Pediarix (Diphtheria Toxoid / Tetanus Toxoid / Acellular Pertussis / Hepatitis B Recombinant Vaccine / Inactivated Poliovirus Vaccine) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

A total of 20,739 doses of PEDIARIX have been administered to 7,028 infants as a 3-dose primary series. 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 Tables 2 and 4). The prevalence of fever was highest on the day of vaccination and the day following vaccination. More than 98% 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). Rates of most other solicited adverse events following PEDIARIX were comparable to rates observed following separately administered US-licensed vaccines (see ADVERSE REACTIONS Table 2).

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.

A total of 5,472 infants were enrolled in a German safety study that was originally designed to compare the safety and reactogenicity of PEDIARIX administered concomitantly at separate sites with 1 of 4 Hib vaccines (GlaxoSmithKline Biologicals [not US-licensed]; Lederle Laboratories, Aventis Pasteur, or Merck & Co [all US-licensed]) at 3, 4, and 5 months of age. ⁴³ After enrollment of 1,569 infants, the study was amended to include a control group that received separate US-licensed vaccines (INFANRIX, Hib vaccine [Aventis Pasteur], and OPV [Lederle Laboratories]). Infants in the separate administration group received one less antigen (hepatitis B) than the infants who received PEDIARIX. Safety data were available for 4,666 infants who received PEDIARIX administered concomitantly at separate sites with 1 of 4 Hib vaccines and for 768 infants in the control group that received separate vaccines. 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).

The primary end-point of the study was the percentage of infants with any grade 3 solicited symptom (redness or swelling >20 mm, fever >103.1°F, or crying, pain, vomiting, diarrhea, loss of appetite, or restlessness that prevented normal daily activities) over the 3-dose primary series in infants who received PEDIARIX (4 groups that received PEDIARIX and Hib vaccines pooled) compared to the group that received INFANRIX and Hib vaccine separately with OPV. Analysis for the primary end-point was performed on the according-to-protocol (ATP) cohort that included only those infants who were enrolled after the protocol amendment to include a control group. Of 3,773 infants in the ATP cohort for whom safety data were available, 16.2% (95% CI: 14.9% to 17.5%) of 3,029 infants who received PEDIARIX and Hib vaccine compared to 20.3% (95% CI: 17.5% to 23.4%) of 744 infants who received separate vaccines were reported to have had at least one grade 3 solicited symptom within 4 days of vaccination (i.e., day of vaccination and the next 3 days). The difference between groups in the rate of grade 3 symptoms was 4.1% (90% CI: 1.4% to 7.1%).

Data for selected solicited symptoms following each dose in a 3-dose primary series are presented in Table 2 for the intent-to-treat (ITT) cohort (includes all infants enrolled before and after the amendment who received the indicated vaccine and for whom at least one symptom sheet was completed).

In this study, 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. 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).

No cases of hypotonic-hyporesponsiveness, encephalopathy, or anaphylaxis were reported in the German study that evaluated the safety of PEDIARIX.

Rates of serious adverse events that are less common than those reported in this safety study are not known at this time.

Additional safety data for PEDIARIX are available for 482 infants enrolled in a US study designed to evaluate lot-to-lot consistency and a bridge for a new manufacturing step. Table 3 presents the local reactions and selected adverse events within 4 days of vaccination with PEDIARIX administered concomitantly with a US-licensed Hib vaccine (Aventis Pasteur) at 2, 4, and 6 months of age. Data on adverse events were collected by parents using standardized diaries for 4 consecutive days after each vaccine dose (i.e., day of vaccination and the next 3 days) with follow-up telephone calls made by study personnel between days 1 and 3.

Post-dose 1 safety data are available from a US study initiated in December 2001, which was designed to assess the safety of PEDIARIX administered concomitantly at separate sites with Hib and pneumococcal conjugate vaccines (Lederle Laboratories), relative to separately administered INFANRIX, ENGERIX-B, IPV (Aventis Pasteur), Hib vaccine (Lederle Laboratories), and pneumococcal conjugate vaccine (Lederle Laboratories) at 2, 4, and 6 months of age. The study was powered to evaluate fever >101.3°F. Enrollment for this study is complete, with 673 infants in the group that received PEDIARIX and 335 infants in the separate vaccines group. Safety data following the second and third doses are expected in 2003. Data for fever within 4 days following dose 1 (i.e., day of vaccination and the next 3 days) are presented in Table 4.

