Hepatitis B Immune Globulin (Human)

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					                                                        PACKAGE INSERT

             Hepatitis B Immune Globulin (Human)
             SolvenUDetergent   Treiated and Filtered

     5       DESCRIPTION

     6       Hepatitis B Immune Globulin (Human), Nabi-HBTM, is a sterile solution of

     7       immunoglobulin (5 -c 1%     protein) containing antibodies to hepatitis 6 surface antigen

     s       (anti-HBs).   It is prepared from plasma donated by individuals with high titers of anti-

     9       HBs. The plasma is purified by an anion-exchange column chromatography method”2

 10          with two added viral reduction steps described below. The product is formulated in

 11          0.075 M sodium chloride, 0.15 M glycine, and 0.01% polysorbate 80, pH 6.25.        It

 12          contains no preservative and is intended for single use by the intramuscular route only.

 13          The product appears as a clear to opalescent, nonturbid liquid.

 I5          The manufacturing steps are designed to reduce the risk of transmission of viral

 16          disease.   The solvent/detergent treatment step, using tri-n-butyl phosphate and Triton@

 17          X-l 00; 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.’ The inactivation and reduction of known

             enveloped and non-enveloped model viruses were validated in laboratory studies as

Lb           summarized in the following table:
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 24    Table 1 Log Reduction           of Test Viruses’
                                                               Test Virus
                                      HIV          BVD            PRV            Polio            BPV
                     Model Virus:      HIV          HCV            HBV         Hepatitis A       PVB19
            Envelope/Genome:        yes/RNA       yes/RNA        yes/DNA        no/RNA           no/DNA
       Manufacturing Step
       dextran sulfate                 NT           N-r            NT              3.32            <l
       anion-exchange                  NT           NT             NT            > 3.52          > 5.34
       solvent/detergent             > 4.67       > 7.43         > 5.26            2.7           > 5.81
       virus filtration              > 6.02       z 7.30         > 6.77            4.25          > 4.97
 25    BVD = Bovine Viral Diarrhea             PRV = Pseudorabies Virus     Polio = Poliovirus
 26    BPV = Bovine Pawovirus                  PvB19 = Pawovirus B19        NT = not tested
29     The product potency is expressed in international units (IU) by comparison to the World

30     Health Organization (WHO) standard.          Each vial contains greater than 312 IU/mL anti-

31     HBs. The potency of each vial of Nabi-HBTM exceeds the potency of anti-H&                 in a U.S.

32     reference hepatitis B immune globulin (FDA).         The U.S. reference has been tested by

33     Nab? against the WHO standard and found to be equal to 208 IU/mL.



36    _ Hepatitis    B Immune Globulin (Human) products provide passive immunization for

37     individuals    exposed   to the hepatitis B virus as evidenced by a reduction in the attack

38     rate of hepatitis B following use.M


40    Clinical studies conducted prior to 1983 with hepatitis B immune globulins similar to

41     Nabi_HBTM”*”      indicate the advantage of simultaneous administration of Hepatitis B

42    Vaccine and Hepatitis B Immune Globulin (Human). The Centers for Disease Control

43    and Prevention Advisory Committee on Immunization Practices (ACIP) advises that the

44    combination prophylaxis be provided based upon the increased efficacy found with that

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 35        regimen in neonates. “Cases    of hepatitis B are rarefy seen following exposure   to HBV

 46        in persons with preexisting anti-HBs.    However, no prospective studies have been

47        performed on the efficacy of concurrent Hepatitis B Vaccine and Hepatitis B Immune

38        Globulin (Human) administration following parenteral exposure, mucous membrane

49        contact, or oral ingestion in adults.


