Vaccine Information: Priorix (Page 2 of 3)

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of PRIORIX. 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 with PRIORIX.

Blood and Lymphatic System Disorders

Thrombocytopenia, thrombocytopenic purpura.

Vascular Disorders

Vasculitis (including Henoch-Schönlein purpura and Kawasaki syndrome).

Immune system Disorders

Anaphylactic reactions.

Infections and Infestations

Meningitis, measles-like illness, mumps-like illness (including orchitis, epididymitis, and parotitis).

Musculoskeletal and Connective Tissue Disorders

Arthralgia, arthritis.

Nervous System Disorders

Encephalitis, cerebellitis, cerebellitis-like symptoms (including transient gait disturbance and transient ataxia), Guillain-Barré syndrome, transverse myelitis, peripheral neuritis, afebrile seizures, syncope.

Skin and Subcutaneous Tissue Disorders

Erythema multiforme.

7 DRUG INTERACTIONS

7.1 Immune Globulins and Blood Products

Immune globulins and other blood products administered concomitantly with PRIORIX contain antibodies that may interfere with vaccine virus replication and decrease the expected immune response. The Advisory Committee on Immunization Practices (ACIP) has specific recommendations for intervals between administration of antibody containing products and live virus vaccines.

7.2 Tuberculin Skin Testing

PRIORIX may result in a temporary suppression of tuberculin reactivity. Therefore, if a tuberculin test is to be done, it should be administered either any time before, simultaneously with, or at least 4 weeks after PRIORIX to avoid false-negative results.

7.3 Use With Other Live Viral Vaccines

PRIORIX can be administered concomitantly with other live viral vaccines. If not given concomitantly, PRIORIX should be given 1 month before or 1 month after administration of other live viral vaccines to avoid potential for immune interference.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

PRIORIX contains live attenuated measles, mumps, and rubella viruses. The vaccine is contraindicated for use in pregnant women because infection during pregnancy with the wild-type viruses is associated with maternal and fetal adverse outcomes. Pregnancy should be avoided for 1 month after vaccination [see Contraindications (4.3), Patient Counseling Information (17)].

Reports have indicated that contracting wild-type measles during pregnancy enhances fetal risk, including increased rates of spontaneous abortion, stillbirth, premature delivery and congenital defects.2,3 Wild-type mumps virus infection during the first trimester of pregnancy may increase the rate of spontaneous abortion. Pregnant women infected with wild-type rubella virus are at increased risk for miscarriage or stillbirth, and their infants are at risk for congenital rubella syndrome.1

Available data on inadvertent administration of PRIORIX to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

There are no animal studies with PRIORIX to inform use during pregnancy.

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

Risk Summary

It is not known whether the vaccine components of PRIORIX are excreted in human milk. Data are not available to assess the effects of PRIORIX on the breastfed infant or on milk production/excretion. Studies have shown that lactating postpartum women vaccinated with live attenuated rubella vaccine may secrete the virus in breast milk and transmit it to breast‑fed infants.4,5 In the breast-fed infants with serological evidence of rubella virus vaccine strain antibodies, none exhibited severe disease; however, one exhibited mild clinical illness typical of acquired rubella.6,7

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PRIORIX and any potential adverse effects on the breastfed child from PRIORIX or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness of PRIORIX in infants younger than 12 months have not been established.

8.5 Geriatric Use

Clinical studies of PRIORIX did not include participants 65 years of age and older to determine whether they respond differently from younger participants.

11 DESCRIPTION

PRIORIX (Measles, Mumps, and Rubella Vaccine, Live) is a suspension for subcutaneous injection. PRIORIX is supplied as a sterile, lyophilized antigen component which is reconstituted at the time of use with the accompanying sterile water diluent. The lyophilized antigen component is a whitish to slightly pink powder.

PRIORIX contains the Schwarz strain of live attenuated measles virus, the RIT 4385 strain of live attenuated mumps virus (derived from the Jeryl Lynn strain), both propagated in chick‑embryo fibroblasts from embryonated eggs of specific pathogen-free flocks and the Wistar RA 27/3 strain of live attenuated rubella virus propagated in MRC-5 human diploid cells. The 3 virus strains are cultured in media containing amino acids, a small amount of neomycin sulfate and bovine serum albumin and are stabilized after multiple washing steps in media free from antibiotics and albumin. The attenuated measles, mumps and rubella viruses are then mixed with a stabilizer prior to lyophilization.

After reconstitution, each approximately 0.5-mL dose contains not less than 3.4 log10 Cell Culture Infective Dose 50% (CCID50 ) of measles virus, 4.2 log10 CCID50 of mumps virus, and 3.3 log10 CCID50 of rubella virus. Each dose also contains 32 mg of anhydrous lactose, 9 mg of sorbitol, 9 mg of amino acids, and 8 mg of mannitol. Each dose may also contain residual amounts of neomycin sulphate (≤25 mcg), ovalbumin (≤60 ng), and bovine serum albumin (≤50 ng), from the manufacturing process. After reconstitution, PRIORIX is a clear peach- to fuchsia pink-colored suspension.

