TWINRIX® [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine] is a sterile bivalent vaccine containing the antigenic components used in producing HAVRIX® (Hepatitis A Vaccine, Inactivated) and ENGERIX-B® [Hepatitis B Vaccine (Recombinant)]. TWINRIX is a sterile suspension of inactivated hepatitis A virus (strain HM175) propagated in MRC-5 cells, and combined with purified surface antigen of the hepatitis B virus. The purified hepatitis B surface antigen (HBsAg) is obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus, in synthetic media containing inorganic salts, amino acids, dextrose, and vitamins. Bulk preparations of each antigen are adsorbed separately onto aluminum salts and then pooled during formulation.

A 1.0-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, 5.0 mg 2-phenoxyethanol as a preservative, sodium chloride, phosphate buffer, polysorbate 20, Water for Injection, traces of formalin (not more than 0.1 mg), a trace amount of thimerosal (<1 mcg mercury) from the manufacturing process, and residual MRC-5 cellular proteins (not more than 2.5 mcg). Neomycin sulfate, an aminoglycoside antibiotic, is included in the cell growth media; only trace amounts (not more than 20 ng) remain following purification. The manufacturing procedures used to manufacture TWINRIX result in a product that contains no more than 5% yeast protein.

TWINRIX is supplied as a sterile suspension for intramuscular administration. The vaccine is ready for use without reconstitution; it must be well shaken before administration to obtain a homogeneous, turbid, white suspension.

TWINRIX is indicated for active immunization of persons 18 years of age or older against disease caused by hepatitis A virus and infection by all known subtypes of hepatitis B virus. As with any vaccine, vaccination with TWINRIX may not protect 100% of recipients. As hepatitis D (caused by the delta virus) does not occur in the absence of HBV infection, it can be expected that hepatitis D will also be prevented by vaccination with TWINRIX.

Immunization is recommended for all susceptible persons 18 years of age or older who are, or will be, at risk of exposure to both hepatitis A and hepatitis B viruses, including but not limited to:

• Travelers: Persons traveling to areas of high/intermediate endemicity for both HAV and HBV who are at increased risk of HBV infection due to behavioral or occupational factors. (See CLINICAL PHARMACOLOGY.) Vaccine recipients should consult with CDC to determine regions of high or intermediate endemicity for hepatitis A and hepatitis B.
• Patients With Chronic Liver Disease, including: - alcoholic cirrhosis
  • chronic hepatitis C
    
  • autoimmune hepatitis
    
  • primary biliary cirrhosis
• Persons at Risk Through Their Work:
  • Laboratory workers who handle live hepatitis A and hepatitis B virus
  • Police and other personnel who render first-aid or medical assistance
  • Workers who come in contact with feces or sewage
  • Healthcare personnel who render first-aid or emergency medical assistance.
  • Personnel employed in day-care centers and correctional facilities.
  • Staff of hemodialysis units.
  • Military recruits and other military personnel at increased risk for HBV.
• Persons at Increased Risk of Disease due to Their Sexual Practices^18,19: - Men who have sex with men.
• Others:
  • Residents of drug and alcohol treatment centers.
  • People living in, or relocating to, areas of high/intermediate endemicity of HAV and who have risk factors for HBV.
  • Patients frequently receiving blood products including persons who have clotting factor disorders (hemophiliacs and other recipients of therapeutic blood products).
  • Users of injectable illicit drugs.
  • Individuals who are at increased risk for HBV infection and who are close household contacts of patients with acute or relapsing hepatitis A and individuals who are at increased risk for HAV infection and who are close household contacts of individuals with acute or chronic hepatitis B infection.

TWINRIX should be administered by intramuscular injection. Do not inject intravenously or intradermally. In adults, the injection should be given in the deltoid region. TWINRIX should not be administered in the gluteal region; such injections may result in a suboptimal response.

Primary immunization for adults consists of 3 doses, given on a 0-, 1-, and 6-month schedule. Alternatively, a 4-dose schedule, given on days 0, 7 and 21 to 30 followed by a booster dose at month 12 may be used. Each 1-mL dose contains 720 EL.U. of inactivated hepatitis A virus and 20 mcg of hepatitis B surface antigen.

When concomitant administration of other vaccines or immunoglobulin (IG) is required, they should be given with different syringes and at different injection sites.

Preparation for Administration: Shake vial or syringe well before withdrawal and use. Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration. With thorough agitation, TWINRIX is a slightly turbid white suspension. Discard if it appears otherwise.

The vaccine should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used. After removal of the appropriate volume from a single-dose vial, any vaccine remaining in the vial should be discarded.

Storage

Store TWINRIX refrigerated between 2° and 8° C (36° and 46° F). Do not freeze. Discard if the

vaccine has been frozen. Do not use after expiration date shown on the label.

TWINRIX is supplied as a slightly turbid white suspension in vials and prefilled TIP-LOK® syringes containing a 1.0-mL single dose.

Single-Dose Vials

NDC 58160-850-01 (package of 1)
NDC 58160-850-11 (package of 10)

Single-Dose Prefilled Disposable TIP-LOK Syringes (packaged without needles)

NDC 58160-850-46 (package of 5)

References

18. Centers for Disease Control and Prevention. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR 1999;47(RR-1):99-104.
19. Centers for Disease Control and Prevention. Hepatitis surveillance report No. 57. Atlanta, GA: DHHS; 2000:12.

Manufactured by GlaxoSmithKline, Rixensart, Belgium, US License No. 1617 Distributed by GlaxoSmithKline, Research Triangle Park, NC 27709

TWINRIX, HAVRIX, ENGERIX-B, and TIP-LOK are registered trademarks of GlaxoSmithKline. ENZYMUN-TEST is a registered trademark of Boehringer Mannheim Immunodiagnostics. AUSAB is a registered trademark of Abbott Laboratories.

©YEAR, GlaxoSmithKline. All rights reserved.

Because clinical trials are conducted under widely varying conditions, adverse event 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.

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

Of 773 volunteers who participated in the comparative trial conducted in the United States, 389 subjects received at least 1 dose of TWINRIX (0-, 1-, and 6-month schedule) and 384 received at least 1 dose each of ENGERIX-B and HAVRIX as separate but simultaneous injections. Solicited adverse events reported following the administration of TWINRIX are shown in Table 5, compared with adverse events reported after administration of ENGERIX-B and HAVRIX.

Table 5. Rate of Adverse Events Reported After Administration of TWINRIX or ENGERIX-B and HAVRIX

Adverse reactions seen with TWINRIX were similar to those observed after vaccination with the monovalent components. The frequency of solicited adverse events did not increase with successive doses of TWINRIX. Most events reported 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 or general 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 experiences were reported to occur within 30 days following vaccination with the frequency shown below. Adverse experiences 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 similar to those reported in other clinical trials and post marketing surveillance.

Incidence 1% to 10% of Injections, Seen in Clinical Trials With TWINRIX:

Local Reactions at Injection Site: Induration.

Respiratory System: Upper respiratory tract infections.

Incidence <1% of Injections, Seen in Clinical Trials With TWINRIX:

Local Reactions at Injection Site: Pruritus, ecchymoses.

Body as a Whole: Sweating, weakness, flushing, influenza-like symptoms.

Cardiovascular System: Syncope.

Gastrointestinal System: Abdominal pain, anorexia, vomiting.

Musculoskeletal System: Arthralgia, myalgia, back pain.

Nervous System: Migraine, paresthesia, vertigo, somnolence, insomnia, irritability, agitation, dizziness.

Respiratory System: Respiratory tract illnesses.

Skin and Appendages: Rash, urticaria, petechiae, erythema. Incidence <1% of Injections, Seen in Clinical Trials With HAVRIXa and/or ENGERIX-B^b:

Body as a Whole: Tingling.^b

Cardiovascular System: Hypotension.^b

Gastrointestinal: Constipation,b dysgeusia.^a

Hematologic/lymphatic: Lymphadenopathy.^a+b

Musculoskeletal System: Elevation of creatine phosphokinase.^a

Nervous System: Hypertonic episode,a photophobia.^a

Postmarketing Reports: Worldwide voluntary reports of adverse events received for TWINRIX, HAVRIX, and/or ENGERIX-B since market introduction of these vaccines are listed below. These lists include serious events or events which have suspected causal connections to components of these or other vaccines or drugs. 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 vaccine exposure.

Postmarketing Reports With TWINRIX:

Body as a Whole: Anaphylaxis/anaphylactoid reactions and allergic reactions.

