NV25182: A Prospective, Observational Safety Study in Children 24 Months of AGE Receiving Oseltamivir for the Tretamtent or Prophylaxis of Influenza Infection

NV25182: A Prospective, Observational Safety Study in Children 24 Months of AGE Receiving Oseltamivir for the Tretamtent or Prophylaxis of Influenza Infection

Primäre Fragestellung dieser Untersuchung sind:
Die Erfassung des Kurzzeit Safety-Profils von Oseltamivir bei Kindern im Alter unter 24 Monaten, bei denen eine Influenza A oder B diagnostiziert oder vermutet wird
Die Erfassung des Kurzzeit Safety-Profils von Oseltamivir bei Kindern im Alter unter 24 Monaten mit einer Influenza-Prophylaxe nach Exposition
Sekundäre Fragestellungen sind:
Die Beschreibung von Dosierung und Behandlungsdauer unter Routine-Bedingungen
Überprüfung des Zusammenhangs von unerwünschten Ereignissen und Behandlungsführung mit Oseltamivir

Tamiflu ®

2

140

Dr. med. Bogdan, Manfred

Medical Affairs Virology

Roche Pharma AG

Emil Barell Str. 1

79639 Grenzach-Wyhlen

Deutschland

manfred.bogdan@roche.com

Telefon: 07624142885

Roche Pharma AG

Emil-Barell-Str. 1

79639 Grenzach-Wyhlen

Deutschland

23.07.2012

Studie bereits abgeschlossen

All patients enrolled in the registry (n=1065) were included in the safety population.
Most of the patients were enrolled during one of the two defined influenza seasons. Thirty-eight (38) patients were enrolled in between the two seasons (“inter-season”) and six patients met eligibility criteria and contributed data during both of the influenza seasons. In total 1065 patients were recruited, 506 of those in Germany.
A total of 340 patients were treated with oseltamivir, 711 patients were not treated with oseltamivir and 14 patients received oseltamivir for prophylaxis.

506

The study population consists of patients aged 24 months and younger who presented with confirmed or presumed influenza A or B infection, or who received oseltamivir for influenza prophylaxis between 16 December 2009 and 31 May 2011.
Inclusion Criteria
The inclusion criteria for enrollment:
• Age ≤ 24 months at time of enrollment
• Diagnosis of influenza A or B (suspect* or confirmed by viral testing) either treated with oseltamivir or with no antivirals OR prescribed oseltamivir for post-exposure influenza prophylaxis
• Parent/legal guardian willing to provide informed consent and be contacted by telephone as part of follow-up
* Suspected influenza is defined as an acute febrile illness characterized by the presence of fever and 1 or more of the following symptoms: cough, coryza/nasal congestion or sore throat.

Exclusion Criteria
Patients were excluded if treated with an influenza antiviral other than oseltamivir for their current illness, including amantadine (Symmatrel®), rimantadine (Flumadine®) or zanamivir (Relenza®).

18 Monate

not applicable

see below

not applicable

see below

not applicable

A total of 340 infants treated with oseltamivir for suspected influenza and an additional 14 treated prophylactically were enrolled in the study. In addition to the oseltamivir-exposed groups, a third group consisting of 711 infants with suspected influenza for whom oseltamivir was not prescribed was included and followed in a similar fashion to the exposed groups. In order for any comparisons with the control group to be meaningful, demographic and baseline characteristics (including symptom severity) for the groups were evaluated. The median age for the treated group was slightly higher than the non-antiviral treated group (12 versus 11 months), and the distribution by age group shows a higher percentage of treated patients in the 3 to < 6 month and > 12 month categories, and a higher percentage of non-antiviral treated patients in the 6 to < 12 month category. Race and gender were similar across the groups, as was the proportion that was born prematurely. The most commonly reported symptoms (fever, coryza and cough) was the same, but sore throat and rales/wheezing/rhonchi were more frequently reported in the non-antiviral patients.
Assessing the severity of symptoms associated with suspected influenza is particularly challenging in infants. By both measures utilized in this study, i.e., the subjective symptom by symptom assessment of the investigator and the three targeted questions regarding tachypnea, chest retractions and drowsiness/listlessness, the infants in the treated and the non-antiviral treated group appeared to be comparable. The patients that were not treated with oseltamivir, however, were more likely to have one or more co-infections at enrollment such as bronchitis and pneumonia. The study enrolled patients being treated in an ambulatory setting at the time of enrollment; however, some patients were hospitalized during the follow-up period.
The majority of patients were prescribed standard doses and regimens of oseltamivir (twice daily for five days), and the median total daily dose and total overall doses were consistent with a 30 mg twice a day regimen or the dosing recommendations per the current SmPC. The average time from symptom onset was 3.4 days (approximately 82 hours), which is on average a longer duration of symptoms prior to treatment than the recommended 48 hours.
The adverse events reported during the study, which covered two consecutive influenza seasons, were consistent with the described clinical picture of influenza or a secondary complication of influenza infection or influenza-like illness, and specifically with the profile observed in the < 24 month population in previous studies and the medical literature. Respiratory events, including cough and rhinitis, and gastrointestinal events, in addition to fever were consistently the most commonly reported events across both treatment groups of both influenza seasons.
Overall, 42 events were reported as possibly or probably related to oseltamivir; although all were considered non-serious, 13 of the events resulted in permanent discontinuation of oseltamivir. Eight of the 13 discontinuations were as a result of vomiting, which is consistent with the product labeling for oseltamivir which states that mild to moderate nausea and vomiting are the most common side effects reported with use of oseltamivir. Notably, one patient discontinued oseltamivir due to severe granulocytopenia and a moderate rash five days after starting treatment. The events were considered possibly related to oseltamivir; however, the patient had also been treated with metamizole, which is an analgesic and antipyretic drug that was banned by the FDA because of its association with agranulocytosis (it remains available in other parts of the world, including Europe). In addition, both leukocytosis and leukocytopenia have been reported in patients with respiratory illnesses, with leukopenia later in illness suggesting that the illness is viral in nature [17].
Of the serious adverse events reported in patients treated with oseltamivir, none were considered potentially related to treatment and all were consistent with the clinical course of influenza or concomitant diseases in infants (e.g., identification of previously unrecognized congenital anomalies). No deaths were reported. Notably, in the US, the pediatric mortality rate during the 2009-2010 influenza season was nearly four times the average rate of the past five influenza seasons, with 19% of pediatric laboratory-confirmed influenza related deaths reported in infants < 2 years of age [18].
Six AEs under the SOC Nervous System Disorders were reported in infants treated with oseltamivir, including febrile convulsion, convulsion (2), fontanelle bulging, lethargy and somnolence; none were considered serious and none were considered possibly or probably related to treatment. The report of mild febrile convulsion was reported in a patient with a history of febrile convulsions, which was considered unlikely to be related to oseltamivir. The reports of convulsions occurred in one patient with a medical history of epilepsy and a second patient who was only 10 weeks of age at enrollment who had a history of intraventricular hemorrhage at baseline.
There does not appear to be any important differences in the rate of adverse events reported between the two influenza seasons. Although higher percentages of AEs were reported in the prophylaxis group during the 2010-2011 season, this difference is likely due to the extremely small sample size (n=2) for the 2009-2010 season, rather than to a real difference in the rate of adverse events.

not applicable

This is the final report for a completed study of the short-term safety of the use of oseltamivir (prophylaxis or treatment) in children 24 months of age or younger. A total of 340 infants treated with oseltamivir for suspected influenza and an additional 14 treated prophylactically were enrolled in the study, which adds meaningfully to the available safety data in this important and vulnerable population. Prophylactic use of oseltamivir in the population was very rare; therefore, the conclusions regarding the safety of prophylactic oseltamivir in infants less than 24 months of age are based on limited data.
Overall, no new safety concerns were identified regarding the short-term safety of treatment with oseltamivir.