ROTARIX powder + suspension for oral suspension medication leaflet

Rotarix oral suspension in pre-filled oral applicator

Rotarix oral suspension in squeezable tube

Rotarix oral suspension in multi-monodose (5 single dose) squeezable tube presentation connected bya bar

Rotavirus vaccine, live

1 dose (1.5 mL) contains:

Human rotavirus RIX4414 strain (live, attenuated)* not less than 106.0 CCID50

*Produced on Vero cells

This product contains 1 073 mg of sucrose, 32 mg of sodium, 10 micrograms of glucose and0.15 microgram of phenylalanine per dose (see section 4.4).

For the full list of excipients, see section 6.1.

Oral suspension.

Rotarix is a clear and colourless liquid.

Rotarix is indicated for the active immunisation of infants aged 6 to 24 weeks for prevention of gastro-enteritis due to rotavirus infection (see sections 4.2, pct. 4.4 and 5.1).

The use of Rotarix should be based on official recommendations.

The vaccination course consists of two doses. The first dose may be administered from the age of 6weeks. There should be an interval of at least 4 weeks between doses. The vaccination course shouldpreferably be given before 16 weeks of age, but must be completed by the age of 24 weeks.

Rotarix may be given with the same posology to preterm infants born after at least 27 weeks ofgestational age (see sections 4.8 and 5.1).

In clinical trials, spitting or regurgitation of the vaccine has rarely been observed and, under suchcircumstances, a replacement dose was not given. However, in the unlikely event that an infant spitsout or regurgitates most of the vaccine dose, a single replacement dose may be given at the samevaccination visit.

It is recommended that infants who receive a first dose of Rotarix complete the 2-dose regimen with

Rotarix. There are no data on safety, immunogenicity or efficacy when Rotarix is administered for thefirst dose and another rotavirus vaccine is administered for the second dose or vice versa.

Rotarix should not be used in children over 24 weeks of age.

Rotarix is for oral use only.

Rotarix should under no circumstances be injected.

For instructions for administration, see section 6.6.

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

Hypersensitivity after previous administration of rotavirus vaccines.

History of intussusception.

Subjects with uncorrected congenital malformation of the gastrointestinal tract that would predisposefor intussusception.

Subjects with Severe Combined Immunodeficiency (SCID) disorder (see section 4.8).

Administration of Rotarix should be postponed in subjects suffering from acute severe febrileillness. The presence of a minor infection is not a contra-indication for immunisation.

The administration of Rotarix should be postponed in subjects suffering from diarrhoea or vomiting.

It is good clinical practice that vaccination should be preceded by a review of the medical historyespecially with regard to the contraindications and by a clinical examination.

There are no data on the safety and efficacy of Rotarix in infants with gastrointestinal illnesses orgrowth retardation. Administration of Rotarix may be considered with caution in such infants when, inthe opinion of the physician, withholding the vaccine entails a greater risk.

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 safety studies indicate an increased risk of intussusception,mostly within 7 days after rotavirus vaccination (see section 4.8). Parents/guardians should be advisedto promptly report such symptoms to their healthcare provider.

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

Asymptomatic and mildly symptomatic HIV infections are not expected to affect the safety or efficacyof Rotarix. A clinical study in a limited number of asymptomatic or mildly symptomatic HIV positiveinfants showed no apparent safety problems (see section 4.8).

Administration of Rotarix to infants who have known or suspected immunodeficiency, including inutero exposure to an immunosuppressive treatment, should be based on careful consideration ofpotential benefits and risks.

Excretion of the vaccine virus in the stools is known to occur after vaccination with peak excretionaround the 7th day. Viral antigen particles detected by ELISA were found in 50% of stools after thefirst dose of Rotarix lyophilised formulation and 4% of stools after the second dose. When these stoolswere tested for the presence of live vaccine strain, only 17% were positive. In two comparativecontrolled trials, vaccine shedding after vaccination with Rotarix liquid formulation was comparableto that observed after vaccination with Rotarix lyophilised formulation.

Cases of transmission of this excreted vaccine virus to seronegative contacts of vaccinees have beenobserved without causing any clinical symptom.

