Bijwerkingen oseltamivir (Tamiflu®)
Oseltamivir is geregistreerd voor de behandeling van influenza bij volwassenen en kinderen vanaf één jaar en voor de preventie van influenza na blootstelling aan een klinisch vastgesteld geval van influenza bij volwassenen en kinderen in de leeftijd van 13 jaar en ouder (Gebu 2005; 39: 133-135). Bij het gebruik van oseltamivir komen vaak bijwerkingen voor, maar deze zijn in het algemeen niet ernstig van aard. De Amerikaanse registratieautoriteit Food and Drug Administration (FDA) en de producent van oseltamivir (Tamiflu®), de firma Roche, hebben gezondheidswerkers in de gezondheidszorg op de hoogte gebracht van nieuwe bijwerkingen van oseltamivir.1 In, met name 'postmarketing surveillance' ofwel fase IV-onderzoek dat is uitgevoerd in Japan, is gerapporteerd over automutilatie en delirium tijdens gebruik van oseltamivir door patiënten met influenza. Patiënten met influenza, en in het bijzonder kinderen, hebben mogelijk een verhoogd risico van automutilatie en verwarring kort nadat zij oseltamivir hebben ingenomen en moeten nauwgezet worden gecontroleerd op tekenen van ongewoon gedrag. Er dient direct contact te worden opgenomen met een arts als een patiënt na inname van oseltamivir ongewoon gedrag vertoont. Deze recent bekend geworden bijwerkingen van oseltamivir zijn opgenomen in de Amerikaanse registratietekst en de patiënteninformatietekst.1 Bij het ter perse gaan van dit nummer van het Geneesmiddelenbulletin was de Nederlandse productinformatie niet aangepast.
Engelstalig onderzoeksrapport van Health Canada :
New influenza drugs zanamivir (RelenzaTM) and oseltamivir (TamifluTM): unexpected serious reactions
Neuraminidase inhibitors represent a new class of antiviral agents that inhibit neuraminidase, an enzyme essential for the replication of influenza A and B viruses.1,2 Zanamivir (RelenzaTM) and oseltamivir phosphate (TamifluTM), approved for sale in Canada in November 1999 and December 1999 respectively, are indicated for the treatment of uncomplicated acute illness due to influenza virus in people 12 years of age or older who have not been symptomatic for more than 2 days.3,4 Zanamivir is supplied as a powder for inhalation via a DiskhalerTM. 3 Oseltamivir is available in capsule form for oral use.4
From Nov. 2, 1999, to June 30, 2000, the Canadian Adverse Drug Reaction Monitoring Programme (CADRMP) received 16 domestic reports of suspected adverse reactions to zanamivir. Six reports were classified as serious and unexpected (Table 1).5
One death associated with the use of zanamivir was reported. The patient, a 52-year-old man with cardiomyopathy, was taking carvedilol, warfarin, digoxin, enalapril and spironolactone concomitantly. About 2 days after starting zanamivir, he was admitted to the hospital in acute renal failure. The creatinine levels were reported to be 81 µmol/L in the month before zanamivir administration and µ600 mol/L on hospital admission (normal range 50-110 µmol/L6) (units not specified in original report, presumably µmol/L). The patient was treated in hospital with intravenous furosemide therapy and underwent dialysis. Blood cultures were subsequently found to be positive for Staphylococcus aureus. The patient died the day following hospital admission.
From Dec. 23, 1999, to June 30, 2000, the CADRMP received 9 domestic reports of suspected adverse reactions to oseltamivir, of which 8 were classified as serious. Seven of the serious reports included reactions classified as unexpected (Table 2).
One death associated with the use of oseltamivir was reported. A 58-year-old man with a history of asthma was admitted to hospital with pulmonary difficulties and hemorrhagic rash 3 days after starting oseltamivir. He was reported to have been unwell with influenza and myalgia for one week with shortness of breath, fever, laryngitis, cough and purulent nasal secretions. The patient was taking prednisone concomitantly. On admission his heart rate and serum creatinine and creatine kinase levels were elevated. His blood pressure was 100/60 mm Hg and temperature 38.8OC. The patient was given intravenous imipenem and other antibiotics. Within 5 hours of hospital admission the patient experienced cardiac arrest, required intubation but died. A culture showed staphylococcal pneumonia. On autopsy the cause of death was determined to be septic shock.
The reports received at the CADRMP for these antiviral drugs lacked information to indicate whether laboratory tests such as virus cultures or serology were conducted to confirm the diagnosis of influenza in these patients.
