Recombivax Hb Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .......................................................................................... 2

TABLE OF CONTENTS ............................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION .................................................................... 4

1 INDICATIONS ............................................................................................................. 4

1.1 Pediatrics ...................................................................................................................... 4

1.2 Geriatrics ...................................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................ 4

4 DOSAGE AND ADMINISTRATION ................................................................................ 4

4.2 Recommended Dose and Dosage Adjustment ............................................................ 4

4.4 Administration ............................................................................................................. 7

5 OVERDOSAGE ............................................................................................................ 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 8

7 WARNINGS AND PRECAUTIONS ............................................................................... 10

7.1 Special Populations .................................................................................................... 10

7.1.1 Pregnant Women ............................................................................................. 10

7.1.2 Breast-feeding .................................................................................................. 10

7.1.3 Pediatrics .......................................................................................................... 11

7.1.4 Geriatrics .......................................................................................................... 11

8 ADVERSE REACTIONS............................................................................................... 11

8.1 Adverse Reaction Overview ....................................................................................... 11

8.2 Clinical Trial Adverse Reactions ................................................................................. 11

8.5 Post-Market Adverse Reactions ................................................................................. 13

9 DRUG INTERACTIONS .............................................................................................. 14

9.4 Drug-Drug Interactions .............................................................................................. 14

10 CLINICAL PHARMACOLOGY ...................................................................................... 15

10.3 Pharmacokinetics ..................................................................................................... 16

11 STORAGE, STABILITY AND DISPOSAL ........................................................................ 17

12 SPECIAL HANDLING INSTRUCTIONS .......................................................................... 17

PART II: SCIENTIFIC INFORMATION ..................................................................................... 18

13 PHARMACEUTICAL INFORMATION .......................................................................... 18

14 CLINICAL TRIALS ...................................................................................................... 19

14.2 Study Results ............................................................................................................ 19

14.4 Immunogenicity ....................................................................................................... 19

15 MICROBIOLOGY ...................................................................................................... 20

16 NON-CLINICAL TOXICOLOGY .................................................................................... 20

PATIENT MEDICATION INFORMATION ................................................................................ 21

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

RECOMBIVAX HB® (hepatitis B vaccine [recombinant]) is indicated for immunization against infection caused by all known subtypes of hepatitis B virus.

The National Advisory Committee of Immunization (NACI) provides additional guidance on the use of hepatitis B vaccines in Canada. Please refer to the Canadian Immunization Guide.

RECOMBIVAX HB® should prevent hepatitis D (caused by the delta virus), since hepatitis D does not occur in the absence of hepatitis B infection.

1.1 Pediatrics

Pediatrics: Based on the data submitted and reviewed by Health Canada, the safety and efficacy of RECOMBIVAX HB® in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use.

1.2 Geriatrics

Clinical studies of RECOMBIVAX HB® used for licensure did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects (see 7 WARNINGS AND PRECAUTIONS, 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

RECOMBIVAX HB® (hepatitis B vaccine [recombinant]) should not be administered to:

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section.

4 DOSAGE AND ADMINISTRATION

4.2 Recommended Dose and Dosage Adjustment

Three-Dose Regimen

The vaccination regimen consists of three doses of vaccine given according to the following schedule:

First injection: at elected date

Second injection: ≥ 1 month after first injection

Third injection: ≥ 1 month after second injection

Within limits, the timing of successive injections may be adjusted to accommodate a variety of needs, such as coadministration with other vaccines.

For infants born of mothers who are HbsAg positive or mothers of unknown HBsAg status, treatment recommendations are described in the subsections titled: Dosage for Infants Born to HBsAg-Positive Mothers.

A minimum of one month should separate successive injections of vaccine. Accelerated three-dose regimens (e.g., 0, 1, 2 months; 0, 2, 4 months) may induce protective antibody earlier in a slightly larger proportion of vaccinees. However, regimens that extend the time interval between the second and third injections (e.g., 0, 1, 6 months; 0, 1, 12 months) will ultimately seroconvert a similar proportion of vaccinees while inducing substantially higher antibody titers than accelerated regimens.

