2.1 Reconstitution Instructions for Oral Administration

For oral use only. Not for injection.

Reconstitute only with accompanying diluent. Do not mix ROTARIX with other vaccines or solutions.

	Remove vial cap and push transfer adapter onto vial (lyophilized vaccine).
	Shake diluent in oral applicator (white, turbid suspension). Connect oral applicator to transfer adapter.
	Push plunger of oral applicator to transfer diluent into vial. Suspension will appear white and turbid.
	Withdraw vaccine into oral applicator.
	Twist and remove the oral applicator.
Ready for oral administration.	Do not use a needle with ROTARIX. Not for injection.

2.2 Recommended Dose and Schedule

The vaccination series consists of two 1-mL doses administered orally. The first dose should be administered to infants beginning at 6 weeks of age. There should be an interval of at least 4 weeks between the first and second dose. The 2-dose series should be completed by 24 weeks of age.

Safety and effectiveness have not been evaluated if ROTARIX were administered for the first dose and another rotavirus vaccine were administered for the second dose or vice versa.

In the event that the infant spits out or regurgitates most of the vaccine dose, a single replacement dose may be considered at the same vaccination visit.

2.3 Infant Feeding

Breastfeeding was permitted in clinical studies. There was no evidence to suggest that breastfeeding reduced the protection against rotavirus gastroenteritis afforded by ROTARIX. There are no restrictions on the infant’s liquid consumption, including breast milk, either before or after vaccination with ROTARIX.

4.1 Hypersensitivity

A demonstrated history of hypersensitivity to any component of the vaccine.

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

4.2 Gastrointestinal Tract Congenital Malformation

Infants with a history of uncorrected congenital malformation of the gastrointestinal tract (such as Meckel’s diverticulum) that would predispose the infant for intussusception should not receive ROTARIX.

4.3 History of Intussusception

Infants with a history of intussusception should not receive ROTARIX [see Warnings and Precautions (5.5)]. In postmarketing experience, intussusception resulting in death following a second dose has been reported following a history of intussusception after the first dose [see Adverse Reactions (6.2)].

4.4 Severe Combined Immunodeficiency Disease

Infants with Severe Combined Immunodeficiency Disease (SCID) should not receive ROTARIX. Postmarketing reports of gastroenteritis, including severe diarrhea and prolonged shedding of vaccine virus, have been reported in infants who were administered live, oral rotavirus vaccines and later identified as having SCID [see Adverse Reactions (6.2)].

5.1 Latex

The tip caps of the prefilled oral applicators of diluent contain natural rubber latex which may cause allergic reactions.

5.2 Gastrointestinal Disorders

Administration of ROTARIX should be delayed in infants suffering from acute diarrhea or vomiting.

Safety and effectiveness of ROTARIX in infants with chronic gastrointestinal disorders have not been evaluated. [See Contraindications (4.2).]

5.3 Altered Immunocompetence

Safety and effectiveness of ROTARIX in infants with known primary or secondary immunodeficiencies, including infants with human immunodeficiency virus (HIV), infants on immunosuppressive therapy, or infants with malignant neoplasms affecting the bone marrow or lymphatic system have not been established.

5.4 Shedding and Transmission

Rotavirus shedding in stool occurs after vaccination with peak excretion occurring around Day 7 after Dose 1.

One clinical trial demonstrated that vaccinees transmit vaccine virus to healthy seronegative contacts [see Clinical Pharmacology (12.2)].

The potential for transmission of vaccine virus following vaccination should be weighed against the possibility of acquiring and transmitting natural rotavirus. Caution is advised when considering whether to administer ROTARIX to individuals with immunodeficient close contacts, such as individuals with malignancies, primary immunodeficiency or receiving immunosuppressive therapy.

5.5 Intussusception

Following administration of a previously licensed oral live rhesus rotavirus-based vaccine, an increased risk of intussusception was observed.1 The risk of intussusception with ROTARIX was evaluated in a pre-licensure randomized, placebo-controlled safety study (including 63,225 infants) conducted in Latin America and Finland. No increased risk of intussusception was observed in this clinical trial following administration of ROTARIX when compared with placebo. [See Adverse Reactions (6.1).]

In a postmarketing, observational study conducted in Mexico, cases of intussusception were observed in temporal association within 31 days following the first dose of ROTARIX, with a clustering of cases in the first 7 days. [See Adverse Reactions (6.2).]

Other postmarketing observational studies conducted in Brazil and Australia also suggest an increased risk of intussusception within the first 7 days following the second dose of ROTARIX.2,3[See Adverse Reactions (6.2).]

