HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use PEDIARIX safely and effectively. See full prescribing information for PEDIARIX.
PEDIARIX [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine]
Suspension for Intramuscular Injection Initial U.S. Approval: 2002
----------------------------INDICATIONS AND USAGE---------------------
PEDIARIX is a vaccine indicated for active immunization against diphtheria, tetanus, pertussis, infection caused by all known subtypes of hepatitis B virus, and poliomyelitis. PEDIARIX is approved for use as a three-dose series in infants born of hepatitis B surface antigen (HBsAg)-negative mothers. PEDIARIX may be given as early as 6 weeks of age through 6 years of age (prior to the 7th birthday). (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------
Three doses (0.5 mL each) by intramuscular injection at 2, 4, and 6 months of age. (2.2)
--------------------- DOSAGE FORMS AND STRENGTHS -------------- Single-dose prefilled syringes containing a 0.5-mL suspension for injection. (3)
-------------------------------CONTRAINDICATIONS ------------------------
should be based on potential benefits and risks. (5.2)
See 17 for PATIENT COUNSELING INFORMATION.
6.3 Postmarketing Spontaneous Reports for PEDIARIX
6.4 Postmarketing Spontaneous Reports for INFANRIX and/or ENGERIX-B
8.4 Pediatric Use
13 NONCLINICAL TOXICOLOGY
Revised: 11/2013
1
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
______________________________________________________________________
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
PEDIARIX® is indicated for active immunization against diphtheria, tetanus, pertussis, infection caused by all known subtypes of hepatitis B virus, and poliomyelitis. PEDIARIX is approved for use as a three-dose series in infants born of hepatitis B surface antigen (HBsAg)-negative mothers. PEDIARIX may be given as early as 6 weeks of age through 6 years of age (prior to the 7th birthday).
2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration
Shake vigorously to obtain a homogeneous, turbid, white suspension. Do not use if resuspension does not occur with vigorous shaking. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.
Attach a sterile needle and administer intramuscularly.
The preferred administration site is the anterolateral aspect of the thigh for children younger than 1 year. In older children, the deltoid muscle is usually large enough for an intramuscular injection. The vaccine should not be injected in the gluteal area or areas where there may be a major nerve trunk. Gluteal injections may result in suboptimal hepatitis B immune response.
Do not administer this product intravenously, intradermally, or subcutaneously.
2.2 Recommended Dose and Schedule
Immunization with PEDIARIX consists of 3 doses of 0.5 mL each, by intramuscular injection, at 2, 4, and 6 months of age (at intervals of 6 to 8 weeks, preferably 8 weeks). The first dose may be given as early as 6 weeks of age. Three doses of PEDIARIX constitute a primary immunization course for diphtheria, tetanus, pertussis, and poliomyelitis and the complete vaccination course for hepatitis B.
2.3 Modified Schedules in Previously Vaccinated Children
Children Previously Vaccinated With Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP): PEDIARIX may be used to complete the first 3 doses of the DTaP series in children who have received 1 or 2 doses of INFANRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed), manufactured by GlaxoSmithKline, identical to the DTaP component of PEDIARIX [see Description (11)] and are also scheduled to receive the other vaccine components of PEDIARIX. Data are not available on the safety and effectiveness of using PEDIARIX following one or more doses of a DTaP vaccine from a different manufacturer.
Children Previously Vaccinated With Hepatitis B Vaccine: PEDIARIX may be used 2
to complete the hepatitis B vaccination series following 1 or 2 doses of another hepatitis B vaccine (monovalent or as part of a combination vaccine), including vaccines from other manufacturers, in children born of HBsAg-negative mothers who are also scheduled to receive the other vaccine components of PEDIARIX.
A 3-dose series of PEDIARIX may be administered to infants born of HBsAg-negative mothers and who received a dose of hepatitis B vaccine at or shortly after birth. However, data are limited regarding the safety of PEDIARIX in such infants [see Adverse Reactions (6.1)]. There are no data to support the use of a 3-dose series of PEDIARIX in infants who have previously received more than one dose of hepatitis B vaccine.
Children Previously Vaccinated With Inactivated Poliovirus Vaccine (IPV):
PEDIARIX may be used to complete the first 3 doses of the IPV series in children who have received 1 or 2 doses of IPV from a different manufacturer and are also scheduled to receive the other vaccine components of PEDIARIX.
2.4 Booster Immunization Following PEDIARIX
Children who have received a 3-dose series with PEDIARIX should complete the DTaP and IPV series according to the recommended schedule.1 Because the pertussis antigens contained in INFANRIX and KINRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine), manufactured by GlaxoSmithKline, are the same as those in PEDIARIX, these children should receive INFANRIX as their fourth dose of DTaP and either INFANRIX or KINRIX as their fifth dose of DTaP, according to the respective prescribing information for these vaccines. KINRIX or another manufacturer’s IPV may be used to complete the 4-dose IPV series according to the respective prescribing information.
3 DOSAGE FORMS AND STRENGTHS
PEDIARIX is a suspension for injection available in 0.5-mL single-dose prefilled TIP-LOK® syringes.
4 CONTRAINDICATIONS 4.1 Hypersensitivity
A severe allergic reaction (e.g., anaphylaxis) after a previous dose of any diphtheria toxoid-, tetanus toxoid-, pertussis antigen-, hepatitis B-, or poliovirus-containing vaccine or any component of this vaccine, including yeast, neomycin, and polymyxin B, is a contraindication to administration of PEDIARIX [see Description (11)].
4.2 Encephalopathy
Encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days of administration of a previous dose of a pertussis-containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis- containing vaccine, including PEDIARIX.
4.3 Progressive Neurologic Disorder
Progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy is a contraindication to administration of any pertussis-containing
3
vaccine, including PEDIARIX. PEDIARIX should not be administered to individuals with such conditions until the neurologic status is clarified and stabilized.
5 WARNINGS AND PRECAUTIONS 5.1 Fever
In clinical trials, administration of PEDIARIX in infants was associated with higher rates of fever, relative to separately administered vaccines [see Adverse Reactions (6.1)].
5.2 Guillain-Barré Syndrome
If Guillain-Barré syndrome occurs within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the decision to give PEDIARIX or any vaccine containing tetanus toxoid should be based on careful consideration of the potential benefits and possible risks.
5.3 Latex
The tip caps of the prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals.
5.4 Syncope
Syncope (fainting) can occur in association with administration of injectable vaccines, including PEDIARIX. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope.
5.5 Adverse Events Following Prior Pertussis Vaccination
If any of the following events occur in temporal relation to receipt of a vaccine containing a pertussis component, the decision to give any pertussis-containing vaccine, including PEDIARIX, should be based on careful consideration of the potential benefits and possible risks:
For children at higher risk for seizures than the general population, an appropriate antipyretic may be administered at the time of vaccination with a vaccine containing a pertussis component, including PEDIARIX, and for the ensuing 24 hours to reduce the possibility of post-vaccination fever.
5.7 Apnea in Premature Infants
Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including PEDIARIX, to infants born prematurely should be based on consideration of the individual infant’s medical status, and the potential benefits and possible risks of vaccination.
5.8 Preventing and Managing Allergic Vaccine Reactions
Prior to administration, the healthcare provider should review the immunization history 4
for possible vaccine sensitivity and previous vaccination-related adverse reactions to allow an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur.
6 ADVERSE REACTIONS 6.1 Clinical Trials Experience
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 23,849 doses of PEDIARIX have been administered to 8,088 infants who received one or more doses as part of the 3-dose series during 14 clinical studies. Common adverse events that occurred in ≥25% of subjects following any dose of PEDIARIX included local injection site reactions (pain, redness, and swelling), fever, drowsiness, irritability/fussiness, and loss of appetite. In comparative studies (including the German and US studies described below), administration of PEDIARIX was associated with higher rates of fever relative to separately administered vaccines [see Warnings and Precautions (5.1)]. 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 Haemophilus influenzae type b (Hib) conjugate vaccines (GlaxoSmithKline [licensed in the US only for booster immunization], Wyeth Pharmaceuticals Inc. [no longer licensed in the US], Sanofi Pasteur SA [US-licensed], or Merck & Co, Inc. [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 oral poliovirus vaccine [OPV] [Wyeth Pharmaceuticals, Inc.; no longer licensed in the US]). In this study, information on adverse events that occurred within 30 days following vaccination was collected. 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® [Hepatitis B Vaccine (Recombinant)], and IPV (Sanofi Pasteur SA) in 335 infants. In both groups, infants received Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US) and 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) concomitantly at separate sites. All vaccines were administered at 2, 4, and 6 months of age. Data on solicited local reactions and general 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). 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
5
onset of chronic illnesses. A total of 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.
Solicited Adverse Events: Data on solicited local reactions and general adverse events from the US safety study are presented in Table 1. This study was powered to evaluate fever >101.3°F following dose 1. The rate of fever ≥100.4°F following each dose was significantly higher in the group that received PEDIARIX compared to separately administered vaccines. Other statistically significant differences between groups in rates of fever, as well as other solicited adverse events, are noted in Table 1. 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 1). Following dose 2, medical attention for fever was sought for 2 infants (0.6%) who received separately administered vaccines (Table 1). 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.
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Table 1. Percentage of Infants With Solicited Local Reactions or General Adverse Events Within 4 Days of Vaccinationa 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 Intent To Treat Cohort)
PEDIARIX, Hib Vaccine, & PCV7
INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
Dose 1
Dose 2
Dose 3
Dose 1
Dose 2
Dose 3
Localb
N
671
653
648
335
323
315
Pain, any
Pain, grade 2 or 3 Pain, grade 3
36.1 11.5 2.4
36.1 10.9 2.5
31.2 10.6 1.7
31.9 9.0 2.7
30.0 8.7 1.5
29.8 8.9 1.3
Redness, any Redness, >5 mm Redness, >20 mm
24.9c 6.0c 0.9
37.2 9.6c 1.2c
40.1 12.7c 2.8
18.2 1.8 0.3
32.8 5.9 0.0
39.0 7.3 1.9
Swelling, any Swelling, >5 mm Swelling, >20 mm
17.3c 5.8c 1.9
26.5c 9.6c 2.5c
28.7 9.3c 3.1
9.6 1.8 0.6
20.4 5.0 0.0
24.8 4.1 1.3
General
N
667
644
645
333
321
311
Feverd, ≥100.4°F Feverd, >101.3°F Feverd, >102.2°F Feverd, >103.1°F Feverd, M.A.
27.9c 7.0 2.2c 0.4 1.2c
38.8c 14.1c 3.6 1.4 0.2
33.5c 8.8 3.4 1.1 0.8
19.8 4.5 0.3 0.0 0.0
30.2 9.7 3.1 0.3 0.6
23.8 5.8 2.3 0.3 0.0
N
671
653
648
335
323
315
Drowsiness, any Drowsiness, grade 2 or 3 Drowsiness, grade 3
57.2 15.8 2.5
51.6 13.8 1.2
40.9 11.4 0.9
54.0 17.6 3.6
48.3 12.4 0.6
38.4 11.1 1.9
Irritability/Fussiness, any Irritability/Fussiness, grade 2 or 3 Irritability/Fussiness, grade 3
60.5 19.8 3.4
64.9 27.9c 4.4
61.1 25.2c 3.5
61.5 19.4 3.9
61.6 21.1 3.4
56.5 19.4 3.2
Loss of appetite, any
Loss of appetite, grade 2 or 3 Loss of appetite, grade 3
30.4 6.6 0.7
30.6 7.8c 0.3
26.2 5.9 0.2
27.8 5.1 0.6
26.6 3.4 0.3
23.8 5.4 0.0
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA).
Modified intent to treat 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).
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Grade 2 defined as sufficiently discomforting to interfere with daily activities. Grade 3 defined as preventing normal daily activities.
a
b Local reactions at the injection site for PEDIARIX or INFANRIX.
Within 4 days of vaccination defined as day of vaccination and the next 3 days.
c
d Axillary temperatures increased by 1°C and oral temperatures increased by 0.5°C to derive equivalent rectal temperature.
Serious Adverse Events: Within 30 days following any dose of vaccine in the US safety study in which all subjects received concomitant Hib and pneumococcal 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).
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). The reported rate of SIDS in the United States from 1990 to 1994 was 1.2/1,000 live births. By chance alone, some cases of SIDS can be expected to follow receipt of pertussis-containing vaccines.
Onset of Chronic Illnesses: In the US safety study in which all subjects received concomitant Hib and pneumococcal 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 (N = 4,666) 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
Rate significantly higher in the group that received PEDIARIX compared to separately administered vaccines [P value <0.05 (2-sided Fisher Exact test) or the 95% CI on the difference between groups (Separate minus PEDIARIX) does not include 0].
8
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 (N = 768) 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 Hib and pneumococcal conjugate vaccines, 4 subjects in the group that received PEDIARIX (N = 673) 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 (N = 335) 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 or US safety studies.
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.
6.2 Postmarketing Safety Surveillance Study
In a safety surveillance study conducted at a health maintenance organization in the US, infants who received one or more doses of PEDIARIX from approximately mid-2003 through mid-2005 were compared to age-, gender-, and area-matched historical controls who received one or more doses of separately administered US-licensed DTaP vaccine from 2002 through approximately mid-2003. Only infants who received 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) concomitantly with PEDIARIX or DTaP vaccine were included in the cohorts. Other US-licensed vaccines were administered according to routine practices at the study sites, but concomitant administration with PEDIARIX or DTaP was not a criterion for inclusion in the cohorts. A birth dose of hepatitis B vaccine had been administered routinely to infants in the historical DTaP control cohort, but not to infants who received PEDIARIX. For each of Doses 1-3, a random sample of 40,000 infants who received PEDIARIX was compared to the historical DTaP control cohort for the incidence of seizures (with or without fever) during the 8-day period following vaccination. For each dose, random samples of 7,500 infants in each cohort were also compared for the incidence of medically-attended fever (fever ≥100.4°F that resulted in hospitalization, an emergency department visit, or an outpatient visit) during the 4- day period following vaccination. Possible seizures and medical visits plausibly related to fever
9
were identified by searching automated inpatient and outpatient data files. Medical record reviews of identified events were conducted to verify the occurrence of seizures or medically- attended fever. The incidence of verified seizures and medically-attended fever from this study are presented in Table 2.
Table 2. Percentage of Infants With Seizures (With or Without Fever) Within 8 Days of Vaccination and Medically-Attended Fever Within 4 Days of Vaccination With PEDIARIX Compared With Historical Controls
PEDIARIX
Historical DTaP Controls
Difference (PEDIARIX–DTaP Controls)
N
n
% (95% CI)
N
n
% (95% CI)
% (95% CI)
All seizures
(with or without fever)
Dose 1, Days 0-7 Dose 2, Days 0-7 Dose 3, Days 0-7 Total doses
40,000 40,000 40,000 120,000
7 3 6 16
0.02 (0.01, 0.04) 0.01 (0.00, 0.02) 0.02 (0.01, 0.03) 0.01 (0.01, 0.02)
39,232 37,405 40,000 116,637
6 4 5 15
0.02 (0.01, 0.03) 0.01 (0.00, 0.03) 0.01 (0.00, 0.03) 0.01 (0.01, 0.02)
0.00 (-0.02, 0.02) 0.00 (-0.02, 0.01) 0.00 (-0.01, 0.02) 0.00 (-0.01, 0.01)
Medically-attended fevera
Dose 1, Days 0-3 Dose 2, Days 0-3 Dose 3, Days 0-3 Total doses
7,500 7,500 7,500 22,500
14 25 21 60
0.19 (0.11, 0.30) 0.33 (0.22, 0.48) 0.28 (0.17, 0.43) 0.27 (0.20, 0.34)
7,500 7,500 7,500 22,500
14 15 19 48
0.19 (0.11, 0.30) 0.20 (0.11, 0.33) 0.25 (0.15, 0.39) 0.21 (0.16, 0.28)
0.00 (-0.14, 0.14) 0.13 (-0.03, 0.30) 0.03 (-0.14, 0.19) 0.05 (-0.01, 0.14)
DTaP – any US-licensed DTaP vaccine. Infants received 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) concomitantly with each dose of PEDIARIX or DTaP. Other US-licensed vaccines were administered according to routine practices at the study sites.
N = number of subjects in the given cohort.
n = number of subjects with events reported in the given cohort.
a
emergency department visit, or an outpatient visit.
Medically-attended fever defined as fever ≥100.4°F that resulted in hospitalization, an
6.3 Postmarketing Spontaneous Reports for PEDIARIX
In addition to reports in clinical trials, 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. Because these events are reported voluntarily from a population of
10
uncertain size, it is not 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 reaction, injection site vesicles, injection site warmth, limb pain, limb swelling.
Immune System Disorders: Anaphylactic reaction, anaphylactoid reaction, hypersensitivity.
Infections and Infestations: Upper respiratory tract infection.
Investigations: Abnormal liver function tests.
Nervous System Disorders: Bulging fontanelle, depressed level of consciousness,
encephalitis, hypotonia, hypotonic-hyporesponsive episode, lethargy, somnolence, syncope. 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.
6.4 Postmarketing Spontaneous Reports for 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. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.
Blood and Lymphatic System Disorders: Idiopathic thrombocytopenic purpuraa,b, lymphadenopathya, thrombocytopeniaa,b.
Gastrointestinal Disorders: Abdominal painb, intussusceptiona,b, nauseab.
General Disorders and Administration Site Conditions: Astheniab, malaiseb. Hepatobiliary Disorders: Jaundiceb.
Immune System Disorders: Anaphylactic shocka, serum sickness–like diseaseb. Musculoskeletal and Connective Tissue Disorders: Arthralgiab, arthritisb, muscular
weaknessb, myalgiab.
Nervous System Disorders: Encephalopathya, headachea, meningitisb, neuritisb,
neuropathyb, paralysisb.
Skin and Subcutaneous Tissue Disorders: Alopeciab, erythema multiformeb, lichen
planusb, pruritusa,b, Stevens Johnson syndromea. Vascular Disorders: Vasculitisb.
a Following INFANRIX (licensed in the United States in 1997).
b Following ENGERIX-B (licensed in the United States in 1989).
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7 DRUG INTERACTIONS
7.1 Concomitant Vaccine Administration
Immune responses following concomitant administration of PEDIARIX, Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US), and 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) were evaluated in a clinical trial [see Clinical Studies (14.3)].
When PEDIARIX is administered concomitantly with other injectable vaccines, they should be given with separate syringes and at different injection sites. PEDIARIX should not be mixed with any other vaccine in the same syringe or vial.
7.2 Immunosuppressive Therapies
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to PEDIARIX.
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy
Pregnancy Category C
Animal reproduction studies have not been conducted with PEDIARIX. It is not known whether PEDIARIX can cause fetal harm when administered to a pregnant woman or if PEDIARIX can affect reproduction capacity.
8.4 Pediatric Use
Safety and effectiveness of PEDIARIX were established in the age group 6 weeks through 6 months on the basis of clinical studies [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. Safety and effectiveness of PEDIARIX in the age group 7 months through 6 years are supported by evidence in infants 6 weeks through 6 months of age. Safety and effectiveness of PEDIARIX in infants younger than 6 weeks of age and children 7 to 16 years of age have not been evaluated.
11 DESCRIPTION
PEDIARIX [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine] is a noninfectious, sterile vaccine for intramuscular administration. Each 0.5-mL dose is formulated to contain 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 mcg of inactivated pertussis toxin (PT), 25 mcg of filamentous hemagglutinin (FHA), 8 mcg of pertactin (69 kiloDalton outer membrane protein), 10 mcg of HBsAg, 40 D-antigen Units (DU) of Type 1 poliovirus (Mahoney), 8 DU of Type 2 poliovirus (MEF-1), and 32 DU of Type 3 poliovirus (Saukett). The diphtheria, tetanus, and pertussis components are the same as those in INFANRIX and KINRIX. The hepatitis B surface antigen is the same as that in ENGERIX-B.
The diphtheria toxin is produced by growing Corynebacterium diphtheriae in Fenton medium containing a bovine extract. Tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein. The bovine materials used in these
12
extracts are sourced from countries which the United States Department of Agriculture (USDA) has determined neither have nor present an undue risk for bovine spongiform encephalopathy (BSE). Both toxins are detoxified with formaldehyde, concentrated by ultrafiltration, and purified by precipitation, dialysis, and sterile filtration.
The acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formaldehyde.
The hepatitis B surface antigen is obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus, in synthetic medium. The surface antigen expressed in the S. cerevisiae cells is purified by several physiochemical steps, which include precipitation, ion exchange chromatography, and ultrafiltration.
The inactivated poliovirus component is an enhanced potency component. Each of the 3 strains of poliovirus is individually grown in VERO cells, a continuous line of monkey kidney cells, cultivated on microcarriers. Calf serum and lactalbumin hydrolysate are used during VERO cell culture and/or virus culture. Calf serum is sourced from countries the USDA has determined neither have nor present an undue risk for BSE. After clarification, each viral suspension is purified by ultrafiltration, diafiltration, and successive chromatographic steps, and inactivated with formaldehyde. The 3 purified viral strains are then pooled to form a trivalent concentrate.
Diphtheria and tetanus toxoids and pertussis antigens (inactivated PT, FHA, and pertactin) are individually adsorbed onto aluminum hydroxide. The hepatitis B component is adsorbed onto aluminum phosphate.
Diphtheria and tetanus toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis component (inactivated PT, FHA, and pertactin) is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice. Potency of the hepatitis B component is established by HBsAg ELISA. The potency of the inactivated poliovirus component is determined by using the D-antigen ELISA and by a poliovirus neutralizing cell culture assay on sera from previously immunized rats.
Each 0.5-mL dose contains aluminum salts as adjuvant (not more than 0.85 mg aluminum by assay) and 4.5 mg of sodium chloride. Each dose also contains ≤100 mcg of residual formaldehyde and ≤100 mcg of polysorbate 80 (Tween 80). Neomycin sulfate and polymyxin B are used in the poliovirus vaccine manufacturing process and may be present in the final vaccine at ≤0.05 ng neomycin and ≤0.01 ng polymyxin B per dose. The procedures used to manufacture the HBsAg antigen result in a product that contains ≤5% yeast protein.