The dose of vaccine to be given on each occasion is as follows:

Two-Dose Regimen - Adolescents (11 to 15 years of age)

An alternate two-dose regimen is available for routine vaccination of adolescents (11 to 15 years of age). The regimen consists of two doses of vaccine (10 mcg) given according to the following schedule:

1st dose: at elected date

2nd dose: 4 to 6 months after the first dose

RECOMBIVAX HB® Dialysis 40 mcg/mL Formulation

RECOMBIVAX HB® DIALYSIS FORMULATION (40 mcg/mL) IS INTENDED ONLY FOR ADULT PREDIALYSIS/ DIALYSIS PATIENTS.

The recommended vaccination regimen for predialysis/dialysis patients is as follows:

Revaccination of Nonresponders

When persons who do not respond (anti-HBs < 10 IU/L) to the primary vaccine series are revaccinated, 15-25% produce an adequate antibody response after one additional dose and 30-50% after three additional doses. However, because data are insufficient concerning the safety of hepatitis B vaccine when additional doses in excess of the recommended two- or three-dose series are administered, revaccination following completion of the primary series is not routinely recommended. Revaccination should only be considered for high-risk individuals, after weighing the benefits of vaccination against the potential risk of experiencing increased local or systemic adverse reactions.

Dosage for Infants Born to HBsAg-positive Mothers

Infants born to HBsAg-positive mothers are at high risk of becoming chronic carriers of hepatitis B virus and of developing the chronic sequelae of hepatitis B virus infection. Well-controlled studies have shown that administration of three 0.5 mL doses of hepatitis B immune globulin starting at birth is 75% effective in preventing establishment of the chronic carrier state in these infants during the first year of life. Protection is transient under these circumstances and the effectiveness of the passively administered hepatitis B immune globulin declines thereafter. Results from clinical studies indicate that administration of one 0.5 mL dose of hepatitis B immune globulin at birth and three 5 mcg (0.5 mL) doses of RECOMBIVAX HB®, the first dose given within one week after birth, was 96% effective in preventing establishment of the chronic carrier state in infants born to HBsAg- and HBeAg-positive mothers. Testing for HBsAg and anti-HBs is recommended at 12-15 months to monitor the final success or failure of therapy. If HBsAg is not detectable, and anti-HBs is present, the child has been protected.

The recommended dosage for infants born to HBsAg-positive mothers is as follows:

Acute Exposure to Blood Containing HBsAg

There are no prospective studies directly testing the efficacy of a combination of hepatitis B immune globulin and RECOMBIVAX HB® in preventing clinical hepatitis B following percutaneous, ocular or mucous membrane exposure to hepatitis B virus. However, recent studies have established the relative efficacies of immune globulins and/or hepatitis B vaccine in various exposure situations. Since most persons with such exposures (e.g., health-care workers) are candidates for the hepatitis B vaccine and since combined hepatitis B immune globulin plus vaccine is more efficacious than hepatitis B immune globulin alone in perinatal exposures, the following guidelines are recommended for persons who have been exposed to hepatitis B virus such as through (1) percutaneous (needlestick), ocular, mucous membrane exposure to blood known or presumed to contain HBsAg, (2) human bites by known or presumed HBsAg carriers, that penetrate the skin, or (3) following intimate sexual contact with known or presumed HBsAg carriers.

Hepatitis B immune globulin (0.06 mL/kg) should be given as soon as possible after exposure and within 24 hours if possible. Hepatitis B vaccine should be given intramuscularly within 7 days of exposure and second and third doses given one and six months, respectively, after the first dose.

4.4 Administration

The deltoid muscle is the preferred site for intramuscular injection in adults. The anterolateral thigh is the recommended site for intramuscular injection in infants and children. Data suggest that injections given in the buttocks are given frequently into fatty tissue instead of into muscle. Such injections may result in a lower seroconversion rate than is expected.

The vaccine should be used as supplied. No dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used.

It is recommended to record lot numbers when the vaccine is administered to a recipient.

FOR INTRAMUSCULAR USE

Do not inject intravenously or intradermally.

RECOMBIVAX HB® (hepatitis B vaccine [recombinant]) is for intramuscular injection. It may, however, be administered subcutaneously to persons at risk of hemorrhage following intramuscular injections. However, when other aluminum-adsorbed vaccines have been administered subcutaneously, an increased incidence of local reactions including subcutaneous nodules has been observed. Therefore, subcutaneous administration should be used only in persons (e.g., hemophiliacs) at risk of hemorrhage following intramuscular injections.

Shake the single-dose vial or single-dose prefilled syringe well before withdrawal and use.

Thorough agitation at the time of administration is necessary to maintain suspension of the vaccine. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. After thorough agitation, RECOMBIVAX HB® is a slightly opaque, white suspension.

Vials:

Withdraw the recommended dose from the vial using a sterile needle and syringe free of preservatives, antiseptics, and detergents.

It is important to use a separate sterile syringe and needle for each individual patient to prevent transmission of hepatitis and other infectious agents from one person to another.

Since none of the formulations contain a preservative, once the single-dose vial has been penetrated, the withdrawn vaccine should be used promptly, and the vial must be discarded.

Pre-filled Syringe:

Securely attach a needle by twisting in a clockwise direction and administer dose of RECOMBIVAX HB® intramuscularly. Discard syringe after use.

5 OVERDOSAGE

There are no data with regard to overdose.

For management of a suspected vaccine overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, health professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Dosage Forms:

RECOMBIVAX HB® (hepatitis B vaccine [recombinant]) is supplied as a sterile, slightly opaque, white suspension for injection in a single-dose vial and prefilled syringes.

The vaccine is used directly as supplied. No dilution or reconstitution is necessary.

Composition:

RECOMBIVAX HB® is available in three presentations, summarized below. Each single dose contains:

All presentations are preservative-free (thimerosal-free).

Manufacturing Process Residuals

Each dose contains less than 1% yeast protein. The vaccine also contains < 15 mcg/mL formaldehyde as all preparations have been treated with formaldehyde prior to adsorption onto amorphous aluminum hydroxyphosphate sulfate.

Packaging

Vials :

Pediatric Presentation: RECOMBIVAX HB® is supplied in 3 mL, single-dose Type I glass vials containing one 0.5 mL dose (5 mcg HbsAg). The vial stopper contains latex. It is available in packages of 1 single-dose vial.

Adult Presentation: RECOMBIVAX HB® is supplied in 3 mL, single-dose Type I glass vials containing one 1.0 mL dose (10 mcg HbsAg). The vial stopper contains latex. It is available in packages of 1 and 10 single-dose vials.

Adult Dialysis Presentation: RECOMBIVAX HB® is supplied in 3 mL, single-dose Type I glass vials containing one 1.0 mL dose (40 mcg HbsAg). The vial stopper contains latex. It is available in packages of 1 single-dose vial.

Pre-filled Syringe:

Pediatric Presentation: RECOMBIVAX HB® is supplied in a prefilled syringe containing 0.5 mL of liquid vaccine (5 mcg HbsAg). The prefilled syringe plunger stopper and tip cap contains latex. It is available in packages of 1 single dose pre-filled syringe.

Adult Presentation: RECOMBIVAX HB® is supplied in a prefilled syringe containing 1.0 mL of liquid vaccine (10 mcg HBsAg). The prefilled syringe plunger stopper and tip cap contains latex. It is available in packages of 1 and 10 single dose pre-filled syringes.

7 WARNINGS AND PRECAUTIONS

Because of the long incubation period for hepatitis B, it is possible for unrecognized infection to be present at the time RECOMBIVAX HB® (hepatitis B vaccine [recombinant]) is given. RECOMBIVAX HB® may not prevent hepatitis B in such patients.

Patients who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of RECOMBIVAX HB® (see 2 CONTRAINDICATIONS).

Use caution when vaccinating latex-sensitive individuals since the vial stopper and the syringe plunger stopper and tip cap contain dry natural latex rubber that may cause allergic reactions.

General

Persons with immunodeficiency or those receiving immunosuppressive therapy require larger vaccine doses and respond less well than healthy individuals.

As with any parenteral vaccine, epinephrine should be available for immediate use should an anaphylactoid reaction occur.

Any serious active infection is reason for delaying use of RECOMBIVAX HB®, except when, in the opinion of the physician, withholding the vaccine entails a greater risk.

Caution and appropriate care should be exercised in administering RECOMBIVAX HB® to individuals with severely compromised cardiopulmonary status or to others in whom a febrile or systemic reaction could pose a significant risk.

The vaccine will not prevent infection caused by other agents such as hepatitis A, hepatitis C and hepatitis E and other pathogens known to infect the liver.

7.1 Special Populations

7.1.1 Pregnant Women

Animal reproduction studies have not been conducted with RECOMBIVAX HB®. It is also not known whether RECOMBIVAX HB® can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. RECOMBIVAX HB® should be given to a pregnant woman only if clearly needed.

7.1.2 Breast-feeding

It is not known whether RECOMBIVAX HB® is excreted in human milk. However, studies with RECOMBIVAX HB® in 12 lactating women have failed to reveal evidence of this vaccine being secreted.

7.1.3 Pediatrics

The potential risk of apnoea and the need for respiratory monitoring for 48-72 hours should be considered when administering the primary immunisation series to very premature infants (born ≤ 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delay.

Hepatitis B vaccination should be delayed until 1 month of age or hospital discharge in infants weighing <2000 g if the mother is documented to be HBsAg negative at the time of the infant’s birth. Infants weighing <2000 g born to HBsAg positive or HBsAg unknown mothers should receive vaccine and hepatitis B immune globulin (HBIG).

RECOMBIVAX HB® has been shown to be generally well-tolerated and highly immunogenic in infants and children of all ages. Newborns have responded well; maternally transferred antibodies did not interfere with the active immune response to the vaccine. See 4 DOSAGE AND ADMINISTRATION for recommended pediatric dosage and recommended dosage for infants born to HBsAg-positive mothers. The safety profile and effectiveness of the dialysis formulation in children have not been established.

7.1.4 Geriatrics

Clinical studies of RECOMBIVAX HB® used for licensure did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. However, in later studies, of hepatitis B vaccines, it has been shown that a diminished antibody response and seroprotective levels can be expected in persons older than 60 years of age.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

RECOMBIVAX HB® (hepatitis B vaccine [recombinant]) is generally well-tolerated. No adverse reactions were reported during clinical trials which could be related to changes in the titers of antibodies to yeast. As with any vaccine, there is the possibility that broad use of the vaccine could reveal rare adverse reactions not observed in clinical trials.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

In a group of studies, 3258 doses of RECOMBIVAX HB®, 10 mcg, were administered to 1252 healthy adults. Vaccine recipients were monitored for 5 days after each dose, and the following adverse reactions were reported:

Incidence Equal to or Greater Than 10% of Injections

Local Reactions at Injection Site

Injection site reactions (consisting principally of local pain, soreness and tenderness and including pruritus, erythema, ecchymoses, swelling, warmth and nodule formation).

Incidence Equal to or Greater Than 1% and Less Than 10% of Injections

Body as a Whole

Fatigue/asthenia

Malaise

Fever ≥ 38^oC

Digestive System

Nausea

Diarrhea

Nervous System

Headache

Respiratory System

Pharyngitis

Upper respiratory infection (NOS)

Incidence Less Than 1% of Injections

Body as a Whole

Sweating

Chills

Flushing

Aching

Sensation of warmth

Integumentary System

Pruritus

Rash

Urticaria

Angioedema

Digestive System

Vomiting

Abdominal pains/cramps

Dyspepsia

Diminished appetite

Musculoskeletal System

Myalgia

Arthralgia

Back pain

Neck pain

Shoulder pain

Neck stiffness

Nervous System

Lightheadedness

Vertigo/dizziness

Paresthesia

Respiratory System

Rhinitis

Cough

Influenza

Special Senses

Earache

Hemic/Lymphatic System

Lymphadenopathy

Psychiatric/Behavioral

Insomnia/Disturbed sleep

Urogenital System

Dysuria

Cardiovascular System

Hypotension

In a study that compared the three-dose regimen (5 mcg) with the two-dose regimen (10 mcg) of RECOMBIVAX HB® in adolescents, the overall frequency of adverse reactions was generally similar.

8.5 Post-Market Adverse Reactions

The following additional adverse reactions have been reported with use of the marketed vaccine; however, in many instances a causal relationship to the vaccine has not been established.

Hematologic

Increased erythrocyte sedimentation rate, thrombocytopenia

Hypersensitivity

Anaphylaxis and symptoms of immediate hypersensitivity reactions including edema, dyspnea, chest discomfort, bronchial spasm, or palpitation have been reported within the first few hours after vaccination. An apparent hypersensitivity syndrome (serum-sickness-like) of delayed onset has been reported days to weeks after vaccination, including: arthritis (usually transient), and dermatologic reactions such as erythema multiforme, ecchymoses and erythema nodosum (see 7 WARNINGS AND PRECAUTIONS).

Immune System

Vasculitis

Polyarteritis nodosa

Integumentary System

Alopecia

Eczema

Musculoskeletal System

Arthritis

Pain in extremity

Nervous System

Peripheral neuropathy including Bell's Palsy, Guillain-Barré syndrome, exacerbation of multiple sclerosis, multiple sclerosis, optic neuritis, seizure, febrile seizure, encephalitis, vasovagal syncope.

Special Senses

Tinnitus

Uveitis

9 DRUG INTERACTIONS

9.4 Drug-Drug Interactions

Use With Other Vaccines

According to the National Advisory Committee on Immunization (NACI),RECOMBIVAX HB® (hepatitis B vaccine [recombinant]) may be administered simultaneously with other vaccines at different sites. A separate needle and syringe should be used for each vaccine.

The safety and immunogenicity of co-administration of RECOMBIVAX HB® with GARDASIL® (quadrivalent human papillomavirus [types 6, 11, 16, 18] recombinant vaccine) (same visit, injections at separate sites) were evaluated in a randomized study of 1,871 women aged 16 to 24 years at enrolment. Immune response and safety profile to both RECOMBIVAX HB® and GARDASIL® were similar whether they were administered at the same visit or at a different visit.

Results from published clinical studies indicate that RECOMBIVAX HB® can be administered concomitantly with DTaP-IPV-Hib (diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis, and Haemophilus influenzae type b conjugate vaccine), or M-M-R® II (measles, mumps and rubella virus vaccine, live, attenuated, Merck Std.), using separate syringes and injection sites for each vaccine. No impairment of immune response to individually tested vaccine antigens was seen in these studies.

In addition, an HBsAg-containing product, COMVAX^† (Haemophilus b conjugate vaccine [meningococcal protein conjugate] and hepatitis B [recombinant] vaccine) was given concomitantly with M-M-R® II and VARIVAX® III (varicella virus vaccine, live, attenuated [Oka/Merck]), using separate syringes and injection sites for each vaccine. No impairment of immune response to these individually tested vaccine antigens was demonstrated.

^† Not marketed in Canada.

Another randomized study conducted in 1993 with COMVAX^†, administered concurrently with routine pediatric vaccines (DTP, OPV/IPV, M-M-R® II, booster dose of DTaP) in 94 infants who completed the study, showed an acceptable response rate for most antigens but a lower response than pre-specified to polio antigens type 1 and type 3, pertussis antigens and rubella. However, the assays, endpoints and time points used differ from currently used criteria. The response to polio was assessed on sera at week-12 (instead of week-4) post-dose 2 and not after the third dose.

