Label: GAMMAKED - human immunoglobulin g injection 

  • NDC Code(s): 76125-900-01, 76125-900-02, 76125-900-10, 76125-900-11, view more
    76125-900-20, 76125-900-21, 76125-900-25, 76125-900-26, 76125-900-50, 76125-900-51
  • Packager: KEDRION BIOPHARMA, INC
  • Category: PLASMA DERIVATIVE
  • DEA Schedule: None
  • Marketing Status: Biologic Licensing Application

Drug Label Information

Updated 09/13

If you are a consumer or patient please visit this version.

  • BOXED WARNING(What is this?)

    WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE

    • Thrombosis may occur with immune globulin products, including GAMMAKED. 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 [5.4], Patient Counseling Information [17]) 
    • For patients at risk of thrombosis, administer GAMMAKED 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 [5.4])
    • 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.(1) GAMMAKED does not contain sucrose.
    • For patients at risk of renal dysfunction or failure, administer GAMMAKED at the minimum concentration available and the minimum infusion rate practicable. (see Warnings and Precautions [5.2])
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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use GAMMAKED™ safely and effectively.
    See full prescribing information for GAMMAKED.

    GAMMAKED™, [Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified]

    Initial U.S. Approval: 2003

    WARNING: THROMBOSIS, RENAL DYSFUNCTION and ACUTE RENAL FAILURE

    See full prescribing information for complete boxed warning.

    • Thrombosis may occur with immune globulin products, including GAMMAKED. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.
    • For patients at risk of thrombosis, administer GAMMAKED 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.
    • 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. GAMMAKED does not contain sucrose.
    • For patients at risk of renal dysfunction or failure, administer GAMMAKED at the minimum concentration available and the minimum infusion rate practicable. (5.2)

    RECENT MAJOR CHANGES

    • Dosage and Administration (2.1, 2.5)                                             11/2012
    • Boxed Warning; Warnings and Precautions, Thrombosis (5.4)        9/2013

    INDICATIONS AND USAGE

    GAMMAKED is an immune globulin injection (human), 10% liquid indicated for treatment of:

    • Primary Humoral Immunodeficiency (PI) (1.1)
    • Idiopathic Thrombocytopenic Purpura (ITP) (1.2)
    • Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (1.3)

    DOSAGE AND ADMINISTRATION

    Intravenous Administration Only: ITP and CIDP

    Indication Dose Initial Infusion
    Rate
    Maintenance Infusion Rate
    (if tolerated)
    ITP (2.3 ) 2 g/kg 1 mg/kg/min 8 mg/kg/min
    CIDP (2.4 ) loading dose
    2 g/kg
    maintenance dose
    1 g/kg
    2 mg/kg/min 8 mg/kg/min
    Every 3 weeks
    • Ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue GAMMAKED if renal function deteriorates. (5.2)
    • For patients at risk of renal dysfunction or thrombosis, administer GAMMAKED at the minimum infusion rate practicable. (5.2, 5.4)

    Intravenous or Subcutaneous Administration: PI (2.2)
    DO NOT ADMINISTER SUBCUTANEOUSLY FOR ITP PATIENTS (5.10)

    *
    See section 2.2.
    Route of
    Administration
    Dose* Infusion Rate Maintenance Infusion Rate
    (if tolerated)
    Intravenous (IV) 300-600 mg/kg 1 mg/kg/min 8 mg/kg/min
    Every 3-4 weeks
    Subcutaneous (SC) 1.37 x current IV dose in mg/kg/IV
    dose interval in weeks
    20 mL/hr/site Not determined during
    the clinical study

    DOSAGE FORMS AND STRENGTHS

    GAMMAKED is supplied in 1 g, 2.5 g, 5 g, 10 g, or 20 g single use bottles. (3)

       1 g 10 mL
    2.5 g 25 mL
        5 g 50 mL
      10 g 100 mL
       20 g 200 mL

    CONTRAINDICATIONS

    • Anaphylactic or severe systemic reactions to human immunoglobulin (4.1)
    • IgA deficient patients with antibodies against IgA and a history of hypersensitivity (4.2)

    WARNINGS AND PRECAUTIONS

    • IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available immediately to treat any acute severe hypersensitivity reactions. (5.1)
    • Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output in patients at risk of developing acute renal failure. (5.2
    • Hyperproteinemia, with resultant changes in serum viscosity and electrolyte imbalances may occur in patients receiving IGIV therapy. (5.3)
    • Thrombosis has occurred in patients receiving IGIV therapy. Monitor patients with known risk factors for thrombosis; consider baseline assessment of blood viscosity for those at risk of hyperviscosity. (5.4)
    • Aseptic Meningitis Syndrome (AMS) has been reported with GAMMAKED and other IGIV treatments, especially with high doses or rapid infusion. (5.5)
    • Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. Monitor patients for hemolysis and hemolytic anemia. (5.6)
    • Monitor patients for pulmonary adverse reactions (transfusion-related acute lung injury [TRALI]). (5.7)
    • Volume overload. (5.8)
    • GAMMAKED is made from human plasma and may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease agent. (5.9)
    • GAMMAKED is not approved for subcutaneous use in ITP patients. Due to a potential risk of hematoma formation, do not administer GAMMAKED subcutaneously in patients with ITP. (5.10)
    • Passive transfer of antibodies may confound serologic testing. (5.12)

    ADVERSE REACTIONS

    Serious adverse reactions which occurred in the clinical trials were an exacerbation of autoimmune pure red cell aplasia in one subject and pulmonary embolism in one subject with a history of PE. The most common adverse reactions observed in ≥ 5% patients were (6.1):

    PIIntravenous: Headache, cough, injection site reaction, nausea, pharyngitis and urticaria.  
         Subcutaneous: Infusion site reactions, headache, fatigue, arthralgia and pyrexia.
    ITP: Headache, vomiting, fever, nausea, back pain and rash.
    CIDP: Headache, fever, chills, hypertension, rash, nausea and asthenia.

    To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics Inc. at 1-800-520-2807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    • The passive transfer of antibodies may transiently interfere with the response to live viral vaccines, such as measles, mumps and rubella. (7

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: no human or animal data. Use only if clearly needed. (8.1)
    • Geriatric: In patients over 65 years of age do not exceed the recommended dose, and infuse GAMMAKED at the minimum infusion rate practicable. (8.5)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 9/2013

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • SPL PRODUCT DATA ELEMENTS

    GAMMAKED™, [Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified]

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  • 1 INDICATIONS AND USAGE

    GAMMAKED is an immune globulin injection (human) 10% liquid that is indicated for the treatment of:

    1.1 Primary Humoral Immunodeficiency (PI)

    GAMMAKED 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.(2-5)

    1.2 Idiopathic Thrombocytopenic Purpura (ITP)

    GAMMAKED is indicated for the treatment of patients with Idiopathic Thrombocytopenic Purpura to raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo surgery.(6,7)

    1.3 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

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

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  • 2 DOSAGE AND ADMINISTRATION

    GAMMAKED consists of 9%–11% protein in 0.16–0.24 M glycine. The buffering capacity of GAMMAKED is 35.0 mEq/L (0.35 mEq/g protein). A dose of 1 g/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. Thus, the acid load delivered with a dose of 1 g/kg of GAMMAKED would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.

    2.1 Preparation and Handling

    • Visually inspect GAMMAKED for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid.
    • Do not freeze. Do not use solutions that have been frozen.
    • The GAMMAKED vial is for single use only. GAMMAKED contains no preservative. Use any vial that has been entered promptly.  Discard partially used vials.
    • Infuse GAMMAKED using a separate line by itself, without mixing with other intravenous fluids or medications the subject might be receiving.  The GAMMAKED infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection.
    • If dilution is required, GAMMAKED may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline. 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.
    • Avoid simultaneous administration of GAMMAKED and Heparin through a single lumen delivery device due to GAMMAKED, Heparin incompatibilities. Flush Heparin Lock (Hep-Lock) through which GAMMAKED was administered with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection, and do not flush with Heparin. See table below.
    Additional Solutions Dilution Line Flush Delivery Device Flush
    5% Dextrose in water Yes Yes Yes
    0.9% Sodium Chloride No Yes Yes
    Heparin No No No
    • Do not mix with immune globulin intravenous (IGIV) products from other manufacturers.
    • Do not use after expiration date.

    2.2 PI

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

    Intravenous (IV)

    The dose of GAMMAKED for patients with PI 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.

    The recommended initial infusion rate is 1 mg/kg/min (0.01 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 renal dysfunction or thrombosis, administer GAMMAKED at the minimum infusion rate practicable. (see Warnings and Precautions [5.2, 5.4])

    If a patient routinely receives a dose of less than 400 mg/kg of GAMMAKED 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.

