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Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of ROTARIX could reveal adverse reactions not observed in clinical trials.
Solicited and unsolicited adverse events, serious adverse events and cases of intussusception were collected in 7 clinical studies. Cases of intussusception and serious adverse events were collected in an additional large safety study. These 8 clinical studies evaluated a total of 71,209 infants who received ROTARIX (N = 36,755) or placebo (N = 34,454). The racial distribution for these studies was as follows: Hispanic 73.4%, white 16.2%, black 1.0%, and other 9.4%; 51% were male.
Solicited Adverse Events
In 7 clinical studies, detailed safety information was collected by parents/guardians for 8 consecutive days following vaccination with ROTARIX (i.e., day of vaccination and the next 7 days). A diary card was completed to record fussiness/irritability, cough/runny nose, the infant's temperature, loss of appetite, vomiting, or diarrhea on a daily basis during the first week following each dose of ROTARIX or placebo. Adverse events among recipients of ROTARIX and placebo occurred at similar rates (Table 1).
Table 1: Solicited Adverse Events Within 8 Days
Following Doses 1 and 2 of ROTARIX or Placebo (Total Vaccinated Cohort)
|Dose 1||Dose 2|
N = 3,284 %
N = 2,013 %
N = 3,201 %
N = 1,973 %
|Loss of appetited||25||25||21||21|
|Total vaccinated cohort = all vaccinated infants for whom
safety data were available.
N = number of infants for whom at least one symptom sheet was completed.
a Defined as crying more than usual.
b Data not collected in 1 of 7 studies; Dose 1: ROTARIX N = 2,583; placebo N = 1,897; Dose 2: ROTARIX N = 2,522; placebo N = 1,863.
c Defined as temperature > 100.4°F ( > 38.0°C) rectally or > 99.5°F ( > 37.5°C) orally.
d Defined as eating less than usual.
Unsolicited Adverse Events
Infants were monitored for unsolicited serious and nonserious adverse events that occurred in the 31-day period following vaccination in 7 clinical studies. The following adverse events occurred at a statistically higher incidence (95% Confidence Interval [CI] of Relative Risk excluding 1) among recipients of ROTARIX (N = 5,082) as compared with placebo recipients (N = 2,902): irritability (ROTARIX 11.4%, placebo 8.7%) and flatulence (ROTARIX 2.2%, placebo 1.3%).
Serious Adverse Events (SAEs)
Infants were monitored for serious adverse events that occurred in the 31-day period following vaccination in 8 clinical studies. Serious adverse events occurred in 1.7% of recipients of ROTARIX (N = 36,755) as compared with 1.9% of placebo recipients (N = 34,454). Among placebo recipients, diarrhea (placebo 0.07%, ROTARIX 0.02%), dehydration (placebo 0.06%, ROTARIX 0.02%), and gastroenteritis (placebo 0.3%, ROTARIX 0.2%) occurred at a statistically higher incidence (95% CI of Relative Risk excluding 1) as compared with recipients of ROTARIX.
During the entire course of 8 clinical studies, there were 68 (0.19%) deaths following administration of ROTARIX (N = 36,755) and 50 (0.15%) deaths following placebo administration (N = 34,454). The most commonly reported cause of death following vaccination was pneumonia, which was observed in 19 (0.05%) recipients of ROTARIX and 10 (0.03%) placebo recipients (Relative Risk: 1.74, 95% CI: 0.76, 4.23).
In a controlled safety study conducted in Latin America and Finland, the risk of intussusception was evaluated in 63,225 infants (31,673 received ROTARIX and 31,552 received placebo). Infants were monitored by active surveillance including independent, complementary methods (prospective hospital surveillance and parent reporting at scheduled study visits) to identify potential cases of intussusception within 31 days after vaccination and, in a subset of 20,169 infants (10,159 received ROTARIX and 10,010 received placebo), up to one year after the first dose.
No increased risk of intussusception following administration of ROTARIX was observed within a 31-day period following any dose, and rates were comparable to the placebo group after a median of 100 days (Table 2). In a subset of 20,169 infants (10,159 received ROTARIX and 10,010 received placebo) followed up to one year after dose 1, there were 4 cases of intussusception with ROTARIX compared with 14 cases of intussusception with placebo [Relative Risk: 0.28 (95% CI: 0.10, 0.81)]. All of the infants who developed intussusceptions recovered without sequelae.
Table 2: Intussusception and Relative Risk With
ROTARIX Compared With Placebo
|Confirmed Cases of Intussusception||ROTARIX
N = 31,673
N = 31,552
|Within 31 days following diagnosis after any dose||6||7|
|Relative Risk (95% CI)||0.85 (0.30, 2.42)|
|Within 100 days following dose 1a||9||16|
|Relative Risk (95% CI)||0.56 (0.25, 1.24)|
|CI = Confidence Interval.
a Median duration after dose 1 (follow-up visit at 30 to 90 days after dose 2).
Among vaccine recipients, there were no confirmed cases of intussusception within the 0- to 14-day period after the first dose (Table 3), which was the period of highest risk for the previously licensed oral live rhesus rotavirus-based vaccine.1
Table 3: Intussusception Cases by Day Range in
Relation to Dose
|Day Range||Dose 1||Dose 2||Any Dose|
N = 31,673
N = 31,552
N = 29,616
N = 29,465
N = 31,673
N = 31,552
Kawasaki disease has been reported in 18 (0.035%) recipients of ROTARIX and 9 (0.021%) placebo recipients from 16 completed or ongoing clinical trials. Of the 27 cases, 5 occurred following ROTARIX in clinical trials that were either not placebocontrolled or 1:1 randomized. In placebo-controlled trials, Kawasaki disease was reported in 17 recipients of ROTARIX and 9 placebo recipients [Relative Risk: 1.71 (95% CI: 0.71, 4.38)]. Three of the 27 cases were reported within 30 days post-vaccination: 2 cases (ROTARIX = 1, placebo = 1) were from placebo-controlled trials [Relative Risk: 1.00 (95% CI: 0.01, 78.35)] and one case following ROTARIX was from a non-placebo-controlled trial. Among recipients of ROTARIX, the time of onset after study dose ranged 3 days to 19 months.
The temporal association between vaccination with ROTARIX and intussusception was evaluated in a hospital-based active surveillance study that identified infants with intussusceptions at participating hospitals in Mexico. Using a self-controlled case series method,4 the incidence of intussusception during the first 7 days after receipt of ROTARIX and during the 31-day period after receipt of ROTARIX was compared to a control period. The control period was from birth to one year, excluding the pre-defined risk period (first 7 days or first 31 days post-vaccination, respectively).
Over a 2-year period, the participating hospitals provided health services to approximately 1 million infants under 1 year of age. Among 750 infants with intussusception, the relative incidence of intussusception in the 31-day period after the first dose of ROTARIX compared to the control period was 1.96 (95.5% CI: 1.46, 2.63)]; the relative incidence of intussusception in the first 7 days after the first dose of ROTARIX compared to the control period was 6.07 (95.5% CI: 4.20, 8.63).
The Mexico study did not take into account all medical conditions that may predispose infants to intussusception. The results may not be generalizable to US infants who have a lower background rate of intussusception than Mexican infants. However, if a temporal increase in the risk for intussusception following ROTARIX similar in magnitude to that observed in the Mexico study does exist in US infants, it is estimated that approximately 1 to 3 additional cases of intussusception hospitalizations would occur per 100,000 vaccinated infants in the US within 7 days following the first dose of ROTARIX. 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.5
Other postmarketing observational studies conducted in Brazil and Australia also suggest an increased risk of intussusception within the first 7 days following the second dose of ROTARIX.2,3
Worldwide passive postmarketing surveillance data suggest that most cases of intussusception reported following ROTARIX occur in the 7-day period after the first dose.
The following adverse events have been reported since market introduction of ROTARIX. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination with ROTARIX.
Intussusception (including death), recurrent intussusceptions (including death), hematochezia, gastroenteritis with vaccine viral shedding in infants with Severe Combined Immunodeficiency Disease (SCID).
Blood and Lymphatic System Disorders
General Disorders and Administration Site Conditions
Read the Rotarix (rotavirus vaccine, live, oral suspension) Side Effects Center for a complete guide to possible side effects
Concomitant Vaccine Administration
In clinical trials, ROTARIX was administered concomitantly with US-licensed and non- US-licensed vaccines. In a US coadministration study in 484 infants, there was no evidence of interference in the immune responses to any of the antigens when PEDIARIX® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine], a US-licensed 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.), and a US-licensed Hib conjugate vaccine (Sanofi Pasteur SA) were coadministered with ROTARIX as compared with separate administration of ROTARIX.
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to ROTARIX. [See WARNINGS AND PRECAUTIONS]
4. Farrington CP, Whitaker HJ, Hocine MN, et al. Case series analysis for censored, perturbed, or curtailed post-event exposures. Biostatistics 2009;10(1):3-16.
5. Tate JE, Simonsen L, Viboud C, et al. Trends in intussusception hospitalizations among US infants, 1993-2004: implications for monitoring the safety of the new rotavirus vaccination program. Pediatrics 2008;121:e1125-e1132.
Read the Rotarix Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 9/26/2014
This monograph has been modified to include the generic and brand name in many instances.
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