DESCRIPTION

Hepatitis B Immune Globulin (Human), Nabi-HB, is a sterile solution of immunoglobulin (5 ± 1% protein) containing antibodies to hepatitis B surface antigen (anti-HBs). It is prepared from plasma donated by individuals with high titers of anti-HBs. The plasma is processed using a modified Cohn 6 / Oncley 9 cold-alcohol fractionation process 1 , 2 with two added viral reduction steps described below. Nabi-HB is formulated in 0.075 M sodium chloride, 0.15 M glycine, and 0.01% polysorbate 80, at pH 6.2. The product is supplied as a nonturbid sterile liquid in single dose vials and appears as clear to opalescent. It contains no preservative and is intended for single use by the intramuscular route only.

The manufacturing steps for Nabi-HB are designed to reduce the risk of transmission of viral disease. The solvent/detergent treatment step, using tri- n -butyl phosphate and Triton® X-100, is effective in inactivating known enveloped viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) 3 . Virus filtration, using a Planova® 35 nm Virus Filter, is effective in reducing some known enveloped and non-enveloped viruses 4 . The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in the following table:

Model Virus:
Envelope/Genome:
HIV
HIV
yes/RNA
BVD
HCV
yes/RNA
Test Virus
PRV
HBV
yes/DNA
EMC
Hepatitis A
no/RNA
PPV
PVB19
no/DNA
Manufacturing Step
         
Precipitation of Cohn
         
Fraction III
> 5.9 3.6 3.7 4.4 3.9
Cuno Filtration
NT NT NT > 6.6 5.4
Solvent/Detergent
> 4.2 > 6.9 > 6.4 NT NT
Nanofiltration
> 7.4 > 6.9 > 5.7 3.0 0.7 *
> 17.5 > 17.4 > 15.8 > 14.0 9.3
PRV = Pseudorabies Virus
NT = not tested
* Value not included in cumulative clearance

Product potency is expressed in international units (IU) by comparison to the World Health Organization (WHO) standard. Each milliliter (mL) of product contains greater than 312 IU anti-HBs. The potency of each milliliter of Nabi-HB exceeds the potency of anti-HBs in a U.S. reference hepatitis B immune globulin (FDA). The U.S. reference has been tested by Nabi® Biopharmaceuticals against the WHO standard and found to be equal to 208 IU/mL.

CLINICAL PHARMACOLOGY

Hepatitis B Immune Globulin (Human) products provide passive immunization for individuals exposed to the hepatitis B virus as evidenced by a reduction in the attack rate of hepatitis B following use 6-9 .

Clinical studies 10 , 11 conducted prior to 1983 with hepatitis B immune globulins similar to Nabi-HB indicate the advantage of simultaneous administration of hepatitis B vaccine and Hepatitis B Immune Globulin (Human). The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) advises that the combination prophylaxis be provided in certain instances of exposure based upon the increased efficacy found with that regimen in neonates 12 . Cases of hepatitis B are rarely seen following exposure to HBV in persons with preexisting anti-HBs. However, no prospective studies have been performed on the efficacy of concurrent hepatitis B vaccine and Hepatitis B Immune Globulin (Human) administration following parenteral exposure, mucous membrane contact, or oral ingestion in adults.

Infants born to HBsAg-positive mothers are at risk of being infected with HBV and becoming chronic carriers 13 . The risk is especially great if the mother is also HBeAg-positive 14 . Studies conducted with hepatitis B immune globulins similar to Nabi-HB indicated that for an infant with perinatal exposure to an HBsAg-positive and HBeAg-positive mother, a regimen combining one dose of Hepatitis B Immune Globulin (Human) at birth with the hepatitis B vaccine series started soon after birth is 85-98% effective in preventing development of the HBV carrier state 15-17 . Regimens involving either multiple doses of Hepatitis B Immune Globulin (Human) alone or the vaccine series alone have a 70-90% efficacy, while a single dose of Hepatitis B Immune Globulin (Human) alone has 50% efficacy 18 .

Since infants have close contact with primary caregivers and they have a higher risk of becoming HBV carriers after acute HBV infection, prophylaxis of an infant less than 12 months of age with Hepatitis B Immune Globulin (Human) and hepatitis B vaccine is indicated if the mother or primary caregiver has acute HBV infection 19 .

