PEDIARIX: Package Insert and Label Information

PEDIARIX- corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated), clostridium tetani toxoid antigen (formaldehyde inactivated), bordetella pertussis toxoid antigen (formaldehyde, glutaraldehyde inactivated), bordetella pertussis filamentous hemagglutinin antigen (formaldehyde inactivated), bordetella pertussis pertactin antigen (formaldehyde inactivated), hepatitis b virus subtype adw2 hbsag surface protein antigen, poliovirus type 1 antigen (formaldehyde inactivated), poliovirus type 2 antigen (formaldehyde inactivated) and poliovirus type 3 antigen (formaldehyde inactivated) injection, suspension
GlaxoSmithKline Biologicals SA

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 3-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 1 or more doses of a DTaP vaccine from a different manufacturer.

Children Previously Vaccinated with Hepatitis B Vaccine

PEDIARIX may be used 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 1 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 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 contain natural rubber latex which may cause allergic reactions.

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 Reactions following Prior Pertussis Vaccination

If any of the following reactions 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.

5.6 Children at Risk for Seizures

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 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 reaction 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 1 or more doses as part of the 3-dose series during 14 clinical studies. Common adverse reactions 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 U.S. 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 United States only for booster immunization], Wyeth Pharmaceuticals Inc. [no longer licensed in the United States], Sanofi Pasteur SA [U.S.-licensed], or Merck & Co, Inc. [U.S.-licensed]) at 3, 4, and 5 months of age and for 768 infants in the control group that received separate U.S.-licensed vaccines (INFANRIX, Hib conjugate vaccine [Sanofi Pasteur SA], and oral poliovirus vaccine [OPV] [Wyeth Pharmaceuticals, Inc.; no longer licensed in the United States]). 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 U.S. study, the safety of PEDIARIX administered to 673 infants was compared with 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 United States) 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 reactions 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 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 Reactions

Data on solicited local reactions and general adverse reactions from the U.S. 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 with separately administered vaccines. Other statistically significant differences between groups in rates of fever, as well as other solicited adverse reactions, 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 1 or more diagnostic studies performed to evaluate the cause of fever.

Table 1. Percentage of Infants with Solicited Local and General Adverse Reactions 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)
Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the United States); 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 1 symptom sheet was completed; for fever, numbers exclude missing temperature recordings or tympanic measurements.M.A. = Medically attended (a visit to or from medical personnel).Grade 2 defined as sufficiently discomforting to interfere with daily activities.Grade 3 defined as preventing normal daily activities.a Within 4 days of vaccination defined as day of vaccination and the next 3 days.b Local reactions at the injection site for PEDIARIX or INFANRIX.c Rate significantly higher in the group that received PEDIARIX compared with 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).d Axillary temperatures increased by 1°C and oral temperatures increased by 0.5°C to derive equivalent rectal temperature.

Adverse Reaction

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

36

36

31

32

30

30

Pain, Grade 2 or 3

12

11

11

9

9

9

Pain, Grade 3

2

3

2

3

2

1

Redness, any

25c

37

40

18

33

39

Redness, >5 mm

6c

10c

13c

2

6

7

Redness, >20 mm

1

1c

3

0

0

2

Swelling, any

17c

27c

29

10

20

25

Swelling, >5 mm

6c

10c

9c

2

5

4

Swelling, >20 mm

2

3c

3

1

0

1

General

n

667

644

645

333

321

311

Feverd , ≥100.4°F

28c

39c

34c

20

30

24

Feverd , >101.3°F

7

14c

9

5

10

6

Feverd , >102.2°F

2c

4

3

0

3

2

Feverd , >103.1°F

1

1

1

0

0

0

Feverd , M.A.

1c

0

1

0

1

0

n

671

653

648

335

323

315

Drowsiness, any

57

52

41

54

48

38

Drowsiness, Grade 2 or 3

16

14

11

18

12

11

Drowsiness, Grade 3

3

1

1

4

1

2

Irritability/Fussiness, any

61

65

61

62

62

57

Irritability/Fussiness, Grade 2 or 3

20

28c

25c

19

21

19

Irritability/Fussiness, Grade 3

3

4

4

4

3

3

Loss of appetite, any

30

31

26

28

27

24

Loss of appetite, Grade 2 or 3

7

8c

6

5

3

5

Loss of appetite, Grade 3

1

0

0

1

0

0

Serious Adverse Events

Within 30 days following any dose of vaccine in the U.S. 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 1 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 1 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 U.S. 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 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 U.S. 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 U.S. 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 U.S. 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 with PEDIARIX administered without a previous dose of hepatitis B vaccine.

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