In this study, medical attention (a visit to or from medical personnel) for fever within 4 days following vaccination was sought for 8 infants who received PEDIARIX (1.2%) and no infants who received separately administered vaccines. Four infants were seen by medical personnel in an office setting; no diagnostic tests were performed in 2 of the infants and a complete blood count (CBC) was done in the other 2 infants. Of 3 infants who were seen in an emergency room, all had a CBC and a blood and urine culture performed; chest X-rays were done in 2 of the infants and a naso-pharyngeal specimen was tested for Respiratory Syncytial Virus in one of the infants. One infant was hospitalized for a work-up that included a CBC, blood and urine cultures, a lumbar puncture, and a chest X-ray. All episodes of medically attended fever resolved within 4 days post-vaccination.

In 12 clinical trials, 5 deaths were reported in 7,028 (0.07%) recipients of PEDIARIX and 1 death was reported in 1,764 (0.06%) 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 12 trials was 0.3/1,000. 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). ⁴⁴ The reported rate of SIDS in the United States from 1990 to 1994 was 1.2/1,000 live births. ⁴⁵ By chance alone, some cases of SIDS can be expected to follow receipt of pertussis-containing vaccines. ³⁹

Limited data are available on the safety of administering PEDIARIX after a birth dose of hepatitis B vaccine (see Table 5). In a study conducted in Moldova, 160 infants received a dose of hepatitis B vaccine within 48 hours of birth followed by 3 doses of PEDIARIX at 6, 10, and 14 weeks of age. No information was collected on the HBsAg status of mothers of enrolled infants.

Although there was no comparator group who received PEDIARIX without a birth dose of hepatitis B vaccine, available data suggest that some local adverse events may occur at a higher rate when PEDIARIX is administered after a birth dose of hepatitis B vaccine.

As with any vaccine, there is the possibility that broad use of PEDIARIX could reveal adverse events not observed in clinical trials.

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. ³⁹ 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.⁴⁶ 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.⁴⁶ 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:    Worldwide voluntary reports of adverse events received for INFANRIX and ENGERIX-B in children younger than 7 years of age since market introduction of these US-licensed vaccines are listed below. This list includes adverse events for which 20 or more reports were received with the exception of intussusception, idiopathic thrombocytopenic purpura, thrombocytopenia, anaphylactic reaction, angioedema, encephalopathy, hypotonic-hyporesponsive episode, and alopecia for which fewer than 20 reports were received. These latter events are included either because of the seriousness of the event or the strength of causal connection to components of this or other vaccines or drugs.

Body as a whole: Asthenia ^b, fever ^a+b, lethargy ^b, malaise ^b, Sudden Infant Death Syndrome ^a+b.

Cardiovascular system: Cyanosis ^a+b, edema ^b, pallor ^b.

Gastrointestinal system: Abdominal pain ^b, anorexia ^b, diarrhea ^a+b, intussusception ^a+b, nausea ^b, vomiting ^a+b.

Hematologic/lymphatic: Idiopathic thrombocytopenic purpura ^a+b, lymphadenopathy ^a, thrombocytopenia ^a+b.

Hepatic: Jaundice ^b, liver function tests abnormal ^b.

Hypersensitivity: Anaphylactic reaction ^a+b, angioedema ^b, hypersensitivity ^a.

Infections: Cellulitis ^a.

Injection site reactions: Injection site reactions ^a+b.

Musculoskeletal: Arthralgia ^b, limb swelling ^a+b.

Nervous system: Convulsions ^a+b, encephalopathy ^a, headache ^b, hypotonia ^a+b, hypotonic hyporesponsive episode ^a, somnolence ^a+b.

Psychiatric: Crying ^a+b, irritability ^a+b.

Respiratory system: Respiratory tract infection ^a.

Skin and appendages: Alopecia ^b, erythema ^a+b, erythema multiforme ^b, petechiae ^b, pruritus ^a+b, rash ^a+b, urticaria ^a+b.

Special senses: Ear pain ^a.

These reactions were reported voluntarily from a population of uncertain size; therefore, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination.

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.⁴⁷ The Act further requires the healthcare provider to report to the US Department of Health and Human Services via VAERS 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. ^47,48 The VAERS toll-free number is 1-800-822-7967.