Hypersensitivity: Arthritis, serum sickness-like syndrome days to weeks after vaccination including arthralgia/arthritis (usually transient), fever, urticaria, erythema multiforme, ecchymoses, and erythema nodosum.

Cardiovascular System: Tachycardia/palpitations.

Skin and Appendages: Erythema multiforme, hyperhydrosis, angioedema, eczema, herpes zoster, erythema nodosum, alopecia.

Gastrointestinal System: Jaundice, hepatitis, abnormal liver function tests, dyspepsia.

Hematologic/lymphatic: Thrombocytopenia.

Nervous System: Convulsions, paresis, encephalopathy, neuropathy, myelitis, Guillain-Barre syndrome, multiple sclerosis, Bell's palsy, transverse myelitis, optic neuritis.

Respiratory System: Dyspnea, bronchospasm including asthma-like symptoms.

Special Senses: Conjunctivitis, visual disturbances, tinnitus, earache.

Postmarketing Reports With HAVRIX and/or ENGERIX-B: Worldwide voluntary reports of adverse events received for HAVRIX and/or ENGERIX-B but not already reported for TWINRIX are listed below.

Hypersensitivity: Stevens-Johnson syndrome.b Special Senses: Keratitis.^b

Other: Congenital abnormality.^a

^aFollowing HAVRIX.
^bFollowing ENGERIX-B.
^a+bFollowing either HAVRIX or ENGERIX-B.

Reporting of Adverse Events: The US Department of Health and Human Services has established 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 1-800-822-7967.²³ Reporting forms may also be obtained at the VAERS website at www.vaers.hhs.gov.

No information provided.

References

23. Centers for Disease Control and Prevention. Vaccine adverse event reporting system - United States. MMWR 1990;39(41):730-733.

There have been rare reports of anaphylaxis/anaphylactoid reactions following routine clinical use of TWINRIX. (See ADVERSE REACTIONS, Postmarketing Reports.)

The tip cap and the rubber plunger of the needleless prefilled syringes contain dry natural latex rubber that may cause allergic reactions in latex sensitive individuals. The vial stopper is latex-free.

Hepatitis A and hepatitis B have relatively long incubation periods. The vaccine may not prevent hepatitis A or hepatitis B infection in individuals who have an unrecognized hepatitis A or hepatitis B infection at the time of vaccination. Additionally, it may not prevent infection in individuals who do not achieve protective antibody titers.

General: Prior to immunization with TWINRIX, the patient's current health status and medical history should be reviewed. The physician should review the patient's immunization history for possible vaccine sensitivity, previous vaccination-related adverse reactions and occurrence of any adverse-event-related symptoms and/or signs, in order to determine the existence of any contraindication to immunization with TWINRIX and to allow an assessment of benefits and risks. Appropriate medical treatment and supervision should be readily available for immediate use in case of a rare anaphylactic reaction following the administration of the vaccine. Epinephrine injection (1:1,000) and other appropriate agents used for the control of immediate allergic reactions must be immediately available. As with other vaccines, although a moderate or severe acute illness is sufficient reason to postpone vaccination, minor illnesses such as mild upper respiratory infections with or without low-grade fever are not contraindications.²⁰

TWINRIX should be given with caution in persons with bleeding disorders such as hemophilia or thrombocytopenia and in persons on anticoagulant therapy, with steps taken to avoid the risk of hematoma following the injection.20

A separate, sterile syringe and needle or a sterile disposable unit should be used for each patient to prevent the transmission of other infectious agents from person to person. Needles should be disposed of properly and should not be recapped.

As with any vaccine, if administered to immunosuppressed persons, including individuals receiving immunosuppressive therapy, the expected immune response may not be obtained.

Multiple Sclerosis: Results from 2 clinical studies indicate that there is no association between hepatitis B vaccination and the development of multiple sclerosis,²¹ and that vaccination with hepatitis B vaccine does not appear to increase the short-term risk of relapse in multiple sclerosis.²²

Carcinogenesis, Mutagenesis, Impairment of Fertility: TWINRIX has not been evaluated for its carcinogenic potential, mutagenic potential, or potential for impairment of fertility.

Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with TWINRIX. It is also not known whether TWINRIX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TWINRIX should be given to a pregnant woman only if clearly indicated (see INDICATIONS AND USAGE).

