Rotateq

rotavirus vaccine, live

Dosage Form: oral solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Rotateq

Rotateq1 is indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the serotypes G1, G2, G3, and G4 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 [see Dosage and Administration (2)].

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Registered trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey 08889 USA

COPYRIGHT © 2006, 2007 MERCK & CO., Inc.

All rights reserved

Rotateq 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 [see Clinical Studies (14)].

There are no restrictions on the infant’s consumption of food or liquid, including breast milk, either before or after vaccination with Rotateq.

Do not mix the Rotateq vaccine with any other vaccines or solutions. Do not reconstitute or dilute [see Dosage and Administration (2.2)].

For storage instructions [see How Supplied/Storage and Handling (16.1)].

Each dose is supplied in a container consisting of a squeezable plastic dosing tube with a twist-off cap, allowing for direct oral administration. The dosing tube is contained in a pouch [see Dosage and Administration (2.2)].

Use with Other Vaccines

In clinical trials, Rotateq was administered concomitantly with other licensed pediatric vaccines [see Adverse Reactions (6.1), Drug Interactions (7.1), and Clinical Studies (14)].

Instructions for Use

To administer the vaccine:
	Tear open the pouch and remove the dosing tube.
	Clear the fluid from the dispensing tip by holding tube vertically and tapping cap.
	Open the dosing tube in 2 easy motions:
	1.   Puncture the dispensing tip by screwing cap clockwise       until it becomes tight.
	2.   Remove cap by turning it counterclockwise.
	Administer dose by gently squeezing liquid into infant's mouth toward the inner cheek until dosing tube is empty. (A residual drop may remain in the tip of the tube.)
	If for any reason an incomplete dose is administered (e.g., infant spits or regurgitates the vaccine), a replacement dose is not recommended, since such dosing was not studied in the clinical trials. The infant should continue to receive any remaining doses in the recommended series.
	Discard the empty tube and cap in approved biological waste containers according to local regulations.

Dosage Forms and Strengths

Rotateq, 2 mL for oral use, is a ready-to-use solution of live reassortant rotaviruses, containing G1, G2, G3, G4 and P1A[8] which contains a minimum of 2.0 – 2.8 x 106 infectious units (IU) per individual reassortant dose, depending on the serotype, and not greater than 116 x 106 IU per aggregate dose.

Each dose is supplied in a container consisting of a squeezable plastic dosing tube with a twist-off cap, allowing for direct oral administration. The dosing tube is contained in a pouch.

Contraindications

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.

 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 [see Adverse Reactions (6.2)].

Warnings and Precautions

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 [see Warnings and Precautions (5.4)].

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, abdominal surgery, and intussusception. Caution is advised when considering administration of Rotateq to these infants.

Intussusception

Following administration of a previously licensed live rhesus rotavirus-based vaccine, an increased risk of intussusception was observed.{1} In the Rotavirus Efficacy and Safety Trial [REST] (n=69,625), the data did not show an increased risk of intussusception for Rotateq when compared to placebo. In post-marketing experience, cases of intussusception have been reported in temporal association with Rotateq. [See Adverse Reactions (6.1 and 6.2).]

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.

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 with Rotateq.

Incomplete Regimen

The clinical studies were not designed to assess the level of protection provided by only one or two doses of Rotateq.

Limitations of Vaccine Effectiveness

Rotateq may not protect all vaccine recipients against rotavirus.

Post-Exposure Prophylaxis

No clinical data are available for Rotateq when administered after exposure to rotavirus.

Adverse Reactions

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

* Relative risk and 95% confidence interval based upon group sequential design stopping criteria employed in REST.
	Rotateq (n=34,837)	Placebo (n=34,788)
Confirmed intussusception cases within 42 days of any dose	6	5
Relative risk (95% CI) *	1.6 (0.4, 6.4)
Confirmed intussusception cases within 365 days of dose 1	13	15
Relative risk (95% CI)	0.9 (0.4, 1.9)

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

	Dose 1		Dose 2		Dose 3		Any Dose
Day Range	Rotateq	Placebo	Rotateq	Placebo	Rotateq	Placebo	Rotateq	Placebo
1-7	0	0	1	0	0	0	1	0
1-14	0	0	1	0	0	1	1	1
1-21	0	0	3	0	0	1	3	1
1-42	0	1	4	1	2	3	6	5

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.

