GAMMAGLOBULIN
DESCRIPTION:
Immune Globulin Intravenous (Human) (IGIV), BHARGLOB*, is a
solvent/detergent treated, sterile, freeze-dried preparation of highly purified
immunoglobulin G (IgG) derived from large pools of human plasma.
ACTIONS/CLINICAL PHARMACOLOGY:
Immune Globulin Intravenous (Human), BHARGLOB, contains a broad spectrum
of IgG antibodies against bacterial and viral agents that are capable of
opsonization and neutralization of microbes and toxins.
Peak levels of IgG are reached immediately after infusion of Immune Globulin
Intravenous (Human), BHARGLOB. It has been shown that, after infusion,
exogenous IgG is distributed relatively rapidly between plasma and extravascular
fluid until approximately half is partitioned in the extravascular space.
Therefore a rapid initial drop in serum IgG levels is to be expected. (REF. 4)
As a class, IgG survives longer In Vivo than other serum proteins. (REF. 4,5)
Studies show that the half-life of Immune Globulin Intravenous (Human),
BHARGLOB, is approximately 37.7 15 days. (REF. 3) Previous studies
reported IgG half-life values of 21 to 25 days. (REF. 4,5,6) The half-life of
IgG can vary considerably from person to person, however. In particular, high
concentrations of IgG and hypermetabolism associated with fever and infection
have been seen to coincide with a shortened half-life of IgG. (REF. 4,5,6,7)
INDICATIONS AND USAGE:
PRIMARY IMMUNODEFICIENCY DISEASES
Immune Globulin Intravenous (Human), BHARGLOB, is indicated for the
treatment of primary immunodeficient states, such as: congenital
agammaglobulinemias, common variable immunodeficiency, Wiskott-Aldrich syndrome,
and severe combined immunodeficiencies. (REF. 6,7) This indication was supported
by a clinical trial of 17 patients with primary immunodeficiency who received a
total of 341 infusions. Immune Globulin Intravenous (Human), BHARGLOB,
is especially useful when high levels or rapid elevation of circulating IgG are
desired or when intramuscular injections are contraindicated (e.g., small muscle
mass).
B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Immune Globulin Intravenous (Human), BHARGLOB, is indicated for
prevention of bacterial infections in patients with hypogammaglobulinemia and/or
recurrent bacterial infections associated with B-cell Chronic Lymphocytic
Leukemia (CLL). In a study of 81 patients, 41 of whom were treated with Immune
Globulin Intravenous (Human), Gammagard(R), bacterial infections were
significantly reduced in the treatment group. (REF. 8,9) In this study, the
placebo group had approximately twice as many bacterial infections as the IGIV
group. The median time to first bacterial infection for the IGIV group was
greater than 365 days. By contrast, the time to first bacterial infection in the
placebo group was 192 days. The number of viral and fungal infections, which
were for the most part minor, was not statistically different between the two
groups.
IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
When a rapid rise in platelet count is needed to prevent and/or to control
bleeding in a patient with Idiopathic Thrombocytopenic Purpura, the
administration of Immune Globulin Intravenous (Human), BHARGLOB, should
be considered.
The efficacy of Immune Globulin Intravenous (Human), Gammagard(R), has been
demonstrated in a clinical study involving 16 patients. Of these 16 patients, 13
had chronic ITP (11 adults, 2 children), and 3 patients had acute ITP (one
adult, 2 children). All 16 patients (100%) demonstrated a clinically significant
rise in platelet count to a level greater than 40,000/mm(cubed) following the
administration of Immune Globulin Intravenous (Human), Gammagard(R). Ten of the
16 patients (62.5%) exhibited a significant rise to greater than 80,000
platelets/mm(cubed). Of these 10 patients, 7 had chronic ITP (5 adults, 2
children), and 3 patients had acute ITP (one adult, 2 children).
