July 29, 2016
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Gamunex-C

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypersensitivity

Severe hypersensitivity reactions may occur with IGIV products, including GAMUNEX-C. In case of hypersensitivity, discontinue GAMUNEX-C infusion immediately and institute appropriate treatment. Have medications such as epinephrine available for immediate treatment of acute hypersensitivity reaction.

GAMUNEX-C 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)

Renal Failure

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) GAMUNEX-C does not contain sucrose. Ensure that patients are not volume depleted prior to the initiation of the infusion of GAMUNEX-C. 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 GAMUNEX-C and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of GAMUNEX-C. (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 GAMUNEX-C at the minimum infusion rate practicable [less than 8 mg IG/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 GAMUNEX-C. 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

Thrombosis may occur following treatment with immune globulin products, including GAMUNEX-C.(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 GAMUNEX-C 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)

Aseptic Meningitis Syndrome (AMS)

AMS may occur infrequently with IGIV treatment, including GAMUNEX-C. 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.

Hemolysis

IGIV products, including GAMUNEX-C, 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, rarely, 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 uncertain.(18)

Monitor patients for clinical signs and symptoms of hemolysis (see Monitoring: Laboratory Tests), 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 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 on-going hemolysis.

Transfusion-related Acute Lung Injury (TRALI)

Noncardiogenic pulmonary edema may occur in patients following treatment with IGIV products, including GAMUNEX-C.(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 after treatment.

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 support.

Volume Overload

The high dose regimen (1 g/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 GAMUNEX-C 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 GAMUNEX-C. 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]

Hematoma Formation

Do not administer GAMUNEX-C subcutaneously in patients with ITP because of the risk of hematoma formation.

Monitoring: Laboratory Tests

  • 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 GAMUNEX-C and at appropriate intervals thereafter.
  • 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 GAMUNEX-C, 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 BOXED 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 GAMUNEX-C is made from human plasma and may contain infectious agents that can cause disease. While the risk GAMUNEX-C 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 GAMUNEX-C can interfere with their immune response to live viral 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)

PI: Self-Administration: Subcutaneous Administration 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

Pregnancy

Risk Summary

There is no data with GAMUNEX-C use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with GAMUNEX-C. It is not known whether GAMUNEX-C can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMUNEX-C 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.

Lactation

Risk Summary

There is no information regarding the presence of GAMUNEX-C 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 GAMUNEX-C and any potential adverse effects on the breastfed infant from GAMUNEX-C or from the underlying maternal condition.

Pediatric Use

PI: Intravenous

GAMUNEX-C was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI subjects exposed to GAMUNEX-C 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.

PI: Subcutaneous

SC GAMUNEX-C 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.

ITP

For treatment of ITP, GAMUNEX-C must be administered by the intravenous route.

GAMUNEX-C was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of the acute ITP subjects exposed to GAMUNEX-C were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that fever was more frequently reported 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 GAMUNEX-C. The death was judged to be unrelated to GAMUNEX-C.

CIDP

The safety and effectiveness of GAMUNEX-C have not been established in pediatric subjects with CIDP.

Geriatric Use

Use caution when administering GAMUNEX-C to patients age 65 and over who are at increased risk for thrombosis or renal insufficiency. (see BOXED WARNING, WARNINGS AND PRECAUTIONS) Do not exceed recommended doses, and administer GAMUNEX-C at the minimum infusion rate practicable. Clinical studies of GAMUNEX-C did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

REFERENCES

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):1788-94.

8. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-51.

9. Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional 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 1993;15:3789.

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;13:129-35.

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.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 4/5/2016

Warnings
Precautions

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