AAP News TODAY 2016 - Sunday, October 23, 2016 - 12
RotaTeq® (Rotavirus Vaccine, Live, Oral, Pentavalent)
Seizures: All seizures reported in the phase 3 trials of RotaTeq (by vaccination group and interval after dose) are shown in Table 3.
(Rotavirus Vaccine, Live, Oral, Pentavalent)
Table 3: Seizures reported by day range in relation to any dose in the phase 3 trials of RotaTeq
BRIEF SUMMARY OF PRESCRIBING INFORMATION
DOSAGE AND ADMINISTRATION
FOR ORAL USE ONLY. NOT FOR INJECTION. The vaccination series consists of three 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.
Seizures reported as serious adverse experiences occurred in <0.1% (27/36,150) of vaccine and <0.1% (18/35,536) of placebo recipients
(not significant). Ten febrile seizures were reported as serious adverse experiences, 5 were observed in vaccine recipients and 5 in
Kawasaki Disease: In the phase 3 clinical trials, infants were followed for up to 42 days of vaccine dose. Kawasaki disease was reported in
5 of 36,150 vaccine recipients and in 1 of 35,536 placebo recipients with unadjusted relative risk 4.9 (95% CI 0.6, 239.1).
A demonstrated history of hypersensitivity to any component of the vaccine. Infants who develop symptoms suggestive of hypersensitivity
after receiving a dose of RotaTeq should not receive further doses of RotaTeq.
Most Common Adverse Events
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.
Solicited Adverse Events: Detailed safety information was collected from 11,711 infants (6,138 recipients of RotaTeq) which included a
subset of subjects in REST and all subjects from Studies 007 and 009 (Detailed Safety Cohort). A Vaccination Report Card was used by
parents/guardians to record the child's temperature and any episodes of diarrhea and vomiting on a daily basis during the first week
following each vaccination. Table 4 summarizes the frequencies of these adverse events and irritability.
Table 4: Solicited adverse experiences within the first week after doses 1, 2, and 3 (Detailed Safety Cohort)
WARNINGS AND PRECAUTIONS
Managing Allergic Reactions: Appropriate medical treatment and supervision must be available to manage possible anaphylactic
reactions following administration of the vaccine.
Immunocompromised Populations: No safety or efficacy data are available from clinical trials regarding the administration of
RotaTeq to infants who are potentially immunocompromised including: Infants with blood dyscrasias, leukemia, lymphomas of any type, or
other malignant neoplasms affecting the bone marrow or lymphatic system; Infants on immunosuppressive therapy (including high-dose
systemic corticosteroids). RotaTeq may be administered to infants who are being treated with topical corticosteroids or inhaled steroids;
Infants with primary and acquired immunodeficiency states, including HIV/AIDS or other clinical manifestations of infection with human
immunodeficiency viruses; cellular immune deficiencies; and hypogammaglobulinemic and dysgammaglobulinemic states. There are
insufficient data from the clinical trials to support administration of RotaTeq to infants with indeterminate HIV status who are born to
mothers with HIV/AIDS; Infants who have received a blood transfusion or blood products, including immunoglobulins within 42 days.
Vaccine virus transmission from vaccine recipient to non-vaccinated contacts has been reported.
Intussusception: Following administration of a previously licensed live rhesus rotavirus reassortant vaccine, an increased risk of
intussusception was observed. 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.
In worldwide passive post-marketing surveillance, cases of intussusception have been reported in temporal association with RotaTeq.
Gastrointestinal Illness: No safety or efficacy data are available for administration of RotaTeq to infants with a history of
gastrointestinal disorders including infants with active acute gastrointestinal illness, infants with chronic diarrhea and failure to thrive, and
infants with a history of congenital abdominal disorders, and abdominal surgery. Caution is advised when considering administration of
RotaTeq to these infants.
Shedding and Transmission: Shedding of vaccine virus was evaluated among a subset of subjects in REST* 4 to 6 days after each
dose and among all subjects who submitted a stool antigen rotavirus positive sample at any time. RotaTeq was shed in the stools of 32 of
360 [8.9%, 95% CI (6.2%, 12.3%)] vaccine recipients tested after dose 1; 0 of 249 [0.0%, 95% CI (0.0%, 1.5%)] vaccine recipients tested after
dose 2; and in 1 of 385 [0.3%, 95% CI (<0.1%, 1.4%)] vaccine recipients after dose 3. In phase 3 studies, shedding was observed as early as 1
day and as late as 15 days after a dose. Transmission of vaccine virus was not evaluated in phase 3 studies. Transmission of vaccine virus
strains from vaccinees to non-vaccinated 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. Caution is advised when considering whether to
administer RotaTeq to individuals with immunodeficient close contacts such as: individuals with malignancies or who are otherwise
immunocompromised; individuals with primary immunodeficiency; or individuals receiving immunosuppressive therapy.