51        Infants born to HBsAg-positive mothers are at risk of being infected with HBV and

52        becoming chronic carriers. 13The risk is especially great if the mother is also HBeAg-

53        positive.”   Studies conducted with hepatitis B immune globulins similar to Nabi-HBm

51        indicated that for an infant with perinatal exposure to an HBsAg-positive and HBeAg-

55        positive mother, a regimen combining one dose of Hepatitis B Immune Globulin

56        (Human) at birth with the Hepatitis B Vaccine series started soon after birth is 8598%

57        effective in preventing development of the HBV carrier state.‘5’7 Regimens involving

58        either multiple doses of Hepatitis B Immune Globulin (Human) alone or the vaccine

59        series alone have a 70-90% efficacy, while a single dose of Hepatitis B Immune

60        Globulin (Human) alone has 50% efficacy.”


62        Since infants have close contact with primary caregivers and they have a higher risk of

63        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 6 Vaccine is

65        indicated if the mother or primary caregiver has acute HBV infection.lg


67        Sexual partners of HBsAg-positive persons are at increased risk of acquiring HBV
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68    infection.      A single dose of Hepatitis            B Immune    Globulin    (Human)       is 75% effective   if

69    administered         within two weeks of the last sexual                     to
                                                                           exposure a person with acute

70    hepatitis     B.”


72    Pharmacokinetics

73    Pharmacokinetics           trials”     of Nabi-HB W, Hepatitis       6 Immune      Globulin    (Human),   given

74    intramuscularly         to 48 healthy      volunteers     demonstrate      pharmacokinetic       parameters

75   similar to those         reported      by Scheiermann       and Kuwert. *’ The half-life        for Nabi-HBTM

76   was 24.8 2 5.6 days. The clearance                     rate was 0.433    * 0.144    L/day and the volume        of

77   distribution      was 15.3 2 6.2 1.


79   Maximum         concentration         of Nabi-HBTM was reached           in 6.6 -e 3.0 days.     The maximum

80   concentration         of anti-HBs       achieved      by Nabi-HBTM      was consistent     with that of another

Sl   licensed       Hepatitis    B Immune        Globulin    (Human)    when compared         in the same

     pharrnacokinetics          trial.     Comparability     of pharmacokinetics        between     Nabi-HBTM and a

83   commercially          available     hepatitis    B immunoglobulin       indicate   that similar efficacy   of Nabi-

     HBTM should          be inferred.



87   Nabi-HBTM.        Hepatitis       B Immune      Globulin   (Human),     is indicated    for treatment   of acute

88   exposure       to blood containing          HBsAg, perinatal      exposure    of infants born to HBsAg-

89   positive      mothers,     sexual     exposure     to HBsAg positive persons           and household    exposure

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 90       to persons              with acute    HBV infection      in the following settings:


 92           .       Acute      Exposure   to Blood Containina        HBsAq

 93                   Following     either parenteral      exposure       (needlestick,   bite, sharps),     direct mucous

 94                   membrane       contact     (accidental   splash),     or oral ingestion   (pipetting    accident),

 95                   involving     HBsAg-positive      materials     such as blood, plasma or serum.


 97       .           Perinatal     Exoosure     of Infants Born to HBsAo-positive           Mothers

 98                   Infants    born to mothers      positive for HBsAg with or without HBeAg.12


100       .           Sexual     Exposure      to HBsAq-positive      Persons

101                   Sexual     partners   of HBsAg-positive       persons.

103       .           Househoid      Exoosure      to Persons with Acute HBV Infection

104                   Infants    less than 12 months old whose mother or primary caregiver                     is positive for

105   .               HBsJg.      Other household       contacts    with an identifiable     blood exposure       to the index

106                   patient.


108       Nabi-HBm               is indicated for intramuscular       use onlv.
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 110      Individuals known to have had an anaphylactic or severe systemic         reaction to human

 111      globulin should not receive Nabi-HB TM, Hepatitis E3immune Globulin (Human), or any

 117,    other human immune globulin. Nabi-HBTM contains less than 40 micrograms/ml_ IgA.

 113     Individuals who are deficient in IgA may have the potential to develop IgA antibodies

 I14     and have an anaphylactoid reaction. The physician must weigh the potential benefit of

 115     treatment with Nabi-HBTM against the potential for hypersensitivity reactions.


117      WARNINGS

118      In patients   who have severe thrombocytopenia      or any coagulation   disorder    that would

119      contraindicate intramuscular injections, Nabi-HB TM, Hepatitis 8 Immune Globulin

110      (Human), should be given only if the expected benefits outweigh the potential risks.


122      Nabi-HBTM is made from human plasma.              Products made from human plasma may

113     contain infectious      agents, such as viruses, that can cause disease. The risk that
        . .

ix      Such products       can transmit an infectious agent has been reduced         by screening

125     plasma donors for prior exposure to certain viruses, by testing for the presence

126     of certain current viral infections, and by inactivating      and/or reducing        certain

117     viruses.    The Nabi-HBTM manufacturing       process includes a solvent/detergent

123     treatment      step (using tri-n-butyl phosphate    and Triton@ X-l 00) that is effective in

129     inactivating     known enveloped    viruses such as HBV, HCV, and HIV.          Nabi-HBTM is

130     filtered using a Planova@        nm Virus Filter that is effective   in reducing the levels
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 131       of some enveloped          and non-enveloped    viruses.   These two processes      are

 132       designed     to increase    product safety.    Despite these measures,     such products

 133       can still potentially   transmit disease.      There is also the possibility    that unknown

 134       infectious   agents may be present in such products.           ALL infections    thought by a

 135       physician    possibly to have been transmitted        by this product should be reported

 136       by the physician     or other health care provider to Nabi at l-800-458-4244.         The

 137       physician    should discuss the risks and benefits of this product with the patient.


 139       PRECAUTIONS

.110       General

 131       Nabi-HBTM, Hepatitis 8 Immune Globulin (Human), must be administered only

 142       intramuscularly for post-exposure prophylaxis. The preferred sites for intramuscular

 143       injections are the anterolateral aspect of the upper thigh and the deltoid muscle of the

 144       upper arm. If the buttock is used due to the volume to be injected, the central region

 14s . -   should be avoided; only the upper, outer quadrant should be used, and the needle

 146       should be directed anteriorly (i.e., not inferiorly or perpendicular to the skin) to minimize

           the possibility of involvement with the sciatic newe.z


149        Drug Interactions

150        Vaccination with live virus vaccines should be deferred until approximately three

151        months after administration of Nabi-HB lH, Hepatitis B Immune Globulin (Human).           It

12         may be necessary to revaccinate persons who received Nabi-HBfM shortly after live

153        virus vaccination.
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 155         There are no available data on concomitant use of Nabi-HBTM and other drugs;

 156         therefore, Nabi-HBTM should not be mixed with other drugs.


 158         Pregnancy    Category   C

 159         Animal reproduction studies have not been conducted with Nabi-HBTM. It is also not

 160         known whether Nabi-HBTM can cause fetal harm when administered to a pregnant

 161     woman or can affect reproduction capacity. Nabi-HBTM should be given to a pregnant

 162     woman only if clearly indicated.


164      Nursing Mothers


166      excreted in human milk, caution should be exercised when Nabi-HBTM is administered

167      to a nursing mother,

       . -

169      Pediatric    Use

170     Safety and effectiveness in the pediatric population have not been established for

171     Nabi-HBTM. However, the safety and effectiveness of similar Hepatitis B immune

172     globulins have been demonstrated      in infants and children.12


174     ADVERSE          REACTIONS

175     Seventy-six male and female volunteers received Nabi-HBTM Hepatitis B Immune

176     Globulin (Human), intramuscularly in pharmacokinetics trials,20 The number of patients

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177        with reactions      related    to the administration       of Nabi-HBTM included          local reactions         such

178        as pain 9 (12%),         ache 2 (3%),     etythema       2 (3%).    heat 1 (l%),     and burning      2 (3%) at the

179        injection site, as well as systemic           reactions     such as headache          20 (26%),      malaise      4

180        (5%),     nausea   4 (5%),     diarrhea     2 (3%) and myalgia 4 (5%).             The majority of reactions

181        were reported       as mild.    The following      adverse     events were reported          once each in

IS2        pharmacokinetics          trials and were probably         related to Nabi-HBY           chills, fatigue,

lS3        lightheadedness,          abdominal    cramping,     and retching.         There   were no serious           adverse

184        events.


186        No anaphylactic         reactions   with Nabi-HB     have been reported.             However,       these

187        reactions,     although     rare, have been reported          following the injection       of human         immune



190        OVERDOSAGE

191        Although      no data are available,        clinical experience       reported     with other human          immune

197        globulins     suggests     that the only manifestations            of overdose     with Nabi-HBTM,       Hepatitis       B

193        Immune       Globulin    (Human),     would be pain and tenderness               at the injection    site.



196        This product is for intramuscular            use only.     The use of this product        by the intravenous

197        route is not indicated.        Parenteral     drug products should be inspected              visually       for

198        particulate    matter and discoloration         prior to administration.



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 200   It is important to use a separate vial, sterile syringe, and needle for each individual

201    patient, in order to prevent transmission of infectious agents from one person to

202    another. Any vial of Nabi-HB TV,Hepatitis B Immune Globulin (Human) that has

203    been entered should be used promptly.                Do not reuse or save for future use. This

204    product contains           no preservative;   therefore,   partially used vials should be

205    discarded           immediately.


207    Hepatitis B Immune Globulin (Human) may be administered at the same time (but at a

20s    different site), or up to one month preceding hepatitis B vaccination without impairing

209    the active immune response to Hepatitis B Vaccine.”


2il    l       Acute ExPosure to Blood Containins HBsAq


2;:            Table 2 summarizes prophylaxis for percutaneous (needlestick, bite, sharps),

214    . _     ocular, or mucous membrane exposure to blood according to the source of

215            exposure and vaccination status of the exposed person. For greatest effectiveness,

216            passive prophylaxis with Hepatitis B Immune Globulin (Human) should be given as

               soon as possible after exposure, as its value after seven days following exposure is

               unclear.”     An injection of 0.06 mUkg of body weight should be administered

               intramuscularly as soon as possible after exposure and within 24 hours, if possible.

               Consult the Hepatitis B Vaccine package insert for dosage information regarding the

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223         For persons who refuse Hepatitis B Vaccine OFare known non-responders   to

224         vaccine, a second dose of Hepatitis B Immune Globulin (Human) should be given

225         one month after the first dose. l2

      . -
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227       Table 2 Recommendations              for Hepatitis   B Prophylaxis    FoIlowing    Percutaneous
228       or Permucosal Exposure”
                                                                     Exposed Person
          Source                                    Unvaccinated                           Vaccinated
          HBsAg-positive                    1. Hepatitis B Immune              1. Test exposed person for
                                            Globulin (Human) X 1               anti-HBs
                                            immediately’                       2. If inadequate antibody*,
                                            2. Initiate HB vaccine series’     Hepatitis 8 Immune Globulin
                                                                               (Human) X 1 immediately plus
                                                                               HB vaccine booster dose
          Known Source - High               1. Initiate HB vaccine series      1. Test source for HBsAg only
          Risk for HBsAg-positive           2. Test source for HBsAg. If       if exposed   is vaccine
                                            positive, Hepatitis B Immune       nonresponder; if source is
                                            Globulin (Human) X 1               HBsAg-positive, give Hepatitis
                                                                               B Immune Globulin (Human) X
                                                                               1 immediately plus HB vaccine
                                                                               booster dose
          Known Source - Low             Initiate HB vaccine series            Nothing required
          Risk for HBsAg-positive
          Unknown Source                 Initiate HB vaccine series            Nothing required
230       * HepatitisB Immune Globulin (Human) dose of 0.06 mVkg IM.
231       Wee manufacturers’ recommendation for appropriate dose.
232       *Less than 10 mlU/mL anti-HBs by radioimmunoassay, negative by enzyme immunoassay.

23        l   Prophylaxis of Infants Born to Mothers who are Positive for HBsAs with or without

235   *       H’BeAq

236   .       Table 3 contains the recommended schedule of hepatitis B prophylaxis for infants

237           born to mothers that are either known to be positive for HBsAg or have not been

              screened.      Infants born to mothers known to be HBsAg-positive should receive 0.5

239           mL Hepatitis B Immune Globulin (Human) after physiologic stabilization of the infant

              and preferably     within 12 hours of birth. The Hepatitis B Vaccine series should be

241           initiated   simultaneously,   if not contraindicated, with the first dose of the vaccine

242           given concurrently with the Hepatitis B Immune Globulin (Human), but at a different
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243         site.   Subsequent     doses of the vaccine       should be administered in accordance with

9;14        the recommendations of the manufacturer.


246         Women admitted for delivery, who were not screened for HBsAg during the prenatal

247         period, should be tested. While test results are pending, the newborn infant should

w9          receive Hepatitis B Vaccine within 12 hours of birth (see manufacturers’

249         recommendations for dose). If the mother is later found to be HBsAg positive, the

250         infant should receive 0.5 mL Hepatitis B Immune Globulin (Human) as sooti as

251         possible and within seven days of birth; however, the efficacy of Hepatitis B Immune

2s          Globulin (Human) administered after 48 hours of age is not known.‘oP’gTesting for

253         HBsAg and anti-HBs is recommended at 12-l 5 months of age. If HBsAg is not

254         detectable and anti-HBs is present, the child has been protected.‘*

258     Table 3 Recommended Schedule of Hepatitis 6 lmmunoprophylaxis                           to Prevent
259 _   Perinatal Transmission of Hepatitis B Virus infection ”
                                                                 Age of Infant
                                          Infant Born to mother known        Infant born to mother not

        First Vaccination’                Birth (within 12 hours)               Birth (within 12 hours)
        Hepatitis B Immune                Birth (within 12 hours)               If mother is found to de HBsAg
        Globulin (Human)’                                                       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*
261     * See manufacturers’ recommendations for appropriate dose.
262     to.5 mL administered IM at a site different from that used for the vaccine.
263     *See ACIP recommendation.
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 264           l    Sexual Exposure to HBsAo-Positive Persons

 265                All   susceptible persons whose sexual partners have acute hepatitis   B infection

 266                should receive a single dose of Hepatitis B Immune Globulin (Human) (0.06 mVkg)

 267                and should begin the Hepatitis B Vaccine series, if not contraindicated, within 14

 268                days of the last sexual contact or if sexual contact with the infected person will

 269                continue. Administering the vaccine with Hepatitis B Immune Globulin (Human)

270                 may improve the efficacy of post exposure treatment.    The vaccine has the added

271                advantage of conferring long-lasting protection.”


273        l       Household Exposure to Persons with Acute HBV Infection

274                Prophylaxis of an infant less than 12 months of age with 0.5 mL Hepatitis B immune

275                Globulin (Human) and Hepatitis B Vaccine is indicated if the mother or primary

276                caregiver has acute HBV infection. Prophylaxis of other household contacts of

277                persons with acute HBV infection is not indicated unless they had an identifiable

275                blood exposure to the index patient, such as by sharing toothbrushes or razors.

279                Such exposures should be treated like sexual exposures.     If the index patient

280                becomes an HBV carrier, all household contacts should receive Hepatitis B

281                Vaccine.”

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284    Nabi-HP’,     Hepatitis B Immune Globulin (Human), is supplied as:


286    NDC Number                  Contents

257    59730~4402- 1        a carton containing a 1 .O mL single dose vial (a31 2 IU) and

288                         package insert

289    59730-4403-   1      a carton containing a 5.0 mL single dose vial (>1560 IU) and

290                         package insert


292    STORAGE

293    Refrigerate between 2 to 8 “C (36 to 46 “F). Do not freeze.   Do not use after expiration

294    date. Use within 6 hours after the vial has been entered.



297    1.    Bowman JM, et. a/.: WinRho: Rh immune globulin prepared by ion exchange for

293          intravenous use. Canadian Med Assoc J 1980; 123:1121-l         125


3m-l   2.    Friesen AD, et a/.: Column ion-exchange preparation and characterization       of an

301          Rh immune globulin (WinRho) for intravenous     use. Journal ofApplied Biochem

302          1981; 3:164-175.
                                           PACKAGE INSERT

 303     3.    Horowitz B: Investigations into the application of tri(n-butyl)phosphate/detergent

 303           mixtures to blood derivatives. Morgenthaler J (ed): Virus Inactivation in Plasma

 305           Products, Curr Stud Hematol Blood Transfus 1989; 56:83-96.


 307    4.     Bumouf T: Value of virus filtration as method for improving the safety of plasma

 308           products. VOX Sang 1996; 70:235-236.


 310    5.     Unpublished data on file, Viral Validation Study Reports, Cangene Corporation.


312     6.    Grady GF, and Lee VA; Hepatitis B immune globulin - prevention of hepatitis

313           from accidental exposure among medical personnel.       N Engl J Med 1975;

314           293:1067-1070.


316     7.    Seeff LB, et a/,: Type B hepatitis after needle-stick exposure:   Prevention with

317           hepatitis B immune globulin. Ann Int Med 1978; 88:285-293.
       . .


319    8.     Krugman S, and Giles JP: Viral hepatitis, type B (MS-2-strain).    Further

320           observations on natural history and prevention.   N Engl J Med 1973; 2881755

311           760.


33     9.     Hoofnagle JH, et al.: Passive - active immunity from hepatitis B immune

323           globulin. Ann lnt Med 1979; 91:813-818.
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325       10.   Beasley RP, et a/_: Efficacy of hepatitis B immune globulin for prevention of

326             perinatal transmission of the hepatitis B virus carrier state: Final report of a

327             randomized double-blind, placebo - controlled trial. Hepatology     1983; 3: 135-

328             141.


330       11.   Szmuness W, et a/.: Passive active immunisation against hepatitis B:

331             lmmunogenicity studies in adult Americans- Lancet 1981; 1:575-577.


333       12.   Centers for Disease Control: Recommendations for protection against viral

334             hepatitis. Recommendations of the Immunization Practices Advisory Committee

335             (ACIP).   MML’VR 1985; 34(22):313-335.


337       13.   Shiraki Y, et al.: Hepatitis B surface antigen and chronic hepatitis in infants born

338             to asymptomatic carrier mothers. Am J Dis Child 1977; 131644647.


340       14.   Beasley RP, et a/.: The e antigen and vertical transmission of hepatitis B

341             surface antigen, Am J Epidemioll977;     105:94-98.

343       15.   Wong VCW, et al.: Prevention of the HBsAg carrier state in newborn infants of

3&I             mothers who are chronic carriers of HBsAg and HBeAg by administration of

345             hepatitis B vaccine and hepatitis B immunoglobulin: Double-blind randomized

346             placebo-controlled study. Lancer 1984; 1:921-926.

347       16.   Poovorawan Y, et al.: Long term hepatitis B vaccine in infants born to hepatitis

                                                   PACKAGE        INSERT

 34x             B e antigen     positive   mothers.   Archives   of Diseases in Childhood 1997; 77:F47-

 349             F51.


351        17.   Stevens CE, et al.: Perinatal Hepatitis B virus transmission in the United States:

352              Prevention by passive-active immunization. JAMA 1985; 253: 1740-l 745.


354        18.   Jhaveri R, et al.: High titer multiple dose therapy with HBIG in newborn            infants

355              of HBsAg positive mothers. J Pediafr 1980: 97:305-308.


357        19.   Centers for Disease Control: Hepatitis B virus: A comprehensive strategy for

355              eliminating    transmission    in the United States through universal childhood

359              vaccination.     Recommendations of the Immunization Practices Advisory

360              Committee (ACIP).          MMWR 1991; 40(13):1-25.


362    20.       Data on file, Nabi”


       21.       Scheiermann N, Kuwert EK: Uptake and elimination of hepatitis B

365              immunoglobulins after intramuscular application in man.          Deve/op Biol Standard

366              1983; 54:347.
                                           PACKAGE INSERT

 367   22.     Centers for Disease Control: General recommendations on immunization_

 368           Recommendations of the Advisory Committee on Immunization Practices (ACIp).

 369           MMWR    1994;   1:6.


371    23.     Ellis EF, Henney CS: Adverse reactions following administration of human

372            gamma globulin. J AIlerg 1969; 43:45-54.


374    Manufactured by:

375    Nab?’

376    Boca Raton, FL 33487

377    U.S. License No. 1022

378    Part No. 07.0210.00

379    March, 1999