of patients are those: (1) age 65 years or over; (2) have chronic respiratory disease that requires regular medication - including chronic obstructive pulmonary disease (COPD) and asthma; (3) have significant cardiovascular disease - this does not mean people with hypertension (high blood pressure); (4) have a lowered resistance to disease this means that is they are immunocompromised; or (5) have diabetes mellitus.
The NICE recommendations are at odds with publicly available information about the safety of zanamivir use, particularly in patients with underlying respiratory disease.
The U.S. Food and Drug Administration (FDA) Division Director responsible for the approval of zanamivir wrote in her July 26, 1999 memorandum that:
"Safety in patients with underlying respiratory disease is the only potentially significant safety concern that was identified by the Advisory Committee and clinical reviewers. This issue was initially raised by the finding of reduced FEV1 [a measure of lung function] following zanamivir (but not placebo) treatment in one out of 12 mildly asthmatic subjects in a phase I study designed for the purpose of assessing safety in this population. Following the team's request for more information on this issue, the sponsor provided preliminary safety data from an ongoing study of the safety and efficacy in patients with asthma or COPD (NAI30008). In a preliminary analysis of 148 patients, there were more frequent declines in FEV1>20% from baseline in patients in the zanamivir group at day six (15% vs. 6% placebo) and at day 28 (10% vs. 3% placebo)." (www.fda.gov/cder/foi/appletter/1999/21036ddm.pdf accessed November 22, 2000)
The above mentioned recently completed NAI30008 study was used by NICE as part of the evidence base for the use of zanamivir in at-risk patients. However, no safety data were presented from the NAI30008 study in the NICE recommendations, for example, the effect of the drug in causing a decline in FEV1.
The original U.S. labeling warned:
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. 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. (http://www.fda.gov/cder/foi/label/1999/21036lbl.pdf accessed November 22, 2000)
The warnings for the drug were strengthened in the U.S. in July 2000:
A WARNING has been added to describe reports of bronchospasm and decline in lung function in some patients receiving Relenza; many, but not all, of these had underlying airways disease such as asthma or chronic obstructive pulmonary disease (COPD). The new WARNINGS section includes a statement that Relenza is not generally recommended for treatment of patients with underlying airways disease such as asthma or COPD, because of the risk of serious adverse events and because efficacy has not been demonstrated in this population. Some patients with serious adverse events during treatment with Relenza have had fatal outcomes, although causality was difficult to assess.
The PRECAUTION section contains expanded information regarding considerations needed if use of Relenza is contemplated in the context of underlying airways disease. The PRECAUTIONS section also contains information about allergic-like reactions in patients receiving Relenza, and about the potential for serious bacterial infections to appear with influenza-like symptoms or as complications of influenza.
The ADVERSE REACTIONS section contains additional information about postmarketing adverse event reports, and about lower respiratory adverse events in pediatric patients with underlying respiratory disease. (http://www.fda.gov/medwatch/safety/2000/relenz.htm
accessed November 22, 2000)
Larry D. Sasich, Pharm.D., M.P.H.
Public Citizen's Health Research Group
Sidney M. Wolfe, M.D.
Public Citizen's Health Research Group