Use With Immunoglobulin

In circumstances where exposure to HBV has recently occurred (e.g. needlestick with contaminated needle) the first dose of Hepatitis B vaccine can be administered simultaneously with HBIg which however must be given at a separate injection site

10 CLINICAL PHARMACOLOGY

Hepatitis B virus is one of at least five hepatitis viruses that cause a systemic infection, with major pathology in the liver. The others are hepatitis A, hepatitis C, hepatitis D, and hepatitis E viruses.

Hepatitis B virus is an important cause of viral hepatitis. There is no specific treatment for this disease. The incubation period for type B hepatitis is relatively long; six weeks to six months may elapse between exposure and the onset of clinical symptoms. The prognosis following infection with hepatitis B virus is variable and dependent on at least three factors: (1) Age - Infants and younger children usually experience milder initial disease than older persons; (2) Dose of Virus - The higher the dose, the more likely acute icteric hepatitis B will result; and, (3) Severity of associated underlying disease - Underlying malignancy or pre-existing hepatic disease predisposes to increased morbidity and mortality.

Persistence of viral infection (the chronic hepatitis B virus carrier state) occurs in 5-10% of persons following acute hepatitis B, and occurs more frequently after initial anicteric hepatitis B than after initial icteric disease. Consequently, carriers of hepatitis B surface antigen (HBsAg) frequently give no history of recognized acute hepatitis. The World Health Organization estimated that more than 2 billion people worldwide have evidence of post or current hepatitis B virus infection, and 350 million are chronic carriers of the virus. The Centers for Disease Control (CDC) estimate that there are approximately 0.5 to 1.0 million chronic carriers of hepatitis B virus in the USA and that this pool of carriers grows by 2-3% (8000 to 16,000 individuals) annually. Chronic carriers represent the largest human reservoir of hepatitis B virus.

The serious complications and sequelae of hepatitis B virus infection include massive hepatic necrosis, cirrhosis of the liver, chronic active hepatitis, and hepatocellular carcinoma. Chronic carriers of HBsAg appear to be at increased risk of developing hepatocellular carcinoma, which accounts for 80 to 90% of primary liver carcinomas. Although a number of etiologic factors are associated with development of hepatocellular carcinoma, the single most important etiologic factor appears to be active infection with the hepatitis B virus. Globally, approximately one million individuals die each year as a direct result of HBV-induced cirrhosis or liver cancer. Based on death certificates, about 100 Canadians died in 1995 due to hepatitis B associated acute or chronic liver disease.

There is also evidence that several diseases other than hepatitis have been associated with hepatitis B virus infection through an immunologic mechanism involving antigen-antibody complexes. Such diseases include a syndrome with rash, urticaria and arthralgia resembling serum sickness; polyarteritis nodosa; membranous glomerulonephritis; and infantile papular acrodermatitis.

Although the vehicles for transmission of the virus are predominantly blood and blood products, viral antigen has also been found in tears, saliva, breast milk, urine, semen and vaginal secretions. Hepatitis B virus is capable of surviving for days on environmental surfaces. Infection may occur when hepatitis B virus, transmitted by infected body fluids, is implanted via mucous surfaces or percutaneously introduced through accidental or deliberate breaks in the skin.

Transmission of hepatitis B virus infection is often associated with close interpersonal contact with an infected individual and with crowded living conditions. In such circumstances, transmission by inoculation via routes other than overt parenteral ones may be quite common. Perinatal transmission of hepatitis B infection from infected mother to child, at, or shortly after birth, can occur if the mother is an HBsAg carrier or if the mother has an acute hepatitis B infection in the third trimester. Infection in infancy by the hepatitis B virus usually leads to the chronic carrier state. Among infants born to women whose sera are positive for both the hepatitis B surface antigen and the e antigen, 85-90% are infected and become chronic carriers.