Rotarix should be administered with caution to individuals with immunodeficient close contacts,such as individuals with malignancies, or who are otherwise immunocompromised or individualsreceiving immunosuppressive therapy.

Contacts of recent vaccinees should observe personal hygiene (e.g. wash their hands after changingchild’s nappies).

The potential risk of apnoea and the need for respiratory monitoring for 48-72h 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 benefit of the vaccination is high in this group of infants, vaccination should not be withheld ordelayed.

A protective immune response may not be elicited in all vaccinees (see section 5.1).

The extent of protection that Rotarix might provide against other rotavirus strains that have not beencirculating in clinical trials is currently unknown. Clinical studies from which efficacy data werederived were conducted in Europe, Central and South America, Africa and Asia (see section 5.1).

Rotarix does not protect against gastro-enteritis due to other pathogens than rotavirus.

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

Rotarix should under no circumstances be injected.

This vaccine contains sucrose and glucose as excipients. Patients with rare hereditary problems offructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should nottake this vaccine.

This vaccine contains 0.15 microgram phenylalanine in each dose. Phenylalanine may be harmful forpatients with phenylketonuria (PKU).

This vaccine contains 32 mg sodium in each dose.

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

Rotarix can be given concomitantly with any of the following monovalent or combination vaccines[including hexavalent vaccines (DTPa-HBV-IPV/Hib)]: diphtheria-tetanus-whole cell pertussisvaccine (DTPw), diphtheria-tetanus-acellular pertussis vaccine (DTPa), Haemophilus influenzaetype b vaccine (Hib), inactivated polio vaccine (IPV), hepatitis B vaccine (HBV), pneumococcalconjugate vaccine and meningococcal serogroup C conjugate vaccine. Clinical studies demonstratedthat the immune responses and the safety profiles of the administered vaccines were unaffected.

Concomitant administration of Rotarix and oral polio vaccine (OPV) does not affect the immuneresponse to the polio antigens. Although concomitant administration of OPV may slightly reduce theimmune response to rotavirus vaccine, clinical protection against severe rotavirus gastro-enteritis wasshown to be maintained in a clinical trial involving more than 4 200 subjects who received Rotarixconcomitantly with OPV.

There are no restrictions on the infant’s consumption of food or liquid, either before or aftervaccination.

Rotarix is not intended for use in adults. There are no data on the use of Rotarix during pregnancy andlactation.

Based on evidence generated in clinical trials, breast-feeding does not reduce the protection againstrotavirus gastro-enteritis afforded by Rotarix. Therefore, breast-feeding may be continued during thevaccination schedule.

Not relevant.

The safety profile presented below is based on data from clinical trials conducted with either thelyophilised or the liquid formulation of Rotarix.

In a total of four clinical trials, approximately 3 800 doses of Rotarix liquid formulation wereadministered to approximately 1 900 infants. Those trials have shown that the safety profile of theliquid formulation is comparable to the lyophilised formulation.

In a total of twenty-three clinical trials, approximately 106 000 doses of Rotarix (lyophilised or liquidformulation) were administered to approximately 51 000 infants.

In three placebo-controlled clinical trials (Finland, India and Bangladesh), in which Rotarix wasadministered alone (administration of routine paediatric vaccines was staggered), the incidence andseverity of the solicited events (collected 8 days post-vaccination), diarrhoea, vomiting, loss ofappetite, fever, irritability and cough/runny nose were not significantly different in the groupreceiving Rotarix when compared to the group receiving placebo. No increase in the incidence orseverity of these events was seen with the second dose.

In a pooled analysis from seventeen placebo-controlled clinical trials (Europe, North America, Latin

America, Asia, Africa) including trials in which Rotarix was co-administered with routine paediatricvaccines (see section 4.5), the following adverse reactions (collected 31 days post-vaccination) wereconsidered as possibly related to vaccination.

