Safety Profile For RotaTeq
REST (Study 006) Design
RotaTeq—studied in REST (Study 006), one of the largest vaccine trials in history8
Evaluate safety of RotaTeq with regard to intussusception and other adverse events.9
Evaluate efficacy of RotaTeq in the prevention of rotavirus gastroenteritis (RGE).9
Evaluate reduction in hospitalizations or emergency department visits for RGE among recipients of RotaTeq.9
Multicenter, double-blind, placebo-controlled, large-scale clinical trial designed with nested substudies to obtain detailed safety and efficacy data.9
- Approximately 34,000 infants enrolled in the United States from 2001 to 2004 (total patient population: nearly 70,000 in 11 countries).9
Healthy infants 6 to 12 weeks of age randomized to receive 3 oral doses of RotaTeq or placebo at 4- to 10- week intervals.9
Active surveillance used to gather safety data for intussusception and other serious adverse events, plus information on acute gastroenteritis-related hospitalizations or emergency department visits.9
- Parents or legal guardians contacted on days 7, 14, and 42 after each dose, and every 6 weeks thereafter for 1 year after first dose.9
REST=Rotavirus Efficacy and Safety Trial.9
REST (Study 006) Results
No increased risk of intussusception (IS) in REST (Study 006)
REST (Study 006) was a double-blind, placebo-controlled, randomized trial designed to evaluate safety with respect to IS.9
|Confirmed IS cases within 42 days of any dose||6||5|
|Confirmed IS cases within 1 year of dose 1||13||15|
In post-marketing experience, IS (including death) and Kawasaki disease have been reported in infants who have received RotaTeq.
Adverse events from Phase III trials
In a subset of more than 11,000 infants in 3 placebo-controlled clinical trials, the presence of adverse events was reported for 42 days after each dose. Fever was observed at similar rates in vaccine and placebo recipients (42.6% vs 42.8%).
Incidence of serious adverse events (SAEs)
In 3 placebo-controlled trials, infants were evaluated for SAEs within 42 days of a dose.
|Urinary tract infection||0.1%||0.1%|
- Hematochezia reported as an SAE for RotaTeq compared with placebo was <0.1% vs <0.1%.
- During 3 placebo-controlled clinical trials, rates of SAEs were similar in infants receiving RotaTeq (2.4%) compared with placebo recipients (2.6%).
Transmission and shedding
Since the rotavirus parent strains of the reassortants in RotaTeq were isolated from human and bovine hosts, RotaTeq replicates poorly in humans and has a low rate of viral shedding.
|Dose 1 (n=360): 8.9%||Dose 2 (n=249): 0.0%||Dose 3 (n=385): 0.3%|
- In clinical trials, shedding was observed as early as 1 day and as late as 15 days after a dose. Transmission was not evaluated in clinical trials.
- Transmission of vaccine virus strains from vaccinees to nonvaccinated contacts has been observed post-marketing.
- The potential risk of transmission of vaccine virus should be weighed against the risk of acquiring and transmitting natural rotavirus.
REST=Rotavirus Efficacy and Safety Trial.
Post-marketing Study Results
Post-marketing Observational Safety Surveillance Studies
FDA’s PRISM study
The temporal association between vaccination with RotaTeq and intussusception was evaluated in the Post-licensure Rapid Immunization Safety Monitoring (PRISM) program, an electronic active surveillance program comprising 3 US health insurance plans.
More than 1.2 million vaccinations of RotaTeq (507,000 of which were first doses) administered to infants 5 through 36 weeks of age were evaluated.
From 2004 through 2011, potential cases of intussusception in either the inpatient or emergency department setting and vaccine exposures were identified through electronic procedure and diagnosis codes.
Medical records were reviewed to confirm intussusception and rotavirus vaccination status.
The risk of intussusception was assessed using self-controlled risk interval and cohort designs, with adjustment for age. Risk windows of 1 to 7 and 1 to 21 days were evaluated.
Cases of intussusception were observed in temporal association within 21 days following the first dose of RotaTeq, with a clustering of cases in the first 7 days.
Based on the results, approximately 1 to 1.5 excess cases of intussusception occur per 100,000 vaccinated US infants within 21 days following the first dose of RotaTeq.
In the first year of life, the background rate of intussusception hospitalizations in the US has been estimated to be approximately 34 per 100,000 infants.
Merck’s post-marketing safety study
In an earlier prospective post-marketing observational cohort study conducted using a large US medical claims database, the risks of intussusception or Kawasaki disease resulting in emergency department visits or hospitalizations during the 30 days following any dose of vaccine were analyzed among 85,150 infants receiving 1 or more doses of RotaTeq from February 2006 through March 2009.
Medical charts were reviewed to confirm these diagnoses. Evaluation included concurrent (n=62,617) and historical (n=100,000 from 2001–2005) control groups of infants who received diphtheria, tetanus, and acellular pertussis vaccine (DTaP) but not RotaTeq.
Confirmed intussusception cases in the group receiving RotaTeq were compared with those in the concurrent DTaP control group and in the historical control group. The data were analyzed postdose 1 and post any dose, in both 7-day and 30-day risk windows.
In addition, general safety was monitored by electronic search of the automated records database for all emergency department visits and hospitalizations in the 30-day period after each dose of RotaTeq compared with: 1) days 31 to 60 after each dose of RotaTeq (self-matched controls) and 2) the 30-day period after each dose of DTaP vaccine (historical control subset from 2004–2005, n=40,000).
A statistically significant increased risk of intussusception after vaccination with RotaTeq was not observed.
One confirmed case of Kawasaki disease (23 days postdose 3) was identified among infants vaccinated with RotaTeq, and 1 confirmed case of Kawasaki disease (22 days postdose 2) was identified among concurrent DTaP controls (relative risk = 0.7; 95% CI: 0.01-55.56).
In safety analyses evaluating multiple follow-up windows after vaccination (days: 0–7, 1–7, 8–14, and 0–30), no safety concerns were identified for infants vaccinated with RotaTeq when compared with self-matched controls and the historical control subset.
CI=confidence interval; FDA=Food and Drug Administration.
Indications and Usage for RotaTeq
RotaTeq® (Rotavirus Vaccine, Live, Oral, Pentavalent) is indicated for the prevention of rotavirus gastroenteritis in infants and children caused by Types G1, G2, G3, G4, and G9 when administered as a 3-dose series to infants between the ages of 6 to 32 weeks. The first dose of RotaTeq should be administered between 6 and 12 weeks of age.
The vaccination series consists of 3 ready-to-use liquid doses of RotaTeq administered orally starting at 6 to 12 weeks of age, with the subsequent doses administered at 4- to 10-week intervals. The third dose should not be given after 32 weeks of age.
Infants with Severe Combined Immunodeficiency Disease (SCID) should not receive RotaTeq. Postmarketing reports of gastroenteritis, including severe diarrhea and prolonged shedding of vaccine virus, have been reported in infants who were administered RotaTeq and later identified as having SCID.
RotaTeq® (Rotavirus Vaccine, Live, Oral, Pentavalent), should not be administered to infants with a demonstrated history of hypersensitivity to the vaccine or any component of the vaccine.
Infants with Severe Combined Immunodeficiency Disease (SCID) should not receive RotaTeq. Post-marketing reports of gastroenteritis, including severe diarrhea and prolonged shedding of vaccine virus, have been reported in infants who were administered RotaTeq and later identified as having SCID.
Infants with a history of intussusception should not receive RotaTeq.
No safety or efficacy data are available from clinical trials regarding the administration of RotaTeq to infants who are potentially immunocompromised.
In a post-marketing observational study in the US, cases of intussusception were observed in temporal association within 21 days following the first dose of RotaTeq, with a clustering of cases in the first 7 days.
No safety or efficacy data are available for administration of RotaTeq to infants with a history of gastrointestinal disorders.
Vaccine virus transmission from vaccine recipient to nonvaccinated contacts has been reported. Caution is advised when considering whether to administer RotaTeq to individuals with immunodeficient contacts.
In clinical trials, the most common adverse events included diarrhea, vomiting, irritability, otitis media, nasopharyngitis, and bronchospasm.
In post-marketing experience, intussusception (including death) and Kawasaki disease have been reported in infants who have received RotaTeq.
RotaTeq may not protect all vaccine recipients against rotavirus.