1.1 Primary Humoral Immunodeficiency (PI)

GAMUNEX is indicated as replacement therapy of primary humoral immunodeficiency. This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.(2-9)

1.2 Idiopathic Thrombocytopenic Purpura (ITP)

GAMUNEX is indicated in Idiopathic Thrombocytopenic Purpura to rapidly raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo surgery.(10-15)

1.3 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

GAMUNEX is indicated for the treatment of CIDP to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapse.

2.1 Preparation and Handling

• GAMUNEX should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid.
• Do not freeze. Solutions that have been frozen should not be used.
• The GAMUNEX vial is for single use only. GAMUNEX contains no preservative. Any vial that has been entered should be used promptly. Partially used vials should be discarded.
• GAMUNEX should be infused using a separate line by itself, without mixing with other intravenous fluids or medications the subject might be receiving.
• GAMUNEX is not compatible with saline. If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W). No other drug interactions or compatibilities have been evaluated.
• Content of vials may be pooled under aseptic conditions into sterile infusion bags and infused within 8 hours after pooling.
• Do not mix with immune globulin intravenous (IGIV) products from other manufacturers.
• Do not use after expiration date.

2.2 Treatment of Primary Humoral Immunodeficiency

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

The dose of GAMUNEX for replacement therapy in primary immune deficiency diseases is 300 to 600 mg/kg body weight (3-6 mL/kg) administered every 3 to 4 weeks. The dosage may be adjusted over time to achieve the desired trough levels and clinical responses.

If a patient routinely receives a dose of less than 400 mg/kg of GAMUNEX every 3 to 4 weeks (less than 4 mL/kg), and is at risk of measles exposure (i.e., traveling to a measles endemic area), administer a dose of at least 400 mg/kg (4 mL/kg) just prior to the expected measles exposure. If a patient has been exposed to measles, a dose of 400 mg/kg (4 mL/kg) should be administered as soon as possible after exposure.

2.3 Treatment of Idiopathic Thrombocytopenic Purpura

GAMUNEX may be administered at a total dose of 2 g/kg, divided in two doses of 1 g/kg (10 mL/kg) given on two consecutive days or into five doses of 0.4 g/kg (4 mL/kg) given on five consecutive days. If after administration of the first of two daily 1 g/kg (10 mL/kg) doses, an adequate increase in the platelet count is observed at 24 hours, the second dose of 1g/kg body weight may be withheld.

Forty-eight ITP subjects were treated with 2 g/kg GAMUNEX, divided in two 1 g/kg doses (10 mL/kg) given on two successive days. With this dose regimen 35/39 subjects (90%) responded with a platelet count from less than or equal to 20 ×109/L to more than or equal to 50 ×109/L within 7 days after treatment.(17)

The high dose regimen (1 g/kg × 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.

2.4 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

GAMUNEX may be initially administered as a total loading dose of 2 g/kg (20 mL/kg) given in divided doses over two to four consecutive days. GAMUNEX may be administered as a maintenance infusion of 1 g/kg (10 mL/kg) administered over 1 day or divided into two doses of 0.5 g/kg (5 mL/kg) given on two consecutive days, every 3 weeks.

2.5 Administration

GAMUNEX should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid and/or if discoloration is observed.

Only administer intravenously. GAMUNEX should be at room temperature during administration.

Only 18 gauge needles should be used to penetrate the stopper for dispensing product from the 10 mL vial; 16 gauge needles or dispensing pins should only be used with 25 mL vial sizes and larger. Needles or dispensing pins should only be inserted once and be within the stopper area delineated by the raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the ring.

Any vial that has been opened should be used promptly. Partially used vials should be discarded.

If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W).

5.1 Sensitivity

Severe hypersensitivity reactions may occur. In case of hypersensitivity, IGIV infusion should be immediately discontinued and appropriate treatment instituted. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction. (See Patient Counseling Information [17])

GAMUNEX contains trace amounts of IgA (average 46 micrograms/mL). It is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity. (See Patient Counseling Information [17])

5.2 Renal Failure

Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV. 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. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of GAMUNEX and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. (See Patient Counseling Information [17]) For patients judged to be at risk for developing renal dysfunction and/or at risk of developing thrombotic events, it may be prudent to reduce the amount of product infused per unit time by infusing GAMUNEX at a rate less than 8 mg IG/kg/min (0.08 mL/kg/min). (See Boxed Warning) (See Dosage and Administration [2.5])

5.3 Hyperproteinemia

Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV therapy. The hyponatremia is likely to be a pseudohyponatremia as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap. Distinguishing true hyponatremia from pseudohyponatremia is clinically critical, 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 disposition to thromboembolic events.(18)

5.4 Thrombotic Events

Thrombotic events have been reported in association with IGIV.(19-21) Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

5.5 Aseptic Meningitis Syndrome (AMS)

An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.(22-24) The syndrome usually begins within several hours to two days following IGIV treatment. 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 are frequently positive with pleocytosis up to several thousand cells per cu mm, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. It appears that patients with a history of migraine may be more susceptible. (See Patient Counseling Information [17])

5.6 Hemolysis

Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.(25–27) Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis.(28) If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done. (See Patient Counseling Information [17])

5.7 Transfusion-related Acute Lung Injury (TRALI)

There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV.(29) TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6 hrs after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.

