Data Sheet

RotaTeq^®

rotavirus vaccine, live, oral, pentavalent

Single dose 2 mL unit dosing tube

Presentation

RotaTeq is available as a single, pre-filled 2 mL unit dose in a plastic dosing tube with a twist-off cap. The dosing tube is contained in a pouch. The container and delivery system are latex-free.

Each 2 mL dose contains the following human-bovine rotavirus reassortants: G1, G2, G3, G4, and P1A[8]. The minimum dose levels of the reassortants are as follows:

G1 2.2 X 10⁶ infectious units
G2 2.8 X 10⁶ infectious units
G3 2.2 X 10⁶ infectious units
G4 2.0 X 10⁶ infectious units
P1A[8] 2.3 X 10⁶ infectious units

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

Therapeutic Class

RotaTeq is a live, oral pentavalent vaccine which protects against rotavirus gastroenteritis.

Indications

RotaTeq is an oral pentavalent vaccine indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the serotypes G1, G2, G3, G4, and G-serotypes that contain P1A[8] (e.g., G9). RotaTeq may be administered as early as six weeks of age.

Dosage and Administration

FOR ORAL USE ONLY. NOT FOR INJECTION.

Posology

The vaccination series consists of three ready-to-use liquid doses of RotaTeq administered orally to infants.

The first dose of RotaTeq should be administered at 6 to 12 weeks of age; the subsequent doses should be administered at a minimum interval of 4 weeks between each dose. The vaccination course should be completed by 32 weeks of age.

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

RotaTeq may be given to pre-term infants according to their chronological age.

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.

The vaccine is to be administered orally without mixing with any other vaccines or solutions. Do not reconstitute or dilute.

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

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.)
	Discard the empty tube and cap in approved biological waste containers according to local regulations.

Use with Other Vaccines

RotaTeq can be administered with diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine, inactivated or oral poliovirus vaccine (IPV or OPV), Haemophilus influenzae type b conjugate vaccine, hepatitis B vaccine, pneumococcal conjugate vaccine, and hexavalent vaccines.

Concomitant administration of RotaTeq and oral poliovirus vaccine (OPV) does not affect the immune response to the poliovirus antigens. Although concomitant administration of OPV may reduce some immune responses to rotavirus vaccine, there is evidence that a high level of efficacy against severe rotavirus gastroenteritis is maintained. The immune responses to RotaTeq are unaffected when OPV is administered two weeks after RotaTeq.

Contraindications

Hypersensitivity to any component of the vaccine.

Individuals who develop symptoms suggestive of hypersensitivity after receiving a dose of RotaTeq should not receive further doses of RotaTeq.

Warnings and Precautions

No safety or efficacy data are available from clinical trials regarding the administration of RotaTeq to:

immunocompromised patients such as
- individuals with malignancies or who are otherwise immunocompromised;
- individuals receiving immunosuppressive therapy;
Individuals infected with HIV; or
individuals who have received a blood transfusion or blood products, including immunoglobulins within 42 days.

Cases of gastroenteritis associated with vaccine virus have been reported post marketing in infants with severe combined immunodeficiency (SCID).

No faecal shedding of vaccine strains was seen in a small subset of infants with serious medical conditions (e.g., cystic fibrosis, failure to thrive, cancer, congenital heart disease, and neutropaenia) that were diagnosed after enrollment in the study. Health care providers may want to consider these data when assessing the benefits and potential risks of administering RotaTeq to infants with serious medical conditions while keeping in mind nearly all children are infected with naturally occurring rotavirus by age 5 years.

In clinical trials, RotaTeq was not administered to infants known to have immunodeficient household members. In these trials, RotaTeq was shed in the stools of 8.9% of vaccine recipients[0] almost exclusively in the week after dose 1 and in only one vaccine recipient (0.3%) after dose 3. There is a theoretical risk that the live virus vaccine can be transmitted to non-vaccinated contacts. Therefore, RotaTeq should be administered with caution to individuals with immunodeficient close contacts such as:

individuals with malignancies or who are otherwise immunocompromised; or
individuals receiving immunosuppressive therapy.

However, because nearly all children are infected with naturally occurring rotavirus by the age of 5 years, vaccination of infants may decrease the risk of exposure of immunodeficient household contacts to naturally occurring rotavirus. The health care provider should assess the potential risks and benefits of administering RotaTeq to infants known to have immunodeficient close contacts.

