ROTATEQ oral solution medication leaflet

RotaTeq oral solution

Rotavirus vaccine (live)

One dose (2 ml) contains:

rotavirus type* G1 not less than 2.2 x 106 IU1, 2rotavirus type* G2 not less than 2.8 x 106 IU1, 2rotavirus type* G3 not less than 2.2 x 106 IU1, 2rotavirus type* G4 not less than 2.0 x 106 IU1, 2rotavirus type* P1A[8] not less than 2.3 x 106 IU1, 2

* human-bovine rotavirus reassortants (live), produced in Vero cells.

1 Infectious Units2 As lower confidence limit (p = 0.95)

This vaccine contains 1080 milligrams sucrose and 37.6 milligrams sodium (see section 4.4).

For the full list of excipients, see section 6.1.

Oral Solution

Pale yellow clear liquid that may have a pink tint

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

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

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 beenestablished.

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 wasat 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 of20-22 weeks. If necessary, the third (last) dose may be given up to the age of 32 weeks (see section5.1).

As no data exist regarding the interchangeability of RotaTeq with another rotavirus vaccine, it isrecommended that infants who receive RotaTeq for the first immunisation against rotavirus shouldreceive 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 orregurgitates 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 replacementdoses should not be given.

No further doses are recommended after completion of the 3-dose vaccination course (see sections 4.4and 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.

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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity after previous administration of rotavirus vaccines.

Previous history of intussusception.

Subjects with congenital malformation of the gastrointestinal tract that could predispose tointussusception.

Infants who have known or suspected immunodeficiency (see sections 4.4 and 4.8).

Administration of RotaTeq should be postponed in infants suffering from acute severe febrile illness.

The presence of a minor infection is not a contraindication for immunisation.

The administration of RotaTeq should be postponed in subjects suffering from acute diarrhoea orvomiting.

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

As with all vaccines, appropriate medical treatment should always be readily available in case of ananaphylactic 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 toimmunocompromised infants, those exposed in utero to an immunosuppressive treatment, infantsinfected with HIV or infants who have received a blood transfusion or immunoglobulins within42 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 inutero to an immunosuppressive treatment should be based on careful consideration of potentialbenefits and risks.

Cases of gastroenteritis associated with vaccine virus have been reported post marketing in infantswith 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 weekafter dose 1 and in only one vaccine recipient (0.3 %) after dose 3. Peak excretion occurred within7 days of dosing. Transmission of vaccine virus strains to non-vaccinated contacts has been observedpost-marketing. RotaTeq should be administered with caution to individuals with close contacts whoare immunodeficient (e.g., individuals with malignancies or who are otherwise immunocompromisedor individuals receiving immunosuppressive therapy). Also, those caring for recent vaccinees shouldobserve careful hygiene especially when handling excreta.

In a clinical study, RotaTeq was administered to approximately 1,000 infants who were born at agestational age of 25 to 36 weeks. The first dose was administered from 6 weeks after birth. The safetyand 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, 55were born at a gestational age of 29 to 31 weeks and the remainder was born at a gestational age ofbetween 32 and 36 weeks. See sections 4.2 and 5.1.

Intussusception

As a precaution, healthcare professionals should follow-up on any symptoms indicative ofintussusception (severe abdominal pain, persistent vomiting, bloody stools, abdominal bloating and/orhigh fever) since data from observational studies indicate an increased risk of intussusception, mostlywithin 7 days after rotavirus vaccination (see section 4.8). Parents/guardians should be advised topromptly 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 (includingchronic diarrhoea) or growth retardation. Administration of RotaTeq may be considered with cautionin 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 anyvaccine, vaccination with RotaTeq may not result in complete protection in all recipients. RotaTeqdoes 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 otherpopulations 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 consideredwhen administering the primary immunisation series to very premature infants (born ≤28 weeks ofgestation) and particularly for those with a previous history of respiratory immaturity. As the benefitof 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. Seesection 2.