The tip caps of the prefilled syringes may contain natural rubber latex; the plungers are not made with natural rubber latex.
13
PEDIARIX is formulated without preservatives.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action
Diphtheria: Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection; a level of 0.1 IU/mL is regarded as protective.2
Tetanus: Tetanus is an acute toxin-mediated disease caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.3,4 A level ≥0.1 IU/mL is considered protective.5
Pertussis: Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. There is no established serological correlate of protection for pertussis.
Hepatitis B: Infection with hepatitis B virus can have serious consequences including acute massive hepatic necrosis and chronic active hepatitis. Chronically infected persons are at increased risk for cirrhosis and hepatocellular carcinoma.
Antibody concentrations ≥10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B virus infection.6
Poliomyelitis: Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Poliovirus neutralizing antibodies confer protection against poliomyelitis disease.7
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
PEDIARIX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.
14 CLINICAL STUDIES
The efficacy of PEDIARIX is based on the immunogenicity of the individual antigens compared to licensed vaccines. Serological correlates of protection exist for the diphtheria, tetanus, hepatitis B, and poliovirus components. The efficacy of the pertussis component, which does not have a well established correlate of protection, was determined in clinical trials of INFANRIX.
14.1 Efficacy of INFANRIX
Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies.
A double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy, sponsored by the National Institutes of Health (NIH), assessed the absolute
14
protective efficacy of INFANRIX when administered at 2, 4, and 6 months of age. The population used in the primary analysis of the efficacy of INFANRIX included 4,481 infants vaccinated with INFANRIX and 1,470 DT vaccinees. After 3 doses, the absolute protective efficacy of INFANRIX against WHO-defined typical pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was 84% (95% CI: 76%, 89%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX was 71% (95% CI: 60%, 78%) against >7 days of any cough and 73% (95% CI: 63%, 80%) against
≥14 days of any cough. A longer unblinded follow-up period showed that after 3 doses and with no booster dose in the second year of life, the efficacy of INFANRIX against WHO-defined pertussis was 86% (95% CI: 79%, 91%) among children followed to 6 years of age. For details see INFANRIX prescribing information.
A prospective efficacy trial was also conducted in Germany employing a household contact study design. In this study, the protective efficacy of INFANRIX administered to infants at 3, 4, and 5 months of age, against WHO-defined pertussis was 89% (95% CI: 77%, 95%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX against ≥7 days of any cough was 67% (95% CI: 52%, 78%) and against ≥7 days of paroxysmal cough was 81% (95% CI: 68%, 89%). For details see INFANRIX prescribing information.
14.2 Immunological Evaluation of PEDIARIX
In a US multicenter study, infants were randomized to 1 of 3 groups: (1) a combination vaccine group that received PEDIARIX concomitantly with Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US) and US-licensed 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.); (2) a separate vaccine group that received US-licensed INFANRIX, ENGERIX-B, and IPV (Sanofi Pasteur SA) concomitantly with the same Hib and pneumococcal conjugate vaccines; and (3) a staggered vaccine group that received PEDIARIX concomitantly with the same Hib conjugate vaccine but with the same pneumococcal conjugate vaccine administered 2 weeks later. The schedule of administration was 2, 4, and
6 months of age. Infants either did not receive a dose of hepatitis B vaccine prior to enrollment or were permitted to receive one dose of hepatitis B vaccine administered at least 30 days prior to enrollment. For the separate vaccine group, ENGERIX-B was not administered at 4 months of age to subjects who received a dose of hepatitis B vaccine prior to enrollment. Among subjects in all 3 vaccine groups combined, 84% were white, 7% were Hispanic, 6% were black, 0.7% were Oriental, and 2.4% were of other racial/ethnic groups.
The immune responses to the pertussis (PT, FHA, and pertactin), diphtheria, tetanus, poliovirus, and hepatitis B antigens were evaluated in sera obtained one month (range 20 to
60 days) after the third dose of PEDIARIX or INFANRIX. Geometric mean antibody concentrations (GMCs) adjusted for pre-vaccination values for PT, FHA, and pertactin and the seroprotection rates for diphtheria, tetanus, and the polioviruses among subjects who received PEDIARIX in the combination vaccine group were shown to be non-inferior to those achieved
15
following separately administered vaccines (Table 3).
Because of differences in the hepatitis B vaccination schedule among subjects in the
study, no clinical limit for non-inferiority was pre-defined for the hepatitis B immune response. However, in a previous US study, non-inferiority of PEDIARIX relative to separately administered INFANRIX, ENGERIX-B, and an oral poliovirus vaccine, with respect to the hepatitis B immune response was demonstrated.
Table 3. Antibody Responses Following PEDIARIX as Compared to Separate Concomitant Administration of INFANRIX, ENGERIX-B, and IPV (One Montha After Administration of Dose 3) in Infants Vaccinated at 2, 4, and 6 Months of Age When Administered Concomitantly With Hib Conjugate Vaccine and Pneumococcal Conjugate Vaccine (PCV7)
PEDIARIX, Hib Vaccine, & PCV7
INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
(N = 154-168)
(N = 141-155)
Anti-Diphtheria Toxoid % ≥0.1 IU/mLb
99.4
98.7
Anti-Tetanus Toxoid % ≥0.1 IU/mLb
100
98.1
Anti-PT % VRc GMCb
98.7 48.1
95.1 28.6
Anti-FHA % VRc GMCb
98.7 111.9
96.5 97.6
Anti-Pertactin % VRc
GMCb
91.7 95.3
95.1 80.6
Anti-Polio 1 % ≥1:8b,d
100
100
Anti-Polio 2 % ≥1:8b,d
100
100
Anti-Polio 3 % ≥1:8b,d
100
100
(N = 114-128)
(N = 111-121)
Anti-HBsAge
% ≥10 mIU/mLf GMC (mIU/mL)f
97.7 1032.1
99.2 614.5
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA).
Assay methods used: ELISA for anti-diphtheria, anti-tetanus, anti-PT, anti-FHA, anti-pertactin, and anti-HBsAg; micro-neutralization for anti-polio (1, 2, and 3).
VR = vaccine response: In initially seronegative infants, appearance of antibodies (concentration ≥5 EL.U./mL); in initially seropositive infants, at least maintenance of pre-vaccination
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concentration.
GMC = geometric mean antibody concentration. GMCs are adjusted for pre-vaccination levels.
a
c
d Poliovirus neutralizing antibody titer.
One month blood sampling, range 20 to 60 days.
b Seroprotection rate or GMC for PEDIARIX not inferior to separately administered vaccines
[upper limit of 90% CI on GMC ratio (separate vaccine group/combination vaccine group) <1.5 for anti-PT, anti-FHA, and anti-pertactin, and upper limit of 95% CI for the difference in seroprotection rates (separate vaccine group minus combination vaccine group) <10% for diphtheria and tetanus and <5% for the 3 polioviruses]. GMCs are adjusted for pre- vaccination levels.
The upper limit of 95% CI for differences in vaccine response rates (separate vaccine group minus combination group) was 0.31, 1.52, and 9.46 for PT, FHA, and pertactin, respectively. No clinical limit defined for non-inferiority.
e
of hepatitis B seroprotection rates and GMCs presented in the table.
Subjects who received a previous dose of hepatitis B vaccine were excluded from the analysis
f
14.3 Concomitant Vaccine Administration
In a US multicenter study [see Clinical Studies (14.2)], there was no evidence for interference with the immune responses to PEDIARIX when administered concomitantly with 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) relative to 2 weeks prior.
Anti-PRP (Hib polyribosyl-ribitol-phosphate) seroprotection rates and GMCs of pneumococcal antibodies one month (range 20 to 60 days) after the third dose of vaccines for the combination vaccine group and the separate vaccine group from the US multicenter study [see Clinical Studies (14.2)], are presented in Table 4.
No clinical limit defined for non-inferiority.
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Table 4. Anti-PRP Seroprotection Rates and GMCs (mcg/mL) of Pneumococcal Antibodies One Montha Following the Third Dose of Hib Conjugate Vaccine and Pneumococcal Conjugate Vaccine (PCV7) Administered Concomitantly With PEDIARIX or With INFANRIX, ENGERIX-B, and IPV
PEDIARIX, Hib Vaccine, & PCV7
INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
(N = 161-168)
(N = 146-156)
% (95% CI)
% (95% CI)
Anti-PRP
≥0.15 mcg/mL
100 (97.8, 100)
99.4 (96.5, 100)
Anti-PRP
≥1.0 mcg/mL
95.8 (91.6, 98.3)
91.0 (85.3, 95.0)
GMC (95% CI)
GMC (95% CI)
Pneumococcal Serotype
4
1.7 (1.5, 2.0)
2.1 (1.8, 2.4)
6B
0.8 (0.7, 1.0)
0.7 (0.5, 0.9)
9V
1.6 (1.4, 1.8)
1.6 (1.4, 1.9)
14
4.7 (4.0, 5.4)
6.3 (5.4, 7.4)
18C
2.6 (2.3, 3.0)
3.0 (2.5, 3.5)
19F
1.1 (1.0, 1.3)
1.1 (0.9, 1.2)
23F
1.5 (1.2, 1.8)
1.8 (1.5, 2.3)
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA).
Assay method used: ELISA for anti-PRP and 7 pneumococcal serotypes. GMC = geometric mean antibody concentration.
a
15 REFERENCES
One month blood sampling, range 20 to 60 days.
7.
16
antibodies to hepatitis B surface antigen and the need for booster vaccination in adult subjects. Postgrad Med J 1987;63(Suppl. 2):129-135.
Sutter RW, Pallansch MA, Sawyer LA, et al. Defining surrogate serologic tests with respect to predicting protective vaccine efficacy: Poliovirus vaccination. In: Williams JC, Goldenthal KL, Burns DL, Lewis Jr BP, eds. Combined vaccines and simultaneous administration. Current issues and perspectives. New York, NY: The New York Academy of Sciences; 1995:289-299.
HOW SUPPLIED/STORAGE AND HANDLING
PEDIARIX is available in 0.5 mL single-dose disposable prefilled TIP-LOK syringes (packaged without needles):
NDC 58160-811-43 Syringe in Package of 10: NDC 58160-811-52
Store refrigerated between 2o and 8oC (36o and 46oF). Do not freeze. Discard if the
vaccine has been frozen.
17 PATIENT COUNSELING INFORMATION
The parent or guardian should be:
19
These highlights do not include all the information needed to use PEDIARIX safely and effectively. See full prescribing information for PEDIARIX.
PEDIARIX [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine]
Suspension for Intramuscular Injection Initial U.S. Approval: 2002
----------------------------INDICATIONS AND USAGE---------------------
PEDIARIX is a vaccine indicated for active immunization against diphtheria, tetanus, pertussis, infection caused by all known subtypes of hepatitis B virus, and poliomyelitis. PEDIARIX is approved for use as a three-dose series in infants born of hepatitis B surface antigen (HBsAg)-negative mothers. PEDIARIX may be given as early as 6 weeks of age through 6 years of age (prior to the 7th birthday). (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------
Three doses (0.5 mL each) by intramuscular injection at 2, 4, and 6 months of age. (2.2)
--------------------- DOSAGE FORMS AND STRENGTHS -------------- Single-dose prefilled syringes containing a 0.5-mL suspension for injection. (3)
-------------------------------CONTRAINDICATIONS ------------------------
- Severe allergic reaction (e.g., anaphylaxis) after a previous dose of any diphtheria toxoid, tetanus toxoid, pertussis, hepatitis B, or poliovirus- containing vaccine, or to any component of PEDIARIX. (4.1)
- Encephalopathy within 7 days of administration of a previous pertussis- containing vaccine. (4.2)
- Progressive neurologic disorders. (4.3)
----------------------- WARNINGS AND PRECAUTIONS-----------------
- In clinical trials, PEDIARIX was associated with higher rates of fever,
relative to separately administered vaccines. (5.1)
- If Guillain-Barré syndrome occurs within 6 weeks of receipt of a prior
vaccine containing tetanus toxoid, the decision to give PEDIARIX
FULL PRESCRIBING INFORMATION: CONTENTS*
- 1 INDICATIONS AND USAGE
- 2 DOSAGE AND ADMINISTRATION
- 2.1 Preparation for Administration
- 2.2 Recommended Dose and Schedule
- 2.3 Modified Schedules in Previously Vaccinated
- 2.1 Preparation for Administration
- 1 INDICATIONS AND USAGE
- 3 DOSAGE FORMS AND STRENGTHS
- 4 CONTRAINDICATIONS
- 4.1 Hypersensitivity
- 4.2 Encephalopathy
- 4.3 Progressive Neurologic Disorder
- 4.1 Hypersensitivity
- 5 WARNINGS AND PRECAUTIONS
- 5.1 Fever
- 5.2 Guillain-Barré Syndrome
- 5.3 Latex
- 5.4 Syncope
- 5.5 Adverse Events Following Prior Pertussis
- 5.6 Children at Risk for Seizures
- 5.7 Apnea in Premature Infants
- 5.8 Preventing and Managing Allergic Vaccine
- 5.1 Fever
- 6 ADVERSE REACTIONS
- 6.1 Clinical Trials Experience
- 6.2 Postmarketing Safety Surveillance Study
- 6.1 Clinical Trials Experience
should be based on potential benefits and risks. (5.2)
- The tip caps of the prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals. (5.3)
- Syncope (fainting) can occur in association with administration of injectable vaccines, including PEDIARIX. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. (5.4)
- If specified adverse events (i.e., temperature ≥105oF, collapse or shock- like state, or inconsolable crying lasting ≥3 hours, within 48 hours after vaccination; seizures within 3 days after vaccination) have occurred following a pertussis-containing vaccine, the decision to give PEDIARIX should be based on potential benefits and risks. (5.5)
- For children at higher risk for seizures, an antipyretic may be administered at the time of vaccination with PEDIARIX. (5.6)
- Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including PEDIARIX, to infants born prematurely should be based on consideration of the individual infant’s medical status, and the potential benefits and possible risks of vaccination. (5.7)
------------------------------ ADVERSE REACTIONS -----------------------
Common solicited adverse events following any dose (≥25%) included local injection site reactions (pain, redness, and swelling), fever (≥100.4°F), drowsiness, irritability/fussiness and loss of appetite. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.
-------------------------------DRUG INTERACTIONS------------------------
Do not mix PEDIARIX with any other vaccine in the same syringe or vial. (7.1)
See 17 for PATIENT COUNSELING INFORMATION.
6.3 Postmarketing Spontaneous Reports for PEDIARIX
6.4 Postmarketing Spontaneous Reports for INFANRIX and/or ENGERIX-B
- 7 DRUG INTERACTIONS
- 7.1 Concomitant Vaccine Administration
- 7.2 Immunosuppressive Therapies
- 7.1 Concomitant Vaccine Administration
- 8 USE IN SPECIFIC POPULATIONS
8.4 Pediatric Use
- 11 DESCRIPTION
- 12 CLINICAL PHARMACOLOGY
13 NONCLINICAL TOXICOLOGY
Revised: 11/2013
1
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
- 14 CLINICAL STUDIES
- 14.1 Efficacy of INFANRIX
- 14.2 Immunological Evaluation of PEDIARIX
- 14.3 Concomitant Vaccine Administration
- 14.1 Efficacy of INFANRIX
- 15 REFERENCES
- 16 HOW SUPPLIED/STORAGE AND HANDLING
- 17 PATIENT COUNSELING INFORMATION
______________________________________________________________________
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
PEDIARIX® is indicated for active immunization against diphtheria, tetanus, pertussis, infection caused by all known subtypes of hepatitis B virus, and poliomyelitis. PEDIARIX is approved for use as a three-dose series in infants born of hepatitis B surface antigen (HBsAg)-negative mothers. PEDIARIX may be given as early as 6 weeks of age through 6 years of age (prior to the 7th birthday).
2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration
Shake vigorously to obtain a homogeneous, turbid, white suspension. Do not use if resuspension does not occur with vigorous shaking. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.
Attach a sterile needle and administer intramuscularly.
The preferred administration site is the anterolateral aspect of the thigh for children younger than 1 year. In older children, the deltoid muscle is usually large enough for an intramuscular injection. The vaccine should not be injected in the gluteal area or areas where there may be a major nerve trunk. Gluteal injections may result in suboptimal hepatitis B immune response.
Do not administer this product intravenously, intradermally, or subcutaneously.
2.2 Recommended Dose and Schedule
Immunization with PEDIARIX consists of 3 doses of 0.5 mL each, by intramuscular injection, at 2, 4, and 6 months of age (at intervals of 6 to 8 weeks, preferably 8 weeks). The first dose may be given as early as 6 weeks of age. Three doses of PEDIARIX constitute a primary immunization course for diphtheria, tetanus, pertussis, and poliomyelitis and the complete vaccination course for hepatitis B.
2.3 Modified Schedules in Previously Vaccinated Children
Children Previously Vaccinated With Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP): PEDIARIX may be used to complete the first 3 doses of the DTaP series in children who have received 1 or 2 doses of INFANRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed), manufactured by GlaxoSmithKline, identical to the DTaP component of PEDIARIX [see Description (11)] and are also scheduled to receive the other vaccine components of PEDIARIX. Data are not available on the safety and effectiveness of using PEDIARIX following one or more doses of a DTaP vaccine from a different manufacturer.
Children Previously Vaccinated With Hepatitis B Vaccine: PEDIARIX may be used 2
to complete the hepatitis B vaccination series following 1 or 2 doses of another hepatitis B vaccine (monovalent or as part of a combination vaccine), including vaccines from other manufacturers, in children born of HBsAg-negative mothers who are also scheduled to receive the other vaccine components of PEDIARIX.
A 3-dose series of PEDIARIX may be administered to infants born of HBsAg-negative mothers and who received a dose of hepatitis B vaccine at or shortly after birth. However, data are limited regarding the safety of PEDIARIX in such infants [see Adverse Reactions (6.1)]. There are no data to support the use of a 3-dose series of PEDIARIX in infants who have previously received more than one dose of hepatitis B vaccine.
Children Previously Vaccinated With Inactivated Poliovirus Vaccine (IPV):
PEDIARIX may be used to complete the first 3 doses of the IPV series in children who have received 1 or 2 doses of IPV from a different manufacturer and are also scheduled to receive the other vaccine components of PEDIARIX.
2.4 Booster Immunization Following PEDIARIX
Children who have received a 3-dose series with PEDIARIX should complete the DTaP and IPV series according to the recommended schedule.1 Because the pertussis antigens contained in INFANRIX and KINRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine), manufactured by GlaxoSmithKline, are the same as those in PEDIARIX, these children should receive INFANRIX as their fourth dose of DTaP and either INFANRIX or KINRIX as their fifth dose of DTaP, according to the respective prescribing information for these vaccines. KINRIX or another manufacturer’s IPV may be used to complete the 4-dose IPV series according to the respective prescribing information.
3 DOSAGE FORMS AND STRENGTHS
PEDIARIX is a suspension for injection available in 0.5-mL single-dose prefilled TIP-LOK® syringes.
4 CONTRAINDICATIONS 4.1 Hypersensitivity
A severe allergic reaction (e.g., anaphylaxis) after a previous dose of any diphtheria toxoid-, tetanus toxoid-, pertussis antigen-, hepatitis B-, or poliovirus-containing vaccine or any component of this vaccine, including yeast, neomycin, and polymyxin B, is a contraindication to administration of PEDIARIX [see Description (11)].
4.2 Encephalopathy
Encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days of administration of a previous dose of a pertussis-containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis- containing vaccine, including PEDIARIX.
4.3 Progressive Neurologic Disorder
Progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy is a contraindication to administration of any pertussis-containing
3
vaccine, including PEDIARIX. PEDIARIX should not be administered to individuals with such conditions until the neurologic status is clarified and stabilized.
5 WARNINGS AND PRECAUTIONS 5.1 Fever
In clinical trials, administration of PEDIARIX in infants was associated with higher rates of fever, relative to separately administered vaccines [see Adverse Reactions (6.1)].
5.2 Guillain-Barré Syndrome
If Guillain-Barré syndrome occurs within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the decision to give PEDIARIX or any vaccine containing tetanus toxoid should be based on careful consideration of the potential benefits and possible risks.
5.3 Latex
The tip caps of the prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals.
5.4 Syncope
Syncope (fainting) can occur in association with administration of injectable vaccines, including PEDIARIX. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope.
5.5 Adverse Events Following Prior Pertussis Vaccination
If any of the following events occur in temporal relation to receipt of a vaccine containing a pertussis component, the decision to give any pertussis-containing vaccine, including PEDIARIX, should be based on careful consideration of the potential benefits and possible risks:
- Temperature of ≥40.5oC (105oF) within 48 hours not due to another identifiable cause;
- Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours;
- Persistent, inconsolable crying lasting ≥3 hours, occurring within 48 hours;
- Seizures with or without fever occurring within 3 days.
For children at higher risk for seizures than the general population, an appropriate antipyretic may be administered at the time of vaccination with a vaccine containing a pertussis component, including PEDIARIX, and for the ensuing 24 hours to reduce the possibility of post-vaccination fever.
5.7 Apnea in Premature Infants
Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including PEDIARIX, to infants born prematurely should be based on consideration of the individual infant’s medical status, and the potential benefits and possible risks of vaccination.
5.8 Preventing and Managing Allergic Vaccine Reactions
Prior to administration, the healthcare provider should review the immunization history 4
for possible vaccine sensitivity and previous vaccination-related adverse reactions to allow an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur.
6 ADVERSE REACTIONS 6.1 Clinical Trials Experience
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 23,849 doses of PEDIARIX have been administered to 8,088 infants who received one or more doses as part of the 3-dose series during 14 clinical studies. Common adverse events that occurred in ≥25% of subjects following any dose of PEDIARIX included local injection site reactions (pain, redness, and swelling), fever, drowsiness, irritability/fussiness, and loss of appetite. In comparative studies (including the German and US studies described below), administration of PEDIARIX was associated with higher rates of fever relative to separately administered vaccines [see Warnings and Precautions (5.1)]. 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 Haemophilus influenzae type b (Hib) conjugate vaccines (GlaxoSmithKline [licensed in the US only for booster immunization], Wyeth Pharmaceuticals Inc. [no longer licensed in the US], Sanofi Pasteur SA [US-licensed], or Merck & Co, Inc. [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 oral poliovirus vaccine [OPV] [Wyeth Pharmaceuticals, Inc.; no longer licensed in the US]). In this study, information on adverse events that occurred within 30 days following vaccination was collected. 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® [Hepatitis B Vaccine (Recombinant)], and IPV (Sanofi Pasteur SA) in 335 infants. In both groups, infants received Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US) and 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) concomitantly at separate sites. All vaccines were administered at 2, 4, and 6 months of age. Data on solicited local reactions and general 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). 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
5
onset of chronic illnesses. A total of 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.
