Gammaplex: Package Insert and Label Information

GAMMAPLEX- human immunoglobulin g solution
Bio Products Laboratory Limited

WARNING: THROMBOSIS, RENAL DYSFUNCTION and ACUTE RENAL FAILURE

  • Thrombosis may occur with immune globulin products, including GAMMAPLEX 10%. 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 [see Warnings and Precautions (5.2), Patient Counseling Information (17)].
  • Renal dysfunction, acute renal failure, osmotic nephrosis, and death1 may occur in predisposed patients who receive immune globulin intravenous (lGIV) products.
  • Patients predisposed to renal dysfunction include those with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs [see Warnings and Precautions (5.1)]. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. GAMMAPLEX 10% does not contain sucrose.
  • For patients at risk of thrombosis, renal dysfunction or acute renal failure, administer GAMMAPLEX 10% 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 Dosage and Administration (2.1, 2.3), Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

1.1 Primary Humoral Immunodeficiency (PI)

GAMMAPLEX 10% is an Immune Globulin Intravenous (Human), 10% Liquid indicated for replacement therapy in primary humoral immunodeficiency (PI) in adults and pediatric patients 2 years of age and older. This includes, but is not limited to, the humoral immune defect in common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

1.2 Chronic Immune Thrombocytopenic Purpura (ITP)

GAMMAPLEX 10% is indicated for the treatment of chronic immune thrombocytopenic purpura (ITP) in adults to raise platelet counts.

2 DOSAGE AND ADMINISTRATION

For Intravenous Use Only

2.1 Dosage

Table 1: Recommended Dosage and Administration for GAMMAPLEX 10%
Indication Dose Initial infusion rate Maintenance infusion rate (if tolerated)
PI 300-800 mg/kg (3-8 mL/kg) every 3-4 weeks 0.5 mg/kg/min (0.005 mL/kg/min) for 15 minutes Increase gradually every 15 minutes to 8 mg/kg/min (0.08 mL/kg/min)
ITP 1 g/kg (10 mL/kg) for 2 consecutive days 0.5 mg/kg/min (0.005 mL/kg/min) for 15 minutes Increase gradually every 15 minutes to 8 mg/kg/min (0.08 mL/kg/min)

Treatment of Primary Humoral Immunodeficiency

As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response.

The recommended dose of GAMMAPLEX 10% for patients with PI is 300 to 800 mg/kg (3 to 8 mL/kg), administered every 3 to 4 weeks. If a patient has been exposed to measles, it may be prudent to administer an extra dose of Immune Globulin Intravenous as soon as possible and within 6 days of exposure. A dose of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at least two weeks. If a patient is at risk of future measles exposure and receives a dose of less than 530 mg/kg every 3-4 weeks, the dose should be increased to at least 530 mg/kg. This should provide a serum level of 240 mIU/mL of measles antibodies for at least 22 days after infusion. Adjust the dosage over time to achieve the desired serum trough levels and clinical response. If a patient misses a dose, administer the missed dose as soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable.

Treatment of Chronic Immune Thrombocytopenic Purpura

The recommended dose of GAMMAPLEX 10% for patients with ITP is 1 g/kg (10 mL/kg) on 2 consecutive days, providing a total dose of 2 g/kg. Carefully consider the relative risks and benefits before prescribing the high dose regimen (i.e. 1 g/kg/day for 2 days) in patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload [see Warnings and Precautions (5)]. Adequate data on the platelet response to the low dose regimen (e.g. 400 mg/kg per day for 5 consecutive days) are not available for GAMMAPLEX 10%.

