DESCRIPTION

Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, (GAMUNEX ^® ) is a ready-to-use sterile solution of human immune globulin protein for intravenous administration. GAMUNEX ^® consists of 9%-11% protein in 0.16-0.24 M glycine. Not less than 98% of the protein has the electrophoretic mobility of gamma globulin. GAMUNEX ^® contains trace levels of fragments, IgA (average 0.046 mg/mL), and IgM. The distribution of IgG subclasses is similar to that found in normal serum. The measured buffer capacity is 35 mEq/L and the osmolality is 258 mOsmol/kg solvent, which is close to physiological osmolality (285-295 mOsmol/kg). The pH of GAMUNEX ^® is 4.0-4.5. GAMUNEX ^® contains no preservative.

GAMUNEX ^® is made from large pools of human plasma by a combination of cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography. Two of the four ethanol fractionation steps of the Cohn-Oncley process have been replaced by tandem anion-exchange chromatography. The IgG proteins are not subjected to heating or chemical or enzymatic modification steps. Fc and Fab functions of the IgG molecule are retained, but do not activate complement or pre-Kallikrein activity in an unspecific manner. The protein is stabilized during the process by adjusting the pH of the solution to 4.0-4.5. Isotonicity is achieved by the addition of glycine. GAMUNEX ^® is incubated in the final container (at the low pH of 4.0-4.3), for a minimum of 21 days at 23° to 27°C. The product is intended for intravenous administration.

The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: human immunodeficiency virus, type I (HIV-1) as the relevant virus for HIV-1 and HIV-2; bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; pseudorabies virus (PRV) as a model for large DNA viruses (e.g. herpes viruses); Reo virus type 3 (Reo) as a model for non-enveloped viruses and for its resistance to physical and chemical inactivation; hepatitis A virus (HAV) as relevant nonenveloped virus, and porcine parvovirus (PPV) as a model for human parvovirus B19.

The following process steps contribute to virus inactivation and/or removal: caprylate precipitation/cloth filtration, caprylate incubation, column chromatography and final container low pH incubation. Caprylate is the basis of two mechanistically distinct virus clearance steps, the caprylate precipitation/cloth filtration step and the caprylate incubation step. During the caprylate precipitation/cloth filtration step, protein impurities and potential enveloped or non-enveloped viral contaminants are precipitated by caprylate and the precipitate is removed from the product stream by filtration through a cloth filter. In a subsequent step, enveloped viruses are inactivated during incubation with caprylate. The table below presents the contribution of each process step to virus reduction and the overall process reduction. Virus removal steps were evaluated independently and in combination to identify those steps, which were mechanistically distinct. Overall virus reduction was calculated only from steps that were mechanistically independent from each other and truly additive. In addition, each step was verified to provide robust virus reduction across the production range for key operating parameters.

Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents ^47-51 .

Several of the individual production steps in the GAMUNEX ^® manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps included Cloth Filtration and Depth Filtration (in sequence, a total of >/= 6.6 logs). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

CLINICAL PHARMACOLOGY

Primary Humoral Immunodeficiency (PI)

In a double-blind, randomized, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies (study 100175) GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, was demonstrated to be at least as efficacious as GAMIMUNE ^® N, Immune Globulin Intravenous (Human), 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 primary efficacy 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). ^{1, 2}

A post hoc analysis of serious infection events during the trial showed five (5) cases of clinically defined pneumonia occurred in 4 GAMUNEX ^® treated subjects and 11 cases of validated or clinically defined pneumonia occurred in 9 GAMIMUNE ^® N 10% treated subjects and 1 case of sepsis occurred in a GAMIMUNE ^® N 10% treated subject. The annual infection rate and 98% confidence interval for serious infections are:

As a secondary endpoint, consequences of infections were recorded and are displayed in the table below:

Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, 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%, Immune Globulin Intravenous (Human), 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 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 preestablished limits of 0.080 and 1.25. Similar results were obtained in the comparison of GAMUNEX ^® 10% to a 5% concentration of GAMUNEX ^® . ^{3, 4}

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 postinfusion. This phase is followed by the elimination phase with a half-life of approximately 35 days ^3,4 . 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 ¹ .