PRIORIX contains no preservative.

The tip caps of the prefilled syringes of sterile water diluent contain natural rubber latex. The plungers of the syringes and the stoppers of the lyophilized antigen component vials are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Humoral immune responses against measles, mumps, and rubella viruses induced by PRIORIX were measured by enzyme-linked immunosorbent assays (ELISAs). IgG antibodies measured by the ELISAs used in clinical studies of PRIORIX have been shown to correlate with the presence of neutralizing antibodies that have been associated with protection [see Clinical Studies (14)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

The effectiveness of PRIORIX is based on a comparison of antibody responses relative to M‑M‑R II. Antibody responses to measles, mumps, and rubella viruses were measured by ELISAs. Analyses evaluated antibody geometric mean concentrations (GMC) and seroresponse rates (SRR). Seroresponse thresholds are 200 mIU/mL, 10 ELU/mL, and 10 IU/mL for anti-measles virus, anti-mumps virus, and anti-rubella virus antibodies, respectively.

14.1 Antibody Responses to Measles, Mumps and Rubella Viruses

Children 12 through 15 Months of Age Who Received PRIORIX as a First Dose

In Study 1 (NCT01702428), 5,003 participants 12 through 15 months of age received a first dose of PRIORIX (n = 3,714) or M‑M‑R II (n = 1,289) [see Adverse Reactions (6.1)]. Antibody responses to measles, mumps, and rubella viruses were measured by ELISAs using sera obtained 42 days following the first dose of either PRIORIX or M-M-R II. Non-inferiority of the immune response after the first dose of PRIORIX compared with M-M-R II was demonstrated in terms of SRR and GMC to measles, mumps, and rubella viruses. The immune responses measured in the U.S. study participants were similar to those in the overall study population. A summary of immune responses is shown in Table 4.

Table 4. Immune Responses after the First Dose of PRIORIX Compared with M‑M‑R II (Study 1, NCT01702428, According-to-Protocol Population)

Parameter

Virus Antigen

PRIORIX

N = 3,187-3,248

M-M-R II

N = 1,107-1,137

Difference

(PRIORIX minus

M-M-R II)

(95% CI)

SRRa (%)

Measles

98

98

0.18

(-0.68, 1.25)

Mumps

98

98

0.81

(-0.10, 1.96)

Rubella

97

99

-1.15

(-2.00, -0.15)

PRIORIX

N = 3,187-3,248

M-M-R II

N = 1,107-1,137

Ratio

(PRIORIX/M-M-R II)

(95% CI)

GMCb

Measles (mIU/mL)

3,165

3,215

0.98

(0.93, 1.05)

Mumps (ELU/mL)

76

73

1.05

(0.99, 1.11)

Rubella (IU/mL)

53

60

0.87

(0.83, 0.92)

According-to-Protocol cohort included all vaccinated participants who met protocol-defined criteria for immunogenicity analysis.
PRIORIX or M-M-R II was administered concomitantly with HAVRIX and VARIVAX; U.S. participants also received PREVNAR 13.
N = Number of participants.
SRR = Seroresponse rate (percentage of initially seronegative participants with concentration above seroresponse threshold for each assay).
GMC = Geometric mean antibody concentration adjusted for country.
CI = Confidence Interval
a Non-inferiority criterion met for all antigens (lower limit of 2-sided 95% CI for the difference [group receiving PRIORIX minus group receiving M-M-R II] was ≥-5%).b Non-inferiority criterion met for all antigens (lower limit of 2-sided 95% CI for the ratio [group receiving PRIORIX over group receiving M-M-R II] was ≥0.67).

Children 12 through 15 Months of Age Who Received a Second Dose of PRIORIX 6 Weeks after the First Dose

In Study 2 (NCT01681992), 4,516 participants 12 through 15 months of age received a first dose of PRIORIX (n = 2,990) or M-M-R II (n = 1,526) followed by a second dose of the same vaccine 6 weeks later [see Adverse Reactions (6.1)]. Antibody responses to measles, mumps, and rubella viruses were measured in a subset of participants (n = 199 – 259 PRIORIX; n = 212 – 257 M‑M‑R II) in sera obtained 42 days following the second dose of either PRIORIX or M‑M‑R II. In a descriptive analysis, the immune response after a second dose was similar between the group receiving PRIORIX and the group receiving M-M-R II in terms of antibody SRR and GMC for all antigens.

Children 4 through 6 Years of Age Who Received PRIORIX as a Second Dose of Measles, Mumps, and Rubella Virus Vaccine.