Seizures

All seizures reported in the phase 3 trials of Rotateq (by vaccination group and interval after dose) are shown in Table 3.

Table 3: Seizures reported by day range in relation to any dose in the phase 3 trials of Rotateq

Day range	1-7	1-14	1-42
Rotateq	10	15	33
Placebo	5	8	24

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 placebo recipients.

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).

Most Common Adverse Events

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)

* 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 temperatures
Adverse experience	Dose 1		Dose 2		Dose 3
	Rotateq	Placebo	Rotateq	Placebo	Rotateq	Placebo
Elevated temperature*	n=5,616 17.1%	n=5,077 16.2%	n=5,215 20.0%	n=4,725 19.4%	n=4,865 18.2%	n=4,382 17.6%
	n=6,130	n=5,560	n=5,703	n=5,173	n=5,496	n=4,989
Vomiting	6.7%	5.4%	5.0%	4.4%	3.6%	3.2%
Diarrhea	10.4%	9.1%	8.6%	6.4%	6.1%	5.4%
Irritability	7.1%	7.1%	6.0%	6.5%	4.3%	4.5%

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

Adverse event	Rotateq N=6,138	Placebo N=5,573
	n (%)	n (%)
Diarrhea	1,479 (24.1%)	1,186 (21.3%)
Vomiting	929 (15.2%)	758 (13.6%)
Otitis media	887 (14.5%)	724 (13.0%)
Nasopharyngitis	422 (6.9%)	325 (5.8%)
Bronchospasm	66 (1.1%)	40 (0.7%)

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.

Table 6: Solicited adverse experiences within the first week of doses 1, 2, and 3 among pre-term infants

* 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 temperatures
	Dose 1		Dose 2		Dose 3
Adverse event	Rotateq	Placebo	Rotateq	Placebo	Rotateq	Placebo
	N=127	N=133	N=124	N=121	N=115	N=108
Elevated temperature*	18.1%	17.3%	25.0%	28.1%	14.8%	20.4%
	N=154	N=154	N=137	N=137	N=135	N=129
Vomiting	5.8%	7.8%	2.9%	2.2%	4.4%	4.7%
Diarrhea	6.5%	5.8%	7.3%	7.3%	3.7%	3.9%
Irritability	3.9%	5.2%	2.9%	4.4%	8.1%	5.4%

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:

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

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 U.S. 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 on line to www.vaers.hhs.gov.{2}

Drug Interactions

Immunosuppressive therapies including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines.

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 [see Clinical Studies (14)]. The safety data available are in the ADVERSE REACTIONS section [see Adverse Reactions (6.1)]. There was no evidence for reduced antibody responses to the vaccines that were concomitantly administered with Rotateq.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with Rotateq. It is also not known whether Rotateq can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Rotateq is not indicated in women of child-bearing age and should not be administered to pregnant females.

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 [see Adverse Reactions (6.1)].

Data are available from clinical studies to support the use of Rotateq in infants with controlled gastroesophageal reflux disease.

Rotateq Description

Rotateq is a live, oral pentavalent vaccine that contains 5 live reassortant rotaviruses. The rotavirus parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant rotaviruses express one of the outer capsid proteins (G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment protein (serotype P7) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the attachment protein, P1A (genotype P[8]), herein referred to as serotype P1A[8], from the human rotavirus parent strain and the outer capsid protein of serotype G6 from the bovine rotavirus parent strain (see Table 7).

Table 7

Name of Reassortant	Human Rotavirus Parent Strains and Outer Surface Protein Compositions	Bovine Rotavirus Parent Strain and Outer Surface Protein Composition	Reassortant Outer Surface Protein Composition (Human Rotavirus Component in Bold)	Minimum Dose Levels (106 infectious units)
G1	WI79 – G1P1A[8]	WC3 - G6, P7[5]	G1P7[5]	2.2
G2	SC2 – G2P2[6]		G2P7[5]	2.8
G3	WI78 – G3P1A[8]		G3P7[5]	2.2
G4	BrB – G4P2[6]		G4P7[5]	2.0
P1A[8]	WI79 – G1P1A[8]		G6P1A[8]	2.3

The reassortants are propagated in Vero cells using standard cell culture techniques in the absence of antifungal agents.