Hepatitis B is endemic throughout the world, and is a serious medical problem in population groups at increased risk (see 1 INDICATIONS). The prevalence of HBsAg in the general population varies between less than 0.5% in the U.S., Canada and Western Europe, 1 to 2% in South America and Southern Europe, 3 to 5% in North Africa and in many parts of the Federation of Russia (formally known as USSR) and 9 to 10% and higher in sub-Saharan Africa, Southeast Asia and Alaska. The overall prevalence of serologic markers of infection varies between 7 and 10% in the U.S. and 60 and 80% in Southeast Asia or Africa. Even in countries like those in Northern and Western Europe and other highly developed countries with a relatively low prevalence of hepatitis B, certain populations are at high risk of acquiring the disease and have cumulative infection rates of up to 70% (see 1 INDICATIONS). In countries or areas with a high prevalence rate, the entire population is at risk and infection tends to occur during childhood.

Numerous epidemiological studies have shown that persons who develop anti-HBs following active infection with the hepatitis B virus are protected against the disease on re-exposure to the virus.

Reports in the literature describe a more virulent form of hepatitis B associated with superinfections or coinfections by delta virus, an incomplete RNA virus. Delta virus can only infect and cause illness in persons infected with hepatitis B virus since the delta agent requires a coat of HBsAg in order to become infectious. Therefore, persons immune to hepatitis B virus infection should also be immune to delta virus infection.

10.3 Pharmacokinetics

Duration of Effect

As with other hepatitis B vaccines, the duration of effect of RECOMBIVAX HB® is unknown at present, and the need for booster doses not defined. However, long-term follow-up (5 to 9 years) of approximately 3000 high-risk vaccinees (infants of carrier mothers, male homosexuals, Alaskan Natives) who developed an anti-HBs titer of ≥10mIU/mL when given a similar plasma-derived vaccine at intervals of 0, 1, and 6 months showed that no subjects developed clinically apparent hepatitis B infection and that 5 subjects developed antigenemia, even though up to half of the subjects failed to maintain a titer at this level. Persistence of vaccine-induced immunologic memory among healthy vaccinees who responded to a primary course of plasma-derived or recombinant hepatitis B vaccine has been demonstrated by an anamnestic antibody response to a booster dose of RECOMBIVAX HB® given 5-12 years later.

Routine booster vaccinations in immunocompetent persons are not recommended since protection has been shown to last for at least 15 years. Studies of long-term protective efficacy, however, will determine whether booster doses of vaccine are ever needed. It is important to recognize that absence of detectable anti-HBs in a person who has been previously demonstrated to have anti-HBs does not mean lack of protection, because immune memory persists. Booster doses in this situation are not indicated.

Immunocompromised persons often respond suboptimally to the vaccine. Subsequent HBV exposures in these individuals can result in disease or the carrier state. Therefore, boosters may be necessary in this population. The optimal timing of booster doses for immunocompromised individuals who are at continued risk of HBV exposure is not known and should be based on the severity of the compromised state and annual monitoring for the presence of anti-HBs.

11 STORAGE, STABILITY AND DISPOSAL

Store vaccine refrigerated at 2°C to 8°C. Storage above and below the recommended temperature may reduce potency. Do not freeze (below 0°C) since freezing destroys potency. Protect from light.

RECOMBIVAX HB® can be administered provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours. Cumulative multiple excursions between 0°C and 2°C are also permitted, as long as the total time between 0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.

Do not use vaccine after the expiration date.

12 SPECIAL HANDLING INSTRUCTIONS

Any unused vaccine or waste material should be disposed in accordance with local requirements.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: hepatitis B vaccine [recombinant]

Product Characteristics:

RECOMBIVAX HB® (hepatitis B vaccine [recombinant]) is a non-infectious subunit viral vaccine consisting of surface antigen (HBsAg or Australia antigen) of hepatitis B virus produced in yeast cells. A portion of the hepatitis B virus gene, coding for HBsAg, is cloned into yeast and the vaccine for hepatitis B is produced from cultures of this recombinant yeast strain according to methods developed in the Merck Research Laboratories.