The rise in platelet count to greater than 40,000/mm(cubed) occurred after a
single 1 g/kg infusion of Gammagard(R) in 8 patients with chronic ITP (6 adults,
2 children), and in 2 patients with acute ITP (one adult, one child). A similar
response was observed after two 1 g/kg infusions in 3 adult patients with
chronic ITP, and one child with acute ITP. The remaining 2 adult patients with
chronic ITP received more than two 1 g/kg infusions before achieving a platelet
count greater than 40,000/mm(cubed). The rise in platelet count was generally
rapid, occurring within 5 days. However, this rise was transient and not
considered curative. Platelet count rises lasted 2 to 3 weeks, with a range of
12 days to 6 months. It should be noted that childhood ITP may resolve
spontaneously without treatment.
CONTRAINDICATIONS:
None known.
WARNINGS:
Immune Globulin Intravenous (Human), BHARGLOB, should only be
administered intravenously. Other routes of administration have not been
evaluated.
Immediate anaphylactic and hypersensitivity reactions are a remote possibility.
Epinephrine should be available for treatment of any acute anaphylactoid
reactions.
Immune Globulin Intravenous (Human), BHARGLOB, contains only trace
amounts of IgA (<3.7 mcgm/mL in a 5% solution). Nonetheless, it should be given
with caution to patients with antibodies to IgA or selective IgA deficiencies.
(REF. 7,10)
PRECAUTIONS:
There is clinical evidence of a possible association between Immune Globulin
Intravenous (human) (IGIV) administration and thrombotic events. The exact cause
of this is unknown; therefore, caution should be exercised in the prescribing
and infusion of IGIV in patients with a history of cardiovascular disease or
thrombotic episodes. (Ref. 12-17)
An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in
association with Immune Globulin Intravenous (Human) (IGIV) treatment.
Discontinuation of IGIV treatment has resulted in remission of AMS within
several days without sequelae. The syndrome usually begins within several hours
to two days following IGIV treatment. It is characterized by symptoms and signs
including severe headache, nuchal rigidity, drowsiness, fever, photophobia,
painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF)
studies are frequently positive with pleocytosis up to several thousand cells
per cu.mm., predominantly from the granulocytic series, and elevated protein
levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs
should receive a thorough neurological examination, including CSF studies, to
rule out other causes of meningitis. AMS may occur more frequently in
association with high dose (2 g/kg) IGIV treatment.
Certain components used in the packaging of this product contain natural rubber
latex.
DRUG INTERACTIONS
See DOSAGE AND ADMINISTRATION Section.
PREGNANCY CATEGORY C
Animal reproduction studies have not been conducted with Immune Globulin
Intravenous (Human), BHARGLOB. It is also not known whether Immune
Globulin Intravenous (Human), BHARGLOB, can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Immune
Globulin Intravenous (Human), BHARGLOB, should be given to a pregnant
woman only if clearly needed.
DRUG INTERACTIONS:
Admixtures of Immune Globulin Intravenous (Human), BHARGLOB, with other
drugs and intravenous solutions have not been evaluated. It is recommended that
Immune Globulin Intravenous (Human), BHARGLOB, be administered
separately from other drugs or medications which the patient may be receiving.
The product should not be mixed with Immune Globulin Intravenous (Human) from
other manufacturers.
Antibodies in immune globulin preparations may interfere with patient responses
to live vaccines, such as those for measles, mumps, and rubella. The immunizing
physician should be informed of recent therapy with Immune Globulin Intravenous
(Human) so that appropriate precautions can be taken.
(See Also DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS:
In general, reported adverse reactions to Immune Globulin Intravenous (Human)
Gammagard(R), in patients with either congenital or acquired immunodeficiencies
are similar in kind and frequency. Various minor reactions, such as headache,
fatigue, chills, backache, leg cramps, lightheadedness, fever, urticaria,
flushing, slight elevation of blood pressure, nausea and vomiting may
occasionally occur. Slowing or stopping the infusion usually allows the symptoms
to disappear promptly.
