Vaccine Information: TWINRIX (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TWINRIX, HAVRIX, or ENGERIX-B. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Postmarketing Experience with TWINRIX

Infections and Infestations: Herpes zoster, meningitis.

Blood and Lymphatic System Disorders: Thrombocytopenia, thrombocytopenic purpura.

Immune System Disorders: Allergic reaction, anaphylactoid reaction, anaphylaxis, serum sickness–like syndrome days to weeks after vaccination (including arthralgia/arthritis, usually transient; fever; urticaria; erythema multiforme; ecchymoses; and erythema nodosum).

Nervous System Disorders: Bell’s palsy, convulsions, encephalitis, encephalopathy, Guillain-Barré syndrome, hypoesthesia, myelitis, multiple sclerosis, neuritis, neuropathy, optic neuritis, paralysis, paresis, transverse myelitis.

Eye Disorders: Conjunctivitis, visual disturbances.

Ear and Labyrinth Disorders: Earache, tinnitus.

Cardiac Disorders: Palpitations, tachycardia.

Vascular Disorders: Vasculitis.

Respiratory, Thoracic, and Mediastinal Disorders: Bronchospasm, including asthma-like symptoms; dyspnea.

Gastrointestinal Disorders: Dyspepsia.

Hepatobiliary Disorders: Hepatitis, jaundice.

Skin and Subcutaneous Tissue Disorders: Alopecia, angioedema, eczema, erythema multiforme, erythema nodosum, hyperhidrosis, lichen planus.

Musculoskeletal and Connective Tissue Disorders: Arthritis, muscular weakness.

General Disorders and Administration Site Conditions: Chills; immediate injection site pain, stinging, and burning sensation; injection site reaction; malaise.

Investigations: Abnormal liver function tests.

Postmarketing Experience with HAVRIX and/or ENGERIX-B

The following list includes adverse reactions for HAVRIX and/or ENGERIX-B not already reported above for TWINRIX.

Eye Disorders: Keratitis.a

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome.a

Congenital, Familial, and Genetic Disorders: Congenital abnormality.b

a Following ENGERIX-B.
b Following HAVRIX.

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Vaccines and Immune Globulin

Do not mix TWINRIX with any other vaccine or product in the same syringe.

When concomitant administration of immunoglobulin is required, it should be given with a different syringe and at a different injection site.

There are no data to assess the concomitant use of TWINRIX with other vaccines.

7.2 Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater-than-physiologic doses), may reduce the immune response to TWINRIX.

7.3 Interference with Laboratory Tests

Hepatitis B surface antigen (HBsAg) derived from hepatitis B vaccines has been transiently detected in blood samples following vaccination. Serum HBsAg detection may not have diagnostic value within 28 days after receipt of a hepatitis B vaccine, including TWINRIX.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no adequate and well-controlled studies of TWINRIX in pregnant women in the U.S. Available data do not suggest an increased risk of major birth defects and miscarriage in women who received TWINRIX within 28 days prior to conception or during pregnancy (see Data).

A developmental toxicity study was performed in female rats administered TWINRIX prior to mating and during gestation (0.2 mL at each occasion). This study revealed no adverse effects on fetal or pre-weaning development (see Data).

Data

Human Data: A pregnancy exposure registry was maintained from 2001 to 2015. The registry prospectively enrolled 245 women who received a dose of TWINRIX during pregnancy or within 28 days prior to conception. After excluding induced abortions (n = 6, including one of a fetus with congenital anomalies), those lost to follow-up (n = 142), those with exposure in the third trimester (n = 1), and those with an unknown exposure timing (n = 9), there were 87 pregnancies with known outcomes with exposure within 28 days prior to conception, or in the first or second trimesters. Miscarriage was reported for 9.6% of pregnancies with exposure to TWINRIX prior to 20 weeks gestation (8/83). Major birth defects were reported for 3.8% of live born infants whose mothers were exposed within 28 days prior to conception or during the first or second trimester (3/80). The rates of miscarriage and major birth defects were consistent with estimated background rates.

