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adverse reactions
ADVERSE REACTIONS A total of 23,849 doses of PEDIARIX have been administered to 8,088 infants who received one or more doses as part of a 3-dose primary series during 14 clinical studies. The most common adverse reactions observed in clinical trials were local injection site reactions (pain, redness, or swelling), fever, and fussiness. In comparative studies, administration of PEDIARIX was associated with higher rates of fever relative to separately administered vaccines (see WARNINGS; see ADVERSE REACTIONS Table 3). The prevalence of fever was highest on the day of vaccination and the day following vaccination. More than 96% of episodes of fever resolved within the 4-day period following vaccination (i.e., the period including the day of vaccination and the next 3 days). In the largest of the 14 studies, conducted in Germany, safety data were available for 4,666 infants who received PEDIARIX administered concomitantly at separate sites with 1 of 4 Hib conjugate vaccines (GlaxoSmithKline Biologicals [not US-licensed]; Wyeth Pharmaceuticals Inc., Sanofi Pasteur SA, or Merck & Co, Inc. [all US-licensed]) at 3, 4, and 5 months of age and for 768 infants in the control group that received separate US-licensed vaccines (INFANRIX, Hib conjugate vaccine [Sanofi Pasteur SA], and OPV [Wyeth Pharmaceuticals Inc.]). Data on adverse events were collected by parents using standardized diary cards for 4 consecutive days following each vaccine dose (i.e., day of vaccination and the next 3 days). Infants were also monitored for unsolicited adverse events that occurred within 30 days following vaccination using diaries which were returned at subsequent visits and were supplemented by spontaneous reports and a medical history as reported by parents. More than 95% of study participants were white. In a US study, the safety of PEDIARIX administered to 673 infants was compared to the safety of separately administered INFANRIX, ENGERIX-B, IPV (Sanofi Pasteur SA) in 335 infants. In both groups, infants received Hib and 7-valent pneumococcal conjugate vaccines (Wyeth Pharmaceuticals Inc.) concomitantly at separate sites. All vaccines were administered at 2, 4, and 6 months of age. The study was powered to evaluate fever >101.3°F following dose 1. Data on solicited adverse events were collected by parents using standardized diary cards for 4 consecutive days following each vaccine dose (i.e., day of vaccination and the next 3 days) and are presented in Table 3. Telephone follow-up was conducted 1 month and 6 months after the third vaccination to inquire about serious adverse events. At the 6-month follow-up, information also was collected on new onset of chronic illnesses. 638 subjects who received PEDIARIX and 313 subjects who received INFANRIX, ENGERIX-B, and IPV completed the 6-month follow-up. Among subjects in both study groups combined, 69% were white, 18% were Hispanic, 7% were black, 3% were Oriental, and 3% were of other racial/ethnic groups. The adverse event information from clinical trials provides a basis for identifying adverse events that appear to be related to vaccine use and for approximating rates. However, because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of PEDIARIX could reveal adverse events not observed in clinical trials. Deaths In 14 clinical trials, 5 deaths were reported among 8,088 (0.06%) recipients of PEDIARIX and 1 death was reported among 2,287 (0.04%) recipients of comparator vaccines. Causes of death in the group that received PEDIARIX included 2 cases of Sudden Infant Death Syndrome (SIDS) and one case of each of the following: Convulsive disorder, congenital immunodeficiency with sepsis, and neuroblastoma. One case of SIDS was reported in the comparator group. The rate of SIDS among all recipients of PEDIARIX across the 14 trials was 0.25/1,000. The rate of SIDS observed for recipients of PEDIARIX in the German safety study was 0.2/1,000 infants (reported rate of SIDS in Germany in the latter part of the 1990s was 0.7/1,000 newborns). 