Immediate anaphylactic and hypersensitivity reactions are a remote possibility.
Epinephrine should be available for treatment of any acute anaphylactoid
reaction. (See WARNINGS.)
PRIMARY IMMUNODEFICIENCY DISEASES
Twenty-one adverse reactions occurred in 341 infusions (6%), when using Immune
Globulin Intravenous (Human), Gammagard(R) (5% solution), in a clinical trial of
17 patients with primary immunodeficiency. (REF. 11) Of the 17 patients, 12
(71%) were adults, and 5 (29%) were children (16 years or younger).
In a cross-over study comparing Gammagard(R) and BHARGLOB (5% solutions)
conducted in a small number (n=10) of primary immunodeficient patients, no
unusual or unexpected adverse reactions were observed in the BHARGLOB
group. The adverse reactions experienced in the BHARGLOB group were
similar in frequency and nature to those observed in the control group
consisting of patients receiving Gammagard(R).
Gammagard(R), reconstituted to a concentration of 10%, was administered
intravenously at rates varying from 2-11 mL/kg/Hr. Systemic reactions occurred
in 23 (10.5%) of 219 infusions. This compares with an adverse reaction incidence
of 6% (only systemic reactions reported) for primary immunodeficient patients
previously treated with a 5% solution at infusion rates varying between 2 and 8
mL/kg/Hr, as described above (also, see reference 11). Local pain or irritation
was experienced during 35 (16%) of 219 infusions. Application of a warm compress
to the infusion site alleviated local symptoms. These local reactions tended to
be associated with hand vein infusions and their incidence may be reduced by
infusions via the antecubital vein.
B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
In the study of patients with B-cell Chronic Lymphocytic Leukemia, the incidence
of adverse reactions associated with Gammagard(R) infusions was approximately
1.3% while that associated with placebo (normal saline) infusions was 0.6%.
(REF. 9)
IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
During the clinical study of Gammagard(R) for the treatment of Idiopathic
Thrombocytopenic Purpura, the only adverse reaction reported was headache which
occurred in 12 of 16 patients (75%). Of these 12 patients, 11 had chronic ITP (9
adults, 2 children), and one child had acute ITP. Oral antihistamines and
analgesics alleviated the symptoms and were used as pretreatment for those
patients requiring additional IGIV therapy. The remaining 4 patients did not
report any side effects and did not require pretreatment.
DOSAGE AND ADMINISTRATION:
PRIMARY IMMUNODEFICIENCY DISEASES
For patients with primary immunodeficiencies, monthly doses of at least 100
mg/kg are recommended. Initially, patients may receive 200-400 mg/kg. As there
are significant differences in the half-life of IgG among patients with primary
immunodeficiencies, the frequency and amount of immunoglobulin therapy may vary
from patient to patient. The proper amount can be determined by monitoring
clinical response. The minimum serum concentration of IgG necessary for
protection has not been established.
B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
For patients with hypogammaglobulinemia and/or recurrent bacterial infections
due to B-cell Chronic Lymphocytic Leukemia, a dose of 400 mg/kg every 3 to 4
weeks is recommended.
IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
For patients with acute or chronic Idiopathic Thrombocytopenic Purpura, a dose
of 1 g/kg is recommended. The need for additional doses can be determined by
clinical response and platelet count. Up to three separate doses may be given on
alternate days if required.
RECONSTITUTION: USE ASEPTIC TECHNIQUE
A. 5% SOLUTION
1. NOTE: RECONSTITUTE IMMEDIATELY BEFORE USE.
2. If refrigerated, warm the Sterile Water for Injection, USP (diluent) and
Immune Globulin Intravenous (Human), BHARGLOB (dried concentrate), to
room temperature.
3. Remove caps from concentrate and diluent bottles to expose central portion of
rubber stoppers.
4. Cleanse stoppers with germicidal solution.
5. Remove protective covering from the spike at one end of the transfer device
(Fig. 1).