Solicited Adverse Events: Data on solicited local reactions and general adverse events from the US safety study are presented in Table 1. This study was powered to evaluate fever >101.3°F following dose 1. The rate of fever ≥100.4°F following each dose was significantly higher in the group that received PEDIARIX compared to separately administered vaccines. Other statistically significant differences between groups in rates of fever, as well as other solicited adverse events, are noted in Table 1. 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 1). Following dose 2, medical attention for fever was sought for 2 infants (0.6%) who received separately administered vaccines (Table 1). 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.
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Table 1. Percentage of Infants With Solicited Local Reactions or General Adverse Events Within 4 Days of Vaccinationa 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 Intent To Treat Cohort)
PEDIARIX, Hib Vaccine, & PCV7
INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
Dose 1
Dose 2
Dose 3
Dose 1
Dose 2
Dose 3
Localb
N
671
653
648
335
323
315
Pain, any
Pain, grade 2 or 3 Pain, grade 3
36.1 11.5 2.4
36.1 10.9 2.5
31.2 10.6 1.7
31.9 9.0 2.7
30.0 8.7 1.5
29.8 8.9 1.3
Redness, any Redness, >5 mm Redness, >20 mm
24.9c 6.0c 0.9
37.2 9.6c 1.2c
40.1 12.7c 2.8
18.2 1.8 0.3
32.8 5.9 0.0
39.0 7.3 1.9
Swelling, any Swelling, >5 mm Swelling, >20 mm
17.3c 5.8c 1.9
26.5c 9.6c 2.5c
28.7 9.3c 3.1
9.6 1.8 0.6
20.4 5.0 0.0
24.8 4.1 1.3
General
N
667
644
645
333
321
311
Feverd, ≥100.4°F Feverd, >101.3°F Feverd, >102.2°F Feverd, >103.1°F Feverd, M.A.
27.9c 7.0 2.2c 0.4 1.2c
38.8c 14.1c 3.6 1.4 0.2
33.5c 8.8 3.4 1.1 0.8
19.8 4.5 0.3 0.0 0.0
30.2 9.7 3.1 0.3 0.6
23.8 5.8 2.3 0.3 0.0
N
671
653
648
335
323
315
Drowsiness, any Drowsiness, grade 2 or 3 Drowsiness, grade 3
57.2 15.8 2.5
51.6 13.8 1.2
40.9 11.4 0.9
54.0 17.6 3.6
48.3 12.4 0.6
38.4 11.1 1.9
Irritability/Fussiness, any Irritability/Fussiness, grade 2 or 3 Irritability/Fussiness, grade 3
60.5 19.8 3.4
64.9 27.9c 4.4
61.1 25.2c 3.5
61.5 19.4 3.9
61.6 21.1 3.4
56.5 19.4 3.2
Loss of appetite, any
Loss of appetite, grade 2 or 3 Loss of appetite, grade 3
30.4 6.6 0.7
30.6 7.8c 0.3
26.2 5.9 0.2
27.8 5.1 0.6
26.6 3.4 0.3
23.8 5.4 0.0
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA).
Modified intent to treat 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).
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Grade 2 defined as sufficiently discomforting to interfere with daily activities. Grade 3 defined as preventing normal daily activities.
a
b Local reactions at the injection site for PEDIARIX or INFANRIX.
Within 4 days of vaccination defined as day of vaccination and the next 3 days.
c
d Axillary temperatures increased by 1°C and oral temperatures increased by 0.5°C to derive equivalent rectal temperature.
Serious Adverse Events: Within 30 days following any dose of vaccine in the US safety study in which all subjects received concomitant Hib and pneumococcal 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).
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). The reported rate of SIDS in the United States from 1990 to 1994 was 1.2/1,000 live births. By chance alone, some cases of SIDS can be expected to follow receipt of pertussis-containing vaccines.
Onset of Chronic Illnesses: In the US safety study in which all subjects received concomitant Hib and pneumococcal 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 (N = 4,666) 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
Rate significantly higher in the group that received PEDIARIX compared to separately administered vaccines [P value <0.05 (2-sided Fisher Exact test) or the 95% CI on the difference between groups (Separate minus PEDIARIX) does not include 0].
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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 (N = 768) 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 Hib and pneumococcal conjugate vaccines, 4 subjects in the group that received PEDIARIX (N = 673) 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 (N = 335) 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 or US safety studies.
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.
6.2 Postmarketing Safety Surveillance Study
In a safety surveillance study conducted at a health maintenance organization in the US, infants who received one or more doses of PEDIARIX from approximately mid-2003 through mid-2005 were compared to age-, gender-, and area-matched historical controls who received one or more doses of separately administered US-licensed DTaP vaccine from 2002 through approximately mid-2003. Only infants who received 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) concomitantly with PEDIARIX or DTaP vaccine were included in the cohorts. Other US-licensed vaccines were administered according to routine practices at the study sites, but concomitant administration with PEDIARIX or DTaP was not a criterion for inclusion in the cohorts. A birth dose of hepatitis B vaccine had been administered routinely to infants in the historical DTaP control cohort, but not to infants who received PEDIARIX. For each of Doses 1-3, a random sample of 40,000 infants who received PEDIARIX was compared to the historical DTaP control cohort for the incidence of seizures (with or without fever) during the 8-day period following vaccination. For each dose, random samples of 7,500 infants in each cohort were also compared for the incidence of medically-attended fever (fever ≥100.4°F that resulted in hospitalization, an emergency department visit, or an outpatient visit) during the 4- day period following vaccination. Possible seizures and medical visits plausibly related to fever
9
were identified by searching automated inpatient and outpatient data files. Medical record reviews of identified events were conducted to verify the occurrence of seizures or medically- attended fever. The incidence of verified seizures and medically-attended fever from this study are presented in Table 2.
Table 2. Percentage of Infants With Seizures (With or Without Fever) Within 8 Days of Vaccination and Medically-Attended Fever Within 4 Days of Vaccination With PEDIARIX Compared With Historical Controls
PEDIARIX
Historical DTaP Controls
Difference (PEDIARIX–DTaP Controls)
N
n
% (95% CI)
N
n
% (95% CI)
% (95% CI)
All seizures
(with or without fever)
Dose 1, Days 0-7 Dose 2, Days 0-7 Dose 3, Days 0-7 Total doses
40,000 40,000 40,000 120,000
7 3 6 16
0.02 (0.01, 0.04) 0.01 (0.00, 0.02) 0.02 (0.01, 0.03) 0.01 (0.01, 0.02)
39,232 37,405 40,000 116,637
6 4 5 15
0.02 (0.01, 0.03) 0.01 (0.00, 0.03) 0.01 (0.00, 0.03) 0.01 (0.01, 0.02)
0.00 (-0.02, 0.02) 0.00 (-0.02, 0.01) 0.00 (-0.01, 0.02) 0.00 (-0.01, 0.01)
Medically-attended fevera
Dose 1, Days 0-3 Dose 2, Days 0-3 Dose 3, Days 0-3 Total doses
7,500 7,500 7,500 22,500
14 25 21 60
0.19 (0.11, 0.30) 0.33 (0.22, 0.48) 0.28 (0.17, 0.43) 0.27 (0.20, 0.34)
7,500 7,500 7,500 22,500
14 15 19 48
0.19 (0.11, 0.30) 0.20 (0.11, 0.33) 0.25 (0.15, 0.39) 0.21 (0.16, 0.28)
0.00 (-0.14, 0.14) 0.13 (-0.03, 0.30) 0.03 (-0.14, 0.19) 0.05 (-0.01, 0.14)
DTaP – any US-licensed DTaP vaccine. Infants received 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) concomitantly with each dose of PEDIARIX or DTaP. Other US-licensed vaccines were administered according to routine practices at the study sites.
N = number of subjects in the given cohort.
n = number of subjects with events reported in the given cohort.
a
emergency department visit, or an outpatient visit.
Medically-attended fever defined as fever ≥100.4°F that resulted in hospitalization, an
6.3 Postmarketing Spontaneous Reports for PEDIARIX
In addition to reports in clinical trials, 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. Because these events are reported voluntarily from a population of
10
uncertain size, it is not 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 reaction, injection site vesicles, injection site warmth, limb pain, limb swelling.
Immune System Disorders: Anaphylactic reaction, anaphylactoid reaction, hypersensitivity.
Infections and Infestations: Upper respiratory tract infection.
Investigations: Abnormal liver function tests.
Nervous System Disorders: Bulging fontanelle, depressed level of consciousness,
encephalitis, hypotonia, hypotonic-hyporesponsive episode, lethargy, somnolence, syncope. 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.
6.4 Postmarketing Spontaneous Reports for 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. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.
Blood and Lymphatic System Disorders: Idiopathic thrombocytopenic purpuraa,b, lymphadenopathya, thrombocytopeniaa,b.
Gastrointestinal Disorders: Abdominal painb, intussusceptiona,b, nauseab.
General Disorders and Administration Site Conditions: Astheniab, malaiseb. Hepatobiliary Disorders: Jaundiceb.
Immune System Disorders: Anaphylactic shocka, serum sickness–like diseaseb. Musculoskeletal and Connective Tissue Disorders: Arthralgiab, arthritisb, muscular
weaknessb, myalgiab.
Nervous System Disorders: Encephalopathya, headachea, meningitisb, neuritisb,
neuropathyb, paralysisb.
Skin and Subcutaneous Tissue Disorders: Alopeciab, erythema multiformeb, lichen
planusb, pruritusa,b, Stevens Johnson syndromea. Vascular Disorders: Vasculitisb.
a Following INFANRIX (licensed in the United States in 1997).
b Following ENGERIX-B (licensed in the United States in 1989).
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7 DRUG INTERACTIONS
7.1 Concomitant Vaccine Administration
Immune responses following concomitant administration of PEDIARIX, Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US), and 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) were evaluated in a clinical trial [see Clinical Studies (14.3)].
When PEDIARIX is administered concomitantly with other injectable vaccines, they should be given with separate syringes and at different injection sites. PEDIARIX should not be mixed with any other vaccine in the same syringe or vial.
7.2 Immunosuppressive Therapies
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to PEDIARIX.
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy
Pregnancy Category C
Animal reproduction studies have not been conducted with PEDIARIX. It is not known whether PEDIARIX can cause fetal harm when administered to a pregnant woman or if PEDIARIX can affect reproduction capacity.
8.4 Pediatric Use
Safety and effectiveness of PEDIARIX were established in the age group 6 weeks through 6 months on the basis of clinical studies [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. Safety and effectiveness of PEDIARIX in the age group 7 months through 6 years are supported by evidence in infants 6 weeks through 6 months of age. Safety and effectiveness of PEDIARIX in infants younger than 6 weeks of age and children 7 to 16 years of age have not been evaluated.
11 DESCRIPTION
PEDIARIX [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine] is a noninfectious, sterile vaccine for intramuscular administration. Each 0.5-mL dose is formulated to contain 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 mcg of inactivated pertussis toxin (PT), 25 mcg of filamentous hemagglutinin (FHA), 8 mcg of pertactin (69 kiloDalton outer membrane protein), 10 mcg of HBsAg, 40 D-antigen Units (DU) of Type 1 poliovirus (Mahoney), 8 DU of Type 2 poliovirus (MEF-1), and 32 DU of Type 3 poliovirus (Saukett). The diphtheria, tetanus, and pertussis components are the same as those in INFANRIX and KINRIX. The hepatitis B surface antigen is the same as that in ENGERIX-B.
The diphtheria toxin is produced by growing Corynebacterium diphtheriae in Fenton medium containing a bovine extract. Tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein. The bovine materials used in these
12
extracts are sourced from countries which the United States Department of Agriculture (USDA) has determined neither have nor present an undue risk for bovine spongiform encephalopathy (BSE). Both toxins are detoxified with formaldehyde, concentrated by ultrafiltration, and purified by precipitation, dialysis, and sterile filtration.
The acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formaldehyde.
The hepatitis B surface antigen is obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus, in synthetic medium. The surface antigen expressed in the S. cerevisiae cells is purified by several physiochemical steps, which include precipitation, ion exchange chromatography, and ultrafiltration.
The inactivated poliovirus component is an enhanced potency component. Each of the 3 strains of poliovirus is individually grown in VERO cells, a continuous line of monkey kidney cells, cultivated on microcarriers. Calf serum and lactalbumin hydrolysate are used during VERO cell culture and/or virus culture. Calf serum is sourced from countries the USDA has determined neither have nor present an undue risk for BSE. After clarification, each viral suspension is purified by ultrafiltration, diafiltration, and successive chromatographic steps, and inactivated with formaldehyde. The 3 purified viral strains are then pooled to form a trivalent concentrate.
Diphtheria and tetanus toxoids and pertussis antigens (inactivated PT, FHA, and pertactin) are individually adsorbed onto aluminum hydroxide. The hepatitis B component is adsorbed onto aluminum phosphate.
Diphtheria and tetanus toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis component (inactivated PT, FHA, and pertactin) is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice. Potency of the hepatitis B component is established by HBsAg ELISA. The potency of the inactivated poliovirus component is determined by using the D-antigen ELISA and by a poliovirus neutralizing cell culture assay on sera from previously immunized rats.
Each 0.5-mL dose contains aluminum salts as adjuvant (not more than 0.85 mg aluminum by assay) and 4.5 mg of sodium chloride. Each dose also contains ≤100 mcg of residual formaldehyde and ≤100 mcg of polysorbate 80 (Tween 80). Neomycin sulfate and polymyxin B are used in the poliovirus vaccine manufacturing process and may be present in the final vaccine at ≤0.05 ng neomycin and ≤0.01 ng polymyxin B per dose. The procedures used to manufacture the HBsAg antigen result in a product that contains ≤5% yeast protein.
The tip caps of the prefilled syringes may contain natural rubber latex; the plungers are not made with natural rubber latex.
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PEDIARIX is formulated without preservatives.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action
Diphtheria: Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection; a level of 0.1 IU/mL is regarded as protective.2
Tetanus: Tetanus is an acute toxin-mediated disease caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.3,4 A level ≥0.1 IU/mL is considered protective.5
Pertussis: Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. There is no established serological correlate of protection for pertussis.
Hepatitis B: Infection with hepatitis B virus can have serious consequences including acute massive hepatic necrosis and chronic active hepatitis. Chronically infected persons are at increased risk for cirrhosis and hepatocellular carcinoma.
Antibody concentrations ≥10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B virus infection.6
Poliomyelitis: Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Poliovirus neutralizing antibodies confer protection against poliomyelitis disease.7
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
PEDIARIX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.
14 CLINICAL STUDIES
The efficacy of PEDIARIX is based on the immunogenicity of the individual antigens compared to licensed vaccines. Serological correlates of protection exist for the diphtheria, tetanus, hepatitis B, and poliovirus components. The efficacy of the pertussis component, which does not have a well established correlate of protection, was determined in clinical trials of INFANRIX.
14.1 Efficacy of INFANRIX
Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies.
A double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy, sponsored by the National Institutes of Health (NIH), assessed the absolute
14
protective efficacy of INFANRIX when administered at 2, 4, and 6 months of age. The population used in the primary analysis of the efficacy of INFANRIX included 4,481 infants vaccinated with INFANRIX and 1,470 DT vaccinees. After 3 doses, the absolute protective efficacy of INFANRIX against WHO-defined typical pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was 84% (95% CI: 76%, 89%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX was 71% (95% CI: 60%, 78%) against >7 days of any cough and 73% (95% CI: 63%, 80%) against
≥14 days of any cough. A longer unblinded follow-up period showed that after 3 doses and with no booster dose in the second year of life, the efficacy of INFANRIX against WHO-defined pertussis was 86% (95% CI: 79%, 91%) among children followed to 6 years of age. For details see INFANRIX prescribing information.
A prospective efficacy trial was also conducted in Germany employing a household contact study design. In this study, the protective efficacy of INFANRIX administered to infants at 3, 4, and 5 months of age, against WHO-defined pertussis was 89% (95% CI: 77%, 95%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX against ≥7 days of any cough was 67% (95% CI: 52%, 78%) and against ≥7 days of paroxysmal cough was 81% (95% CI: 68%, 89%). For details see INFANRIX prescribing information.
14.2 Immunological Evaluation of PEDIARIX
In a US multicenter study, infants were randomized to 1 of 3 groups: (1) a combination vaccine group that received PEDIARIX concomitantly with Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US) and US-licensed 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.); (2) a separate vaccine group that received US-licensed INFANRIX, ENGERIX-B, and IPV (Sanofi Pasteur SA) concomitantly with the same Hib and pneumococcal conjugate vaccines; and (3) a staggered vaccine group that received PEDIARIX concomitantly with the same Hib conjugate vaccine but with the same pneumococcal conjugate vaccine administered 2 weeks later. The schedule of administration was 2, 4, and
6 months of age. Infants either did not receive a dose of hepatitis B vaccine prior to enrollment or were permitted to receive one dose of hepatitis B vaccine administered at least 30 days prior to enrollment. For the separate vaccine group, ENGERIX-B was not administered at 4 months of age to subjects who received a dose of hepatitis B vaccine prior to enrollment. Among subjects in all 3 vaccine groups combined, 84% were white, 7% were Hispanic, 6% were black, 0.7% were Oriental, and 2.4% were of other racial/ethnic groups.
The immune responses to the pertussis (PT, FHA, and pertactin), diphtheria, tetanus, poliovirus, and hepatitis B antigens were evaluated in sera obtained one month (range 20 to
60 days) after the third dose of PEDIARIX or INFANRIX. Geometric mean antibody concentrations (GMCs) adjusted for pre-vaccination values for PT, FHA, and pertactin and the seroprotection rates for diphtheria, tetanus, and the polioviruses among subjects who received PEDIARIX in the combination vaccine group were shown to be non-inferior to those achieved
15
following separately administered vaccines (Table 3).
Because of differences in the hepatitis B vaccination schedule among subjects in the
study, no clinical limit for non-inferiority was pre-defined for the hepatitis B immune response. However, in a previous US study, non-inferiority of PEDIARIX relative to separately administered INFANRIX, ENGERIX-B, and an oral poliovirus vaccine, with respect to the hepatitis B immune response was demonstrated.
Table 3. Antibody Responses Following PEDIARIX as Compared to Separate Concomitant Administration of INFANRIX, ENGERIX-B, and IPV (One Montha After Administration of Dose 3) in Infants Vaccinated at 2, 4, and 6 Months of Age When Administered Concomitantly With Hib Conjugate Vaccine and Pneumococcal Conjugate Vaccine (PCV7)
PEDIARIX, Hib Vaccine, & PCV7
INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
(N = 154-168)
(N = 141-155)
Anti-Diphtheria Toxoid % ≥0.1 IU/mLb
99.4
98.7
Anti-Tetanus Toxoid % ≥0.1 IU/mLb
100
98.1
Anti-PT % VRc GMCb
98.7 48.1
95.1 28.6
Anti-FHA % VRc GMCb
98.7 111.9
96.5 97.6
Anti-Pertactin % VRc
GMCb
91.7 95.3
95.1 80.6
Anti-Polio 1 % ≥1:8b,d
100
100
Anti-Polio 2 % ≥1:8b,d
100
100
Anti-Polio 3 % ≥1:8b,d
100
100
(N = 114-128)
(N = 111-121)
Anti-HBsAge
% ≥10 mIU/mLf GMC (mIU/mL)f
97.7 1032.1
99.2 614.5
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA).
Assay methods used: ELISA for anti-diphtheria, anti-tetanus, anti-PT, anti-FHA, anti-pertactin, and anti-HBsAg; micro-neutralization for anti-polio (1, 2, and 3).
VR = vaccine response: In initially seronegative infants, appearance of antibodies (concentration ≥5 EL.U./mL); in initially seropositive infants, at least maintenance of pre-vaccination
16
concentration.
GMC = geometric mean antibody concentration. GMCs are adjusted for pre-vaccination levels.
a
c
d Poliovirus neutralizing antibody titer.
One month blood sampling, range 20 to 60 days.
b Seroprotection rate or GMC for PEDIARIX not inferior to separately administered vaccines
[upper limit of 90% CI on GMC ratio (separate vaccine group/combination vaccine group) <1.5 for anti-PT, anti-FHA, and anti-pertactin, and upper limit of 95% CI for the difference in seroprotection rates (separate vaccine group minus combination vaccine group) <10% for diphtheria and tetanus and <5% for the 3 polioviruses]. GMCs are adjusted for pre- vaccination levels.
The upper limit of 95% CI for differences in vaccine response rates (separate vaccine group minus combination group) was 0.31, 1.52, and 9.46 for PT, FHA, and pertactin, respectively. No clinical limit defined for non-inferiority.
e
of hepatitis B seroprotection rates and GMCs presented in the table.
Subjects who received a previous dose of hepatitis B vaccine were excluded from the analysis
f
14.3 Concomitant Vaccine Administration
In a US multicenter study [see Clinical Studies (14.2)], there was no evidence for interference with the immune responses to PEDIARIX when administered concomitantly with 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) relative to 2 weeks prior.
Anti-PRP (Hib polyribosyl-ribitol-phosphate) seroprotection rates and GMCs of pneumococcal antibodies one month (range 20 to 60 days) after the third dose of vaccines for the combination vaccine group and the separate vaccine group from the US multicenter study [see Clinical Studies (14.2)], are presented in Table 4.
No clinical limit defined for non-inferiority.