22 The reported rate of SIDS in the United States from 1990 to 1994 was 1.2/1,000 live births. 23 By chance alone, some cases of SIDS can be expected to follow receipt of pertussis-containing vaccines. 20 Serious Adverse Events Within 30 days following any dose of vaccine in the US safety study in which all subjects received concomitant pneumococcal and Hib conjugate vaccines, 7 serious adverse events were reported in 7 subjects (1% [7/673]) who received PEDIARIX (1 case each of pyrexia, gastroenteritis, and culture negative clinical sepsis and 4 cases of bronchiolitis) and 5 serious adverse events were reported in 4 subjects (1% [4/335]) who received INFANRIX, ENGERIX-B, and IPV (uteropelvic junction obstruction and testicular atrophy in one subject and 3 cases of bronchiolitis). Onset of Chronic Illnesses In the US safety study in which all subjects received concomitant pneumococcal and Hib conjugate vaccines, 21 subjects (3%) who received PEDIARIX and 14 subjects (4%) who received INFANRIX, ENGERIX-B, and IPV reported new onset of a chronic illness during the period from 1 to 6 months following the last dose of study vaccines. Among the chronic illnesses reported in the subjects who received PEDIARIX, there were 4 cases of asthma and 1 case each of diabetes mellitus and chronic neutropenia. There were 4 cases of asthma in subjects who received INFANRIX, ENGERIX-B, and IPV. Seizures In the German safety study over the entire study period, 6 subjects in the group that received PEDIARIX reported seizures. Two of these subjects had a febrile seizure, 1 of whom also developed afebrile seizures. The remaining 4 subjects had afebrile seizures, including 2 with infantile spasms. Two subjects reported seizures within 7 days following vaccination (1 subject had both febrile and afebrile seizures, and 1 subject had afebrile seizures), corresponding to a rate of 0.22 seizures per 1,000 doses (febrile seizures 0.07 per 1,000 doses, afebrile seizures 0.14 per 1,000 doses). No subject who received concomitant INFANRIX, Hib vaccine, and OPV reported seizures. In a separate German study that evaluated the safety of INFANRIX in 22,505 infants who received 66,867 doses of INFANRIX administered as a 3-dose primary series, the rate of seizures within 7 days of vaccination with INFANRIX was 0.13 per 1,000 doses (febrile seizures 0.0 per 1,000 doses, afebrile seizures 0.13 per 1,000 doses). Over the entire study period in the US safety study in which all subjects received concomitant pneumococcal and Hib conjugate vaccines, 4 subjects in the group that received PEDIARIX reported seizures. Three of these subjects had a febrile seizure and 1 had an afebrile seizure. Over the entire study period, 2 subjects in the group that received INFANRIX, ENGERIX-B, and IPV reported febrile seizures. There were no afebrile seizures in this group. No subject in either study group had seizures within 7 days following vaccination. Other Neurological Events of Interest No cases of hypotonic-hyporesponsiveness or encephalopathy were reported in either the German safety study or the US safety study. Solicited Adverse Events Table 3 presents data from the US safety study on solicited local and systemic adverse events within 4 days of vaccination with PEDIARIX or INFANRIX, ENGERIX-B, and IPV, administered concomitantly with Hib and 7-valent pneumococcal conjugate vaccines (Wyeth Pharmaceuticals Inc.). In this study, medical attention (a visit to or from medical personnel) for fever within 4 days following vaccination was sought in the group who received PEDIARIX for 8 infants after the first dose (1.2%), 1 infant following the second dose (0.2%), and 5 infants following the third dose (0.8%) (Table 3). Following dose 2, medical attention for fever was sought for 2 infants (0.6%) who received separately administered vaccines (Table 3). Among infants who had a medical visit for fever within 4 days following vaccination, 9 of 14 who received PEDIARIX and 1 of 2 who received separately administered vaccines, had one or more diagnostic studies performed to evaluate the cause of fever. Safety of PEDIARIX