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Adverse reactions associated with HibTITER (diphtheria crm197 protein conjugate) have been evaluated in 401 infants who were vaccinated initially at 1 to 6 months of age and were given 1,118 doses independent of DTP vaccine. Observations were made during the day of vaccination and days 1 and 2 postvaccination. A temperature > 38.3°C was recorded at least once during the observation period following 2% of the vaccinations. Local erythema, warmth, or swelling ( ≥ 2 cm) was observed following 3.3% of vaccinations. The incidence of temperature > 38.3°C was greater during the first postvaccination day than during the day of vaccination or the second postvaccination day. The incidence of local erythema, warmth, or swelling was similar during the day of vaccination and the first postvaccination day; it was lower during the second postvaccination day. All side effects have been infrequent, mild, and transient with no serious sequelae (Table 1). No difference in the rates of these complaints was reported after dose 1, 2, or 3.
TABLE 1: Number of Subjects (Percent) Manifesting Side Effects
Associated with HibTITER (diphtheria crm197 protein conjugate) Administered Independently from DTP* (Infants Vaccinated
Initially at 1-6 Months of Age)
| Dose 1
n = 401
| Dose 2
n = 383
| Dose 3
n = 334
|Symptoms||Same Day As Vacc.||+1 Day||+2 Days||Same Day As Vacc.||+1 Day||+2 Days||Same Day As Vacc.||+1 Day||+2 Days|
|Temp > 38.3°C||0||2||2||2||3||2||2||6||5|
|-||< 1%||< 1%||< 1%||< 1%||< 1%||< 1%||1.8%||1.5%|
|Redness > 2 cm||1||0||0||1||6||0||5||4||0|
|< 1%||-||-||< 1%||1.6%||-||1.5%||1.2%||-|
|Warmth ≥ 2 cm||1||1||0||2||1||0||1||6||0|
|< 1%||< 1%||-||< 1%||< 1%||-||< 1%||1.8%||-|
|Swelling ≥ 2 cm||5||1||0||2||2||0||1||0||0|
|1.2%||< 1%||-||< 1%||< 1%||-||< 1%||-||-|
|*DTP and HibTITER given 2 weeks apart with DTP having been given first.|
The following complaints were also observed after 1,118 vaccinations with HibTITER (diphtheria crm197 protein conjugate) : irritability (133), sleepiness (91), prolonged crying [ ≥ 4 hours] (38), appetite loss (23), vomiting (9), diarrhea (2), and rash (1).
Additional safety data with HibTITER (diphtheria crm197 protein conjugate) are available from the efficacy studies conducted in young infants.30 There were 79,483 doses given to 30,844 infants at approximately 2, 4, and 6 months of age in California, usually at the same time as DTP (but at a separate injection site) and OPV; approximately 100,000 doses have been given to 53,000 infants at 4 and 6 months in Finland at the same time as a combined DTP and inactivated polio (IPV) vaccine (but at a separate injection site). The rate and type of reactions associated with the vaccinations were no different from those seen when DTP or DTP-IPV was administered alone. These included fever, local reactions, rash, and one hyporesponsive episode with a single seizure. The safety of HibTITER (diphtheria crm197 protein conjugate) was also evaluated in the California study by direct phone questioning of the parents or guardians of 6,887 vaccine recipients. The incidence and type of side effects reported within 24 hours of vaccination were similar to those cited in Table 1. In addition, analysis of emergency room (ER) visits within 30 days and hospitalization within 60 days after receipt of 23,800 doses of HibTITER (diphtheria crm197 protein conjugate) showed no increase in the rates of any type of ER visit or hospitalization.
Table 2 details the side effects associated with a single vaccination of HibTITER (diphtheria crm197 protein conjugate) given (without DTP) to infants of 15 to 23 months of age.
TABLE 2: Selected Adverse Reactions* in Children of 15-23
Months of Age Following Vaccination with HibTITER (diphtheria crm197 protein conjugate)
|Adverse Reaction||No. of Subjects||Reaction Within 24 h||% Postvaccination At 48 h|
|Fever > 38.3°C||354||1.4||0.6|
|* The following complaints were reported after vaccination of these 354 children in the indicated number of children: diarrhea (9), vomiting (5), prolonged crying [ > 4 hours] (4), and rashes (2).|
Similar results have been observed in the analysis of 2,285 subjects of 18 to 60 months of age, vaccinated as part of a postmarketing safety study of HibTITER (diphtheria crm197 protein conjugate) .20 These data were collected by telephone survey 24 to 48 hours postvaccination. Additional observations included irritability, restless sleep, and Gl symptoms (diarrhea, vomiting, and loss of appetite) in the group that received HibTITER (diphtheria crm197 protein conjugate) alone. A cause and effect relationship between these observations and the vaccinations has not been established.
Post Approval Experience
The following adverse reactions have been identified during post approval use of HibTITER (diphtheria crm197 protein conjugate) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to the vaccine for post marketing surveillance information.
Injection Site Reactions
Anaphylactoid/anaphylactic reactions (including shock), angioneurotic edema, convulsions,53 erythema multiforme, facial edema, febrile seizures, Guillain-Barré syndrome,54headache, hives (urticaria), hypersensitivity reaction, lethargy, and malaise. Also reported, hypotonia or hyporesponsive-hypotonic-episodes (in many instances pertussis-containing vaccine was coadministered).
There have been spontaneous reports of apnea in temporal association with the administration of HibTITER (diphtheria crm197 protein conjugate) . In most cases HibTITER (diphtheria crm197 protein conjugate) was administered concomitantly with other vaccines including DTP, DTaP, hepatitis B vaccine, IPV, OPV, pneumococcal 7-valent conjugate vaccine, MMR, and/or meningococcal group C conjugate vaccine (not licensed in the US). In addition, in some of the reports existing medical conditions such as prematurity and/or history of apnea were present.