17
Table 4. Anti-PRP Seroprotection Rates and GMCs (mcg/mL) of Pneumococcal Antibodies One Montha Following the Third Dose of Hib Conjugate Vaccine and Pneumococcal Conjugate Vaccine (PCV7) Administered Concomitantly With PEDIARIX or With INFANRIX, ENGERIX-B, and IPV
PEDIARIX, Hib Vaccine, & PCV7
INFANRIX, ENGERIX-B, IPV, Hib Vaccine, & PCV7
(N = 161-168)
(N = 146-156)
% (95% CI)
% (95% CI)
Anti-PRP
≥0.15 mcg/mL
100 (97.8, 100)
99.4 (96.5, 100)
Anti-PRP
≥1.0 mcg/mL
95.8 (91.6, 98.3)
91.0 (85.3, 95.0)
GMC (95% CI)
GMC (95% CI)
Pneumococcal Serotype
4
1.7 (1.5, 2.0)
2.1 (1.8, 2.4)
6B
0.8 (0.7, 1.0)
0.7 (0.5, 0.9)
9V
1.6 (1.4, 1.8)
1.6 (1.4, 1.9)
14
4.7 (4.0, 5.4)
6.3 (5.4, 7.4)
18C
2.6 (2.3, 3.0)
3.0 (2.5, 3.5)
19F
1.1 (1.0, 1.3)
1.1 (0.9, 1.2)
23F
1.5 (1.2, 1.8)
1.8 (1.5, 2.3)
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA).
Assay method used: ELISA for anti-PRP and 7 pneumococcal serotypes. GMC = geometric mean antibody concentration.
a
15 REFERENCES
- Centers for Disease and Control and Prevention. Recommended immunization schedules for persons aged 0-18 years—United States, 2010. MMWR 2010;58(51&52).
- Vitek CR and Wharton M. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders;2008:139-156.
- Wassilak SGF, Roper MH, Kretsinger K, and Orenstein WA. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders;2008:805-839.
- Department of Health and Human Services, Food and Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review; Proposed rule. Federal Register December 13, 1985;50(240):51002-51117.
- Centers for Disease Control and Prevention. General Recommendations on Immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(RR-15):1-48.
- Ambrosch F, Frisch-Niggemeyer W, Kremsner P, et al. Persistence of vaccine-induced 18
One month blood sampling, range 20 to 60 days.
7.
16
antibodies to hepatitis B surface antigen and the need for booster vaccination in adult subjects. Postgrad Med J 1987;63(Suppl. 2):129-135.
Sutter RW, Pallansch MA, Sawyer LA, et al. Defining surrogate serologic tests with respect to predicting protective vaccine efficacy: Poliovirus vaccination. In: Williams JC, Goldenthal KL, Burns DL, Lewis Jr BP, eds. Combined vaccines and simultaneous administration. Current issues and perspectives. New York, NY: The New York Academy of Sciences; 1995:289-299.
HOW SUPPLIED/STORAGE AND HANDLING
PEDIARIX is available in 0.5 mL single-dose disposable prefilled TIP-LOK syringes (packaged without needles):
NDC 58160-811-43 Syringe in Package of 10: NDC 58160-811-52
Store refrigerated between 2o and 8oC (36o and 46oF). Do not freeze. Discard if the
vaccine has been frozen.
17 PATIENT COUNSELING INFORMATION
The parent or guardian should be:
- informed of the potential benefits and risks of immunization with PEDIARIX, and of the
importance of completing the immunization series.
- informed about the potential for adverse reactions that have been temporally associated with
administration of PEDIARIX or other vaccines containing similar components.
- instructed to report any adverse events to their healthcare provider.
- given the Vaccine Information Statements, which are required by the National Childhood
Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/nip).
PEDIARIX, INFANRIX, KINRIX, TIP-LOK, and ENGERIX-B are registered trademarks of the GlaxoSmithKline group of companies.
Manufactured by GlaxoSmithKline Biologicals Rixensart, Belgium, US License 1617, and Novartis Vaccines and Diagnostics GmbH Marburg, Germany, US License 1754 Distributed by GlaxoSmithKline
Research Triangle Park, NC 27709
©2013, GlaxoSmithKline group of companies. All rights reserved. PDX:22PI
19
AHFS Category 80:08
Diphtheria and Tetanus
Toxoids and Acellular
Pertussis Vaccine Adsorbed
DAPTACEL?
DESCRIPTION
DAPTACEL™, Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, for intramuscular use, manufactured by Aventis Pasteur Limited, is a sterile suspension of pertussis antigens and diphtheria and tetanus toxoids adsorbed on aluminum phosphate in a sterile isotonic sodium chloride solution. After shaking, the vaccine is a white homogeneous cloudy suspension. Each dose of
DAPTACEL™ contains the following active ingredients:
pertussis toxoid 10 µg
filamentous hemagglutinin (FHA) 5 µg
pertactin (PRN) 3 µg
fimbriae types 2 and 3 5 µg
diphtheria toxoid 15 Lf
tetanus toxoid 5 Lf
Other ingredients per dose include 3.3 mg (0.6% v/v) 2-phenoxyethanol as the preservative, 0.33 mg of aluminum as the adjuvant, ≤0.1 mg residual formaldehyde and <50 ng residual glutaraldehyde. The acellular pertussis vaccine components are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium1modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. The fimbriae types 2 and 3 are extracted from the bacterial cells and the pertussis toxin, FHA and PRN are prepared from the supernatant. These proteins are purified by sequential filtration, saltprecipitation, ultrafiltration and chromatography. Pertussis toxin is inactivated with glutaraldehyde and FHA is treated with formaldehyde. The individual antigens are adsorbed separately onto aluminum phosphate. Corynebacterium diphtheriae is grown in modified Mueller’s growth medium.2 After ammonium sulfate fractionation, the diphtheria toxin is detoxified with formalin and diafiltered. Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion.3 Tetanus toxin is detoxified with formalin and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate. The adsorbed diphtheria, tetanus and acellular pertussis components are combined in a sterile isotonic sodium chloride solution containing 2-phenoxyethanol as preservative. Both diphtheria and tetanus toxoids induce at least 2 units of antitoxin per mL in the guinea pig potency test. The potency of the acellular pertussis vaccine components is evaluated by the antibody response of immunized mice to pertussis toxin, FHA, PRN and fimbriae types 2 and 3 measured by enzyme-linked immunosorbent assay (ELISA).
CLINICAL PHARMACOLOGY
Simultaneous immunization of infants and children against diphtheria, tetanus and pertussis with conventional whole-cell pertussis DTP vaccine (Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed - For Pediatric Use) has been a routine practice in the US since the late 1940s. This has played a major role in markedly reducing disease and deaths from these infections.4 DTaP (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) vaccines were first available for use in infants in the US in 1996 and have been routinely recommended for all doses of the vaccination series for infants and children <7 years of age since 1997.5 Diphtheria Corynebacterium diphtheriae may cause both localized and generalized disease. The systemic intoxication is caused by diphtheria exotoxin, an extracellular protein of toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibody to diphtheria toxin. Both toxigenic and nontoxigenic strains of C. diphtheriae can cause disease but only strains that produce diphtheria toxin cause severe manifestations such as myocarditis and neuritis. Diphtheria is a serious disease, with the highest case-fatality rates among infants and the elderly.4,6 Prior to the widespread use of diphtheria toxoid in the late 1940s, diphtheria disease was common in the US. More than 200,000 cases, primarily among children, were reported in 1921. Approximately 5% – 10% of cases were fatal; the highest case-fatality rates were in the very young and the elderly. More recently, reported cases of diphtheria of all types declined fro m 306 in 1975 to 59 in 1979; most were cutaneous diphtheria reported from a single state. After 1979, cutaneous diphtheria was no longer reportable.4 From 1980 through 2000, only 50 cases of diphtheria were reported in the US. During the period 1980–1996, six fatal cases of diphtheria were reported. Only 1 case of diphtheria was reported each year in 1998–2000 with no fatalities.7 Of 40 reported cases with known age in 1982-1998, 63% were in persons ≥20 years of age. Most cases have occurred in unimmunized or inadequately immunized persons. Although diphtheria disease is rare in the US, it appears that C. diphtheriae continues to circulate in areas of the country with previously endemic diphtheria.8
Page 2 of 12
Diphtheria continues to occur in other parts of the world. A major epidemic of diphtheria occurred in the newly Independent States of the former Soviet Union beginning in 1990. This epidemic resulted in approximately 150,000 cases and 5,000 deaths during the years 1990-1997.9 This outbreak is believed to be due to several factors, including a lack of routine immunization of adults in these countries.10 Complete immunization significantly reduces the risk of developing diphtheria and immunized persons who develop disease have milder illness. Following adequate immunization with diphtheria toxoid, protection is thought to last for at least 10 years. Immunization does not, however, eliminate carriage of C. diphtheriae in the pharynx, nose or on the skin.
4 Tetanus
Tetanus manifests systemic toxicity primarily by neuromuscular dysfunction caused by a potent exotoxin elaborated by Clostridium tetani. Spores of C. tetani are ubiquitous. Serological tests indicate that naturally acquired immunity to tetanus toxin does not occur in the US. Thus, universal primary immunization, with subsequent maintenance of adequate antitoxin levels by means of appropriately timed boosters, is necessary to protect all age groups. Tetanus toxoid is a highly effective antigen and a completed primary series generally induces protective levels of serum antitoxin that persist for 10 years or more.4 Following routine use of tetanus toxoid in the US, the occurrence of tetanus disease decreased dramatically from 560 reported cases in 1947 to an average of 50-100 cases reported annually from the mid 1970s through the late 1990s to 35 cases in 2000.7 The casefatality rate has been relatively constant at approximately 30%. During the years 1982-1998, 52% of reported cases were among persons 60 years of age or older. In the mid to late 1990s, the age distribution of reported cases shifted to a younger age group, in part due to an increased number of cases among injection drug users in California. From 1995-1997, persons 20-59 years of age accounted for 60% of all cases, with persons 60 years of age or older accounting for only 35%. In the US, tetanus occurs almost exclusively among unvaccinated or inadequately vaccinated persons.8
Pertussis
Pertussis (whooping cough) is a disease of the respiratory tract caused by Bordetella pertussis. This gram-negative coccobacillus
produces a variety of biologically active components. The role of the different components produced by B. pertussis in either the
pathogenesis of, or immunity to, pertussis is not well understood.6 Pertussis is highly communicable (attack rates of 90% have been reported for susceptible individuals exposed to a case in the home11) and can cause severe disease, particularly among young infants. Since pertussis became a nationally reportable disease in the US in 1922, the highest number of pertussis cases (approximately 260,000) was reported in 1934. Following the introduction and widespread use of whole-cell pertussis DTP vaccine among infants and children in the mid to late 1940s, pertussis incidence gradually declined, reaching a historical low of 1,010 cases reported in 1976.12 During the 1980s and 1990s, the number of reported pertussis cases in the US has gradually increased, particularly among adolescents and adults.12,13 Improvements in the diagnosis and reporting of pertussis in older age groups is thought to have contributed, at least in part, to the increase in reported cases. The number of cases of pertussis reported among children aged 6 months to 4 years has remained stable throughout the 1990s, suggesting that protection offered by vaccination has continued with the introduction of DTaP vaccines.12 During 1997-2000, a total of 29,134 cases were reported, for an estimated average annual incidence rate of 2.7 per 100,000 population.12 Among 29,048 cases for whom age was known, 29% were aged < 1 year, 12% were aged 1-4 years, 10% were aged 5–9 years, 29% were aged 10-19 years and 20% were ≥20 years of age.12 Average annual incidence rates during 1997-2000 were highest among infants aged <1 year (55.5 cases per 100,000 population) and lower in children aged 1–4 years (5.5), children aged 5–9 years (3.6), persons aged 10-19 years (5.5) and persons aged ≥20 years (0.8).12 The severity of pertussis remains highest in infants. Of 7,203 infants <6 months of age reported as having pertussis during the period 1997-2000, 63% were hospitalized, 12% had pneumonia, 1.4% had one or more seizures, 0.2% had encephalopathy and 0.8% died.12 Atypical infection, including nonspecific symptoms of bronchitis or upper respiratory tract infection, may occur at any age but more commonly in older children and adults, including some who were previously immunized. In these cases, pertussis may not be diagnosed because classic signs, particularly the inspiratory whoop, may be absent. Older preschool-aged and school-aged children, as well as adolescents and adults who develop pertussis, may play a role in transmission to young infants.8 Concerns about the safety of whole-cell pertussis DTP vaccines prompted the development of less reactogenic DTaP vaccines that contain purified antigens of B. pertussis. The pertussis component of DTaP vaccines contains inactivated pertussis toxin and may contain one or more of FHA, PRN and fimbriae types 2 and 3. DTaP vaccines were first available for use in infants in the US in 1996 and have been routinely recommended by the Advisory Committee on Immunization Practices (ACIP) for all doses of the vaccination series for infants and children <7 years of age since 1997.5 Since 1991, 7 studies conducted in Europe and Africa have evaluated the efficacy of 8 DTaP vaccines administered to infants. The vaccines, produced by different manufacturers, contained a varying number and quantity of antigens. The derivation and formulation of the individual antigens also varied among different vaccines. The studies differed in study design and 3, including the Sweden I Efficacy
Trial (1992–1995), were randomized placebo-controlled clinical trials. Because of these and other differences, comparisons among studies should be made with caution. Within individual studies, however, the efficacy of acellular pertussis vaccines can be compared directly with that of a placebo control or whole-cell pertussis DTP. The efficacy of 3 doses of acellular pertussis vaccines in preventing moderate to severe pertussis disease was within the range expected for most whole-cell pertussis DTP vaccines. Point estimates of the efficacy of DTaP vaccines ranged from 59% - 89%.5 The effectiveness of pertussis vaccine among US children aged 7–18 months in 1998 and 1999 was calculated using the screening method. During this time, the National Immunization Survey reported 66% of children aged ≤18 months received DTaP rather than wholecell pertussis DTP.12 The screening estimate of 88% reflects the effectiveness of the overall vaccination program that used approximately two thirds DTaP and one third whole-cell pertussis DTP in children aged 7–18 months. This estimate is similar to that observed in clinical
trials for acellular pertussis vaccines. During 1997–2000, the incidence rates were highest among infants aged <1 year, lower in children aged 1–4 years and remained stable among children aged 5-9 years.12
Page 3 of 12
Efficacy of DAPTACEL™
Pertussis
A randomized, double-blinded, placebo-controlled efficacy and safety study was conducted in Sweden from 1992-1995 (Sweden I Efficacy Trial) under the sponsorship of the National Institute of Allergy and Infectious Diseases (NIAID). A total of 9,829 infants received 1 of 4 vaccines: DAPTACEL™ (n = 2,587); another investigational acellular pertussis vaccine (n = 2,566); whole-cell pertussis DTP vaccine (n = 2,102); or DT vaccine as placebo (Swedish National Bacteriological Laboratory, n = 2,574). Infants were immunized at 2, 4 and 6 months of age. The mean length of follow-up was 2 years after the third dose of vaccine. The protective efficacy of DAPTACEL™ against pertussis after 3 doses of vaccine using the World Health Organization (WHO) case definition (≥21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiologic link to a confirmed case) was 84.9% (95% confidence interval [CI] 80.1 to 88.6).14 The protective efficacy of DAPTACEL™ against mild pertussis (≥1 day of cough
with laboratory confirmation) was 77.9% (95% CI 72.6 to 82.2).15 Protection against pertussis by DAPTACEL™ was sustained for the 2-year follow-up period.14,15 In order to assess the antibody response to the pertussis antigens of DAPTACEL™ in the US population, 2 lots of DAPTACEL™, including the lot used in the Sweden I Efficacy Trial, were administered to US infants in the US Bridging Study.15 In this study, antibody responses following 3 doses of DAPTACEL™ given to US children at 2, 4 and 6 months of age were compared to those from a subset of the infants
enrolled in the Sweden I Efficacy Trial. Assays were performed in parallel on the available sera from the US and Swedish infants. Antibody responses to all the antigens were similar except for those to the PRN component. For both lots of DAPTACEL™, the geometric mean concentration (GMC) and percent response to PRN in US infants (Lot 006, n = 107; Lot 009, n = 108) were significantly lower after 3 doses of vaccine than in Swedish infants (n = 83). In a separate study performed in Canada (Phase II), in which children received 4 doses of DAPTACEL™ at 2, 4, 6 and 17–18 months of age, antibody responses following the fourth dose (n = 275) were equivalent or higher than those seen in the Swedish infants after 3 doses. While a serologic correlate of protection for pertussis has not been established, the antibody response to all antigens in North American infants after 4 doses of DAPTACEL™ at 2, 4, 6 and 17-20 months of age was comparable to that achieved in Swedish infants in whom efficacy was demonstrated after 3 doses of DTaP at 2, 4 and 6 months of age.15 Diphtheria and Tetanus In a Canadian clinical study, 324 children were enrolled to receive DAPTACEL™ at 2, 4, 6 and 17–18 months of age. The proportion of children with post-dose 3 diphtheria (n = 313) and tetanus (n = 313) antitoxin levels ≥0.01 IU/mL was 100% and ≥0.10 IU/mL was 85% and 100%, respectively.15 The proportion with post-dose 4 diphtheria (n = 296) and tetanus (n = 296) antitoxin levels ≥0.10 IU/mL was 100%.15 The efficacy of the diphtheria and tetanus toxoids used in DAPTACEL™ was determined on the basis of immunogenicity studies with a comparison to a serological correlate of protection (0.01 antitoxin units/mL) established by the Panel on Review of Bacterial Vaccines and Toxoids.16 In the US Bridging Study, for which data are only available following 3 doses, 99.2% (n = 261) achieved diphtheria antitoxin levels of ≥0.01 IU/mL, 80.6% (n = 261) achieved levels of ≥0.10 IU/mL and 100% (n = 260) achieved tetanus antitoxin levels of 0.01 U/mL and 0.10 U/mL.15 Concurrently Administered Vaccines In a clinical trial conducted in the US, DAPTACEL™ was given simultaneously with Haemophilus influenzae type b vaccine and with live oral poliovirus vaccine (OPV) at 2, 4 and 6 months of age according to local practices. Two hundred eighty-one infants received 3 doses of Haemophilus influenzae type b vaccine and 305 received 3 doses of OPV. Immune responses to these vaccines were evaluated in a subset of 258 children. One month after the third dose, 96.9% (n = 253) achieved anti-PRP antibody levels of at least 0.15 µg/mL, 82.7% (n = 216) achieved antibody levels of at least 1.0 µg/mL; and 100% (n = 178), had protective neutralizing antibody of ≥1:8 for poliovirus types 1 and 2 and 98.3% (n = 175) for poliovirus type 3.15 In the same study, hepatitis B vaccine (supplied by different manufacturers) was also given to children by different schedules. Hepatitis B vaccine was given concurrently with DAPTACEL™ at 2 and 6 months of age to a subset of infants who received a birth dose of hepatitis B vaccine. Of infants with adequate serum available for serology testing (n = 82), 97% achieved anti-HBs antibody levels ≥10 mIU/mL post dose 3.15 No immunogenicity data are available for concurrent administration of DAPTACEL™ with IPV; pneumococcal conjugate vaccine; measles, mumps and rubella vaccine (MMR) or varicella vaccine. INDICATIONS AND USAGE DAPTACEL™ is indicated for active immunization against diphtheria, tetanus and pertussis in infants and children 6 weeks through 6 years of age (prior to seventh birthday). Children who have had well-documented pertussis (culture positive for B. pertussis or epidemiologic linkage to a culture positive case) should complete the vaccination series with DT; some experts recommend including acellular pertussis vaccine as well. Although welldocumented
pertussis disease is likely to confer immunity, the duration of protection is unknown.17 DAPTACEL™ is not to be used for the treatment of B. pertussis, C. diphtheriae or C. tetani infections. When passive protection is required, Tetanus Immune Globulin and/or Diphtheria Antitoxin may also be administered at separate sites with separate needles and syringes.4 (See DOSAGE AND ADMINISTRATION.) As with any vaccine, vaccination with DAPTACEL™ may not protect 100% of susceptible individuals. CONTRAINDICATIONS This vaccine is contraindicated in children and adults seven years of age and older. Hypersensitivity to any component of the vaccine is a contraindication to further administration.5 Page 4 of 12 The following events after receipt of DAPTACEL™ are contraindications to further administration of any pertussis-containing vaccine:5 • An immediate anaphylactic reaction. Because of uncertainty as to which component of the vaccine may be responsible, no further vaccination with diphtheria, tetanus or pertussis components should be carried out. Alternatively, such individuals may be referred to an allergist for evaluation if further immunizations are to be considered. • Encephalopathy not attributable to another identifiable cause (e.g., an acute, severe central nervous system disorder occurring within 7 days after vaccination and consisting of major alterations in consciousness, unresponsiveness or generalized or focal seizures that persist more than a few hours, without recovery within 24 hours). In such cases, DT vaccine should be administered for the remaining doses in the vaccination schedule. The decision to administer or delay vaccination because of a current or recent febrile illness depends on the severity of symptoms and on the etiology of the disease. According to the ACIP, all vaccines can be administered to persons with mild illness such as diarrhea, mild upper-respiratory infection with or without low-grade fever, or other low-grade febrile illness.17,18 However, children with moderate or serious illness should not be immunized until recovered.4 Elective immunization procedures should be deferred during an outbreak of poliomyelitis because of the risk of provoking paralysis.19,20,21
WARNINGS
The stopper to the vial of this product contains dry natural latex rubber that may cause allergic reactions. If any of the following events occur within the specified period after administration of a whole-cell pertussis DTP or DTaP vaccine, providers and parents should evaluate the risks and benefits of subsequent doses of whole-cell pertussis DTP or DTaP vaccines:5 • Temperature of ≥40.5°C (105°F) within 48 hours, not attributable to another identifiable cause. • Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours. • Persistent crying lasting ≥3 hours within 48 hours. • Convulsions with or without fever within 3 days. When a decision is made to withhold pertussis vaccine, immunization with DT vaccine should be continued.4 Because of the risk of hemorrhage, DAPTACEL™ should not be given to children with any coagulation disorder, including thrombocytopenia, which would contraindicate intramuscular injection unless the potential benefit clearly outweighs the risk of administration. Studies suggest that, when given whole-cell pertussis DTP vaccine, infants and children with a history of convulsions in first-degree family members have a 2.4-fold increased risk for neurologic events.22 However, ACIP has concluded that a history of convulsions or other central nervous system disorders in parents or siblings is not a contraindication to pertussis vaccination and that children with such family histories should receive DTaP vaccines according to the recommended schedule.4,17,18 If an infant or young child with a personal or family history of febrile or non-febrile convulsions is to be immunized, acetaminophen or other appropriate antipyretic should be given at the time of DTaP vaccination and for the ensuing 24 hours according to the respective package insert recommended dosage to reduce the possibility of post-vaccination fever.4,17,18 A committee of the Institute of Medicine (IOM) has concluded that the evidence is consistent with a causal relationship between wholecell pertussis DTP vaccine and acute neurologic illness and, under special circumstances, between whole-cell pertussis DTP vaccine and chronic neurologic disease in the context of the National Childhood Encephalopathy Study (NCES) report.23,24 However, the IOM committee concluded that the evidence was insufficient to determine whether whole-cell pertussis DTP vaccine increased the overall risk of chronic neurologic disease.24 Acute encephalopathy (with or without permanent neurological injury) or permanent neurological
injury has not been reported following administration of DAPTACEL™ but the experience with this vaccine is insufficient to rule this out.