In Study 3 (NCT01621802), 4,007 participants 4 through 6 years of age received PRIORIX (n = 2,917) or M‑M‑R II (n = 1,090) as a second dose following administration of an initial dose of a combined measles, mumps, and rubella virus-containing vaccine in the second year of life [see Adverse Reactions (6.1)]. Prior to vaccination, the percentages of participants with antibody levels above the seroresponse thresholds were 98.0% for measles, 95.7% for mumps, and 98.7% for rubella. Antibody responses to measles, mumps, and rubella viruses were measured by ELISAs using sera obtained 42 days following of either PRIORIX or M‑M‑R II as a second dose. The non-inferiority of PRIORIX to M-M-R II when administered with KINRIX and VARIVAX was demonstrated in terms of SRR and GMC to measles, mumps, and rubella viruses at Day 42 (Table 5).

Table 5. Immune Responses to PRIORIX Compared with M-M-R II as a Second Dose in Children 4 through 6 Years of Age (Study 3, NCT01621802, According-to-Protocol Population)

Parameter

Virus Antigen

PRIORIX

N = 690-698

M-M-R II

N = 245-250

Difference

(PRIORIX minus

M-M-R II)

(97.5% CI)

SRRa (%)

Measles

100

100

0.00

(-0.72, 1.98)

Mumps

100

100

0.00

(-0.72, 1.97)

Rubella

100

100

-0.14

(-0.98, 1.84)

PRIORIX

N = 690-691

M-M-R-II

N = 245-248

Ratio (PRIORIX/

M-M-R II)

(97.5% CI)

GMCb

Measles (mIU/mL)

4,285

4,333

0.99

(0.92, 1.06)

Mumps (ELU/mL)

171

188

0.91

(0.83, 1.00)

Rubella (IU/mL)

97

94

1.03

(0.97, 1.09)

According-to-Protocol cohort included all vaccinated participants who met protocol-defined criteria for immunogenicity analysis.
N = Number of participants.
SRR = Seroresponse rate (percentage of participants with concentration above seroresponse threshold for each assay).
GMC = Geometric mean antibody concentration adjusted for pre-vaccination concentration.
CI = Confidence Interval.
a Non-inferiority criterion met for all antigens (lower limit of 2-sided 97.5% CI for the difference [group receiving PRIORIX minus group receiving M-M-R II] was ≥-5%).b Non-inferiority criterion met for all antigens (lower limit of 2-sided 97.5% CI for the ratio [group receiving PRIORIX over group receiving M-M-R II] was ≥0.67).

Individuals 7 Years of Age and Older Who Received PRIORIX as a Second Dose of Measles, Mumps, and Rubella Vaccine

In Study 4 (NCT02058563), 860 participants 7 years of age and older received PRIORIX (n = 426) or M‑M‑R II (n = 434) as a second dose following previous administration of a combined measles, mumps, and rubella virus-containing vaccine [see Adverse Reactions (6.1)]. Prior to vaccination, the percentages of participants with antibody levels above the seroresponse thresholds were 93.1% for measles, 88.0% for mumps, and 81.9% for rubella. Antibody responses to measles, mumps, and rubella viruses were measured in sera obtained 42 days following the second dose of either PRIORIX or M-M-R II. The non-inferiority of the immune response after the second dose of PRIORIX compared with M-M-R II was demonstrated in terms of SRR and antibody GMC to measles, mumps, and rubella antigens. A summary of immune responses is shown in Table 6.

Table 6. Immune Responses to PRIORIX as a Second Dose Compared with M‑M‑R II (Study 4, NCT02058563, According-to-Protocol Population)

Parameter

Virus Antigen

PRIORIX

N = 405

M-M-R II

N = 414

Difference

(PRIORIX minus

M-M-R II)

(95% CI)

SRRa (%)

Measles

99

99

-0.51

(-2.22, 1.02)

Mumps

98

100

-1.25

(-3.10, 0.23)

Rubella

100

100

-0.25

(-1.57, 0.90)

PRIORIX

N = 404

M-M-R II

N = 413

Ratio

(PRIORIX / MMR II) (95% CI)

GMCb

Measles (mIU/mL)

1,754

1,783

0.98

(0.89, 1.09)

Mumps (ELU/mL)

114

110

1.04

(0.94, 1.15)

Rubella (IU/mL)

76

74

1.03

(0.94, 1.12)

According-to-Protocol cohort included all vaccinated participants who met protocol-defined criteria for immunogenicity analysis.
N = Number of participants.
SRR = Seroresponse rate (percentage of participants with concentration above seroresponse threshold for each assay).
GMC = Geometric mean antibody concentration adjusted for gender, age, country, and pre‑vaccination concentration.
CI = Confidence Intervals.
a Non-inferiority criterion met for all antigens (lower limit of 2-sided 95% CI for the difference [group receiving PRIORIX minus group receiving M-M-R II] was ≥-5%).b Non-inferiority criterion met for all antigens (lower limit of 2-sided 95% CI for the ratio [group receiving PRIORIX over group receiving M-M-R II] was ≥0.67).

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