2.1 Dose and Schedule

After reconstitution, a single dose of PRIORIX is approximately 0.5 mL.

Administer according to the following schedule:

•

First dose – 12 through 15 months of age

•

Second dose – 4 through 6 years of age

If PRIORIX is not administered according to this schedule and 2 doses of measles-, mumps- and rubella-virus vaccine are recommended for an individual, there should be a minimum of 4 weeks between the first and second dose.

PRIORIX may be administered as a second dose to individuals who have received a first dose of another measles, mumps and rubella virus-containing vaccine.

2.2 Preparation

Reconstitute the Lyophilized Antigen Component, Live only with the accompanying Sterile Water Diluent Component to form PRIORIX. The reconstituted vaccine should be a clear peach- to fuchsia pink-colored suspension. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, do not administer the vaccine.

Figure 1. Hold the prefilled syringe by the barrel and unscrew the syringe cap by twisting it counterclockwise. Align the needle to the axis of the syringe and attach by gently connecting the needle hub into the Luer Lock Adaptor (LLA) and rotate a quarter turn clockwise until you feel it lock.	Figure 2. Cleanse the vial stopper. Transfer the entire contents of the prefilled syringe into the lyophilized antigen component vial.	Figure 3. Shake the vial well until the powder is completely dissolved. Do not invert the vial while shaking.	Figure 4. After reconstitution, withdraw the entire contents of the reconstituted vaccine into the same syringe and after changing the needle, administer subcutaneously.

2.3 Administration

Administer PRIORIX immediately after reconstitution. If not used immediately, store refrigerated between 36° and 46° F (2° and 8°C) and administer within 8 hours. Discard reconstituted vaccine if not used within 8 hours.

4.1 Severe Allergic Reactions

Do not administer PRIORIX to individuals with a history of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine or after a previous dose of any measles, mumps, and rubella virus-containing vaccine [see Description (11)].

4.2 Immunosuppression

Due to the risk of disseminated vaccine virus infection, do not administer PRIORIX to individuals with severe humoral or cellular (primary or acquired) immunodeficiency.

4.3 Pregnancy

Do not administer PRIORIX to individuals who are pregnant. Pregnancy should be avoided for 1 month after vaccination [see Use in Specific Populations (8.1)].

5.1 Allergic Vaccine Reactions

Appropriate medical treatment used to manage immediate allergic reactions must be available in the event an acute anaphylactic reaction occurs following administration of PRIORIX.

5.2 Febrile Seizures

There is a risk of febrile seizure following immunization with PRIORIX [see Adverse Reactions (6.1)].

5.3 Thrombocytopenia

Thrombocytopenia and thrombocytopenic purpura have been reported following vaccination with PRIORIX [see Adverse Reactions (6.2)].

5.4 Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including PRIORIX. Procedures should be in place to avoid injury from fainting.

5.5 Latex

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

5.6 Risk of Vaccine Virus Transmission

Live attenuated rubella vaccine virus has been detected in the nose and throat of individuals 7 to 28 days after vaccination with a rubella virus containing vaccine. No documented confirmed cases of transmitted rubella vaccine virus have been reported.1

5.7 Limitation of Vaccine Effectiveness

Vaccination with PRIORIX may not protect all susceptible individuals.

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.

The safety of PRIORIX was evaluated in 6 clinical studies, in which a total of 12,151 participants (6,391 in the United States) received at least 1 dose of PRIORIX: 8,780 children (4,148 in the United States) 12 through 15 months of age; 2,917 children (1,950 in the United States) 4 through 6 years of age; and 454 adults and children (293 in the United States) 7 years of age and older. Across the 6 studies, participants who received PRIORIX are as follows: 51.6% were male; 64.6% were White, 18.4% were Asian, 6.1% were Black, and 10.9% were of other racial groups (including American Indian/Native American, Native Hawaiian/Pacific Islander, Arabic/North African and Other); and 14.3% were of Hispanic/Latino ethnicity. The racial/ethnic distribution of participants who received PRIORIX and M‑M‑R II was similar.

