RotaTeq is indicated for the active immunisation of infants from the age of 6 weeks to 32 weeks for prevention of gastroenteritis due to rotavirus infection (see sections 4.2, 4.4 and 5.1).

RotaTeq is to be used on the basis of official recommendations.

Posology

From birth to 6 weeks

RotaTeq is not indicated in this subset of paediatric population.

The safety and efficacy of RotaTeq in individuals from birth to 6 weeks of age have not been established.

From 6 weeks to 32 weeks

The vaccination course consists of three doses.

The first dose may be administered from the age of 6 weeks and no later than the age of 12 weeks.

RotaTeq may be given to infants who were born prematurely provided that the period of gestation was at least 25 weeks. These infants should receive the first dose of RotaTeq at least six weeks after birth (see sections 4.4 and 5.1).

There should be intervals of at least 4 weeks between doses.

It is preferable that the vaccination course of three doses should be completed by the age of

20-22 weeks. If necessary, the third (last) dose may be given up to the age of 32 weeks (see section 5.1).

As no data exist regarding the interchangeability of RotaTeq with another rotavirus vaccine, it is recommended that infants who receive RotaTeq for the first immunisation against rotavirus should receive this same vaccine for the subsequent doses.

If it is observed or strongly suspected that an incomplete dose has been swallowed (e.g., infant spits or regurgitates the vaccine), a single replacement dose may be given at the same vaccination visit, however, this has not been studied in clinical trials. If the problem recurs, additional replacement doses should not be given.

No further doses are recommended after completion of the 3-dose vaccination course (see sections 4.4 and 5.1 regarding available information on persistence of protection).

From 33 weeks to 18 years

RotaTeq is not indicated in this subset of paediatric population.

Method of administration

RotaTeq is for oral administration only.

RotaTeq SHOULD UNDER NO CIRCUMSTANCES BE INJECTED.

RotaTeq may be given without regard to food, liquid, or breast milk. See section 6.6 for administration instructions.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

As with all vaccines, appropriate medical treatment should always be readily available in case of an anaphylactic event following the administration of the vaccine (see section 4.8).

No safety or efficacy data are available from clinical trials regarding administration of RotaTeq to immunocompromised infants, those exposed in utero to an immunosuppressive treatment, infants infected with HIV or infants who have received a blood transfusion or immunoglobulins within 42 days of dosing. Asymptomatic HIV infection is not expected to affect the safety or efficacy of

RotaTeq. However, in the absence of sufficient data, administration of RotaTeq to asymptomatic HIV- infected infants is not recommended. Administration of RotaTeq to infants who have been exposed in utero to an immunosuppressive treatment should be based on careful consideration of potential benefits and risks.

Cases of gastroenteritis associated with vaccine virus have been reported post marketing in infants with severe combined immunodeficiency (SCID, see section 4.3).

In trials, RotaTeq was shed in the stools of 8.9 % of vaccine recipients almost exclusively in the week after dose 1 and in only one vaccine recipient (0.3 %) after dose 3. Peak excretion occurred within

7 days of dosing. Transmission of vaccine virus strains to non-vaccinated contacts has been observed post-marketing. RotaTeq should be administered with caution to individuals with close contacts who are immunodeficient (e.g., individuals with malignancies or who are otherwise immunocompromised or individuals receiving immunosuppressive therapy). Also, those caring for recent vaccinees should observe careful hygiene especially when handling excreta.

In a clinical study, RotaTeq was administered to approximately 1,000 infants who were born at a gestational age of 25 to 36 weeks. The first dose was administered from 6 weeks after birth. The safety and efficacy of RotaTeq were comparable between this subset of infants and infants born at term.

However, 19 of the approximately 1,000 infants were born at a gestational age of 25 to 28 weeks, 55 were born at a gestational age of 29 to 31 weeks and the remainder was born at a gestational age of between 32 and 36 weeks. See sections 4.2 and 5.1.

Intussusception

As a precaution, healthcare professionals should follow-up on any symptoms indicative of intussusception (severe abdominal pain, persistent vomiting, bloody stools, abdominal bloating and/or high fever) since data from observational studies indicate an increased risk of intussusception, mostly within 7 days after rotavirus vaccination (see section 4.8). Parents/guardians should be advised to promptly report such symptoms to their healthcare provider.

