Panzyga: Package Insert and Label Information

PANZYGA- human immunoglobulin g solution
Octapharma USA Inc

PANZYGA, Immune Globulin Intravenous (Human) — ifas

10% Liquid Preparation

WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE

Thrombosis may occur with immune globulin intravenous (IGIV) products, including PANZYGA. 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 WARNING and PRECAUTIONS [ 5.4 ], PATIENT COUNSELING INFORMATION [ 17 ])

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive IGIV products, including PANZYGA. Patients predisposed to renal dysfunction include those with a degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV product containing sucrose. PANZYGA does not contain sucrose.

For patients at risk of thrombosis, renal dysfunction or acute renal failure, administer PANZYGA 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 [ 2.3 ], WARNINGS and PRECAUTIONS [ 5.2 , 5.4 ])

1 INDICATIONS AND USAGE

1.1 Primary Humoral Immunodeficiency Diseases (PI)

PANZYGA is indicated for treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older. This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

1.2 Chronic Immune Thrombocytopenia (ITP)

PANZYGA is indicated for the treatment of adult patients with ITP to raise platelet counts to control or prevent bleeding.

2 DOSAGE AND ADMINISTRATION

For intravenous use only.

2.1 Dose

Indication Dose Initial Infusion Rate (first 30 min) Maximum Infusion Rate in New Patients** (as tolerated) Maximum Infusion Rate in Experienced Patients*** (as tolerated)
Treatment of Primary Humoral Immunodeficiency (PI)* 300 to 600 mg/kg body weight (3-6 mL/kg) administered every 3 to 4 weeks 1 mg/kg/min (0.01 mL/kg/min) 8 mg/kg/min (0.08 mL/kg/min) 12 or 14 mg/kg/min (0.12 or 0.14 mL/kg/min)
Treatment of Chronic Immune Thrombocytopenia (ITP) 2 g/kg, divided into two daily doses of 1 g/kg (10 mL/kg) given on two consecutive days 1 mg/kg/min (0.01 mL/kg/min) 8 mg/kg/min (0.08 mL/kg/min)

*Significant differences in the half-life of IgG among patients with PI may necessitate the dose and frequency of immunoglobulin therapy to vary from patient to patient. Determine the proper dose and frequency by monitoring the clinical response. Adjust dose over time to achieve the desired trough levels of IgG and clinical responses.

**Patients receiving PANZYGA (or another IGIV) for the first time or more than 8 weeks since a prior treatment.

*** Experienced patients received greater than 3 (12 mg/kg/min) to 6 (14 mg/kg/min) infusions every 3-4 weeks.

Following the initial infusion, the infusion rate may be gradually increased every 15-30 minutes to a maximum of 14 mg/kg/min (0.14 mL/kg/min) in PI and to 8 mg/kg/min (0.08 mL/kg/min) in chronic ITP in adults, as tolerated. The recommended ramp-up for an infusion is 1, 2, 4, and 8 mg/kg/min (0.01, 0.02, 0.04, and 0.08 mL/kg/min) in new PI and ITP patients (i.e., patients who have not previously received any IGIV product), and 1, 4, 8, and 12 or 14 mg/kg/min (0.01, 0.04, 0.08, and 0.12 or 0.14 mL/kg/min) in experienced PI patients (i.e., patients who have previously received any IGIV product)

Measles Exposure

If a patient with primary humoral immunodeficiency has been exposed to measles, it may be prudent to administer an extra dose of IGIV 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 with primary humoral immunodeficiency 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.

2.2 Administration

  • Inspect parenteral products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use PANZYGA if it is turbid and/or if discoloration is observed. Using a needle, no larger than a 16-gauge needle, insert the needle only once within the stopper area (delineated by the raised ring for penetration). Penetrate the stopper perpendicularly to its plane and within the ring.
  • PANZYGA bottles may be pooled under aseptic conditions into sterile infusion bags. Infuse within 8 hours after pooling.
  • Administer at room or body temperature only by the intravenous route, using an in-line filter with pore size 0.2-200 microns.
  • Do not administer PANZYGA simultaneously with another intravenous preparation in the same infusion set, including immune globulin products from another manufacturer.
  • After administration, flush the infusion line with either normal saline or 5% dextrose in water.
  • Monitor the patient carefully throughout the infusion. Certain adverse drug reactions are related to the rate of infusion, and will disappear promptly after slowing or stopping the infusion. In such cases, after symptoms subside, resume the infusion at a lower rate. Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients at risk of renal dysfunction or thromboembolic events, administer PANZYGA at the minimum infusion rate practicable. Do not exceed 3.3 mg/kg/min (0.033 mL/kg/min). Discontinue if renal function deteriorates.