Infants with active gastrointestinal illness, chronic diarrhoea or growth retardation, or a history of congenital abdominal disorders or intussusception were not to be included in the clinical studies. Administration of RotaTeq may be considered with caution in such infants when, in the opinion of the physician, withholding the vaccine entails a greater risk.

Any acute infection or 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 itself and mild upper respiratory infection are not contraindications to vaccination with RotaTeq.

As with any vaccine, vaccination with RotaTeq may not result in complete protection in all recipients.

The clinical studies were not designed to assess the level of protection provided by only 1 or 2 doses of RotaTeq. Post hoc analyses of data from a large clinical study suggest that RotaTeq provides protection against hospitalisations and emergency department visits for rotavirus gastroenteritis during administration of the 3-dose vaccination series starting from 14 days post dose 1.

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

Pregnancy

RotaTeq is a paediatric vaccine and is not indicated for use in adults. There have been no adequate, well-controlled studies in women or animals.

Nursing Mothers

As RotaTeq is a paediatric vaccine and is not indicated for use in adults, information on the safety of the vaccine when used during lactation is not available.

Paediatric Use

Safety and efficacy have not been established in infants less than 6 weeks of age or in individuals older than 32 weeks of age. The first dose of vaccine should be administered by 12 weeks of age, and the vaccination course should be completed by 32 weeks of age. Safety, including the risk of intussusception, has not been studied in infants who received a vaccine dose after the age of 32 weeks. (See Dosage and Administration for the recommended dosage schedule.)

Animal Toxicology

A single and repeated dose oral toxicity study in mice suggests no special hazard to humans. The dose administered to mice was approximately 2.79 X 10⁸ infectious units per kg (about 14-fold the projected infant dose).

Carcinogenesis, Mutagenesis, Reproduction

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

Effects on Ability to Drive and Use Machines

Not applicable.

Adverse Effects

71,725 infants were evaluated in 3 placebo-controlled clinical trials including 36,165 infants who received RotaTeq and 35,560 infants who received placebo. Parents/guardians were contacted on days 7, 14, and 42 after each dose regarding intussusception and any other serious adverse events.

The vaccine is generally well tolerated.

In the large-scale (34,837 vaccine recipients and 34,788 placebo recipients), placebo-controlled Rotavirus Efficacy and Safety Trial (REST), RotaTeq did not increase the risk of intussusception relative to placebo (see Table 1). Active surveillance was employed to identify potential cases of intussusception at days 7, 14, and 42 after each dose and every 6 weeks thereafter for 1 year after dose one. There were no confirmed cases of intussusception during the 42-day period after dose one, and there was no clustering of cases among vaccine recipients at any time period after any dose. Following the 1-year safety follow-up period, 4 cases of intussusception were reported in children who had received placebo during the study.

Table 1
Confirmed Cases of Intussusception in Recipients of RotaTeq as Compared with Placebo Recipients during REST

	RotaTeq (n=34,837)	Placebo (n=34,788)
Confirmed intussusception cases within 42 days after each dose	6	5
Relative Risk (95% CI)^†	1.6 (0.4, 6.4)	--

Confirmed intussusception cases within 365 days after dose one	13	15
Relative Risk (95% CI)	0.9 (0.4, 1.9)	--

^† Relative Risk and 95% Confidence Interval based upon group sequential design stopping criteria employed in REST.

Kawasaki's disease was reported in the phase III clinical trials in <0.1% (5/36,150) of vaccine recipients and <0.1% (1/35,536) of placebo recipients within 42 days of any dose (not statistically significant).

In 11,711 infants (6,138 recipients of RotaTeq) from the 3 studies, a Vaccination Report Card was used by parents/guardians to record the child's temperature and any episodes of diarrhoea and vomiting on a daily basis during the first week following each vaccination. Table 2 summarises the frequencies of these adverse events, regardless of cause.

Table 2
Adverse Experiences of Special Clinical Interest
within the First Week after the First Dose

Adverse Event	First Dose
	RotaTeq	Placebo
Elevated Temperature (≥100.5°F [38.1°C] rectal equivalent)	17.1%	16.2%

Vomiting	6.7%	5.4%

Diarrhoea	10.4%	9.1%

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. The following vaccine-related adverse experiences were observed among recipients of RotaTeq at a frequency at least 0.3% greater than that observed among placebo recipients.

Very Common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Very Rare (<1/10,000).

