Information Pertaining to Labeling Revision for ProQuad

On February 27, 2008, FDA approved a revised label for ProQuad, Merck's vaccine to protect against measles, mumps, rubella (MMR) and varicella (chickenpox), in children 12 months through 12 years of age. The new label alerts healthcare professionals and consumers to new and evolving information in the Post-Marketing Surveillance section on the possible risk of febrile seizures after ProQuad vaccination.

Increased rate of fever was previously identified as a safety signal in the ProQuad prelicensure studies. To better understand the risk of febrile seizures that might be associated with ProQuad vaccination, Merck committed to conduct a large, postmarketing study at the time of licensure. In January 2006, Merck initiated a large Phase 4 observational study to evaluate the risk of febrile seizures in 25,000 children receiving their first dose of ProQuad. The study was recently completed and the data are undergoing analysis, but the interim results of the study are reflected in this labeling revision.

The interim analysis of Merck's post-marketing study showed that febrile seizures occurred more frequently 5 to 12 days following vaccination of approximately 14,000 children with ProQuad (0.5 per 1,000) when compared with a historical, age and sex-matched control group vaccinated with MMR and varicella vaccines administered separately at the same visit (0.2 per 1,000). In the 0-30 day time period following vaccination, the incidence of febrile seizures with ProQuad (1 per 1,000) was not greater than that observed in children vaccinated with ProQuad's individual components, MMR and varicella vaccines, at the same visit (1.3 per 1000).

The Centers for Disease Control and Prevention (CDC) also supported a post-licensure observational study to assess the risk of febrile seizures following vaccination with ProQuad when compared to vaccination with MMR and varicella vaccines, given separately at the same visit. Preliminary results from the CDC study show an increased risk of febrile seizure 7-10 days after vaccination with ProQuad versus MMR and varicella vaccines (9 per 10,000 vaccinations versus 4 per 10,000 vaccinations).

Febrile seizures are known to occur in children who have not been vaccinated, and have also been reported following administration of MMR or varicella vaccine given at different visits.

An increased risk of febrile seizures following MMR vaccination has been previously documented. The period of greatest risk occurs 8 to 14 days after vaccination, and this risk translates into approximately one additional febrile seizure for every 3,000-4,000 children vaccinated with MMR when compared with children not vaccinated with MMR, or an increase of 2.5 to 3.4 febrile seizures per 10,000 vaccinations.

ProQuad's label was also revised to include two additional changes.

In the section Post-Marketing Reports, encephalitis (infection of the brain) was added to reflect the receipt of reports following ProQuad vaccination. Previously, this adverse reaction was listed under adverse events seen after MMR or varicella vaccination. Encephalitis has been reported approximately once for every 3 million doses of MMR vaccine. Post-marketing surveillance of more than 400 million doses distributed worldwide (1978 to 2003) indicates that encephalitis is rarely reported after MMR vaccination. In no case has it been shown conclusively that encephalitis was caused by a vaccine virus infection of the central nervous system. There was no proven causal relationship between ProQuad and any of the reported cases that prompted the change in the label.

In the section Adverse Experiences after vaccination with MMR II and VARIVAX, the term epididymitis was added under a new section, Reproductive Systems and Breast Disorders. Wild type mumps infection is known to cause epididymitis (inflammation of a part of the male reproductive system) and/or orchitis. None of the reports of epididymitis following MMR vaccination had a proven causal relationship with mumps vaccine virus and one report indicated that it was due to wild type mumps infection. Epididymitis has not been reported following ProQuad vaccination.

FDA has not made any changes to the Indications for Use of ProQuad, nor has the Agency issued new or revised Warnings or Precautions. Based on interim study results reviewed by FDA, ProQuad continues to be safe and effective and its benefits continue to outweigh its risks.

The use of ProQuad vaccine reduces the number of injections children need to protect against measles, mumps, rubella and varicella (chickenpox).

ProQuad is currently in very limited distribution in the United States, due to manufacturing issues unrelated to vaccine safety or efficacy. ProQuad vaccine is not expected to be widely available before 2009; however, some clinics may have ProQuad vaccine in stock.

Key Facts:

The preliminary results from Merck show an increased risk of febrile seizure 5 to 12 days after vaccination with ProQuad versus MMR and varicella vaccines, (5 per 10,000 vaccinations versus 2 per 10,000 vaccinations, respectively). The rate of having a febrile seizure 5 to 12 days after vaccination was approximately 2.5 times higher after ProQuad than after MMR and varicella vaccines given separately at the same visit.

In the Merck study, the risk of febrile seizure during the 30 days after vaccination was not significantly different between children who were given ProQuad (1.0 per 1000) versus those given MMR and varicella vaccines separately at the same visit (1.3 per 1000), suggesting the period of increased risk for febrile seizure after ProQuad is brief. These results are preliminary and based on a small sample size.

The preliminary results from CDC show an increased risk of febrile seizure 7 to 10 days after vaccination with ProQuad versus MMR and varicella vaccines given separately at the same visit, (9 per 10,000 vaccinations versus 4 per 10,000 vaccinations, respectively). The rate of having a febrile seizure 7-10 days after vaccination was approximately 2 times higher with ProQuad than with MMR and varicella vaccines given separately at the same visit.

Febrile seizures generally have an excellent prognosis. Most febrile seizures occur in young children between the ages of 6 and 59 months; the peak age is 14 to 18 months which overlaps with the ages when the first doses of MMR and varicella vaccines are recommended.

Based on interim study results reviewed by FDA, ProQuad continues to be safe and effective and its benefits continue to outweigh its risks. Providers can choose either ProQuad vaccine or MMR and varicella vaccines separately for prevention of measles, mumps, rubella and varicella diseases among their patient population.

CDC also has information for clinicians on their website (http://www.cdc.gov/vaccinesafety/vsd/mmrv.htm).

FDA and CDC are looking very carefully at this finding and will continue to evaluate the data from these studies as they are finalized. FDA and CDC will provide updates and take any necessary actions based on this continued evaluation. FDA plays a critical role in evaluating and assuring vaccine safety at every stage of the product life cycle from pre-market testing and development through post-market surveillance and risk management.