Sexual partners of HBsAg-positive persons are at increased risk of acquiring HBV infection. A single dose of Hepatitis B Immune Globulin (Human) is 75% effective if administered within two weeks of the last sexual exposure to a person with acute hepatitis B 19 .

Pharmacokinetics

Pharmacokinetics trials 20 of Nabi-HB, Hepatitis B Immune Globulin (Human), given intramuscularly to 50 healthy volunteers demonstrated pharmacokinetic parameters similar to those reported by Scheiermann and Kuwert 21 . The half-life for Nabi-HB was 23.1 ± 5.5 days. The clearance rate was 0.35 ± 0.12 L/day and the volume of distribution was 11.2 ± 3.4 L.

Maximum concentration of Nabi-HB was reached in 6.5 ± 4.3 days. The maximum concentration of anti-HBs and the area under the time-concentration curve achieved by Nabi-HB were bioequivalent to that of another licensed Hepatitis B Immune Globulin (Human) when compared in the same pharmacokinetics trial. Comparability of pharmacokinetics between Nabi-HB and a commercially available hepatitis B immunoglobulin indicate that similar efficacy of Nabi-HB should be inferred.

INDICATIONS AND USAGE

Nabi-HB, Hepatitis B Immune Globulin (Human), is indicated for treatment of acute exposure to blood containing HBsAg, perinatal exposure of infants born to HBsAg-positive mothers, sexual exposure to HBsAg-positive persons and household exposure to persons with acute HBV infection in the following settings:

Nabi-HB is indicated for intramuscular use only.

CONTRAINDICATIONS

Individuals known to have had an anaphylactic or severe systemic reaction to human globulin should not receive Nabi-HB, Hepatitis B Immune Globulin (Human), or any other human immune globulin. Nabi-HB contains less than 100 micrograms per mL IgA. Individuals who are deficient in IgA may have the potential to develop IgA antibodies and have an anaphylactoid reaction. The physician must weigh the potential benefit of treatment with Nabi-HB against the potential for hypersensitivity reactions.

WARNINGS

In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, Nabi-HB, Hepatitis B Immune Globulin (Human), should be given only if the expected benefits outweigh the potential risks.

Nabi-HB is made from human plasma. Products made from human plasma may contain infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products can transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viral infections, and by inactivating and/or reducing certain viruses. The Nabi-HB manufacturing process includes a solvent/detergent treatment step (using tri- n -butyl phosphate and Triton® X-100) that is effective in inactivating known enveloped viruses such as HBV, HCV, and HIV. Nabi-HB is filtered using a Planova® 35 nm Virus Filter that is effective in reducing the levels of some enveloped and non-enveloped viruses. These two processes are designed to increase product safety. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other health care provider to Nabi® Biopharmaceuticals at 1-800-458-4244. The physician should discuss the risks and benefits of this product with the patient.

PRECAUTIONS

General

Nabi-HB, Hepatitis B Immune Globulin (Human), must be administered only intramuscularly for post-exposure prophylaxis. The preferred sites for intramuscular injections are the anterolateral aspect of the upper thigh and the deltoid muscle. If the buttock is used due to the volume to be injected, the central region should be avoided; only the upper, outer quadrant should be used, and the needle should be directed anterior (i.e., not inferior or perpendicular to the skin) to minimize the possibility of involvement with the sciatic nerve 22 .

The 50 healthy volunteers who received Nabi-HB in pharmacokinetic studies were followed for 84 days for pos-sible development of anti-HCV antibodies. No subject seroconverted.

Drug Interactions

Vaccination with live virus vaccines should be deferred until approximately three months after administration of Nabi-HB, Hepatitis B Immune Globulin (Human). It may be necessary to revaccinate persons who received Nabi-HB shortly after live virus vaccination.

There are no available data on concomitant use of Nabi-HB and other drugs; therefore, Nabi-HB should not be mixed with other drugs.

Pregnancy Category C

Animal reproduction studies have not been conducted with Nabi-HB. It is also not known whether Nabi-HB can cause fetal harm when administered to a pregnant woman or can affect a woman's ability to conceive. Nabi-HB should be given to a pregnant woman only if clearly indicated.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nabi-HB is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established for Nabi-HB. However, the safety and effectiveness of similar hepatitis B immune globulins have been demonstrated in infants and children 12 .

Geriatric Use

Clinical studies of Nabi-HB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

ADVERSE REACTIONS

Fifty male and female volunteers received Nabi-HB, Hepatitis B Immune Globulin (Human), intramuscularly in pharmacokinetics trials 20 . The number of patients with reactions related to the administration of Nabi-HB included local reactions such as erythema 6 (12%) and ache 2 (4%) at the injection site, as well as systemic reactions such as headache 7 (14%), myalgia 5 (10%), malaise 3 (6%), nausea 2 (4%), and vomiting 1 (2%). The majority (92%) of reactions were reported as mild. The following adverse events were reported in the pharmacokinetics trials and were considered probably related to Nabi-HB: elevated alkaline phosphatase 2 (4%), ecchymosis 1 (2%), joint stiffness 1 (2%), elevated AST 1 (2%), decreased WBC 1 (2%), and elevated creatinine 1 (2%). All adverse events were mild in intensity. There were no serious adverse events.

No anaphylactic reactions with Nabi-HB have been reported. However, these reactions, although rare, have been reported following the injection of human immune globulins 23 .

OVERDOSAGE

Although no data are available, clinical experience reported with other human immune globulins suggests that the only manifestations of overdose with Nabi-HB, Hepatitis B Immune Globulin (Human), would be pain and tenderness at the injection site.

DOSAGE AND ADMINISTRATION

This product is for intramuscular use only. The use of this product by the intravenous route is not indicated. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

It is important to use a separate vial, sterile syringe, and needle for each individual patient, in order to prevent transmission of infectious agents from one person to another. Any vial of Nabi-HB, Hepatitis B Immune Globulin (Human) that has been entered should be used promptly. Do not reuse or save for future use. This product contains no preservative; therefore, partially used vials should be discarded immediately.

Hepatitis B Immune Globulin (Human) may be administered at the same time (but at a different site), or up to one month preceding hepatitis B vaccination without impairing the active immune response to hepatitis B vaccine 11 .

Table 2 Recommendations for Hepatitis B Prophylaxis Following Percutaneous or Permucosal Exposure 12

 
Exposed Person
Source
Unvaccinated
Vaccinated
HBsAg-positive
1. Hepatitis B Immune Globulin (Human) X 1 immediately *
2. Initiate HB vaccine series **/*
1. Test exposed person for anti-HBs
2. If inadequate antibody **/** , Hepatitis B Immune Globulin (Human) X 1 immediately plus either HB vaccine booster dose or second dose of Hepatitis B Immune Globulin (Human) one month later §
Known Source - High
Risk for HBsAg-positive
1. Initiate HB vaccine series
2. Test source for HBsAg. If positive, Hepatitis B Immune Globulin (Human) X 1
1. Test source for HBsAg only if exposed is vaccine nonresponder; if source is HBsAg-positive, give Hepatitis B Immune Globulin (Human) X 1 immediately plus either HB vaccine booster dose or second dose of Hepatitis B Immune Globulin (Human) one month later §
Known Source - Low
Risk for HBsAg-positive
Initiate HB vaccine series
Nothing required
Unknown Source
Initiate HB vaccine series
Nothing required
* Hepatitis B Immune Globulin (Human) dose of 0.06 mL/kg IM.
**/* See manufacturers' recommendation for appropriate dose.
**/** Less than 10 mIU/mL anti-HBs by radioimmunoassay, negative by enzyme immunoassay.
§Two doses of Hepatitis B Immune Globulin (Human) is preferred if no response after at least four doses of vaccine.

Table 3 Recommended Schedule of Hepatitis B Immunoprophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus Infection 19
 
Age of Infant
Administer
Infant Born to mother known
to be HBsAg-positive
Infant born to mother not screened for HBsAg
First Vaccination *
Birth (within 12 hours)
Birth (within 12 hours)
Birth (within 12 hours)
If mother is found to be HBsAg-positive, administer dose to infant as soon as possible, not later than 1 week after birth
Second Vaccination *
1 month
1-2 months
Third Vaccination *
6 months **/**
6 months **/**
* See manufacturers' recommendations for appropriate dose.
**/* 0.5 mL administered IM at a site different from that used for the vaccine.
**/** See ACIP recommendation.