Infections and Infestations

Uncommon: nasopharyngitis (0.6% vaccine recipients, 0.3% placebo recipients)

Gastrointestinal disorders

Very Common: diarrhoea (17.6% vaccine recipients, 15.1% placebo recipients), vomiting (10.1% vaccine recipients, 8.1% placebo recipients)

General disorders and administration site conditions

Very Common: pyrexia (20.9% vaccine recipients, 18.7% placebo recipients)

Other Adverse Events

Otitis media and bronchospasm occurred in more vaccine than placebo recipients (14.5% versus 13.0% and 1.1% versus 0.7%, respectively) overall; however, among cases that were considered to be vaccine-related in the opinion of the study investigator, the incidence was the same for vaccine and placebo recipients for otitis media (0.3%) and bronchospasm (<0.1%).

Administration of other licensed vaccines was permitted in all studies. The safety of RotaTeq when administered concomitantly with pre-specified licensed vaccines including Haemophilus influenzae type b and hepatitis B vaccine, diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine, inactivated poliovirus vaccine (IPV), pneumococcal conjugate vaccine, and hexavalent vaccines was evaluated in all 3 phase III, placebo-controlled studies. In a subsequent controlled study, the safety of RotaTeq when administered concomitantly with oral poliovirus vaccine was evaluated. RotaTeq was well tolerated; the frequency of adverse experiences observed was generally similar to that seen in the control group.

Laboratory Adverse Experiences

Routine laboratory evaluations were not performed during the conduct of clinical trials; therefore, no laboratory adverse experiences were reported.

Post-marketing Reports

The following adverse experiences have been spontaneously reported during post-approval use of RotaTeq. Because these experiences were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.

Skin and subcutaneous tissue disorders: urticaria

Interactions

There are no known medicine interactions. (See Dosage and Administration, Use With Other Vaccines.)

Overdosage

There are no data with regard to overdose.

Actions

The human rotavirus serotypes (G1, G2, G3, G4, and P1A[8]) have been selected for RotaTeq because these strains caused over 90% of rotavirus disease in North America, Europe, and Australia and over 88% of rotavirus disease worldwide between 1973 and 2003.

Efficacy

The protective efficacy of RotaTeq was evaluated in two ways:

The efficacy of RotaTeq for prevention of rotavirus gastroenteritis was evaluated among 6,983 infants who received vaccine (n=3,484) or placebo (n=3,499) in 2 studies: the Rotavirus Efficacy and Safety Trial (REST) and Study 007. Efficacy evaluations included efficacy against any severity of rotavirus gastroenteritis and efficacy against severe rotavirus gastroenteritis.
The reduction in health care contacts for rotavirus gastroenteritis, including hospitalisations and emergency department visits, was evaluated among 68,038 infants in REST and in a subset of 20,736 infants in the Extension study among the Finnish cohort of REST. The infants were followed for up to 2 years post-vaccination in REST and those in the Extension study continued to be followed for up to 3 years post-vaccination. No safety data were collected during the Extension study. The reductions in routine visits to a physician and parent/legal guardian work loss days were also evaluated in REST.

The third dose of vaccine or placebo was administered to infants as old as 32 weeks of age. Concomitant administration of other licensed childhood vaccines except for oral poliovirus vaccine (OPV) was permitted in all phase III studies.

Efficacy against any severity of gastroenteritis caused by naturally occurring rotavirus of the composite of the G serotypes (G1-G4) included in the vaccine was 73.8%, and efficacy against severe rotavirus gastroenteritis was 98.2% through the first rotavirus season after completion of vaccination. RotaTeq also provided protection against non-vaccine G serotypes. Based on limited data, the efficacy against any severity of gastroenteritis caused by the non-vaccine G serotype (G9) was 74.1%. The efficacy of RotaTeq through two rotavirus seasons after completion of vaccination against any severity of rotavirus gastroenteritis was 71.3%.

RotaTeq reduced the rate of hospitalisations, emergency department visits, non-urgent care visits, and parent/legal guardian work loss days. The rate reductions for health care contacts (hospitalisations and emergency department visits) caused by serotypes G1-G4 in REST and the Extension study combined were as follows:

94.4% for hospitalisations and emergency department visits (RotaTeq n=34,035 infants, placebo n=34,003 infants);
- 94.3% for hospitalisations; and
- 94.4% for emergency department visits.

During year 3 (RotaTeq n=3,112 infants, placebo n=3,126 infants), there were no health care contacts for rotavirus gastroenteritis in the vaccine group and there was 1 (non-typeable) in the placebo group.

