Rotarix powder and solvent for oral suspension

Rotavirus vaccine, live

After reconstitution, 1 dose (1ml) contains:

*Produced on Vero cells

Excipients:

This product contains sucrose 9 mg and sorbitol 13.5 mg (see section 4.4)

For a full list of excipients, see section 6.1.

Powder and solvent for oral suspension.

The powder is white.

The solvent is a turbid liquid with a slow settling white deposit and a colourless supernatant.

Rotarix is indicated for the active immunisation of infants from the age of 6 weeks for prevention of gastro-enteritis due to rotavirus infection (see section 4.2).

In clinical trials, efficacy was demonstrated against gastro-enteritis due to rotavirus of types G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8] (see sections 4.4 and 5.1).

The use of Rotarix should be based on official recommendations.

Posology

The vaccination course consists of two doses. The first dose may be administered from the age of 6 weeks. There should be an interval of at least 4 weeks between doses. The vaccination course should preferably 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 of gestational age (see sections 4.8 and 5.1).

In clinical trials, spitting or regurgitation of the vaccine has rarely been observed and, under such circumstances, a replacement dose was not given. However, in the unlikely event that an infant spits out or regurgitates most of the vaccine dose, a single replacement dose may be given at the same vaccination 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 the first dose and another rotavirus vaccine is administered for the second dose or vice versa.

Method of administration

Rotarix is for oral use only.

Rotarix should under no circumstances be injected.

Hypersensitivity to the active substance or to any of the excipients.

Hypersensitivity after previous administration of rotavirus vaccines.

Previous history of intussusception.

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

Administration of Rotarix should be postponed in subjects suffering from acute severe febrile illness. 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 history especially 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 or growth retardation. Administration of Rotarix may be considered with caution in such infants when, in the opinion of the physician, withholding the vaccine entails a greater risk.

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

Administration of Rotarix to infants who have known or suspected immunodeficiency should be based on careful consideration of potential benefits and risks.

Excretion of the vaccine virus in the stools is known to occur after vaccination with peak excretion around the 7th day. Viral antigen particles detected by ELISA were found in 50% of stools after the first dose and 4% of stools after the second dose. When these stools were tested for the presence of live vaccine strain, only 17% were positive.

Cases of transmission of this excreted vaccine virus to seronegative contacts of vaccinees have been observed 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 individuals receiving immunosuppressive therapy.

Contacts of recent vaccinees should observe personal hygiene (e.g. wash their hands after changing child's nappies).

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

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

In clinical trials, efficacy was demonstrated against gastro-enteritis due to rotavirus of types G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]. The extent of protection that Rotarix might provide against other serotypes is unknown. Clinical studies from which efficacy data were derived were conducted in Europe and Central and South America (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.

The vaccine contains sucrose and sorbitol as excipients. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this vaccine.

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 pertussis vaccine (DTPw), diphtheria-tetanus-acellular pertussis vaccine (DTPa), Haemophilus influenzae type b vaccine (Hib), inactivated polio vaccine (IPV), hepatitis B vaccine (HBV), pneumococcal conjugate vaccine and meningococcal serogroup C conjugate vaccine. Clinical studies demonstrated that the immune responses and the safety profiles of the administered vaccines were unaffected.

Concominant administration of Rotarix and oral polio vaccine (OPV) does not affect the immune response to the polio antigens. Although concomitant administration of OPV may slightly reduce the immune response to rotavirus vaccine, clinical protection against severe rotavirus gastro-enteritis was shown to be maintained in a clinical trial involving more than 4200 subjects who received Rotarix concomitantly with OPV.

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

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

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

Not relevant.

•Clinical trials

In a total of eleven placebo-controlled clinical trials, approximately 77800 doses of Rotarix were administered to approximately 40200 infants.

In two clinical trials (Finland), Rotarix was administered alone (administration of routine paediatric vaccines was staggered). The incidence of diarrhoea, vomiting, loss of appetite, fever and irritability was not different in the group receiving Rotarix when compared to the group receiving placebo. No increase in the incidence or severity of these reactions was seen with the second dose.

In the remaining nine trials (Europe, Canada, USA, Latin America, Singapore, South-Africa), Rotarix was co-administered with routine paediatric vaccines (see section 4.5). The adverse reaction profile observed in these subjects was similar to the adverse reaction profile observed in subjects receiving the same paediatric vaccines and placebo.

Adverse reactions are listed below per system organ class and frequency.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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)

Nervous system disorders

Uncommon: somnolence

Respiratory, thoracic and mediastinal disorders

Rare: hoarseness, rhinorrhoea

Gastrointestinal disorders

Very common: loss of appetite

Common: diarrhoea, vomiting, abdominal pain, flatulence, regurgitation of food

Uncommon: constipation

Skin and subcutaneous tissue disorders

Rare: dermatitis, rash

Musculoskeletal and connective tissue disorders

Rare: muscle cramp

Infections and infestations

Rare: upper respiratory tract infection

General disorders and administration site conditions

Common: fever, fatigue

Psychiatric disorders

Very common: irritability

Uncommon: sleep disorder, crying

The risk of intussusception has been evaluated in a large safety trial conducted in Latin America and Finland where 63225 subjects were enrolled. This trial gave evidence of no increased risk of intussusception in the Rotarix group when compared with the placebo group as shown in the table below.

*CI: confidence interval

Safety in preterm infants

In a clinical study, 670 pre-term infants from 27 to 36 weeks of gestational age were administered Rotarix and 339 received placebo. The first dose was administered from 6 weeks after birth. Serious adverse events were observed in 5.1% of recipients of Rotarix as compared with 6.8% of placebo recipients. Similar rates of other adverse events were observed in Rotarix and placebo 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 or placebo. The safety profile was similar between Rotarix and placebo recipients.