The antigen is harvested and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the adw subtype of HBsAg. The HBsAg protein is released from the yeast cells by cell disruption and purified by a series of physical and chemical methods. Each dose contains less than 1% yeast protein. The vaccine produced by the Merck method has been shown to be comparable to the plasma-derived vaccine in terms of protective efficacy (chimpanzee and human).

The vaccine against hepatitis B, prepared from recombinant yeast cultures, is free of association with human blood or blood products.

Each lot of hepatitis B vaccine is tested for sterility.

14 CLINICAL TRIALS

14.2 Study Results

Clinical studies have established that RECOMBIVAX HB® (hepatitis B vaccine [recombinant]), when injected into the deltoid muscle, induced protective levels of antibody in greater than 90% of healthy individuals who received the recommended 3-dose regimen. Studies with hepatitis B vaccine derived from plasma have shown that a lower response rate (81%) to vaccine may be obtained if the vaccine is administered as a buttock injection. A protective antibody (anti-HBs) level has been defined as 10 or more sample ratio units (SRU) as determined by radioimmunoassay or a positive by enzyme immunoassay.

Responsiveness to the vaccine was age dependent. The seroprotection rate for children 1-10 years of age and adolescents 11-15 years of age were 100% and 99%, respectively. In contrast, the seroprotection rate for adults ranged from 95 to 98% for those from 20 to 39 years of age and 91% for those of 40 years of age or older.

The protective efficacy of three 5 mcg doses of RECOMBIVAX HB® has been demonstrated in neonates born of mothers positive for both HBsAg and HBeAg. In a clinical study of infants who received one dose of Hepatitis B Immune Globulin at birth followed by the recommended three-dose regimen of RECOMBIVAX HB®, efficacy in prevention of chronic hepatitis B infection was 96% in 47 infants at six months and 100% in 19 infants at nine months.

Post-Exposure

Studies have established the relative efficacies of immune globulin and/or hepatitis B vaccine in accidental percutaneous or permucosal exposure to HBsAg-positive blood; or sexual exposure to HBsAg-positive persons (see 4 DOSAGE AND ADMINISTRATION).

It has been demonstrated that doses of up to 5 mL of Hepatitis B Immune Globulin, when administered simultaneously with the first dose of RECOMBIVAX HB® at separate body sites, did not interfere with the induction of protective antibodies against hepatitis B virus elicited by the three-dose vaccine regimen.

Interchangeability

Hepatitis B vaccines produced by different manufacturers can be used interchangeably despite different doses and schedules. The dose used should be that recommended by the manufacturer.

14.4 Immunogenicity

For adolescents (11 to 15 years of age), the immunogenicity of a two-dose regimen (10 mcg at 0 and 4-6 months) was compared with that of the standard three-dose regimen (5 mcg at 0, 1 and 6 months) in an open, randomized, multicenter study. The proportion of adolescents receiving the two-dose regimen who developed a protective level of antibody one month after the last dose (99% of 255 subjects) appears similar to that among adolescents who received the three-dose regimen (98% of 121 subjects). After adolescents (11 to 15 years of age) received the first 10 mcg dose of the two-dose regimen, the proportion who developed a protective level of antibody was approximately 72%.

Predialysis and Dialysis Patients

Immunocompromised persons respond less well to RECOMBIVAX HB® than do healthy individuals. Vaccine-induced levels of anti-HBs are lower in pre-dialysis and hemodialysis patients than are the levels in healthy individuals. Eighty-six percent (86%) of pre-dialysis and hemodialysis patients who received three 40 mcg doses of RECOMBIVAX HB® developed protective levels of anti-HBs.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Carcinogenicity: RECOMBIVAX HB® has not been evaluated for the potential to cause carcinogenicity.

Genotoxicity: RECOMBIVAX HB® has not been evaluated for the potential to cause genotoxicity.

Reproductive and Developmental Toxicology: RECOMBIVAX HB® has not been evaluated for the potential to cause reproductive and developmental toxicity.