Non-urgent care visits and parent/legal guardian work loss days were evaluated for up to 2 years after vaccination in REST. The rate reductions were as follows:

86.0% for non-urgent care visits (RotaTeq n=2,834, placebo n=2,839 infants); and
86.6% for parent/legal guardian work loss days (RotaTeq n=34,035 infants, placebo n=34,003 infants).

Efficacy of RotaTeq against rotavirus gastroenteritis through the first full rotavirus season after completion of vaccination and reduction in hospitalisations and emergency department visits for rotavirus gastroenteritis for up to 3 years postvaccination by G-serotype are shown in Table 3.

Table 3
Efficacy of RotaTeq against rotavirus gastroenteritis

Reduction in incidence of rotavirus gastroenteritis through one full season post-vaccination in REST and Study 007 (RotaTeq n=3,484*) (% [95 % CI])
		Serotype
Severe disease (G1-G4)	Any severity (G1-G4)	G1	G2	G3	G4	G9
98.2% [89.6, 100]^†	73.8% [67.2, 79.3]^†	75.0% [68.2, 80.5]^†	63.4% [2.7, 88.2]^†	55.6% [<0, 92.6]	48.1% [<0, 91.6]	74.1% [<0, 99.5]
Reduction in hospitalisations and emergency department visits for rotavirus gastroenteritis for up to 2 years post-vaccination in REST and for up to 3 years post-vaccination in the Extension study** (RotaTeq n=34,035*) (% [95 % CI])
G1-G4		G1	G2	G3	G4	G9
94.4% [91.6, 96.2]^†		95.5% [92.8, 97.2]^†	81.9% [16.1, 98.0]^†	89.0% [53.3, 98.7]^†	83.4% [51.2, 95.8]^†	94.2% [62.2, 99.9]^†

* n= Number Vaccinated
^† Statistically Significant
** There were no typeable episodes of rotavirus gastroenteritis leading to hospitalisations or emergency department visits for rotavirus gastroenteritis in year 3.

Efficacy between Doses

The protective efficacy of RotaTeq against the incidence of rotavirus gastroenteritis of any severity caused by serotypes G1-G4 in the intervals between doses was not statistically significant. This was evaluated in a post hoc analysis of data from the clinical efficacy cohort of REST (n=5,673 infants).

However, the protective efficacy of RotaTeq as measured by a reduction in the rate of hospitalisations and emergency department visits for rotavirus gastroenteritis caused by serotypes G1-G4 in the intervals between doses during administration of the 3-dose vaccination series was evaluated in post hoc analyses of data from REST (n=68,038 infants). The results of these analyses are presented in Table 4.

Table 4
Reduction in hospitalisations and emergency department visits for rotavirus gastroenteritis in the intervals between doses during administration of the 3-dose vaccination series in REST

	RotaTeq n=34,035 infants; Placebo n=34,003 infants
	From ≥14 days after dose 1 until dose 2	From 14 ≥days after dose 2 until dose 3
Serotype	G1-G4	G1-G4
Efficacy estimate % and [95% Confidence Interval]	100 [72.2, 100]	90.9 [62.9, 99.0]

Efficacy and Safety in Pre-term Infants

RotaTeq or placebo was administered to 2,070 pre-term infants (25 to 36 weeks gestational age), including 1,007 recipients of RotaTeq, according to their chronological age in a placebo-controlled study. Among a subset of 308 pre-term infants who were followed for all adverse experiences, the safety profile was generally similar among those infants receiving RotaTeq as compared with those receiving placebo. The incidence of fever, vomiting, diarrhoea, or irritability was generally similar among vaccine and placebo recipients.

In a subset of 204 vaccinated infants (99 in the vaccine group), protective efficacy, as measured by a reduction in the incidence of rotavirus gastroenteritis of any severity caused by vaccine serotypes (G1-G4) that occurred at least 14 days after the third dose of vaccine through the first full rotavirus season after vaccination, was 70.3% [95% CI <0, 94.7]. In 2,070 vaccinated infants (1,007 in the vaccine group) in REST, protective efficacy, as measured by a reduction in the rate of hospitalisations and emergency department visits for rotavirus gastroenteritis caused by G1-G4 from 14 days for up to 2 years after the third dose, was 100% [95% CI 74, 100]. Likewise, the protective efficacy, as measured by a reduction in the rate of hospitalisations and emergency department visits for rotavirus gastroenteritis caused by any serotype from 14 days for up to 2 years after the third dose, was 100% [95% CI 82, 100].

