Children 12 through 23 months of age: In clinical trials, ProQuad was administered alone to 6038 children 12 through 23 months of age. ProQuad was generally well tolerated.
Children received either the refrigerator-stable formulation or the frozen formulation of ProQuad and were monitored for 6 weeks post vaccination. The safety profiles were similar for the two formulations. The safety of the frozen formulation of ProQuad was compared with the safety of M-M-R II and VARIVAX given concomitantly at separate injection sites. The safety profile for ProQuad was similar to the component vaccines.
The only systemic vaccine-related adverse experiences that were reported at a significantly greater rate in individuals who received ProQuad than in individuals who received M-M-R II and VARIVAX concomitantly at separate injection sites were fever (≥ 38.9°C [≥ 102°F] oral equivalent or abnormal) (21.5% versus 14.9%, respectively), and measles-like rash (3.0% versus 2.1%, respectively). Both fever and measles-like rash usually occurred within 5 to 12 days following the vaccination, were of short duration, and resolved with no long-term sequelae. Pain/tenderness/soreness at the injection site was reported at a statistically lower rate in individuals who received ProQuad than in individuals who received M-M-R II and VARIVAX concomitantly at separate injection sites (22.0% versus 26.7%, respectively). The only vaccine-related injection-site adverse experience that was more frequent among recipients of ProQuad than recipients of M-M-R II and VARIVAX was rash at the injection site (2.3% versus 1.5%, respectively).
Across clinical studies, the following adverse experiences were reported as vaccine-related by the investigator in individuals after a single dose of ProQuad (excluding single events with a frequency ≤0.02%). Several adverse experiences were solicited in the clinical studies and are designated with the symbol (†).
[Very common (≥ 1/10); Common (≥ 1/100, <1/10); Uncommon (≥ 1/1,000, <1/100); Rare (≥ 1/10,000, <1/1,000)]: Infections and infestations: Common: upper respiratory infection.
Uncommon: gastroenteritis, ear infection/otitis, nasopharyngitis, otitis media, pharyngitis, roseola, viral infection, viral rash.
Rare: bronchiolitis, candidiasis, infectious croup, tonsillitis, varicella†, viral gastroenteritis.
Blood and lymphatic disorders: Rare: lymphadenopathy.
Immune system disorders: Rare: allergy/hypersensitivity.
Metabolism and nutrition disorders: Uncommon: anorexia, decreased appetite.
Psychiatric disorders: Common: irritability.
Uncommon: crying, insomnia, sleep disorder.
Rare: agitation, clinging, emotional changes.
Nervous system disorders: Uncommon: febrile seizure, somnolence.
Rare: ataxia, headache, lethargy.
Eye disorders: Rare: conjunctivitis, tearing, visual discomfort.
Ear and labyrinth disorders: Rare: ear pain.
Vascular disorders: Rare: flushing.
Respiratory, thoracic, and mediastinal disorders: Uncommon: cough, nasal congestion, respiratory congestion, rhinorrhea.
Gastrointestinal disorders: Common: diarrhea, vomiting.
Rare: flatulence, nausea, teething.
Skin and subcutaneous tissue disorders: Common: measles-like rash†, rash, varicella-like rash†.
Uncommon: dermatitis (including contact, atopic, and diaper rash), eczema, erythema, miliaria rubra/heat rash, rubella-like rash†, urticaria, viral exanthema.
Rare: acne, drug eruption, exanthema.
General disorders and administration site conditions: Very common: fever ≥38.9°C ([≥ 102°F] oral equivalent or abnormal)†, erythema† or pain/tenderness/soreness† at the injection site.
Common: ecchymosis or swelling† at the injection site, injection site rash†.
Uncommon: asthenia/fatigue, induration or warmth at the injection site, injection site hemorrhage, injection site mass/lump, malaise.
Rare: flu-like/influenza-like illness, injection site discoloration, injection site reaction, pain, pain/tenderness/soreness.
Injury and poisoning, and procedural complications: Rare: contusion, non-venomous bite/sting.
Other Adverse Experiences: Additionally, adverse experiences reported with post-marketing use of ProQuad and/or in clinical studies and/or post-marketing use of M-M-R II, the component vaccines, and VARIVAX without regard to causality or frequency are summarised as follows.
Infections and infestations: atypical measles, cellulitis, epididymitis, herpes zoster‡, infection, influenza, measles, orchitis, parotitis, respiratory infection, skin infection, varicella (vaccine strain).
Blood and the lymphatic system disorders: aplastic anemia, lymphadenitis, regional lymphadenopathy, thrombocytopenia.
