TWINRIX- hepatitis a and hepatitis b (recombinant) vaccine_injection, suspension

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

TWINRIX is indicated for active immunization against disease caused by hepatitis A virus and infection by all known subtypes of hepatitis B virus. TWINRIX is approved for use in persons 18 years of age or older. TWINRIX is a vaccine indicated for active immunization against disease caused by hepatitis A virus and infection by all known subtypes of hepatitis B virus.

3 The vaccine should be re-suspended before use. When re-suspended, the vaccine will have a uniform hazy white appearance. Upon storage, a fine white deposit with a clear colorless layer above may be present. Re-suspend the vaccine following the steps below. Hold the syringe upright in a closed hand. Shake the syringe by tipping it upside down and back upright again. Repeat this action vigorously for at least 15 seconds. Inspect the vaccine again: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered. Attach a sterile needle to the prefilled syringe and administer intramuscularly. TWINRIX should be administered by intramuscular injection only as a 1-mL dose. Administer in the deltoid region. Do not administer in the gluteal region; such injections may result in a suboptimal response. Do not administer this product intravenously, intradermally, or subcutaneously. Standard dosing schedule consists of 3 doses (1-mL each), given intramuscularly at 0, 1, and 6 months. Alternatively, an accelerated schedule of 4 doses (1-mL each), given intramuscularly on Days 0, 7, and 21 to 30 followed by a booster dose at Month 12 may be used.

Following any dose of TWINRIX, the most common (>=10%) solicited injection site reactions were injection site soreness (35% to 41%) and redness (8% to 11%); the most common solicited systemic adverse reactions were headache (13% to 22%) and fatigue (11% to 14%). 1 To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822-7967 or. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. The safety of TWINRIX has been evaluated in clinical trials involving the administration of approximately 7,500 doses to more than 2,500 individuals. study, 773 subjects (aged 18 to 70 years) were randomized 1:1 to receive TWINRIX (0-, 1-, and 6-month schedule) or concurrent administration of ENGERIX-B (0-, 1-, and 6-month schedule) and HAVRIX (0- and 6-month schedule). Solicited local adverse reactions and systemic adverse events were recorded by parents/guardians on diary cards for 4 days (Days 0 to 3) after vaccination. Unsolicited adverse events were recorded for 31 days after vaccination. Solicited reactions reported following the administration of TWINRIX or ENGERIX-B and HAVRIX are presented in Table 1. Rates of Local Adverse Reactions and Systemic Adverse Reactions within 4 Days of Vaccination a b c Local TWINRIX ENGERIX-B HAVRIX Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 (n = 385) % (n = 382) % (n = 374) % (n = 382) % (n = 376) % (n = 369) % (n = 382) % (n = 369) % Soreness 37 35 41 41 25 30 53 47 Redness 8 9 11 6 7 9 7 9 Swelling 4 4 6 3 5 5 5 5 Systemic TWINRIX ENGERIX-B and HAVRIX Dose 1 Dose 2 Dose 3 Dose 1 d Dose 2 e Dose 3 d (n = 385) % (n = 382) % (n = 374) % (n = 382) % (n = 376) % (n = 369) % Headache 22 15 13 19 12 14 Fatigue 14 13 11 14 9 10 Diarrhea 5 4 6 5 3 3 Nausea 4 3 2 7 3 5 Fever 4 3 2 4 2 4 Vomiting 1 1 0 1 1 1 a b c d e Most solicited local adverse reactions and systemic adverse reactions seen with TWINRIX were considered by the subjects as mild and self-limiting and did not last more than 48 hours. In a clinical trial in which TWINRIX was given on a 0-, 7-, and 21- to 30-day schedule followed by a booster dose at 12 months, solicited local adverse reactions or systemic adverse reactions were comparable to those seen in other clinical trials of TWINRIX given on a 0-, 1-, and 6-month schedule. Among 2,299 subjects in 14 clinical trials, the following adverse reactions were reported to occur within 30 days following vaccination: Incidence 1% to 10% of Injections, Seen in Clinical Trials with TWINRIX Infections and Infestations: General Disorders and Administration Site Conditions Incidence <1% of Injections, Seen in Clinical Trials with TWINRIX Infections and Infestations: Metabolism and Nutrition Disorders: Psychiatric Disorders: Nervous System Disorders: Ear and Labyrinth Disorders: Vascular Disorders: Gastrointestinal Disorders: Skin and Subcutaneous Tissue Disorders: Musculoskeletal and Connective Tissue Disorders: General Disorders and Administration Site Conditions: Incidence <1% of Injections, Seen in Clinical Trials with HAVRIX and/or ENGERIX-B Blood and Lymphatic System Disorders: a+b Nervous System Disorders: a a b Eye Disorders: a Vascular Disorders: b Gastrointestinal Disorders: b Investigations: a a+b a b Adverse reactions within 30 days of vaccination in the U. clinical trial of TWINRIX given on a 0-, 7-, and 21- to 30-day schedule followed by a booster dose at 12 months were comparable to those reported in other clinical trials. 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: Blood and Lymphatic System Disorders: Immune System Disorders: Nervous System Disorders: Eye Disorders: Ear and Labyrinth Disorders: Cardiac Disorders: Vascular Disorders: Respiratory, Thoracic, and Mediastinal Disorders: Gastrointestinal Disorders: Hepatobiliary Disorders: Skin and Subcutaneous Tissue Disorders: Musculoskeletal and Connective Tissue Disorders: General Disorders and Administration Site Conditions: Investigations: 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: a Skin and Subcutaneous Tissue Disorders: a Congenital, Familial, and Genetic Disorders: b a b.

Severe allergic reaction (e. , anaphylaxis) after a previous dose of any hepatitis A-containing or hepatitis B-containing vaccine, or to any component of TWINRIX, including yeast and neomycin, is a contraindication to administration of TWINRIX [see Description ( 11 Severe allergic reaction (e. , anaphylaxis) after a previous dose of any hepatitis A-containing or hepatitis B-containing vaccine, or to any component of TWINRIX, including yeast and neomycin.

Risk Summary All pregnancies have a risk of birth defect, loss, or other adverse outcomes. 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. 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). 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. 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. Safety and effectiveness in pediatric patients younger than 18 years have not been established. 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.

Do not mix TWINRIX with any other vaccine or product in the same syringe. 1 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. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater-than-physiologic doses), may reduce the immune response to TWINRIX. 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.

NONCLINICAL TOXICOLOGY
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).]
CLINICAL STUDIES
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). Seroconversion and Seroprotection Rates in Worldwide Clinical Trials Dose of TWINRIX n % Seroconversion for Hepatitis A a % Seroprotection for Hepatitis B b 1 1,587 93. 8 2 1,571 98. 2 3 1,551 99. 5 a b One of the 11 trials was a comparative trial conducted in a U. 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. 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. The absolute difference in anti-HBsAg seroprotection rates between groups was 2. 8% (90% CI: -1. 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. Seroconversion and Seroprotection Rates in a U. Clinical Trial Vaccine n Timepoint % Seroconversion for Hepatitis A a % Seroprotection for Hepatitis B b TWINRIX 264 Month 1 91. 9 Month 2 97. 2 Month 7 99. 4) HAVRIX and ENGERIX-B 269 Month 1 98. 5 Month 2 98. 4 Month 7 99. 1) a b Table 4. Geometric Mean Titers in a U. 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) 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. of hepatitis A antigen at 0, 1, and 6 months, whereas vaccinees receiving HAVRIX received 2 doses of 1440 EL. of the same antigen (at 0 and 6 months). However, these differences in peak titer have not been shown to be clinically significant. In 496 healthy adults, the safety and immunogenicity of TWINRIX given on a 0-, 7-, and 21- to 30-day schedule followed by a booster dose at 12 months (n = 250), was compared with separate vaccinations with monovalent hepatitis A vaccine (HAVRIX at 0 and 12 months) and hepatitis B vaccine (ENGERIX-B at 0, 1, 2, and 12 months) as a control group (n = 246). Following a booster dose at Month 12, seroprotection rates for hepatitis B and seroconversion rates for hepatitis A at Month 13 following TWINRIX were non-inferior to the control group. The absolute difference in anti-HBs seroprotection rates between groups (HAVRIX + ENGERIX-B minus TWINRIX) was -2. 99 (95% CI: -7. Non-inferiority was demonstrated as the upper limit of the 95% CI was lower than the pre-defined limit of 7%. The absolute difference in anti-HAV seroprotection rates between groups (HAVRIX + ENGERIX-B minus TWINRIX) was 0 (95% CI: -1. The immune responses are presented in Table 5. Seroconversion and Seroprotection Rates up to 1 Month after the Last Dose of Vaccines (According-to-Protocol Cohort) Timepoint TWINRIX a HAVRIX and ENGERIX-B b (n = 194-204) (n = 197-207) % Seroconversion for Hepatitis A c Day 37 98. 7) Day 90 100 (98. 0) Month 12 96. 2) Month 13 100 (98. 1, 100) 100 (98. 1, 100) % Seroprotection for Hepatitis B d Day 37 63. 5) Day 90 83. 3) Month 12 82. 4) Month 13 96. 4) a b c d The effect of age on immune response to TWINRIX was studied in 2 trials. The first trial evaluated subjects aged 41 to 63 years (N = 72; mean age = 50). All subjects were seropositive for anti-HAV antibodies following the third dose of TWINRIX. For the hepatitis B response, 94% of subjects were seroprotected after the third dose of TWINRIX. The second trial included subjects aged 19 years and older with a comparison between those older than 40 years (n = 183, aged 41 to 70 years; mean age: 48) and those aged 40 years or younger (n = 191; aged 19 to 40 years; mean age: 33). More than 99% of subjects in both age groups achieved a seropositive response for anti-HAV antibodies, and GMTs were comparable between the age groups. In the older subjects who received TWINRIX, 92. 9% (95% CI: 88. 2) achieved seroprotection against hepatitis B compared with 96. 9% (95% CI: 93. 8) of the younger subjects. The GMT was 1,890 mIU/mL in the older subjects compared with 2,285 mIU/mL in the younger subjects. Two clinical trials involving a total of 129.
REFERENCES
1. N Engl J Med. 2. N Engl J Med. 3. N Engl J Med. 4. J Bio Stand.

GlaxoSmithKline Biologicals SA

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