In pre- and post-licensure clinical studies of TWINRIX, 45 pregnant women were inadvertently administered TWINRIX following their last menstrual period. Among such pregnancies, after excluding elective terminations (n = 1) and those lost to follow-up (n = 1), there were 43 pregnancies with known outcomes all with exposure in the first trimester. Miscarriage was reported in 16% of pregnancies (7/43) and major birth defects were reported in 2.6% of live births (1/38). The rates of miscarriage and major birth defects were consistent with estimated background rates.

Animal Data: In a developmental toxicity study, female rats were administered TWINRIX by intramuscular injection on Day 30 prior to mating and on gestation Days 6, 8, 11, and 15. The total dose was 0.2 mL (divided) at each occasion (a single human dose is 1 mL). No adverse effects on pre-weaning development up to post-natal Day 25 were observed. There were no fetal malformations or variations.

8.2 Lactation

Risk Summary

There is no information regarding the presence of TWINRIX in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TWINRIX and any potential adverse effects on the breastfed child from TWINRIX or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients younger than 18 years have not been established.

8.5 Geriatric Use

Clinical studies of TWINRIX did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Studies (14.1, 14.3)].

11 DESCRIPTION

TWINRIX [Hepatitis A & Hepatitis B (Recombinant) Vaccine] is a bivalent vaccine containing the antigenic components used in producing HAVRIX (Hepatitis A Vaccine) and ENGERIX-B [Hepatitis B Vaccine (Recombinant)]. TWINRIX is a sterile suspension for intramuscular administration that contains inactivated hepatitis A virus (strain HM175) and noninfectious HBsAg. The hepatitis A virus is propagated in MRC-5 human diploid cells and inactivated with formalin. The purified HBsAg is obtained by culturing genetically engineered Saccharomyces cerevisiae yeast cells, which carry the surface antigen gene of the hepatitis B virus. Bulk preparations of each antigen are adsorbed separately onto aluminum salts and then pooled during formulation.

A 1-mL dose of vaccine contains 720 ELISA Units of inactivated hepatitis A virus and 20 mcg of recombinant HBsAg protein. One dose of vaccine also contains 0.45 mg of aluminum in the form of aluminum phosphate and aluminum hydroxide as adjuvants, amino acids, sodium chloride, phosphate buffer, polysorbate 20, and Water for Injection. From the manufacturing process, each 1-mL dose of TWINRIX also contains residual formalin (not more than 0.1 mg), MRC-5 cellular proteins (not more than 2.5 mcg), neomycin sulfate (an aminoglycoside antibiotic included in the cell growth media; not more than 20 ng), and yeast protein (no more than 5%).

TWINRIX is available in prefilled syringes. The tip caps of the prefilled syringes contain natural rubber latex; the plungers are not made with natural rubber latex.

TWINRIX is formulated without preservatives.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Hepatitis A

The course of infection with hepatitis A virus (HAV) is extremely variable, ranging from asymptomatic infection to fulminant hepatitis.3

The presence of antibodies to HAV (anti-HAV) confers protection against hepatitis A disease. However, the lowest titer needed to confer protection has not been determined. Natural infection provides lifelong immunity even when antibodies to hepatitis A are undetectable. Seroconversion is defined as antibody titers equal to or greater than the assay cut-off (cut-off values vary depending on the assay used) in those previously seronegative.

Hepatitis B

Infection with hepatitis B virus (HBV) can have serious consequences including acute massive hepatic necrosis and chronic active hepatitis. Chronically infected persons are at increased risk for cirrhosis and hepatocellular carcinoma.

Antibody concentrations ≥10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B virus infection.4

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

TWINRIX has not been evaluated for its carcinogenic or mutagenic potential, or for impairment of male fertility in animals. Vaccination of female rats with TWINRIX had no effect on fertility. [See Use in Specific Populations (8.1).]

14 CLINICAL STUDIES

14.1 Immunogenicity: Standard 0-, 1-, and 6-Month Dosing Schedule

In 11 clinical trials, sera from 1,551 healthy adults aged 17 to 70 years, including 555 male subjects and 996 female subjects, were analyzed following administration of 3 doses of TWINRIX on a 0-, 1-, and 6-month schedule. Seroconversion (defined as equal to or greater than assay cut-off depending on assay used) for antibodies against HAV was elicited in 99.9% of vaccinees, and protective antibodies (defined as ≥10 mIU/mL) against HBV surface antigen were detected in 98.5% of vaccinees, 1 month after completion of the 3-dose series (Table 2).