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

In a randomized, observer-blind, controlled clinical study (Study 1, NCT01702428) conducted in 5 countries (United States [including Puerto Rico], Estonia, Finland, Mexico and Spain), 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) given concomitantly with HAVRIX (Hepatitis A Vaccine) and VARIVAX (Varicella Virus Vaccine Live, Merck & Co., Inc.); children enrolled in the United States also received PREVNAR 13 (Pneumococcal 13-valent Conjugate Vaccine, Pfizer Inc.) concomitantly. In the overall population, 51.3% were male; 75.6% were White, 4.8% were Black, 3.5% were Asian, 16.1% were of other racial groups (including American Indian/Native American, Native Hawaiian/Pacific Islander, Arabic/North African and Other); and 18.6% were of Hispanic/Latino ethnicity. The median age of participants was 12 months (range: 11 to 16 months). Local solicited adverse reactions were recorded by parents or guardians using standardized diary cards for 4 days. Systemic solicited adverse reactions of drowsiness, loss of appetite, and irritability were collected for 15 days, and fever, rash, parotid/salivary gland swelling, febrile convulsions, and signs of meningeal irritation (i.e., neck stiffness with or without photophobia or headache) were collected for 43 days (Table 1). Unsolicited adverse events that occurred within 43 days following vaccination were recorded using diary cards supplemented by medical review. Data on solicited adverse reactions and unsolicited adverse events were transcribed into the study database during an on-site visit on Day 42 and via telephone contact on Day 180.

Total vaccinated cohort for safety included all vaccinated participants for whom safety data were available.
N = Number of participants.

n = Number of participants presenting with solicited adverse reaction described.
a HAVRIX and VARIVAX were administered concomitantly with PRIORIX or M-M-R II; participants in the U.S. also received PREVNAR 13 concomitantly with PRIORIX (n = 1,847) or M-M-R II (n = 654).
b 4 Days, 15 Days, and 43 Days included the day of vaccination and the subsequent 3, 14, and 42 days, respectively.
c Neck stiffness with or without photophobia or headache.

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

In a randomized, observer-blind, controlled clinical study (Study 2, NCT01681992) conducted in six countries (United States [including Puerto Rico], Czech Republic, Finland, Malaysia, Spain and Thailand), 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. The first dose was given concomitantly with HAVRIX and VARIVAX; children enrolled in the United States (including Puerto Rico) also received PREVNAR 13 concomitantly. In the overall population, 51.7% were male; 68.4% were White, 24.4% were Asian, 3.2% were Black, and 4.0% were of other racial groups (including American Indian/Native American, Native Hawaiian/Pacific Islander, Arabic/North African and Other); and 5.6% were of Hispanic/Latino ethnicity. The median age of participants was 12 months (range: 11 to 16 months). Local solicited adverse reactions were recorded by parents or guardians using standardized diary cards for 4 days, and systemic adverse reactions of fever, rash, parotid/salivary gland swelling, febrile convulsions, and signs of meningeal irritation (i.e., neck stiffness with or without photophobia or headache) were collected for 43 days. Unsolicited adverse events that occurred within 43 days following vaccination were recorded using diary cards supplemented by medical review. Data on solicited adverse reactions and unsolicited adverse events were transcribed into the study database during on-site visits on Day 42, Day 84, and Day 222. The safety profile of PRIORIX following the second dose was similar to the safety profile following the first dose of PRIORIX.

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

In a randomized, observer-blind, controlled clinical study (Study 3, NCT01621802) conducted in 3 countries (United States, South Korea, and Taiwan), 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. PRIORIX and M-M-R II were given concomitantly with KINRIX (DTaP-IPV) [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine] and VARIVAX in a subset of subjects (n = 802 receiving PRIORIX, n = 298 receiving M-M-R II) enrolled in the United States. In the overall population, 52.5% were male; 42.4% were White, 37.2% were Asian, 8.2% were Black, and 12.3% were of other racial groups (including American Indian/Native American, Native Hawaiian/Pacific Islander, Arabic/North African and Other) and 17.2% were of Hispanic/Latino ethnicity. The median age of participants was 4 years (range: 3 to 6 years). In a subset of participants who received concomitantly administered vaccines, data on local solicited adverse reactions were recorded by parents or guardians using standardized diary cards for 4 days. Systemic solicited adverse reactions of drowsiness and loss of appetite were collected for 4 days, and fever, rash, parotid/salivary gland swelling, febrile convulsions, and signs of meningeal irritation (i.e., neck stiffness with or without photophobia or headache) were collected for 43 days (Table 2). Unsolicited adverse events that occurred within 43 days following vaccination were recorded using diary cards supplemented by medical review. Data on solicited adverse reactions and unsolicited adverse events were transcribed into the study database during an on‑site visit on Day 42 and via telephone contact on Day 180.

Total vaccinated cohort for safety included all vaccinated participants for whom safety data were available.
N = Number of participants.

n = Number of participants presenting with solicited adverse reaction described.
a 4 Days and 43 Days included the day of vaccination and the subsequent 3 and 42 days, respectively.
b Neck stiffness with or without photophobia or headache.

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

In a randomized, observer-blind, controlled clinical study (Study 4, NCT02058563) conducted in 3 countries (United States, Slovakia, and Estonia), 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. Participants 7 through 17 years were enrolled if they had received one dose of a combined measles, mumps, and rubella virus-containing vaccine on or after their first birthday and participants 18 years of age or older were enrolled if they previously received at least one dose of a combined measles, mumps, and rubella virus-containing vaccine. In the overall population, 46.2% were male; 73.8% were White, 0.2% were Asian, 24.0% were Black, and 1.9% were of other racial groups (including American Indian/Native American, Native Hawaiian/Pacific Islander, Arabic/North African and Other) and 13.3% were of Hispanic/Latino ethnicity. The median age of participants was 26 years (range: 7 to 59 years). Data on solicited local and systemic adverse reactions were recorded by the participants or their parents or guardians using standardized diary cards for 4 days and 43 days, respectively (Table 3). Unsolicited adverse events that occurred within 43 days following vaccination were recorded using diary cards supplemented by medical review. Data on solicited adverse reactions and unsolicited adverse events were transcribed into the study database during an on-site visit on Day 42 and via telephone contact on Day 180.

Total vaccinated cohort for safety included all vaccinated participants for whom safety data were available.
N = Number of participants.

n = Number of participants presenting with solicited adverse reaction described.
a Participants received a first dose of either M-M-R II, PRIORIX, or a non-U.S. combined measles, mumps, rubella and varicella virus vaccine.
b 4 Days and 43 Days included the day of vaccination and the subsequent 3 and 42 days, respectively.
c Neck stiffness with or without photophobia or headache.

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.

7.1 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.

8.1 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.

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)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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.

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).

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.

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).

14.2 Concomitant Administration

Concomitant Administration with HAVRIX, VARIVAX, and PREVNAR 13

The concomitant use of PRIORIX or M-M-R II with HAVRIX and VARIVAX was evaluated in Study 1 (NCT01702428) in children 12 through 15 months of age. All participants received PRIORIX or M-M-R II administered concomitantly with HAVRIX and VARIVAX. Children enrolled in the U.S. also received PREVNAR 13 concomitantly.

In subsets of participants in Study 1, immune responses to the antigens contained in HAVRIX, VARIVAX, and PREVNAR 13 were measured in sera obtained 42 days after concomitant administration of PRIORIX or M-M-R II. There was no evidence that PRIORIX interfered with the antibody responses to these vaccines relative to the antibody responses when M-M-R II was concomitantly administered.

Concomitant Administration with KINRIX and VARIVAX

The concomitant use of PRIORIX or M-M-R II with KINRIX and VARIVAX was evaluated in Study 3 (NCT01621802) in children 4 through 6 years of age. A subset of participants received PRIORIX or M-M-R II administered concomitantly with KINRIX and VARIVAX.

Immune responses to the antigens contained in KINRIX and VARIVAX were measured in sera obtained 42 days after concomitant administration of PRIORIX or M‑M‑R II. There was no evidence that PRIORIX interfered with the antibody responses to these vaccines relative to the antibody responses when M-M-R II was concomitantly administered.

16.1 Storage before Reconstitution

Vials of lyophilized antigen component: Store refrigerated between 36° and 46°F (2° and 8°C). Protect vials from light.

Prefilled ungraduated syringes of sterile water diluent: Store refrigerated between 36° and 46°F (2° and 8°C) or at controlled room temperature up to 77°F (25°C).

Do not freeze lyophilized antigen component or sterile water diluent.

16.2 Storage after Reconstitution

Administer PRIORIX immediately after reconstitution. If not used immediately, store refrigerated between 36° and 46°F (2° and 8°C) and administer within 8 hours. Discard reconstituted vaccine if not used within 8 hours.

Do not freeze. Discard if the reconstituted vaccine has been frozen.