•Post marketing surveillance:

Respiratory, thoracic and mediastinal disorders:

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

No case of overdose has been reported.

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

Protective efficacy

Clinical studies have been conducted in Europe and Latin America to evaluate the protective efficacy of Rotarix against any and severe rotavirus gastro-enteritis.

A clinical study performed in Europe evaluated Rotarix given according to different European schedules (2, 3 months; 2, 4 months; 3, 4 months; 3, 5 months) in 4000 subjects. Severity of gastro-enteritis was defined according to the Vesikari 20-point scale which evaluates the full clinical picture of rotavirus gastro-enteritis by taking into account the severity and duration of diarrhoea and vomiting, the severity of fever and dehydration as well as the need for treatment.

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

^† Severe gastro-enteritis defined as a score 11 on the Vesikari scale

(§) ATP cohort for efficacy

* Statistically significant (p < 0.05)

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.

A clinical study performed in Latin America evaluated Rotarix in more than 20000 subjects. Severity of gastro-enteritis was defined according to WHO criteria. The protective vaccine efficacy against severe rotavirus gastro-enteritis requiring hospitalisation and/or rehydration therapy in a medical facility and the type specific vaccine efficacy after two doses of Rotarix are presented in the table below:

(§)ATP cohort for efficacy

* Statistically significant (p < 0.05)

# The numbers of cases, on which the estimates of efficacy against G4P[8] were based, were very small (1 case in 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 against severe rotavirus gastro-enteritis (Vesikari score 11) caused by rotavirus G2P[4] type during the first year of life.

* In these studies, the point estimates and confidence intervals were respectively: 100% (95% CI: -1858.0;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.

Immune response

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

The following table shows the percentage of subjects with serum anti-rotavirus IgA antibody titers 20U/ml (by ELISA) one to two months after the second dose of vaccine or placebo as observed in different studies.

Immune response in preterm infants

In a clinical study conducted in preterm infants, born after at least 27 weeks of gestational age, the immunogenicity of Rotarix was assessed in a subset of 147 subjects and showed that Rotarix is immunogenic in this population; 85.7% (95% CI: 79.0;90.9) of subjects achieved serum anti-rotavirus IgA antibody titers 20U/ml (by ELISA) one month after the second dose of vaccine.

Evaluation of pharmacokinetic properties is not required for vaccines.

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

Powder

Sucrose

Dextran

Sorbitol

Amino acids

Dulbecco's Modified Eagle Medium (DMEM)

Solvent

Calcium carbonate

Xanthan gum

Sterile water

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

3 years.

After reconstitution:

After the reconstitution, the vaccine should be administered immediately. If not used immediately,

in-use storage should not be longer than 24 hours and at a temperature between 2-25°C.

Store in a refrigerator (2°C – 8°C).

Do not freeze.

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

For storage conditions of the reconstituted product, see section 6.3.

1 dose of powder in a glass container (type I glass) with a stopper (rubber butyl)

1ml of solvent in an oral applicator (type I glass) with a plunger stopper and a protective tip cap (rubber butyl).

Transfer adapter for reconstitution (1/dose)

in the following pack sizes:

- pack size of 1 glass container of powder plus 1 oral applicator of solvent

- pack size of 5 glass containers of powder plus 5 oral applicators of solvent

- pack size of 10 glass containers of powder plus 10 oral applicators of solvent

- pack size of 25 glass containers of powder plus 25 oral applicators of solvent

Not all pack sizes may be marketed.

A white deposit and clear supernatant is observed upon storage of the oral applicator containing the solvent. The solvent should be inspected visually both before and after shaking for any foreign particulate matter and/or abnormal physical appearance prior to reconstitution.

The reconstituted vaccine is slightly more turbid than the solvent and is milky white in appearance.

The reconstituted vaccine should also be inspected visually for any foreign particulate matter and/or abnormal physical appearance prior to administration. In the event of either being observed, discard the vaccine. Any unused vaccine or waste material should be disposed of in accordance with local requirements.

Instructions for reconstitution and administration of the vaccine:

1. Remove the plastic cover from the glass container containing the powder.

2. Connect the transfer adapter onto the glass container by pushing it downwards until the transfer adapter is properly and securely placed.

3. Shake the oral applicator containing the solvent vigorously. The shaken suspension will appear as a turbid liquid with a slow settling white deposit.

4. Remove the protective tip cap from the oral applicator.

5. Connect the oral applicator into the transfer adapter by pushing it firmly on this device.

6. Transfer the entire content of the oral applicator into the glass container containing the powder.

7. With the oral applicator still attached, shake the glass container and examine it for complete suspension of the powder. The reconstituted vaccine will appear more turbid than the solvent alone. This appearance is normal.

8. Withdraw the entire mixture back into the oral applicator.

9. Remove the oral applicator from the transfer adapter.

10. This vaccine is for oral administration only. The child should be seated in a reclining position. Administer the entire content of the oral applicator orally (by administering the entire content of the oral applicator on the inside of the cheek).

11. Do not inject.

If the reconstituted vaccine is to be stored temporarily before administration, replace the protective tip cap on the oral applicator. The oral applicator containing the reconstituted vaccine should be shaken gently again before oral administration. Do not inject.

GlaxoSmithKline Biologicals s.a.

Rue de l'Institut 89

B-1330 Rixensart, Belgium

EU/1/05/330/001

Date of first authorisation: 21 February 2006

21/08/2009