Temperature ≥100.5°F [38.1°C] rectal equivalent obtained by adding 1 degree F to otic and oral temperatures and 2 degrees F to axillary
Other Adverse Events: Parents/guardians of the 11,711 infants were also asked to report the presence of other events on the
Vaccination Report Card for 42 days after each dose. Fever was observed at similar rates in vaccine (N=6,138) and placebo (N=5,573)
recipients (42.6% vs. 42.8%). Adverse events that occurred at a statistically higher incidence (i.e., 2-sided p-value <0.05) within the 42 days
of any dose among recipients of RotaTeq as compared with placebo recipients are shown in Table 5.
Table 5: Adverse events that occurred at a statistically higher incidence within 42 days of any dose among recipients of RotaTeq as
compared with placebo recipients
Incomplete Regimen: The clinical studies were not designed to assess the level of protection provided by only one or two doses
Safety in Pre-Term Infants: RotaTeq or placebo was administered to 2,070 pre-term infants (25 to 36 weeks gestational age, median
34 weeks) according to their age in weeks since birth in REST. All pre-term infants were followed for serious adverse experiences; a subset
of 308 infants was monitored for all adverse experiences. There were 4 deaths throughout the study, 2 among vaccine recipients (1 SIDS
and 1 motor vehicle accident) and 2 among placebo recipients (1 SIDS and 1 unknown cause). No cases of intussusception were reported.
Serious adverse experiences occurred in 5.5% of vaccine and 5.8% of placebo recipients. The most common serious adverse experience
was bronchiolitis, which occurred in 1.4% of vaccine and 2.0% of placebo recipients. Parents/guardians were asked to record the child's
temperature and any episodes of vomiting and diarrhea daily for the first week following vaccination. The frequencies of these adverse
experiences and irritability within the week after dose 1 are summarized in Table 6.
Limitations of Vaccine Effectiveness: RotaTeq may not protect all vaccine recipients against rotavirus.
Table 6: Solicited adverse experiences within the first week of doses 1, 2, and 3 among pre-term infants
Febrile Illness: Febrile illness may be reason for delaying use of RotaTeq except when, in the opinion of the physician, withholding the
vaccine entails a greater risk. Low-grade fever (<100.5°F [38.1°C]) itself and mild upper respiratory infection do not preclude vaccination
Post-Exposure Prophylaxis: No clinical data are available for RotaTeq when administered after exposure to rotavirus.
Clinical Studies Experience: 71,725 infants were evaluated in 3 placebo-controlled clinical trials including 36,165 infants in the group
that received RotaTeq and 35,560 infants in the group that received placebo. Parents/guardians were contacted on days 7, 14, and 42 after
each dose regarding intussusception and any other serious adverse events. The racial distribution was as follows: White (69% in both
groups); Hispanic-American (14% in both groups); Black (8% in both groups); Multiracial (5% in both groups); Asian (2% in both groups);
Native American (RotaTeq 2%, placebo 1%); and Other (<1% in both groups). The gender distribution was 51% male and 49% female in both
vaccination groups. Because clinical trials are conducted under conditions that may not be typical of those observed in clinical practice,
the adverse reaction rates presented below may not be reflective of those observed in clinical practice.
Serious Adverse Events: Serious adverse events occurred in 2.4% of recipients of RotaTeq when compared to 2.6% of placebo
recipients within the 42-day period of a dose in the phase 3 clinical studies of RotaTeq. The most frequently reported serious adverse
events for RotaTeq compared to placebo were: bronchiolitis (0.6% RotaTeq vs. 0.7% Placebo), gastroenteritis (0.2% RotaTeq vs. 0.3%
Placebo), pneumonia (0.2% RotaTeq vs. 0.2% Placebo), fever (0.1% RotaTeq vs. 0.1% Placebo), and urinary tract infection (0.1% RotaTeq
vs. 0.1% Placebo).
Deaths: Across the clinical studies, 52 deaths were reported. There were 25 deaths in the RotaTeq recipients compared to 27 deaths in the
placebo recipients. The most commonly reported cause of death was sudden infant death syndrome, which was observed in 8 recipients of
RotaTeq and 9 placebo recipients.
Intussusception: In REST, 34,837 vaccine recipients and 34,788 placebo recipients were monitored by active surveillance to identify
potential cases of intussusception at 7, 14, and 42 days after each dose, and every 6 weeks thereafter for 1 year after the first dose. For the
primary safety outcome, cases of intussusception occurring within 42 days of any dose, there were 6 cases among RotaTeq recipients and
5 cases among placebo recipients (see Table 1). The data did not suggest an increased risk of intussusception relative to placebo.
Table 1: Confirmed cases of intussusception in recipients of RotaTeq as compared with placebo recipients during REST
Confirmed intussusception cases within 42 days of any dose
Relative risk (95% CI)†
Confirmed intussusception cases within 365 days of dose 1
Relative risk (95% CI)
Temperature ≥100.5°F [38.1°C] rectal equivalent obtained by adding 1 degree F to otic and oral temperatures and 2 degrees F to axillary
Post-Marketing Experience: The following adverse events have been identified during post-approval use of RotaTeq from reports to the
Vaccine Adverse Event Reporting System (VAERS). Reporting of adverse events following immunization to VAERS is voluntary, and the
number of doses of vaccine administered is not known; therefore, it is not always possible to reliably estimate the adverse event frequency
or establish a causal relationship to vaccine exposure using VAERS data. In post-marketing experience, the following adverse events have
been reported following the use of RotaTeq: Immune system disorders-Anaphylactic reaction. Gastrointestinal disorders-Intussusception
(including death), Hematochezia, Gastroenteritis with vaccine viral shedding in infants with Severe Combined Immunodeficiency Disease
(SCID). Skin and subcutaneous tissue disorders-Urticaria, Angioedema. Infections and infestations-Kawasaki disease, Transmission of
vaccine virus strains from vaccine recipient to non-vaccinated contacts.
Reporting Adverse Events: Parents or guardians should be instructed to report any adverse reactions to their health care provider.
Health care providers should report all adverse events to the US Department of Health and Human Services' Vaccine Adverse Events
Reporting System (VAERS). VAERS accepts all reports of suspected adverse events after the administration of any vaccine, including but
not limited to the reporting of events required by the National Childhood Vaccine Injury Act of 1986. For information or a copy of the vaccine
reporting form, call the VAERS toll-free number at 1-800-822-7967 or report online to www.vaers.hhs.gov.
Immunosuppressive therapies including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater
than physiologic doses), may reduce the immune response to vaccines.
Among vaccine recipients, there were no confirmed cases of intussusception within the 42-day period after the first dose, which was the
period of highest risk for the rhesus rotavirus-based product (see Table 2).
Table 2: Intussusception cases by day range in relation to dose in REST
0.9 (0.4, 1.9)
Relative risk and 95% confidence interval based upon group sequential design stopping criteria employed in REST.
1.6 (0.4, 6.4)
Concomitant Vaccine Administration: In clinical trials, RotaTeq was administered concomitantly with diphtheria and tetanus toxoids
and acellular pertussis (DTaP), inactivated poliovirus vaccine (IPV), H. influenzae type b conjugate (Hib), hepatitis B vaccine, and
pneumococcal conjugate vaccine. The safety data available are in the ADVERSE REACTIONS section. There was no evidence for reduced
antibody responses to the vaccines that were concomitantly administered with RotaTeq.
USE IN SPECIFIC POPULATIONS
Pediatric Use: Safety and efficacy have not been established in infants less than 6 weeks of age or greater than 32 weeks of age. Data
are available from clinical studies to support the use of RotaTeq in pre-term infants according to their age in weeks since birth. Data are
available from clinical studies to support the use of RotaTeq in infants with controlled gastroesophageal reflux disease.
Carcinogenesis, Mutagenesis, Impairment of Fertility: RotaTeq has not been evaluated for its carcinogenic or mutagenic potential or its
potential to impair fertility.
All of the children who developed intussusception recovered without sequelae with the exception of a 9-month-old male who developed
intussusception 98 days after dose 3 and died of post-operative sepsis. There was a single case of intussusception among 2,470 recipients
of RotaTeq in a 7-month-old male in the phase 1 and 2 studies (716 placebo recipients).
Hematochezia: Hematochezia reported as an adverse experience occurred in 0.6% (39/6,130) of vaccine and 0.6% (34/5,560) of placebo
recipients within 42 days of any dose. Hematochezia reported as a serious adverse experience occurred in <0.1% (4/36,150) of vaccine and
<0.1% (7/35,536) of placebo recipients within 42 days of any dose.
*Rotavirus Efficacy and Safety Trial.
PATIENT COUNSELING INFORMATION
Information for Parents/Guardians: Parents or guardians should be given a copy of the required vaccine information and be given
the "Patient Information" appended to the Prescribing Information. Parents and/or guardians should be encouraged to read the patient
information that describes the benefits and risks associated with the vaccine and ask any questions they may have during the visit.
For more detailed information, please read the Prescribing Information.
Copyright © 2016 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. VACC-1169148-0009 07/16