After a Previous Dose of Hepatitis B Vaccine Limited data are available on the safety of administering PEDIARIX after a previous dose of hepatitis B vaccine. In 2 separate studies, 160 Moldovan infants and 96 US infants, respectively, received 3 doses of PEDIARIX following 1 previous dose of hepatitis B vaccine. Neither study was designed to detect significant differences in rates of adverse events associated with PEDIARIX administered after a previous dose of hepatitis B vaccine compared to PEDIARIX administered without a previous dose of hepatitis B vaccine. Table 3. Percentage of US Infants With Solicited Local Reactions or Systemic Adverse Events Within 4 Days of Vaccination a at 2, 4, and 6 Months of Age With PEDIARIX Administered Concomitantly With Hib Conjugate Vaccine and 7-valent Pneumococcal Conjugate Vaccine (PCV7) or With Separate Concomitant Administration of INFANRIX, ENGERIX-B, IPV, Hib Conjugate Vaccine, and PCV7 (Modified ITT cohort) PEDIARIX, Hib Vaccine, & PCV7 INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Local b N 671 653 648 335 323 315 Pain, any 36.1 36.1 31.2 31.9 30.0 29.8 Pain, grade 2 or 3 11.5 10.9 10.6 9.0 8.7 8.9 Pain, grade 3 2.4 2.5 1.7 2.7 1.5 1.3 Redness, any 24.9 c 37.2 40.1 18.2 32.8 39.0 Redness, >5 mm 6.0 c 9.6 c 12.7 c 1.8 5.9 7.3 Redness, >20 mm 0.9 1.2 c 2.8 0.3 0.0 1.9 Swelling, any 17.3 c 26.5 c 28.7 9.6 20.4 24.8 Swelling, >5 mm 5.8 c 9.6 c 9.3 c 1.8 5.0 4.1 Swelling, >20 mm 1.9 2.5 c 3.1 0.6 0.0 1.3 Systemic N 667 644 645 333 321 311 Fever d , ≥100.4°F 27.9 c 38.8 c 33.5 c 19.8 30.2 23.8 Fever d , >101.3°F 7.0 14.1 c 8.8 4.5 9.7 5.8 Fever d , >102.2°F 2.2 c 3.6 3.4 0.3 3.1 2.3 Fever d , >103.1°F 0.4 1.4 1.1 0.0 0.3 0.3 Fever d , M.A. 1.2 c 0.2 0.8 0.0 0.6 0.0 N 671 653 648 335 323 315 Drowsiness, any 57.2 51.6 40.9 54.0 48.3 38.4 Drowsiness, grade 2 or 3 15.8 13.8 11.4 17.6 12.4 11.1 Drowsiness, grade 3 2.5 1.2 0.9 3.6 0.6 1.9 Irritability/Fussiness, any 60.5 64.9 61.1 61.5 61.6 56.5 Irritability/Fussiness, grade 2 or 3 19.8 27.9 c 25.2 c 19.4 21.1 19.4 Irritability/Fussiness, grade 3 3.4 4.4 3.5 3.9 3.4 3.2 Loss of appetite, any 30.4 30.6 26.2 27.8 26.6 23.8 Loss of appetite, grade 2 or 3 6.6 7.8 c 5.9 5.1 3.4 5.4 Loss of appetite, grade 3 0.7 0.3 0.2 0.6 0.3 0.0 Modified ITT cohort = all vaccinated subjects for whom safety data were available. N = number of infants for whom at least one symptom sheet was completed; for fever, numbers exclude missing temperature recordings or tympanic measurements. M.A. = Medically attended (a visit to or from medical personnel). Grade 2 defined as sufficiently discomforting to interfere with daily activities. Grade 3 defined as preventing normal daily activities. a Within 4 days of vaccination defined as day of vaccination and the next 3 days. b Local reactions at the injection site for PEDIARIX or INFANRIX. c Rate significantly higher in the group that received PEDIARIX compared to separately administered vaccines [ P <0.05 (2-sided Fisher Exact test) or the 95% CI on the difference between groups (Separate minus PEDIARIX) does not include 0]. d Axillary temperatures increased by 1°C and oral temperatures increased by 0.5°C to derive equivalent rectal temperature. Additional Adverse Events Rarely, an anaphylactic reaction (i.e., hives, swelling of the mouth, difficulty breathing, hypotension, or shock) has been reported after receiving preparations containing diphtheria, tetanus, and/or pertussis antigens. 20 Arthus-type hypersensitivity reactions, characterized by severe local reactions, may follow receipt of tetanus toxoid. A review by the IOM found evidence for a causal relationship between receipt of tetanus toxoid and both brachial neuritis and Guillain-Barré syndrome. 24 A few cases of demyelinating diseases of the CNS have been reported following some tetanus toxoid-containing vaccines or tetanus and diphtheria toxoid-containing vaccines, although the IOM concluded that the evidence was inadequate to accept or reject a causal relationship. 24 A few cases of peripheral mononeuropathy and of cranial mononeuropathy have been reported following tetanus toxoid administration, although the IOM concluded that the evidence was inadequate to accept or reject a causal relationship. Postmarketing Reports With PEDIARIX Worldwide voluntary reports of adverse events received for PEDIARIX since market introduction of this vaccine are listed below. This list includes serious adverse events or events which have a suspected causal connection to components of PEDIARIX or other vaccines or drugs. Because these 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. Cardiac Disorders: Cyanosis. Gastrointestinal Disorders: Diarrhea, vomiting. General Disorders and Administration Site Conditions: Fatigue, injection site cellulitis, injection site induration, injection site itching, injection site nodule/lump, injection site pain, injection site reaction, injection site redness, injection site swelling, injection site vesicles, injection site warmth, irritability, limb pain, limb swelling, pyrexia, Sudden Infant Death Syndrome. Immune System Disorders: Anaphylactic reaction, anaphylactoid reaction, hypersensitivity. Infections and Infestations: Upper respiratory tract infection. Investigations: Abnormal liver function tests. Metabolism and Nutrition Disorders: Anorexia. Nervous System Disorders: Bulging fontanelle, convulsions, depressed level of consciousness, encephalitis,febrile convulsion, hypotonia, hypotonic-hyporesponsive episode, lethargy, somnolence. Psychiatric Disorders: Crying, insomnia, nervousness, restlessness, screaming, unusual crying. Respiratory, Thoracic, and Mediastinal Disorders: Apnea, cough, dyspnea. Skin and Subcutaneous Tissue Disorders: Angioedema, erythema, rash, urticaria. Vascular Disorders: Pallor, petechiae. Postmarketing Reports With INFANRIX and/or ENGERIX-B Worldwide voluntary reports of adverse events received for INFANRIX and/or ENGERIX-B in children younger than 7 years of age but not already reported for PEDIARIX are listed below. This list includes serious adverse events or events which have a suspected causal connection to components of INFANRIX and/or ENGERIX-B or other vaccines or drugs. Because these 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. Blood and Lymphatic System Disorders: Idiopathic thrombocytopenic purpura a,b , lymphadenopathy a , thrombocytopenia a,b . Gastrointestinal Disorders: Abdominal pain b , intussusception a,b , nausea b . General Disorders and Administration Site Conditions: Asthenia b , malaise b . Hepatobiliary Disorders: Jaundice b . Immune System Disorders: Anaphylactic shock a , serum sickness–like disease b . Musculoskeletal and Connective Tissue Disorders: Arthralgia b , arthritis b , muscular weakness b , myalgia b . Nervous System Disorders: Encephalopathy a , headache b , meningitis b , neuritis b , neuropathy b , paralysis b . Skin and Subcutaneous Tissue Disorders: Alopecia b , erythema multiforme b , lichen planus b , pruritus a,b , Stevens-Johnson syndrome a . Vascular Disorders: Vasculitis b . a Following INFANRIX. b Following ENGERIX-B. Reporting Adverse Events The National Childhood Vaccine Injury Act requires that the manufacturer and lot number of the vaccine administered be recorded by the healthcare provider in the vaccine recipient's permanent medical record, along with the date of administration of the vaccine and the name, address, and title of the person administering the vaccine. 25 The Act further requires the healthcare provider to report to the US Department of Health and Human Services the occurrence following immunization of any event set forth in the Vaccine Injury Table including: Anaphylaxis or anaphylactic shock within 7 days, encephalopathy or encephalitis within 7 days, brachial neuritis within 28 days, or an acute complication or sequelae (including death) of an illness, disability, injury, or condition referred to above, or any events that would contraindicate further doses of vaccine, according to this prescribing information. 25,26 These events should be reported to VAERS. The VAERS toll-free number is 1-800-822-7967. Reporting forms may also be obtained at the VAERS website at www.vaers.hhs.gov.