    Subcutaneous (SC)

    The dose should be individualized based on the patient’s clinical response to GAMMAKED therapy and serum IgG trough levels. Begin treatment with GAMMAKED one week after the patient’s last IGIV infusion. See below under "Initial Weekly Dose". Prior to switching treatment from IGIV to GAMMAKED, obtain the patient’s serum IgG trough level to guide subsequent dose adjustments. See below under "Dose Adjustment".

    Establish the initial weekly dose of GAMMAKED by converting the monthly IGIV dose into a weekly equivalent and increasing it using a dose adjustment factor. The goal is to achieve a systemic serum IgG exposure (Area Under the Concentration-Time Curve [AUC]) not inferior to that of the previous IGIV treatment. If the patient has not been previously treated with IV GAMMAKED, convert the monthly IGIV dose by multiplying by 1.37, then dividing this dose into weekly doses based on the patient’s previous IGIV treatment interval. Monitor the patient’s clinical response, and adjust dose accordingly.

    Initial Weekly Dose
    To calculate the initial weekly dose of subcutaneous administration of GAMMAKED, multiply the previous IGIV dose in grams by the dose adjustment factor of 1.37; then divide this by the number of weeks between doses during the patient’s IGIV treatment (i.e., 3 or 4).

    Initial Dose

    To convert the GAMMAKED dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 10.

    Dose Adjustment 
    Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level. To determine if a dose adjustment may be considered, measure the patient’s serum IgG trough level on IGIV and as early as 5 weeks after switching from IGIV to subcutaneous. The target serum IgG trough level on weekly SC treatment is projected to be the last IGIV trough level plus 340 mg/dL. To determine if further dose adjustments are necessary, monitor the patient’s IgG trough level every 2 to 3 months.

    To adjust the dose based on trough levels, calculate the difference (in mg/dL) of the patient’s serum IgG trough level from the target IgG trough level (the last IGIV trough level + 340 mg/dL). Then find this difference in Table 1 and the corresponding amount (in mL) by which to increase or decrease the weekly dose based on the patient’s body weight. However, the patient’s clinical response should be the primary consideration in dose adjustment.

    Table 1: Adjustment (±mL) of the Weekly Subcutaneous Dose Based on the Difference (±mg/dL) From the Target Serum IgG Trough Level
    *
    Dose adjustment in mL is based on the slope of the serum IgG trough level response to subcutaneous administration of GAMMAKED dose increments (about 6.0 mg/dL per increment of 1 mg/kg per week).
    Difference From
    Target IgG Trough
    Level (mg/dL)
    Body Weight (kg)
    10 15 20 30 40 50 60 70 80 90 100 110 120
    Dose Adjustment (mL per Week)*
     50 1 1 2 3 3 4 5 6 7 8 8 9 10
    100 2 3 3 5 7 8 10 12 13 15 17 18 20
    150 3 4 5 8 10 13 15 18 20 23 25 28 30
    200 3 5 7 10 13 17 20 23 27 30 33 37 40
    250 4 6 8 13 17 21 25 29 33 38 42 46 50
    300 5 8 10 15 20 25 30 35 40 45 50 55 60
    350 6 9 12 18 23 29 35 41 47 53 58 64 70
    400 7 10 13 20 27 33 40 47 53 60 67 73 80
    450 8 11 15 23 30 38 45 53 60 68 75 83 90
    500 8 13 17 25 33 42 50 58 67 75 83 92 100

    For example, if a patient with a body weight of 70 kg has an actual IgG trough level of 900 mg/dL and the target level is 1000 mg/dL, this results in a difference of 100 mg/dL. Therefore, increase the weekly dose of subcutaneous dose by 12 mL.

    Monitor the patient’s clinical response, and repeat the dose adjustment as needed.

    Dosage requirements for patients switching to GAMMAKED from another Immune Globulin Subcutaneous (IGSC) product have not been studied. If a patient on GAMMAKED does not maintain an adequate clinical response or a serum IgG trough level equivalent to that of the previous IGSC treatment, the physician may want to adjust the dose. For such patients, Table 1 also provides guidance for dose adjustment to achieve a desired IGSC trough level.

    2.3 ITP

    DO NOT ADMINISTER SUBCUTANEOUSLY (see Warnings and Precautions [5.10])

    GAMMAKED 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 1 g/kg (10 mL/kg) body weight may be withheld.

    Forty-eight ITP subjects were treated with 2 g/kg GAMMAKED, 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 x109/L to more than or equal to 50 x109/L within 7 days after treatment. 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.

    The recommended initial infusion rate is 1 mg/kg/min (0.01 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 renal dysfunction or thrombosis, administer Gammaked at the minimum infusion rate practicable. (see Warnings and Precautions [5.2, 5.4])

    2.4 CIDP

    GAMMAKED 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. GAMMAKED 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.

    The recommended initial infusion rate is 2 mg/kg/min (0.02 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 renal dysfunction or thrombosis, administer Gammaked at the minimum infusion rate practicable. (see Warnings and Precautions [5.2, 5.4])

    2.5 Administration

    Administer intravenously for PI, ITP and CIDP.

    GAMMAKED may also be administered subcutaneously for the treatment of PI.

    • Administer GAMMAKED at room temperature.
    • Inspect GAMMAKED visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.
    • Do not use if turbid and/or if discoloration is observed.

    Intravenous

    • Use only 18 gauge needles to penetrate the stopper for dispensing product from the 10 mL vial.
    • Use 16 gauge needles or dispensing pins only with 25 mL vial sizes and larger.
    • Insert needles or dispensing pins only once and be within the stopper area delineated by the raised ring.
    • Penetrate the stopper perpendicular to the plane of the stopper within the ring.
    GAMMAKED™ vial size Gauge of needle to penetrate stopper
    10 mL 18 gauge
    25, 50, 100, 200 mL 16 gauge
    • Use promptly any vial that has been opened.
    • Discard partially used vials.
    • If dilution is required, GAMMAKED may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline. Infuse GAMMAKED using a separate line by itself, without mixing with other intravenous fluids or medications the subject might be receiving.  The GAMMAKED infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection.

    Subcutaneous for PI Only

    Instructions for Administration

    • Prior to use, allow the solution to reach ambient room temperature.
    • DO NOT SHAKE.
    • Do not use if the solution is cloudy or has particulates.
    • Check the product expiration date on the vial. Do not use beyond the expiration date.
    1. Use aseptic technique when preparing and administering GAMMAKED for injection.
    2. Remove the protective cap from the vial to expose the central portion of the rubber stopper.
    3. Wipe the rubber stopper with alcohol and allow to dry.
    4. Using a sterile syringe and needle, prepare to withdraw GAMMAKED by first injecting air into the vial that is equivalent to the amount of GAMMAKED to be withdrawn. Then withdraw the desired volume of GAMMAKED. If multiple vials are required to achieve the desired dose, repeat this step. (Figure 1
    5. Follow the manufacturer’s instructions for filling the pump reservoir and preparing the pump, administration tubing and Y-site connection tubing, if needed. Be sure to prime the administration tubing to ensure that no air is left in the tubing or needle by filling the tubing/needle with GAMMAKED.
    6. Select the number and location of injection sites. (Figure 2)
    7. Cleanse the injection site(s) with antiseptic solution using a circular motion working from the center of the site and moving to the outside. Sites should be clean, dry, and at least two inches apart. (Figure 3
    8. Grasp the skin between two fingers and insert the needle into the subcutaneous tissue. (Figure 4
    9. Repeat priming and needle insertion steps using a new needle, administration tubing and a new infusion site. Secure the needle in place by applying sterile gauze or transparent dressing over the site. (Figure 5)
    10. If using multiple, simultaneous injection sites, use Y-site connection tubing and secure to the administration tubing.
    11. Infuse GAMMAKED following the manufacturer’s instructions for the pump. (Figure 6)
    Administration

    Rate of Administration

    Intravenous

    Following initial infusion (see table below), the infusion rate may be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg per minute) as tolerated.

    Indication Initial Infusion Rate
    (first 30 minutes)
    Maximum Infusion Rate
    (if tolerated)
    PI 1 mg/kg/min 8 mg/kg/min
    ITP 1 mg/kg/min 8 mg/kg/min
    CIDP 2 mg/kg/min 8 mg/kg/min

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

    Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

    Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients at risk of renal dysfunction or thrombosis, administer GAMMAKED at the minimum infusion rate practicable and discontinue GAMMAKED if renal function deteriorates.