In January 2000 the US Food and Drug Administration (FDA) issued a Public Health Advisory highlighting points to consider when prescribing influenza drugs.7 Caution was advised when prescribing zanamivir to patients with underlying asthma or chronic obstructive pulmonary disease. The FDA received several reports of deterioration of respiratory function (e.g., bronchospasm, respiratory arrest) following inhalation of zanamivir in patients with these conditions. If zanamivir is prescribed to patients with underlying airway disease, the FDA recommends the use of careful monitoring, proper observation and appropriate supportive care, including the availability of short-acting bronchodilators. These views are also reflected in the Canadian product information for RelenzaTM.3 The advisory also cautioned prescribers of the need to continue evaluation of patients receiving antiviral agents to identify those in whom primary or concomitant bacterial infection could occur. Vaccination remains the primary method of preventing and controlling influenza. The product monographs for both RelenzaTM and TamifluTM caution that the use of these products should not affect the evaluation of individuals for annual influenza vaccination.3,4
A Dear Health Care Professional letter was issued in Canada by the manufacturer of RelenzaTM on July 11, 2000,8 stating that "reports of bronchospasm and decline in respiratory function among patients without evidence of underlying airways disease have also been received." Along with the July 2000 US Relenza Drug Warning,9 it also reminded prescribers that:
· the safety and efficacy of the drug have not been shown in patients with underlying respiratory disease; and
· the drug should be stopped if bronchospasm or a decline in lung function develops.
Neuraminidase inhibitors have been available for a relatively short time and typically would only be prescribed for a limited period each year. The safety profile of a new drug evolves with time, particularly as it is used in different patient populations with a variety of pre-existing conditions and taking a variety of other medications. As this year's influenza season approaches, health care professionals are requested to continue reporting any suspected reactions associated with these products to further establish their safety profiles.
Written by: Lynn Macdonald, BSP, Bureau of Licensed Product Assessment.
Bron: Health Canada
The U.S. Food and Drug Administration (FDA), reacting to reports of self-injury, suicide and delirium, added a warning to the label on the popular anti-viral drug Tamiflu (oseltamivir phosphate). The FDA and the drug’s manufacturer, Hoffman-La Roche Inc., did so after reports surfaced in Japan of children who took the drug and then exhibited psychiatric symptoms, including confusion and delirium. Tamiflu is one of four treatments for seasonal flu in the U.S. It is usually taken to prevent or lessen the severity of the virus.
In a detailed report prepared by the FDA’s Division of Drug Risk Evaluation for its pediatric advisory committee, staff from the FDA described some of the cases in which otherwise normal children, most under 17, exhibited bizarre psychiatric behavior shortly after taking Tamiflu. Side effects occurred usually within a day of taking the drug and included panic attacks, delusions, delirium, convulsions, depression, loss of consciousness, and in some cases, suicide.
Reported cases from the report include three people who fell to their deaths after taking the drug, including a 14-year-old boy who climbed atop the railing of his family’s condominium. The report also tells the story of an 8-year-old boy who, after taking a single dose of Tamiflu, wouldn’t answer to his own name and was growling. Another case involved a 14-year-old girl, struck with paranoia, who swore someone was watching her from outside her home and that her salad had been poisoned. The report also cites two men fell to their deaths after taking Tamiflu, and one of them left a suicide note. None of the cases had any reported psychological or neurological problems before taking the medication.
“We are concerned that when/if the use of this drug increases in the U.S. … there may be increasing cases of adverse consequence in the U.S,” the FDA report stated.
The reports came mostly from Japan because Tamiflu is prescribed far more frequently than in the U.S. (24.5 million times in 4 years in Japan, versus 6.5 million prescriptions during the same period in th U.S.).
The new, supplementary information on the Tamiflu label states: “People with the flu, particularly children, may be at an increased risk of self-injury and confusion shortly after taking TAMIFLU and should be closely monitored for signs of unusual behavior.”It is still unclear how Tamiflu might contribute to such behavior, but experts have noted that in the majority of cases, the symptoms ceased after use of the drug was discontinued.In a prepared statement, Tamiflu maker Roche Pharmaceuticals said that it “agreed with the FDA” on the label revision, but stressed that “there is no evidence of a causal relationship between the use of oseltamivir and the likelihood of neuropsychiatric events in influenza patients.”
Hoffman-La Roche said in a statement that reports of psychiatric side effects from Tamiflu were rare. “While any relative contribution of Tamiflu to these events is unknown, Roche is committed to working closely with the FDA to ensure that the product label accurately reflects the reports,” it said.
People with the flu, particularly children, may be at an increased risk of self-injury and confusion shortly after taking Tamiflu and should be closely monitored for signs of unusual behavior. A healthcare professional should be contacted immediately if the patient taking Tamiflu shows any signs of unusual behavior