Pregnancy Exposure Registry: Healthcare providers are encouraged to register pregnant women who receive TWINRIX in the GlaxoSmithKline vaccination pregnancy registry by calling 1-888-825-5249.

Nursing Mothers: It is not known whether TWINRIX is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TWINRIX is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric Use: Clinical studies of TWINRIX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

References

20. Centers for Disease Control and Prevention. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(RR-15):1-48.
21. Ascherio A, Zhang SM, Hernán MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001;344(5):327-332.
22. Confavreux C, Suissa S, Saddier P, et al. Vaccination and the risk of relapse in multiplesclerosis. N Engl J Med 2001;344(5):319-326.

No information provided.

Hypersensitivity to any component of the vaccine, including yeast and neomycin, is a contraindication (see DESCRIPTION). This vaccine is contraindicated in patients with previous hypersensitivity to TWINRIX or monovalent hepatitis A or hepatitis B vaccines.

Several hepatitis viruses (A, B, C, D, and E) are known to cause a systemic infection resulting in major pathologic changes in the liver. Features of hepatitis A and hepatitis B are described below.

Hepatitis A: The hepatitis A virus (HAV) belongs to the picornavirus family.

Hepatitis A is a highly contagious disease with the predominant mode of transmission being person-to-person via the fecal-oral route. Infection has been shown to be spread (1) by contaminated water or food; (2) by infected food handlers¹; (3) after breakdown in usual sanitary conditions or after floods or natural disasters; (4) by ingestion of raw or undercooked shellfish (oysters, clams, mussels) from contaminated waters²; (5) during travel to areas of the world with poor hygienic conditions³; (6) among institutionalized children and adults⁴; (7) in day-care centers⁵; (8) by parenteral transmission, either blood transfusions or sharing needles with infected people⁶; and (9) sexually, especially among men who have sex with men.⁷

The incubation period for hepatitis A averages 28 days (range: 15 to 50 days).7 The course of hepatitis A infection is extremely variable, ranging from asymptomatic infection to icteric hepatitis and death.⁸

Chronic shedding of HAV in feces has not been demonstrated, but relapses of hepatitis A can occur in as many as 20% of patients^9,10 and fecal shedding of HAV may recur at this time.9 Approximately 70% of pediatric patients less than 6 years of age infected with hepatitis A are asymptomatic, and serve as a reservoir for infection among adults.7

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. At present, studies show the duration of protection afforded by TWINRIX against hepatitis A lasts at least 4 years.¹¹

Hepatitis B: The hepatitis B virus (HBV) belongs to a family of genetically related DNA-containing animal viruses, which are hepatotropic. The incubation period of hepatitis B ranges between 30 and 180 days.¹²

HBV infection occurs throughout the world with highly variable prevalences. A human reservoir of persistently infected persons is present in nearly all communities of the world. In the United States, parenteral drug abuse, unprotected sexual activity, occupationally acquired infection, or travelers returning from high prevalence countries may be the principal mechanisms of HBV transmission.

Modes of transmission of hepatitis B virus include sexual contact with an infected person, percutaneous or mucosal exposure to infectious blood, and perinatal exposure to an infected mother. Antibody concentrations ≥10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B.¹³

Clinical infection with hepatitis B may occur in 2 major forms: Asymptomatic or symptomatic hepatitis. Asymptomatic HBV infection can be subclinical or inapparent. In subclinical infection, patients have abnormal liver enzymes without jaundice, while inapparent asymptomatic infection is identified only by serological testing. One in 4 adults who has symptomatic disease has jaundice (anicteric/icteric hepatitis).

HBV infection can have serious consequences including acute massive hepatic necrosis, chronic active hepatitis, and cirrhosis of the liver. As many as 90% of infants and approximately 5%of adults who are infected with HBV will become HBV carriers.7 More than 350 million people are chronic carriers of HBV worldwide.7 The Centers for Disease Control and Prevention (CDC) estimates that there are approximately 1 million to 1.25 million chronic carriers of HBV in the United States.7 The annual number of unreported infections may be 10 times greater than the number of reported cases.7 Close contact (sexual contact or household contact) or exposure to blood from infected individuals is associated with increased risk of infection.7 Those patients who become chronic carriers can infect others and are at increased risk of developing primary hepatocellular carcinoma. Among other factors, infection with HBV may be the single most important factor for development of this carcinoma.^7,14