Studies with Other Vaccines

The immunogenicity of RotaTeq and diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine, inactivated poliovirus vaccine (IPV), Haemophilus influenzae type b conjugate vaccine (HIB), hepatitis B vaccine, and pneumococcal conjugate vaccine was evaluated among 1,358 infants. The immune responses to the specified vaccines were unaffected by RotaTeq. In addition, the studies demonstrated the efficacy of RotaTeq (89.5%) when administered with these vaccines.

Concomitant administration of RotaTeq and oral polio vaccine (OPV) did not affect the immune response to the polio antigens in a controlled study of 735 vaccinated infants. Although concomitant administration of OPV reduced some immune responses to RotaTeq, the seroconversion rates (≥ than 3-fold rise from baseline) for serum IgA were >93%. There is evidence that a high level of efficacy against severe rotavirus gastroenteritis is maintained. The immune responses to RotaTeq are unaffected when OPV is administered two weeks after RotaTeq.

The safety profile, including the incidences of fever, vomiting, diarrhoea, and irritability, was generally similar among subjects receiving the specified concomitant vaccines with RotaTeq and subjects receiving the specified concomitant vaccines with placebo.

In one study, 7,367 infants received a hexavalent (DTaP, IPV, Hib, and hepatitis B) vaccine concomitantly with RotaTeq. The frequency of overall serious adverse experiences (SAEs), regardless of causal relationship, was 2.9% in recipients of RotaTeq and 3.2% in placebo recipients. More detailed safety information was evaluated among a subset of 638 infants receiving RotaTeq with a hexavalent vaccine. The safety profile, including the incidences of fever, vomiting, diarrhoea, and irritability, was generally similar among subjects receiving a hexavalent vaccine with RotaTeq and subjects receiving a hexavalent vaccine with placebo.

Immunogenicity

The immunologic mechanism by which RotaTeq protects against rotavirus gastroenteritis is unknown. A relationship between antibody responses to RotaTeq and protection against rotavirus gastroenteritis has not been established. However, RotaTeq induces antibodies that neutralise human serotypes G1, G2, G3, G4 and P1A[8]. In phase III studies, 92.9% to 100% of recipients of RotaTeq achieved a significant rise in serum anti-rotavirus IgA after a three-dose regimen.

Pharmacokinetics

Nil

Pharmaceutical Precautions

Store and transport refrigerated at 2°C to 8°C.
Protect from light until administered.
The product must be used before the expiration date.

RotaTeq should be administered as soon as possible after being removed from refrigeration. When out of refrigeration at room temperature at or below 25°C, administration may be delayed for up to 48 hours. After this time, the vaccine should be discarded in approved biological waste containers according to local regulations.

Medicine Classification

Prescription Medicine

Package Quantities

RotaTeq comes as a single dose 2 mL unit dosing tube.

Further Information

Chemistry

Pharmacotherapeutic group: viral vaccines
ATC code: J07BH02

RotaTeq is a live, oral pentavalent vaccine for use in the prevention of rotavirus gastroenteritis. The vaccine 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 VP7 proteins (serotype G1, G2, G3, or G4) from the human rotavirus parent strains and the VP4 attachment protein (serotype P7[5]) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the VP4 attachment protein (serotype P1A[8]) from the human rotavirus parent strain and the outer capsid VP7 protein (serotype G6) from the bovine rotavirus parent strain (see Table 5).

Table 5

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)
G1	WI79 - G1, P1A[8]	WC3 - G6, P7[5]	G1, P7[5]
G2	SC2 - G2, P2A[6]		G2, P7[5]
G3	WI78 - G3, P1A[8]		G3, P7[5]
G4	BrB - G4, P2A[6]		G4, P7[5]
P1A[8]	WI79 - G1, P1A[8]		G6, P1A[8]

Inactive Ingredients

The reassortants are suspended in a buffered stabiliser solution. Each vaccine dose contains sucrose, sodium citrate, sodium phosphate monobasic monohydrate, sodium hydroxide, polysorbate 80 and also culture media. There are no preservatives or thimerosal present.

Name and Address

Merck Sharp & Dohme (New Zealand) Limited
P O Box 99 851
Newmarket
Auckland
NEW ZEALAND
Tel: 0800 500 673

Date of Preparation

2 June 2009

DP-ROT-0609(020609)

INFORMATION FOR HEALTH PROFESSIONALS