This vaccine contains 37.6 mg sodium per dose, equivalent to 1.88% of the WHO recommendedmaximum 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 atapproximately 2, 4 and 6 months of age demonstrated that the immune responses and the safetyprofiles 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 theco-administered vaccines were unaffected compared to separate administrations.

Co-administration of RotaTeq with a group C meningococcal conjugate vaccine (MenCC, the vaccinestudied 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-administrationresulted in an acceptable safety profile.

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

Therefore, RotaTeq can be given concomitantly with monovalent or combination infant vaccinescontaining 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 arenot available and animal fertility or reproduction studies have not been performed.

Not relevant.

In a subset of infants from 3 placebo-controlled clinical trials (n=6,130 recipients of RotaTeq and5,560 placebo recipients), RotaTeq was evaluated for all adverse events within 42 days of vaccinationwith or without concomitant use of other paediatric vaccines. Overall, 47 % of infants given RotaTeqexperienced an adverse reaction compared with 45.8 % of infants given placebo. The most commonlyreported 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 and35,536 placebo recipients) of 3 clinical trials for up to 42 days after each dose. The overall frequencyof these serious adverse reactions was 0.1 % among recipients of RotaTeq and 0.2 % among placeborecipients.

b. Tabulated summary of adverse reactions

Adverse reactions more common in the vaccine group in clinical trials are listed below per systemorgan 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)

Adverse reactions following administration of RotaTeq in clinical trials and adverse events reportedpost-marketing (in italics)

System Organ Class Frequency Adverse Reaction/Event

Infections and infestations Common Upper respiratory tract infection

Uncommon Nasopharyngitis, otitis media

Immune system disorders Not known Anaphylactic reaction‡

Respiratory, thoracic and Rare Bronchospasmmediastinal disorders

Gastrointestinal disorders Very common Diarrhoea, vomiting

Uncommon Haematochezia†, Abdominal pain upper

Very Rare Intussusception α *

Skin and subcutaneous tissue Uncommon Rashdisorders

Rare Urticaria†

Not known Angioedema‡

General disorders and Very common Pyrexiaadministration site conditions

Not known Irritability‡† This adverse reaction was identified through post-marketing surveillance. Thefrequency 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 placeborecipients (<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 vaccinescarry an increased risk of intussusception, with up to 6 additional cases per 100,000 infants within7 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 countriesranged from 25 to 101 per 100,000 infants per year. It remains unclear whether rotavirus vaccinesaffect 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 withrecommended doses of RotaTeq.

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

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 areduction 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 fullrotavirus season after vaccination.

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

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

Reduction in incidence of RV gastroenteritis through one full season post-vaccination(RotaTeq n=2,834) (% [95 % CI])

Efficacy against any severity by rotavirus genotype

Severe* Any G1 G2 G3 G4 G9disease severity(G1-G4) (G1-G4)98.0 % 74.0 % 74.9 % 63.4 % 82.7 % 48.1 % 65.4 %[88.3, 100.0]† [66.8, [67.3, 80.9]† [2.6, 88.2]† [<0, 99.6] [<0, 91.6] [<0, 99.3]79.9]†

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

Reduction in hospitalisations and emergency department visits for RV gastroenteritis for up to 2 yearspost-vaccination(RotaTeq n=34,035) (% [95 % CI])

G1-G4 G1 G2 G3 G4 G994.5 % 95.1 % 87.6 % 93.4 % 89.1 % 100 %[91.2, 96.6]† [91.6, [0, 98.5] [49.4, 99.1] † [52.0, [69.6, 100] †97.1]† 97.5]†† Statistically significant

The reduction in incidence of RV gastroenteritis caused by genotypes G1-G4 during the secondrotavirus 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 casesthan for G1. The efficacy observed against G2P[4] most likely resulted from the G2 component of thevaccine.

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] amonginfants 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 werefollowed 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 datafrom the FES increased the number by 136 encounters in total, including 9 in the vaccine group and127 in the placebo group. Overall, 31 % and 25 % of the encounters in the respective groups occurredduring the FES.

Based upon combined data from REST and the FES, the reduction up to 3 years post-vaccination inthe 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. Duringyear 3, there were no health care contacts for RV gastroenteritis in the vaccine group (n=3,112) andone (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 providethe level and duration of protection against rotavirus gastroenteritis that was observed in the clinicalstudies. However, post hoc analyses indicated that RotaTeq achieved some reduction in the numbersof cases of rotavirus gastroenteritis of sufficient severity to require hospitalisation or an emergencydepartment visit before completion of all three doses (i.e. from approximately 14 days afteradministration of the first dose onwards).

Efficacy in premature infants

In REST, RotaTeq was administered to approximately 1,000 infants who were born at a gestationalage of 25 to 36 weeks. The efficacy of RotaTeq was comparable between this subset of infants andinfants 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 wasanalysed among 85,150 infants receiving one or more doses of RotaTeq (17,433 person-years offollow-up).

During the 0-30 day follow-up period after vaccination, there were no statistically significantdifference 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-upperiod 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 infantsvaccinated 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 concernswere identified.

Effectiveness study data

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

Study design Study population Endpoints Effectiveness RV seasons(Region) % [95%CI]

Claims 33,140 vaccinated Hospitalization and Emergency 100% [87,100] 2007-2008database 26,167 unvaccinated Department (ED) visits due toanalysis (US) Aged ≥7 months RVGE

Received 3 doses

Outpatients due to RVGE 96% [76,100]

Hospitalization and ED visitsdue to all cause gastroenteritis 59% [47,68]

Cohort study 1,895 vaccinated with 3 Hospitalization due to RVGE 98% [83,100] 2007-2008(France) doses 2008-20092,102 unvaccinated

Aged <2 years

Case-control 402 cases Hospitalization and ED visits 80% [74,84] 2011-2012study (US) 2,559 controls* due to RVGE 2012-2013

Aged <8 years Strain-specific

Received 3 doses - G1P[8] 89% [55,97]

- G2P[4] 87% [65,95]

- G3P[8] 80% [64,89]

- G12P[8] 78% [71,84]

Age-specific

- 1st year of life 91% [78,96]

- 2nd year of life 82% [69,89]

- 3rd year of life 88% [78,93]

- 4th year of life 76% [51,88]

- 5th year of life 60% [16,81]

- 6th-7th year of life 69% [43,84]

*RV-negative acute gastroenteritis controls

The immunological mechanism by which RotaTeq protects against rotavirus gastroenteritis is notcompletely understood. No immunological correlate of protection has currently been identified forrotavirus vaccines. In phase III studies between 92.5 % and 100 % of recipients of RotaTeq achieved asignificant rise in serum anti-rotavirus IgA after a three-dose regimen. The vaccine induces an immuneresponse (i.e., appearance of serum neutralising antibody) to the five human-rotavirus proteinsexpressed 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 doseadministered to mice was approximately 2.79 x 108 infectious units per kg (about 14-fold the projectedinfant 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.

2 years

RotaTeq should be administered promptly after removal from refrigeration.

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 notdilute.

To administer the vaccine:

Tear open the protective bag and remove the dosing tube.

Clear the fluid from the dispensing tip by holding tube vertically and tapping thetwist-off cap.

Open the dosing tube in 2 easy motions:

1. Puncture the dispensing tip by screwing cap clockwise until it becomestight.

2. Remove cap by turning it counterclockwise.

Administer dose by gently squeezing liquid into infant's mouth toward the innercheek until dosing tube is empty. (A residual drop may remain in the tip of thetube.)

Discard the empty tube and cap in approved biological waste containersaccording to local regulations.

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

Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands.

EU/1/06/348/001

EU/1/06/348/002

Date of first authorisation: 27 June 2006

Date of latest renewal: 18 May 2011

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.