In worldwide passive postmarketing surveillance, cases of intussusception have been reported in temporal association with ROTARIX [see Adverse Reactions (6.2)].

5.6 Post-exposure Prophylaxis

Safety and effectiveness of ROTARIX when administered after exposure to rotavirus have not been evaluated.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Solicited and unsolicited adverse events, serious adverse events, and cases of intussusception were collected in 7 clinical studies. Cases of intussusception and serious adverse events were collected in an additional large safety study. These 8 clinical studies evaluated a total of 71,209 infants who received ROTARIX (n = 36,755) or placebo (n = 34,454). The racial distribution for these studies was as follows: Hispanic 73.4%, white 16.2%, black 1.0%, and other 9.4%; 51% were male.

Solicited Adverse Reactions

In 7 clinical studies, detailed safety information was collected by parents/guardians for 8 consecutive days following vaccination with ROTARIX (i.e., day of vaccination and the next 7 days). A diary card was completed to record fussiness/irritability, cough/runny nose, the infant’s temperature, loss of appetite, vomiting, or diarrhea on a daily basis during the first week following each dose of ROTARIX or placebo. Adverse reactions among recipients of ROTARIX and placebo occurred at similar rates (Table 1).

Unsolicited Adverse Reactions

Infants were monitored for unsolicited serious and non-serious adverse events that occurred in the 31-day period following vaccination in 7 clinical studies. The following adverse reactions occurred at a statistically higher incidence (95% Confidence Interval [CI] of Relative Risk excluding 1) among recipients of ROTARIX (n = 5,082) as compared with placebo recipients (n = 2,902): irritability (ROTARIX 11.4%, placebo 8.7%) and flatulence (ROTARIX 2.2%, placebo 1.3%).

Serious Adverse Reactions

Infants were monitored for serious adverse events that occurred in the 31-day period following vaccination in 8 clinical studies. Serious adverse reactions occurred in 1.7% of recipients of ROTARIX (n = 36,755) as compared with 1.9% of placebo recipients (n = 34,454). Among placebo recipients, diarrhea (placebo 0.07%, ROTARIX 0.02%), dehydration (placebo 0.06%, ROTARIX 0.02%), and gastroenteritis (placebo 0.3%, ROTARIX 0.2%) occurred at a statistically higher incidence (95% CI of Relative Risk excluding 1) as compared with recipients of ROTARIX.

Deaths

During the entire course of 8 clinical studies, there were 68 (0.19%) deaths following administration of ROTARIX (n = 36,755) and 50 (0.15%) deaths following placebo administration (n = 34,454). The most commonly reported cause of death following vaccination was pneumonia, which was observed in 19 (0.05%) recipients of ROTARIX and 10 (0.03%) placebo recipients (Relative Risk: 1.74, 95% CI: 0.76, 4.23).

Intussusception

In a controlled safety study conducted in Latin America and Finland, the risk of intussusception was evaluated in 63,225 infants (31,673 received ROTARIX and 31,552 received placebo). Infants were monitored by active surveillance including independent, complementary methods (prospective hospital surveillance and parent reporting at scheduled study visits) to identify potential cases of intussusception within 31 days after vaccination and, in a subset of 20,169 infants (10,159 received ROTARIX and 10,010 received placebo), up to one year after the first dose.

No increased risk of intussusception following administration of ROTARIX was observed within a 31-day period following any dose, and rates were comparable to the placebo group after a median of 100 days (Table 2). In a subset of 20,169 infants (10,159 received ROTARIX and 10,010 received placebo) followed up to one year after Dose 1, there were 4 cases of intussusception with ROTARIX compared with 14 cases of intussusception with placebo (Relative Risk: 0.28 [95% CI: 0.10, 0.81]). All of the infants who developed intussusception recovered without sequelae.

Among vaccine recipients, there were no confirmed cases of intussusception within the 0- to 14-day period after the first dose (Table 3), which was the period of highest risk for the previously licensed oral live rhesus rotavirus-based vaccine.1

Kawasaki Disease

Kawasaki disease has been reported in 18 (0.035%) recipients of ROTARIX and 9 (0.021%) placebo recipients from 16 completed or ongoing clinical trials. Of the 27 cases, 5 occurred following ROTARIX in clinical trials that were either not placebo-controlled or 1:1 randomized. In placebo-controlled trials, Kawasaki disease was reported in 17 recipients of ROTARIX and 9 placebo recipients (Relative Risk: 1.71 [95% CI: 0.71, 4.38]). Three of the 27 cases were reported within 30 days post-vaccination: 2 cases (ROTARIX = 1, placebo = 1) were from placebo-controlled trials (Relative Risk: 1.00 [95% CI: 0.01, 78.35]) and one case following ROTARIX was from a non–placebo-controlled trial. Among recipients of ROTARIX, the time of onset after study dose ranged 3 days to 19 months.

6.2 Postmarketing Experience

The temporal association between vaccination with ROTARIX and intussusception was evaluated in a hospital-based active surveillance study that identified infants with intussusception at participating hospitals in Mexico. Using a self-controlled case series method,4 the incidence of intussusception during the first 7 days after receipt of ROTARIX and during the 31-day period after receipt of ROTARIX was compared with a control period. The control period was from birth to one year, excluding the pre-defined risk period (first 7 days or first 31 days post-vaccination, respectively).

Over a 2-year period, the participating hospitals provided health services to approximately 1 million infants under 1 year of age. Among 750 infants with intussusception, the relative incidence of intussusception in the 31‑day period after the first dose of ROTARIX compared with the control period was 1.96 (95.5% CI: 1.46, 2.63)]; the relative incidence of intussusception in the first 7 days after the first dose of ROTARIX compared with the control period was 6.07 (95.5% CI: 4.20, 8.63).

The Mexico study did not take into account all medical conditions that may predispose infants to intussusception. The results may not be generalizable to U.S. infants who have a lower background rate of intussusception than Mexican infants. However, if a temporal increase in the risk for intussusception following ROTARIX similar in magnitude to that observed in the Mexico study does exist in U.S. infants, it is estimated that approximately 1 to 3 additional cases of intussusception hospitalizations would occur per 100,000 vaccinated infants in the U.S. within 7 days following the first dose of ROTARIX. In the first year of life, the background rate of intussusception hospitalizations in the U.S. has been estimated to be approximately 34 per 100,000 infants.5

Other postmarketing observational studies conducted in Brazil and Australia also suggest an increased risk of intussusception within the first 7 days following the second dose of ROTARIX.2,3

Worldwide passive postmarketing surveillance data suggest that most cases of intussusception reported following ROTARIX occur in the 7-day period after the first dose.

The following adverse reactions have been identified during post-approval use of ROTARIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination.

Gastrointestinal Disorders

Intussusception (including death), recurrent intussusception (including death), hematochezia, gastroenteritis with vaccine viral shedding in infants with SCID.

Blood and Lymphatic System Disorders

Idiopathic thrombocytopenic purpura.

Vascular Disorders

Kawasaki disease.

General Disorders and Administration Site Conditions

Maladministration.

7.1 Concomitant Vaccine Administration

In clinical trials, ROTARIX was administered concomitantly with U.S.-licensed and non–U.S.-licensed vaccines. In a U.S. coadministration study in 484 infants, there was no evidence of interference in the immune responses to any of the antigens when PEDIARIX [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine], a U.S.-licensed 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.), and a U.S.-licensed Hib conjugate vaccine (Sanofi Pasteur SA) were coadministered with ROTARIX as compared with separate administration of ROTARIX.

7.2 Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to ROTARIX. [See Warnings and Precautions (5.3).]

8.4 Pediatric Use

Safety and effectiveness of ROTARIX in infants younger than 6 weeks or older than 24 weeks of age have not been evaluated.

The effectiveness of ROTARIX in pre-term infants has not been established. Safety data are available in pre-term infants (ROTARIX = 134, placebo = 120) with a reported gestational age ≤36 weeks. These pre-term infants were followed for serious adverse events up to 30 to 90 days after Dose 2. Serious adverse events were observed in 5.2% of recipients of ROTARIX as compared with 5.0% of placebo recipients. No deaths or cases of intussusception were reported in this population.

12.1 Mechanism of Action

Prior to rotavirus vaccination programs, rotavirus infected nearly all children by the time they were 5 years of age. Severe, dehydrating rotavirus gastroenteritis occurs primarily among children aged 3 to 35 months.6 Among children up to 3 years of age, approximately 16% of cases before 6 months of age result in hospitalization.7

The exact immunologic mechanism by which ROTARIX protects against rotavirus gastroenteritis is unknown [see Clinical Pharmacology (12.2)]. ROTARIX contains a live, attenuated human rotavirus that replicates in the small intestine and induces immunity.

12.2 Pharmacodynamics

Immunogenicity

A relationship between antibody responses to rotavirus vaccination and protection against rotavirus gastroenteritis has not been established. Seroconversion was defined as the appearance of anti-rotavirus IgA antibodies (concentration ≥20 U/mL) post-vaccination in the serum of infants previously negative for rotavirus. In 2 safety and efficacy studies, one to two months after a 2-dose series, 86.5% of 787 recipients of ROTARIX seroconverted compared with 6.7% of 420 placebo recipients and 76.8% of 393 recipients of ROTARIX seroconverted compared with 9.7% of 341 placebo recipients, respectively.

Shedding and Transmission

A prospective, randomized, double-blind, placebo-controlled study was performed in the Dominican Republic in twins within the same household to assess whether transmission of vaccine virus occurs from a vaccinated infant to a non-vaccinated infant. One hundred pairs of healthy twins 6 to 14 weeks of age (gestational age ≥32 weeks) were randomized with one twin to receive ROTARIX (n = 100) and the other twin to receive placebo (n = 100). Twenty subjects in each arm were excluded for reasons such as having rotavirus antibody at baseline. Stool samples were collected on the day of or 1 day prior to each dose, as well as 3 times weekly for 6 consecutive weeks after each dose of ROTARIX or placebo. Transmission was defined as presence of the vaccine virus strain in any stool sample from a twin receiving placebo.

Transmitted vaccine virus was identified in 15 of 80 twins receiving placebo (18.8% [95% CI: 10.9, 29.0]). Median duration of the rotavirus shedding was 10 days in twins who received ROTARIX as compared with 4 days in twins who received placebo in whom the vaccine virus was transmitted. In the 15 twins who received placebo, no gastrointestinal symptoms related to transmitted vaccine virus were observed.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

ROTARIX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

14.1 Efficacy Studies

The data demonstrating the efficacy of ROTARIX in preventing rotavirus gastroenteritis come from 24,163 infants randomized in two placebo-controlled studies conducted in 17 countries in Europe and Latin America. In these studies, oral polio vaccine (OPV) was not coadministered; however, other routine childhood vaccines could be concomitantly administered. Breastfeeding was permitted in both studies.

A randomized, double-blind, placebo-controlled study was conducted in 6 European countries. A total of 3,994 infants were enrolled to receive ROTARIX (n = 2,646) or placebo (n = 1,348). Vaccine or placebo was given to healthy infants as a 2-dose series with the first dose administered orally from 6 through 14 weeks of age followed by one additional dose administered at least 4 weeks after the first dose. The 2-dose series was completed by 24 weeks of age. For both vaccination groups, 98.3% of infants were white and 53% were male.

The clinical case definition of rotavirus gastroenteritis was an episode of diarrhea (passage of 3 or more loose or watery stools within a day), with or without vomiting, where rotavirus was identified in a stool sample. Severity of gastroenteritis was determined by a clinical scoring system, the Vesikari scale, assessing the duration and intensity of diarrhea and vomiting, the intensity of fever, use of rehydration therapy, or hospitalization for each episode. Scores range from 0 to 20, where higher scores indicate greater severity. An episode of gastroenteritis with a score of 11 or greater was considered severe.8

The primary efficacy endpoint was prevention of any grade of severity of rotavirus gastroenteritis caused by naturally occurring rotavirus from 2 weeks after the second dose through one rotavirus season (according to protocol, ATP). Other efficacy evaluations included prevention of severe rotavirus gastroenteritis, as defined by the Vesikari scale, and reductions in hospitalizations due to rotavirus gastroenteritis and all-cause gastroenteritis regardless of presumed etiology. Analyses were also done to evaluate the efficacy of ROTARIX against rotavirus gastroenteritis among infants who received at least one vaccination (total vaccinated cohort, TVC).

Efficacy of ROTARIX against any grade of severity of rotavirus gastroenteritis through one rotavirus season was 87.1% (95% CI: 79.6, 92.1); TVC efficacy was 87.3% (95% CI: 80.3, 92.0). Efficacy against severe rotavirus gastroenteritis through one rotavirus season was 95.8% (95% CI: 89.6, 98.7); TVC efficacy was 96.0% (95% CI: 90.2, 98.8) (Table 4). The protective effect of ROTARIX against any grade of severity of rotavirus gastroenteritis observed immediately following Dose 1 administration and prior to Dose 2 was 89.8% (95% CI: 8.9, 99.8).

Efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through one rotavirus season was 100% (95% CI: 81.8, 100); TVC efficacy was 100% (95% CI: 81.7, 100) (Table 4). ROTARIX reduced hospitalizations for all-cause gastroenteritis regardless of presumed etiology by 74.7% (95% CI: 45.5, 88.9).

A randomized, double-blind, placebo-controlled study was conducted in 11 countries in Latin America and Finland. A total of 63,225 infants received ROTARIX (n = 31,673) or placebo (n = 31,552). An efficacy subset of these infants consisting of 20,169 infants from Latin America received ROTARIX (n = 10,159) or placebo (n = 10,010). Vaccine or placebo was given to healthy infants as a 2-dose series with the first dose administered orally from 6 through 13 weeks of age followed by one additional dose administered at least 4 weeks after the first dose. The 2-dose series was completed by 24 weeks of age. For both vaccination groups, the racial distribution of the efficacy subset was as follows: Hispanic 85.8%, white 7.9%, black 1.1%, and other 5.2%; 51% were male.

The clinical case definition of severe rotavirus gastroenteritis was an episode of diarrhea (passage of 3 or more loose or watery stools within a day), with or without vomiting, where rotavirus was identified in a stool sample, requiring hospitalization and/or rehydration therapy equivalent to World Health Organization (WHO) plan B (oral rehydration therapy) or plan C (intravenous rehydration therapy) in a medical facility.

The primary efficacy endpoint was prevention of severe rotavirus gastroenteritis caused by naturally occurring rotavirus from 2 weeks after the second dose through one year (ATP). Analyses were done to evaluate the efficacy of ROTARIX against severe rotavirus gastroenteritis among infants who received at least one vaccination (TVC). Reduction in hospitalizations due to rotavirus gastroenteritis was also evaluated (ATP).

Efficacy of ROTARIX against severe rotavirus gastroenteritis through one year was 84.7% (95% CI: 71.7, 92.4); TVC efficacy was 81.1% (95% CI: 68.5, 89.3) (Table 5).

Efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through one year was 85.0% (95% CI: 69.6, 93.5); TVC efficacy was 80.8% (95% CI: 65.7, 90.0) (Table 5).

14.2 Efficacy through Two Rotavirus Seasons

The efficacy of ROTARIX persisting through two rotavirus seasons was evaluated in two studies.

In the European study, the efficacy of ROTARIX against any grade of severity of rotavirus gastroenteritis through two rotavirus seasons was 78.9% (95% CI: 72.7, 83.8). Efficacy in preventing any grade of severity of rotavirus gastroenteritis cases occurring only during the second season post-vaccination was 71.9% (95% CI: 61.2, 79.8). The efficacy of ROTARIX against severe rotavirus gastroenteritis through two rotavirus seasons was 90.4% (95% CI: 85.1, 94.1). Efficacy in preventing severe rotavirus gastroenteritis cases occurring only during the second season post-vaccination was 85.6% (95% CI: 75.8, 91.9).

The efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through two rotavirus seasons was 96.0% (95% CI: 83.8, 99.5).

In the Latin American study, the efficacy of ROTARIX against severe rotavirus gastroenteritis through two years was 80.5% (95% CI: 71.3, 87.1). Efficacy in preventing severe rotavirus gastroenteritis cases occurring only during the second year post-vaccination was 79.0% (95% CI: 66.4, 87.4). The efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through two years was 83.0% (95% CI: 73.1, 89.7).

The efficacy of ROTARIX beyond the second season post-vaccination was not evaluated.

14.3 Efficacy against Specific Rotavirus Types

The type-specific efficacy against any grade of severity and severe rotavirus gastroenteritis caused by G1P[8], G3P[8], G4P[8], G9P[8], and combined non-G1 (G2, G3, G4, G9) types was statistically significant through one year. Additionally, type-specific efficacy against any grade of severity and severe rotavirus gastroenteritis caused by G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and combined non-G1 (G2, G3, G4, G9) types was statistically significant through two years (Table 6).

16.1 Storage before Reconstitution

•

Lyophilized vaccine in vials: Store refrigerated at 2° to 8°C (36° to 46°F). Protect vials from light.

•

Diluent in oral applicators: Store refrigerated at 2° to 8°C (36° to 46°F) or at a controlled room temperature up to 25°C (77°F). Do not freeze. Discard if the diluent has been frozen.

16.2 Storage after Reconstitution

ROTARIX should be administered within 24 hours of reconstitution. After reconstitution, store refrigerated at 2° to 8°C (36° to 46°F) or at a controlled room temperature up to 25°C (77°F). Discard the reconstituted vaccine in biological waste container if not used within 24 hours. Do not freeze. Discard if the reconstituted vaccine has been frozen.