Vaccine Information: ProQuad (Page 2 of 4)

6.2 Post-Marketing Experience

The following adverse events have been identified during post-approval use of either the components of ProQuad or ProQuad. Because the events 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 vaccine exposure.

Infections and infestations

Subacute sclerosing panencephalitis, encephalitis, aseptic meningitis, meningitis, measles, atypical measles, pneumonia, respiratory infection, infection, varicella (vaccine strain), influenza, herpes zoster, orchitis, epididymitis, cellulitis, skin infection, retinitis, bronchitis, parotitis, sinusitis, impetigo, herpes simplex, candidiasis, rhinitis.

The vaccine virus (Oka/Merck strain) contained in ProQuad may establish latency of varicella zoster virus in immunocompetent individuals, with the potential for later development of herpes zoster.

Cases of encephalitis or meningitis caused by vaccine strain varicella virus have been reported in immunocompetent individuals previously vaccinated with VARIVAX (same varicella vaccine strain as in ProQuad) months to years after vaccination. Reported cases were commonly associated with preceding or concurrent herpes zoster rash.

Blood and the lymphatic system disorders

Aplastic anemia, thrombocytopenia, regional lymphadenopathy, lymphadenitis.

Immune system disorders

Anaphylaxis and related phenomena such as angioneurotic edema, facial edema, and peripheral edema, anaphylactoid reaction.

Psychiatric disorders

Agitation, apathy, nervousness.

Nervous system disorders

Measles inclusion body encephalitis, acute disseminated encephalomyelitis, transverse myelitis, cerebrovascular accident, encephalopathy, Guillain-Barré syndrome, optic neuritis, Bell’s palsy, polyneuropathy, ataxia, hypersomnia, afebrile convulsions or seizures, febrile seizure, headache, syncope, dizziness, tremor, paraesthesia.

Eye disorders

Necrotizing retinitis (in immunocompromised individuals), retrobulbar neuritis, ocular palsies, edema of the eyelid, irritation eye.

Ear and labyrinth disorders

Nerve deafness, ear pain.

Vascular disorders

Extravasation blood.

Respiratory, thoracic and mediastinal disorders

Pneumonitis, pulmonary congestion, wheezing, bronchial spasm, epistaxis, sore throat.

Gastrointestinal disorders

Hematochezia, abdominal pain, mouth ulcer.

Skin and subcutaneous tissue disorders

Stevens-Johnson syndrome, Henoch-Schönlein purpura, erythema multiforme, acute hemorrhagic edema of infancy, purpura, skin induration, panniculitis, pruritus.

Musculoskeletal, connective tissue and bone disorders

Arthritis, arthralgia, pain of the hip, leg, or neck; myalgia; musculoskeletal pain.

General disorders and administration site conditions

Injection-site complaints including wheal and flare, warm to touch, stiffness, warm sensation, inflammation, injection-site hemorrhage, injection-site injury.

6.3 Post-Marketing Observational Safety Surveillance Study

Safety was evaluated in an observational study that included 69,237 children vaccinated with ProQuad 12 months to 12 years old. A historical comparison group included 69,237 age-, gender-, and date-of-vaccination (day and month)-matched subjects who were given M-M-R II and VARIVAX concomitantly. The primary objective was to assess the incidence of febrile seizures occurring within various time intervals after vaccination in 12- to 60-month-old children who had neither been vaccinated against measles, mumps, rubella, or varicella, nor had a history of the wild-type infections (N=31,298 vaccinated with ProQuad, including 31,043 who were 12 to 23 months old). The incidence of febrile seizures was also assessed in a historical control group of children who had received their first vaccination with M-M-R II and VARIVAX concomitantly (N=31,298, including 31,019 who were 12 to 23 months old). The secondary objective was to assess the general safety of ProQuad in the 30-day period after vaccination in children 12 months to 12 years old.

In pre-licensure clinical studies, an increase in fever was observed 5 to 12 days after vaccination with ProQuad (dose 1) compared to M-M-R II and VARIVAX (dose 1) given concomitantly. In the post-marketing observational surveillance study, results from the primary safety analysis revealed an approximate two-fold increase in the risk of febrile seizures in the same 5 to 12 day timeframe after vaccination with ProQuad (dose 1). The incidence of febrile seizures 5 to 12 days after ProQuad (dose 1) (0.70 per 1000 children) was higher than that in children receiving M-M-R II and VARIVAX concomitantly (0.32 per 1000 children) [RR 2.20, 95% confidence interval (CI): 1.04, 4.65]. The incidence of febrile seizures 0 to 30 days after ProQuad (dose 1) (1.41 per 1000 children) was similar to that observed in children receiving M-M-R II and VARIVAX concomitantly [RR 1.10 (95% CI: 0.72, 1.69)]. See Table 9. General safety analyses revealed that the risks of fever (RR=1.89; 95% CI: 1.67, 2.15) and skin eruption (RR=1.68; 95% CI: 1.07, 2.64) were significantly higher after ProQuad (dose 1) compared with those who received concomitant first doses of M-M-R II and VARIVAX, respectively. All medical events that resulted in hospitalization or emergency room visits were compared between the group given ProQuad and the historical comparison group, and no other safety concerns were identified in this study.