Table 2. Seroconversion and Seroprotection Rates in Worldwide Clinical Trials

Dose of TWINRIX

n

% Seroconversion

for Hepatitis Aa

% Seroprotection

for Hepatitis Bb

1

1,587

93.8

30.8

2

1,571

98.8

78.2

3

1,551

99.9

98.5

a Anti‑HAV titer ≥assay cut‑off: 20 mIU/mL (HAVAB Test) or 33 mIU/mL (ENZYMUN‑TEST).
b Anti‑HBsAg titer ≥10 mIU/mL (AUSAB Test).

One of the 11 trials was a comparative trial conducted in a U.S. population given either TWINRIX (on a 0-, 1-, and 6-month schedule) or HAVRIX (0- and 6-month schedule) and ENGERIX-B (0-, 1-, and 6-month schedule). The monovalent vaccines were given concurrently in opposite arms. Of the 773 adults (aged 18 to 70 years) enrolled in this trial, an immunogenicity analysis was performed in 533 subjects who completed the study according to protocol. Of these, 264 subjects received TWINRIX and 269 subjects received HAVRIX and ENGERIX-B. Seroconversion rates against HAV and seroprotection rates against HBV are presented in Table 3; geometric mean titers (GMTs) are presented in Table 4. The absolute difference in anti-HAV seropositivity rates between groups was 0.36% (90% CI: -1.8, 3.1). Non-inferiority in terms of anti-HAV response was demonstrated (lower limit of the 90% CI was higher than the pre-specified non-inferiority criterion of -4.3%). The absolute difference in anti-HBsAg seroprotection rates between groups was 2.8% (90% CI: -1.3, 7.7). Non-inferiority in terms of anti-HBV response was demonstrated (lower limit of the 90% CI was higher than the pre-specified non-inferiority criterion of -9.4%).

Table 3. Seroconversion and Seroprotection Rates in a U.S. Clinical Trial

Vaccine

n

Timepoint

% Seroconversion for Hepatitis Aa (95% CI)

% Seroprotection for Hepatitis Bb (95% CI)

TWINRIX

264

Month 1

91.6

17.9

Month 2

97.7

61.2

Month 7

99.6 (97.9, 100.0)

95.1 (91.7, 97.4)

HAVRIX and ENGERIX-B

269

Month 1

98.1

7.5

Month 2

98.9

50.4

Month 7

99.3 (97.3, 99.9)

92.2 (88.3, 95.1)

CI = Confidence Interval
a Anti-HAV titer ≥assay cut-off: 33 mIU/mL (ENZYMUN-TEST).
b Anti-HBsAg titer ≥10 mIU/mL (AUSAB Test).
Table 4. Geometric Mean Titers in a U.S. Clinical Trial

Vaccine

n

Timepoint

GMT to Hepatitis A

(95% CI)

GMT to Hepatitis B

(95% CI)

TWINRIX

263

Month 1

335

8

259

Month 2

636

23

264

Month 7

4756 (4152, 5448)

2099 (1663, 2649)

HAVRIX and ENGERIX-B

268

Month 1

444

6

269

Month 2

257

18

269

Month 7

2948 (2638, 3294)

1871 (1428, 2450)

GMT = Geometric mean titer; CI = Confidence Interval.

Since the immune responses to hepatitis A and hepatitis B induced by TWINRIX were non-inferior to the monovalent vaccines, efficacy is expected to be similar to the efficacy for each of the monovalent vaccines.

The antibody titers achieved 1 month after the final dose of TWINRIX were higher than titers achieved 1 month after the final dose of HAVRIX in this clinical trial. This may have been due to a difference in the recommended dosage regimens for these 2 vaccines, whereby vaccinees receiving TWINRIX received 3 doses of 720 EL.U. of hepatitis A antigen at 0, 1, and 6 months, whereas vaccinees receiving HAVRIX received 2 doses of 1440 EL.U. of the same antigen (at 0 and 6 months). However, these differences in peak titer have not been shown to be clinically significant.

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