Reporting of Adverse Reactions
Any suspected adverse events following immunization should be reported by the healthcare professional to the US Department of Health and Human Services (DHHS). The National Vaccine Injury Compensation Program requires that the manufacturer and lot number of the vaccine administered be recorded by the healthcare professional in the vaccine recipient's permanent medical record (or in a permanent office log or file), along with the date of administration of the vaccine and the name, address, and title of the person administering the vaccine. The DHHS has established the Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine, including but not limited to the reporting of events required by the National Childhood Vaccine Injury Act of 1986.42 The VAERS FDA web site is: http://www.fda.gov/cber/vaers/vaers.htm
The VAERS toll-free number for VAERS forms and information is 800-822-7967.
Read the HibTITER (diphtheria crm197 protein conjugate) Side Effects Center for a complete guide to possible side effects
Children receiving therapy with immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may not respond optimally to active immunization.37,38,39 (See PRECAUTIONS, General.)
As with other intramuscular injections, HibTITER (diphtheria crm197 protein conjugate) should be given with caution to children on anticoagulant therapy.
No impairment of the antibody response to the individual antigens was demonstrated when HibTITER (diphtheria crm197 protein conjugate) was given at the same time but at separate sites as diphtheria tetanus pertussis vaccine (DTP) plus oral polio vaccine (OPV) to children 2 to 20 months of age or measles-mumps-rubella (MMR) to children 15 ± 1 month of age.20,43,44
There are no clinical studies where a direct comparison of the immune responses to HibTITER (diphtheria crm197 protein conjugate) was compared with the concurrent administration of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), hepatitis B vaccine (Hep B), inactivated poliovirus vaccine (IPV), 7-valent Conjugate Vaccine-Diphtheria CRM197Protein (Prevnar), or Varicella vaccine. However, in clinical trials where HibTITER (diphtheria crm197 protein conjugate) and DTaP or HibTITER (diphtheria crm197 protein conjugate) , DTaP, IPV, and Hep B vaccines were administered concurrently with or without Prevnar in children at 2, 4, and 6 months of age, the percentage of children achieving Hib antibody levels of ≥ 0.15 or ≥ 1.0 µg/mL were similar.45,46 In one study where children 12-15 months of age were administered a booster dose of HibTITER (diphtheria crm197 protein conjugate) concurrently with DTaP and Prevnar, some suppression of the Hib antibody response was observed, but over 97% of children achieved titers of ≥ 1.0 µg/mL.47,48 However, in another study where a booster dose of HibTITER (diphtheria crm197 protein conjugate) was administered to children at 12-15 months of age concurrently with or without Prevnar the percentage of children achieving Hib antibody levels of ≥ 0.15 or ≥ 1.0 µg/mL was found to be similar.49,50
HibTITER (diphtheria crm197 protein conjugate) and DTaP administered concurrently with and without Prevnar at 2, 4, and 6, and 12-15 months of age did not impair immune responses to the seven Pneumococcal vaccine serotypes in Prevnar.47,48,51,52
There are no clinical trials where the local and systemic reactogenicity of HibTITER (diphtheria crm197 protein conjugate) was directly compared with the concurrent administration of DTaP, Hep B, IPV, Prevnar, or Varicella vaccines.
The American Academy of Pediatrics (AAP), the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP) encourage routine simultaneous administration of DTaP, IPV, Haemophilus influenzae type b vaccine, pneumococcal conjugate vaccine, measles-mumps-rubella (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.32,33,34,35
20. Unpublished data available from Lederle Laboratories.
30. Black SB, Shinefield HR, Lampert D, et al. Safety and immunogenicity of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in infancy. Pediatr Infect Dis J. 1991;10:92-96.
32. Recommendations of the AAP: Haemophilus influenzae type b conjugate vaccines: recommendations for immunization of infants and children 2 months of age and older: update. Pediatrics. 1991;88:169-172.
33. Recommendation of the ACIP: Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. MMWR. 1991;40:1-7.
34. Centers for Disease Control and Prevention. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR. 2002;51(No. RR-2);1-36.
35. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000: 26, 266-72.
37. American Academy of Pediatrics: Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1991.
38. Recommendation of the ACIP: Immunization of children infected with human T-lymphotrophic virus type III/lymphadenopathy-associated virus. MMWR. 1986;35(38):595-606.
39. Immunization of children infected with human immunodeficiency virus – supplementary ACIP statement. MMWR. 1988;37(12):181-183.
42. CDC. Vaccine Adverse Event Reporting System – United States. MMWR. 1990;39:730-733.
43. Paradiso PR. Combined childhood immunizations. JAMA. 1992;268:1685.
44. Paradiso PR, Hogerman DA, Madore DV, et al. Safety and immunogenicity of a combined diphtheria, tetanus, pertussis and Haemophilus influenzae type b vaccine in young infants. Pediatrics. 1993;92(6):827-32.
45. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P12.
46. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P16.
47. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P7.
48. Shinefield H, Black S, Ray P, et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatr Infect Dis J. 1999;18:757-63.
49. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P3.
50. Rennels MB, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics. 1998;101(4):604-11.
51. Wyeth Pharmaceuticals, Data on File: Prevnar Study D118-P8.
52. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19:187-95.
53. Milstein JB, Gross TP, Kuritsky JN. Adverse reactions reported following receipt of Haemophilus influenzae type b vaccine: an analysis after one year of marketing. Pediatrics. 1987;80:270-274.
54. D'Cruz DF, Shapiro ED, Spiegelman KN, et al. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome) after immunization with Haemophilus influenzae type b conjugate vaccine. J Pediatr. 1989;115:743-746.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/9/2009
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