Table 9: Confirmed Febrile Seizures Days 5 to 12 and 0 to 30 After Vaccination with ProQuad (dose 1) Compared to Concomitant Vaccination with M-M-R II and VARIVAX (dose 1) in Children 12 to 60 Months of Age
Time Period ProQuad cohort (N=31,298) MMR+V cohort (N=31,298) Relative risk (95% CI)
n Incidence per 1000 n Incidence per 1000
5 to 12 Days 22 0.70 10 0.32 2.20 (1.04, 4.65)
0 to 30 Days 44 1.41 40 1.28 1.10 (0.72, 1.69)

In this observational post-marketing study, no case of febrile seizure was observed during the 5 to 12 day postvaccination time period among 26,455 children who received ProQuad as a second dose of M-M-R II and VARIVAX. In addition, detailed general safety data were available from more than 25,000 children who received ProQuad as a second dose of M-M-R II and VARIVAX, most of them (95%) between 4 and 6 years of age, and an analysis of these data by an independent, external safety monitoring committee did not identify any specific safety concern.

7 DRUG INTERACTIONS

7.1 Immune Globulins and Transfusions

Administration of immune globulins and other blood products concurrently with ProQuad vaccine may interfere with the expected immune response [see Warnings and Precautions (5.7)] {9-11}. The ACIP has specific recommendations for intervals between administration of antibody containing products and live virus vaccines.

7.2 Salicylates

Reye syndrome has been reported following the use of salicylates during wild-type varicella infection. Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination with ProQuad [see Warnings and Precautions (5.8) and Patient Counseling Information (17)].

7.3 Corticosteroids and Immunosuppressive Drugs

ProQuad vaccine should not be administered to individuals receiving immunosuppressive therapy, including high dose corticosteroids. Vaccination with ProQuad vaccine can result in disseminated disease and extensive vaccine-associated rash in individuals on immunosuppressive drugs [see Contraindications (4.2)].

7.4 Drug/Laboratory Test Interactions

Live, attenuated measles, mumps, and rubella virus vaccines given individually may result in a temporary depression of tuberculin skin sensitivity. Therefore, if a tuberculin test is to be done, it should be administered either any time before, simultaneously with, or at least 4 to 6 weeks after ProQuad.

7.5 Use with Other Vaccines

At least 1 month should elapse between a dose of a measles-containing vaccine and a dose of ProQuad, and at least 3 months should elapse between administration of 2 doses of ProQuad or varicella-containing vaccines.

ProQuad may be administered concomitantly with Haemophilus influenzae type b conjugate (meningococcal protein conjugate) and hepatitis B (recombinant). Additionally, ProQuad may be administered concomitantly with pneumococcal 7-valent conjugate vaccine, and/or hepatitis A (inactivated) vaccines [see Clinical Studies (14)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

ProQuad vaccine contains live attenuated measles, mumps, rubella and varicella 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.

For women who are inadvertently vaccinated when pregnant or who become pregnant within 3 months of administration of ProQuad, the healthcare provider should be aware of the following: (1) Reports have indicated that contracting wild-type measles during pregnancy enhances fetal risk. Increased rates of spontaneous abortion, stillbirth, congenital defects, and prematurity have been observed subsequent to infection with wild-type measles during pregnancy. There are no adequate studies of the attenuated (vaccine) strain of measles virus in pregnancy; (2) Mumps infection during the first trimester of pregnancy may increase the rate of spontaneous abortion. Although mumps vaccine virus has been shown to infect the placenta and fetus, there is no evidence that it causes congenital malformations in humans {12}; (3) In a 10-year survey involving over 700 pregnant women who received rubella vaccine within 3 months before or after conception (of whom 189 received the Wistar RA 27/3 strain), none of the newborns had abnormalities compatible with congenital rubella syndrome {13}; and (4) Wild-type varicella, if acquired during pregnancy, can sometimes cause congenital varicella syndrome.

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

There are no relevant animal data.

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US 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 {14,15}.

Data

Human Data

In a 10-year CDC survey involving over 700 pregnant women who received rubella vaccine within 3 months before or after conception (of whom 189 received the Wistar RA 27/3 strain), none of the newborns had abnormalities compatible with congenital rubella syndrome {13}.

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