Hepatitis A Inactivated & Hepatitis B

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 hepatitis B virus surface antigen (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 vials and prefilled syringes. The tip caps of the prefilled syringes may contain natural rubber latex; the plungers are not made with natural rubber latex. The vial stoppers are not made with natural rubber latex.

TWINRIX is formulated without preservatives.

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.

Mechanism Of Action

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.

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

Clinical Studies

In 11 clinical trials, sera from 1,551 healthy adults 17 to 70 years of age, 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).9

Table 2:Seroconversion and Seroprotection Rates in Worldwide Clinical Trials

One of the 11 trials was a comparative trial conducted in a US 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 (18 to 70 years of age) 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; 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 US Clinical Trial

Table 4: Geometric Mean Titers in a US Clinical Trial

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 TWINRIX vaccinees received 3 doses of 720 EL.U. of hepatitis A antigen at 0, 1, and 6 months, whereas HAVRIX vaccinees 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.

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 to 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: -7.80, 1.49). 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: -1.91, 1.94). Non-inferiority was demonstrated as the upper limit of the 95% CI was lower than the pre-defined limit of 7%. The immune responses are presented in Table 5.

Table 5: Seroconversion and Seroprotection Rates up to One Month After the Last Dose of Vaccines (According To Protocol Cohort)

The effect of age on immune response to TWINRIX was studied in 2 trials. The first trial evaluated subjects 41 to 63 years of age (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 19 years of age and older with a comparison between those older than 40 years of age (N = 183, 41 to 70 years of age; mean age = 48) with those 40 years of age or younger (N = 191; 19 to 40 years of age; mean age 33). Over 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, 96.2) achieved seroprotection against hepatitis B compared to 96.9% (95% CI: 93.3, 98.8) of the younger subjects. The GMT was 1,890 mIU/mL in the older subjects compared to 2,285 mIU/mL in the younger subjects.

Two clinical trials involving a total of 129 subjects demonstrated that antibodies to both HAV and HBV surface antigen persisted for at least 4 years after the first vaccine dose in a 3-dose series of TWINRIX, given on a 0-, 1-, and 6-month schedule. For comparison, after the recommended immunization regimens for HAVRIX and ENGERIX-B, respectively, similar studies involving a total of 114 subjects have shown that seropositivity to HAV and HBV also persists for at least 4 years.

REFERENCES

3. Lemon SM. Type A viral hepatitis: new developments in an old disease. N Engl J Med. 1985;313(17):1059-1067.

4. Frisch-Niggemeyer W, Ambrosch F, Hofmann H. The assessment of immunity against hepatitis B after vaccination. J Bio Stand. 1986;14(3):255-258.

You should not receive this vaccine if you are allergic to yeast or neomycin (Mycafradin, Neo-Fradin, Neo-Tab), or if you have ever had a life-threatening allergic reaction to any vaccine containing hepatitis A or hepatitis B.

Before receiving this vaccine, tell the doctor if you have multiple sclerosis, a bleeding or blood clotting disorder, seizures, a weak immune system, if you are taking a blood thinner, or if you are allergic to rubber.

Vaccination with hepatitis A and hepatitis B is recommended for all adults who are at risk of getting hepatitis A or B. Risk factors include: having more than one sex partner in 6 months; being a homosexual male; having sexual contact with infected people; having cirrhosis or chronic hepatitis C; using intravenous (IV) drugs; being on dialysis or receiving blood transfusions; working in healthcare or public safety and being exposed to infected blood or body fluids; being in the military or traveling to high-risk areas; and living with a person who has either hepatitis A or B infection.

Be sure you receive all recommended doses of this vaccine. If you do not receive the full series of vaccines, you may not be fully protected against the disease.

You should not receive a booster vaccine if you had a life-threatening allergic reaction after the first shot.

Hepatitis A and hepatitis B vaccine will not protect you against infection with hepatitis C or E, or other viruses that affect the liver. It will also not protect you from hepatitis if you are already infected with the virus, even if you do not yet show symptoms.

Keep track of any and all side effects you have after receiving this vaccine. When you receive a booster dose, you will need to tell the doctor if the previous shots caused any side effects.

Becoming infected with hepatitis A or B is much more dangerous to your health than receiving the vaccine to protect against these diseases. Like any medicine, this vaccine can cause side effects, but the risk of serious side effects is extremely low.

Hepatitis A and hepatitis B vaccine will not protect you against infection with hepatitis C or E, or other viruses that affect the liver. It will also not protect you from hepatitis A or B if you are already infected with the virus, even if you do not yet show symptoms.

You should not receive this vaccine if you are allergic to yeast or neomycin (Mycafradin, Neo-Fradin, Neo-Tab), or if you have ever had a life-threatening allergic reaction to any vaccine containing hepatitis A or hepatitis B.

Before receiving this vaccine, tell the doctor if you have:

• multiple sclerosis;
• a bleeding or blood clotting disorder such as hemophilia or easy bruising;
• a history of seizures;
• an allergy to latex rubber;
• a weak immune system caused by disease, bone marrow transplant, or by using certain medicines or receiving cancer treatments; or
• if you are taking a blood thinner such as warfarin (Coumadin).

You can still receive a vaccine if you have a cold or fever. In the case of a more severe illness with a fever or any type of infection, wait until you get better before receiving this vaccine.

FDA pregnancy category C. It is not known whether hepatitis A and hepatitis B vaccine is harmful to an unborn baby. Before receiving this vaccine, tell your doctor if you are pregnant.

It is not known whether hepatitis A and hepatitis B vaccine passes into breast milk or if it could harm a nursing baby. Do not receive this vaccine without telling your doctor if you are breast-feeding a baby.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of TWINRIX could reveal adverse events not observed in clinical trials.

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 events were headache (13% to 22%) and fatigue (11% to 14%).

The safety of TWINRIX has been evaluated in clinical trials involving the administration of approximately 7,500 doses to more than 2,500 individuals.

In a US study, 773 subjects (18 to 70 years of age) 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 events reported following the administration of TWINRIX or ENGERIX-B and HAVRIX are presented in Table 1.

Table 1: Rates of Local Adverse Reactions and Systemic Adverse Events Within 4 Days of With or ENGERIX-B and

Most solicited local adverse reactions and systemic adverse events 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 events 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 events were reported to occur within 30 days following vaccination:

Infections and Infestations: Upper respiratory tract infections.

General Disorders and Administration Site Conditions: Injection site induration.

Infections and Infestations: Respiratory tract illnesses.

Metabolism and Nutrition Disorders: Anorexia.

Psychiatric Disorders: Agitation, insomnia.

Nervous System Disorders: Dizziness, migraine, paresthesia, somnolence, syncope.

Ear and Labyrinth Disorders: Vertigo.

Vascular Disorders: Flushing.

Gastrointestinal Disorders: Abdominal pain, vomiting.

Skin and Subcutaneous Tissue Disorders: Erythema, petechiae, rash, sweating, urticaria.

Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, myalgia.

General Disorders and Administration Site Conditions: Injection site ecchymosis, injection site pruritus, influenza-like symptoms, irritability, weakness.

Blood and Lymphatic System Disorders: Lymphadenopathy.a+b

Nervous System Disorders: Dysgeusia,a hypertonia,atingling.b

Eye Disorders: Photophobia.a

Vascular Disorders: Hypotension.b

Gastrointestinal Disorders: Constipation.b

Investigations: Creatine phosphokinase increased.a

a+b Following either HAVRIX or ENGERIX-B.
a Following HAVRIX.
b Following ENGERIX-B.

Adverse events within 30 days of vaccination in the US 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.

Postmarketing Experience

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

The following list includes serious events or events which have suspected causal connection to components of 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-Barr� 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, hyperhydrosis, 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.

The following list includes serious events or events which have suspected causal connection to components of HAVRIX and/or ENGERIX-B, not already reported above for TWINRIX.

Eye Disorders: Keratitis.b

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

Congenital, Familial and Genetic Disorders: Congenital abnormality.a

a Following HAVRIX.
b Following ENGERIX-B.

Read the entire FDA prescribing information for Twinrix (Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine)