Privigen: Package Insert and Label Information

PRIVIGEN- human immunoglobulin g liquid
CSL Behring AG

WARNING: THROMBOSIS, RENAL DYSFUNCTION AND ACUTE RENAL FAILURE

Thrombosis may occur with immune globulin products 1-3 , including PRIVIGEN. 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 (5.3), Patient Counseling Information (17)].

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Patients predisposed to renal dysfunction include those with any 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 products containing sucrose. 4 PRIVIGEN does not contain sucrose.

For patients at risk of thrombosis, renal dysfunction or failure, administer PRIVIGEN 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 (2.5), Warnings and Precautions (5.2, 5.3)].

1 INDICATIONS AND USAGE

PRIVIGEN is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment of the following conditions.

1.1 Primary Humoral Immunodeficiency

PRIVIGEN is indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

1.2 Chronic Immune Thrombocytopenic Purpura

PRIVIGEN is indicated for the treatment of patients age 15 years and older with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts.

1.3 Chronic Inflammatory Demyelinating Polyneuropathy

PRIVIGEN is indicated for the treatment of adults with chronic inflammatory demyelinating polyneuropathy (CIDP) to improve neuromuscular disability and impairment.

Limitation of Use:

PRIVIGEN maintenance therapy in CIDP has not been studied for periods longer than 6 months. After responding during an initial treatment period, not all patients require indefinite maintenance therapy with PRIVIGEN in order to remain free of CIDP symptoms. Individualize the duration of any treatment beyond 6 months based upon the patient’s response and demonstrated need for continued therapy.

2 DOSAGE AND ADMINISTRATION

Table 1. Recommended Dosage and Administration for PRIVIGEN
Indication Dose Initial infusion rate Maintenance infusion rate(as tolerated)
Primary Immunodeficiency 200-800 mg/kg (2-8 mL/kg)every 3-4 weeks 0.5 mg/kg/min(0.005 mL/kg/min) Increase to 8 mg/kg/min (0.08 mL/kg/min)
Chronic Immune Thrombocytopenic Purpura 1 g/kg (10 mL/kg) for 2 consecutive days 0.5 mg/kg/min(0.005 mL/kg/min) Increase to 4 mg/kg/min (0.04 mL/kg/min)
Chronic Inflammatory Demyelinating Polyneuropathy Loading dose: 2 g/kg (20 mL/kg) in divided doses over 2 to 5 consecutive days Maintenance dose: 1 g/kg (10 mL/kg) administered in 1 to 2 infusions on consecutive days, every 3 weeks 0.5 mg/kg/min(0.005 mL/kg/min) Increase to 8 mg/kg/min(0.08 mL/kg/min)

2.1 Dosage for Primary Humoral Immunodeficiency (PI)

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 PRIVIGEN for patients with PI is 200 to 800 mg/kg (2 to 8 mL/kg), administered every 3 to 4 weeks. 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.

Adjust the dosage over time to achieve the desired serum IgG trough levels and clinical responses. No randomized, controlled trial data are available to determine an optimal trough level in patients receiving immune globulin therapy.

Measles Exposure

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.

2.2 Dosage for Chronic Immune Thrombocytopenic Purpura (ITP)

The recommended dose of PRIVIGEN for patients with chronic ITP is 1 g/kg (10 mL/kg) administered daily for 2 consecutive days, resulting in a total dosage of 2 g/kg.

Carefully consider the relative risks and benefits before prescribing the high dose regimen (e.g., 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 (5.9)].

2.3 Dosage for Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

PRIVIGEN may be initially administered as a total loading dose of 2 g/kg (20 mL/kg) given in divided doses over two to five consecutive days. PRIVIGEN may be administered as a maintenance infusion of 1 g/kg (10 mL/kg) administered in a single infusion given in one day or divided into two doses given on two consecutive days, every 3 weeks. Maintenance therapy beyond 6 months has not been studied.

The recommended initial infusion rate is 0.5 mg/kg/min (0.005 mL/kg/min). If the infusion is well tolerated, the rate may be gradually increased to a maximum of 8 mg/kg/min (0.08 mL/kg/min). For patients judged to be at risk for thrombosis, renal dysfunction, or volume overload, administer PRIVIGEN at the minimum infusion rate practicable [see Warnings and Precautions (5.2, 5.3)].