For subjects with a predisposition for intussusception, see section 4.3.

Safety or efficacy data are not available for infants with active gastrointestinal illnesses (including chronic diarrhoea) or growth retardation. 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.

The level of protection provided by RotaTeq is based on the completion of all 3 doses. As with any vaccine, vaccination with RotaTeq may not result in complete protection in all recipients. RotaTeq does not protect against gastroenteritis due to other pathogens than rotavirus.

Clinical trials of efficacy against rotavirus gastroenteritis were performed in Europe, the United States, Latin America, and Asia. During these trials, the most common circulating rotavirus genotype was G1P[8], while rotavirus genotypes G2P[4], G3P[8], G4P[8], and G9P[8] were identified less often.

The extent of protection that RotaTeq might provide against other rotavirus types and in other populations is unknown.

No clinical data are available on the use of RotaTeq for post-exposure prophylaxis.

The potential risk of apnoea and the need for respiratory monitoring for 48-72 h should be considered when administering the primary immunisation series to very premature infants (born ≤28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed.

RotaTeq SHOULD UNDER NO CIRCUMSTANCES BE INJECTED.

Sucrose

RotaTeq contains sucrose. Patients with rare hereditary problems of fructose intolerance,

glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this vaccine. See section 2.

Sodium

This vaccine contains 37.6 mg sodium per dose, equivalent to 1.88% of the WHO recommended maximum daily intake of 2 g sodium for an adult. See section 2.

Co-administration of RotaTeq with vaccines containing one or more of the following antigens at approximately 2, 4 and 6 months of age demonstrated that the immune responses and the safety profiles of the administered vaccines were unaffected:

-      Diphtheria-tetanus-acellular pertussis vaccine (DTaP)

-      Haemophilus influenzae type b vaccine (Hib)

-      Inactivated poliomyelitis vaccine (IPV)

-      Hepatitis B vaccine (HBV)

-      Pneumococcal conjugate vaccine (PCV)

Co-administration of RotaTeq with DTaP-IPV-HBV-Hib vaccine (Infanrix hexa) at approximately 2, 3, and 4 months of age demonstrated that the immune responses and the safety profiles of the

co-administered vaccines were unaffected compared to separate administrations.

Co-administration of RotaTeq with a group C meningococcal conjugate vaccine (MenCC, the vaccine studied was a tetanus toxoid conjugate) at 3 and 5 months of age (and mostly at the same time as DTaP-IPV-Hib vaccine), followed by a third dose of RotaTeq at approximately 6 months of age, demonstrated that the immune responses to RotaTeq and MenCC were unaffected. Co-administration resulted in an acceptable safety profile.

Concomitant administration of RotaTeq and oral poliomyelitis vaccine (OPV) did not affect the immune response to the poliovirus antigens. Although concomitant administration of OPV slightly reduced the immune response to rotavirus vaccine, there is currently no evidence that clinical protection against severe rotavirus gastroenteritis would be affected. The immune response to RotaTeq was unaffected when OPV was administered two weeks after RotaTeq.

Therefore, RotaTeq can be given concomitantly with monovalent or combination infant vaccines containing one or more of the following antigens: DTaP, Hib, IPV or OPV, HBV, PCV and MenCC.

RotaTeq is intended for use in infants only. Thus human data on use during pregnancy or lactation are not available and animal fertility or reproduction studies have not been performed.

Not relevant.

a.  Summary of the safety profile

In a subset of infants from 3 placebo-controlled clinical trials (n=6,130 recipients of RotaTeq and 5,560 placebo recipients), RotaTeq was evaluated for all adverse events within 42 days of vaccination with or without concomitant use of other paediatric vaccines. Overall, 47 % of infants given RotaTeq experienced an adverse reaction compared with 45.8 % of infants given placebo. The most commonly reported adverse reactions that occurred more frequently with vaccine than with placebo were pyrexia (20.9 %), diarrhoea (17.6 %) and vomiting (10.1 %).

