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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
Erythema 354 2.0
Swelling 354 1.7
Tenderness 354 3.7 0.3
* 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

Injection site reactions including hypersensitivity (including urticaria), induration, inflammation, mass, and skin discoloration.

Systemic Events

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.