(See ADVERSE REACTIONS.)
Infants and children with recognized possible or potential underlying neurologic conditions seem to be at enhanced risk for the appearance of manifestations of the underlying neurologic disorder within 2 or 3 days following whole-cell pertussis DTP vaccine immunization.4 Whether to administer DAPTACEL™ to children with proven or suspected underlying neurologic disorders must be decided on an individual basis after consideration of the risks and benefits. An important consideration includes the current local incidence of pertussis. The ACIP has issued guidelines for such children.25 PRECAUTIONS
General Care is to be taken by the health-care provider for the safe and effective use of this vaccine. Epinephrine Hydrochloride Solution (1:1,000), other appropriate agents and equipment must be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. Health-care providers must be familiar with current recommendations for the initial management of anaphylaxis in non-hospital settings, including proper airway management.17,26
Before an injection of any vaccine, all known precautions should be taken to prevent adverse reactions. This includes a review of the patient’s history with respect to possible sensitivity to the vaccine, similar vaccines or to dry natural latex rubber (see WARNINGS),
previous immunization history, current health status (see CONTRAINDICATIONS) and a current knowledge of the literature concerning the use of the vaccine under consideration including the nature of adverse events that may follow its use. The expected immune response to DAPTACEL™ may not be obtained in immunosuppressed persons.4 Pertussis-containing vaccines are not contraindicated in persons with HIV infection.17 Special care should be taken to ensure that the injection does not enter a blood vessel. A separate, sterile syringe and needle or a sterile disposable unit should be used for each patient to prevent transmission of hepatitis or other infectious agents from person to person. Needles should not be recapped but should be disposed of according to biohazard waste guidelines.
Page 5 of 12
Information for Vaccine Recipients and Parents/Guardians Before administration of this vaccine, health-care personnel should inform the parent, guardian or other responsible adult of the benefits and risks of the vaccine and the importance of completing the immunization series unless a contraindication to further immunization exists. (See ADVERSE REACTIONS and WARNINGS.)
The physician should inform the parent or guardian about the potential for adverse reactions that have been temporally associated with DAPTACEL™ and other pertussis-containing vaccines. The health-care provider should provide the Vaccine Information Statements (VIS) which are required by the National Childhood Vaccine Injury Act of 1986 to be given with each immunization. The parent or guardian should be instructed to report any serious adverse reactions to their health-care provider. IT IS EXTREMELY IMPORTANT WHEN A CHILD RETURNS FOR THE NEXT DOSE IN THE SERIES THAT THE PARENT OR GUARDIAN SHOULD BE QUESTIONED CONCERNING ANY SYMPTOMS AND/OR SIGNS OF AN ADVERSE REACTION AFTER THE PREVIOUS DOSE OF VACCINE. (See CONTRAINDICATIONS and ADVERSE REACTIONS.)
Adverse events following immunization should be reported by health-care providers to the Vaccine Adverse Events Reporting System (VAERS). (See ADVERSE REACTIONS, Reporting of Adverse Events.) Drug Interactions As with other intramuscular (I.M.) injections, use with caution in patients on anticoagulant therapy. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines. Although no specific studies with pertussis vaccine are available, if immunosuppressive therapy is to be soon discontinued, it seems reasonable to defer immunization until the patient has been off therapy for one month; otherwise, the patient should be vaccinated while still on therapy.4 If DAPTACEL™ is administered to persons with an immunodeficiency disorder, on immunosuppressive therapy or after a recent injection of immune globulin, an adequate immunologic response may not occur.
For information regarding simultaneous administration with other vaccines refer to DOSAGE AND ADMINISTRATION.
If passive immunization is needed for tetanus or diphtheria prophylaxis, Tetanus Immune Globulin (Human) (TIG), or Diphtheria Antitoxin,if used, should be given in a separate site, with a separate needle and syringe.18 Carcinogenesis, Mutagenesis, Impairment of Fertility DAPTACEL™ has not been evaluated for its carcinogenic or mutagenic potential or impairment of fertility.
Pregnancy Category C
Animal reproduction studies have not been conducted with DAPTACEL™. It is not known whether DAPTACEL™ can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. DAPTACEL™ is NOT recommended for use in a pregnant woman.
Geriatric Use
This product is NOT recommended for use in adult populations.
Pediatric Use
SAFETY AND EFFECTIVENESS OF DAPTACEL™ IN INFANTS BELOW 6 WEEKS OF AGE HAVE NOT BEEN ESTABLISHED. (See DOSAGE AND ADMINISTRATION.)
THIS VACCINE IS NOT RECOMMENDED FOR PERSONS 7 YEARS OF AGE OR OLDER. Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) is to be used in individuals 7 years of age or older. ADVERSE REACTIONS Over 11,400 doses of DAPTACEL™ have been administered to infants and toddlers in 6 clinical studies. In all, 3,694 children received a total of 3 doses and 476 children received 4 doses of DAPTACEL™.14,15,27,28,29,30,31 In the Sweden I Efficacy Trial, DAPTACEL™ was compared with DT and a whole-cell pertussis DTP vaccine. A standard diary card was kept for 14 days after each dose and follow-up telephone calls were made 1 and 14 days after each injection. Telephone calls were made monthly to monitor the occurrence of severe events and/or hospitalizations for the 2 months after the last injection. There were fewer of the common local and systemic reactions following DAPTACEL™ than following the whole-cell pertussis DTP vaccine. As shown in Table 1, the 2,587 infants who enrolled to receive DAPTACEL™ at 2, 4 and 6 months of age had similar rates of reactions within 24 hours as recipients of DT and significantly lower rates than infants receiving whole-cell pertussis DTP.14 The rates of local reactions reported 1 day after any dose were lower in the DAPTACEL™ and DT groups than in the whole-cell pertussis DTP vaccine group.
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TABLE 114,15 PERCENTAGE OF INFANTS FROM SWEDEN I EFFICACY TRIAL WITH LOCAL OR SYSTEMIC REACTIONS WITHIN 24 HOURS POST-DOSE 1, 2 AND 3 OF DAPTACEL™ COMPARED WITH DT AND WHOLE-CELL PERTUSSIS DTP VACCINES
Dose 1 Dose 2 Dose 3
(2 MONTHS) (4 MONTHS) (6 MONTHS)
EVENT DAPTACEL™ DT DTP DAPTACEL™ DT DTP DAPTACEL™ DT DTP
N = 2,587 N = 2,574 N = 2,102 N = 2,563 N = 2,555 N = 2,040 N = 2,549 N = 2,538 N = 2,001
Local
Tenderness
(Any) 8.0* 8.4 59.5 10.1* 10.3 60.2 10.8* 10.0 50.0
Redness
≥2 cm 0.3* 0.3 6.0 1.0* 0.8 5.1 3.7* 2.4 6.4
Swelling
≥2 cm 0.9* 0.7 10.6 1.6* 2.0 10.0 6.3*§ 3.9 10.5
Systemic
Fever? ≥38°C
(100.4°F) 7.8* 7.6 72.3 19.1* 18.4 74.3 23.6* 22.1 65.1
Fretfulness?? 32.3 33.0 82.1 39.6 39.8 85.4 35.9 37.7 73.0
Anorexia 11.2* 10.3 39.2 9.1* 8.1 25.6 8.4* 7.7 17.5
Drowsiness 32.7* 32.0 56.9 25.9* 25.6 50.6 18.9* 20.6 37.6
Crying
≥1 hour 1.7* 1.6 11.8 2.5* 2.7 9.3 1.2* 1.0 3.3
Vomiting 6.9* 6.3 9.5 5.2** 5.8 7.4 4.3 5.2 5.5
N = Number of evaluable subjects
* p<0.001: DAPTACEL™ versus whole-cell pertussis DTP
** p<0.003: DAPTACEL™ versus whole-cell pertussis DTP
§ p<0.0001: DAPTACEL™ versus DT
? Rectal temperature
?? Statistical comparisons were not made for this variable
DT: Swedish National Biologics Laboratories
DTP: Aventis Pasteur Inc.
The incidence of serious and less common selected systemic events in this trial are summarized in Table 2.14,15
TABLE 214,15 SELECTED SYSTEMIC EVENTS: RATES PER 1,000 DOSES AFTER VACCINATION AT 2, 4, AND 6 MONTHS OF AGE
IN SWEDEN I EFFICACY TRIAL
Dose 1 Dose 2 Dose 3
(2 MONTHS) (4 MONTHS) (6 MONTHS)
EVENT DAPTACEL™ DT DTP DAPTACEL™ DT DTP DAPTACEL™ DT DTP
N = 2,587 N = 2,574 N = 2,102 N = 2,565 N = 2,556 N = 2,040 N = 2,551 N = 2,539 N = 2,002
Rectal temperature 0.39 0.78 3.33 0 0.78 3.43 0.39 1.18 6.99
≥40°C (104°F) within
48 hours of vaccination
Hypotonic- 0 0 1.9 0 0 0.49 0.39 0 0
hyporesponsive
episode within 24 hours
of vaccination
Persistent crying ≥3 1.16 0 8.09 0.39 0.39 1.96 0 0 1.0
hours within 24 hours
of vaccination
Seizures within 72 0 0.39 0 0 0.39 0.49 0 0.39 0
hours of vaccination
N = Number of evaluable subjects
One case of whole limb swelling and generalized symptoms, with resolution within 24 hours, was observed following dose 2 of DAPTACEL™. No episodes of anaphylaxis or encephalopathy were observed. No seizures were reported within 3 days of vaccination with DAPTACEL™. Over the entire study period, 6 seizures were reported in the DAPTACEL™ group, 9 in the DT group and 3 in the whole-cell pertussis DTP group, for overall rates of 2.3, 3.5 and 1.4 per 1,000 vaccinees, respectively. One case of infantile spasms was reported in the DAPTACEL™ group. There were no instances of invasive bacterial infection or death.14,15 Rates of serious adverse events that are less common than those reported in the Sweden I Efficacy Trial are not known at this time. Table 3 summarizes the safety results from the Phase II Study in Canada in children who were immunized at 2, 4, 6 and 17–18 months of age with DAPTACEL™. For adverse events, parents recorded information for 72 hours post-immunization in a diary card. Local reactions of redness and swelling were assessed and measured by the parents using a template with graded size markings. Study staff collected the information from the parents during a structured telephone interview at 2–6, 8–12, 24, 48 and 72 hours and 7 days postimmunization and recorded the information in the case report form.15,29 Local and systemic adverse events were consistently less common in DAPTACEL™ recipients at 2, 4 and 6 months of age than in those who received whole-cell pertussis DTP vaccine. Following the fourth dose, the same trends were observed, except for rates of severe redness and swelling which did not differ between the 2 vaccine groups. Rates of local reactions of redness and swelling were increased following the fourth dose compared with the first 3 doses as was mild tenderness but there was no increase in severe tenderness.
TABLE 315,29 PERCENTAGE OF CHILDREN FROM PHASE II STUDY IN CANADA WITH LOCAL OR SYSTEMIC REACTIONS WITHIN 72 HOURS OF VACCINATION WITH DAPTACEL™ AND WHOLE-CELL PERTUSSIS DTP VACCINE AT 2, 4,
6 AND 17–18 MONTHS OF AGE
Dose 1 Dose 2 Dose 3 Dose 4
(2 MONTHS) (4 MONTHS) (6 MONTHS) (18 MONTHS)
EVENT DAPTACEL™ DTP# DAPTACEL™ DTP# DAPTACEL™ DTP# DAPTACEL™ DTP#
N = 324 N = 108 N = 321 N = 106 N = 320 N = 104 N = 301 N = 97
Local
Redness
Any 12.7* 44.4 20.6* 57.5 22.2* 51.9 36.5* 55.7
≥10 mm 1.2* 13.9 7.8* 22.6 10.0* 17.3 27.9 36.1
≥35 mm 0.3* 3.7 0.3* 5.7 1.6 1.9 21.9 20.6
Swelling
Any 4.3* 23.1 4.3* 32.1 4.7* 25.0 18.6* 28.9
≥10 mm 1.9* 15.7 2.2* 21.7 3.8* 14.4 15.9* 25.8
≥35 mm 0.3* 6.5 0* 5.7 0.9* 4.8 11.3 15.5
Tenderness†
Any 10.2* 37.0 7.5* 51.9 8.8* 48.1 23.9* 86.6
Moderate + Severe 0.9* 13.0 1.2* 20.8 1.3* 17.3 3.0* 53.6
Severe 0* 4.6 0.3* 7.5 0* 4.8 0.3* 12.4
Systemic
Fever†§
Any ≥37.5°C (99.5°F) 12.0* 43.7 7.7* 50.0 14.8* 53.2 14.5* 67.9
≥38°C (100.4°F) 0.7 1.9 0* 7.8 1.2* 11.7 1.9* 17.9
≥40°C (104°F) 0.3 0 0 1.0 0 1.1 0 0
Irritabilityϒ
Any 41.0* 65.7 41.4* 68.9 40.9* 67.3 36.9* 79.4
Moderate + Severe 9.0* 18.5 6.9* 22.6 5.0* 22.1 5.0* 24.7
Severe 0 1.9 0.3 0 0 1.0 0 2.1
AnorexiaΩ
Any 16.0 22.2 9.0* 16.0 11.6* 23.1 17.6* 41.2
Moderate + Severe 1.5 3.7 0.9 2.8 1.3 1.9 2.0* 13.4
Severe 0 0 0.3 0 0 0 0 2.1
Drowsiness∇
Any 43.2 52.8 21.8* 33.0 14.4* 32.7 13.3* 29.9
Moderate + Severe 7.7 8.3 2.8* 7.5 1.3 0 1.0* 6.2
Severe 0.3 0 0 0 0 0 0 0
Crying ≥3 Hours 0.6 0.9 0.3 0.9 0 1.0 0 1.0
N = Number of evaluable subjects
# DTP: whole-cell pertussis DTP vaccine (Aventis Pasteur Limited)
* Significantly less reactogenic than whole-cell DTP vaccine, p<0.05
† Moderate = sustained cry with gentle pressure at injection site; Severe = cries when leg is moved
‡ Temperature measurements were axillary
§ Number of evaluable subjects for DAPTACEL™/DTP = 301/103, 298/102, 257/94 and 207/78 at 2, 4, 6 and 18 months, respectively ϒ Moderate = more difficulty with settling, even with cuddling; Severe = persistent crying/screaming and inability to console
Ω Moderate = missed one or two feeds; Severe = little or no intake for more than two feeds
∇ Moderate = sleeping much more than normal; Severe = sleeping most of the time with difficulty arousing
The US Bridging Study was designed, in part, to assess the safety of DAPTACEL™ in infants at 2, 4 and 6 months of age, with routinely recommended, concurrently given childhood vaccines (Haemophilus influenzae type b vaccine, OPV and hepatitis B). For adverse events, parents recorded information for 72 hours post-immunization in a diary card. Local reactions were assessed and measured by the parents. Study staff collected the information from the parents during a structured telephone interview on days 4 and 14 post-immunization and recorded the information in the case report form.15 The incidence of redness, swelling, pain or tenderness at the injection site and systemic symptoms after each dose is shown as pooled data from 2 lots of DAPTACEL™ (Lots 006 and 009) in Table 4. Fever ≥38°C (100.4°F) was observed in 9.9% – 11.9% of subjects. The incidence of severe systemic symptoms including irritability, tiredness, anorexia, rash and vomiting ranged from 0.3% – 0.6%. One afebrile seizure occurred within 24 hours post dose 2 immunization (n = 321).15
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In an ongoing study (P3T06) initiated in May 2001 and anticipated to be completed in 2004, which was designed to assess the safety of DAPTACEL™ given with routinely recommended vaccines (Haemophilus influenzae type b vaccine, IPV, hepatitis B and pneumococcal conjugate vaccine) in the US (in which 777 children have received their first dose, 350 have received their second dose and 86 their third dose with safety data still being collected from children in this study), one afebrile seizure was reported within 24 hours of receipt of dose 1.
TABLE 415 PERCENTAGE OF CHILDREN FROM US BRIDGING STUDY WITH ANY LOCAL AND SYSTEMIC REACTIONS WITHIN
72 HOURS OF VACCINATION WITH DAPTACEL™ AT 2, 4 AND 6 MONTHS OF AGE (LOTS 006 AND 009 POOLED)
Dose 1 Dose 2 Dose 3
EVENT (2 MONTHS) (4 MONTHS) (6 MONTHS)
N = 321 N = 317 N = 315
Local
Redness
Any 12.5 15.8 19.7
<1 inch 11.8 15.1 18.7
≥1 inch 0.6 0.6 1.0
Swelling
Any 14.3 15.4 17.8
<1 inch 13.7 15.1 16.2
≥1 inch 0.6 0.3 1.6
Tenderness
Any 30.5 19.6 15.9
Moderate + Severe 8.1 4.4 1.0
Severe 0 0 0
Systemic
Fever*†
Any ≥38°C (100.4°F) 11.9 9.9 9.9
≥39°C (102.2°F) 0.3 0.3 0.6
≥40°C (104°F) 0 0 0
Irritability
Any 72.0 61.2 56.2
Moderate + Severe 33.6 25.2 18.7
Severe 0.3 0.3 0
Anorexia
Any 26.2 14.8 17.8
Moderate + Severe 5.6 3.8 4.8
Severe 0 0.3 0
Drowsiness
Any 62.0 44.8 35.6
Moderate + Severe 24.0 8.5 7.3
Severe 0.6 0.3 0
Crying ≥3 Hours 0.3 0 0
N = Number of evaluable subjects
* Rectal temperature
† N = 319, 314 and 313 at 2, 4 and 6 months respectively
Moderate = discomforting enough to interfere with or limit usual daily activity
Severe = disabling, unable to perform daily activities
NIAID sponsored a multicenter Phase I/II clinical trial to compare the safety and immunogenicity of 13 acellular pertussis vaccines with a conventional whole-cell pertussis DTP vaccine in infants in the US. The common local and systemic adverse experiences, after all 3 doses, for DAPTACEL™ and the participating acellular vaccines that have subsequently been licensed in the US were generally similar in type and frequency and were reduced in comparison to the whole-cell pertussis DTP vaccine.28 Additional adverse reactions evaluated in conjunction with pertussis, diphtheria and tetanus vaccination are as follows:
• As with other aluminum-containing vaccines, a nodule may be palpable at the injection sites for several weeks. Sterile abscess formation at the site of injection has been reported.4,32
• Rarely, anaphylactic reactions (i.e., hives, swelling of the mouth, difficulty breathing, hypotension or shock) have been reported after receiving preparations containing diphtheria, tetanus and/or pertussis antigens.4 Arthus-type hypersensitivity reactions, characterized by severe local reactions (generally starting 2-8 hours after an injection), may follow receipt of tetanus toxoid. A few cases of peripheral neuropathy have been reported following tetanus toxoid administration, although the evidence is inadequate to accept or reject a causal relation.33
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A review by the Institute of Medicine (IOM) found a causal relation between tetanus toxoid and brachial neuritis and Guillain-Barré syndrome.34 The following illnesses have been reported as temporally associated with some vaccines containing tetanus toxoid: neurological complications35,36 including cochlear lesion, brachial plexus neuropathies,37 paralysis of the radial nerve,33 paralysis of the recurrent nerve, accommodation paresis and EEG disturbances with encephalopathy (with or without permanent intellectual or motor function impairment).38,39 In the differential diagnosis of polyradiculoneuropathies following administration of a vaccine containing tetanus toxoid, tetanus toxoid should be considered as a possible etiology.39 Onset of infantile spasms has occurred in infants who have recently received whole-cell pertussis DTP or DT. Analysis of data from the National Childhood Encephalopathy Study (NCES) on children with infantile spasms failed to demonstrate that receipt of DT or whole-cell pertussis DTP vaccines was causally related to infantile spasms.23,40 The incidence of onset of infantile spasms increases at 3-9 months of age, the time period in which the second and third doses of whole-cell pertussis DTP are generally given. Therefore, some cases of infantile spasms can be expected to be related by chance alone to recent receipt of whole-cell pertussis DTP.4 Persistent, inconsolable crying lasting ≥3 hours and high-pitched, unusual screaming, 1% and 0.1% respectively, after 15,752 doses of whole-cell pertussis DTP vaccine have been reported.38 Convulsions and hypotonic-hyporesponsive episodes (HHE) have each been reported to occur at a frequency of about 1:1,750 injections of whole-cell pertussis DTP.17,26,38 Most convulsions are brief, generalized and self-limited and are usually associated with fever. Neither febrile nor afebrile convulsions associated with whole-cell pertussis DTP vaccine have been shown to be associated with subsequent seizure disorder.17 Persistent, inconsolable crying ≥3 hours, convulsions and HHE have also been reported following DTaP vaccines, including DAPTACEL™.5
In another large study (Sweden II Efficacy Trial), 3 DTaP vaccines and a whole-cell pertussis DTP vaccine, none of which are licensed in the US, were evaluated to assess relative safety and efficacy.41 This study included HCPDT, a vaccine made of the same components as
DAPTACEL™ but containing twice the amount of PT and four times the amount of FHA (20 µg pertussis toxoid and 20 µg FHA). Hypotonichyporesponsive episodes (HHE) were observed following 29 (0.047%) of 61,220 doses of HCPDT; 16 (0.026%) of 61,219 doses of an acellular pertussis vaccine made by another manufacturer; and 34 (0.056%) of 60,792 doses of a whole-cell pertussis DPT vaccine. There were 4 additional cases of HHE in other studies using HCPDT vaccine for an overall rate of 33 (0.047%) in 69,525 doses.15,41 (See CONTRAINDICATIONS and PRECAUTIONS.)