Serious adverse reactions were assessed in all participants (36,150 recipients of RotaTeq and

35,536 placebo recipients) of 3 clinical trials for up to 42 days after each dose. The overall frequency of these serious adverse reactions was 0.1 % among recipients of RotaTeq and 0.2 % among placebo recipients.

b.  Tabulated summary of adverse reactions

Adverse reactions more common in the vaccine group in clinical trials are listed below per system organ class and frequency. Based on pooled data from 3 clinical trials in which 6,130 infants received RotaTeq and 5,560 received placebo, the adverse reactions listed occurred with excess incidences in RotaTeq recipients compared to placebo recipients of between 0.2 % and 2.5 %.

Frequencies are reported as:

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), Not known (cannot be estimated from the available data)

^† This adverse reaction was identified through post-marketing surveillance. The frequency category was estimated based on relevant clinical trials.

^α The frequency category was estimated based on observational study data.

*  See section 4.4.

^‡ Post-marketing adverse events (frequency cannot be estimated from the available data).

c.  Description of selected adverse reactions

Kawasaki disease was reported in 5 of 36,150 vaccine recipients (<0.1 %) and 1 of 35,536 placebo recipients (<0.1 %) with a relative risk (RR) of 4.9 [95 % CI, 0.6 – 239.1] (not statistically significant). No increased risk of Kawasaki disease was observed among infants receiving RotaTeq in a large post- marketing observational safety surveillance study (see section 5.1).

Intussusception

Data from observational safety studies performed in several countries indicate that rotavirus vaccines carry an increased risk of intussusception, with up to 6 additional cases per 100,000 infants within

7 days of vaccination. There is limited evidence of a smaller increased risk following the second dose. The background incidence of intussusception in infants less than one year of age in these countries ranged from 25 to 101 per 100,000 infants per year. It remains unclear whether rotavirus vaccines affect the overall incidence of intussusception based on longer periods of follow up (see section 4.4).

d.  Other special populations

Apnoea in very premature infants (born ≤28 weeks of gestation) (see section 4.4)

Gastroenteritis with vaccine viral shedding in infants with Severe Combined Immunodeficiency Disease (SCID) has been reported post-marketing.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via.

·          Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

·         Other GCC States:

Please contact the relevant competent authority.

There have been reports of administration of higher than recommended doses of RotaTeq.

In general, the adverse event profile reported with overdose was comparable to that observed with recommended doses of RotaTeq.

Pharmacotherapeutic group: Vaccines, Viral Vaccine ATC code: J07BH02. Efficacy

In clinical trials, efficacy was demonstrated against gastroenteritis due to rotavirus of genotypes G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8].

The protective efficacy of RotaTeq was evaluated in two ways in the placebo-controlled Rotavirus Efficacy and Safety Trial (REST):

1.             In 5,673 vaccinated infants (2,834 in the vaccine group) protective efficacy was measured as a reduction in the incidence of rotavirus (RV) gastroenteritis caused by vaccine G genotypes (G1-G4) that occurred at least 14 days after the third dose of vaccine through the first full rotavirus season after vaccination.

2.             In 68,038 vaccinated infants (34,035 in the vaccine group) protective efficacy was measured as a reduction in the rate of hospitalisations and emergency department visits for RV gastroenteritis from 14 days after the third dose.

The results of these analyses are presented in the following tables.

*  Severe defined as a score >16/24 using a validated clinical scoring system based on the intensity and duration of symptoms (fever, vomiting, diarrhoea and behavioural changes)

^† Statistically significant

^† Statistically significant

The reduction in incidence of RV gastroenteritis caused by genotypes G1-G4 during the second rotavirus season after vaccination was 88.0 % [95 % CI 49.4, 98.7] for severe disease and 62.6 % [95 % CI 44.3, 75.4] for disease of any severity.

Efficacy against genotypes G2P[4], G3P[8], G4P[8] and G9P[8] rotavirus was based on fewer cases than for G1. The efficacy observed against G2P[4] most likely resulted from the G2 component of the vaccine.

In a combined post-hoc analysis of REST and another phase III study, the vaccine efficacy against G1-, G2-, G3- and G4-serotype RVG cases (any severity) was 61.5 % [95 % CI: 14.2; 84.2] among infants who were >26 to ≤32 weeks of age at dose 3.

There was an extension of REST conducted in Finland only. This Finnish Extension Study (FES) included a subset of 20,736 subjects that had been enrolled previously in REST. The infants were followed for up to 3 years post-vaccination in the FES.

In REST there were 403 healthcare encounters (20 in the vaccine group and 383 in the placebo group) associated with G1-G4 and G9 RV gastroenteritis in the per protocol population. The additional data from the FES increased the number by 136 encounters in total, including 9 in the vaccine group and 127 in the placebo group. Overall, 31 % and 25 % of the encounters in the respective groups occurred during the FES.

Based upon combined data from REST and the FES, the reduction up to 3 years post-vaccination in the rate of hospitalisations and emergency department visits for RV gastroenteritis was 94.4 %

(95 % CI: 91.6, 96.2) for genotypes G1-G4, 95.5 % (95 % CI: 92.8, 97.2) for genotype G1, 81.9 %

(95 % CI: 16.1, 98.0) for genotype G2, 89.0 % (95 % CI: 53.3, 98.7) for genotype G3, 83.4 %

(95 % CI: 51.2, 95.8) for genotype G4, and 94.2 % (95 % CI: 62.2, 99.9) for genotype G9. During year 3, there were no health care contacts for RV gastroenteritis in the vaccine group (n=3,112) and one (non-typeable) in the placebo group (n=3,126).

A complete 3-dose vaccination series of RotaTeq should be administered (see section 4.2) to provide the level and duration of protection against rotavirus gastroenteritis that was observed in the clinical studies. However, post hoc analyses indicated that RotaTeq achieved some reduction in the numbers of cases of rotavirus gastroenteritis of sufficient severity to require hospitalisation or an emergency department visit before completion of all three doses (i.e. from approximately 14 days after administration of the first dose onwards).

Efficacy in premature infants

In REST, RotaTeq was administered to approximately 1,000 infants who were born at a gestational age of 25 to 36 weeks. The efficacy of RotaTeq was comparable between this subset of infants and infants born at term.

Post-marketing observational safety surveillance study

In a large prospective post-marketing observational study in the US, the risk of Kawasaki disease was analysed among 85,150 infants receiving one or more doses of RotaTeq (17,433 person-years of follow-up).

During the 0-30 day follow-up period after vaccination, there were no statistically significant difference in the rate of Kawasaki disease compared with the expected background rate. In addition, there was no statistically significant increased risk of this adverse event during the 0-30 day follow-up period compared with a concurrent control group of infants who received DTaP, but not RotaTeq (n=62,617, 12,339 person-years of follow-up). One chart-confirmed case was recorded among infants vaccinated with RotaTeq compared with one chart-confirmed case among concurrent DTaP controls (relative risk = 0.7, 95 % CI: 0.01-55.56). In the general safety analyses, no specific safety concerns were identified.

Effectiveness study data

Post marketing studies demonstrating effectiveness to prevent RV gastroenteritis (RVGE)

*RV-negative acute gastroenteritis controls

Immunogenicity

The immunological mechanism by which RotaTeq protects against rotavirus gastroenteritis is not completely understood. No immunological correlate of protection has currently been identified for rotavirus vaccines. In phase III studies between 92.5 % and 100 % of recipients of RotaTeq achieved a significant rise in serum anti-rotavirus IgA after a three-dose regimen. The vaccine induces an immune response (i.e., appearance of serum neutralising antibody) to the five human-rotavirus proteins expressed on the reassortants (G1, G2, G3, G4 and P[8]).

Not applicable.

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

Sucrose

Sodium citrate

Sodium dihydrogen phosphate monohydrate

Sodium hydroxide

Polysorbate 80

Culture media (containing inorganic salts, amino acids and vitamins) Purified water

In the absence of compatibility studies, this vaccine must not be mixed with other medicinal products.

Store and transport refrigerated (2 °C to 8 °C).

Keep the dosing tube in the outer carton in order to protect from light.

2 ml solution in a pre-filled squeezable tube (LDPE), with a twist-off cap (HDPE) in a protective bag, pack size of 1 or 10 pre-filled squeezable tube(s).

Not all pack sizes may be marketed.

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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.