    Subcutaneous for PI Only

    For PI, it is recommended that GAMMAKED is infused at a rate of 20 mL/hr per infusion site.

    In the SC clinical study, the mean volume administered per infusion site was 34 mL (17–69 mL) and the majority of infusions were administered at a rate of 20 mL/hr per site. Multiple simultaneous infusion sites were enabled by administration tubing and Y-site connection tubing. Most subjects utilized 4 infusion sites per infusion with abdomen and thighs being the most commonly used sites. The maximum number of infusion sites is 8. Injection sites should be at least 2 inches apart.

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  • 3 DOSAGE FORMS AND STRENGTHS

    GAMMAKED is supplied in 1 g, 2.5 g, 5 g, 10 g, or 20 g single use bottles.

    • 1 g protein in 10 mL solution
    • 2.5 g protein in 25 mL solution
    • 5 g protein in 50 mL solution
    • 10 g protein in 100 mL solution
    • 20 g protein in 200 mL solution
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  • 4 CONTRAINDICATIONS

    4.1 Hypersensitivity Reactions to Immune Globulins

    GAMMAKED is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.

    4.2 IgA Sensitive Patients with History of Hypersensitivity Reaction

    GAMMAKED is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity.

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypersensitivity

    Severe hypersensitivity reactions may occur with IGIV products, including GAMMAKED. In case of hypersensitivity, discontinue GAMMAKED infusion immediately and institute appropriate treatment. Have medications such as epinephrine available for immediate treatment of acute hypersensitivity reaction.

    GAMMAKED contains trace amounts of IgA (average 46 micrograms/mL). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. It is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity reaction. (see Contraindications [4])

    5.2 Renal Failure

    Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death may occur upon use of IGIV products, especially those containing sucrose.(17) GAMMAKED does not contain sucrose. Assure that patients are not volume depleted prior to the initiation of the infusion of GAMMAKED. 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. Assess renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, prior to the initial infusion of GAMMAKED and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of GAMMAKED. (see Patient Counseling Information [17]) For patients judged to be at risk for developing renal dysfunction, including patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs, administer GAMMAKED at the minimum infusion rate practicable [less than 8 mg IG/kg/min (0.08 mL/kg/min)]. (see Dosage and Administration [2.5])

    5.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

    Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV treatment, including GAMMAKED. It is clinically critical to distinguish true hyponatremia from a pseudohyponatremia that is associated with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a possible predisposition to thrombosis.(8)

    5.4 Thrombosis

    Thrombosis may occur following treatment with immune globulin products, including GAMMAKED. 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 GAMMAKED 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])

    5.5 Aseptic Meningitis Syndrome (AMS)

    AMS may occur infrequently with IGIV treatment, including GAMMAKED. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.  The syndrome usually begins within several hours to two days following IGIV 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 cu 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. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV.

    5.6 Hemolysis

    IGIV products, including GAMMAKED, may contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.(12-14) Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration, and acute hemolysis consistent with intravascular hemolysis, has been reported. (see Adverse Reactions [6])

    The following risk factors may be related to the development of hemolysis: high doses (e.g., ≥2 grams/kg, single administration or divided over several days) and non-O blood group.(29) Underlying inflammatory state in an individual patient may increase the risk of hemolysis, but its role is uncertain.(30)

    Monitor patients for clinical signs and symptoms of hemolysis (see Warnings and Precautions [5.11]), particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform 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.

    5.7 Transfusion-related Acute Lung Injury (TRALI)

    Noncardiogenic pulmonary edema may occur in patients following treatment with IGIV products, including GAMMAKED.(16) 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. (see Patient Counseling Information [17]) 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.

    5.8 Volume Overload

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

    5.9 Transmissible Infectious Agents

    Because GAMMAKED is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for GAMMAKED. ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Therapeutics Inc. [1-800-520-2807]

    5.10 Hematoma Formation

    Do not administer GAMMAKED subcutaneously in patients with ITP because of the risk of hematoma formation.

    5.11 Monitoring: Laboratory Tests

    • Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMMAKED and at appropriate intervals thereafter.
    • 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, because of the potentially increased risk of thrombosis.
    • If signs and/or symptoms of hemolysis are present after an infusion of GAMMAKED, 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.

    5.12 Interference with Laboratory Tests

    After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.

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  • 6 ADVERSE REACTIONS

    PI: Intravenous: The most common adverse reactions observed at a rate ≥5% in subjects with intravenous treatment in the clinical trials were headache, cough, injection site reaction, nausea, pharyngitis and urticaria.

    PI: Subcutaneous: The most common adverse reactions observed at a rate ≥5% of subjects with subcutaneous treatment in the clinical trials were infusion site reactions, headache, fatigue, arthralgia and pyrexia.

    ITP: The most common adverse reactions observed at a rate ≥5% in subjects in the clinical trials were headache, vomiting, fever, nausea, back pain and rash.

    CIDP: The most common adverse reactions observed at a rate ≥5% in subjects in the clinical trial were headache, fever, chills, hypertension, rash, nausea and asthenia.

    6.1 Clinical Trials Experience

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

    PI: Intravenous Administration

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

    In four different clinical trials to study PI, out of 157 subjects treated with GAMMAKED, 4 subjects discontinued due to the following adverse events: Coombs negative hypochromic anemia, autoimmune pure red cell aplasia, arthralgia/hyperhidrosis/fatigue/myalgia/nausea and migraine.

    In a study of 87 subjects, 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion, such as diphenhydramine and acetaminophen.

    Table 2 lists all adverse events occurring in greater than 10% of subjects irrespective of the causality assessment.

    Table 2:  Adverse Events Occurring in >10% of Subjects Irrespective of Causality
      GAMMAKED™ GAMIMUNE® N, 10%
    No. of subjects: 87 No. of subjects: 85
    No. of subjects with AE No. of subjects with AE
    Adverse Event (percentage of all subjects) (percentage of all subjects)
    Cough increased 47 (54%) 46 (54%)
    Rhinitis 44 (51%) 45 (53%)
    Pharyngitis 36 (41%) 39 (46%)
    Headache 22 (25%) 28 (33%)
    Fever 24 (28%) 27 (32%)
    Diarrhea 24 (28%) 27 (32%)
    Asthma 25 (29%) 17 (20%)
    Nausea 17 (20%) 22 (26%)
    Ear pain 16 (18%) 12 (14%)
    Asthenia 9 (10%) 13 (15%)

    Table 3 lists the adverse reactions reported by at least 5% of subjects during the 9-month treatment.

    Table 3:  Adverse Reactions Occurring in ≥5% of Subjects
    GAMMAKED™ GAMIMUNE® N, 10%
    No. of subjects: 87 No. of subjects: 85
    No. of subjects with adverse reaction No. of subjects with adverse reaction
    Adverse Reactions (percentage of all subjects) (percentage of all subjects)
    Headache 7 (8%) 8 (9%)
    Cough increased 6 (7%) 4 (5%)
    Injection site reaction 4 (5%) 7 (8%)
    Nausea 4 (5%) 4 (5%)
    Pharyngitis 4 (5%) 3 (4%)
    Urticaria 4 (5%) 1 (1%)

    Table 4 lists the frequency of adverse reactions, which were reported by at least 5% of subjects, and their relationship to infusions administered.

    Table 4: Adverse Experience Frequency
    GAMMAKED™ GAMIMUNE® N, 10%
    No. of infusions: 825 No. of infusions: 865
    Adverse Experience Number (percentage of all infusions) Number (percentage of all infusions)
    Cough increased  All 154 (18.7%) 148 (17.1%)
    Drug related 14 (1.7%) 11 (1.3%)
    Pharyngitis All 96 (11.6%) 99 (11.4%)
    Drug related 7 (0.8%) 9 (1.0%)
    Headache  All 57 (6.9%) 69 (8.0%)
    Drug related 7 (0.8%) 11 (1.3%)
    Fever All 41 (5.0%) 65 (7.5%)
    Drug related 1 (0.1%) 9 (1.0%)
    Nausea All 31 (3.8%) 43 (5.0%)
    Drug related 4 (0.5%) 4 (0.5%)
    Urticaria All 5 (0.6%) 8 (0.9%)
    Drug related 4 (0.5%) 5 (0.6%)

    The mean number of adverse reactions per infusion that occurred during or on the same day as an infusion was 0.21 in both the GAMMAKED and GAMIMUNE® N, 10% [Immune Globulin Intravenous (Human), 10%] 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 infusion rate was reduced for 11 of 222 exposed subjects (7 GAMMAKED, 4 GAMIMUNE N, 10%) 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 GAMMAKED or GAMIMUNE N, 10% in clinical trials.