6. Place the diluent bottle on a flat surface and, while holding the bottle to
prevent slipping, insert the spike of the transfer device PERPENDICULARLY
THROUGH THE CENTER of the bottle stopper.
CAUTION: FAILURE TO USE CENTER OF STOPPER MAY RESULT IN DISLODGING THE STOPPER.
Click here for illustration(s).
Press down firmly so that the transfer device fits snugly against the diluent
bottle (Fig. 2). A slight twist at the end of the downward push helps ensure a
snug fit.
7. Remove the protective covering from the other end of the transfer device.
Hold diluent bottle to prevent slipping. CAUTION: FAILURE TO USE CENTER OF
STOPPER MAY RESULT IN DISLODGING THE STOPPER AND LOSS OF VACUUM.
Invert concentrate bottle and press firmly onto the transfer device until the
concentrate bottle fits snugly against the transfer device.
8. Invert bottle/transfer device assembly (Fig. 3). Diluent will flow into the
concentrate bottle. When diluent transfer is complete, remove empty diluent
bottle and transfer device from concentrate bottle. Discard transfer device
after single use.
9. Thoroughly wet the dried material by tilting or inverting and gently rotating
the bottle (Fig. 4). DO NOT SHAKE. AVOID FOAMING.
10. Repeat gentle rotation as long as undissolved product is observed.
Click here for illustration(s).
B. 10% SOLUTION
Follow steps 1-4 as previously described in A.
5. To prepare a 10% solution, reconstitute with the appropriate volume of
diluent by using a sterile hypodermic syringe and needle. Table 2 indicates the
volume of diluent required for a 5% or 10% concentration. Using aseptic
technique, draw required volume into a sterile hypodermic syringe and needle.
The diluent is then injected into the concentrate bottle.
TABLE 2
REQUIRED DILUENT VOLUME
---------------------------------------------------------------------------------------------------------------------------
2.5 G 5 G 10 G
CONCENTRATION BOTTLE BOTTLE BOTTLE
5% 50 mL 96 mL 192 mL
10% 25 mL 48 mL 96 mL
6. Discard any unused diluent after single use.
7. Thoroughly wet the dried material by tilting or inverting and gently rotating
the bottle (Fig. 4). DO NOT SHAKE. AVOID FOAMING.
8. Repeat gentle rotation as long as undissolved product is observed.
RATE OF ADMINISTRATION
It is recommended that initially a 5% solution be infused at a rate of 0.5
mL/kg/Hr. If infusion at this rate and concentration causes the patient no
distress, the administration rate may be gradually increased to a maximum rate
of 4 mL/kg/Hr. Patients who tolerate the 5% concentration at 4 mL/kg/Hr can be
infused with the 10% concentration starting at 0.5 mL/kg/Hr. If no adverse
effects occur, the rate can be increased gradually up to a maximum of 8
mL/kg/Hr.
It is recommended that antecubital veins be used especially for 10% solutions,
if possible. This may reduce the likelihood of the patient experiencing
discomfort at the infusion site (see ADVERSE REACTIONS).
A rate of administration which is too rapid may cause flushing and changes in
pulse rate and blood pressure. Slowing or stopping the infusion usually allows
the symptoms to disappear promptly.
DRUG INTERACTIONS
Admixtures of Immune Globulin Intravenous (Human), BHARGLOB, with other
drugs and intravenous solutions have not been evaluated. It is recommended that
Immune Globulin Intravenous (Human), BHARGLOB, be administered
separately from other drugs or medications which the patient may be receiving.
The product should not be mixed with Immune Globulin Intravenous (Human) from
other manufacturers.
Antibodies in immune globulin preparations may interfere with patient responses
to live vaccines, such as those for measles, mumps, and rubella. The immunizing
physician should be informed of recent therapy with Immune Globulin Intravenous
(Human) so that appropriate precautions can be taken.
ADMINISTRATION
Immune Globulin Intravenous (Human), BHARGLOB, should be administered as
soon after reconstitution as possible. Administration should begin not more than
2 hours after reconstitution.
The reconstituted material should be at room temperature during administration.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Do not use if particulate matter and/or discoloration is observed.
Follow directions for use which accompany the administration set provided. If
another administration set is used, ensure that the set contains a similar
filter.
REFERENCES:
1. Prince AM, Horowitz B, Brotman B: Sterilisation of hepatitis and HTLV-III
viruses by exposure to tri(n-butyl) phosphate and sodium cholate. LANCET 1:706-
710, 1986
2. Horowitz B, Wiebe ME, Lippin A, Et Al: Inactivation of viruses in labile
blood derivatives: I. Disruption of lipid enveloped viruses by tri(n-butyl)
phosphate detergent combinations. TRANSFUSION 25:516-522, 1985
3. Unpublished data in the files of Baxter Healthcare Corporation.
4. Waldmann TA, Storber W: Metabolism of immunoglobulins. PROG ALLERGY 13:1-110,
1969
5. Morell A, Riesen W: Structure, function and catabolism of immunoglobulins in
IMMUNOHEMOTHERAPY. Nydegger UE (ed), London, Academic Press, 1981, pp 17-26
6. Stiehm ER: Standard and special human immune serum globulins as therapeutic
agents. PEDIATRICS 63:301-319, 1979
7. Buckley RH: Immunoglobulin replacement therapy: Indications and
contraindications for use and variable IgG levels achieved in IMMUNOGLOBULINS:
CHARACTERISTICS AND USE OF INTRAVENOUS PREPARATIONS. Alving BM, Finlayson JS
(eds), Washington, DC, U.S. Department of Health and Human Services, 1979, pp 3-
8
8. Bunch C, Chapel HM, Rai K, Et Al: Intravenous Immune Globulin reduces
bacterial infections in Chronic Lymphocytic Leukemia: A controlled randomized
clinical trial. BLOOD 70 SUPPL 1:753, 1987
9. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic
Leukemia: Intravenous immunoglobulin for the prevention of infection in Chronic
Lymphocytic Leukemia: A randomized, controlled clinical trial. N ENG J MED
319:902-907, 1988
10. Burks AW, Sampson HA, Buckley RH: Anaphylactic reactions after gammaglobulin
administration in patients with hypogammaglobulinemia: Detection of IgE
antibodies to IgA. N ENG J MED 314:560-564, 1986
11. Ochs HD, Lee ML, Fischer SH, Et Al: Efficacy of a New Intravenous
Immunoglobulin Preparation in Primary Immunodeficient Patients. CLINICAL
THERAPEUTICS 9:512-522, 1987
12. Reinhart WH, Berchtold PE. Effect of high- dose intravenous immunoglobulin
therapy on blood rheology. LANCET 339:662-664, 1992
13. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: Risk
of precipitating thromboembolic events. NEUROLOGY 44:223-226, 1994
14. Harkness K, Howell SJL, Davies-Jones GAB. Encephalopathy associated with
intravenous immunoglobulin treatment for Guillain-Barre syndrome. JOURNAL OF
NEUROLOGY 60:586-598, 1996.
15. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during
treatment of autoimmune thrombocytopenia with intravenous immuno globulin in
elderly patients. LANCET ii:217-18, 1986
16. Silbert PL, Knezevic WV, Bridge DT. Cerebral infarction complicating
intravenous immunoglobulin therapy for polyneuritis cranialis. NEUROLOGY 42:257-
258, 1992
17. Duhem C, Dicato MA, Ries F. Side effects of intravenous immune globulins.
CLIN EXP IMMUNOL 97: (SUPPL 1) 70-83, 1994
BIBLIOGRAPHY
Bussel JB, Kimberly RP, Inman RD, Et Al: Intravenous gammaglobulin treatment of
chronic idiopathic thrombocytopenic purpura. BLOOD 62:480-486, 1983
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