Immune system disorders: anaphylactoid reaction, anaphylaxis and related phenomenon such as angioneurotic edema, facial edema, and peripheral edema, anaphylaxis in individuals with or without an allergic history.
Psychiatric disorders: apathy, nervousness.
Nervous system disorders: Acute disseminated encephalomyelitis (ADEM), afebrile convulsions or seizures, aseptic meningitis (see as follows), Bell's palsy, cerebrovascular accident, dizziness, dream abnormality, encephalitis‡ (see as follows), encephalopathy (see as follows), Guillain Barré syndrome, hypersomnia, measles inclusion body encephalitis (see CONTRAINDICATIONS), meningitis‡, ocular palsies, paraesthesia, polyneuritis, polyneuropathy, subacute sclerosing panencephalitis (see as follows), syncope, transverse myelitis, tremor.
‡Cases caused by wild-type varicella or vaccine strain varicella have been reported in immunocompromised or immunocompetent individuals administered VARIVAX (same varicella vaccine strain as in ProQuad).
Eye disorders: edema of the eyelid, irritation, necrotizing retinitis (reported only in immunocompromised individuals), optic neuritis, retinitis, retrobulbar neuritis.
Ear and labyrinth disorders: nerve deafness.
Vascular disorders: extravasation.
Respiratory, thoracic and mediastinal disorders: bronchial spasm, bronchitis, epistaxis, pneumonitis (see CONTRAINDICATIONS), pneumonia, pulmonary congestion, rhinitis, sinusitis, sneezing, sore throat.
Gastrointestinal disorders: abdominal pain, hematochezia, mouth ulcer.
Skin and subcutaneous tissue disorders: erythema multiforme, Henoch-Schönlein purpura, herpes simplex, impetigo, panniculitis, pruritus, purpura, skin induration, Stevens-Johnson syndrome, sunburn, acute hemorrhagic edema of infancy.
Musculoskeletal, connective tissue and bone disorders: arthritis and/or arthralgia (usually transient and rarely chronic [see as follows]), musculoskeletal pain, myalgia, pain of the hip, leg, or neck, swelling.
General disorders and administration site conditions: injection site complaints (burning and/or stinging of short duration, eczema, edema/swelling, hive-like rash, hematoma, induration, lump, vesicles, wheal and flare), inflammation, lip abnormality, papillitis, roughness/dryness, stiffness, trauma, varicella-like rash, venipuncture site hemorrhage, warm sensation, warm to touch.
Death from various, and in some cases unknown, causes has been reported rarely following vaccination with measles, mumps, and rubella vaccines; however, a causal relationship has not been established in healthy individuals (see CONTRAINDICATIONS). No deaths or permanent sequelae were 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.
Encephalitis and encephalopathy have been reported approximately once for every 3 million doses of the combination of measles, mumps, and rubella vaccine contained in M-M-R II. Since 1978, post-marketing surveillance of M-M-R II indicates that serious adverse events such as encephalitis and encephalopathy continue to be rarely reported. The risk of such serious neurological disorders following live measles virus vaccine administration remains far less than that for encephalitis and encephalopathy with wild-type measles (1 per 1000 reported cases).
In severely immunocompromised individuals 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); disseminated mumps and rubella vaccine virus infection have also been reported.
Arthralgia and/or arthritis (usually transient and rarely chronic), and polyneuritis are features of infection with wild-type rubella and vary in frequency and severity with age and gender, being greatest in adult females and least in prepubertal children. Following vaccination in children, reactions in joints are generally uncommon (0 to 3%) and of brief duration. In women, incidence rates for arthritis and arthralgia are generally higher than those seen in children (12 to 20%), and the reactions tend to be more marked and of longer duration. Symptoms may persist for a matter of months or on rare occasions for years. In adolescent girls, the reactions appear to be intermediate in incidence between those seen in children and adult women. Even in older women (35 to 45 years), these reactions are generally well tolerated and rarely interfere with normal activities.
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. Only rarely have vaccine recipients developed chronic joint symptoms.
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. This is far less than the association with infection with wild-type measles, 6 to 22 cases of SSPE per million cases of measles. The results of a retrospective case-controlled study conducted by the US Centers for Disease Control and Prevention 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 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.
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) [relative risk (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. 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. (See table.)
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In this observational post-marketing study, no case of febrile seizure was observed during the 5 to 12 day post-vaccination time period among 26,455 children who received ProQuad as a second dose of M-M-R II and/or VARIVAX (25,212 as second dose of M-M-R II and VARIVAX, 1,056 as a second dose of M-M-R II, and 187 as a second dose of VARIVAX). In addition, detailed general safety data were available from the 25,212 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.