Combined Diphtheria, Tetanus Toxoids, Acellular Pertussis, Hepatitis B, Inactivated Poliomyelitis, Adsorbed Conjugated Haemophilus Influenzae

Adverse Drug Reaction Overview

INFANRIX hexa® (combined diphtheria and tetanus toxoids, acellular pertussis, hepatitis B (recombinant), inactivated poliomyelitis, and adsorbed conjugated Haemophilus influenzae type b vaccine) is generally well tolerated.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

During a study conducted in the United States, a total of 785 documented doses of study vaccines were given to 267 subjects included in the According To Protocol (ATP) reactogenicity analysis. Solicited and unsolicited symptoms occurring during the 8-day follow-up period after vaccination were reported. Most reported solicited local symptoms and solicited general symptoms were mild to moderate in intensity. There were no statistically significant differences between the two groups in the incidence of soreness, redness or swelling at the injection site (regardless of side/site/dose) or fever. The percentage of subjects per group experiencing symptoms (both solicited and unsolicited) during the 8 days after vaccination is outlined in Table 1.

Table 1 : Percentage of U.S. Infants with Local or Systemic Reactions within 8 Days of Primary Vaccination with either INFANRIX hexa® or Commercially Available INFANRIX®, ENGERIX®-B, and OPV Administered Simultaneously with Hib at Separate Sites (Per subject analysis).

Event	INFANRIX hexa® (N=134)	INFANRIX®, ENGERIX® -B, H1b vaccine, OPV (N=133)
Local	%	%
Pain, any	42.54	52.63
Pain, severe	1.49	2.26
Redness, any	48.51	47.37
Redness, > 20 mm	2.24	3.01
Swelling, any	35.82	40.60
Swelling, > 20 mm	3.73	4.51
Systemic	%	%
Temperature
≥ 38°C	55.97	51.88
> 39.5°C	0.75	2.26
Diarrhea, any	35.82	33.08
Grade 3	0.75	2.26
Eating/drinking less than usual, any	49.25	57.14
Grade 3	2.24	2.26
Irritability/fussiness, any	82.84	86.47
Grade 3	6.72	6.02
Sleeping less than usual, any	50.75	56.39
Grade 3	2.24	3.76
Sleeping more than usual, any	62.69	67.67
Grade 3	3.73	1.50
Unusual crying for more than one hour, any	42.54	41.35
Grade 3	3.73	2.26
Vomiting, any	25.37	20.30
Grade 3	0.75	0.75
N= number of infants

The safety profile presented below is based on data from more than 16,000 subjects.

As has been observed for DTaP and DTaP-containing combinations, an increase in local reactogenicity and fever was reported after booster vaccination with INFANRIX hexa® with respect to the primary course.

Frequencies per dose as defined by CIOMS:

Very common: ≥ 10%

Appetite lost, irritability, crying abnormal, restlessness, pain, redness, local swelling at the injection site ( ≤ 50 mm), fever ≥ 38°C, and fatigue.

Common: ≥ 1% and < 10%

Nervousness, vomiting, diarrhea, local swelling at the injection site ( > 50 mm)*, fever > 39.5°C, pruritis** and injection site reactions, including induration.

Uncommon: ≥ 0.1% and < 1%

Upper respiratory tract infection, somnolence, cough** and diffuse swelling of the injected limb, sometimes involving the adjacent joint*.

Rare: ≥ 0.01% and < 0.1%

Bronchitis and rash.

Very rare: < 0.01%

Convulsions (with or without fever)***, dermatitis, bronchospasm, and urticaria**.

* Children primed with acellular pertussis vaccines are more likely to experience swelling reactions after booster administration in comparison with children primed with whole cell vaccines. These reactions resolve over an average of 4 days.

**Observed with other GSK DTaP-containing vaccines

*** Analysis of post-marketing reporting rates suggests a potential increased risk of convulsions (with or without fever) and hypotonic hyporesponsive episode when comparing groups which reported use of INFANRIX hexa® with Prevnar® 13 to those which reported use of INFANRIX hexa® alone.

Local reactions after immunization usually consist of swelling or induration, tenderness, and redness or erythema at the injection site. More severe local reactions occasionally occur, such as inflammatory cellulitis without bacterial infection after DTP-containing vaccines.

Post-Marketing Adverse Drug Reaction

Over 12 million doses of INFANRIX hexa® have been distributed overall for primary and booster vaccinations. Extremely rare cases of Sudden Unexpected Death (SUD) in close temporal association to vaccination with INFANRIX hexa® have been reported in the first year of life. However, a causal relationship has not been established. The observed number of SUD cases following INFANRIX hexa® is below the number of cases expected to occur by chance.

Blood And Lymphatic System Disorders

Lymphadenopathy, thrombocytopenia

Immune System Disorders

Allergic reactions (including anaphylactic and anaphylactoid reactions)

Nervous System Disorders

Collapse or shock-like state (hypotonic hyporesponsive episode)***.

Respiratory, Thoracic And Mediastinal Disorders

Apnea** [see section “WARNINGS AND PRECAUTIONS” for apnea in very premature infants ( ≤ 28 weeks of gestation)].

Skin and Subcutaneous Tissue Disorders

Angioneurotic oedema**

General Disorders and Administration Site Conditions

Extensive swelling reactions, swelling of the entire injected limb*, vesicles at the injection site

*Children primed with acellular pertussis vaccines are more likely to experience swelling reactions after booster administration in comparison with children primed with whole cell vaccines. These reactions resolve over an average of 4 days.

**Observed with other GSK DTaP-containing vaccines

*** Analysis of post-marketing reporting rates suggests a potential increased risk of convulsions (with or without fever) and hypotonic hyporesponsive episode when comparing groups which reported use of INFANRIX hexa® with Prevnar® 13 to those which reported use of INFANRIX hexa® alone.

Experience with Hepatitis B Vaccine

Paralysis, neuropathy, Guillain-Barré syndrome, encephalopathy, encephalitis, meningitis, allergic reactions mimicking serum sickness, neuritis, hypotension, vasculitis, lichen planus, erythema multiforme, arthritis and muscular weakness have been reported extremely rarely during post-marketing surveillance following vaccination with ENGERIX®-B (Hepatitis B vaccine, GlaxoSmithKline) in infants < 2 years old. The causal relationship to the vaccine has not been established.