Sudden Infant Death Syndrome (SIDS) has occurred in infants following administration of whole-cell pertussis DTP and DTaP. Large case-control studies of SIDS in the US have shown that receipt of whole-cell pertussis DTP was not causally related to SIDS.42,43 It should be recognized that the first 3 immunizing doses of whole-cell pertussis DTP and DTaP (including DAPTACEL™) are usually administered to infants 2-6 months of age and that approximately 85% of SIDS cases occur at ages 1-6 months with the peak incidence occurring at 6 weeks to 4 months of age. By chance alone, some cases of SIDS can be expected to follow receipt of wholecell pertussis DTP17 and acellular pertussis vaccines. A review by a committee of the IOM concluded that available evidence did not indicate a causal relation between whole-cell pertussis DTP vaccine and SIDS.23 Whole-cell pertussis DTP vaccine has been associated with acute encephalopathy.23 A 10-year follow-up to the National Childhood Encephalopathy Study (NCES) of children who experienced acute neurologic disorders in infancy concluded that serious acute neurologic illness increased the risk of chronic neurologic disease or death.44 A committee of the Institute of Medicine (IOM) has concluded that, because whole-cell pertussis DTP may cause acute neurologic illness, whole-cell pertussis DTP may also cause chronic neurologic disease in the context of the NCES report.24 However, the IOM committee concluded that the evidence was insufficient to indicate whether or not whole-cell pertussis DTP increased the overall risk of chronic neurologic disease.24 A bulging fontanel associated with increased intracranial pressure which occurred within 24 hours following whole-cell pertussis DTP immunization has been reported, although a causal relationship has not been established.45,46,47 Reporting of Adverse Events The National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act of 1986, requires physicians and other health-care providers who administer vaccines to maintain permanent vaccination records of the manufacturer and lot number of the vaccine administered 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. The Act (or statute) further requires the health-care professional to report to the Secretary of the US Department of Health and Human Services the occurrence following immunization of any events set forth in the statute or 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 DAPTACEL™ package insert.17,48 Reporting by parents or guardians of all adverse events after vaccine administration should be encouraged. Adverse events following immunization with vaccine should be reported by health-care providers to VAERS. Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a toll-free number 1-800-822-7967.48,49 Health-care providers should also report these events to the Pharmacovigilance Department, Aventis Pasteur Inc., Discovery
Drive, Swiftwater, PA 18370 or call 1-800-822-2463.
DOSAGE AND ADMINISTRATION
DAPTACEL™ is a sterile white homogenous cloudy suspension of acellular pertussis vaccine components and diphtheria and tetanus toxoids adsorbed on aluminum in a sterile isotonic sodium chloride solution and containing 2-phenoxyethanol as preservative. Inspect the vial visually for extraneous particulate matter and/or discoloration before administration. If these conditions exist, the product should not be administered.
JUST BEFORE USE, SHAKE THE VIAL WELL, until a uniform, cloudy suspension results. WITHDRAW AND INJECT A 0.5 mL DOSE. When administering a dose from a rubber-stoppered vial, do not remove either the rubber stopper or the metal seal holding it in place. Aseptic technique must be used for withdrawal of each dose.
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Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. After insertion of the needle into the muscle, aspirate to ensure that the needle has not entered a blood vessel. Administer the vaccine intramuscularly (I.M.). In children younger than 1 year (i.e., infants), the anterolateral aspect of the thigh provides the largest muscle and is the preferred site of injection. In older children, the deltoid muscle is usually large enough for I.M.
injection. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk.17 Fractional doses (doses <0.5 mL) should not be given. The effect of fractional doses on the frequency of serious adverse events and on efficacy has not been determined. Do NOT administer this product intravenously or subcutaneously. Immunization Series A 0.5 mL dose of DAPTACEL™ is approved for administration as a 4 dose series at 2, 4 and 6 months of age, at intervals of 6–8 weeks and at 17–20 months of age. (See CLINICAL PHARMACOLOGY.) The customary age for the first dose is 2 months of age, but it may be given as early as 6 weeks of age and up to the seventh birthday. The interval between the third and fourth dose should be at least 6 months. It is recommended that DAPTACEL™ be given for all doses in the series because no data on the interchangeability of DAPTACEL™ with other DTaP vaccines exist. At this time, data are insufficient to establish the frequency of adverse events following a fifth dose of DAPTACEL™ in children who have previously received 4 doses of DAPTACEL™.50 DAPTACEL™ may be used to complete the immunization series in infants who have received 1 or more doses of whole-cell pertussis DTP. However, the safety and efficacy of DAPTACEL™ in such infants have not been fully demonstrated.5 PERSONS 7 YEARS OF AGE AND OLDER SHOULD NOT BE IMMUNIZED WITH DAPTACEL™ OR ANY OTHER PERTUSSIS-CONTAINING VACCINES.18
DAPTACEL™ should not be combined through reconstitution or mixed with any other vaccine.If any recommended dose of pertussis vaccine cannot be given, DT (For Pediatric Use) should be given as needed to complete the series. Pre-term infants should be vaccinated according to their chronological age from birth.17 Interruption of the recommended schedule with a delay between doses should not interfere with the final immunity achieved with DAPTACEL™. There is no need to start the series over again, regardless of the time between doses.
Simultaneous Vaccine Administration
In clinical trials, DAPTACEL™ was routinely administered, at separate sites, concomitantly with one or more of the following vaccines:
OPV, hepatitis B vaccine and Haemophilus influenzae type b vaccine.15 No safety and immunogenicity data are currently available on the simultaneous administration of pneumococcal conjugate vaccine, MMR vaccine and varicella vaccine and no immunogenicity data are currently available on the simultaneous administration of IPV. Two afebrile seizures, occurring within 24 hours of immunization, have been reported from 2 US trials where DAPTACEL™ was given with other concomitant vaccines. (See ADVERSE REACTIONS.) When concomitant administration of other vaccines is required, they should be given with different syringes and at different injection sites. ACIP encourages routine simultaneous administration of DTaP, IPV, Haemophilus influenzae type b vaccine, pneumococcal conjugate vaccine, MMR, varicella vaccine and hepatitis B vaccine for children who are the recommended age to receive these vaccines and for whom no specific contraindications exist at the time of the visit, unless, in the judgment of the provider, complete vaccination of the child will not be compromised by administering different vaccines at different visits. Simultaneous administration is particularly
important if the child might not return for subsequent vaccinations.18 (See CLINICAL PHARMACOLOGY.) If passive immunization is needed for tetanus prophylaxis, Tetanus Immune Globulin (Human) (TIG) is the product of choice. It provides longer protection than antitoxin of animal origin and is associated with few adverse reactions. The currently recommended prophylactic dose of TIG for wounds of average severity is 250 units intramuscularly. When tetanus toxoid-containing vaccines and TIG and/or Diphtheria Antitoxin are administered concurrently, separate syringes and separate sites should be used.
HOW SUPPLIED
Vial, 1 x 1 Dose - Product No. 49281-286-01
Vial, 5 x 1 Dose - Product No. 49281-286-05
STORAGE
DAPTACEL™ should be stored at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Product which has been exposed to freezing should not be
used. Do not use after expiration date.
REFERENCES
1. Stainer DW, Scholte MJ. A simple chemically defined medium for the production of phase I Bordetella pertussis. J Gen Microbiol
1970;63:211-220.
2. Stainer DW. Production of diphtheria toxin. In: Manclark CR, ed. Proceeding of an informal consultation on the World Health
Organization requirements for diphtheria, tetanus, pertussis and combined vaccines. United States Public Health Service,
Bethesda, MD. DHHS Publication No. (FDA) 91-1174. 1991:7-11.
3. Mueller JH, Miller PA. Variable factors influencing the production of tetanus toxin. J Bacteriol 1953;67:271-277.
4. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Diphtheria, Tetanus, and Pertussis:
Recommendations for vaccine use and other preventive measures. MMWR 1991;40(RR-10):1-28.
5. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Pertussis vaccination: Use of acellular pertussis
vaccines among infants and young children. MMWR 1997;46(RR-7):1-25.
6. Plotkin SA, et al. Vaccines. 3rd ed. Philadelphia,W. B. Saunders Company. 1999:140-157,293-344,441-474.
7. Centers for Disease Control and Prevention (CDC). Notice to readers: Final 2000 reports of notifiable diseases. MMWR
2001;50(33):1-10.
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8. Atkinson W, et al, editors. Epidemiology and Prevention of Vaccine-Preventable Diseases. 6th ed.Centers for Disease Control and
Prevention (CDC); Public Health Foundation. 2000:51-72.
9. American Public Health Association (APHA). Control of Communicable Diseases Manual. 2000;(17):166-167.
10. Hardy IRB, et al. Current situation and control strategies for resurgence of diphtheria in newly independent states of the former
Soviet Union. Lancet 1996;347:1739-1744.
11. Bedson SP, et al.The prevention of whooping-cough by vaccination. A Medical Research Council Investigation. Br Med J
1951;1:1463-1471.
12. Centers for Disease Control and Prevention (CDC). Pertussis-United States,1997-2000. MMWR 2002;51(4):1-92.
13. Güris D, et al. Changing epidemiology of pertussis in the United States: Increasing reported incidence among adolescents and
adults, 1990-1996. Clin Infect Dis 1999;28:1230-1237.
14. Gustafsson L, et al. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine.
N Engl J Med 1996;6:349-355.
15. Aventis Pasteur Limited: Data on File.
16. Department of Health and Human Services, Food and Drug Administration. Biological Products; Bacterial Vaccines and Toxoids;
Implementation of Efficacy Review; Proposed Rule. Federal Register 1985; 50(240):51002-51117.
17. American Academy of Pediatrics. In: Pickering LK, ed. 2000 Red Book: Report on the Committee of Infectious Diseases. 25th ed.
Elk Grove Village, IL: American Academy of Pediatrics 2000:17,31-35,51-53,54,65,68,442-443,759-765.
18. Recommendations of the Advisory Committee on Immunization Practices (ACIP). General recommendations on immunization.
MMWR 1994;43(RR-1):1-38.
19. Expanded programme on immunization, injection and paralytic poliomyelitis. Wkly Epidem Rec 1980;5:38-40.
20. Sutter RW, et al. Attributable risk of DTP (diphtheria and tetanus toxoids and pertussis vaccine) injection in provoking paralytic
poliomyelitis during a large outbreak in Oman. J Infect Dis 1992;165:444-449.
21. Christie AB. Infectious diseases: Epidemiology and Clinical Practice. 4th ed. Edinburgh, Churchill Livingstone. 1987;2:817-825.
22. Livengood JR, et al. Family history of convulsion and use of pertussis vaccine. J Pediatr 1989;115(4):527-531.
23. Howson CP, et al. Adverse Effects of Pertussis and Rubella Vaccines, Pertussis Vaccines and CNS Disorders. Institute of Medicine
(IOM). National Academy Press,Washington, DC, 1991:7-169.
24. Institute of Medicine (IOM). DTP vaccine and chronic nervous system dysfunction: A new analysis. National Academy Press,
Washington, DC, 1994;Supplement:1-17.
25. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Update: Vaccine side effects, adverse reactions,
contraindications, and precautions. MMWR 1996;45(RR-12):1-35.
26. National Advisory Committee on Immunization (NACI): Canadian Immunization Guide, 5th ed. Minister of Public Works and
Government Services Canada. 1998:9-13,133-139.
27. Edwards KM, et al. Comparison of 13 acellular pertussis vaccines: Overview and serologic response. American Academy of
Pediatrics 1995;Supplement:548-557.
28. Decker MD, et al. Comparison of 13 acellular pertussis vaccines: Adverse reactions. Pediatr 1995;96:557-566.
29. Halperin SA et al. Adverse reactions and antibody response to four doses of acellular or whole-cell pertussis combined with
diphtheria and tetanus toxoids in the first 19 months of life. Vaccine 1996;14(18):767-772.
30. Halperin SA, et al. Safety and immunogenicity of two acellular pertussis vaccines with different pertussis toxoid and filamentous
hemagglutinin content in infants 2-6 months old. Scand J Infect Dis 1995;27:279-287.
31. Halperin SA, et al. Acellular pertussis vaccine as a booster dose for seventeen- to nineteen-month-old children immunized with
either whole cell acellular pertussis vaccine at two, four and six months of age. Pediatr Infect Dis J 1995;14:792-797.
32. Fawcett HA, Smith NP. Injection-site granuloma due to aluminum. Arch Dermatol 1984;120:1318-1322.
33. Blumstein GI, et al. Peripheral neuropathy following tetanus toxoid administration. JAMA 1966;198:1030-1031.
34. Institute of Medicine (U.S.). Adverse Effects of Pertussis and Rubella Vaccines. Howson CP, et al, editors. Washington: National
Academy Press. 1991:154-157.
35. Rutledge SL, et al. Neurological complications of immunizations. J Pediatr 1986;109:917-924.
36. Walker AM, et al. Neurologic events following diphtheria-tetanus-pertussis immunization. Pediatr 1988;81:345-349.
37. Tsairis P, et al. Natural history of brachial plexus neuropathy. Arch Neurol 1972;27:109-117.
38. Cody CL, et al. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatr
1981;68(5):650-660.
39. Schlenska GK. Unusual neurological complications following tetanus toxoid administration. J Neurol 1977;215:299-302.
40. Alderslade R, et al. The National Childhood Encephalopathy Study: a report on 1000 cases of serious neurological disorders in
infants and young children from the NCES Research Team. In: Department of Health and Social Security. Whooping cough: reports
from the Committee on the Safety of Medicines and the Joint Committee on Vaccination and Immunization. London: Her Majesty’s
Stationery Office 1981:79-169.
41. Olin P, et al. Randomized controlled trial of two-component, three-component, and five-component acellular pertussis vaccines
compared with whole-cell pertussis vaccine. Lancet 1997:1569-1577.
42. Griffin MR, et al. Risk of sudden infant death syndrome after immunization with the diphtheria-tetanus-pertussis vaccine. N Engl J
Med 1988:618-623.
43. Hoffman HJ, et al. Diphtheria-tetanus-pertussis immunization and sudden infant death: Results of the National Institute of Child
Health and Human Development cooperative epidemiological study of sudden infant death syndrome risk factors. Pediatr
1987;79(4):598-611.
44. Miller D, et al. Pertussis Immunisation and Serious Acute Neurological Illnesses in Children. Academic Department of Public Health,
St. Mary’s Hospital Medical School, University of London, 1993.
45. Jacob J, et al. Increased intracranial pressure after diphtheria, tetanus and pertussis immunization. Am J Dis Child 1979;133:217-
218.
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46. Mathur R, et al. Bulging fontanel following triple vaccine. Indian Pediatr 1981;18(6):417-418.
47. Shendurnikar N, et al. Bulging fontanel following DTP vaccine. Indian Pediatr 1986;23(11):960.
48. Centers for Disease Control and Prevention (CDC). National Childhood Vaccine Injury Act: Requirements for permanent vaccination
records and for reporting of selected events after vaccination. MMWR 1988;37(13):197-200.
49. Center for Disease Control and Prevention (CDC). Vaccine Adverse Event Reporting System – United States. MMWR 1990;39:730-
733.
50. Pichichero MD, et al. Safety and immunogenicity of six acellular pertussis vaccines and one whole-cell pertussis vaccine given as
a fifth dose in four six-year-old children. Pediatr 2000;105(1),e11:1-8.
Manufactured by: Product information
Aventis Pasteur Limited as of May 2002.
Toronto Ontario Canada
Distributed by:
Aventis Pasteur Inc.
Swiftwater PA 18370 USA Printed in Canada.
US Patents: 4500639, 4687738, 4784589, 4997915, 5444159, 5667787, 5877298. R0-0502 USA
3973
Diphtheria and Tetanus
Toxoids and Acellular
Pertussis Vaccine Adsorbed
DAPTACEL?
DESCRIPTION
DAPTACEL™, Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, for intramuscular use, manufactured by Aventis Pasteur Limited, is a sterile suspension of pertussis antigens and diphtheria and tetanus toxoids adsorbed on aluminum phosphate in a sterile isotonic sodium chloride solution. After shaking, the vaccine is a white homogeneous cloudy suspension. Each dose of
DAPTACEL™ contains the following active ingredients:
pertussis toxoid 10 µg
filamentous hemagglutinin (FHA) 5 µg
pertactin (PRN) 3 µg
fimbriae types 2 and 3 5 µg
diphtheria toxoid 15 Lf
tetanus toxoid 5 Lf
Other ingredients per dose include 3.3 mg (0.6% v/v) 2-phenoxyethanol as the preservative, 0.33 mg of aluminum as the adjuvant, ≤0.1 mg residual formaldehyde and <50 ng residual glutaraldehyde. The acellular pertussis vaccine components are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium1modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. The fimbriae types 2 and 3 are extracted from the bacterial cells and the pertussis toxin, FHA and PRN are prepared from the supernatant. These proteins are purified by sequential filtration, saltprecipitation, ultrafiltration and chromatography. Pertussis toxin is inactivated with glutaraldehyde and FHA is treated with formaldehyde. The individual antigens are adsorbed separately onto aluminum phosphate. Corynebacterium diphtheriae is grown in modified Mueller’s growth medium.2 After ammonium sulfate fractionation, the diphtheria toxin is detoxified with formalin and diafiltered. Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion.3 Tetanus toxin is detoxified with formalin and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate. The adsorbed diphtheria, tetanus and acellular pertussis components are combined in a sterile isotonic sodium chloride solution containing 2-phenoxyethanol as preservative. Both diphtheria and tetanus toxoids induce at least 2 units of antitoxin per mL in the guinea pig potency test. The potency of the acellular pertussis vaccine components is evaluated by the antibody response of immunized mice to pertussis toxin, FHA, PRN and fimbriae types 2 and 3 measured by enzyme-linked immunosorbent assay (ELISA).
CLINICAL PHARMACOLOGY
Simultaneous immunization of infants and children against diphtheria, tetanus and pertussis with conventional whole-cell pertussis DTP vaccine (Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed - For Pediatric Use) has been a routine practice in the US since the late 1940s. This has played a major role in markedly reducing disease and deaths from these infections.4 DTaP (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) vaccines were first available for use in infants in the US in 1996 and have been routinely recommended for all doses of the vaccination series for infants and children <7 years of age since 1997.5 Diphtheria Corynebacterium diphtheriae may cause both localized and generalized disease. The systemic intoxication is caused by diphtheria exotoxin, an extracellular protein of toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibody to diphtheria toxin. Both toxigenic and nontoxigenic strains of C. diphtheriae can cause disease but only strains that produce diphtheria toxin cause severe manifestations such as myocarditis and neuritis. Diphtheria is a serious disease, with the highest case-fatality rates among infants and the elderly.4,6 Prior to the widespread use of diphtheria toxoid in the late 1940s, diphtheria disease was common in the US. More than 200,000 cases, primarily among children, were reported in 1921. Approximately 5% – 10% of cases were fatal; the highest case-fatality rates were in the very young and the elderly. More recently, reported cases of diphtheria of all types declined fro m 306 in 1975 to 59 in 1979; most were cutaneous diphtheria reported from a single state. After 1979, cutaneous diphtheria was no longer reportable.4 From 1980 through 2000, only 50 cases of diphtheria were reported in the US. During the period 1980–1996, six fatal cases of diphtheria were reported. Only 1 case of diphtheria was reported each year in 1998–2000 with no fatalities.7 Of 40 reported cases with known age in 1982-1998, 63% were in persons ≥20 years of age. Most cases have occurred in unimmunized or inadequately immunized persons. Although diphtheria disease is rare in the US, it appears that C. diphtheriae continues to circulate in areas of the country with previously endemic diphtheria.8
Page 2 of 12
Diphtheria continues to occur in other parts of the world. A major epidemic of diphtheria occurred in the newly Independent States of the former Soviet Union beginning in 1990. This epidemic resulted in approximately 150,000 cases and 5,000 deaths during the years 1990-1997.9 This outbreak is believed to be due to several factors, including a lack of routine immunization of adults in these countries.10 Complete immunization significantly reduces the risk of developing diphtheria and immunized persons who develop disease have milder illness. Following adequate immunization with diphtheria toxoid, protection is thought to last for at least 10 years. Immunization does not, however, eliminate carriage of C. diphtheriae in the pharynx, nose or on the skin.
4 Tetanus
Tetanus manifests systemic toxicity primarily by neuromuscular dysfunction caused by a potent exotoxin elaborated by Clostridium tetani. Spores of C. tetani are ubiquitous. Serological tests indicate that naturally acquired immunity to tetanus toxin does not occur in the US. Thus, universal primary immunization, with subsequent maintenance of adequate antitoxin levels by means of appropriately timed boosters, is necessary to protect all age groups. Tetanus toxoid is a highly effective antigen and a completed primary series generally induces protective levels of serum antitoxin that persist for 10 years or more.4 Following routine use of tetanus toxoid in the US, the occurrence of tetanus disease decreased dramatically from 560 reported cases in 1947 to an average of 50-100 cases reported annually from the mid 1970s through the late 1990s to 35 cases in 2000.7 The casefatality rate has been relatively constant at approximately 30%. During the years 1982-1998, 52% of reported cases were among persons 60 years of age or older. In the mid to late 1990s, the age distribution of reported cases shifted to a younger age group, in part due to an increased number of cases among injection drug users in California. From 1995-1997, persons 20-59 years of age accounted for 60% of all cases, with persons 60 years of age or older accounting for only 35%. In the US, tetanus occurs almost exclusively among unvaccinated or inadequately vaccinated persons.8
Pertussis
Pertussis (whooping cough) is a disease of the respiratory tract caused by Bordetella pertussis. This gram-negative coccobacillus
produces a variety of biologically active components. The role of the different components produced by B. pertussis in either the
pathogenesis of, or immunity to, pertussis is not well understood.6 Pertussis is highly communicable (attack rates of 90% have been reported for susceptible individuals exposed to a case in the home11) and can cause severe disease, particularly among young infants. Since pertussis became a nationally reportable disease in the US in 1922, the highest number of pertussis cases (approximately 260,000) was reported in 1934. Following the introduction and widespread use of whole-cell pertussis DTP vaccine among infants and children in the mid to late 1940s, pertussis incidence gradually declined, reaching a historical low of 1,010 cases reported in 1976.12 During the 1980s and 1990s, the number of reported pertussis cases in the US has gradually increased, particularly among adolescents and adults.12,13 Improvements in the diagnosis and reporting of pertussis in older age groups is thought to have contributed, at least in part, to the increase in reported cases. The number of cases of pertussis reported among children aged 6 months to 4 years has remained stable throughout the 1990s, suggesting that protection offered by vaccination has continued with the introduction of DTaP vaccines.12 During 1997-2000, a total of 29,134 cases were reported, for an estimated average annual incidence rate of 2.7 per 100,000 population.12 Among 29,048 cases for whom age was known, 29% were aged < 1 year, 12% were aged 1-4 years, 10% were aged 5–9 years, 29% were aged 10-19 years and 20% were ≥20 years of age.12 Average annual incidence rates during 1997-2000 were highest among infants aged <1 year (55.5 cases per 100,000 population) and lower in children aged 1–4 years (5.5), children aged 5–9 years (3.6), persons aged 10-19 years (5.5) and persons aged ≥20 years (0.8).12 The severity of pertussis remains highest in infants. Of 7,203 infants <6 months of age reported as having pertussis during the period 1997-2000, 63% were hospitalized, 12% had pneumonia, 1.4% had one or more seizures, 0.2% had encephalopathy and 0.8% died.12 Atypical infection, including nonspecific symptoms of bronchitis or upper respiratory tract infection, may occur at any age but more commonly in older children and adults, including some who were previously immunized. In these cases, pertussis may not be diagnosed because classic signs, particularly the inspiratory whoop, may be absent. Older preschool-aged and school-aged children, as well as adolescents and adults who develop pertussis, may play a role in transmission to young infants.8 Concerns about the safety of whole-cell pertussis DTP vaccines prompted the development of less reactogenic DTaP vaccines that contain purified antigens of B. pertussis. The pertussis component of DTaP vaccines contains inactivated pertussis toxin and may contain one or more of FHA, PRN and fimbriae types 2 and 3. DTaP vaccines were first available for use in infants in the US in 1996 and have been routinely recommended by the Advisory Committee on Immunization Practices (ACIP) for all doses of the vaccination series for infants and children <7 years of age since 1997.5 Since 1991, 7 studies conducted in Europe and Africa have evaluated the efficacy of 8 DTaP vaccines administered to infants. The vaccines, produced by different manufacturers, contained a varying number and quantity of antigens. The derivation and formulation of the individual antigens also varied among different vaccines. The studies differed in study design and 3, including the Sweden I Efficacy
Trial (1992–1995), were randomized placebo-controlled clinical trials. Because of these and other differences, comparisons among studies should be made with caution. Within individual studies, however, the efficacy of acellular pertussis vaccines can be compared directly with that of a placebo control or whole-cell pertussis DTP. The efficacy of 3 doses of acellular pertussis vaccines in preventing moderate to severe pertussis disease was within the range expected for most whole-cell pertussis DTP vaccines. Point estimates of the efficacy of DTaP vaccines ranged from 59% - 89%.5 The effectiveness of pertussis vaccine among US children aged 7–18 months in 1998 and 1999 was calculated using the screening method. During this time, the National Immunization Survey reported 66% of children aged ≤18 months received DTaP rather than wholecell pertussis DTP.12 The screening estimate of 88% reflects the effectiveness of the overall vaccination program that used approximately two thirds DTaP and one third whole-cell pertussis DTP in children aged 7–18 months. This estimate is similar to that observed in clinical
trials for acellular pertussis vaccines. During 1997–2000, the incidence rates were highest among infants aged <1 year, lower in children aged 1–4 years and remained stable among children aged 5-9 years.12
Page 3 of 12
Efficacy of DAPTACEL™
Pertussis
A randomized, double-blinded, placebo-controlled efficacy and safety study was conducted in Sweden from 1992-1995 (Sweden I Efficacy Trial) under the sponsorship of the National Institute of Allergy and Infectious Diseases (NIAID). A total of 9,829 infants received 1 of 4 vaccines: DAPTACEL™ (n = 2,587); another investigational acellular pertussis vaccine (n = 2,566); whole-cell pertussis DTP vaccine (n = 2,102); or DT vaccine as placebo (Swedish National Bacteriological Laboratory, n = 2,574). Infants were immunized at 2, 4 and 6 months of age. The mean length of follow-up was 2 years after the third dose of vaccine. The protective efficacy of DAPTACEL™ against pertussis after 3 doses of vaccine using the World Health Organization (WHO) case definition (≥21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiologic link to a confirmed case) was 84.9% (95% confidence interval [CI] 80.1 to 88.6).14 The protective efficacy of DAPTACEL™ against mild pertussis (≥1 day of cough
with laboratory confirmation) was 77.9% (95% CI 72.6 to 82.2).15 Protection against pertussis by DAPTACEL™ was sustained for the 2-year follow-up period.14,15 In order to assess the antibody response to the pertussis antigens of DAPTACEL™ in the US population, 2 lots of DAPTACEL™, including the lot used in the Sweden I Efficacy Trial, were administered to US infants in the US Bridging Study.15 In this study, antibody responses following 3 doses of DAPTACEL™ given to US children at 2, 4 and 6 months of age were compared to those from a subset of the infants
enrolled in the Sweden I Efficacy Trial. Assays were performed in parallel on the available sera from the US and Swedish infants. Antibody responses to all the antigens were similar except for those to the PRN component. For both lots of DAPTACEL™, the geometric mean concentration (GMC) and percent response to PRN in US infants (Lot 006, n = 107; Lot 009, n = 108) were significantly lower after 3 doses of vaccine than in Swedish infants (n = 83). In a separate study performed in Canada (Phase II), in which children received 4 doses of DAPTACEL™ at 2, 4, 6 and 17–18 months of age, antibody responses following the fourth dose (n = 275) were equivalent or higher than those seen in the Swedish infants after 3 doses. While a serologic correlate of protection for pertussis has not been established, the antibody response to all antigens in North American infants after 4 doses of DAPTACEL™ at 2, 4, 6 and 17-20 months of age was comparable to that achieved in Swedish infants in whom efficacy was demonstrated after 3 doses of DTaP at 2, 4 and 6 months of age.15 Diphtheria and Tetanus In a Canadian clinical study, 324 children were enrolled to receive DAPTACEL™ at 2, 4, 6 and 17–18 months of age. The proportion of children with post-dose 3 diphtheria (n = 313) and tetanus (n = 313) antitoxin levels ≥0.01 IU/mL was 100% and ≥0.10 IU/mL was 85% and 100%, respectively.15 The proportion with post-dose 4 diphtheria (n = 296) and tetanus (n = 296) antitoxin levels ≥0.10 IU/mL was 100%.15 The efficacy of the diphtheria and tetanus toxoids used in DAPTACEL™ was determined on the basis of immunogenicity studies with a comparison to a serological correlate of protection (0.01 antitoxin units/mL) established by the Panel on Review of Bacterial Vaccines and Toxoids.16 In the US Bridging Study, for which data are only available following 3 doses, 99.2% (n = 261) achieved diphtheria antitoxin levels of ≥0.01 IU/mL, 80.6% (n = 261) achieved levels of ≥0.10 IU/mL and 100% (n = 260) achieved tetanus antitoxin levels of 0.01 U/mL and 0.10 U/mL.15 Concurrently Administered Vaccines In a clinical trial conducted in the US, DAPTACEL™ was given simultaneously with Haemophilus influenzae type b vaccine and with live oral poliovirus vaccine (OPV) at 2, 4 and 6 months of age according to local practices. Two hundred eighty-one infants received 3 doses of Haemophilus influenzae type b vaccine and 305 received 3 doses of OPV. Immune responses to these vaccines were evaluated in a subset of 258 children. One month after the third dose, 96.9% (n = 253) achieved anti-PRP antibody levels of at least 0.15 µg/mL, 82.7% (n = 216) achieved antibody levels of at least 1.0 µg/mL; and 100% (n = 178), had protective neutralizing antibody of ≥1:8 for poliovirus types 1 and 2 and 98.3% (n = 175) for poliovirus type 3.15 In the same study, hepatitis B vaccine (supplied by different manufacturers) was also given to children by different schedules. Hepatitis B vaccine was given concurrently with DAPTACEL™ at 2 and 6 months of age to a subset of infants who received a birth dose of hepatitis B vaccine. Of infants with adequate serum available for serology testing (n = 82), 97% achieved anti-HBs antibody levels ≥10 mIU/mL post dose 3.15 No immunogenicity data are available for concurrent administration of DAPTACEL™ with IPV; pneumococcal conjugate vaccine; measles, mumps and rubella vaccine (MMR) or varicella vaccine. INDICATIONS AND USAGE DAPTACEL™ is indicated for active immunization against diphtheria, tetanus and pertussis in infants and children 6 weeks through 6 years of age (prior to seventh birthday). Children who have had well-documented pertussis (culture positive for B. pertussis or epidemiologic linkage to a culture positive case) should complete the vaccination series with DT; some experts recommend including acellular pertussis vaccine as well. Although welldocumented
pertussis disease is likely to confer immunity, the duration of protection is unknown.17 DAPTACEL™ is not to be used for the treatment of B. pertussis, C. diphtheriae or C. tetani infections. When passive protection is required, Tetanus Immune Globulin and/or Diphtheria Antitoxin may also be administered at separate sites with separate needles and syringes.4 (See DOSAGE AND ADMINISTRATION.) As with any vaccine, vaccination with DAPTACEL™ may not protect 100% of susceptible individuals. CONTRAINDICATIONS This vaccine is contraindicated in children and adults seven years of age and older. Hypersensitivity to any component of the vaccine is a contraindication to further administration.5 Page 4 of 12 The following events after receipt of DAPTACEL™ are contraindications to further administration of any pertussis-containing vaccine:5 • An immediate anaphylactic reaction. Because of uncertainty as to which component of the vaccine may be responsible, no further vaccination with diphtheria, tetanus or pertussis components should be carried out. Alternatively, such individuals may be referred to an allergist for evaluation if further immunizations are to be considered. • Encephalopathy not attributable to another identifiable cause (e.g., an acute, severe central nervous system disorder occurring within 7 days after vaccination and consisting of major alterations in consciousness, unresponsiveness or generalized or focal seizures that persist more than a few hours, without recovery within 24 hours). In such cases, DT vaccine should be administered for the remaining doses in the vaccination schedule. The decision to administer or delay vaccination because of a current or recent febrile illness depends on the severity of symptoms and on the etiology of the disease. According to the ACIP, all vaccines can be administered to persons with mild illness such as diarrhea, mild upper-respiratory infection with or without low-grade fever, or other low-grade febrile illness.17,18 However, children with moderate or serious illness should not be immunized until recovered.4 Elective immunization procedures should be deferred during an outbreak of poliomyelitis because of the risk of provoking paralysis.19,20,21
WARNINGS
The stopper to the vial of this product contains dry natural latex rubber that may cause allergic reactions. If any of the following events occur within the specified period after administration of a whole-cell pertussis DTP or DTaP vaccine, providers and parents should evaluate the risks and benefits of subsequent doses of whole-cell pertussis DTP or DTaP vaccines:5 • Temperature of ≥40.5°C (105°F) within 48 hours, not attributable to another identifiable cause. • Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours. • Persistent crying lasting ≥3 hours within 48 hours. • Convulsions with or without fever within 3 days. When a decision is made to withhold pertussis vaccine, immunization with DT vaccine should be continued.4 Because of the risk of hemorrhage, DAPTACEL™ should not be given to children with any coagulation disorder, including thrombocytopenia, which would contraindicate intramuscular injection unless the potential benefit clearly outweighs the risk of administration. Studies suggest that, when given whole-cell pertussis DTP vaccine, infants and children with a history of convulsions in first-degree family members have a 2.4-fold increased risk for neurologic events.22 However, ACIP has concluded that a history of convulsions or other central nervous system disorders in parents or siblings is not a contraindication to pertussis vaccination and that children with such family histories should receive DTaP vaccines according to the recommended schedule.4,17,18 If an infant or young child with a personal or family history of febrile or non-febrile convulsions is to be immunized, acetaminophen or other appropriate antipyretic should be given at the time of DTaP vaccination and for the ensuing 24 hours according to the respective package insert recommended dosage to reduce the possibility of post-vaccination fever.4,17,18 A committee of the Institute of Medicine (IOM) has concluded that the evidence is consistent with a causal relationship between wholecell pertussis DTP vaccine and acute neurologic illness and, under special circumstances, between whole-cell pertussis DTP vaccine and chronic neurologic disease in the context of the National Childhood Encephalopathy Study (NCES) report.23,24 However, the IOM committee concluded that the evidence was insufficient to determine whether whole-cell pertussis DTP vaccine increased the overall risk of chronic neurologic disease.24 Acute encephalopathy (with or without permanent neurological injury) or permanent neurological
injury has not been reported following administration of DAPTACEL™ but the experience with this vaccine is insufficient to rule this out.
(See ADVERSE REACTIONS.)
Infants and children with recognized possible or potential underlying neurologic conditions seem to be at enhanced risk for the appearance of manifestations of the underlying neurologic disorder within 2 or 3 days following whole-cell pertussis DTP vaccine immunization.4 Whether to administer DAPTACEL™ to children with proven or suspected underlying neurologic disorders must be decided on an individual basis after consideration of the risks and benefits. An important consideration includes the current local incidence of pertussis. The ACIP has issued guidelines for such children.25 PRECAUTIONS
General Care is to be taken by the health-care provider for the safe and effective use of this vaccine. Epinephrine Hydrochloride Solution (1:1,000), other appropriate agents and equipment must be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. Health-care providers must be familiar with current recommendations for the initial management of anaphylaxis in non-hospital settings, including proper airway management.17,26
Before an injection of any vaccine, all known precautions should be taken to prevent adverse reactions. This includes a review of the patient’s history with respect to possible sensitivity to the vaccine, similar vaccines or to dry natural latex rubber (see WARNINGS),
previous immunization history, current health status (see CONTRAINDICATIONS) and a current knowledge of the literature concerning the use of the vaccine under consideration including the nature of adverse events that may follow its use. The expected immune response to DAPTACEL™ may not be obtained in immunosuppressed persons.4 Pertussis-containing vaccines are not contraindicated in persons with HIV infection.17 Special care should be taken to ensure that the injection does not enter a blood vessel. A separate, sterile syringe and needle or a sterile disposable unit should be used for each patient to prevent transmission of hepatitis or other infectious agents from person to person. Needles should not be recapped but should be disposed of according to biohazard waste guidelines.
Page 5 of 12
Information for Vaccine Recipients and Parents/Guardians Before administration of this vaccine, health-care personnel should inform the parent, guardian or other responsible adult of the benefits and risks of the vaccine and the importance of completing the immunization series unless a contraindication to further immunization exists. (See ADVERSE REACTIONS and WARNINGS.)
The physician should inform the parent or guardian about the potential for adverse reactions that have been temporally associated with DAPTACEL™ and other pertussis-containing vaccines. The health-care provider should provide the Vaccine Information Statements (VIS) which are required by the National Childhood Vaccine Injury Act of 1986 to be given with each immunization. The parent or guardian should be instructed to report any serious adverse reactions to their health-care provider. IT IS EXTREMELY IMPORTANT WHEN A CHILD RETURNS FOR THE NEXT DOSE IN THE SERIES THAT THE PARENT OR GUARDIAN SHOULD BE QUESTIONED CONCERNING ANY SYMPTOMS AND/OR SIGNS OF AN ADVERSE REACTION AFTER THE PREVIOUS DOSE OF VACCINE. (See CONTRAINDICATIONS and ADVERSE REACTIONS.)
Adverse events following immunization should be reported by health-care providers to the Vaccine Adverse Events Reporting System (VAERS). (See ADVERSE REACTIONS, Reporting of Adverse Events.) Drug Interactions As with other intramuscular (I.M.) injections, use with caution in patients on anticoagulant therapy. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines. Although no specific studies with pertussis vaccine are available, if immunosuppressive therapy is to be soon discontinued, it seems reasonable to defer immunization until the patient has been off therapy for one month; otherwise, the patient should be vaccinated while still on therapy.4 If DAPTACEL™ is administered to persons with an immunodeficiency disorder, on immunosuppressive therapy or after a recent injection of immune globulin, an adequate immunologic response may not occur.
For information regarding simultaneous administration with other vaccines refer to DOSAGE AND ADMINISTRATION.
If passive immunization is needed for tetanus or diphtheria prophylaxis, Tetanus Immune Globulin (Human) (TIG), or Diphtheria Antitoxin,if used, should be given in a separate site, with a separate needle and syringe.18 Carcinogenesis, Mutagenesis, Impairment of Fertility DAPTACEL™ has not been evaluated for its carcinogenic or mutagenic potential or impairment of fertility.
Pregnancy Category C
Animal reproduction studies have not been conducted with DAPTACEL™. It is not known whether DAPTACEL™ can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. DAPTACEL™ is NOT recommended for use in a pregnant woman.
Geriatric Use
This product is NOT recommended for use in adult populations.
Pediatric Use
SAFETY AND EFFECTIVENESS OF DAPTACEL™ IN INFANTS BELOW 6 WEEKS OF AGE HAVE NOT BEEN ESTABLISHED. (See DOSAGE AND ADMINISTRATION.)
THIS VACCINE IS NOT RECOMMENDED FOR PERSONS 7 YEARS OF AGE OR OLDER. Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) is to be used in individuals 7 years of age or older. ADVERSE REACTIONS Over 11,400 doses of DAPTACEL™ have been administered to infants and toddlers in 6 clinical studies. In all, 3,694 children received a total of 3 doses and 476 children received 4 doses of DAPTACEL™.14,15,27,28,29,30,31 In the Sweden I Efficacy Trial, DAPTACEL™ was compared with DT and a whole-cell pertussis DTP vaccine. A standard diary card was kept for 14 days after each dose and follow-up telephone calls were made 1 and 14 days after each injection. Telephone calls were made monthly to monitor the occurrence of severe events and/or hospitalizations for the 2 months after the last injection. There were fewer of the common local and systemic reactions following DAPTACEL™ than following the whole-cell pertussis DTP vaccine. As shown in Table 1, the 2,587 infants who enrolled to receive DAPTACEL™ at 2, 4 and 6 months of age had similar rates of reactions within 24 hours as recipients of DT and significantly lower rates than infants receiving whole-cell pertussis DTP.14 The rates of local reactions reported 1 day after any dose were lower in the DAPTACEL™ and DT groups than in the whole-cell pertussis DTP vaccine group.
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TABLE 114,15 PERCENTAGE OF INFANTS FROM SWEDEN I EFFICACY TRIAL WITH LOCAL OR SYSTEMIC REACTIONS WITHIN 24 HOURS POST-DOSE 1, 2 AND 3 OF DAPTACEL™ COMPARED WITH DT AND WHOLE-CELL PERTUSSIS DTP VACCINES
Dose 1 Dose 2 Dose 3
(2 MONTHS) (4 MONTHS) (6 MONTHS)
EVENT DAPTACEL™ DT DTP DAPTACEL™ DT DTP DAPTACEL™ DT DTP
N = 2,587 N = 2,574 N = 2,102 N = 2,563 N = 2,555 N = 2,040 N = 2,549 N = 2,538 N = 2,001
Local
Tenderness
(Any) 8.0* 8.4 59.5 10.1* 10.3 60.2 10.8* 10.0 50.0
Redness
≥2 cm 0.3* 0.3 6.0 1.0* 0.8 5.1 3.7* 2.4 6.4
Swelling
≥2 cm 0.9* 0.7 10.6 1.6* 2.0 10.0 6.3*§ 3.9 10.5
Systemic
Fever? ≥38°C
(100.4°F) 7.8* 7.6 72.3 19.1* 18.4 74.3 23.6* 22.1 65.1
Fretfulness?? 32.3 33.0 82.1 39.6 39.8 85.4 35.9 37.7 73.0
Anorexia 11.2* 10.3 39.2 9.1* 8.1 25.6 8.4* 7.7 17.5
Drowsiness 32.7* 32.0 56.9 25.9* 25.6 50.6 18.9* 20.6 37.6
Crying
≥1 hour 1.7* 1.6 11.8 2.5* 2.7 9.3 1.2* 1.0 3.3
Vomiting 6.9* 6.3 9.5 5.2** 5.8 7.4 4.3 5.2 5.5
N = Number of evaluable subjects
* p<0.001: DAPTACEL™ versus whole-cell pertussis DTP
** p<0.003: DAPTACEL™ versus whole-cell pertussis DTP
§ p<0.0001: DAPTACEL™ versus DT
? Rectal temperature
?? Statistical comparisons were not made for this variable
DT: Swedish National Biologics Laboratories
DTP: Aventis Pasteur Inc.