The reassortants are suspended in a buffered stabilizer solution. Each vaccine dose contains sucrose, sodium citrate, sodium phosphate monobasic monohydrate, sodium hydroxide, polysorbate 80, cell culture media, and trace amounts of fetal bovine serum. Rotateq contains no preservatives.

In the manufacturing process for Rotateq, a porcine-derived material is used. DNA from porcine circoviruses (PCV) 1 and 2 has been detected in Rotateq. PCV-1 and PCV-2 are not known to cause disease in humans.

Rotateq is a pale yellow clear liquid that may have a pink tint.

The plastic dosing tube and cap do not contain latex.

Rotateq - Clinical Pharmacology

Rotavirus is a leading cause of severe acute gastroenteritis in infants and young children, with over 95% of these children infected by the time they are 5 years old.{3} The most severe cases occur among infants and young children between 6 months and 24 months of age.{4}

Mechanism of Action

The exact immunologic mechanism by which Rotateq protects against rotavirus gastroenteritis is unknown [see Clinical Studies (14.6)]. Rotateq is a live viral vaccine that replicates in the small intestine and induces immunity.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Rotateq has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility.

Clinical Studies

Overall, 72,324 infants were randomized in 3 placebo-controlled, phase 3 studies conducted in 11 countries on 3 continents. The data demonstrating the efficacy of Rotateq in preventing rotavirus gastroenteritis come from 6,983 of these infants from the US (including Navajo and White Mountain Apache Nations) and Finland who were enrolled in 2 of these studies: REST and Study 007. The third trial, Study 009, provided clinical evidence supporting the consistency of manufacture and contributed data to the overall safety evaluation.

The racial distribution of the efficacy subset was as follows: White (Rotateq 68%, placebo 69%); Hispanic-American (Rotateq 10%, placebo 9%); Black (2% in both groups); Multiracial (Rotateq 4%, placebo 5%); Asian (<1% in both groups); Native American (Rotateq 15%, placebo 14%); and Other (<1% in both groups). The gender distribution was 52% male and 48% female in both vaccination groups.

The efficacy evaluations in these studies included: 1) Prevention of any grade of severity of rotavirus gastroenteritis; 2) Prevention of severe rotavirus gastroenteritis, as defined by a clinical scoring system; and 3) Reduction in hospitalizations due to rotavirus gastroenteritis.

The vaccine was given as a three-dose series to healthy infants with the first dose administered between 6 and 12 weeks of age and followed by two additional doses administered at 4- to 10-week intervals. The age of infants receiving the third dose was 32 weeks of age or less. Oral polio vaccine administration was not permitted; however, other childhood vaccines could be concomitantly administered. Breast-feeding was permitted in all studies.

The case definition for rotavirus gastroenteritis used to determine vaccine efficacy required that a subject meet both of the following clinical and laboratory criteria: (1) greater than or equal to 3 watery or looser-than-normal stools within a 24-hour period and/or forceful vomiting; and (2) rotavirus antigen detection by enzyme immunoassay (EIA) in a stool specimen taken within 14 days of onset of symptoms. The severity of rotavirus acute gastroenteritis was determined by a clinical scoring system that took into account the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral changes.

The primary efficacy analyses included cases of rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 that occurred at least 14 days after the third dose through the first rotavirus season post vaccination.

Analyses were also done to evaluate the efficacy of Rotateq against rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 at any time following the first dose through the first rotavirus season postvaccination among infants who received at least one vaccination (Intent-to-treat, ITT).

Rotavirus Efficacy and Safety Trial

Primary efficacy against any grade of severity of rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 74.0% (95% CI: 66.8, 79.9) and the ITT efficacy was 60.0% (95% CI: 51.5, 67.1). Primary efficacy against severe rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 98.0% (95% CI: 88.3, 100.0), and ITT efficacy was 96.4% (95% CI: 86.2, 99.6). See Table 8.

Table 8: Efficacy of Rotateq against any grade of severity of and severe* G1-4 rotavirus gastroenteritis through the first rotavirus season postvaccination in REST