The safety of HAVRIX has been evaluated in clinical trials involving more than 31,000 individuals receiving doses ranging from 360 EL.U. to 1440 EL.U. and during postmarketing experience in Europe. As with all pharmaceuticals, however, it is possible that expanded commercial use of the vaccine could reveal rare adverse events not observed in clinical studies.

The frequency of solicited adverse events tended to decrease with successive doses of HAVRIX. Most events reported were considered by the subjects as mild and did not last for more than 24 hours.

Of solicited adverse events in clinical trials, the most frequently reported by volunteers was injection-site soreness (56% of adults and 21% of children); however, less than 0.5% of soreness was reported as severe. Headache was reported by 14% of adults and less than 9% of children. Other solicited and unsolicited events occurring during clinical trials are listed below:

Incidence 1% to 10% of Injections:

Local Reactions at Injection Site: Induration, redness, swelling.

Body as a Whole: Fatigue, fever (>37.5°C), malaise.

Gastrointestinal: Anorexia, nausea.

Incidence <1% of Injections:

Local Reaction at Injection Site: Hematoma.

Dermatologic: Pruritus, rash, urticaria.

Respiratory: Pharyngitis, other upper respiratory tract infections.

Gastrointestinal: Abdominal pain, diarrhea, dysgeusia, vomiting.

Musculoskeletal: Arthralgia, elevation of creatine phosphokinase, myalgia.

Hematologic: Lymphadenopathy.

Central Nervous System: Hypertonic episode, insomnia, photophobia, vertigo.

Additional Safety Data: Safety data were obtained from 2 additional sources in which large populations were vaccinated. In an outbreak setting in which 4,930 individuals were immunized with a single dose of either 720 EL.U. or 1440 EL.U. of HAVRIX, the vaccine was well tolerated and no serious adverse events due to vaccination were reported. Overall, less than 10% of vaccinees reported solicited general adverse events following the vaccine. The most common solicited local adverse event was pain at the injection site, reported in 22.3% of subjects at 24 hours and decreasing to 2.4% by 72 hours. In a field efficacy trial, 19,037 children received the 360 EL.U. dose of HAVRIX. The most commonly reported adverse events following administration of HAVRIX were injection-site pain (9.5%) and tenderness (8.1%), which were reported following first doses of HAVRIX. Other adverse events were infrequent and comparable to the control vaccine ENGERIX-B. Additionally, no serious adverse events due to the vaccine were reported. The large trial further allowed for analysis of rare adverse events, including hospitalization and death. No significant differences were found between the cohorts.

In subjects with chronic liver disease, HAVRIX was safe and well tolerated. Local injection site reactions were similar among all 4 groups, and no serious adverse reactions attributed to the vaccine were reported in subjects with chronic liver disease.

Safety Data for HAVRIX 720 EL.U./0.5 mL Beginning at 11 Months of Age: In the multicenter study described under CLINICAL PHARMACOLOGY, parents/guardians recorded local and general symptoms on diary cards for 4 days (Days 0 to 3) after vaccination. In the 3 groups of children who received HAVRIX alone, safety data were available for 723 children who received 1,396 documented doses of HAVRIX. Additional safety data were available for 181 children who received HAVRIX coadministered with INFANRIX and Hib conjugate vaccine (PRP-T). Most adverse events were mild and transient. The frequencies of solicited local and systemic reactions following receipt of HAVRIX were monitored during the 4-day observation period.

The following rates of solicited adverse events in children who received their first dose of HAVRIX alone at between 11 and 25 months of age were observed. Among local reactions: pain was reported in 15-21% of subjects, redness in 16-21%, swelling in 8% of subjects. Among general reactions, irritability was reported in 24-36% of subjects, loss of appetite in 16-19% of subjects, drowsiness in 15-17% of subjects and fever >39.5°C in ≤2% of subjects. Following the booster dose of HAVRIX, among local reactions: pain was reported in 16-21% of subjects, redness in 17-22%, swelling in 8-10% of subjects. Following the booster dose of HAVRIX, among general reactions, irritability was reported in 19-29% of subjects, loss of appetite in 14-18% of subjects, drowsiness in 13-16% of subjects and fever >39.5°C in ≤1% of subjects.

Drowsiness and loss of appetite occurred at statistically significantly higher rates in subjects 15 to 18 months of age who received Hib conjugate vaccine (PRP-T) and INFANRIX concomitantly with HAVRIX as compared to subjects 15 to 18 months of age who received Hib conjugate vaccine (PRP-T) and INFANRIX (drowsiness 34% and 22% and loss of appetite 29% and 19%, respectively). With the exception of fever (>39.5°C), the solicited general symptoms occurred at statistically significantly higher rates in subjects 15 to 18 months of age who received Hib conjugate vaccine (PRP-T) and INFANRIX concomitantly with HAVRIX as compared to subjects 15 to 18 months of age who received HAVRIX alone (irritability 46% and 30%, drowsiness 34% and 17%, and loss of appetite 29% and 17%, respectively).

A febrile seizure was reported in an 18-month old subject two days after receiving the first dose of HAVRIX. Other serious adverse events reported during the course of this study included a single case each of hepatitis ~5 months post dose 1, insulin-dependent diabetes ~4 months post dose 1, and Kawasaki's disease ~3½ months post dose 1. The association of these events with vaccination is unknown.

Postmarketing Reports: Rare voluntary reports of adverse events in people receiving HAVRIX that have been reported since market introduction of the vaccine include the following:

Local: Localized edema.

While no causal relationship has been established, the following rare events have been reported:

Body as a Whole: Anaphylaxis/anaphylactoid reactions, somnolence.

Cardiovascular: Syncope.

Hepatobiliary: Jaundice, hepatitis.

Dermatologic: Erythema multiforme, hyperhydrosis, angioedema.

Respiratory: Dyspnea.

Hematologic: Lymphadenopathy, thrombocytopenia.

Central Nervous System: Convulsions, encephalopathy, dizziness, neuropathy, myelitis, paresthesia, Guillain-Barr© syndrome, multiple sclerosis.

Other: Congenital abnormality. Reporting of Adverse Events: The US Department of Health and Human Services has established the Vaccine Adverse Events Reporting System (VAERS) to accept 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. The toll-free number for VAERS forms and information is 1-800-822-7967.⁷ Reporting forms may also be obtained at the VAERS website at www.vaers.org.

HAVRIX may be given concurrently with Hib conjugate vaccines in children 15 to 18 months of age (see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS). The safety of HAVRIX given concomitantly with INFANRIX has been evaluated (see ADVERSE REACTIONS). Insufficient data are available to assess the immune response of a fourth dose of DTaP vaccine when administered with HAVRIX.

There are limited data to assess the concomitant use of HAVRIX with other vaccines. (See Immune Response to Concomitantly Administered Vaccines.)

REFERENCES

7.    Centers for Disease Control. Vaccine Adverse Event Reporting System - United States. MMWR 1990;39(41):730-733.

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