2.4 Preparation and Handling

  • PRIVIGEN is a clear or slightly opalescent, colorless to pale yellow solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy, turbid, or if it contains particulate matter.
  • DO NOT SHAKE.
  • Do not freeze. Do not use if PRIVIGEN has been frozen.
  • PRIVIGEN should be at room temperature (up to 25ºC [77ºF]) at the time of administration.
  • Do not use PRIVIGEN beyond the expiration date on the product label.
  • The PRIVIGEN vial is for single-use only. Promptly use any vial that has been entered. PRIVIGEN contains no preservative. Discard partially used vials or unused product in accordance with local requirements.
  • Infuse PRIVIGEN using a separate infusion line. Prior to use, the infusion line may be flushed with Dextrose Injection, USP (D5W) or 0.9% Sodium Chloride for Injection, USP.
  • Do not mix PRIVIGEN with other IGIV products or other intravenous medications. However, PRIVIGEN may be diluted with Dextrose Injection, USP (D5W).
  • An infusion pump may be used to control the rate of administration.
  • If large doses of PRIVIGEN are to be administered, several vials may be pooled using aseptic technique. Begin infusion within 8 hours of pooling.

2.5 Administration

PRIVIGEN is for intravenous administration only.

Monitor the patient’s vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.

Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombosis, administer PRIVIGEN at the minimum dose and infusion rate practicable, and discontinue PRIVIGEN administration if renal function deteriorates [see Boxed Warning, Warnings and Precautions (5.2, 5.3)].

The following patients may be at risk of developing systemic reactions (mimicking symptoms of an inflammatory response or infection) on rapid infusion of PRIVIGEN (greater than 4 mg/kg/min [0.04 mL/kg/min]): 1) those who have never received PRIVIGEN or another IgG product or who have not received it within the past 8 weeks, and 2) those who are switching from another IgG product. These patients should be started at a slow rate of infusion (e.g., 0.5 mg/kg/min [0.005 mL/kg/min] or less) and gradually increase as tolerated.

3 DOSAGE FORMS AND STRENGTHS

PRIVIGEN is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion.

4 CONTRAINDICATIONS

  • PRIVIGEN is contraindicated in patients who have a history of anaphylactic or severe systemic reaction to the administration of human immune globulin.
  • PRIVIGEN is contraindicated in patients with hyperprolinemia because it contains the stabilizer L-proline [see Description (11)].
  • PRIVIGEN is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

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

PRIVIGEN contains trace amounts of IgA (≤25 mcg/mL) [see Description (11)]. Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions with administration of PRIVIGEN. PRIVIGEN is contraindicated in patients with antibodies against IgA and a history of hypersensitivity.

5.2 Renal Dysfunction and Acute Renal Failure

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. 4 PRIVIGEN does not contain sucrose. Acute renal failure may also occur as a result of PRIVIGEN-induced hemolysis. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of PRIVIGEN and at appropriate intervals thereafter.

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure.4 If renal function deteriorates, consider discontinuing PRIVIGEN. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency, or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are obese, those who use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer PRIVIGEN at the minimum rate of infusion practicable [see Boxed Warning, Dosage and Administration (2.5].

5.3 Thrombosis

Thrombosis may occur following treatment with immune globulin products1-3 , including PRIVIGEN. 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 PRIVIGEN 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 (2.5), Patient Counseling Information (17)].

5.4 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur following treatment with IGIV products, including PRIVIGEN. The hyponatremia is likely to be a pseudohyponatremia, as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap. It is critical to distinguish true hyponatremia from pseudohyponatremia, as 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 thromboembolic events.5

5.5 Aseptic Meningitis Syndrome (AMS)

AMS may occur infrequently following treatment with PRIVIGEN [see Adverse Reactions (6)] and other human immune globulin products. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae.6 AMS usually begins within several hours to 2 days following IGIV treatment.

AMS is characterized by the following signs and symptoms: 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 cubic millimeter, 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 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

PRIVIGEN 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.7-9 Delayed hemolytic anemia can develop subsequent to PRIVIGEN therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.10 Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of PRIVIGEN.

The following risk factors may be associated with the development of hemolysis: high doses (e.g., ≥2 g/kg), given either as a single administration or divided over several days, and non-O blood group.11 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,12 but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP, CIDP, and PI.9

Closely monitor patients for clinical signs and symptoms of hemolysis, 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 on-going hemolysis.

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