Adverse reactions reported are listed according to the following frequency:

Frequencies are reported as:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1 000 to < 1/100)

Rare (≥ 1/10 000 to < 1/1 000)

Very rare (< 1/10 000)

System Organ Class Frequency Adverse reactions

Gastrointestinal disorders Common Diarrhoea

Uncommon Abdominal pain, flatulence

Very rare Intussusception (see section 4.4)

Not known* Haematochezia

Not known* Gastroenteritis with vaccine viralshedding in infants with Severe

Combined Immunodeficiency(SCID) disorder

Skin and subcutaneous tissue Uncommon Dermatitisdisorders

Very rare Urticaria

General disorders and Common Irritabilityadministration site conditions

Respiratory, thoracic and Not known* Apnoea in very prematuremediastinal disorders infants (≤ 28 weeks of gestation)(see section 4.4)

* Because these events were reported spontaneously, it is not possible to reliably estimate their frequency.

Intussusception

Data from observational safety studies performed in several countries indicate that rotavirus vaccinescarry an increased risk of intussusception, mostly within 7 days of vaccination. Up to 6 additionalcases per 100 000 infants have been observed in these countries against a background incidence of 25to 101 per 100 000 infants (less than one year of age) per year, respectively.

There is limited evidence of a smaller increased risk following the second dose.

It remains unclear whether rotavirus vaccines affect the overall incidence of intussusception based onlonger periods of follow-up (see section 4.4).

Safety in preterm infants

In a clinical study, 670 pre-term infants from 27 to 36 weeks of gestational age were administered

Rotarix lyophilised formulation and 339 received placebo. The first dose was administered from 6weeks after birth. Serious adverse events were observed in 5.1% of recipients of Rotarix as comparedwith 6.8% of placebo recipients. Similar rates of other adverse events were observed in Rotarix andplacebo recipients. No cases of intussusception were reported.

Safety in infants with human immunodeficiency (HIV) infection

In a clinical study, 100 infants with HIV infection were administered Rotarix lyophilised formulationor placebo. The safety profile was similar between Rotarix and placebo recipients.

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.

Some cases of overdose have been reported. In general, the adverse event profile reported in thesecases was similar to that observed after administration of the recommended dose of Rotarix.

Pharmaco-therapeutic group: rotavirus diarrhoea vaccines, ATC code: J07BH01

Protective efficacy of the lyophilised formulation

In clinical trials, efficacy was demonstrated against gastro-enteritis due to rotavirus of the mostcommon genotypes G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]. In addition, efficacy againstuncommon rotavirus genotypes G8P[4] (severe gastro-enteritis) and G12P[6] (any gastro-enteritis) hasbeen demonstrated. These strains are circulating worldwide.

Clinical studies have been conducted in Europe, Latin America, Africa and Asia to evaluate theprotective efficacy of Rotarix against any and severe rotavirus gastro-enteritis (RVGE).

Severity of gastro-enteritis was defined according to two different criteria:

- the Vesikari 20-point scale, which evaluates the full clinical picture of rotavirus gastro-enteritis bytaking into account the severity and duration of diarrhoea and vomiting, the severity of fever anddehydration as well as the need for treatmentor

- the clinical case definition based on World Health Organization (WHO) criteria

Clinical protection was assessed in the ATP cohort for efficacy, which includes all subjects from the

ATP cohort for safety who entered into the concerned efficacy follow-up period.

Protective efficacy in Europe

A clinical study performed in Europe evaluated Rotarix given according to different Europeanschedules (2, 3 months; 2, 4 months; 3, 4 months; 3, 5 months) in 4 000 subjects.

After two doses of Rotarix, the protective vaccine efficacy observed during the first and second yearof life is presented in the following table:

1st year of life 2nd year of life

Rotarix N=2 572 Rotarix N=2 554

Placebo N=1 302 Placebo N=1 294

Vaccine efficacy (%) against any and severe rotavirus gastro-enteritis[95% CI]

Genotype Any severity Severe† Any severity Severe†

G1P[8] 95.6 96.4 82.7 96.5[87.9;98.8] [85.7;99.6] [67.8;91.3] [86.2;99.6]

G2P[4] 62.0* 74.7* 57.1 89.9[<0.0;94.4] [<0.0;99.6] [<0.0;82.6] [9.4;99.8]

G3P[8] 89.9 100 79.7 83.1*[9.5;99.8] [44.8;100] [<0.0;98.1] [<0.0;99.7]

G4P[8] 88.3 100 69.6* 87.3[57.5;97.9] [64.9;100] [<0.0;95.3] [<0.0;99.7]

G9P[8] 75.6 94.7 70.5 76.8[51.1;88.5] [77.9;99.4] [50.7;82.8] [50.8;89.7]

Strains with P[8] 88.2 96.5 75.7 87.5genotype [80.8;93.0] [90.6;99.1] [65.0;83.4] [77.8;93.4]

Circulating 87.1 95.8 71.9 85.6rotavirus strains [79.6;92.1] [89.6;98.7] [61.2;79.8] [75.8;91.9]

Vaccine efficacy (%) against rotavirus gastro-enteritis requiring medicalattention[95% CI]

Circulating 91.8 76.2rotavirus strains [84;96.3] [63.0;85.0]

Vaccine efficacy (%) against hospitalisation due to rotavirus gastro-enteritis[95% CI]

Circulating 100 92.2rotavirus strains [81.8;100] [65.6;99.1]† Severe gastro-enteritis was defined as a score ≥11 on the Vesikari scale

* Not statistically significant (p ≥ 0.05). These data should be interpreted with caution.

Vaccine efficacy during the first year of life progressively increased with increasing disease severity,reaching 100% (95% CI: 84.7;100) for Vesikari scores ≥ 17.

Protective efficacy in Latin America

A clinical study performed in Latin America evaluated Rotarix in more than 20 000 subjects. Severityof gastro-enteritis (GE) was defined according to WHO criteria. The protective vaccine efficacyagainst severe rotavirus (RV) gastro-enteritis requiring hospitalisation and/or rehydration therapy in amedical facility and the genotype specific vaccine efficacy after two doses of Rotarix are presented inthe table below:

Genotype Severe rotavirus gastro- Severe rotavirus gastro-enteritis† (1st year of life) enteritis† (2nd year of life)

Rotarix N=9 009 Rotarix N=7 175

Placebo N=8 858 Placebo N=7 062

Efficacy (%) Efficacy (%)[95% CI ] [95% CI ]

All RVGE 84.7 79.0[71.7;92.4] [66.4;87.4]

G1P[8] 91.8 72.4[74.1;98.4] [34.5;89.9]

G3P[8] 87.7 71.9*[8.3;99.7] [<0.0;97.1]

G4P[8] 50.8#* 63.1[<0.0;99.2] [0.7;88.2]

G9P[8] 90.6 87.7[61.7;98.9] [72.9;95.3]

Strains with P[8] 90.9 79.5genotype [79.2;96.8] [67.0;87.9]† Severe rotavirus gastro-enteritis was defined as an episode of diarrhoea with or without vomiting that requiredhospitalisation and/or re-hydration therapy in a medical facility (WHO criteria)

* Not statistically significant (p ≥ 0.05). These data should be interpreted with caution# The numbers of cases, on which the estimates of efficacy against G4P[8] were based, were very small (1 casein the Rotarix group and 2 cases in the placebo group)

A pooled analysis of five efficacy studies*, showed a 71.4% (95% CI: 20.1;91.1) efficacy againstsevere rotavirus gastro-enteritis (Vesikari score ≥ 11) caused by rotavirus G2P[4] genotype during thefirst year of life.

* In these studies, the point estimates and confidence intervals were respectively: 100% (95%

CI: -1 858.0;100), 100% (95% CI: 21.1;100), 45.4% (95% CI: -81.5;86.6), 74.7% (95%

CI: -386.2;99.6). No point estimate was available for the remaining study.

Protective efficacy in Africa

A clinical study performed in Africa (Rotarix: N = 2 974; placebo: N = 1 443) evaluated Rotarix givenat approximately 10 and 14 weeks of age (2 doses) or 6, 10 and 14 weeks of age (3 doses). Thevaccine efficacy against severe rotavirus gastro-enteritis during the first year of life was 61.2% (95%

CI: 44.0;73.2). The protective vaccine efficacy (pooled doses) observed against any and severerotavirus gastro-enteritis is presented in the following table:

Genotype Any rotavirus gastro-enteritis Severe rotavirus gastro-

Rotarix N=2 974 enteritis†

Placebo N=1 443 Rotarix N=2 974

Placebo N=1 443

Efficacy (%) Efficacy (%)[95% CI] [95% CI]

G1P[8] 68.3 56.6[53.6;78.5] [11.8;78.8]

G2P[4] 49.3 83.8[4.6;73.0] [9.6;98.4]

G3P[8] 43.4* 51.5*[<0.0;83.7] [<0.0;96.5]

G8P[4] 38.7* 63.6[<0.0;67.8] [5.9;86.5]

G9P[8] 41.8* 56.9*[<0.0;72.3] [<0.0;85.5]

G12P[6] 48.0 55.5*[9.7;70.0] [<0.0; 82.2]

Strains with P[4] 39.3 70.9genotype [7.7;59.9] [37.5;87.0]

Strains with P[6] 46.6 55.2*genotype [9.4;68.4] [<0.0;81.3]

Strains with P[8] 61.0 59.1genotype [47.3;71.2] [32.8;75.3]† Severe gastro-enteritis was defined as a score ≥ 11 on the Vesikari scale

* Not statistically significant (p ≥ 0.05). These data should be interpreted with caution.

Sustained efficacy up to 3 years of age in Asia

A clinical study conducted in Asia (Hong Kong, Singapore and Taiwan) (Total vaccinated cohort:

Rotarix: N = 5 359; placebo: N = 5 349) evaluated Rotarix given according to different schedules (2, 4months of age; 3, 4 months of age).

During the first year, significantly fewer subjects in the Rotarix group reported severe rotavirus gastro-enteritis caused by the circulating wild-type RV compared to the placebo group from 2 weeks after

Dose 2 up to one year of age (0.0% versus 0.3%), with a vaccine efficacy of 100% (95% CI:72.2;100).

The protective vaccine efficacy after two doses of Rotarix observed against severe rotavirus gastro-enteritis up to 2 years of age is presented in the following table:

Efficacy up to 2 years of age

Rotarix N= 5 263

Placebo N= 5 256

Vaccine efficacy (%) against severe rotavirus gastro-enteritis [95% CI]

Genotype Severe†

G1P[8] 100 [80.8;100]

G2P[4] 100* [<0.0;100]

G3P[8] 94.5 [64.9;99.9]

G9P[8] 91.7 [43.8;99.8]

Strains with P[8] genotype 95.8 [83.8;99.5]

Circulating rotavirus strains 96.1 [85.1;99.5]

Vaccine efficacy (%) against rotavirus gastro-enteritis requiring hospitalisationand/or rehydration therapy in a medical facility [95% CI]

Circulating rotavirus strains 94.2 [82.2;98.8]† Severe gastro-enteritis was defined as a score ≥ 11 on the Vesikari scale

* Not statistically significant (p ≥ 0.05). These data should be interpreted with caution.

During the third year of life, there were no cases of severe RV gastro-enteritis in the Rotarix group(N=4 222) versus 13 (0.3%) in the placebo group (N=4 185). Vaccine efficacy was 100% (95% CI:67.5; 100). The severe RV gastro-enteritis cases were due to RV strains G1P[8], G2P[4], G3P[8] and

G9P[8]. The incidence of severe RV gastro-enteritis associated with the individual genotypes was toosmall to allow calculation of efficacy. The efficacy against severe RV gastro-enteritis requiringhospitalisation was 100% (95% CI: 72.4;100).

Protective efficacy of the liquid formulation

Since the immune response observed after 2 doses of Rotarix liquid formulation was comparable tothe immune response observed after 2 doses of Rotarix lyophilised formulation, the levels of vaccineefficacy observed with the lyophilised formulation can be extrapolated to the liquid formulation.

Immune response

The immunologic mechanism by which Rotarix protects against rotavirus gastro-enteritis is notcompletely understood. A relationship between antibody responses to rotavirus vaccination andprotection against rotavirus gastro-enteritis has not been established.

The following table shows the percentage of subjects initially seronegative for rotavirus (IgA antibodytitres < 20 U/mL) (by ELISA) with serum anti-rotavirus IgA antibody titres ≥ 20 U/mL one to twomonths after the second dose of vaccine or placebo as observed in different studies with Rotarixlyophilised formulation.

Schedule Studies Vaccine Placeboconducted in

N % ≥ 20 U/mL N % ≥ 20 U/mL[95% CI] [95% CI]2, 3 months France, 239 82.8 127 8.7

Germany [77.5;87.4] [4.4;15.0]2, 4 months Spain 186 85.5 89 12.4[79.6;90.2] [6.3;21.0]3, 5 months Finland, Italy 180 94.4 114 3.5[90.0;97.3] [1.0;8.7]3, 4 months Czech 182 84.6 90 2.2

Republic [78.5;89.5] [0.3;7.8]2, 3 to 4 Latin 393 77.9% 341 15.1%months America; 11 [73.8;81.6] [11.7;19.0]countries10, 14 weeks South Africa, 221 58.4 111 22.5and 6, 10, 14 Malawi [51.6;64.9] [15.1;31.4]weeks(Pooled)

In three comparative controlled trials, the immune response elicited by Rotarix liquid formulation wascomparable to the one elicited by Rotarix lyophilised formulation.

Immune response in preterm infants

In a clinical study conducted in preterm infants, born after at least 27 weeks of gestational age, theimmunogenicity of Rotarix was assessed in a subset of 147 subjects and showed that Rotarix isimmunogenic in this population; 85.7% (95% CI: 79.0;90.9) of subjects achieved serum anti-rotavirus

IgA antibody titres ≥ 20 U/mL (by ELISA) one month after the second dose of vaccine.

In observational studies, vaccine effectiveness was demonstrated against severe gastro-enteritisleading to hospitalisation due to rotavirus of common genotypes G1P[8], G2P[4], G3P[8], G4P[8] and

G9P[8] as well as the less common rotavirus genotypes G9P[4] and G9P[6]. All of these strains arecirculating worldwide.

Effectiveness after 2 doses in preventing RVGE leading to hospitalisation

Countries Age range N (1) Strains Effectiveness

Period (cases/controls) % [95% CI]

High Income countries

Belgium < 4 yrs 160/198 All 90 [81;95]2008-2010(2) 3-11 m 91 [75;97]< 4 yrs 41/53 G1P[8] 95 [78;99]< 4 yrs 80/103 G2P[4] 85 [64;94]3-11 m 83 [22;96] (3)< 4 yrs 12/13 G3P[8] 87* [<0;98](3)< 4 yrs 16/17 G4P[8] 90 [19;99] (3)

Singapore < 5 yrs 136/272 All 84 [32;96]2008-2010(2) 89/89 G1P[8] 91 [30;99]

Taiwan < 3 yrs 184/1 623(4) All 92 [75;98]2009-2011 G1P[8] 95 [69;100]

US < 2 yrs 85/1 062(5) All 85 [73;92]2010-2011 G1P[8] 88 [68;95]

G2P[4] 88 [68;95]8-11 m All 89 [48;98]

US < 5 yrs 74/255(4) All 68 [34;85]2009-2011

Middle Income Countries

Bolivia < 3 yrs 300/974 All 77 [65;84](6)2010-2011 6-11 m 77 [51;89]< 3 yrs G9P[8] 85 [69;93]6-11 m 90 [65;97]< 3 yrs G3P[8] 93 [70;98]

G2P[4] 69 [14;89]

G9P[6] 87 [19;98]

Brazil < 2 yrs 115/1 481 All 72 [44;85](6)2008-2011 G1P[8] 89 [78;95]

G2P[4] 76 [64;84]

Brazil < 3 yrs 249/249 (5) All 76 [58;86]2008-2009(2) 3-11 m 96 [68;99]< 3 yrs 222/222 (5) G2P[4] 75 [57;86]3-11 m 95 [66;99] (3)

El Salvador < 2 yrs 251/770 (5) All 76 [64;84](6)2007-2009 6-11 m 83 [68;91]

Guatemala < 4 yrs NA(7) All 63 [23;82]2012-2013

Mexico < 2 yrs 9/17(5) G9P[4] 94 [16;100]

Low Income Countries

Malawi < 2 yrs 81/286(5) All 63 [23;83]2012-2014m: monthsyrs: years

* Not statistically significant (p ≥ 0.05). These data should be interpreted with caution.(1) The number of fully vaccinated (2 doses) and unvaccinated cases and controls is given.(2) GSK sponsored studies(3) Data from a post-hoc analysis(4) Vaccine effectiveness was calculated using rotavirus-negative hospital control participants (estimates from

Taiwan were calculated using combined rotavirus-negative hospital control and non-diarrhoea hospitalcontrol participants).

(5) Vaccine effectiveness was calculated using neighbourhood controls.(6) In subjects who did not receive the full course of vaccination, the effectiveness after one dose ranged from51% (95% CI: 26;67, El Salvador) to 60% (95% CI: 37;75, Brazil).(7) NA: Not available. Vaccine effectiveness estimate is based on 41 fully vaccinated cases and 175 fullyvaccinated controls.

Impact on mortality§

Impact studies with Rotarix conducted in Panama, Brazil and Mexico showed a decrease in all-causediarrhoea mortality ranging from 17% to 73% in children less than 5 years of age, within 2 to 4 yearsafter vaccine introduction.

Impact on hospitalisation§

In a retrospective database study in Belgium conducted in children 5 years of age and younger, thedirect and indirect impact of Rotarix vaccination on rotavirus-related hospitalisation ranged from 64%(95% CI: 49;76) to 80% (95% CI: 77;83) two years after vaccine introduction. Similar studies in

Armenia, Australia, Brazil, Canada, El Salvador and Zambia showed a reduction of 45 to 93%between 2 and 4 years after vaccine introduction.

In addition, nine impact studies on all-cause diarrhoea hospitalisation conducted in Africa and Latin

America showed a reduction of 14% to 57% between 2 and 5 years after vaccine introduction.

§NOTE: Impact studies are meant to establish a temporal relationship but not a causal relationshipbetween the disease and vaccination. Natural fluctuations of the incidence of the disease may alsoinfluence the observed temporal effect.

Not applicable.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dosetoxicity.

Sucrose

Di-sodium Adipate

Dulbecco’s Modified Eagle Medium (DMEM) (containing phenylalanine, sodium, glucose, and othersubstances)

Sterile water

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

- Pre-filled oral applicator: 3 years

- Squeezable tube fitted with a membrane and a tube cap: 3 years

- Multi-monodose (5 single dose) squeezable tube presentation connected by a bar: 2 years

The vaccine should be used immediately after opening.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package, in order to protect from light.

Pre-filled oral applicator1.5 mL of oral suspension in a pre-filled oral applicator (type I glass) with a plunger stopper (rubberbutyl) and a protective tip cap (rubber butyl), in pack sizes of 1, 5, 10 or 25.

Squeezable tube1.5 mL of oral suspension in a squeezable tube (polyethylene) fitted with a membrane and a tube cap(polypropylene), in pack sizes of 1, 10 or 50.

Multi-monodose (5-single dose) squeezable tube presentation connected by a bar1.5 mL of oral suspension in a squeezable tube (polyethylene) presented in a multi-monodose (5-single dose) squeezable tube presentation connected by a bar, in pack size of 50 tubes.

Not all pack sizes may be marketed.

The vaccine is presented as a clear, colourless liquid, free of visible particles, for oral administration.

The vaccine is ready to use (no reconstitution or dilution is required).

The vaccine is to be administered orally without mixing with any other vaccines or solutions.

The vaccine should be inspected visually for any foreign particulate matter and/or abnormal physicalappearance. In the event of either being observed, discard the vaccine.

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

Instructions for administration of the vaccine in a pre-filled oral applicator:

Oral applicator

Tip-Cap1. Remove the protective tip cap from2. This vaccine is for oral 3. Do not inject.

the oral applicator. administration only. The childshould be seated in a recliningposition. Administer orally (i.e. intothe child’s mouth, towards the innercheek) the entire content of the oralapplicator.

Discard the empty oral applicator and tip cap in approved biological waste containers according tolocal regulations.

Instructions for administration of the vaccine in a squeezable tube:

Please read the instructions for use all the way through before starting to give the vaccine.

A What you need to do before giving Rotarix

* Check the expiry date.

* Check the tube has not been damaged nor is alreadyopen.

* Check the liquid is clear and colourless, without anyparticles in it.

If you notice anything abnormal, do not use the vaccine.

* This vaccine is given orally - straight from the tube.

* It is ready to use - you do not need to mix it withanything.

B Get the tube ready1. Pull off the cap

* Keep the cap - you need this to pierce themembrane.

* Hold the tube upright.

2. Repeatedly flick the top of the tube until it is clear ofany liquid

* Clear any liquid from the thinnest section of the tubeby flicking just below the membrane.

3. Position the cap to open the tube

* Keep the tube held upright.

* Hold the side of tube

* There is a small spike inside the top of the cap - in thecentre.

* Turn the cap upside down (180°).

4. To open the tube

* You do not need to twist. Press the cap down topierce the membrane.

* Then lift off the cap.

C Check the tube has opened correctly1. Check the membrane has been pierced

* There should be a hole at the top of the tube.

2. What to do if the membrane has not been pierced

* If the membrane has not been pierced return tosection B and repeat steps 2, 3 and 4.

D Give the vaccine

* Once the tube is open check the liquid is clear,without any particles in it.

If you notice anything abnormal, do not use thevaccine.

* Give the vaccine straight away.

1. Position the child to give the vaccine

* Seat the child leaning slightly backwards.

2. Administer the vaccine

* Squeeze the liquid gently into the side of the child’smouth - towards the inside of their cheek.

* You may need to squeeze the tube a few times to getall of the vaccine out - it is okay if a drop remains inthe tip of the tube.

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

Instructions for administration of the vaccine in a multi-monodose (5 single dose) squeezable tubepresentation connected by a bar:

Please read the instructions for use all the way through before starting to give the vaccine.

* This vaccine is given orally straight from an individual tube.

* One oral tube delivers one dose of vaccine.

* This vaccine is ready to use - do not mix it with anything else.

A. What you need to do before giving Rotarix

Connecting Expiry date: MM-YYYY1. Check the expiry date on the connecting bar. bar2. Check the liquid in the oral tubes is clear, colourless

Neckand free from any particles.

- Do not use any of the oral tubes on theconnecting bar if you notice anything unusual. Body3. Check that each individual oral tube is not damagedand is still sealed.

- Do not use the affected oral tube if you notice Tabanything unusual.

Monodoseoral tube

B. Get the oral tube ready1. To separate one oral tube from the others starting at Expiry date: MM-YYYYone end:a) Hold the tab of one of the end oral tubes toseparate it from the others. Pullb) With your other hand, hold the tab of the oraltube next to it.c) Pull the tab and tear it away from the oral tubenext to it.

2. To open the separated oral tube:

d) Keep the separated oral tube held upright.e) Hold the tab of the separated oral tube in onehand and the connecting bar in the other hand. Do Twist Pullnot hold the body of the oral tube, you maysqueeze out some of the vaccine.

f) Twist the separated oral tube.g) Pull it from the connecting bar.

C. Give the vaccine orally immediately after opening1. To position the child to receive the vaccine:

* Seat the child leaning slightly backwards.

2. To administer the vaccine orally:

* Squeeze the liquid gently into the side of thechild’s mouth, towards the inside of their Oraladministrationcheek. only

* You may need to squeeze the oral tube a fewtimes to get all of the vaccine out - it is okay ifa drop stays in the oral tube.

D. Store remaining doses in the fridge immediately

Put back in

Unused oral tubes that are still attached to the connecting bar fridge immediatelymust be put back in the fridge immediately after anoral tube has been used. This is so that the unused oral tubes can 2°C to 8°C

be used for the next vaccination.

Discard the used oral tubes in approved biological wastecontainers according to local regulations.

GlaxoSmithKline Biologicals SA

Rue de l'Institut 89

B-1330 Rixensart, Belgium

Pre-filled oral applicator

EU/1/05/330/005

EU/1/05/330/006

EU/1/05/330/007

EU/1/05/330/008

Squeezable tube

EU/1/05/330/009

EU/1/05/330/010

EU/1/05/330/011

Multi-monodose (5-single dose) squeezable tube presentation connected by a bar

EU/1/05/330/012

Date of first authorisation: 21 February 2006

Date of latest renewal: 14 January 2016

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

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