The incidence of serious and less common selected systemic events in this trial are summarized in Table 2.14,15
TABLE 214,15 SELECTED SYSTEMIC EVENTS: RATES PER 1,000 DOSES AFTER VACCINATION AT 2, 4, AND 6 MONTHS OF AGE
IN SWEDEN I EFFICACY TRIAL
Dose 1 Dose 2 Dose 3
(2 MONTHS) (4 MONTHS) (6 MONTHS)
EVENT DAPTACEL™ DT DTP DAPTACEL™ DT DTP DAPTACEL™ DT DTP
N = 2,587 N = 2,574 N = 2,102 N = 2,565 N = 2,556 N = 2,040 N = 2,551 N = 2,539 N = 2,002
Rectal temperature 0.39 0.78 3.33 0 0.78 3.43 0.39 1.18 6.99
≥40°C (104°F) within
48 hours of vaccination
Hypotonic- 0 0 1.9 0 0 0.49 0.39 0 0
hyporesponsive
episode within 24 hours
of vaccination
Persistent crying ≥3 1.16 0 8.09 0.39 0.39 1.96 0 0 1.0
hours within 24 hours
of vaccination
Seizures within 72 0 0.39 0 0 0.39 0.49 0 0.39 0
hours of vaccination
N = Number of evaluable subjects
One case of whole limb swelling and generalized symptoms, with resolution within 24 hours, was observed following dose 2 of DAPTACEL™. No episodes of anaphylaxis or encephalopathy were observed. No seizures were reported within 3 days of vaccination with DAPTACEL™. Over the entire study period, 6 seizures were reported in the DAPTACEL™ group, 9 in the DT group and 3 in the whole-cell pertussis DTP group, for overall rates of 2.3, 3.5 and 1.4 per 1,000 vaccinees, respectively. One case of infantile spasms was reported in the DAPTACEL™ group. There were no instances of invasive bacterial infection or death.14,15 Rates of serious adverse events that are less common than those reported in the Sweden I Efficacy Trial are not known at this time. Table 3 summarizes the safety results from the Phase II Study in Canada in children who were immunized at 2, 4, 6 and 17–18 months of age with DAPTACEL™. For adverse events, parents recorded information for 72 hours post-immunization in a diary card. Local reactions of redness and swelling were assessed and measured by the parents using a template with graded size markings. Study staff collected the information from the parents during a structured telephone interview at 2–6, 8–12, 24, 48 and 72 hours and 7 days postimmunization and recorded the information in the case report form.15,29 Local and systemic adverse events were consistently less common in DAPTACEL™ recipients at 2, 4 and 6 months of age than in those who received whole-cell pertussis DTP vaccine. Following the fourth dose, the same trends were observed, except for rates of severe redness and swelling which did not differ between the 2 vaccine groups. Rates of local reactions of redness and swelling were increased following the fourth dose compared with the first 3 doses as was mild tenderness but there was no increase in severe tenderness.
TABLE 315,29 PERCENTAGE OF CHILDREN FROM PHASE II STUDY IN CANADA WITH LOCAL OR SYSTEMIC REACTIONS WITHIN 72 HOURS OF VACCINATION WITH DAPTACEL™ AND WHOLE-CELL PERTUSSIS DTP VACCINE AT 2, 4,
6 AND 17–18 MONTHS OF AGE
Dose 1 Dose 2 Dose 3 Dose 4
(2 MONTHS) (4 MONTHS) (6 MONTHS) (18 MONTHS)
EVENT DAPTACEL™ DTP# DAPTACEL™ DTP# DAPTACEL™ DTP# DAPTACEL™ DTP#
N = 324 N = 108 N = 321 N = 106 N = 320 N = 104 N = 301 N = 97
Local
Redness
Any 12.7* 44.4 20.6* 57.5 22.2* 51.9 36.5* 55.7
≥10 mm 1.2* 13.9 7.8* 22.6 10.0* 17.3 27.9 36.1
≥35 mm 0.3* 3.7 0.3* 5.7 1.6 1.9 21.9 20.6
Swelling
Any 4.3* 23.1 4.3* 32.1 4.7* 25.0 18.6* 28.9
≥10 mm 1.9* 15.7 2.2* 21.7 3.8* 14.4 15.9* 25.8
≥35 mm 0.3* 6.5 0* 5.7 0.9* 4.8 11.3 15.5
Tenderness†
Any 10.2* 37.0 7.5* 51.9 8.8* 48.1 23.9* 86.6
Moderate + Severe 0.9* 13.0 1.2* 20.8 1.3* 17.3 3.0* 53.6
Severe 0* 4.6 0.3* 7.5 0* 4.8 0.3* 12.4
Systemic
Fever†§
Any ≥37.5°C (99.5°F) 12.0* 43.7 7.7* 50.0 14.8* 53.2 14.5* 67.9
≥38°C (100.4°F) 0.7 1.9 0* 7.8 1.2* 11.7 1.9* 17.9
≥40°C (104°F) 0.3 0 0 1.0 0 1.1 0 0
Irritabilityϒ
Any 41.0* 65.7 41.4* 68.9 40.9* 67.3 36.9* 79.4
Moderate + Severe 9.0* 18.5 6.9* 22.6 5.0* 22.1 5.0* 24.7
Severe 0 1.9 0.3 0 0 1.0 0 2.1
AnorexiaΩ
Any 16.0 22.2 9.0* 16.0 11.6* 23.1 17.6* 41.2
Moderate + Severe 1.5 3.7 0.9 2.8 1.3 1.9 2.0* 13.4
Severe 0 0 0.3 0 0 0 0 2.1
Drowsiness∇
Any 43.2 52.8 21.8* 33.0 14.4* 32.7 13.3* 29.9
Moderate + Severe 7.7 8.3 2.8* 7.5 1.3 0 1.0* 6.2
Severe 0.3 0 0 0 0 0 0 0
Crying ≥3 Hours 0.6 0.9 0.3 0.9 0 1.0 0 1.0
N = Number of evaluable subjects
# DTP: whole-cell pertussis DTP vaccine (Aventis Pasteur Limited)
* Significantly less reactogenic than whole-cell DTP vaccine, p<0.05
† Moderate = sustained cry with gentle pressure at injection site; Severe = cries when leg is moved
‡ Temperature measurements were axillary
§ Number of evaluable subjects for DAPTACEL™/DTP = 301/103, 298/102, 257/94 and 207/78 at 2, 4, 6 and 18 months, respectively ϒ Moderate = more difficulty with settling, even with cuddling; Severe = persistent crying/screaming and inability to console
Ω Moderate = missed one or two feeds; Severe = little or no intake for more than two feeds
∇ Moderate = sleeping much more than normal; Severe = sleeping most of the time with difficulty arousing
The US Bridging Study was designed, in part, to assess the safety of DAPTACEL™ in infants at 2, 4 and 6 months of age, with routinely recommended, concurrently given childhood vaccines (Haemophilus influenzae type b vaccine, OPV and hepatitis B). For adverse events, parents recorded information for 72 hours post-immunization in a diary card. Local reactions were assessed and measured by the parents. Study staff collected the information from the parents during a structured telephone interview on days 4 and 14 post-immunization and recorded the information in the case report form.15 The incidence of redness, swelling, pain or tenderness at the injection site and systemic symptoms after each dose is shown as pooled data from 2 lots of DAPTACEL™ (Lots 006 and 009) in Table 4. Fever ≥38°C (100.4°F) was observed in 9.9% – 11.9% of subjects. The incidence of severe systemic symptoms including irritability, tiredness, anorexia, rash and vomiting ranged from 0.3% – 0.6%. One afebrile seizure occurred within 24 hours post dose 2 immunization (n = 321).15
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Page 8 of 12
In an ongoing study (P3T06) initiated in May 2001 and anticipated to be completed in 2004, which was designed to assess the safety of DAPTACEL™ given with routinely recommended vaccines (Haemophilus influenzae type b vaccine, IPV, hepatitis B and pneumococcal conjugate vaccine) in the US (in which 777 children have received their first dose, 350 have received their second dose and 86 their third dose with safety data still being collected from children in this study), one afebrile seizure was reported within 24 hours of receipt of dose 1.
TABLE 415 PERCENTAGE OF CHILDREN FROM US BRIDGING STUDY WITH ANY LOCAL AND SYSTEMIC REACTIONS WITHIN
72 HOURS OF VACCINATION WITH DAPTACEL™ AT 2, 4 AND 6 MONTHS OF AGE (LOTS 006 AND 009 POOLED)
Dose 1 Dose 2 Dose 3
EVENT (2 MONTHS) (4 MONTHS) (6 MONTHS)
N = 321 N = 317 N = 315
Local
Redness
Any 12.5 15.8 19.7
<1 inch 11.8 15.1 18.7
≥1 inch 0.6 0.6 1.0
Swelling
Any 14.3 15.4 17.8
<1 inch 13.7 15.1 16.2
≥1 inch 0.6 0.3 1.6
Tenderness
Any 30.5 19.6 15.9
Moderate + Severe 8.1 4.4 1.0
Severe 0 0 0
Systemic
Fever*†
Any ≥38°C (100.4°F) 11.9 9.9 9.9
≥39°C (102.2°F) 0.3 0.3 0.6
≥40°C (104°F) 0 0 0
Irritability
Any 72.0 61.2 56.2
Moderate + Severe 33.6 25.2 18.7
Severe 0.3 0.3 0
Anorexia
Any 26.2 14.8 17.8
Moderate + Severe 5.6 3.8 4.8
Severe 0 0.3 0
Drowsiness
Any 62.0 44.8 35.6
Moderate + Severe 24.0 8.5 7.3
Severe 0.6 0.3 0
Crying ≥3 Hours 0.3 0 0
N = Number of evaluable subjects
* Rectal temperature
† N = 319, 314 and 313 at 2, 4 and 6 months respectively
Moderate = discomforting enough to interfere with or limit usual daily activity
Severe = disabling, unable to perform daily activities
NIAID sponsored a multicenter Phase I/II clinical trial to compare the safety and immunogenicity of 13 acellular pertussis vaccines with a conventional whole-cell pertussis DTP vaccine in infants in the US. The common local and systemic adverse experiences, after all 3 doses, for DAPTACEL™ and the participating acellular vaccines that have subsequently been licensed in the US were generally similar in type and frequency and were reduced in comparison to the whole-cell pertussis DTP vaccine.28 Additional adverse reactions evaluated in conjunction with pertussis, diphtheria and tetanus vaccination are as follows:
• As with other aluminum-containing vaccines, a nodule may be palpable at the injection sites for several weeks. Sterile abscess formation at the site of injection has been reported.4,32
• Rarely, anaphylactic reactions (i.e., hives, swelling of the mouth, difficulty breathing, hypotension or shock) have been reported after receiving preparations containing diphtheria, tetanus and/or pertussis antigens.4 Arthus-type hypersensitivity reactions, characterized by severe local reactions (generally starting 2-8 hours after an injection), may follow receipt of tetanus toxoid. A few cases of peripheral neuropathy have been reported following tetanus toxoid administration, although the evidence is inadequate to accept or reject a causal relation.33
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A review by the Institute of Medicine (IOM) found a causal relation between tetanus toxoid and brachial neuritis and Guillain-Barré syndrome.34 The following illnesses have been reported as temporally associated with some vaccines containing tetanus toxoid: neurological complications35,36 including cochlear lesion, brachial plexus neuropathies,37 paralysis of the radial nerve,33 paralysis of the recurrent nerve, accommodation paresis and EEG disturbances with encephalopathy (with or without permanent intellectual or motor function impairment).38,39 In the differential diagnosis of polyradiculoneuropathies following administration of a vaccine containing tetanus toxoid, tetanus toxoid should be considered as a possible etiology.39 Onset of infantile spasms has occurred in infants who have recently received whole-cell pertussis DTP or DT. Analysis of data from the National Childhood Encephalopathy Study (NCES) on children with infantile spasms failed to demonstrate that receipt of DT or whole-cell pertussis DTP vaccines was causally related to infantile spasms.23,40 The incidence of onset of infantile spasms increases at 3-9 months of age, the time period in which the second and third doses of whole-cell pertussis DTP are generally given. Therefore, some cases of infantile spasms can be expected to be related by chance alone to recent receipt of whole-cell pertussis DTP.4 Persistent, inconsolable crying lasting ≥3 hours and high-pitched, unusual screaming, 1% and 0.1% respectively, after 15,752 doses of whole-cell pertussis DTP vaccine have been reported.38 Convulsions and hypotonic-hyporesponsive episodes (HHE) have each been reported to occur at a frequency of about 1:1,750 injections of whole-cell pertussis DTP.17,26,38 Most convulsions are brief, generalized and self-limited and are usually associated with fever. Neither febrile nor afebrile convulsions associated with whole-cell pertussis DTP vaccine have been shown to be associated with subsequent seizure disorder.17 Persistent, inconsolable crying ≥3 hours, convulsions and HHE have also been reported following DTaP vaccines, including DAPTACEL™.5
In another large study (Sweden II Efficacy Trial), 3 DTaP vaccines and a whole-cell pertussis DTP vaccine, none of which are licensed in the US, were evaluated to assess relative safety and efficacy.41 This study included HCPDT, a vaccine made of the same components as
DAPTACEL™ but containing twice the amount of PT and four times the amount of FHA (20 µg pertussis toxoid and 20 µg FHA). Hypotonichyporesponsive episodes (HHE) were observed following 29 (0.047%) of 61,220 doses of HCPDT; 16 (0.026%) of 61,219 doses of an acellular pertussis vaccine made by another manufacturer; and 34 (0.056%) of 60,792 doses of a whole-cell pertussis DPT vaccine. There were 4 additional cases of HHE in other studies using HCPDT vaccine for an overall rate of 33 (0.047%) in 69,525 doses.15,41 (See CONTRAINDICATIONS and PRECAUTIONS.)
Sudden Infant Death Syndrome (SIDS) has occurred in infants following administration of whole-cell pertussis DTP and DTaP. Large case-control studies of SIDS in the US have shown that receipt of whole-cell pertussis DTP was not causally related to SIDS.42,43 It should be recognized that the first 3 immunizing doses of whole-cell pertussis DTP and DTaP (including DAPTACEL™) are usually administered to infants 2-6 months of age and that approximately 85% of SIDS cases occur at ages 1-6 months with the peak incidence occurring at 6 weeks to 4 months of age. By chance alone, some cases of SIDS can be expected to follow receipt of wholecell pertussis DTP17 and acellular pertussis vaccines. A review by a committee of the IOM concluded that available evidence did not indicate a causal relation between whole-cell pertussis DTP vaccine and SIDS.23 Whole-cell pertussis DTP vaccine has been associated with acute encephalopathy.23 A 10-year follow-up to the National Childhood Encephalopathy Study (NCES) of children who experienced acute neurologic disorders in infancy concluded that serious acute neurologic illness increased the risk of chronic neurologic disease or death.44 A committee of the Institute of Medicine (IOM) has concluded that, because whole-cell pertussis DTP may cause acute neurologic illness, whole-cell pertussis DTP may also cause chronic neurologic disease in the context of the NCES report.24 However, the IOM committee concluded that the evidence was insufficient to indicate whether or not whole-cell pertussis DTP increased the overall risk of chronic neurologic disease.24 A bulging fontanel associated with increased intracranial pressure which occurred within 24 hours following whole-cell pertussis DTP immunization has been reported, although a causal relationship has not been established.45,46,47 Reporting of Adverse Events The National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act of 1986, requires physicians and other health-care providers who administer vaccines to maintain permanent vaccination records of the manufacturer and lot number of the vaccine administered 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. The Act (or statute) further requires the health-care professional to report to the Secretary of the US Department of Health and Human Services the occurrence following immunization of any events set forth in the statute or 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 DAPTACEL™ package insert.17,48 Reporting by parents or guardians of all adverse events after vaccine administration should be encouraged. Adverse events following immunization with vaccine should be reported by health-care providers to VAERS. Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a toll-free number 1-800-822-7967.48,49 Health-care providers should also report these events to the Pharmacovigilance Department, Aventis Pasteur Inc., Discovery
Drive, Swiftwater, PA 18370 or call 1-800-822-2463.
DOSAGE AND ADMINISTRATION
DAPTACEL™ is a sterile white homogenous cloudy suspension of acellular pertussis vaccine components and diphtheria and tetanus toxoids adsorbed on aluminum in a sterile isotonic sodium chloride solution and containing 2-phenoxyethanol as preservative. Inspect the vial visually for extraneous particulate matter and/or discoloration before administration. If these conditions exist, the product should not be administered.
JUST BEFORE USE, SHAKE THE VIAL WELL, until a uniform, cloudy suspension results. WITHDRAW AND INJECT A 0.5 mL DOSE. When administering a dose from a rubber-stoppered vial, do not remove either the rubber stopper or the metal seal holding it in place. Aseptic technique must be used for withdrawal of each dose.
Page 10 of 12
Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. After insertion of the needle into the muscle, aspirate to ensure that the needle has not entered a blood vessel. Administer the vaccine intramuscularly (I.M.). In children younger than 1 year (i.e., infants), the anterolateral aspect of the thigh provides the largest muscle and is the preferred site of injection. In older children, the deltoid muscle is usually large enough for I.M.
injection. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk.17 Fractional doses (doses <0.5 mL) should not be given. The effect of fractional doses on the frequency of serious adverse events and on efficacy has not been determined. Do NOT administer this product intravenously or subcutaneously. Immunization Series A 0.5 mL dose of DAPTACEL™ is approved for administration as a 4 dose series at 2, 4 and 6 months of age, at intervals of 6–8 weeks and at 17–20 months of age. (See CLINICAL PHARMACOLOGY.) The customary age for the first dose is 2 months of age, but it may be given as early as 6 weeks of age and up to the seventh birthday. The interval between the third and fourth dose should be at least 6 months. It is recommended that DAPTACEL™ be given for all doses in the series because no data on the interchangeability of DAPTACEL™ with other DTaP vaccines exist. At this time, data are insufficient to establish the frequency of adverse events following a fifth dose of DAPTACEL™ in children who have previously received 4 doses of DAPTACEL™.50 DAPTACEL™ may be used to complete the immunization series in infants who have received 1 or more doses of whole-cell pertussis DTP. However, the safety and efficacy of DAPTACEL™ in such infants have not been fully demonstrated.5 PERSONS 7 YEARS OF AGE AND OLDER SHOULD NOT BE IMMUNIZED WITH DAPTACEL™ OR ANY OTHER PERTUSSIS-CONTAINING VACCINES.18
DAPTACEL™ should not be combined through reconstitution or mixed with any other vaccine.If any recommended dose of pertussis vaccine cannot be given, DT (For Pediatric Use) should be given as needed to complete the series. Pre-term infants should be vaccinated according to their chronological age from birth.17 Interruption of the recommended schedule with a delay between doses should not interfere with the final immunity achieved with DAPTACEL™. There is no need to start the series over again, regardless of the time between doses.
Simultaneous Vaccine Administration
In clinical trials, DAPTACEL™ was routinely administered, at separate sites, concomitantly with one or more of the following vaccines:
OPV, hepatitis B vaccine and Haemophilus influenzae type b vaccine.15 No safety and immunogenicity data are currently available on the simultaneous administration of pneumococcal conjugate vaccine, MMR vaccine and varicella vaccine and no immunogenicity data are currently available on the simultaneous administration of IPV. Two afebrile seizures, occurring within 24 hours of immunization, have been reported from 2 US trials where DAPTACEL™ was given with other concomitant vaccines. (See ADVERSE REACTIONS.) When concomitant administration of other vaccines is required, they should be given with different syringes and at different injection sites. ACIP encourages routine simultaneous administration of DTaP, IPV, Haemophilus influenzae type b vaccine, pneumococcal conjugate vaccine, MMR, varicella vaccine and hepatitis B vaccine for children who are the recommended age to receive these vaccines and for whom no specific contraindications exist at the time of the visit, unless, in the judgment of the provider, complete vaccination of the child will not be compromised by administering different vaccines at different visits. Simultaneous administration is particularly
important if the child might not return for subsequent vaccinations.18 (See CLINICAL PHARMACOLOGY.) If passive immunization is needed for tetanus prophylaxis, Tetanus Immune Globulin (Human) (TIG) is the product of choice. It provides longer protection than antitoxin of animal origin and is associated with few adverse reactions. The currently recommended prophylactic dose of TIG for wounds of average severity is 250 units intramuscularly. When tetanus toxoid-containing vaccines and TIG and/or Diphtheria Antitoxin are administered concurrently, separate syringes and separate sites should be used.
HOW SUPPLIED
Vial, 1 x 1 Dose - Product No. 49281-286-01
Vial, 5 x 1 Dose - Product No. 49281-286-05
STORAGE
DAPTACEL™ should be stored at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Product which has been exposed to freezing should not be
used. Do not use after expiration date.
REFERENCES
1. Stainer DW, Scholte MJ. A simple chemically defined medium for the production of phase I Bordetella pertussis. J Gen Microbiol
1970;63:211-220.
2. Stainer DW. Production of diphtheria toxin. In: Manclark CR, ed. Proceeding of an informal consultation on the World Health
Organization requirements for diphtheria, tetanus, pertussis and combined vaccines. United States Public Health Service,
Bethesda, MD. DHHS Publication No. (FDA) 91-1174. 1991:7-11.
3. Mueller JH, Miller PA. Variable factors influencing the production of tetanus toxin. J Bacteriol 1953;67:271-277.
4. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Diphtheria, Tetanus, and Pertussis:
Recommendations for vaccine use and other preventive measures. MMWR 1991;40(RR-10):1-28.
5. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Pertussis vaccination: Use of acellular pertussis
vaccines among infants and young children. MMWR 1997;46(RR-7):1-25.
6. Plotkin SA, et al. Vaccines. 3rd ed. Philadelphia,W. B. Saunders Company. 1999:140-157,293-344,441-474.
7. Centers for Disease Control and Prevention (CDC). Notice to readers: Final 2000 reports of notifiable diseases. MMWR
2001;50(33):1-10.
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8. Atkinson W, et al, editors. Epidemiology and Prevention of Vaccine-Preventable Diseases. 6th ed.Centers for Disease Control and
Prevention (CDC); Public Health Foundation. 2000:51-72.
9. American Public Health Association (APHA). Control of Communicable Diseases Manual. 2000;(17):166-167.
10. Hardy IRB, et al. Current situation and control strategies for resurgence of diphtheria in newly independent states of the former
Soviet Union. Lancet 1996;347:1739-1744.
11. Bedson SP, et al.The prevention of whooping-cough by vaccination. A Medical Research Council Investigation. Br Med J
1951;1:1463-1471.
12. Centers for Disease Control and Prevention (CDC). Pertussis-United States,1997-2000. MMWR 2002;51(4):1-92.
13. Güris D, et al. Changing epidemiology of pertussis in the United States: Increasing reported incidence among adolescents and
adults, 1990-1996. Clin Infect Dis 1999;28:1230-1237.
14. Gustafsson L, et al. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine.
N Engl J Med 1996;6:349-355.
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Manufactured by: Product information
Aventis Pasteur Limited as of May 2002.
Toronto Ontario Canada
Distributed by:
Aventis Pasteur Inc.
Swiftwater PA 18370 USA Printed in Canada.
US Patents: 4500639, 4687738, 4784589, 4997915, 5444159, 5667787, 5877298. R0-0502 USA
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