Idiopathic Thrombocytopenic Purpura (ITP)

The mechanism of action of high doses of immunoglobulins in the treatment of Idiopathic Thrombocytopenic Purpura (ITP) has not been fully elucidated. Several lines of evidence suggest that Fc-receptor blockade of phagocytes as well as down regulation of autoreactive B-cells by antiidiotypic antibodies provided by IGIV may constitute the main mechanisms of action ^5-10 .

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 × 10 ⁹ /L to more than 50 × 10 ⁹ /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).

General

GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria or their toxins, which were demonstrated to be effective in the prevention or attenuation of lethal infections in animal models. GAMUNEX ^® proved to be effective in preventing severe infections in patients with Primary Humoral Immunodeficiency (PI).

Glycine (aminoacetic acid) is a nonessential amino acid normally present in the body. Glycine is a major ingredient in amino acid solutions employed in intravenous alimentation ¹² . While toxic effects of glycine administration have been reported ¹³ , the doses and rates of administration were 3-4 fold greater than those for GAMUNEX ^® . In another study it was demonstrated that intravenous bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects ¹⁴ . GAMUNEX ^® doses of 1 g/kg correspond to a glycine dose of 0.15 g/kg. 0.2M Glycine stabilizer has been used safely in GAMIMUNE ^® N since 1992.

Caprylate is a saturated medium-chain (C8) fatty acid of plant origin, which is subjected to rapid beta-oxidation. Medium chain fatty acids are considered to be essentially non-toxic. Human subjects receiving medium chain fatty acids parenterally have tolerated doses of 3.0 to 9.0 g/kg/day for periods of several months without adverse effects ¹⁵ . Residual Caprylate concentrations in the final container are no more than 0.216 g/L (1.3 mmol/L).

The buffering capacity of GAMUNEX ^® is 35.0 mEq/L (0.35 mEq/g protein). A dose of 1000 mg/kg body weight therefore represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole blood in a normal individual is 45-50 mEq/L of blood, or 3.6 mEq/kg body weight ¹⁶ . Thus, the acid load delivered with a dose of 1000 mg/kg of GAMUNEX ^® would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.

INDICATIONS AND USAGE

Primary Humoral Immunodeficiency (PI)

GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, is indicated as replacement therapy of primary immunodeficiency states in which severe impairment of antibody forming capacity has been shown, such as congenital agammaglobulinemia, common variable immunodeficiency, X-linked immunodeficiency with hyper IgM, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies ^17-24 .

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 ^5-10 .

CONTRAINDICATIONS

GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, is contraindicated in individuals with known anaphylactic or severe systemic response to Immune Globulin (Human). Individuals with severe, selective IgA deficiencies (serum IgA <0.05 g/L) who have known antibody against IgA (anti-IgA antibody) should only receive GAMUNEX ^® with utmost cautionary measures, due to the risk of severe immediate hypersensitivity reactions including anaphylaxis. No experience is available on tolerability of GAMUNEX ^® in subjects with selective IgA deficiency since they were excluded from participation in the clinical trials with GAMUNEX ^® .

WARNINGS

See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure.

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 that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections.

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.

GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, should be administered only intravenously. On rare occasions, treatment with an immune globulin preparation may cause a precipitous fall in blood pressure and a clinical picture of anaphylaxis, even when the patient is not known to be sensitive to immune globulin preparations. Epinephrine and other appropriate supportive care should be available for the treatment of an acute anaphylactic reaction.

PRECAUTIONS

General

Any vial that has been entered should be used promptly. Partially used vials should be discarded. Visually inspect each bottle before use. Do not use if turbid. Solution that has been frozen should not be used.

An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) treatment. The syndrome usually begins within several hours to two days following Immune Globulin Intravenous (Human) treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting.

AMS may occur more frequently in association with high dose (2 g/kg) and/or rapid infusion of Immune Globulin Intravenous (Human) treatment. Discontinuation of Immune Globulin Intravenous (Human) treatment has resulted in remission of AMS within several days without sequelae ^26-28 .

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 ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. 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).

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. ^29,30,31 Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. [See ADVERSE REACTIONS : Laboratory Abnormalities ]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis ³² [See PRECAUTIONS : Laboratory Tests ].

Transfusion-Related Acute Lung Injury (TRALI)

There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. ³³ 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. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum [see PRECAUTIONS : Laboratory Tests ].

Thrombotic events

Thrombotic events have been reported in association with IGIV ^34,35,36 (See ADVERSE REACTIONS ). 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 [See PRECAUTIONS : Laboratory Tests ].

Information for Patients

Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians.

Laboratory Tests

If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done [see PRECAUTIONS : General ].

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

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 [see PRECAUTIONS ].

Drug Interactions

Antibodies in GAMUNEX ^® may interfere with the response to live viral vaccines such as measles, mumps and rubella. Therefore, use of such vaccines should be deferred until approximately 6 months after GAMUNEX ^® administration. Please see DOSAGE AND ADMINISTRATION for other drug interactions.

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.

ADVERSE REACTIONS

General

Increases in creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following infusion with Immune Globulin Intravenous (Human) products, predominantly with products containing sucrose as stabilizer. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment ³⁷ . GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer. In the studies undertaken to date with GAMUNEX ^® , no increase in creatinine and blood urea nitrogen was observed.

Although not necessarily observed for GAMUNEX ^® , adverse events similar to those previously reported with the administration of intravenous and intramuscular immunoglobulin products may occur.

Post Marketing

The following adverse reactions have been identified and reported during the post marketing use of GAMUNEX ^® .

Very rare adverse events:

Reversible aseptic meningitis, reversible hemolytic anemia.

The following adverse reactions have been identified and reported during the post marketing use of IGIV products.

Rare and uncommon adverse events:

apnea, ARDS, bullous dermatitis, cardiac arrest, coma, epidermolysis, erythema multiforme, loss of consciousness, leukopenia, pancytopenia, Steven-Johnson syndrome, transfusion related acute lung injury (TRALI) and vascular collapse.

Other adverse events:

bronchospasm, cyanosis, hepatic dysfunction, hypoxemia, pulmonary edema, seizures/convulsions, thromboembolism, tremor, dyspnea, hypotension, pyrexia, rigors, hemolysis, positive direct antiglobulin (Coombs) test, back pain, and abdominal pain.

As post-marketing reporting of adverse events is voluntary and at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently.

True allergic/anaphylactic reactions to GAMUNEX ^® may occur in recipients with documented prior histories of severe allergic reactions to intramuscular immunoglobulin, but some subjects may tolerate cautiously administered intravenous immunoglobulin without adverse effects ^38,39 . Very rarely an anaphylactoid reaction may occur in subjects with no prior history of severe allergic reactions to either intramuscular or intravenous immunoglobulin. ³⁹

Laboratory Abnormalities

During the course of the clinical program, ALT and AST elevations, similar to those reported for other IGIV products ^{40, 41} , were identified in some subjects. For ALT, in the primary humoral immunodeficiency (PI) study (100175) treatment emergent elevations above the upper limit of normal were transient and observed among 14/80 (18%) of subjects in the GAMUNEX ^® group versus 5/88 (6%) of subjects in the GAMIMUNE ^® N group (p = 0.026). In the ITP study which employed a higher dose per infusion, but a maximum of only two infusions, the reverse finding was observed among 3/44 (7%) of subjects in the GAMUNEX ^® group versus 8/43 (19%) of subjects in the GAMIMUNE ^® N group (p = 0.118). Elevations of ALT and AST were generally mild (<3 times upper limit of normal), transient, and were not associated with obvious symptoms of liver dysfunction.

GAMUNEX ^® may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG ₄ class. Direct antiglobin tests (DAT or direct Coombs tests), which are carried out in some centers as a safety check prior to red blood cell transfusions, may become positive temporarily. GAMUNEX ^® does not contain irregular antibodies to Rhesus antigens or other non-ABO RBC antigens. Hemolytic events were not detected in association with positive DAT findings in clinical trials. ^{1, 3, 4, 11, 42}

Primary Humoral Immunodeficiencies (PI)

In three randomized clinical trials, 119 subjects with primary humoral immunodeficiencies were exposed to 939 infusions with GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified. The rates of discontinuation from controlled clinical trials of GAMUNEX ^® due to adverse events were comparable to those of the GAMIMUNE ^® N, Immune Globulin Intravenous (Human), treatment group. For the Primary Humoral Immunodeficiency studies, 2 subjects (1.4%) treated with GAMUNEX ^® discontinued due to adverse events (Coombs negative hypochromic anemia, autoimmune pure red cell aplasia). Both events were considered unrelated to study drug as per the investigator.

Two pharmacokinetic trials were carried out in 18-20 subjects each with primary humoral immunodeficiencies, who received 100-600 mg/kg GAMUNEX ^® or GAMIMUNE ^® N, 10% for three infusions on a 3 or 4 week infusion interval and then crossed over to three infusions of the alternate product (studies 100152, 100174). In a third trial investigating therapeutic equivalence, 172 subjects were randomized to GAMUNEX ^® or GAMIMUNE ^® N for a nine-month double-blinded treatment with either of the two products at a dose between 200 and 600 mg/kg on a 3 or 4 week infusion interval (study 100175). In this trial, only 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion. Generally, diphenhydramine and acetaminophen were used. Any adverse events in trial 100175, irrespective of the causality assessment, reported by at least 15% of subjects during the 9-month treatment are given in the table below.

The severity of the adverse events across the treatment groups is displayed below.

The subset of drug related adverse events in trial 100175 reported by at least 3% of subjects during the 9-month treatment are given in the table below.

Adverse events, which were reported by at least 5% of subjects, were also analyzed by frequency and in relation to infusions administered. The analysis is displayed below.

The mean number of adverse events per infusion that occurred during or on the same day as an infusion was 0.21 in both the GAMUNEX ^® and GAMIMUNE ^® N treatment groups.

In all three trials in primary humoral immunodeficiencies, the maximum infusion rate was 0.08 mL/kg/min (8 mg/kg/min). The actual infusion rate was reduced for 11 of 222 exposed subjects (7 GAMUNEX ^® , 4 GAMIMUNE ^® N) at 17 occasions. In most instances, mild to moderate hives/urticaria, itching, pain or reaction at infusion site, anxiety or headache was the main reason. There was one case of severe chills. There were no anaphylactic or anaphylactoid reactions to GAMUNEX ^® or GAMIMUNE ^® N.

In trial 100175, serum samples were drawn to monitor the viral safety at baseline and one week after the first infusion (for parvovirus B19), eight weeks after first and fifth infusion, and 16 weeks after the first and fifth infusion of IGIV (for hepatitis C) and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, Polymerase Chain Reaction [PCR]), and serological testing. There were no treatment emergent findings of viral transmission for either GAMUNEX ^® , or GAMIMUNE ^® N. ^{1, 3, 4}

Idiopathic Thrombocytopenic Purpura (ITP)

Two randomized clinical trials in acute or chronic ITP were conducted with GAMUNEX ^® . Seventy-six subjects with acute or chronic ITP were exposed to 170 infusions with GAMUNEX ^® (study 100176 and 100213). The rates of discontinuation from controlled clinical trials of GAMUNEX ^® due to adverse events were comparable to those of the GAMIMUNE ^® N treatment group. Altogether, 2 subjects (3%) treated with GAMUNEX ^® discontinued due to adverse events (headache, fever, vomiting, hives).

Study 100176 was a randomized double-blind therapeutic equivalence study, where 97 ITP subjects with acute or chronic ITP were randomized to a single dose of 2 g/kg of GAMUNEX ^® or GAMIMUNE ^® N. The total dose was divided into two 1 g/kg doses given on two consecutive days at a maximum infusion rate of 0.08 mL/kg/min. 48 subjects were exposed to 95 infusions with GAMUNEX ^® . One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX ^® . The death was unrelated to GAMUNEX ^® .

As expected, the adverse event rate of IGIV in this ITP trial was higher than observed in the replacement therapy for Primary Humoral Immunodeficiencies (PI), but was within the range reported earlier for IGIV ⁴³ . It should be noted that the dose per infusion is 2-2.5 fold higher than in Primary Humoral Immunodeficiency and that the total dose was given on two consecutive days. Administration of other IGIV product(s) at 1g/kg/day for 2 consecutive days has been associated with a higher adverse event rate than when the same total dose of product(s) was administered over a 5 day period ⁵ . Finally, no pre-medication with corticosteroids was permitted by the protocol. Only 12 subjects treated in each treatment group were pretreated with medication prior to infusion. Generally, diphenhydramine and/or acetaminophen were used. More than 90% of the observed drug related adverse events were of mild to moderate severity and of transient nature.

Any adverse events in trial 100176, irrespective of the causality assessment, reported by at least 15% of subjects during the 3-month trial are given in the table below.

The severity of the adverse events across the treatment groups is displayed below:

The subset of drug related adverse events in trial 100176 reported by at least 3% of subjects during the 3-month trial are given in the table below.

The actual infusion rate was reduced for only 4 of the 97 exposed subjects (1 GAMUNEX ^® , 3 GAMIMUNE ^® N) on 4 occasions. Mild to moderate headache, nausea, and fever were the reported reasons. There were no anaphylactic or anaphylactoid reactions to GAMUNEX ^® or GAMIMUNE ^® N.

At baseline, nine days after the first infusion (for parvovirus B19), and 3 months after the first infusion of IGIV and at any time of premature discontinuation of the study, serum samples were drawn to monitor the viral safety of the ITP subjects. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, PCR), and serological testing. There were no treatment related emergent findings of viral transmission for either GAMUNEX ^® , or GAMIMUNE ^® N ¹¹ .

Although the incidences of abnormal hematocrit, hemoglobin, RBC and glucose were twice as high in the GAMUNEX ^® group, the actual mean changes from baseline in these parameters were not different between study drugs and the magnitudes of these mean changes were small and clinically insignificant. These changes were attributed to pre-existing differences at baseline for the hematology parameters, which continued through the study with no incremental effect carried forward. For glucose, confounding variables such as non-fasting samples further suggest the finding to be by random chance.

DOSAGE AND ADMINISTRATION

Dosage

General

For patients judged to be at increased 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 ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, at a rate less than 8 mg/kg/min (0.08 mL/kg/min). No prospective data are presently available to identify a maximum safe dose, concentration, and rate of infusion in patients determined to be at increased risk of acute renal failure. In the absence of prospective data, recommended doses should not be exceeded and the concentration and infusion rate should be the minimum level practicable. Reduction in dose, concentration, and/or rate of administration in patients at risk of acute renal failure has been proposed in the literature in order to reduce the risk of acute renal failure ⁴⁴ .

Primary Humoral Immunodeficiency (PI)

GAMUNEX ^® doses between 300 and 600 mg/kg (3 and 6 mL/kg), which represented the dose range for 92% of the subjects in the therapeutic equivalence trial (100175), may be used for infection prophylaxis. The dose should be individualized taking into account dosing intervals (e.g. 3 or 4 weeks) and GAMUNEX ^® dose (between 300 and 600 mg/kg). A target serum IgG trough level (i.e. prior to the next infusion) of at least 5 g/L has been proposed in the literature ^{22, 45} , however no randomized controlled trial data are available to validate this recommendation. In a clinical trial with 73 subjects with Primary Immune Deficiencies, treated for nine months with GAMUNEX ^® , the relationship of validated infections and serum IgG levels at trough are shown in the table below:

Idiopathic Thrombocytopenic Purpura (ITP)

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 × 10 ⁹ /L to more than or equal to 50 × 10 ⁹ /L within 7 days after treatment. ¹¹

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.

Administration

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.

It is recommended that GAMUNEX ^® should initially be infused at a rate of 0.01 mL/kg per minute (1 mg/kg per minute) for the first 30 minutes. If well-tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg per minute). If side effects occur, the rate may be reduced, or the infusion interrupted until symptoms subside. The infusion may then be resumed at the rate which is comfortable for the patient.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Only 18 gauge needles should be used to penetrate the stopper for dispensing product from 10mL vial sizes; 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 within the stopper area delineated by the raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the ring.

Content of vials may be pooled under aseptic conditions into sterile infusion bags and infused within 8 hours after pooling.

It is recommended to infuse GAMUNEX ^® using a separate line by itself, without mixing with other intravenous fluids or medications the patient might be receiving.

A number of factors could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use.

HOW SUPPLIED

GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, is supplied in the following sizes:

STORAGE

GAMUNEX ^® , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, may be stored for 36 months at 2-8°C (36-46°F), AND product may be stored at temperatures not to exceed 25°C (77°F) for up to 6 months anytime during the 36 month shelf life, after which the product must be immediately used or discarded. Do not freeze. Do not use after expiration date.

Rx only

REFERENCES

1. Kelleher J, F.G., Cyrus P, Schwartz L, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Immune Deficiency (PID). 2000. Report on file.
2. Data on File.
3. Bayever E, M.F., Sundaresan P, Collins S, Randomized, Double-Blind, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100152). MMRR-1512/1, 1999.
4. Lathia C, E.B., Sundaresan PR, Schwartz L, A Randomized, Open-Label, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 5% with IGIV-Chromatography 10% in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100174) . 2000.
5. Blanchette, V.S., M.A. Kirby, and C. Turner, Role of intravenous immunoglobulin G in autoimmune hematologic disorders. Semin Hematol, 1992. 29 (3 Suppl 2): p. 72-82.
6. Lazarus, A.H., J. Freedman, and J.W. Semple, Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP): mechanisms of action. Transfus Sci, 1998. 19 (3): p. 289-94.
7. Semple, J.W., A.H. Lazarus, and J. Freedman, The cellular immunology associated with autoimmune thrombocytopenic purpura: an update. Transfus Sci, 1998. 19 (3): p. 245-51.
8. Imbach, P.A., Harmful and beneficial antibodies in immune thrombocytopenic purpura. Clin Exp Immunol, 1994. 97 (Suppl 1): p. 25-30.
9. Bussel, J.B., Fc receptor blockade and immune thrombocytopenic purpura. Semin Hematol, 2000. 37 (3): p. 261-6.
10. Imbach, P., et al., Immunthrombocytopenic purpura as a model for pathogenesis and treatment of autoimmunity. Eur J Pediatr, 1995. 154 (9 Suppl 4): p. S60-4.
11. Cyrus P, F.G., Kelleher J, Schwartz L, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety, and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2000. Report on file.
12. Wretlind, A., Complete intravenous nutrition. Theoretical and experimental background. Nutr Metab, 1972. 14 : p. Suppl:1-57.
13. Hahn, R.G., H.P. Stalberg, and S.A. Gustafsson, Intravenous infusion of irrigating fluids containing glycine or mannitol with and without ethanol. J Urol, 1989. 142 (4): p. 1102-5.
14. Tai VM, M.E., Lee-Brotherton V, Manley JJ, Nestmann ER, Daniels JM. Safety Evaluation of Intravenous Glycine in Formulation Development. in J Pharm Pharmaceut Sci ( www.ualberta.ca/-csps ). 2000.
15. Traul, K.A., et al., Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol, 2000. 38 (1): p. 79-98.
16. Guyton, A., Textbook of Medical Physiology. 5th Edition. 1976, Philadelphia: W.B. Saunders. 499-500.
17. Ammann, A.J., et al., Use of intravenous gamma-globulin in antibody immunodeficiency: results of a multicenter controlled trial. Clin Immunol Immunopathol, 1982. 22 (1): p. 60-7.
18. Buckley, R.H. and R.I. Schiff, The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med, 1991. 325 (2): p. 110-7.