Reduced Risk of Hepatocellular Carcinoma: According to the Centers for Disease Control and Prevention (CDC), hepatitis B vaccine is recognized as an anti-cancer vaccine because it can prevent primary liver cancer.¹⁵ In a Taiwanese study, the institution of universal childhood immunization against hepatitis B virus has been shown to decrease the incidence of hepatocellular carcinoma among children.¹⁶ In a Korean study in adult males, vaccination against the hepatitis B virus has been shown to decrease the incidence and risk of developing hepatocellular carcinoma in adults.¹⁷

Clinical Trials: Immunogenicity in Adults: Sera from 1,551 healthy adult volunteers ages 17 to 70, including 555 male subjects and 996 female subjects, in 11 clinical trials were analyzed following administration of 3 doses of TWINRIX on a 0-, 1-, and 6-month schedule. Seroconversion for antibodies against HAV was elicited in 99.9% of vaccinees, and protective antibodies against HBV were detected in 98.5%, 1 month after completion of the 3-dose series.

Table 1. Immunogenicity in TWINRIX 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 a total of 773 adults (ages 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 against HAV and seroprotection against HBV are shown in Table 2.

Table 2. Percentage of Seroconversion or Seroprotection Rates in the TWINRIX 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 (Table 3).

Table 3. Geometric Mean Titers in the TWINRIX US Clinical Trial

It was noted that 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 these clinical trials. 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.

Two clinical trials involving a total of 129 subjects demonstrated that antibodies to both HAV and HBV 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.

The effect of age on immune response to TWINRIX was studied in 2 trials comparing subjects over 40 years of age (n = 183, mean age = 48 in one trial and n = 72, mean age = 50 in the other) with those ≤40 (n = 191; mean age 32.5). The response to the hepatitis A component of TWINRIX declined slightly with age, but >99% of subjects achieved protective antibody levels in both age groups, and antibody titers were comparable to 2 doses of hepatitis A vaccine alone in age matched controls.

The response to hepatitis B immunization is known to decline in vaccinees over 40 years of age. TWINRIX elicited a seroprotective response to hepatitis B in 97% of younger subjects and 93% to 94% of the older subjects, as compared to 92% of older subjects given hepatitis B vaccine alone. Geometric mean titers elicited by TWINRIX were 2,285 in the younger subjects and 1,890 or 1,038 for the older subjects in the 2 trials. Hepatitis B vaccine alone gave titers of 2,896 in younger subjects and 1,157 in those over 40 years of age.

It has been shown in open randomized clinical trials that combining the hepatitis A antigen with the hepatitis B surface antigen in TWINRIX resulted in comparable anti-HAV or anti-HBsAg titers, relative to vaccination with the individual monovalent vaccines or the concomitant administration of each vaccine in opposite arms.

Accelerated Dosing Schedule: 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, the seroprotection rate for hepatitis B and seroconversion rate for hepatitis A at month 13 (the coprimary endpoints) following TWINRIX were non-inferior as compared to the control group. The immune responses for the According to Protocol (ATP) cohort for immunogenicity are shown in Table 4 and Figure 1.

At day 37, following 3 doses of TWINRIX, the seroprotection rate for hepatitis B was 63.2% and in the control group, who received 2 doses of ENGERIX-B, was 43.5%. This difference of 19.76% [95% CI for the difference is 10.16% to 28.99%] is statistically significant (p <0.001). No statistical significant difference in the hepatitis A seroconversion rates was observed between groups at day 37. At day 90, the hepatitis A seroconversion rate following TWINRIX was 100% compared to 95.6% in the control group (p = 0.004). At month 12 before the booster dose, the hepatitis A seroconversion rates between groups, 96.9% following TWINRIX and 86.9% in the control group, were statistically significantly different (p <0.001).

Table 4. Seroconversion and Seroprotection Rates Up to One Month After the Last Dose of Vaccines (According To Protocol Cohort)

Figure 1. Seroconversion and Seroprotection Rates Up to One Month After the Last Dose of Vaccines (According To Protocol Cohort)

Immune Response to Simultaneously Administered Vaccines: Limited immunogenicity data are available on the concurrent administration of TWINRIX with other vaccines.