2.2 Preparation and Handling

  • GAMMAPLEX 10% is a clear or slightly opalescent, colorless solution. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or turbid, or if it contains particulate matter
  • GAMMAPLEX 10% vials are for single use only. Dispose of partially used or unused product
  • GAMMAPLEX 10% contains no antimicrobial preservatives. Therefore, prompt administration after preparation is necessary
  • Do not shake
  • Administer GAMMAPLEX 10% at room temperature (up to 25°C [77°F])
  • Do not use any solution that has been frozen [see How Supplied/ Storage and Handling (16)]
  • Infuse GAMMAPLEX 10% using a separate infusion line
  • Do not mix GAMMAPLEX 10% with other intravenous medications (including normal saline) or other IGIV products
  • An infusion pump may be used to control the rate of administration
  • For administration of large doses, pool multiple vials using aseptic technique

2.3 Administration

  • Hydrate the patient adequately prior to the initiation of infusion
  • Infuse GAMMAPLEX 10% intravenously using an intravenous infusion set. See Table 1 for recommended infusion rates
  • Monitor vital signs throughout the infusion
  • Slow or stop the infusion if adverse reactions occur
  • If symptoms subside, the infusion may be resumed at a lower rate that is comfortable for the patient
  • The observation time of patients after GAMMAPLEX 10% administration may vary. If the patient (a) has not received GAMMAPLEX 10% or another IgG product, (b) is switched from an alternative IGIV product or (c) has had a long interval since the previous infusion, prolong the observation time for adverse reactions after GAMMAPLEX 10% infusion
  • Certain severe adverse reactions may be related to the rate of infusion. Slowing or stopping the infusion often allows the reaction to disappear
  • Close monitoring of the infusion rate in pediatric patients is recommended
  • Ensure that patients with pre-existing renal insufficiency are not volume depleted
  • For patients at increased risk of renal dysfunction, thrombotic events, or volume overload, administer GAMMAPLEX 10% at the minimum infusion rate practicable. Consider discontinuing GAMMAPLEX 10% administration if renal function deteriorates [see Boxed Warning, Warnings and Precautions (5.1, 5.2, 5.8)]

3 DOSAGE FORMS AND STRENGTHS

GAMMAPLEX 10% is a liquid solution containing 10% IgG (100 mg/mL).

4 CONTRAINDICATIONS

  • GAMMAPLEX 10% is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin
  • GAMMAPLEX 10% is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity

5 WARNINGS AND PRECAUTIONS

5.1 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 10%. 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 10% at the minimum infusion rate practicable [see Dosage and Administration (2.3)].

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 10% and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing GAMMAPLEX 10%.

5.2 Thrombotic Events

Thrombosis may occur following treatment with immune globulin products, including GAMMAPLEX 10%2. 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 10% 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 (2.3), Patient Counseling Information (17)].

5.3 Hypersensitivity

Severe hypersensitivity reactions may occur [see Contraindications (4)]. In case of hypersensitivity, discontinue GAMMAPLEX 10% infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

GAMMAPLEX 10% contains trace amounts of IgA (<20 micrograms/mL) [see Description (11)]. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. GAMMAPLEX 10% is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction [see Contraindications (4)].

5.4 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.

5.5 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 Counseling Information (17)]. 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.

5.6 Hemolysis

GAMMAPLEX 10% 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; 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 IGIV7 , but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP and PI4.

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.

5.7 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 treatment.

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 ventilatory support.

5.8 Volume Overload

Carefully consider the relative risks and benefits before prescribing the high dose regimen (for chronic ITP) in patients at increased risk of volume overload.

5.9 Transmissible Infectious Agents

As GAMMAPLEX 10% 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 10%. 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. 1-844-427-5872 or MedInfo@BPL-US.com.

Before prescribing GAMMAPLEX 10%, the physician should discuss the risks and benefits of its use with the patient [see Patient Counseling Information (17)].

5.10 Laboratory Tests

  • 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 interpretation
  • 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 years, volume depletion, sepsis, paraproteinemia, or those receiving nephrotoxic agents, and monitor as appropriate (BUN, serum creatinine, urine output) during therapy with GAMMAPLEX 10%
  • Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with polycythemia, cryoglobulins, fasting chylomicronemia/markedly high triglycerides, or monoclonal gammopathies
  • 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 10%, 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
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