19. Cunningham-Rundles, C. and C. Bodian, Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol, 1999. 92 (1): p. 34-48.
20. Nolte, M.T., et al., Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol, 1979. 36 (2): p. 237-43.
21. Pruzanski, W., et al., Relationship of the dose of intravenous gammaglobulin to the prevention of infections in adults with common variable immunodeficiency. Inflammation, 1996. 20 (4): p. 353-9.
22. Roifman, C.M., H. Levison, and E.W. Gelfand, High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet, 1987. 1 (8541): p. 1075-7.
23. Sorensen, R.U. and S.H. Polmar, Efficacy and safety of high-dose intravenous immune globulin therapy for antibody deficiency syndromes. Am J Med, 1984. 76 (3A): p. 83-90.
24. Stephan, J.L., et al., Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr, 1993. 123 (4): p. 564-72.
25. Cayco, A.V., M.A. Perazella, and J.P. Hayslett, 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): p. 1788-94.
26. Casteels-Van Daele, M., et al., Intravenous immune globulin and acute aseptic meningitis [letter]. N Engl J Med, 1990. 323 (9): p. 614-5.
27. Kato, E., et al., Administration of immune globulin associated with aseptic meningitis [letter]. Jama, 1988. 259 (22): p. 3269-71.
28. Scribner, C.L., et al., Aseptic meningitis and intravenous immunoglobulin therapy [editorial; comment]. Ann Intern Med, 1994. 121 (4): p. 305-6.
29. Copelan E.A., Stohm P.L., Kennedy M.S., Tutschka P.J. Hemolysis following intravenous immune globulin therapy. Transfusion 1986. 26 : 410-412.
30. Thomas M.J., Misbah S.A., Chapel H.M., Jones M., Elrington G., Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993. 15 :3789.
31. Wilson J.R., Bhoopalam N., Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle & Nerve 1997. 20 :1142-1145.
32. Kessary-Shoham H., Levy Y., Shoenfeld Y., Lorber M., Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced ecrythrocyte sequestration. J Autoimmune 1999. 13 :129-135.
33. Rizk A., Gorson K.C., Kenney L., Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001. 41 :264-268.
34. Dalakas M.C. High-dose intravenous Immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology, 44 : 223-226.
35. Woodruff R.K., Grigg A.P., Firkin F.C., Smith I.L. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986. 2 :217-218.
36. Wolberg A.S., Kon R.H., Monroe D.M., Hjoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000. 65 ,30-34.
37. Winward, D.B. and M.T. Brophy, Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report. Pharmacotherapy, 1995. 15 (6): p. 765-72.
38. Peerless, A.G. and E.R. Stiehm, Intravenous gammaglobulin for reaction to intramuscular preparation [letter]. Lancet, 1983. 2 (8347): p. 461.
39. Data on file.
40. Stangel, M.M., et al., Side effects of intravenous immunoglobulins in neurological autoimmune disorders A prospective study. J Neurol, 2003. 250 (7): p. 818-21.
41. Ebeling, F., et al., Tolerability and kinetics of a solvent-detergent-treated intravenous immunoglobulin preparation in hypogammaglobulinaemia patients. Vox Sang, 1995. 69 (2): p. 91-4.
42. Kelleher J., S.L., IGIV-C 10% Rapid Infusion Trial in Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2001 . Report on file.
43. George, J.N., et al., Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology [see comments]. Blood, 1996. 88 (1): p. 3-40.
44. Tan, E., et al., Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol, 1993. 50 (2): p. 137-9.
45. Eijkhout, H.W., et al., The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med, 2001. 135 (3): p. 165-74.
46. Pierce L.R., Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev, 2003. 17 :241-251.
47. Stenland CJ, Lee DC, Brown P, et al. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 2002. 42 (11):1497-500.
48. Lee DC, Stenland CJ, Miller, JL, et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 2001. 41 (4):449-55.
49. Lee DC, Stenland CJ, Hartwell, RC, et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 2000. 84 (1):77-89.
50. Cai K, Miller JL, Stenland, CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597 (1):28-35.
51. Trejo SR, Hotta JA, Lebing W, et al. Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 2003. 84 (3):176-87.

Talecris Biotherapeutics, Inc.

Research Triangle Park, NC 27709 USA

U.S. License No.1716 08936212 (Rev. July 2005)