Safety Alerts
An update on the risk of intussusception with rotavirus vaccines
Audiences
Healthcare professional
Industry member
Product type
Therapeutic Products
22 August 2011
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In October 1999, the first marketed rotavirus vaccine (RotaShield®) was withdrawn in the United States (US) after studies suggested an elevated risk of intussusceptions (IS) which translated to nine additional cases of IS per 100,000 infants who received RotaShield®. Consequently, due to the concern with IS, large-scale clinical trials involving more than 60,000 infants for the new generation rotavirus vaccines, Rotarix®, (GlaxoSmithKline) and RotaTeq® (Merck Sharp & Dohme), were conducted to evaluate the risk of IS prior to licensure. As pre-registration safety studies may not always detect rare events, post-marketing studies to further evaluate the potential for IS were also being conducted. This article updates healthcare professionals on the recent findings from the post-marketing studies on the risk of IS with Rotarix® and RotaTeq®. Rotavirus vaccination is an optional vaccination in Singapore.
Postmarketing studies in Mexico and Brazil
A study was conducted by the Pan American Health Organisation and US Centres for Disease Control and Prevention to determine IS risk and health benefits of rotavirus vaccination in Brazil and Mexico.1 The authors used case-series and case-control methods to assess the association between Rotarix® and IS. Infants with IS (n = 615) were identified through active surveillance at 69 hospitals (16 in Mexico and 53 in Brazil), and age-matched infants from the same neighbourhood (n = 2,050) were enrolled as controls. The infants were observed from the time they were 45 days of age until they were 245 days of age. The primary risk window was one to seven days after Rotarix® vaccination, but the authors also assessed the risk at the following additional timepoints: eight to 14 days, and 15 to 21 days after vaccination with both doses.
An increased risk of IS one to seven days after the first dose of Rotarix® was identified among infants in Mexico with both the case-series method (incidence ratio 5.3; 95%CI 3.0 - 9.3) and the case–control method (odds ratio 5.8; 95%CI 2.6 - 13.0). No significant risk was found after the first dose among infants in Brazil, but an increased risk by a factor of 1.9 to 2.6 was seen one to seven days after the second dose. In Mexico, a two-fold risk of IS after vaccination was also noted during the second and third weeks after dose two.
In conclusion, a combined annual excess of IS in Mexico (approximately one per 51,000 infants) and in Brazil (approximately one per 68,000 infants) and five deaths due to IS was attributable to Rotarix®. The authors also performed a benefit-risk analysis using existing epidemiologic and vaccination data to model the benefits and risks associated with having a vaccination program in Mexico and Brazil. Using this modelling, the vaccine was found to prevent approximately 80,000 hospitalisations and1,300 deaths from diarrhoea each year in these two countries.
An interim analysis of a similar study sponsored by GSK Biologicals² in a different population in Mexico also suggests an increased risk of IS in the 31-day period after the first dose, with a cluster of cases occurring during the first week after vaccination (relative risk 1.8; 99% CI 1.0 - 3.1).
Post-marketing studies in Australia
In Australia, two post-marketing studies were conducted to investigate whether Rotarix® and RotaTeq® are associated with an increased risk of IS.
The first study was conducted through the active surveillance of IS cases in four tertiary centres and a separate surveillance system involving national retrospective reporting of IS cases by paediatricians. This study found a four-fold increased risk of IS in babies within one week of being given the first dose of either vaccine, compared with historical data on hospitalisations coded as IS, but no overall increase in rates of IS up to the age of nine months.
Following this, a large self-controlled case series study using data on all hospitalised cases coded as IS from three Australian states was commissioned by the Australia Therapeutic Goods Administration (TGA). This study found a statistically significant four-fold increase in the occurrence of IS in the first one to seven days following the first dose of either Rotarix® (relative risk 3.89; 95%CI 1.53 - 9.89) or RotaTeq® (relative risk 4.12; 95%CI 1.26 - 13.48) compared with other time periods after vaccination. This increase in risk translates to approximately two additional cases of IS occurring in every 100,000 first doses of vaccine administered, or six additional cases each year in children under 12 months of age in Australia.
Despite the small increase in risk of IS following the first dose of rotavirus vaccination, the TGA considers that the overall benefit-risk balance of both vaccines remains positive. In Australia, since the introduction of these vaccines into the National Immunisation Programme emergency department visits for acute gastroenteritis and hospitalisations for rotavirus gastroenteritis in young children have reduced by over 70%.³
In December 2010, the Global Advisory Committee on Vaccine Safety to the World Health Organisation reviewed and debated the emerging data.⁴ The Committee continues to recommend that rotavirus vaccination be administered to infants to prevent severe and potentially fatal rotavirus disease.
Local situation
Rotarix® and RotaTeq® have been licensed in Singapore since October 2005 and July 2007 respectively for the vaccination of infants six weeks and older against gastroenteritis due to rotavirus infection. To date, HSA has received a total of six cases of IS following receipt of rotavirus vaccines. Four of the reports were associated with Rotarix®*. Of these, two were associated with the second dose of Rotarix®, occurring on day four and day 18 after vaccination. The other two reports occurred five and seven days after first dose vaccination. For RotaTeq®, IS was associated with the second dose of the vaccine, occurring 18 days and four weeks after vaccination. All the patients have either recovered or were recovering at the time of reporting.
*The data provided should not be used to draw comparisons on the safety of different brands of rotavirus vaccines as this is confounded by factors such as extent of use.
Regulatory actions by HSA and advisory to healthcare professionals
In early 2011, additional information has been added to existing “Postmarketing Experience” subsection under “Adverse Reactions” of the local package insert of Rotarix® to inform healthcare providers about the possible increased risk of IS in the 31 day time period after the first dose of Rotarix®. This information has also been included in the “Warnings and Precautions” section. More recently, GSK has updated on an overseas report of a fatal case of IS following the second dose in a child who experienced IS after the first dose. HSA is currently working with GSK to strengthen the local PI to reflect this new contraindication.
As a precaution, healthcare professionals are advised to be vigilant of any symptoms indicative of IS (vomiting, palpable abdominal mass, abdominal pain, bloody stools, or diarrhoea) following vaccination with Rotarix® or RotaTeq®. Parents should be advised to seek treatment early if the child has vomiting, abdominal pain, blood in the stool or change in bowel movements at any time after vaccination, even if it has been several weeks since the last dose of the vaccine. Healthcare professionals are encouraged to report any adverse reactions suspected to be associated with rotavirus vaccines to the Vigilance Branch of HSA.
HSA will continue to closely monitor the safety profile of rotavirus vaccines and keep healthcare professionals updated on any new significant findings.