Included as part of the "PRECAUTIONS" Section
Severe hypersensitivity reactions may occur with IGIV products, including GAMMAKED. In case of
hypersensitivity, discontinue GAMMAKED infusion immediately and institute appropriate treatment.
Have medications such as epinephrine available for immediate treatment of acute hypersensitivity
GAMMAKED contains trace amounts of IgA (average 46 micrograms/mL). Patients with known
antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and
anaphylactic reactions. It is contraindicated in IgA deficient patients with antibodies against IgA and
history of hypersensitivity reaction. [see CONTRAINDICATIONS]
Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic
nephrosis and death may occur upon use of IGIV products, especially those containing sucrose.(7,8)
GAMMAKED does not contain sucrose. Ensure that patients are not volume depleted prior to the
initiation of the infusion of GAMMAKED. Periodic monitoring of renal function and urine output is
particularly important in patients judged to have a potential increased risk for developing acute renal
failure. Assess renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine,
prior to the initial infusion of GAMMAKED and again at appropriate intervals thereafter. If renal
function deteriorates, consider discontinuation of GAMMAKED. [see PATIENT INFORMATION] For patients judged to be at risk for developing renal dysfunction, including patients with any
degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion,
sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs, administer GAMMAKED at the
minimum infusion rate practicable [less than 8 mg/kg/min (0.08 mL/kg/min)]. [see DOSAGE AND ADMINISTRATION]
Hyperproteinemia, Increased Serum Viscosity, And Hyponatremia
Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV
treatment, including GAMMAKED. It is clinically critical to distinguish true hyponatremia from a
pseudohyponatremia that is associated 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 thrombosis.(9)
Thrombosis may occur following treatment with immune globulin products, including
GAMMAKED.(10-12) 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 GAMMAKED 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 BOX WARNING, DOSAGE AND ADMINISTRATION, PATIENT INFORMATION]
Aseptic Meningitis Syndrome (AMS)
AMS may occur infrequently with IGIV treatment, including GAMMAKED. 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. AMS is characterized by the
following symptoms and signs: severe headache, nuchal rigidity, drowsiness, fever, photophobia,
painful eye movements, 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 with elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a
thorough neurological examination on patients exhibiting such symptoms and signs 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.
GAMMAKED may contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction
and hemolysis.(13-16) Delayed hemolytic anemia can develop subsequent to IGIV therapy due to
enhanced RBC sequestration, and acute hemolysis consistent with intravascular hemolysis, has been
reported. [see ADVERSE REACTIONS]
The following risk factors may be related to the development of hemolysis: high doses (e.g., ≥ 2
grams/kg, single administration or divided over several days) and non-O blood group.(17) Underlying
inflammatory state in an individual patient may increase the risk of hemolysis, but its role is
Closely monitor patients for clinical signs and symptoms of hemolysis [see Monitoring: Laboratory Tests], particularly patients with risk factors noted above and those with pre-existing anemia and/or
cardiovascular or pulmonary compromise. Consider appropriate laboratory testing in higher risk
patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately
36 hours and again 7 to 10 days post infusion. If clinical signs and symptoms of hemolysis or a
significant drop in hemoglobin or hematocrit have been observed, perform additional 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 ongoing
Transfusion-Related Acute Lung Injury (TRALI)
Noncardiogenic pulmonary edema may occur in patients following treatment with IGIV products,
including GAMMAKED.(19) TRALI is characterized by severe respiratory distress, pulmonary edema,
hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours
Monitor patients for pulmonary adverse reactions. [see PATIENT INFORMATION] If TRALI is
suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both
the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory
The high dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid
volumes or where fluid volume may be a concern.
Transmission Of Infectious Agents
Because GAMMAKED 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, vCJD or CJD have ever been
identified for GAMMAKED. 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
Therapeutics Inc. [1-800-520-2807].
Do not administer GAMMAKED subcutaneously in patients with ITP because of the risk of hematoma
- 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 BUN and serum creatinine, before the initial infusion of GAMMAKED and at appropriate
- 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, because of the potentially increased risk of thrombosis.
- If signs and/or symptoms of hemolysis are present after an infusion of GAMMAKED, perform
appropriate laboratory testing for confirmation.
- If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and
anti-HLA 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.
Patient Counseling Information
[see BOX WARNING and WARNINGS AND PRECAUTIONS]
Instruct patients to immediately report the following signs and symptoms to their healthcare provider:
- Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath [see WARNINGS AND PRECAUTIONS]
- Symptoms of thrombosis which may include: pain and/or swelling of an arm or leg with warmth over
the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or
discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one
side of the body [see WARNINGS AND PRECAUTIONS]
- Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements,
nausea, and vomiting [see WARNINGS AND PRECAUTIONS]
- Increased heart rate, fatigue, yellowing of the skin or eyes, and dark-colored urine [see WARNINGS AND PRECAUTIONS]
- Trouble breathing, chest pain, blue lips or extremities, and fever [see WARNINGS AND PRECAUTIONS]
Inform patients that GAMMAKED is made from human plasma and may contain infectious agents that can
cause disease. While the risk GAMMAKED can transmit an infectious agent has been reduced by
screening plasma donors for prior exposure, testing donated plasma, and by inactivating or removing
pathogens during manufacturing, patients should report any symptoms that concern them. [see WARNINGS AND PRECAUTIONS]
Inform patients that GAMMAKED can interfere with their immune response to live virus vaccines such
as measles, mumps and rubella. Inform patients to notify their healthcare professional of this potential
interaction when they are receiving vaccinations. [see DRUG INTERACTIONS]
Self-Adminis tration: Subcutaneous Adminis tration Only
Advise the patient to read the FDA-approved patient labeling (Instructions for Use: Subcutaneous
Infusion for Primary Humoral Immunodeficiency).
Provide the patient with instructions on subcutaneous infusion for home treatment, if the physician
believes that home administration is appropriate for the patient.
- The type of equipment to be used along with its maintenance,
- proper infusion techniques, selection of appropriate infusion sites (e.g., abdomen, thighs, upper
arms, and/or lateral hip),
- maintenance of a treatment diary, and
- measures to be taken in case of adverse reactions in the patient instructions.
Use In Specific Populations
There are no data with GAMMAKED use in pregnant women to inform a drug-associated risk. Animal
reproduction studies have not been conducted with GAMMAKED. It is not known whether
GAMMAKED can cause fetal harm when administered to a pregnant woman or can affect reproduction
capacity. GAMMAKED should be given to a pregnant woman only if clearly needed. In the U.S. general
population, the estimated background risk of major birth defect and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
There is no information regarding the presence of GAMMAKED in human milk, the effect on the
breastfed infant, and the effects on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for GAMMAKED and any
potential adverse effects on the breastfed infant from GAMMAKED or from the underlying maternal
GAMMAKED was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI
subjects exposed to GAMMAKED were children. Pharmacokinetics, safety and efficacy were similar
to those in adults with the exception that vomiting was more frequently reported in pediatrics (3 of 18
subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels.
SC GAMMAKED was evaluated in three pediatric subjects (age range 13-15 years) with PI along with
adults, and separately in a second trial in 11 children and adolescents (age range 2-16 years).
Pharmacokinetics and safety were similar to those in adults. No pediatric-specific dose requirements
were necessary to achieve circulating IgG levels. Efficacy and safety in pediatric patients under 2 years
of age using the SC route of administration have not been established.
For treatment of ITP, GAMMAKED must be administered by the intravenous route.
GAMMAKED was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of the acute
ITP subjects exposed to GAMMAKED were children. Pharmacokinetics, safety and efficacy were
similar to those in adults with the exception that fever was more frequently repored in pediatrics (6 of
12 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels.
One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of
GAMMAKED. The death was judged to be unrelated to GAMMAKED.
The safety and effectiveness of GAMMAKED have not been established in pediatric subjects with
Use caution when administering GAMMAKED to patients age 65 and over who are at increased risk for
thrombosis or renal insufficiency. [see BOX WARNING, WARNINGS AND PRECAUTIONS] Do not
exceed recommended doses, and administer GAMMAKED at the minimum infusion rate practicable.
Clinical studies of GAMMAKED did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects.
7. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin
therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol 1997;8(11):1788-
8. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev
9. Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in postinfusional
hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol 2003;73:97-100.
10. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating
thromboembolic events. Neurology 1994;44:223-6.
11. Woodruff RK, Grigg AP, Firkin FC, et al. Fatal thrombotic events during treatment of autoimmune
thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-8.
12. Wolberg AS, Kon RH, Monroe DM, et al. Coagulation factor XI is a contaminant in intravenous
immunoglobulin preparations. Am J Hematol 2000;65:30-4.
13. Copelan EA, Strohm PL, Kennedy MS, et al. Hemolysis following intravenous immune globulin
therapy. Transfusion 1986;26:410-2.
14. Thomas MJ, Misbah SA, Chapel HM, et al. Hemolysis after high-dose intravenous Ig. Blood
15. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin.
Muscle & Nerve 1997;20:1142-5.
16. Kessary-Shoham H, Levy Y, Shoenfeld Y, et al. In vivo administration of intravenous
immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmune 1999;13:129-
17. 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;4:1993-7.
18. Daw Z, Padmore R, Neurath D, et al. Hemolytic transfusion reactions after administration of
intravenous immune (gamma) globulin: A case series analysis. Transfusion 2008;48:1598-601.
19. Rizk A, Gorson KC, Kenney L, et al. Transfusion-related acute lung injury after the infusion of
IVIG. Transfusion 2001;41:264-8.