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Flebogamma® 10% DIF
For intravenous use only
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INDICATIONS AND USAGE
Flebogamma 10% DIF is a human immune globulin intravenous (IGIV) that is indicated for the treatment of primary immune
deficiency (PI), including the humoral immune defect in common variable immunodeficiency, x-linked agammaglobulinemia,
severe combined immunodeficiency, and Wiskott - Aldrich syndrome.
DOSAGE AND ADMINISTRATION
The recommended dose of Flebogamma 10% DIF for patients with PI is 300 to 600 mg/kg body weight (3.0 to 6.0 mL/kg),
administered every 3 to 4 weeks.
The infusion of Flebogamma 10% DIF should be initiated at a rate of 0.01 mL/kg body weight/minute (1.0 mg/kg/minute).
If there are no adverse drug reactions, the infusion rate for subsequent infusions can be slowly increased to the maximum
rate of 0.08 mL/kg/minute (8 mg/kg/minute).
Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal
dysfunction or thrombotic events, administer Flebogamma 10% DIF at the minimum infusion rate practicable, and consider
discontinuation of administration if renal function deteriorates.
Flebogamma 10% DIF is contraindicated in patients who have had a history of anaphylactic or severe systemic reactions
to the administration of human immune globulin and in IgA deficient patients with antibodies to IgA and a history of
WARNINGS AND PRECAUTIONS
10% DIF against those of alternative therapies in all patients
for whom Flebogamma 10% DIF is being considered.
10% DIF, the physician should discuss risks and benefits of its use with patients.
Severe hypersensitivity reactions may occur. In case of hypersensitivity, discontinue Flebogamma 10% DIF infusion
immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment
of acute hypersensitivity reactions.
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 Flebogamma 10% DIF and at appropriate intervals thereafter. If renal function
deteriorates, consider discontinue use of Flebogamma 10% DIF.
In patients who are at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to
acute renal failure, administer Flebogamma 10% DIF at the minimum rate of infusion practicable.
Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Flebogamma 10% DIF
therapy. It is clinically critical to distinguish true hyponatremia from a pseudo-hyponatremia that is temporally or causally
related to hyperproteinemia with concomitant decreased calculated serum osmolarity 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 higher risk of thrombotic events.
Thrombotic events may occur during or following treatment with Flebogamma 10% DIF. Monitor patients at risk for
thrombotic events, including those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age,
impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and known or suspected hyperviscosity.
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 judged to be at risk of developing thrombotic events, administer Flebogamma 10% DIF at the minimum rate
of infusion practicable (see Dosage and Administration [2.3]).
Aseptic Meningitis Syndrome (AMS)
AMS may occur infrequently with Flebogamma 10% DIF treatment. Discontinuation of IGIV treatment has resulted in
remission of AMS within several days without sequelae (3-4).
AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever,
photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling 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 to patients exhibiting such signs and symptoms, including CSF studies, to rule out
other causes of meningitis.
AMS may occur more frequently following high doses (2 g/kg) and/or rapid infusion of IGIV.
Flebogamma 10% DIF 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 reaction and hemolysis (5-6). Delayed
hemolytic anemia may develop subsequent to Flebogamma 10% DIF therapy due to enhanced RBC sequestration (7),
and acute hemolysis, consistent with intravascular hemolysis, has been reported.
Monitor patients for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after
Flebogamma 10% DIF infusion, perform appropriate confirmatory laboratory testing (see Patient Counseling Information ).
Transfusion-Related Acute Lung Injury (TRALI)
Non-cardiogenic pulmonary edema may occur in patients following Flebogamma 10% DIF treatment (11). 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 treatment.
Monitor patients for pulmonary adverse reactions (see Patient Counseling Information ). If TRALI is suspected,
perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and
patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.
All patients, but especially individuals receiving Flebogamma 10% DIF for the first time or being restarted on the
product after a treatment hiatus of more than 8 weeks, may be at a higher risk for the development of fever, chills, nausea,
and vomiting. Careful monitoring of recipients and adherence to recommendations regarding dosage and administration
may reduce the risk of these types of events (see Dosage and Administration [2.3]).
Transmissible Infectious Agents
Because Flebogamma 10% DIF is made from human plasma, it may carry a risk of transmitting infectious agents, e.g.,
viruses, and theoretically, the Creutzfeldt-Jakob (CJD) agent. No cases of transmission of viral diseases or CJD have ever
been identified for Flebogamma 10% DIF. All infections suspected by a physician possibly to have been transmitted by this
product should be reported by the physician or other healthcare provider to Grifols Biologicals at 1-888-474-3657.
Before prescribing or administering Flebogamma 10% DIF, the physician should discuss the risks and benefits of
its use with the patient (see Patient Counseling Information ).
Monitoring: Laboratory Tests
risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine,
before the initial infusion of Flebogamma 10% DIF and at appropriate intervals thereafter.
cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal
gammopathies, because of the potentially increased risk of thrombosis.
10% DIF, perform
appropriate laboratory testing for confirmation.
antibodies in both the product and patient s serum.
Interference with Laboratory Tests
After infusion of IgG, 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 interpretation. Passive transmission of antibodies to erythrocyte
antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs ) test.
The most common adverse reactions (reported in I 5% of clinical trial subjects) occurring during or within 72 hours of the
end of an infusion were headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal
cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing,
rash, arthralgia, and edema. The most serious adverse reactions observed with
Flebogamma 10% DIF were back pain, chest discomfort, and headache (2 patients); and chest pain, maculopathy,
rigors, tachycardia, bacterial pneumonia, and vasovagal syncope (1 patient).
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed
in clinical practice.
In a multicenter, open-label, non-randomized, historically controlled clinical study, 46 individuals with primary humoral
immunodeficiency received infusion doses of Flebogamma 10% DIF at 300 to 600 mg/kg body weight every 3 weeks
(mean dose 469 mg/kg) or 4 weeks (mean dose 457 mg/kg) for up to 12 months (see Clinical Studies [14.1]). Routine
pre-medication was not allowed. Of the 601 infusions administered, 130 infusions (22%) in 21 (47%) subjects were
given pre-medications (antipyretic, antihistamine, or antiemetic agent) because of experience with consecutive infusion-
related adverse reactions.
One subject experienced four serious adverse events (AEs, bacterial pneumonia, subcutaneous abscess and two episodes
of cellulitis) and withdrew from the study. Two other subjects who participated in the study discontinued prematurely due
to AEs (back pain/chest pain/headache; and chills/tachycardia). Three subjects experienced four serious non-related AEs
(drug abuse/depression; hernia; and sinusitis).
Forty-five (98%) subjects experienced at least 1 AE irrespective of the relationship with the product, and these subjects
reported a total of 723 AEs. Thirty-eight subjects (83%) had an adverse reaction at some time during the study that was
considered product-related. Of the 21 subjects receiving pre-medications, 12 (57%) subjects reported adverse reactions
during or within 72 hours after the infusion in 48 of the 130 pre-medicated infusions (37%).
Table 2. Treatment-related Adverse Events Occurring in I 5% of Subjects with PI during a
Flebogamma 10% DIF Infusion or within 72 Hours after the End of an infusion
has been reported to be associated with renal dysfunction, acute renal failure, osmotic
nephropathy, with any
degree of pre-existing renal insufficiency, diabetes mellitus, advanced age
volume depletion, sepsis, paraproteinemia, or those receiving known nephrotoxic
drugs (see Warnings and Precautions [5.2]). Flebogamma® 10% DIF does not contain sucrose.
® 10% DIF at the
tminimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and
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