    In the IV efficacy and safety study, 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.

    PI: Subcutaneous Administration (PK and Safety Study)

    Adverse experiences were divided into 2 types: 1) Local infusion site reactions, and 2) Non-infusion site adverse events. Table 5 lists those adverse events occurring in ≥ 2% of infusions during the SC phase of the study.

    Table 5: Most Frequent Adverse Experience (≥ 2% of infusions) by Infusion Irrespective of Causality in the SC Phase
    *
    Rate is calculated by the total number of events divided by the number of infusions received (725)
    Adverse Experience  
    (≥2% of infusions) Number
    (Number of infusions: 725) (Rate*)
    Local Infusion Site Reactions 427 (0.59)
          Mild 389 (0.54)
          Moderate   29 (0.04)
          Severe     9 (0.01)
    Non-infusion Site Adverse Events  
          Headache   37 (0.05)
          Sinusitis   11 (0.02)

    Table 6 lists the adverse reactions occurring in ≥5% of subjects and the frequency of adverse reactions per infusion.  All local infusion site reactions were a priori considered drug-related.

    Table 6: Most Frequent Adverse Reactions (≥5% of subjects) by Subject and Infusion in the SC phase
    *
    Rate is calculated by the total number of events divided by the number of infusions received (725)
    Adverse Reactions

    No. of Subjects

    No. of Adverse Reactions
    (≥5% of subjects) n=32 (% ) (Rate*)
    Local Infusion Site Reactions 24 (75%) 427 (0.59)
    Non-infusion Site Adverse Reactions    
          Headache 4 (13%) 21  (0.03)
          Arthralgia 2 (6.3%) 4   (0.01)
          Fatigue 2 (6.3%) 3  (≤0.01)
          Pyrexia 2 (6.3%) 2  (≤0.01)

    There were no serious bacterial infections in the SC phase of the PK and safety study.

    Local Infusion Site Reactions

    Local infusion site reactions with SC GAMMAKED consisted of erythema, pain and swelling. The majority of local infusion site reactions resolved within 3 days. The number of subjects experiencing an infusion site reaction and the number of infusion site reactions decreased over time as subjects received continued weekly SC infusions. At the beginning of the SC phase (week 1), a rate of approximately 1 infusion site reaction per infusion was reported, whereas at the end of the study (week 24) this rate was reduced to 0.5 infusion site reactions per infusion, a reduction of 50%.

    ITP

    In two different clinical trials to study ITP, out of 76 subjects treated with GAMMAKED, 2 subjects discontinued due to the following adverse events: Hives and Headache/Fever/Vomiting.

    One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMMAKED. The death was judged to be unrelated to GAMMAKED.

    No pre-medication with corticosteroids was permitted by the protocol. Twelve ITP 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.

    The infusion rate was reduced for 4 of the 97 exposed subjects (1 GAMMAKED, 3 GAMIMUNE N, 10%) on 4 occasions. Mild to moderate headache, nausea, and fever were the reported reasons.

    Table 7 lists any adverse events, irrespective of the causality, reported by at least 5% of subjects during the 3-month efficacy and safety study.

    Table 7: Adverse Events Occurring in ≥ 5% of Subjects Irrespective of Causality
      GAMMAKED™ GAMIMUNE® N, 10%
    No. of subjects: 48 No. of subjects: 49
      No. of subjects with AE No. of subjects with AE
     Adverse Event (percentage of all subjects) (percentage of all subjects)
    Headache 28 (58%) 30 (61%)
    Ecchymosis, Purpura 19 (40%) 25 (51%)
    Hemorrhage (All systems) 14 (29%) 16 (33%)
    Epistaxis 11 (23%) 12 (24%)
    Petechiae 10 (21%) 15 (31%)
    Fever 10 (21%) 7 (14%)
    Vomiting 10 (21%) 10 (20%)
    Nausea 10 (21%) 7 (14%)
    Thrombocytopenia 7 (15%) 8 (16%)
    Accidental injury 6 (13%) 8 (16%)
    Rhinitis 6 (13%) 6 (12%)
    Pharyngitis 5 (10%) 5 (10%)
    Rash 5 (10%) 6 (12%)
    Pruritis 4 (8%) 1 (2%)
    Asthenia 3 (6%) 5 (10%)
    Abdominal Pain 3 (6%) 4 (8%)
    Arthralgia 3 (6%) 6 (12%)
    Back Pain 3 (6%) 3 (6%)
    Dizziness 3 (6%) 3 (6%)
    Flu Syndrome 3 (6%) 3 (6%)
    Neck Pain 3 (6%) 1 (2%)
    Anemia 3 (6%) 0 (0%)
    Dyspepsia 3 (6%) 0 (0%)

    Table 8 lists the adverse reactions reported by at least 5% of subjects during the 3-month efficacy and safety study.

    Table 8: Adverse Reactions Occurring in ≥5% of Subjects
      GAMMAKED™ GAMIMUNE® N, 10%
    No. of subjects: 48 No. of subjects: 49
     Adverse Reaction Number (percentage of all subjects) Number (percentage of all subjects)
    Headache 24 (50%) 24 (49%)
    Vomiting  6 (13%)  8 (16%)
    Fever  5 (10%)  5 (10%)
    Nausea  5 (10%)    4 (8%)
    Back Pain   3 (6%)   2 (4%)
    Rash   3 (6%)   0 (0%)

    Serum samples were drawn to monitor the viral safety of the ITP subjects 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. 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 GAMMAKED or GAMIMUNE N, 10%.

    CIDP

    In the CIDP efficacy and safety study, 113 subjects were exposed to GAMMAKED and 95 were exposed to Placebo. (see Clinical Studies [14]) As a result of the study design, the drug exposure with GAMMAKED was almost twice that of Placebo, with 1096 GAMMAKED infusions versus 575 Placebo infusions. Therefore, adverse reactions are reported per infusion (represented as frequency) to correct for differences in drug exposure between the 2 groups. The majority of loading-doses were administered over 2 days. The majority of maintenance-doses were administered over 1 day. Infusions were administered in the mean over 2.7 hours.

    Table 9 shows the numbers of subjects per treatment group in the CIDP clinical trial, and the reason for discontinuation due to adverse events.

    Table 9: Reasons for Discontinuation Due to Adverse Events
    Number of Subjects Number of Subjects
     Discontinued
    due to Adverse Events
    Adverse Event
    GAMMAKED™ 113 3 (2.7%) Urticaria, Dyspnea,
    Bronchopneumonia
    Placebo 95 2 (2.1%) Cerebrovascular Accident,
    Deep Vein Thrombosis

    Table 10 shows adverse events reported by at least 5% of subjects in any treatment group irrespective of causality.

    Table 10: Adverse Events Irrespective of Causality Occurring in ≥ 5% of Subjects
    *
    Reported in ≥5% of subjects in any treatment group irrespective of causality.
    Calculated by the total number of adverse events divided by the number of infusions received (1096 for GAMMAKED and 575 for Placebo)
    GAMMAKED™
    No. of subjects: 113
    Placebo
    No. of subjects: 95
     MedDRA
    Preferred Term*

    No. of
    Subjects
    (%)

    No. of
    Adverse
    Events
    Incidence
     density

    No. of
    Subjects
    (%)

    No. of
    Adverse
    Events
    Incidence
    density
    Any Adverse Event 85 (75) 377 0.344 45 (47) 120 0.209
    Headache 36 (32) 57 0.052 8 (8) 15 0.026
    Pyrexia (fever) 15 (13) 27 0.025 0 0 0
    Hypertension 10 (9) 20 0.018 4 (4) 6 0.010
    Rash 8 (7) 13 0.012 1 (1) 1 0.002
    Arthralgia 8 (7) 11 0.010 1 (1) 1 0.002
    Asthenia 9 (8) 10 0.009 3 (3) 4 0.007
    Chills 9 (8) 10 0.009 0 0 0
    Back pain 9 (8) 10 0.009 3 (3) 3 0.005
    Nausea 7 (6) 9 0.008 3 (3) 3 0.005
    Dizziness 7 (6) 3 0.006 1 (1) 1 0.002
    Influenza 6 (5) 6 0.005 2 (2) 2 0.003

    The most common adverse reactions with GAMMAKED were headache and pyrexia. Table 11 lists adverse reactions reported by at least 5% of subjects in any treatment group.

    Table 11: Adverse Reactions Occurring in ≥ 5% of Subjects
    *
    Reported in ≥5% of subjects in any treatment group.
    Calculated by the total number of adverse reactions divided by the number of infusions received (1096 for GAMMAKED and 575 for Placebo).
    GAMMAKED™
    No. of subjects: 113
    Placebo
    No. of subjects: 95
     MedDRA
    Preferred Term*
    No. of
    Subjects
    (%)
    No. of
    Adverse
    Events
    Incidence
     density
    No. of
    Subjects
    (%)
    No. of
    Adverse
    Events
    Incidence
    density
    Any Adverse Reaction 62 (55) 194 0.177 16 (17) 25 0.043
    Headache 31 (27) 44 0.040 6  (6) 7 0.012
    Pyrexia (fever) 15 (13) 26 0.024 0       0 0
    Chills 8 (7) 9 0.008 0       0 0
    Hypertension 7 (6) 16 0.015 3 (3)  3 0.005
    Rash 6 (5) 8 0.007 1 (1)  1 0.002
    Nausea 6 (5) 7 0.006 3 (3)  3 0.005
    Asthenia 6 (5) 6 0.005 0       0 0

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

    Laboratory Abnormalities

    During the course of the clinical program, ALT and AST elevations were identified in some subjects.

    • For ALT, in the IV PI study treatment emergent elevations above the upper limit of normal were transient and observed among 14/80 (18%) of subjects in the GAMMAKED group versus 5/88 (6%) of subjects in the GAMIMUNE N, 10% group (p=0.026).
    • In the SC PI study treatment emergent laboratory abnormalities during the SC phase occurred in several subjects. Four subjects (4/32, 13%) had elevated Alkaline Phosphatase and one subject (1/32, 3%) had a low Alkaline Phosphatase. One subject (1/32, 3%) had an elevated ALT and three subjects (3/32, 9%) had an elevated AST. No elevations were >1.6 times the upper limit of normal.
    • 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 GAMMAKED group versus 8/43 (19%) of subjects in the GAMIMUNE N, 10% group (p=0.118).
    • In the CIDP study, 15/113 (13%) of subjects in the GAMMAKED group and 7/95 (7%) in the Placebo group (p=0.168) had a treatment emergent transient elevation of ALT.

    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.

    GAMMAKED may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4 class. Direct antiglobulin 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. Hemolytic events not associated with positive DAT findings were observed in clinical trials.

    6.2 Postmarketing Experience

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

    GAMMAKED Postmarketing Experience

    The following adverse reactions have been identified and reported during the post marketing use of GAMMAKED:

    Hematologic:  Hemolytic anemia
    Infections and Infestations: Aseptic meningitis

    The following adverse reactions have been identified and reported during the overall post marketing use of IGIV products:(17)

    • Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
    • Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
    • Neurological: Coma, loss of consciousness, seizures/convulsions, tremor
    • Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
    • Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs test)
    • General/Body as a Whole: Pyrexia, rigors
    • Musculoskeletal: Back pain
    • Gastrointestinal: Hepatic dysfunction, abdominal pain
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  • 7 DRUG INTERACTIONS

    GAMMAKED may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline. Admixtures of GAMMAKED with other drugs and intravenous solutions have not been evaluated. It is recommended that GAMMAKED be administered separately from other drugs or medications which the patient may be receiving. The product should not be mixed with IGIVs from other manufacturers.

    The infusion line may be flushed before and after administration of GAMMAKED with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection.

    Avoid simultaneous administration of GAMMAKED and Heparin through a single lumen delivery device due to GAMMAKED, Heparin incompatibilities. Flush Heparin Lock (Hep-Lock) through which GAMMAKED was administered with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection, and do not flush with Heparin.

    Various passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing.

    Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, rubella and varicella. Inform the immunizing physician of recent therapy with GAMMAKED so that appropriate measures may be taken. (see Patient Counseling Information [17])

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category C. Animal reproduction studies have not been conducted with GAMMAKED. It is not known whether GAMMAKED can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMMAKED should be given to a pregnant woman only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.(18, 19)

    8.3 Nursing Mothers

    Use of GAMMAKED has not been evaluated in nursing mothers.

    8.4 Pediatric Use

    PI: Intravenous

    GAMMAKED was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI subjects exposed to GAMMAKED were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that vomiting was more frequently reported in pediatrics (3 of 18 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels.

    PI: Subcutaneous

    SC GAMMAKED was evaluated in only three pediatric subjects (age range 13-15) with PI. This number of pediatric subjects was too small for separate evaluation of pharmacokinetics and safety to determine whether they respond differently from adults. (see Clinical Studies [14]) Efficacy and safety in pediatric patients using the SC route of administration have not been established.

    ITP

    For treatment of ITP, GAMMAKED must be administered by the intravenous route.

    GAMMAKED was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of the acute ITP subjects exposed to GAMMAKED were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that fever was more frequently reported in pediatrics (6 of 12 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels. One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMMAKED. The death was judged to be unrelated to GAMMAKED.

    CIDP

    The safety and effectiveness of GAMMAKED has not been established in pediatric subjects with CIDP.

    8.5 Geriatric Use

    Use caution when administering GAMMAKED to patients age 65 and over who are at increased risk for thrombosis or renal insufficiency. (see Boxed Warning, Warnings and Precautions [5.2, 5.4]) Do not exceed recommended doses, and administer GAMMAKED at the minimum infusion rate practicable. Clinical studies of GAMMAKED did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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  • 10 OVERDOSAGE

    With intravenous administration, overdose of GAMMAKED may lead to fluid overload and hyperviscosity. Patients at risk of complications of fluid overload and hyperviscosity include elderly patients and those with cardiac renal impairment.

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  • 11 DESCRIPTION

    GAMMAKED is a ready-to-use sterile solution of human immune globulin protein for intravenous and subcutaneous (PI indication only) administration. GAMMAKED 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. GAMMAKED 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. GAMMAKED doses of 1 g/kg correspond to a glycine dose of 0.15 g/kg. While toxic effects of glycine administration have been reported, the doses and rates of administration were 3–4 fold greater than those for GAMMAKED. In another study it was demonstrated that intravenous bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects.(20) Caprylate is a saturated medium-chain (C8) fatty acid of plant origin. 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.(21) Residual caprylate concentrations in the final container are no more than 0.216 g/L (1.3 mmol/L). 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 GAMMAKED is 4.0–4.5. GAMMAKED contains no preservative and is latex-free.

    GAMMAKED is made from large pools of human plasma by a combination of cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography. Isotonicity is achieved by the addition of glycine. GAMMAKED is incubated in the final container (at the low pH of 4.0–4.3). The product is intended for intravenous administration and may be administered subcutaneously in treatment of PI.

    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); Reovirus 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 non-enveloped virus, and porcine parvovirus (PPV) as a model for human parvovirus B19.

    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.

    Table 12: Log10 Virus Reduction
    *
    C/I - Interference by caprylate precluded determination of virus reduction for this step. Although removal of viruses is likely to occur at the caprylate precipitation/depth filtration step, BVDV is the only enveloped virus for which reduction is claimed. The presence of caprylate prevents detection of other, less resistant enveloped viruses and therefore their removal cannot be assessed.
    Not Applicable - This step has no effect on non-enveloped viruses.
    Some mechanistic overlap occurs between depth filtration and other steps. Therefore, Grifols Therapeutics Inc. has chosen to exclude this step from the global virus reduction calculations.
    §
    CAP - The presence of caprylate in the process at this step prevents detection of enveloped viruses, and their removal cannot be assessed.
    Process Step Log10 Virus Reduction
    Enveloped Viruses Non-enveloped Viruses
    HIV PRV BVDV Reo HAV PPV
    Caprylate Precipitation/Depth Filtration C/I* C/I 2.7 ≥3.5 ≥3.6 4.0
    Caprylate Incubation ≥4.5 ≥4.6 ≥4.5 NA NA NA
    Depth Filtration CAP§ CAP CAP ≥4.3 ≥2.0 3.3
    Column Chromatography ≥3.0 ≥ 3.3 4.0 ≥4.0 ≥1.4 4.2
    Low pH Incubation ≥6.5 ≥4.3 ≥5.1 NA NA NA
    Global Reduction ≥14.0 ≥12.2 ≥16.3 ≥7.5 ≥5.0 8.2

    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.(22-26)

    Several of the individual production steps in the GAMMAKED manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include two depth filtrations (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.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    PI

    GAMMAKED supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria, viral, parasitic, mycoplasma agents, and their toxins. The mechanism of action in PI has not been fully elucidated.

    ITP

    The mechanism of action of high doses of immunoglobulins in the treatment of ITP has not been fully elucidated.

    CIDP

    The precise mechanism of action in CIDP has not been fully elucidated.

