Included as part of the PRECAUTIONS section.
Renal Dysfunction / Failure
Acute renal dysfunction/failure, osmotic nephropathy, and
death1 may occur upon use of human IGIV products. Ensure that patients are not
volume depleted before administering Gammaplex. In patients who are at risk of
developing renal dysfunction, because of pre-existing renal insufficiency,
predisposition to acute renal failure (such as diabetes mellitus, hypovolemia,
overweight, use of concomitant nephrotoxic medicinal products or age > 65
years), administer Gammaplex at the minimum infusion rate practicable [see DOSAGE
Periodic monitoring of renal function and urine output is
particularly important in patients judged to be at increased risk of developing
acute renal failure. Assess renal function, including measurement of blood urea
nitrogen (BUN) and serum creatinine, before the initial infusion of Gammaplex
and at appropriate intervals thereafter. If renal function deteriorates,
consider discontinuing Gammaplex.
Thrombosis may occur following treatment with immune
globulin products, including Gammaplex2. Risk factors may include: advanced
age, prolonged immobilization, hypercoagulable conditions, history of venous or
arterial thrombosis, use of estrogens, indwelling central vascular catheters,
hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the
absence of known risk factors.
Consider baseline assessment of blood viscosity in
patients at risk for hyperviscosity, including those with cryoglobulins,
fasting chylomicronemia / markedly high triacylglycerols (triglycerides), or monoclonal
gammopathies. For patients at risk of thrombosis, administer Gammaplex at the
minimum dose and infusion rate practicable. Ensure adequate hydration in
patients before administration. Monitor for signs and symptoms of thrombosis
and assess blood viscosity in patients at risk for hyperviscosity [see BOXED
WARNING, DOSAGE AND ADMINISTRATION, PATIENT INFORMATION].
Severe hypersensitivity reactions may occur [see
CONTRAINDICATIONS]. In case of hypersensitivity, discontinue Gammaplex
infusion immediately and institute appropriate treatment. Medications such as
epinephrine should be available for immediate treatment of acute
Gammaplex contains trace amounts of IgA ( < 10
μg/mL) [see DESCRIPTION]. Patients with known antibodies to IgA may
have a greater risk of developing potentially severe hypersensitivity and
anaphylactic reactions. Gammaplex is contraindicated in patients with
antibodies against IgA and a history of hypersensitivity reaction [see
Hyperproteinemia, Increased Serum Viscosity, And Hyponatremia
Hyperproteinemia, increased serum viscosity, and
hyponatremia may occur in patients receiving IGIV therapy. It is critical to
clinically distinguish true hyponatremia from a pseudohyponatremia that is
associated with or causally related to hyperproteinemia with concomitant
decreased calculated serum osmolality or elevated osmolar gap, because
treatment aimed at decreasing serum free water in patients with
pseudohyponatremia may lead to volume depletion, a further increase in serum
viscosity, and a possible predisposition to thrombotic events2.
Aseptic Meningitis Syndrome (AMS)
AMS may occur with IGIV treatment. AMS usually begins
within several hours to 2 days following IGIV treatment. Discontinuation of
IGIV treatment has resulted in remission of AMS within several days without sequelae3.
AMS is characterized by the following signs and symptoms:
severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye
movements, nausea, and vomiting [see PATIENT INFORMATION].
Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several
thousand cells per cubic millimeter, predominantly from the granulocytic
series, and elevated protein levels up to several hundred mg/dL, but negative
culture results. Conduct a thorough neurological examination on patients
exhibiting such signs and symptoms, including CSF studies, to rule out other causes
of meningitis. AMS may occur more frequently in association with high doses (2
g/kg) and/or rapid infusion of IGIV.
Gammaplex may contain blood group antibodies that can act
as hemolysins and induce in vivo coating of red blood cells (RBCs) with
immunoglobulin, causing a positive direct antiglobulin test (DAT) (Coombs'
test) result and hemolysis4. Delayed hemolytic anemia can develop
subsequent to IGIV therapy due to enhanced RBC sequestration and acute
hemolysis, consistent with intravascular hemolysis, has been reported5.
Cases of severe hemolysis-related renal dysfunction/failure or disseminated
intravascular coagulation have occurred following infusion of IGIV.
The following risk factors may be associated with the
development of hemolysis following IGIV administration: high doses (e.g.,
≥ 2 g/kg), given either as a single administration or divided over several
days, and non-O blood group6. Other individual patient factors, such
as an underlying inflammatory state (as may be reflected by, for example,
elevated C-reactive protein or erythrocyte sedimentation rate), have been
hypothesized to increase the risk of hemolysis following administration of IGIV
7, but their role is uncertain. Hemolysis has been reported
following administration of IGIV for a variety of indications, including ITP
Closely monitor patients for clinical signs and symptoms
of hemolysis, particularly patients with risk factors noted above. Consider
appropriate laboratory testing in higher risk patients, including measurement
of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96
hours post infusion. If clinical signs and symptoms of hemolysis or a
significant drop in hemoglobin or hematocrit have been observed, perform
confirmatory laboratory testing. If transfusion is indicated for patients who
develop hemolysis with clinically compromising anemia after receiving IGIV,
perform adequate cross-matching to avoid exacerbating on-going hemolysis.
Transfusion-related Acute Lung Injury (TRALI)
Noncardiogenic pulmonary edema may occur in patients
following IGIV treatment8. TRALI is characterized by severe
respiratory distress, pulmonary edema, hypoxemia, normal left ventricular
function and fever. Symptoms typically appear within 1 to 6 hours following
Monitor patients for pulmonary adverse reactions. If
TRALI is suspected, perform appropriate tests for the presence of
anti-neutrophil antibodies in both the product and the patient's serum.
TRALI may be managed using oxygen therapy with adequate
Carefully consider the relative risks and benefits before
prescribing the high dose regimen (for chronic ITP) in patients at increased
risk of volume overload.
Transmissible Infectious Agents
Because Gammaplex is made from human blood, it may carry
a risk of transmitting infectious agents, e.g., viruses, the variant
Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the
Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral
diseases or CJD have been associated with the use of Gammaplex. All infections
suspected by a physician possibly to have been transmitted by this product
should be reported by the physician or other healthcare providers to BPL Inc.
Before prescribing Gammaplex, the physician should
discuss the risks and benefits of its use with the patient [see PATIENT INFORMATION].
- After infusion of immunoglobulin, the transitory rise of
the various passively transferred antibodies in the patient's blood may yield
positive serological testing results, with the potential for misleading
- Passive transmission of antibodies to erythrocyte
antigens (e.g., A, B, and D) may cause a positive direct or indirect
antiglobulin (Coombs') test.
- Clinically assess patients with known renal dysfunction,
diabetes mellitus, age greater than 65, volume depletion, sepsis,
paraproteinemia, or those receiving nephrotoxic agents, and monitor as
appropriate (BUN, serum creatinine, urine output) during therapy with
- Consider baseline assessment of blood viscosity in
patients at risk for hyperviscosity, including those with polycythemia,
cryoglobulins, fasting chylomicronemia/markedly high triglycerides, or
- Consider measuring hemoglobin or hematocrit at baseline
and approximately 36 to 96 hours post infusion in patients at higher risk of
hemolysis. If signs and/or symptoms of hemolysis are present after an infusion
of Gammaplex, perform appropriate laboratory testing for confirmation.
- If TRALI is suspected, perform appropriate tests for the
presence of anti-neutrophil antibodies in both the product and patient's serum.
Use In Specific Populations
Pregnancy Category C
Animal reproduction studies have not been conducted with
Gammaplex. It is also not known whether Gammaplex can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Gammaplex
should be given to a pregnant woman only if clearly needed. Immunoglobulins
cross the placenta from maternal circulation increasingly after 30 weeks of
Use of Gammaplex has not been evaluated in nursing
Treatment of Primary Humoral Immunodeficiency
Gammaplex was evaluated in six (6) pediatric patients
with primary humoral immunodeficiency in one study (2 between ages of 9 and 10,
and 4 between ages 12 and 16), and 25 patients in a second study (3 between
ages of 2 to 5, 12 between ages of 6 to 11, and 10 between ages of 12 to 16).
No pediatric-specific dose requirements were necessary to achieve the desired
serum IgG levels.[see Clinical Studies].
Safety and efficacy of Gammaplex was not evaluated and
established in pediatric patients below the age of two years.
Fourteen subjects (56%) had an AR at some time during the
pediatric clinical trial that was considered product-related. Of these 14
subjects, two had ARs that were considered definitely related to Gammaplex
including headache, fatigue and myalgia. Seven subjects with the 21-day
infusion cycle had at least one AR (7 of 14 subjects, 50%), as did seven
subjects with the 28-day infusion cycle (7 of 11 subjects, 64%).
Treatment of Chronic Immune Thrombocytopenic Purpura
Gammaplex was evaluated in three (3) pediatric subjects
with chronic immune thrombocytopenic purpura (two aged 6 and one aged 12). This
number of pediatric patients was too small for separate evaluation from the
adult patients for efficacy, however 31 pediatric patients have received
Gammaplex in the PI studies demonstrating safety in this population [see Clinical
Use caution when administering Gammaplex to patients age
65 and over who are judged to be at increased risk of developing renal
insufficiency or thrombotic events [see BOXED WARNING, WARNINGS AND
PRECAUTIONS]. Do not exceed recommended doses, and administer Gammaplex at
the minimum infusion rate practicable.
Eight (8) patients with primary humoral immunodeficiency
at or over the age of 65 were included within the clinical evaluation of
Gammaplex. This number of geriatric patients was too small for separate
evaluation from the younger patients for safety or efficacy [see Clinical
2. Dalakas MC. High-dose intravenous immunoglobulin and
serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;
3. Gabor EP. Meningitis and skin reaction after
intravenous immune globulin therapy. Ann Intern Med 1997; 127:1130.
4. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia
associated with intravenous immunoglobulin. Muscle Nerve 1997; 20:1142-1145.
5. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M,
Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead
to enhanced erythrocyte sequestration. J Autoimmun 1999; 13:129-135.
6. Kahwaji J, Barker E, Pepkowitz S, et al. Acute
Hemolysis After High-Dose Intravenous Immunoglobulin Therapy in Highly HLA
Sensitized Patients. Clin J Am Soc Nephrol 2009;4:1993-1997.
7. Daw Z, Padmore R, Neurath D, et al. Hemolytic
transfusion reactions after administration of intravenous immune (gamma)
globulin: A case series analysis. Transfusion 2008;48:1598-1601.
8. Rizk A, Gorson KC, Kenney L, Weinstein R.
Transfusion-related acute lung injury after the infusion of IVIG. Transfusion
9. Pierce LR, Jain N. Risks associated with the use of
intravenous immunoglobulin. Trans Med Rev 2003; 17:241-251.
10. Siber GA, Werner BG, Halsey NA, Reid R, Almeido-Hill
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measles and rubella immunization. J Pediatr 1993; 122:204-211.
11. Salisbury D, Ramsay M, Noakes K, eds. Immunisation
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of Health, 2009; p426.
12. Sidiropoulos D, Herrmann U, Morell A, von Muralt G,
Barandun S. Transplacental passage of intravenous immunoglobulin in the last
trimester of pregnancy. J Pediatr 1986; 109:505-508.