References

1. Dienstag JL, Routenberg JA, Purcell RH, et al. Foodhandler-associated outbreak of hepatitis type A. An immune electron microscopic study. Ann Intern Med 1975;83:647-650.
2. Mackowiak PA, Caraway CT, Portnoy BL. Oyster-associated hepatitis: Lessons from the Louisiana experience. Am J Epidemiol 1976;103(2):181-191.
3. Woodson RD, Clinton JJ. Hepatitis prophylaxis abroad. Effectiveness of immune serum globulin in protecting Peace Corps volunteers. JAMA 1969;209(7):1053-1058.
4. Krugman S, Giles JP. Viral hepatitis. New light on an old disease. JAMA 1970;212(6):1019-1029.
5. Hadler SC, Erben JJ, Francis DP, et al. Risk factors for hepatitis A in day-care centers. J Infect Dis 1982;145(2):255-261.
6. Hadler SC. Global impact of hepatitis A virus infection changing patterns. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore, MD: Williams & Wilkins; 1991:14-20.
7. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. 10th ed. Washington DC: Public Health Foundation; 2007:197-234.
8. Lemon SM. Type A viral hepatitis. New developments in an old disease. N Engl J Med 1985;313(17):1059-1067.
9. Sjogren MH, Tanno H, Fay O, et al. Hepatitis A virus in stool during clinical relapse. Ann Intern Med 1987;106:221-226.
10. Chiriaco P, Guadalupi C, Armigliato M, et al. Polyphasic course of hepatitis type A in children. J Infect Dis 1986;153(2):378-379.
11. Data on file (TWR101), GlaxoSmithKline.
12. Koff RS. Hepatitis B and hepatitis D. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious diseases. Philadelphia, PA: WB Saunders Company; 1992:709-716.
13. Frisch-Niggemeyer W, Ambrosch F, Hofmann H. The assessment of immunity against hepatitis B after vaccination. J Bio Stand 1986;14(3):255-258.
14. Beasley RP, Hwang LY, Stevens CE, et al. Efficacy of hepatitis B immune globulin for prevention of perinatal transmission of the hepatitis B virus carrier state: Final report of a randomized double-blind, placebo-controlled trial. Hepatology 1983;3(2):135-141.
15. Centers for Disease Control and Prevention. Proposed vaccine information materials for hepatitis B, Haemophilus influenza type B (Hib), varicella (chickenpox), and measles, mumps, rubella (MMR) vaccines. Federal Register September 3, 1998;63(171):47026-47031.
16. Chang MH, Chen CJ, Lai MS. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336(26):1855-1859.
17. Lee MS, Kim DH, Kim H, et al. Hepatitis B vaccination and reduced risk of primary liver cancer among male adults: A cohort study in Korea. Int J Epidemiol 1998;27:316-319.

Information for Vaccine Recipients: Vaccine recipients should be informed by their healthcare provider of the potential benefits and risks of immunization with TWINRIX. When educating vaccine recipients regarding potential side effects, clinicians should emphasize that components of TWINRIX cannot cause hepatitis A or hepatitis B infection.

Vaccine recipients should be instructed to report any severe or unusual adverse reactions to their healthcare provider.

The vaccine recipients should be given the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the CDC website (www.cdc.gov/nip). The Vaccine Adverse Events Reporting System (VAERS) toll-free number is 1-800-822-7967. Reporting forms may also be obtained at the VAERS website at www.vaers.hhs.gov.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

HEPATITIS-A/HEPATITIS-B VACCINE - INJECTION

(hep-uh-TIE-tuss B/hep-uh-TIE-tuss A)

COMMON BRAND NAME(S): Twinrix

USES: This combination medication is used to help prevent infection from the hepatitis A and B viruses. Hepatitis A infection can be mild with no symptoms or a severe illness that can rarely cause liver failure and death. Hepatitis B infection can cause serious problems including liver failure, persistent hepatitis B infection, cirrhosis, and liver cancer. Preventing infection with these viruses can prevent these problems.

Hepatitis A/B combination vaccine is made from whole, killed hepatitis A virus and a genetically engineered (man-made in the laboratory) piece of hepatitis B virus. It does not contain live virus, so you can not get hepatitis from the vaccine. This vaccine causes the body to make immune defensive substances (antibodies) against hepatitis A and B viruses that can protect you from infection with them. Hepatitis A/B vaccine does not protect you from other virus infections (e.g., HIV virus which causes AIDS, hepatitis C/E, HPV virus which causes genital warts and other problems).

The vaccine is recommended for persons at an increased risk of getting these infections. Those at an increased risk include health care personnel, laboratory workers who handle blood and patient specimens, police, fire and emergency medical personnel who give first aid treatment, hemophiliacs, dialysis patients, household and intimate contacts of persons with persistent hepatitis B or active hepatitis A infections, persons with multiple sex partners, men who have sex with men, sex workers, injection drug abusers, and persons traveling to high-risk areas.

HOW TO USE: This vaccine is usually given by injection into the shoulder muscle by a health care professional. Hepatitis A/B vaccine is a slightly milky, white suspension. Before giving this medication, inspect it visually for particles or discoloration. If either is present, do not use the liquid. Shake the vial or prefilled syringe well before giving the dose. Do not dilute. Use the full recommended dose of the vaccine. Discard any remaining vaccine left in single-dose vials.

A series of 3 injections is usually given over 6 months. Your doctor will give you a vaccination schedule, which must be followed closely for best effectiveness. If you have an infection with fever at the time a vaccination is scheduled, your doctor may choose to delay the injection until you are better.

Dosage is based on your age. Different brands of hepatitis A/B vaccine are available for different ages and may be given differently.

If you are receiving the first hepatitis A/B vaccine injection at a time when your doctor feels you may have been exposed to either hepatitis A or B, you will also receive an injection of immune globulin. Immune globulin is a dose of antibodies against the viruses and will immediately help protect you from developing an infection. These antibodies only last a few months. For long-term protection, it is important to follow your vaccination schedule exactly.

SIDE EFFECTS: Pain/redness/swelling at the injection site, fever, tiredness, headache, nausea, and diarrhea may occur. Less common side effects may include bruising/itching at the injection site, sweating, dizziness, weakness, muscle/joint aches, cold symptoms, vomiting, temporary loss of appetite, abdominal cramps, constipation, swollen glands (lymph nodes), irritability, agitation, and trouble sleeping. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Report all side effects to your doctor before you receive the next injection.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fast/irregular heartbeat, fainting, severe headache (migraine).

Tell your doctor immediately if any of these rare but very serious side effects occur: tingling/numbness, inability to make muscles of the legs/arms/face work (paralysis), vision changes, seizures, easy bruising/bleeding, mental/mood changes (e.g., unusual behavior, confusion, severe drowsiness, severe tiredness, stiff neck, visual sensitivity to light).

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before getting hepatitis A/B vaccine, tell your doctor or pharmacist if you are allergic to it; or to yeast, neomycin, formalin, or other vaccines; or if you have any other allergies. Some vials and prefilled syringes may use latex rubber stoppers or plungers. Tell your doctor if you are allergic to latex.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: bleeding problems (e.g., hemophilia, low platelets, anticoagulant treatment), current illness with fever.

Some brands of this product may contain a small amount of mercury from a preservative (thimerosal). Consult your doctor for more information.

If you are a hemodialysis patient, you may not respond as well to the vaccine and will need to have hepatitis A or B antibody levels checked yearly. If antibodies drop too low over time, you may be given a booster vaccine.

If you have decreased immune function from other medications (see also Drug Interactions) or other illness (e.g., HIV, leukemia, lymphoma, other cancer), your body may not make enough antibodies to protect you from hepatitis A or B infection. Antibody levels should be checked after the vaccine series.

The elderly may not make as many antibodies to the vaccine and should have their antibody levels checked after the vaccine series.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them

Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of medications that can decrease immune function: corticosteroids (e.g., prednisone), cancer chemotherapy, organ transplant drugs (e.g., cyclosporine, azathioprine).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting the hepatitis A/B vaccine series.

Other vaccines may be given at the same time as hepatitis A/B vaccine, but should be given with separate syringes and at different injection sites.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (e.g., hepatitis A or B antibody levels) may be performed periodically for some patients at risk of a poor response to the vaccine. Consult your doctor for more details.

MISSED DOSE: It is important to receive each vaccination as scheduled. Be sure to ask when each dose should be received and make a note on a calendar to help you remember.

STORAGE: Store refrigerated between 36-46 degrees F (2-8 degrees C) away from light. Do not freeze. Discard any product that has been frozen. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.