3 DOSAGE FORMS AND STRENGTHS

Solution containing 10% IgG (100 mg/mL) (See How Supplied/Storage and Handling ( 16 )).

4 CONTRAINDICATIONS

  • PANZYGA is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin.
  • PANZYGA is contraindicated in IgA-deficient patients with antibodies against IgA and history of hypersensitivity .

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur (See Contraindications ( 4 )) . [ 1 ] In case of hypersensitivity, discontinue PANZYGA infusion immediately and institute appropriate treatment. Have epinephrine available for immediate treatment of severe acute hypersensitivity reactions.

PANZYGA contains trace amounts of IgA (average 100 µg/mL in a 10% solution). IgA-deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactoid reactions when administered PANZYGA (See Contraindications ( 4 )) .

5.2 Renal Failure

Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur upon use of PANZYGA in predisposed patients.

Ensure that patients are not volume depleted prior to the initiation of the infusion of PANZYGA.

For patients at risk of renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as individuals with diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or those receiving known nephrotoxic drugs), administer PANZYGA at the minimum infusion rate practicable (See Boxed Warning, and Dosage and Administration ( 2 )).

Periodic monitoring of renal function tests and urine output is particularly important in patients judged to be at risk of developing acute renal failure. Assess renal function, including a measurement of blood urea nitrogen (BUN)/serum creatinine, prior to the initial infusion of PANZYGA and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of the product.

5.3 Hyperproteinemia, Increased Serum Viscosity and Hyponatremia

Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving PANZYGA therapy. It is clinically critical to distinguish true hyponatremia from pseudohyponatremia 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 higher risk of thromboembolic events.[ 2 ]

5.4 Thrombotic Events

Thrombosis may occur following treatment with immune globulin products, including PANZYGA. Risk factors 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 thrombotic events, administer PANZYGA 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.[ 3-5 ] (See BOXED WARNING, DOSAGE and ADMINSTRATION [ 2.3 ], PATIENT COUNSELING INFORMATION [ 17 ])

5.5 Aseptic Meningitis Syndrome

Aseptic meningitis syndrome (AMS) may occur with PANZYGA treatment. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following infusion with PANZYGA. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. 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 in patients exhibiting such symptoms and signs, including CSF studies, to rule out other causes of meningitis. Patients with a history of migraine may be more susceptible.[ 6 ]

AMS may occur more frequently following high doses (≥ 2 g/kg) and/or rapid infusion of IGIV.

5.6 Hemolysis

PANZYGA 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 hemolysis. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration and acute hemolysis, consistent with intravascular hemolysis, has been reported. 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 or more), given either as a single administration or divided over several days, and non-O blood group.[ 7 ] 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 [ 8 ], 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, including direct antiglobulin test. 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 [Transfusion-Related Acute Lung Injury (TRALI)] may occur in patients administered IGIV.[ 9 ] TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Signs and symptoms typically appear within 1 to 6 hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.

Monitor recipients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-HLA and anti-neutrophil antibodies in both the product and patient’s serum.

5.8 Hypertension

Elevations of systolic blood pressure to 180 mm Hg or more and/or of diastolic blood pressure to more than 120 mm Hg (hypertensive urgency) can be observed during and/or shortly following infusion of IVIG. Such elevations are reported more often among patients with a history of hypertension. Check patients for a history of hypertension and current antihypertensive medication use. Monitor blood pressure prior to, during, and following PANZYGA infusion.

5.9 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.

5.10 Transmission of Infectious Agents

Because PANZYGA is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the variant Creutzfeldt-Jakob disease and Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors and by including virus inactivation/removal steps in the manufacturing process of PANZYGA. Report all infections thought by a physician or other healthcare provider to have been possibly transmitted by this product to Octapharma at 1-866-766-4860. Discuss the risks and benefits of PANZYGA with the patient before prescribing or administering this product.

5.11 Monitoring Laboratory Tests

  • After infusion of immunoglobulin, the transitory rise of the 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 nephrotic agents, and monitor as appropriate (BUN; serum creatinine, urine output) during therapy with PANZYGA.
  • 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 PANZYGA, 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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