Vaccine Information: ProQuad (Page 3 of 6)

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 in some cases described in the literature or 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 (see below), encephalitis (see below), aseptic meningitis (see below), 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.

Although not reported following vaccination with ProQuad, 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 (see below).

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 [see Contraindications (4.2)] , acute disseminated encephalomyelitis, transverse myelitis, cerebrovascular accident, encephalopathy (see below), 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 [see Contraindications (4.3)] , 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 and/or arthralgia (usually transient and rarely chronic, see below); pain of the hip, leg, or neck; myalgia; musculoskeletal pain.

General disorders and administration site conditions

Injection-site complaints (burning and/or stinging of short duration, edema/swelling, hive-like rash, discoloration, hematoma, induration, lump, vesicles, wheal and flare), varicella-like rash, warm to touch, stiffness, warm sensation, inflammation, injection-site hemorrhage, injection-site injury.

Deaths have been reported following vaccination with measles, mumps, and rubella vaccines; however, a causal relationship has not been established in healthy individuals. Death as a direct consequence of disseminated measles vaccine virus infection has been reported in severely immunocompromised individuals in whom a measles-containing vaccine is contraindicated and who were inadvertently vaccinated. However, there were no deaths or permanent sequelae reported in a published post-marketing surveillance study in Finland involving 1.5 million children and adults who were vaccinated with M-M-R II during 1982 to 1993 {3}.

Encephalitis and encephalopathy have been reported approximately once for every 3 million doses of M-M-R II or measles-, mumps-, and rubella-containing vaccine administered since licensure of these vaccines.

The risk of serious neurological disorders following live measles virus vaccine administration remains less than the risk of encephalitis and encephalopathy following infection with wild-type measles (1 per 1000 reported cases) {4,5}.

In severely immunocompromised individuals who have been inadvertently vaccinated with measles-containing vaccine; measles inclusion body encephalitis, pneumonitis, and fatal outcome as a direct consequence of disseminated measles vaccine virus infection have been reported [see Contraindications (4.2)]. In this population, disseminated mumps and rubella vaccine virus infection have also been reported.

Recipients of rubella vaccine may develop chronic joint symptoms. Arthralgia and/or arthritis, and polyneuritis after wild-type rubella virus infection vary in frequency and severity with age and gender, being greatest in adult females and least in pre-pubertal children. Following vaccination in children, reactions in joints are uncommon (0 to 3%) and of brief duration. In women, incidence rates for arthritis and arthralgia are higher than those seen in children (12 to 26%), and the reactions tend to be more marked and of longer duration (e.g. , months or years). In adolescent girls, the reactions appear to be intermediate in incidence between those seen in children and adult women.

Chronic arthritis has been associated with wild-type rubella infection and has been related to persistent virus and/or viral antigen isolated from body tissues. Chronic joint symptoms have been reported following administration of rubella-containing vaccine.

There have been reports of subacute sclerosing panencephalitis (SSPE) in children who did not have a history of infection with wild-type measles but did receive measles vaccine. Some of these cases may have resulted from unrecognized measles in the first year of life or possibly from the measles vaccination. Based on estimated measles vaccine distribution in the United States (US), the association of SSPE cases to measles vaccination is about one case per million vaccine doses distributed. The association with wild-type measles virus infection is 6 to 22 cases of SSPE per million cases of measles. The results of a retrospective case-controlled study suggest that the overall effect of measles vaccine has been to protect against SSPE by preventing measles with its inherent higher risk of SSPE.

Cases of aseptic meningitis have been reported to Vaccine Adverse Event Reporting System (VAERS) following measles, mumps, and rubella vaccination. Although a causal relationship between other strains of mumps vaccine and aseptic meningitis has been shown, there is no evidence to link Jeryl Lynn™ mumps vaccine to aseptic meningitis.

Cases of thrombocytopenia have been reported after use of measles vaccine; measles, mumps, and rubella vaccine; and after varicella vaccination. Post-marketing experience with live measles, mumps, and rubella vaccine indicates that individuals with current thrombocytopenia may develop more severe thrombocytopenia following vaccination. In addition, individuals who experienced thrombocytopenia following the first dose of a live measles, mumps, and rubella vaccine may develop thrombocytopenia with repeat doses. Serologic testing for antibody to measles, mumps, or rubella should be considered in order to determine if additional doses of vaccine are needed [see Warnings and Precautions (5.5)].

The reported rate of zoster in recipients of VARIVAX appears not to exceed that previously determined in a population-based study of healthy children who had experienced wild-type varicella {6}. In clinical trials, 8 cases of herpes zoster were reported in 9454 vaccinated individuals 12 months to 12 years of age during 42,556 person-years of follow-up. This resulted in a calculated incidence of at least 18.8 cases per 100,000 person-years. All 8 cases reported after VARIVAX were mild and no sequelae were reported. The long-term effect of VARIVAX on the incidence of herpes zoster is unknown at present.

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 [see Adverse Reactions (6.2), Infections and Infestations].

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.

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