  

HOW SUPPLIED

Nabi-HB, Hepatitis B Immune Globulin (Human), is supplied as:

NDC Number
59730-4202-1
59730-4204-1
a carton containing a 1 mL dose in a single-use vial (>312 IU) and package insert
59730-4203-1
59730-4205-1
a carton containing a 5 mL dose in a single-use vial (>1560 IU) and package insert

STORAGE

Refrigerate between 2 to 8 °C (36 to 46 °F). Do not freeze. Do not use after expiration date. Use within 6 hours after the vial has been entered.

REFERENCES

  1. Cohn E.J., Strong W.L., Mulford D.J., Ashworth J.N., Melin M., Taylor H.L. Preparation and Properties of Serum and Plasma Proteins IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 1946, 68: 459-475.
  2. Oncley J.L, Melin M, Richert D.A, Cameron J. W, Gross P.M. The separation of antibodies, isoagglutinins, prothrombin, plasminogen and b1-lipoproteins into sub-fractions of human plasma. J Am Chem Soc 1949, 71:541-550.
  3. Horowitz B: Investigations into the application of tri( n -butyl)phosphate/detergent mixtures to blood derivatives. Morgenthaler J (ed): Virus Inactivation in Plasma Products, Curr Stud Hematol Blood Transfus 1989; 56:83-96.
  4. Burnouf T: Value of virus filtration as method for improving the safety of plasma products. Vox Sang 1996; 70:235-236.
  5. Unpublished data on file, Viral Validation Study Reports, Nabi® Biopharmaceuticals.
  6. Grady GF, and Lee VA: Hepatitis B immune globulin - prevention of hepatitis from accidental exposure among medical personnel. N Engl J Med 1975; 293:1067-1070.
  7. Seeff LB, et al. : Type B hepatitis after needle-stick exposure: Prevention with hepatitis B immune globulin. Ann Int Med 1978; 88:285-293.
  8. Krugman S, and Giles JP: Viral hepatitis, type B (MS-2-strain). Further observations on natural history and prevention. N Engl J Med 1973; 288:755-760.
  9. Hoofnagle JH, et al. : Passive - active immunity from hepatitis B immune globulin. Ann Int Med 1979; 91:813-818.
  10. Beasley RP, 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; 3:135-141.
  11. Szmuness W, et al. : Passive active immunisation against hepatitis B: Immunogenicity studies in adult Americans. Lancet 1981; 1:575-577.
  12. Centers for Disease Control: Recommendations for protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1985; 34(22):313-335.
  13. Shiraki Y, et al. : Hepatitis B surface antigen and chronic hepatitis in infants born to asymptomatic carrier mothers. Am J Dis Child 1977; 131:644-647.
  14. Beasley RP, et al. : The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977; 105:94-98.
  15. Wong VCW, et al. : Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin: Double-blind randomized placebo-controlled study. Lancet 1984; 1:921-926.
  16. Poovorawan Y, et al. : Long term hepatitis B vaccine in infants born to hepatitis B e antigen positive mothers. Archives of Diseases in Childhood 1997; 77:F47-F51.
  17. Stevens CE, et al. : Perinatal Hepatitis B virus transmission in the United States: Prevention by passive-active immunization. JAMA 1985; 253:1740-1745.
  18. Jhaveri R, et al. : High titer multiple dose therapy with HBIG in newborn infants of HBsAg positive mothers. J Pediatr 1980; 97:305-308.
  19. Centers for Disease Control: Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991; 40(13):1-25.
  20. Data on file, Nabi® Biopharmaceuticals
  21. Scheiermann N, Kuwert EK: Uptake and elimination of hepatitis B immunoglobulins after intramuscular application in man. Develop Biol Standard 1983; 54:347.
  22. Centers for Disease Control: General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1994; 43:1-38.
  23. Ellis EF, Henney CS: Adverse reactions following administration of human gamma globulin. J Allerg 1969; 43:45-54.

Manufactured by:

Nabi® Biopharmaceuticals

Boca Raton, FL 33487

U.S. License No. 1687

June 2003

3-683-1118

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug's identity should be verified by chemical analysis.

images/pills/p06324c1.jpg



Copyright© 2006 Thomson PDR