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Letter to healthcare professionals re: Synagis (palivizumab) - Abbott Laboratories Limited

Date: 2003-02-10

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MHPD DPSC

IMPORTANT INFORMATION
on SYNAGIS® (palivizumab)

December 16th, 2002

Dear Colleagues,

An article was recently published in the November issue of the journal Pediatrics entitled "Reported Adverse Drug Events in Infants and Children Under 2 Years of Age".¹ The authors' primary message is that (1) adverse events in children are underreported and (2) that drugs are often marketed without studies assessing their safe use in children. In this article, palivizumab is listed as the most commonly cited drug as principal suspect for serious or fatal outcome in children under the age of 2, despite the fact that neither of these concerns apply to palivizumab. Palivizumab has been studied exclusively in high-risk pediatric populations. Several postmarketing programs including prospective adverse event data collection have been conducted.^2-5 These programs have produced more complete data collection of adverse events than the passive reporting systems criticized in this paper.

Furthermore, the data as presented are misleading and may cause clinicians and parents to draw erroneous conclusions regarding the safety of palivizumab. It is important to provide assessment of this publication, and place these data in the proper context. It is noteworthy to mention that the authors themselves state that MedWatch reports do not establish a causal link between the event and the medication, and their study does not provide sufficient information to evaluate the risks and benefits of any specific drug, or to form proper justification for identifying the need for new or additional warnings in the prescribing information.

The following details are for your consideration in evaluating this article:

· The data source presented in this paper consists of all adverse events reported in the Medwatch FDA database that were coincident with the administration of drugs given to children less than 2 years of age from November 1997 to December 2000.

· Reporting to the FDA Medwatch program is spontaneous, largely voluntary, and reports may contain limited information. There is no information as to the underlying medical conditions in the population under evaluation in this paper, nor are there any details of the cases. Thus, while deaths were reported to be coincidental to the use of palivizumab, because of the shortcomings of spontaneous adverse event reporting, a causal association cannot be determined.

· An important methodological flaw of this study is that the data reported represents a frequency count of adverse events for a 38-month period, rather than an adverse event rate (patients with adverse events over number of patients exposed to drug or number of doses administered). The frequency count of adverse events reported by Moore et al. is only a "numerator analysis" and does not take into account the number of patients or doses given. These data are therefore misleading and incomplete, since no denominator of patients exposed to the drug is provided. Without a denominator, no valid conclusions can be drawn from this comparison.

· US safety data⁶ covering the same time period as described in this paper, but with a denominator, showed no evidence of increased rates of serious adverse events or deaths in over 250,000 infants who had received more than 1 million palivizumab doses.

· In Canada, similar results were obtained from an observational, prospective, longitudinal, multicenter study (COMPOSS) published in the Pediatrics Infectious Disease Journal (2002). ⁷ This study including 444 evaluable patients enrolled over an 8-month period across 6 provinces during the 1999-2000 RSV season. Results revealed that only 2 subjects, or 0.45%, discontinued palivizumab due to perceived adverse effects reported by the parent/caregiver. No deaths related to palivizumab administration were cited.

· The data from the Abbott safety database in general, as well as data from the Canadian observational study (COMPOSS)⁷ are very comparable to the results from the IMpact-RSV trial where the mortality for infants who received palivizumab was 0.4% (or 4/1,000 patients) while the mortality rate for children receiving placebo was 1% (or 10/1,000 patients).⁸ There was also no increase in frequency of deaths in palivizumab-treated infants compared to data for high-risk premature infants from the Center for Disease Control.^9,10

· The data do not reflect the fact that palivizumab is only prescribed for, and used in, high-risk infants and children who are known to have greater morbidity and mortality rates than their healthy counterparts. It is well known that premature infants have higher mortality rates than infants born at term. Infant mortality rates in high-risk, premature infants, (defined as deaths for any cause under 1 year of age,) reported by the CDC range from 1% to 18%.^9,10

When all of the relevant data available is utilized, and all of the appropriate methods by which safety data is collected are included, the safety profile of palivizumab is again affirmed.

We hope you have found this letter informative and comprehensive. However, if you have any questions or wish to discuss this issue further, please do not hesitate to contact Abbott Laboratories' Medical Information department.

Sincerely,

original signed by

Rafik Zakhari, M.D.
Medical Director,
Abbott Laboratories, Limited

Abbott Laboratories, Limited / Laboratories Abbott, Limitée
P.O.Box / C.P. 6150, Station / succursale Centre-ville
Montréal (Québec) H3C 3K6

References

1 Moore, TJ, Weiss, S, Kaplan, S, Blaisdell, CJ. Reported Adverse Drug Events in Infants and Children Under 2 Years of Age PEDIATRICS 2002, 110: e53.

2 Cohen A, Hirsch RL, Sorrentino M, Top F, Carlin D, McClain B and the Synagis Outcomes Survey Group. First year experience using Synagis® (palivizumab) humanized monoclonal antibody for protection from RSV lower respiratory tract infection. 2nd World Congress of Pediatric Infectious Diseases, November 2-6, 1999.

3 Cohen A and Sorrentino M. Effectiveness of palivizumab for preventing serious RSV disease. Journal of Respiratory Diseases for Pediatricians. 2000;2 (Suppl 4):S30-S32.

4 Hudak M, et al. Synagis® (palivizumab) prophylaxis of respiratory syncytial virus (RSV) infection - patient demographics and preliminary results from the 2000-2001 Synagis® Outcomes Registry. J Perinatol. 2001; 21:500.

5 Hudak, M et al. Palivizumab prophylaxis of RSV disease - Results of 5,097 children - The 2001-2002 Outcomes Registry. Journal of Perinatology 2002;22:619.

6 Connor, E.M., et al. Safety Surveillance in Children Treated with Palivizumab (PLV). J Perinatol. 2002;52:619.

7 Oh, P.I. et al. Palivizumab prophylaxis for respiratory syncytial virus in Canada: utilization and outcomes. Pediatr Infect Dis J, 2002;21:512-8.

8 Connor EM and the Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998;102:531-537.

9 CDC: Deaths: Preliminary data for 2000. National Vital Statistics Report. Vol. 49, No. 12; October 9, 2001.

10 CDC: Infant mortality statistics from the 1998 period linked birth/infant death data set. National Vital Statistics Report Update. Vol. 48, No. 12; July 20, 2000.

Any suspected adverse reactions can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0201C2
OTTAWA, Ontario, K1A 1B9
Tel: (613) 957-0337 or Fax: (613) 957-0335
Toll free for consumers and health professionals:
Tel: 866 234-2345, Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

The AR Reporting Form and the AR Guidelines can be found on the TPD web site or in The Canadian Compendium of Pharmaceuticals and Specialties.