IGIV recipients should be monitored for pulmonary adverse reactions. (See Patient Counseling Information [17]) If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum.

5.8 Volume Overload

The high dose regimen (1 g/kg × 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.

5.9 General

Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1-800-520-2807]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient. (See Patient Counseling Information [17])

5.10 Laboratory Tests

If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done.

If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum.

Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

6.1 Adverse Drug Reaction Overview

The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX for PI was an exacerbation of autoimmune pure red cell aplasia in one subject.

The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX for ITP was myocarditis in one subject that occurred 50 days post study drug infusion and was not considered drug related.

The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX for CIDP was pulmonary embolism (PE) in one subject with a history of PE.

The most common drug related adverse reactions observed at a rate ≥5% in subjects with PI were headache, cough, injection site reaction, nausea, pharyngitis and urticaria.

The most common drug related adverse reactions observed at a rate ≥5% in subjects with ITP were headache, vomiting, fever, nausea, back pain and rash.

The most common drug related adverse reactions observed at a rate ≥5% in subjects with CIDP were headache, fever, chills, hypertension, rash, nausea and asthenia.

6.2 Clinical Trials Adverse Drug Reactions

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

Adverse events similar to those previously reported with the administration of intravenous and intramuscular immunoglobulin products may occur. Cases of reversible aseptic meningitis, migraine, isolated cases of reversible hemolytic anemia and reversible increases in liver function tests have been observed with GAMUNEX. Immediate anaphylactic reactions can possibly occur (<0.01%). Epinephrine should be available for treatment of any acute anaphylactoid reaction. (see Warnings and Precautions [5.1])

6.3 Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with GAMUNEX. It is not known whether GAMUNEX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMUNEX should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

GAMUNEX has not been evaluated in nursing mothers.

8.4 Pediatric Use

8.5 Geriatric Use

Patients > 65 years of age may be at increased risk for developing certain adverse reactions such as thromboembolic events and acute renal failure. (See Boxed Warning, Warnings and Precautions [5.2]) Clinical studies of GAMUNEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

12.3 Pharmacokinetics

Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX in 38 subjects with Primary Humoral Immunodeficiencies given 3 infusions 3 or 4 weeks apart of test product at a dose of 100-600 mg/kg body weight per infusion. One trial compared the pharmacokinetic characteristics of GAMUNEX to GAMIMUNE N, 10% (study 100152), and the other trial compared the pharmacokinetics of GAMUNEX (10% strength) with a 5% concentration of this product (study 100174). The ratio of the geometric least square means for dose-normalized IgG peak levels of GAMUNEX and GAMIMUNE N, 10% was 0.996. The corresponding value for the dose-normalized area under the curve (AUC) of IgG levels was 0.990. The results of both PK parameters were within the pre-established limits of 0.080 and 1.25. Similar results were obtained in the comparison of GAMUNEX 10% to a 5% concentration of GAMUNEX.(31,32)

The main pharmacokinetic parameters of GAMUNEX, measured as total IgG in study 100152 are displayed below:

The two pharmacokinetic trials with GAMUNEX show the IgG concentration/time curve follows a biphasic slope with a distribution phase of about 5 days characterized by a fall in serum IgG levels to about 65-75% of the peak levels achieved immediately post-infusion. This phase is followed by the elimination phase with a half-life of approximately 35 days.(31, 32) IgG trough levels were measured over nine months in the therapeutic equivalence trial (100175). Mean trough levels were 7.8 +/- 1.9 mg/mL for the GAMUNEX treatment group and 8.2 +/- 2.0 mg/mL for the GAMIMUNE N, 10% control group.(30)

14.1 Treatment of Primary Humoral Immunodeficiency

In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies (study 100175) GAMUNEX was demonstrated to be at least as efficacious as GAMIMUNE N, 10% in the prevention of any infection, i.e. validated plus clinically defined, non-validated infections of any organ system, during a nine month treatment period. Twenty six subjects were excluded from the Per Protocol analysis (2 due to non-compliance and 24 due to protocol violations). The endpoint was the proportion of subjects with at least one of the following validated infections: pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis.

The annual rate of validated infections (Number of Infections/year/subject) was 0.18 in the group treated with GAMUNEX and 0.43 in the group treated with GAMIMUNE N, 10% (p=0.023). The annual rates for any infection (validated plus clinically-defined, non-validated infections of any organ system) were 2.88 and 3.38, respectively (p=0.300).(30, 43)

14.2 Treatment of Idiopathic Thrombocytopenic Purpura

A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to prove the hypothesis that GAMUNEX was at least as effective as GAMIMUNE N, 10% in raising platelet counts from less than or equal to 20 ×109/L to more than 50 ×109/L within 7 days after treatment with 2 g/kg IGIV (study 100176). Twenty-four percent of the subjects were less than or equal to 16 years of age.

GAMUNEX was demonstrated to be at least as effective as GAMIMUNE N, 10% in the treatment of adults and children with acute or chronic ITP.(11)

A trial was conducted to evaluate the clinical response to rapid infusion of GAMUNEX in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMUNEX on three occasions for treatment of relapses. The infusion rate was randomly assigned to 0.08, 0.11, or 0.14 mL/kg/min (8, 11 or 14 mg/kg/min). Pre-medication with corticosteroids to alleviate infusion-related intolerability was not permitted. Pre-treatment with antihistamines, anti-pyretics and analgesics was permitted. The average dose was approximately 1 g/kg body weight at all three prescribed rates of infusion (0.08, 0.11 and 0.14 mL/kg/min). All patients were administered each of the three planned infusions except seven subjects. Based on 21 patients per treatment group, the a posteriori power to detect twice as many drug-related adverse events between groups was 23%. Of the seven subjects that did not complete the study, five did not require additional treatment, one withdrew because he refused to participate without concomitant medication (prednisone) and one experienced an adverse event (hives); however, this was at the lowest dose rate level (0.08 mL/kg/min).

14.3 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

A multi-center, randomized, double-blind Placebo-controlled trial (study 100538, The Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMUNEX.(44) This study included two separately randomized study periods to assess whether GAMUNEX was more effective than Placebo for the treatment of CIDP (assessed in the Efficacy Period for up to 24 weeks) and whether long-term administration of GAMUNEX could maintain long-term benefit (assessed in the 24 week Randomized Withdrawal Period).

In the Efficacy Period, there was a requirement for Rescue (crossover) to the alternate study drug if the subject did not improve and maintain this improvement until the end of the 24 week treatment period. Subjects entering the Rescue phase followed the same dosing and schedule as in the Efficacy period. Any subject who was Rescued (crossed over) and did not improve and maintain this improvement was withdrawn from the study.

Subjects who completed 24 weeks treatment in the Efficacy period or Rescue phase and responded to therapy were eligible for entry into a double-blind Randomized Withdrawal Period. Eligible subjects were re-randomized to GAMUNEX or Placebo. Any subject who relapsed was withdrawn from the study.

The Efficacy Period and the Rescue treatment started with a loading dose of 2 g/kg bw of GAMUNEX or equal volume of Placebo given over 2-4 consecutive days. All other infusions (including the first infusion of the Randomized Withdrawal Period) were given as maintenance doses of 1 g/kg bw (or equivalent volume of Placebo) every three weeks.

The Responder rates of the GAMUNEX and Placebo treatment groups was measured by the INCAT score. The INCAT (Inflammatory Neuropathy Cause and Treatment) scale is used to assess functional disability of both upper and lower extremities in demyelinating polyneuropathy. The INCAT scale has upper and lower extremity components (maximum of 5 points for upper (arm disability) and maximum of 5 points for lower (leg disability)) that add up to a maximum of 10-points (0 is normal and 10 is severely incapacitated).(45) At the start of the efficacy portion of the study, the INCAT scores were as follows: Upper Extremity mean was 2.2 ± 1.0, and median was 2.0 with a range of 0 to 5; Lower Extremity mean was 1.9 ± 0.9, and median was 2.0 with a range of 1 to 5; Total Overall Score mean was 4.2 ± 1.4, and median was 4.0 with a range of 2 to 9. A Responder was defined as a subject with at least 1-point improvement from baseline in the adjusted INCAT score that was maintained through 24 weeks.

Significantly more subjects with CIDP responded to GAMUNEX: 28 of 59 subjects (47.5%) responded to GAMUNEX compared with 13 of 58 subjects (22.4%) administered Placebo (25% difference; [95% CI: 7%-43%]; p=0.006). The study included both subjects who were IGIV naive and subjects who had previous IGIV experience. The outcome was influenced by the group of subjects who experienced prior therapy with IGIV, as shown by the outcomes table, below.

Time to relapse for the subset of 57 subjects who previously responded to GAMUNEX was evaluated: 31 were randomly reassigned to continue to receive GAMUNEX and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive GAMUNEX experienced a significantly longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with GAMUNEX versus 45% with Placebo (hazard ratio, 0.19 [95% confidence interval, 0.05, 0.70]).

The following table shows outcomes for the Rescue Phase (which are supportive data):

The following Kaplan-Meier curves show the outcomes for the Randomized Withdrawal Period: