ROTARIX: Package Insert and Label Information

ROTARIX- rotavirus vaccine, live, oral
GlaxoSmithKline Biologicals SA

1 INDICATIONS AND USAGE

ROTARIX is indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9) when administered as a 2-dose series [see Clinical Studies (14.3)]. ROTARIX is approved for use in infants 6 weeks and up to 24 weeks of age.

2 DOSAGE AND ADMINISTRATION

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).

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.

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.

Push plunger of oral applicator to transfer diluent into vial. Suspension will appear white and turbid.

Withdraw vaccine into oral applicator.

Withdraw vaccine into oral applicator.

Twist and remove the oral applicator.

Twist and remove the oral applicator.

Ready for oral administration.

Ready for oral administration.

Do not use a needle with ROTARIX. Not for injection.

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.

3 DOSAGE FORMS AND STRENGTHS

ROTARIX is available as a vial of lyophilized vaccine to be reconstituted with a liquid diluent in a prefilled oral applicator.

Each 1-mL dose contains a suspension of at least 106.0 median Cell Culture Infective Dose (CCID50 ) of live, attenuated human G1P[8] rotavirus after reconstitution.

4 CONTRAINDICATIONS

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 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

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).

Table 1. Solicited Adverse Reactions within 8 Days Following Doses 1 and 2 of ROTARIX or Placebo (Total Vaccinated Cohort)
Total vaccinated cohort = All vaccinated infants for whom safety data were available.n = Number of infants for whom at least one symptom sheet was completed.a Defined as crying more than usual.b Data not collected in 1 of 7 studies; Dose 1: ROTARIX n = 2,583; placebo n = 1,897; Dose 2: ROTARIX n = 2,522; placebo n = 1,863.c Defined as temperature ≥100.4°F (≥38.0°C) rectally or ≥99.5°F (≥37.5°C) orally.d Defined as eating less than usual.

Adverse Reaction

Dose 1

Dose 2

ROTARIX

Placebo

ROTARIX

Placebo

n = 3,284

n = 2,013

n = 3,201

n = 1,973

%

%

%

%

Fussiness/irritabilitya

52

52

42

42

Cough/runny noseb

28

30

31

33

Feverc

25

33

28

34

Loss of appetited

25

25

21

21

Vomiting

13

11

8

8

Diarrhea

4

3

3

3

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.

Table 2. Intussusception and Relative Risk with ROTARIX Compared with Placebo
CI = Confidence Interval.a Median duration after Dose 1 (follow-up visit at 30 to 90 days after Dose 2).

Confirmed Cases of Intussusception

ROTARIX

Placebo

n = 31,673

n = 31,552

Within 31 days following diagnosis after any dose

6

7

Relative Risk (95% CI)

0.85 (0.30, 2.42)

Within 100 days following Dose 1a

9

16

Relative Risk (95% CI)

0.56 (0.25, 1.24)

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

Table 3. Intussusception Cases by Day Range in Relation to Dose

Day Range

Dose 1

Dose 2

Any Dose

ROTARIX

Placebo

ROTARIX

Placebo

ROTARIX

Placebo

n = 31,673

n = 31,552

n = 29,616

n = 29,465

n = 31,673

n = 31,552

0-7

0

0

2

0

2

0

8-14

0

0

0

2

0

2

15-21

1

1

2

1

3

2

22-30

0

1

1

2

1

3

Total (0-30)

1

2

5

5

6

7

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.

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