Primary Immunodeficiency (PI)

GAMMAGARD S/D is indicated for the treatment of primary immunodeficiency (PI) associated with defects in humoral immunity, in adults and children two years and older. This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.1,2,3

B-cell Chronic Lymphocytic Leukemia (CLL)

GAMMAGARD S/D is indicated for prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell chronic lymphocytic leukemia (CLL).4

Idiopathic Thrombocytopenic Purpura (ITP)

GAMMAGARD S/D is indicated for the treatment of adult chronic idiopathic thrombocytopenic purpura to increase platelet count and to prevent and/or to control bleeding.

Kawasaki Syndrome

GAMMAGARD S/D is indicated for the prevention of coronary artery aneurysms associated with Kawasaki syndrome in pediatric patients.5

2.1 Preparation and Handling

2.2 Dose

2.3 Administration

Administer GAMMAGARD S/D as soon after reconstitution as possible and administer the reconstituted material at room temperature.

The recommended initial 5% solution infusion rate is 0.5 mL/kg/hour. The infusion rate may be gradually increased to a maximum rate of 4 mL/kg/hour as tolerated for patients with no history of adverse reactions to IGIV and no significant risk factors for renal dysfunction or thrombotic complications. Patients who tolerate the 5% concentration at 4 mL/kg/hour can be infused with the 10% concentration starting at 0.5 mL/kg/hour. The rate can be increased gradually up to a maximum of 8 mL/kg/hour if no adverse effects occur.9

Monitor patient vital signs throughout the infusion. Certain adverse reactions such as headaches, flushing and changes in pulse rate and blood pressure may be related to the rate of infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that does not result in reoccurrence of the symptoms.

It is recommended that, if possible, the antecubital veins are used, especially for 10% solutions, to reduce the likelihood of discomfort at the infusion site. [See Adverse Reactions (6)]

Adverse reactions may occur more frequently in patients who receive human IGIV for the first time, upon switching brands, or if there has been a long hiatus since the previous infusion. In such cases, start at a lower rate and gradually increase as tolerated.

There are no prospective studies demonstrating that any concentration or rate of infusion is completely safe. However, the risk may be decreased at lower rates of infusion.10 For patients who are judged to be at risk of renal dysfunction or thrombotic complications, administer GAMMAGARD S/D at the minimum practicable rate of infusion and gradually titrate up to a more conservative maximal rate of less than 3.3 mg/kg/min (< 2mL/kg/hour of a 10% or < 4mL/kg/hour of a 5% solution). [See Warnings and Precautions (5.3)]

5.1 Hypersensitivity

Severe hypersensitivity reactions and anaphylactic reactions with a fall in blood pressure have occurred in patients receiving GAMMAGARD S/D, including patients who tolerated previous treatments with GAMMAGARD S/D, even though it contains low levels of IgA. If hypersensitivity reaction develops, discontinue GAMMAGARD S/D infusion immediately and institute appropriate treatment.

This product has an IgA concentration less than 1 µg/mL. Preparations depleted of IgA (0.4 to 2.9 µg/mL) were shown to be better tolerated by a limited number of patients who reacted to IGIV preparations with higher IgA concentrations. However, the concentration of IgA that will not provoke a reaction is not known, and therefore all IGIV preparations carry the risk of inducing an anaphylactic reaction to IgA. In such instances, a risk of anaphylaxis may exist despite the fact that GAMMAGARD S/D, IgA < 1 µg/mL, contains < 1 µg/mL IgA.

5.2 Renal Dysfunction/Failure

Acute renal failure has been reported in association with GAMMAGARD S/D. Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death have been reported in patients receiving IGIV, particularly those products containing sucrose.10 GAMMAGARD S/D does not contain sucrose.

Ensure that patients are not volume depleted prior to the initiation of the infusion of GAMMAGARD S/D. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs, etc.), administer GAMMAGARD S/D at an infusion rate less than 4 mL/kg/hour (< 3.3 mg IG/kg/min) for a 5% solution or at a rate less than 2 mL/kg/hour (< 3.3 mg IG/kg/min) for a 10 % solution. [See Dosage and Administration (2)]

Monitor renal function and urine output in patients judged to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of GAMMAGARD S/D and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of GAMMAGARD S/D.

5.3 Thrombosis

Thrombosis may occur following treatment with immune globulin products, including GAMMAGARD S/D. 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 GAMMAGARD S/D at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. [See Boxed Warning, Dosage and Administration (2.3), Patient Counseling Information (17)]

5.4 Aseptic Meningitis Syndrome (AMS)

AMS has been reported to occur in association with immune globulin therapy, including GAMMAGARD S/D. AMS may occur more frequently in female patients. Discontinuation of immune globulin treatment has resulted in remission of AMS within several days without sequelae. The syndrome of AMS usually begins within several hours to two days following immune globulin treatment.

AMS is characterized by the following symptoms and signs: 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 mm, 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 symptoms and signs, including CSF studies, to rule out other causes of meningitis.

5.5 Hemolysis

Hemolytic anemia can develop subsequent to IGIV therapy, including GAMMAGARD S/D11. [See Adverse Reactions (6.2)] GAMMAGARD S/D contains blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells (RBC) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Acute intravascular hemolysis has been reported, and delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. [See Adverse Reactions (6.2)]

Monitor patients for clinical signs and symptoms of hemolysis. If signs or symptoms of hemolysis are present after GAMMAGARD S/D infusion, perform appropriate confirmatory laboratory testing.

5.6 Transfusion-Related Acute Lung Injury (TRALI)

Non-cardiogenic pulmonary edema (TRALI) has been reported in patients following the administration of immunoglobulin products, including GAMMAGARD S/D therapy. [See Adverse Reactions (6.2)] TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment.

Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.7 Transmissible Infectious Agents

Because GAMMAGARD S/D is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses the variant Creutzfeldt-Jakob disease (vCJD) agent and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens.

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 Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327)(in the U.S.) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The physician should discuss the risks and benefits of this product with the patient.

5.8 Hyperproteinemia, Increased Serum Viscosity, and Alterations in Serum Sodium Levels

Hyperproteinemia and increased serum viscosity may occur in patients receiving GAMMAGARD S/D. Alterations in serum sodium levels, such as hypernatremia acutely, or pseudohyponatemia after equilibration of the sodium, may occur with the administration of GAMMAGARD S/D.

The amount of sodium in the product may add materially to the recommended daily allowance of dietary sodium for patients on a low sodium diet. In these patients, calculate the amount of sodium from the product and use it when determining dietary sodium intake. GAMMAGARD S/D contains approximately 0.85% NaCl or approximately 3340 mg sodium/liter at a 5% concentration. A 70 kg patient receiving 1g/kg (1.4 L) of the product would receive 4676 mg of sodium.

5.9 Monitoring: Laboratory Tests

• Monitor renal function and urine output in patients at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMMAGARD S/D and at appropriate intervals thereafter.10
• Assess baseline blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies because of the potentially increased risk of thrombosis.
• If signs or symptoms of hemolysis are present after an infusion of GAMMAGARD S/D, perform appropriate laboratory testing for confirmation.
• If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient's serum.

5.10 Interference with Laboratory Tests

• After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient's blood may yield false 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.
• Administration of GAMMAGARD S/D can lead to false positive readings in assays that depend on detection of beta-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product.

6.1 Clinical Trials Experience

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

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

The following adverse reactions have been reported during postmarketing use of GAMMAGARD S/D (Table 5).

In addition to the events listed above, the following events have been identified for IGIV products in general:

8.1 Pregnancy

8.2 Lactation

Risk Summary

There is no information regarding the presence of GAMMAGARD S/D in human milk, its effects on the breastfed infant or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GAMMAGARD S/D and any potential adverse effects on the breastfed infant from GAMMAGARD S/D or from the underlying maternal condition.

8.4 Pediatric Use

Clinical studies for the treatment of PI did not include sufficient numbers of subjects aged 16 and younger to determine whether they respond differently from adults. Five children under the age of 16 were treated in the initial trial of GAMMAGARD. The mean age of subjects in the phase 4 study was 17.8 years (range 1.7 to 55.3).

Efficacy and safety of GAMMAGARD S/D in pediatric patients with chronic ITP has not been established.

Efficacy and safety of GAMMAGARD S/D in pediatric patients with Kawasaki disease has been established. Virtually all patients treated for Kawasaki disease were less than 5 years of age, with approximately 20% under the age of 1 year.

8.5 Geriatric Use

Limited information is available for the geriatric use. Clinical studies of GAMMAGARD S/D for the treatment of PI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. When administering GAMMAGARD S/D to patients age 65 and over who are at increased risk for developing thromboembolic events or renal insufficiency, do not exceed the recommended dose and administer GAMMAGARD S/D at the minimum infusion rate practicable. [See Boxed Warning, Warnings and Precautions(5.2, 5.4) and Dosage and Administation (2.2)]

12.1 Mechanism of Action

GAMMAGARD S/D, Immune Globulin Intravenous (Human), supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. GAMMAGARD S/D also contains a spectrum of antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies and the mechanisms of action of IgG in GAMMAGARD S/D have not been fully elucidated.

12.3 Pharmacokinetics

Following infusion, IGIV products show a biphasic decay curve. The initial (α) phase is characterized by an immediate post-infusion peak in serum IgG and is followed by rapid decay due to equilibration between the plasma and extravascular fluid compartments. The second (β) phase is characterized by a slower and constant rate of decay. As a class, IgG survives longer in vivo than other serum proteins. Peak levels of IgG are reached within 30 minutes after an intravenous infusion of GAMMAGARD S/D. In previous studies, where radio-labeled IgG was injected to subjects, the IgG half-life was 21 to 25 days in healthy individuals or 17.7 to 37.6 days in immunodeficient patients. The half-life of IgG can vary considerably from person to person, however. In particular, high serum concentrations of IgG and hypermetabolism associated with fever and infection have been seen to coincide with a shortened half-life of IgG.

The pharmacokinetics of GAMMAGARD S/D were evaluated in 15 subjects with PI, 10 of whom were previously treated. In the previously treated subjects, the half-life of GAMMAGARD S/D was approximately 37.7 ± 15 days compared to 34.1 ± 15.7 days for GAMMAGARD. The half-lives of the IgG subclasses were similar, ranging from 28.1 ± 11.2 days for IgG4 to 42.3 ± 26.6 days for IgG1. The half-life of pneumococcal antibody in these subjects was 41.4 ± 28.5 days. Pharmacokinetics did not differ between the previously licensed IGIV and GAMMAGARD S/D formulations administered to the previously treated patients. The pharmacokinetics of the GAMMAGARD S/D formulation in previously untreated patients were not significantly different from the results obtained in previously treated patients. The mean trough IgG concentration in the previously untreated patients was 1186 ± 614 mg/dL and the peak post-infusion concentration was 1859 ± 872 mg/dL. The mean dose was 460 ± 194 mg/kg.

Primary Immunodeficiency (PI)

Intravenous use of GAMMAGARD was initially evaluated in a study of 17 subjects with PI. Twelve (71%) were adults and 5 (29%) were children 16 years or younger. Six subjects received a series of 5 infusions at 4-week intervals, with the starting infusion dose of 100 mg/kg and then increased to 200, 300, and 400 mg/kg at rates of 0.1 to 0.2 mg/kg/hour. Five of the 6 subjects completed the 5 infusions and received another 6 monthly infusions with the following doses each administered twice: 200-400 mg/kg at 0.1 to 0.2 g/kg/hour, 400 mg/kg at 0.1 to 0.4 g/kg/hour and 400-800 mg/kg at 0.1 to 0.4 g/ kg/hour. Then all of the 17 subjects received GAMMAGARD at 400 mg/kg every 4 weeks at a rate of 0.1 to 0.4 g/kg/hour. Fifteen of the subjects were treated for 56 to 77 weeks in this study. There were no instances of pneumonia or other infections that would qualify as an acute bacterial infection. The overall rate of non-serious bacterial infections was 4.4 per subject per year.

In a study of 15 subjects with PI to compare the pharmacokinetics of GAMMAGARD S/D with GAMMAGARD, the subjects received a total of 28 infusions, half with GAMMAGARD S/D and half with GAMMAGARD. Five systemic AEs were reported during the study and 2 occurred with GAMMAGARD S/D treatment. The study then enrolled an additional 38 patients with the diagnosis of PI (8), ITP (13), CVID (5), CLL (2) and other miscellaneous diseases (3) to evaluate acute tolerability and the viral safety of GAMMAGARD S/D.

The mean age of the subjects was 12 years old (range 0.7 to 57.2 years); 17 were males and 21 were females. The subjects received an average of 10 (range 1-22) infusions over an average of 7.7 months (range 0.3-11 months). A total of 394 infusions were administered and all were completed. The average dose was 460 mg/kg (range: 188-1110 mg/kg). Incidence of infections was not recorded, although one subject had a recurrence of chronic cellulitis. Adverse events and viral safety data were analyzed. [See Adverse Reactions(6)]

GAMMAGARD S/D was compared to Gamimune N in a double-blind, crossover study of 36 PI subjects. The mean age of subjects was 17.8 years (range 1.7 to 55.3 years); 22 subjects were male and 14 were female. Eighteen were naïve to IGIV therapy. Each subject received 6 infusions of both products. There were a total of 211 GAMMAGARD S/D infusions and 210 Gamimune N infusions. The dose of GAMMAGARD S/D administered was 300-600 mg/kg every 14 to 28 days for previously untreated subjects and the same as their pre-study dose and frequency for previously treated subjects. The infusions were started at 1.0 mL/kg/hour and increased every 30 minutes to a maximum of 4.8 mL/kg/hour as tolerated. The mean dose administered for both products was 440 mg/kg. The mean infusion rate was 2.35 ± 0.54 mL/kg/hour for GAMMAGARD S/D and 2.33 ± 0.71 for Gamimune N. Two subjects withdrew from the study. One subject was pregnant, and the other subject was withdrawn by his parents after the eighth infusion for reasons other than adverse events.

The use of GAMMAGARD S/D as a 10% solution and the maximal rate of infusion were evaluated in a postmarketing study of 27 subjects with PI. Subjects were treated with GAMMAGARD S/D at 400 mg/kg every 4 weeks for up to 12 months. Each subject received an initial infusion of GAMMAGARD S/D 5% solution at 4 mL/kg/hour. Subsequently, the concentration was increased to 7.5% and then to 10% as tolerated. Thereafter, the infusion rate was gradually increased to a maximal 8 mL/kg/hour as tolerated. There were 276 infusions administered and 26 of the 27 subjects were able to reach the maximum infusion rate and concentration.

B-cell Chronic Lymphocytic Leukemia (CLL)

The efficacy of GAMMAGARD in reducing bacterial infections of B-cell CLL patients has been demonstrated in a double-blind, placebo-controlled trial of 81 subjects.4 Subjects were treated with 400 mg/kg/dose of GAMMAGARD or saline solution every 3 weeks for a total of 17 infusions. Forty-one subjects received GAMMAGARD and 40 subjects received saline. The infection outcomes, including the frequency of bacterial/viral/fungal infections, mean time to first bacterial infections, were compared between the two groups and are shown in Table 7.

Patients receiving GAMMAGARD had fewer infections with Streptococcus pneumoniae and Haemophilus influenza, but the incidence of other gram negative infections was similar.

Idiopathic Thrombocytopenic Purpura (ITP)

The efficacy of GAMMAGARD has been demonstrated in a clinical study involving 16 patients: thirteen had chronic ITP (11 adults, 2 children), and 3 had acute ITP (one adult, 2 children). All 16 patients (100%) demonstrated a rise in platelet count to a level greater than 40,000/mm3 following the administration of GAMMAGARD. Ten of the 16 patients (62.5%) exhibited a platelets rise to greater than 80,000 /mm3. Of these 10 patients, 7 had chronic ITP (5 adults, 2 children), and 3 had acute ITP (one adult, 2 children).

Increase in platelet count to greater than 40,000/mm3 occurred after a single 1 g/kg infusion of GAMMAGARD in 8 patients with chronic ITP (6 adults, 2 children), and in 2 patients with acute ITP (one adult, one child). A similar response was observed after two 1 g/kg infusions in 3 adult patients with chronic ITP, and one child with acute ITP. The remaining 2 adult patients with chronic ITP received more than two 1 g/kg infusions before achieving a platelet count greater than 40,000/mm3. The rise in platelet count occurred within 5 days. However, this rise was transient and not considered curative. Platelet count rises lasted 2 to 3 weeks, with a range of 12 days to 6 months. It should be noted that childhood ITP may resolve spontaneously without treatment.

Kawasaki Syndrome

The efficacy of GAMMAGARD S/D for reducing the incidence of coronary artery aneurysm in patients with Kawasaki syndrome has been demonstrated in a clinical study of 44 patients.7 The incidence of coronary artery aneurysm in patients with Kawasaki syndrome receiving GAMMAGARD either at a single dose of 1 g/kg (n=22) or at a dose of 400 mg/kg for four consecutive days (n=22), beginning within seven days of onset of fever, was 3/44 (6.8%). This was significantly different (p=0.008) from a comparable group of patients that received aspirin only in previous trials and of whom 42/185 (22.7%) developed coronary artery aneurysms. All patients in the GAMMAGARD trial received concomitant aspirin therapy and none experienced hypersensitivity reactions (urticaria, bronchospasm or generalized anaphylaxis).

Store GAMMAGARD S/D at a temperature not to exceed 25ºC (77ºF) for 24 months.

Do not Freeze.

Not made with natural rubber latex.