    12.2 Pharmacodynamics

    Immunoglobulins are fractionated blood products made from pooled human plasma. Immunoglobulins are endogenous proteins produced by B lymphocyte cells. The main component of GAMMAKED is IgG (≥98%) with a sub-class distribution of IgG1, IgG2, IgG3 and IgG4 of approximately 62.8%, 29.7%, 4.8% and 2.7% respectively.

    12.3 Pharmacokinetics

    Intravenous Administration

    Two randomized pharmacokinetic crossover trials were carried out with GAMMAKED 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 GAMMAKED to GAMIMUNE N, 10% and the other trial compared the pharmacokinetics of GAMMAKED (10% strength) with a 5% concentration of this product. The ratio of the geometric least square means for dose-normalized IgG peak levels of GAMMAKED 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 GAMMAKED 10% to a 5% concentration of GAMMAKED.

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

    Table 13: PK Parameters of GAMMAKED™ and GAMIMUNE® N, 10%
    *
    Partial AUC: defined as pre-dose concentration to the last concentration common across both treatment periods in the same patient.
    Only 15 subjects were valid for the analysis of T 1/2.
      GAMMAKED™ GAMIMUNE® N, 10%
      N Mean SD Median N Mean SD Median
    Cmax
    (mg/mL)
    17 19.04 3.06 19.71 17 19.31 4.17 19.30
    Cmax-norm
    (kg/mL)
    17 0.047 0.007 0.046 17 0.047 0.008 0.047
    AUC(0-tn)* (mg*hr/mL) 17 6746.48 1348.13 6949.47 17 6854.17 1425.08 7119.86
    AUC(0-tn) norm*
    (kg*hr/mL)
    17 16.51 1.83 16.95 17 16.69 2.04 16.99
    T1/2
    (days)
    16 35.74 8.69 33.09 16 34.27 9.28 31.88

    The two pharmacokinetic trials with GAMMAKED 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. IgG trough levels were measured over nine months in the therapeutic equivalence trial. Mean trough levels were 7.8 ± 1.9 mg/mL for the GAMMAKED treatment group and 8.2 ± 2.0 mg/mL for the GAMIMUNE N, 10% control group.

    PI: Subcutaneous Administration

    In a single sequence, open-label, crossover trial, the pharmacokinetics, safety, and tolerability of SC administered GAMMAKED in subjects with PI were evaluated.  A total of 32 and 26 subjects received GAMMAKED as IV or SC for PK study, respectively.  Subjects received GAMMAKED 200-600 mg/kg IV every 3-4 weeks for at least 3 months, at which time they entered the IV phase of the study. Subjects were crossed over to weekly SC infusions. The weekly SC dose was determined by multiplying the total IV dose by 1.37 and dividing the resultant new total dose by 3 or 4 depending on the previous IV interval. The PK endpoint parameter (AUC of total plasma IgG) following IV and SC administration is summarized below in Table 14. The lower bound of the 90% confidence interval for the geometric mean ratio of AUC (SC vs. IV) was 0.861, therefore, meeting the pre-specified non-inferiority margin between the two modes of administration.

    Table 14: Summary of PK Endpoint of AUC
    *
    Adj. AUC 0-τ,SC:  Adjusted steady-state area under the concentration vs. time curve following SC administration based on IV dosing schedule, calculated as AUC 0-τ,SC multiplied by 3 or 4 for subjects on every-3-week or every-4-week IV dosing schedule, respectively.
    Route of
    Administration
    Statistics AUC0-τ,IV
    (mg*h/mL)
    AUC0-τ,SC
    (mg*h/mL)
    Adj.AUC0-τ,SC *
    (mg*h/mL)
    IV
    (n = 32)
    Mean 7640 NA NA
    %CV 15.9
    Range 5616-10400
    SC
    (n = 26)
    Mean NA 1947 6858
    %CV 20.4 18.1
    Range 1300-2758 5169-10364
    CV, coefficient of variation; NA, not applicable

    The mean trough concentration (mean Ctrough) of plasma total IgG following IV and SC administration are presented in Table 15.

    Table 15: Mean Plasma Trough Concentrations of Total IgG (mg/mL) in Plasma
      IV
    Mean Ctrough
    SC
    Mean Ctrough
    n 32 28
    Mean (mg/mL) 9.58 11.4
    %CV 22.3 20.4
    Range 6.66-14.0 8.10-16.2

    In contrast to plasma total IgG levels observed with monthly IV GAMMAKED treatment (rapid peaks followed by a slow decline), the plasma IgG levels in subjects receiving weekly SC GAMMAKED therapy were relatively stable (Figure 7).

    Figure 7
    Close
  • 14 CLINICAL STUDIES

    PI: Intravenous Administration

    In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies GAMMAKED 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 analysis for efficacy was based on the annual rate of bacterial infections, pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis.

    Table 16: Efficacy Results per Protocol Analysis
      GAMMAKED™
    (n=73)
    No. of subjects with
    at least one infection
    GAMIMUNE® N, 10%
    (n=73)
    No. of subjects with
    at least one infection
    Mean Difference
    (90% confidence interval)
    p-Value
    Validated Infections 9 (12%) 17 (23%) -0.117
    (-0.220, -0.015)
    0.06
    Acute Sinusitis 4 (5%) 10 (14%)    
    Exacerbation of
    Chronic Sinusitis
    5 (7%) 6 (8%)    
    Pneumonia 0 (0%) 2 (3%)    
    Any Infection  56 (77%)  57 (78%)  -0.020  0.78
    (Validated plus
    Clinically defined
    non-validated
    Infections)
          (-0.135, 0.096)  

    The annual rate of validated infections (Number of Infections/year/subject) was 0.18 in the group treated with GAMMAKED 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).

    ITP

    A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to prove the hypothesis that GAMMAKED was at least as effective as GAMIMUNE N, 10% in raising platelet counts from less than or equal to 20 x109/L to more than 50 x109/L within 7 days after treatment with 2 g/kg IGIV. Twenty-four percent of the subjects were less than or equal to 16 years of age.

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

      Table 17: Platelet Response of Per Protocol Analysis
    GAMMAKED™
    (n=39)
    GAMIMUNE® N, 10%
    (n=42)
    Mean Difference
    (90% confidence interval)
    By Day 7 35 (90%) 35 (83%) 0.075
      (-0.037, 0.186)
    By Day 23 35 (90%) 36 (86%) 0.051
      (-0.058, 0.160)
    Sustained for 7 days 29 (74%) 25 (60%) 0.164
      (0.003, 0.330)

    A trial was conducted to evaluate the clinical response to rapid infusion of GAMMAKED in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMMAKED 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).

    CIDP

    A multi-center, randomized, double-blind, Placebo-controlled trial (The Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMMAKED.(27)  This study included two separately randomized periods to assess whether GAMMAKED 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 GAMMAKED 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 GAMMAKED 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 body weight of GAMMAKED 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 GAMMAKED 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).(28) 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.

    More subjects with CIDP responded to GAMMAKED: 28 of 59 subjects (47.5%) responded to GAMMAKED 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 naïve 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 GAMMAKED was evaluated: 31 were randomly reassigned to continue to receive GAMMAKED and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive GAMMAKED experienced a longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with GAMMAKED versus 45% with Placebo (hazard ratio, 0.19; 95% confidence interval, 0.05, 0.70).

    Table 18: Outcomes in Intent-to-Treat Population Efficacy Period
    *
    p-value based on Fisher's exact method
    Efficacy Period GAMMAKED™ Placebo p-value*
    Responder Non-Responder Responder Non-Responder
    All Subjects 28/59 (47.5%) 31/59 (52.5%) 13/58 (22.4%) 45/58 (77.6%) 0.006
    IGIV -
    Naïve Subjects

    17/39 (43.6%)

    22/39 (56.4%)

    13/46 (28.3%)

    33/46 (71.7%)

    0.174
    IGIV -
    Experienced Subjects

    11/20 (55.0%)

    9/20 (45.0%)

    0/12 (0%)

    12/12 (100%)

    0.002

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

    Table 19: Outcomes in Rescue Phase
    *
    p-value based on Fisher's exact method
    GAMMAKED™ Placebo p-value*
    Rescue Phase Success Failure Success Failure
    All Subjects 25/45
    (55.6%)
    20/45 
    (44.4%)
    6/23
    (26.1%)
    17/23
    (73.9%)
    0.038
    IGIV - Naïve Subjects 19/33
    (57.6%)
    14/33
    (42.4%)
    6/18
    (33.3%)
    12/18
    (66.7%)
    0.144
    IGIV - Experienced Subjects 6/12
    (50%)
    6/12
    (50%)
    0/5
     (0%)
    5/5
    (100%)
    0.102

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

    Figure 8
    Close
  • 15 REFERENCES

    1. Cayco AV, Perazella MA, Hayslett JP. 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.
    2. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med, 1991. 325(2): p. 110-7.
    3. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol, 1999. 92(1): p. 34-48.
    4. 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.
    5. Stephan JL, 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.
    6. Blanchette VS, Kirby MA, Turner C. Role of intravenous immunoglobulin G in autoimmune hematologic disorders. Semin Hematol, 1992. 29(3 Suppl 2): p. 72-82.
    7. Lazarus AH, Freedman J, Semple JW. Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP): mechanisms of action. Transfus Sci, 1998. 19(3): p. 289-94.
    8. Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol 73:97-100 (2003).
    9. Dalakas MC. High-dose intravenous Immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994, 44:223-226.
    10. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-218.
    11. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65,30-34.
    12. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26: 410-412.
    13. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993;15:3789.
    14. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle & Nerve 1997; 20:1142-1145.
    15. Kessary-Shoham H. Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmune 1999; 13:129-135.
    16. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001:41:264-268.
    17. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003; 17,241-251.
    18. Hammarstrom L, Smith CI. Placental transfer of intravenous immunoglobulin. Lancet 1986: 1:681.
    19. Sidiropoulos D, Herrmann U, Morell A, von Muralt G, Barandun S. Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr 1986; 109:505-508.
    20. Tai VM, Mitchell EJ, Lee-Brotherton V, Manley JJ, Nestmann ER, Daniels JM. Safety evaluation of intravenous glycine in formulation development. J Pharm Pharmaceut Sci. 2000;3:198.
    21. Traul KA, et al. Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol, 2000. 38(1): p. 79-98.
    22. 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.
    23. 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.
    24. 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.
    25. Cai K, Miller JL, Stenland CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35.
    26. 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.
    27. Hughes RAC, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate/chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized Placebo-controlled trial. Lancet Neurol 2008. 7:136-144.
    28. Hughes R, Bensa S, Willison H, Van den BP, Comi G, Illa I, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001 Aug;50(2):195-201.
    29. Kahwaji J, Barker E, Pepkowitz S, et al. Acute hemolysis after high-dose intravenous immunoglobulin therapy in highly HLA sensitized patients. Clin J Am Soc Nephrol 2009;4:1993-1997.
    30. Daw Z, Padmore R, Neurath D, et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: A case series analysis. Transfusion 2008;48:1598-1601.
    Close
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    GAMMAKED is supplied in single-use, tamper evident vials (shrink band) containing the labeled amount of functionally active IgG. The three larger vial size labels incorporate integrated hangers. The components used in the packaging for GAMMAKED are latex-free.

    GAMMAKED is supplied in the following sizes:

    NDC Number  Size Grams Protein
    76125-900-01   10 mL     1
    76125-900-25   25 mL   2.5
    76125-900-50   50 mL      5
    76125-900-10 100 mL    10
    76125-900-20 200 mL    20
    • DO NOT FREEZE
    • GAMMAKED may be stored for 36 months at 2-8°C (36-46°F) from the date of manufacture, 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 use after expiration date.
    Close
  • 17 PATIENT COUNSELING INFORMATION

    (see Boxed Warning and Warnings and Precautions Sections)

    Instruct patients to immediately report the following signs and symptoms to their healthcare provider:

    • Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (see Warnings and Precautions [5.2])
    • Symptoms of thrombosis which may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body. (see Warnings and Precautions [5.4])
    • Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting (see Warnings and Precautions [5.5])
    • Increased heart rate, fatigue, yellowing of the skin or eyes, and dark-colored urine (see Warnings and Precautions [5.6])
    • Trouble breathing, chest pain, blue lips or extremities, and fever (see Warnings and Precautions [5.7])

    Inform patients that GAMMAKED is made from human plasma and may contain infectious agents that can cause disease. While the risk GAMMAKED can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and by inactivating or removing certain viruses during manufacturing, patients should report any symptoms that concern them. (see Warnings and Precautions [5.9])

    Inform patients that GAMMAKED can interfere with their immune response to live viral vaccines such as measles, mumps and rubella. Inform patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations. (see Drug Interactions [7])

    PI: Self-Administration: Subcutaneous Administration Only

    Provide the patient with instructions on subcutaneous infusion for home treatment, if the physician believes that home administration is appropriate for the patient.

    • The type of equipment to be used along with its maintenance,
    • proper infusion techniques, selection of appropriate infusion sites (e.g., abdomen, thighs, upper arms, and/or lateral hip),
    • maintenance of a treatment diary,
    • measures to be taken in case of adverse reactions in the patient instructions.

    Manufactured by:
    Grifols Therapeutics Inc.
    Research Triangle Park, NC 27709 USA
    U.S. License No. 1871

    Distributed by:
    Kedrion Biopharma, Inc.
    400 Kelby Street
    Fort Lee, NJ 07024

    (3036429/3036430)
    Revised 9/2013

    GAMMAKED

    Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified

    Subcutaneous Infusion for Primary Humoral Immunodeficiency

    Information for Patients

    Please read this information about GAMMAKED carefully before using this medicine. This information does not take the place of talking with your healthcare professional, and it does not include all of the important information about GAMMAKED. If you have any questions after reading this, contact your healthcare professional.

    What is the most important information I should know about GAMMAKED?

    GAMMAKED should be infused under your skin (in the subcutaneous tissue). DO NOT inject GAMMAKED into a blood vessel or directly into a muscle.

    What is GAMMAKED?

    GAMMAKED (găm´-ə-kĕd) is an immunoglobulin used to treat primary immune deficiency (PI). Immunoglobulin is another name for the purified antibodies from human plasma that defend the body against infections such as viruses and bacteria. People with PI lack the healthy antibodies needed to fight off these infections. GAMMAKED provides those healthy antibodies and will help lower the number and severity of infections you could get.

    Who should NOT take GAMMAKED?

    Do not take GAMMAKED if you have known severe allergic reactions or a severe response to Immune Globulin (Human). Tell your doctor if you have had a serious reaction to other medicines that contain immune globulin. Also tell your doctor if you have an immunoglobulin A (IgA) deficiency.

    How should I take GAMMAKED?

    You will take GAMMAKED through infusions given just below the skin (in the subcutaneous tissue). As directed by your physician, one or more injection sites on your body will be selected. The number and location of the injection sites depends on the amount you need to receive. Typically, people use 1 to 4 needles in different locations on your body at one time. You may use up to 8 needles as directed by your doctor. The needles are attached with a tube to the pump. You will need to have infusions once a week.

    Instructions for administering GAMMAKED are at the end of this patient package insert (see "Steps for Administration"). Only use GAMMAKED by yourself after you have been instructed by your doctor or healthcare professional.

    What should I avoid while taking GAMMAKED?

    Certain types of vaccines (ones containing a live virus) may not work as well for you if you are also receiving immunoglobulin products like GAMMAKED. The antibodies in GAMMAKED may prevent the vaccine from working. Before you get a vaccine, tell the doctor or nurse that you are taking GAMMAKED.

    Tell your doctor or healthcare professional if you are pregnant or plan to become pregnant, or if you are nursing.

    What are possible side effects of GAMMAKED?

    The most common side effects with GAMMAKED when given under the skin (subcutaneously) are:

    • Redness, swelling, and itching at the injection site
    • Headache
    • Fatigue
    • Pain (including pain in the back, joints, arms, legs)
    • Fever

    Tell your doctor right away or go to the emergency room if you have hives, trouble breathing, wheezing, dizziness, or fainting. These could be signs of a bad allergic reaction.

    Tell your doctor right away if you have any of the following symptoms. They could be signs of a rare, but serious problem.

    • Decreased urination, sudden weight gain, fluid retention/swelling in your legs, and/or shortness of breath. They could be signs of a serious kidney problem called renal failure.
    • Pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body. These could be signs of a blood clot in your body (thrombosis). Immediately report symptoms of thrombosis.
    • Severe headache, stiff neck, fatigue, fever, sensitivity to light, painful eye movements, nausea and vomiting. These could be signs of a type of brain inflammation called aseptic meningitis.
    • Increased heart rate, fatigue, yellow skin or eyes, and dark colored urine. These could be signs of a type of blood problem called hemolytic anemia.
    • Chest pains, trouble breathing, blue lips or extremities, and fever. These could be signs of a lung problem called TRALI (transfusion-related acute lung injury).
    • Fever over 100° F. This could be a sign of an infection.

    Tell your doctor about any side effects that concern you. You can ask your doctor to give you the full prescribing information available to healthcare professionals.

    Steps for Administration
    Infuse GAMMAKED only after you have been trained by your doctor or healthcare professional. Below are step-by-step instructions to help you remember how to use GAMMAKED. Ask your doctor or healthcare professional about any instructions you do not understand.

    Before Using GAMMAKED

    • GAMMAKED comes in single-use vials. Do not let it freeze. Keep it refrigerated. If needed, GAMMAKED can be stored at room temperature for up to 6 months but you must use it within that time or you must throw it away.
    • Do not shake the vials.
    • Prior to use, allow the solution to come to room temperature (68-77°F or 20-25°C). This can take 60 minutes or longer.
    • Do not use the vial if:
      • the solution is cloudy, discolored or contains particles. The solution should be clear and colorless to pale yellow.
      • the protective cap or plastic shrink band around the cap is missing.
      • the expiration date has passed.
    • Sanitize your infusion set-up area by preparing a clean, flat, non-porous surface such as a kitchen counter. Avoid using porous surfaces such as wood. Clean the surface with an alcohol wipe using a circular motion from the center outward.

    Step 1:
     Wash and dry your hands thoroughly before administering GAMMAKED

    • Your healthcare provider may recommend that you use antibacterial soap or that you wear gloves.

     Step 1

    Step 2:
    Remove the protective cap and sanitize the rubber stopper

    • Remove the protective cap from the vial to expose the central portion of the rubber stopper.
    • Wipe the rubber stopper with alcohol and allow to dry.

     Step 2      

    Step 3:
    Use aseptic technique when preparing and administering GAMMAKED

    • Do not allow your fingers or other objects to touch the inner stem of the plunger, the syringe tip, or other areas that will come in contact with your GAMMAKED solution. This is called aseptic technique and is designed to prevent transmission of germs.
    • Using aseptic technique, attach each needle to the syringe tip.

     Step 3

    Step 4:
    Prepare the syringe and draw GAMMAKED solution into syringe

    • Remove cap from needle.
    • Pull the syringe plunger back to the level matching the amount of GAMMAKED to be withdrawn from the vial.
    • Place the GAMMAKED bottle on a clean flat surface and insert the needle into the center of the vial stopper.
    • Inject air into the vial. The amount of air should match the amount of GAMMAKED to be withdrawn.
    • Turn the vial upside down and withdraw the correct amount of GAMMAKED. If multiple vials are required to achieve the correct dose, repeat Step 4.

    Step 4

     

    Step 5:
    Fill the pump reservoir and prepare the infusion pump

    • Follow the pump manufacturer’s instructions for filling the pump reservoir and preparing the infusion pump, administration tubing and Y-site connection tubing, if needed.
    • Be sure to prime the administration tubing to ensure that no air is left in the tubing or needle by filling the tubing/needle with GAMMAKED. To prime, hold the syringe in one hand and the administration tubing’s capped needle in the other. Gently squeeze on the plunger until you see a drop of GAMMAKED exit from the needle.

    Example Equipment

    Step 5

    Step 6:
    Select the number and location of infusion sites

    • Select one or more infusion sites as directed by your healthcare provider.
    • The number and location of injection sites depends on the volume of the total dose.

     Step 6

    Step 7:
    Prepare the infusion site

    • Cleanse the infusion site(s) with antiseptic solution using a circular motion working from the center of the site and moving to the outside.
    • Sites should be clean, dry, and at least 2 inches apart.

     Step 7   

    Step 8:
    Insert the needle

    • Grasp the skin between two fingers and insert the needle into the subcutaneous tissue.

     Step 8

    Step 9:
    Do not inject GAMMAKED into a blood vessel

    • After inserting each needle into tissue (and before your infusion), make sure that a blood vessel has not been accidentally entered. To do this, attach a sterile syringe to the end of the primed administration tubing. Pull back on the syringe plunger and watch for any blood flowing back into administration tubing.
    • If you see any blood, remove and discard the needle and administration tubing.

     Step 9a

    • Repeat priming and needle insertion steps using a new needle, administration tubing and a new infusion site.
    • Secure the needle in place by applying sterile gauze or transparent dressing over the site.

     Step 9b

    Step 10:
    Repeat for other sites, as needed

    • If using multiple, simultaneous infusion sites, use Y-site connection tubing and secure to the administration tubing.

    Step 11:
    Infuse GAMMAKED following the pump manufacturer’s instructions for the infusion pump

     Step 11

    Step 12:
    After infusion, turn off pump and dispose of used supplies

    • Follow manufacturer’s instructions to turn off pump.
    • Undo and discard any dressing or tape.
    • Gently remove the inserted needle(s) or catheter(s).
    • Discard any unused solution in an appropriate waste container as instructed.
    • Discard any used administration equipment in an appropriate waste container.
    • Store your supplies in a safe place.
    • Follow manufacturer's instructions to care for the infusion pump.

    Step 13:
    Record each infusion

    • Remove the peel-off label with the product lot number from the GAMMAKED vial and use this to complete the patient record.
    • Remember to bring your journal with you when you visit your physician or healthcare provider.

    Be sure to tell your doctor about any problems you have doing your infusions. Your doctor may ask to see your journal, so be sure to take it with you each time you visit the doctor’s office.

    Call your doctor for medical advice about side effects. You can also report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    Manufactured by:
    Grifols Therapeutics Inc.
    Research Triangle Park, NC 27709 USA
    U.S. License No. 1871

    Distributed by:
    Kedrion Biopharma, Inc.
    400 Kelby Street
    Fort Lee, NJ 07024

    Revised 9/2013

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  • PACKAGE LABEL

    Immune Globulin
    Injection
    (Human), 10%

    gammaked™
    caprylate/chromatography purified

    Solution for Infusion 

    10 Grams Protein in 100 ml

    NDC
    76125-900-10

    The patient and physician should discuss the risks and benefits of this product.

    FOR INTRAVENOUS OR SUBCUTANEOUS ADMINISTRATION.

    Refer to package insert for dosage and administration and compatibility with other solutions.

    Single Dose Vial

    Do not use if turbid.

    Discard unused portion. Do not store after entry into bottle.
                        
    Contains no preservative

    Do not freeze.

    Each milliliter (mL) contains approximately 100 mg of protein, not less than 98% of which is immunoglobulin, and approximately 15 mg glycine.

    If the shrink band is absent or shows any sign of tampering, do not use the product and notify Grifols Therapeutics Inc. immediately.

    Not Returnable for Credit or Exchange

    Rx only

    Manufactured by:

    Grifols Therapeutics Inc.
    Research Triangle Park, NC 27709 USA
    U.S. License No. 1871
                        
    Distributed by:
    Kedrion Biopharma, Inc.
    400 Kelby Street
    Fort Lee, NJ 07024

    Contents:
    One bottle of Gammaked

    No preservative

    Sterile, Non-pyrogenic

    Gammaked 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.

    Date removed
    from refrigeration:

    Carton: 08941186

    Carton

    NDC 76125-900-11

    Immune Globulin Injection (Human), 10%

    gammaked™ caprylate/chromatography purified

    Solution for Infusion

    10 Grams Protein in 100 ml

    Manufactured by:
    Grifols Therapeutics Inc.
    Research Triangle Park, NC 27709 USA
    U.S. License No. 1871

    Distributed by: Kedrion Biopharma, Inc.
    400 Kelby Street, Fort Lee, NJ 07024

    The patient and physician should discuss the risks and benefits of this product.

    FOR INTRAVENOUS OR SUBCUTANEOUS ADMINISTRATION.

    Refer to package insert for dosage and administration and compatibility with other solutions.

    Gammaked 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.

    Single Dose Vial

    Do not use if turbid. 

    Rx only
                         
    Gammaked

    Lot
    08941161

    Lot
    Exp.

    Vial
    Close
  • INGREDIENTS AND APPEARANCE
    GAMMAKED  
    human immunoglobulin g injection
    Product Information
    Product Type PLASMA DERIVATIVE Item Code (Source) NDC:76125-900
    Route of Administration INTRAVENOUS DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Human Immunoglobulin G (Human Immunoglobulin G) Human Immunoglobulin G 10 g  in 100 mL
    Inactive Ingredients
    Ingredient Name Strength
    Glycine  
    Product Characteristics
    Color WHITE (Clear liquid, colorless to pale yellow) Score     
    Shape Size
    Flavor Imprint Code
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:76125-900-01 1 in 1 CARTON
    1 NDC:76125-900-02 10 mL in 1 VIAL, GLASS; Combination Product Type = C112160
    2 NDC:76125-900-25 1 in 1 CARTON
    2 NDC:76125-900-26 25 mL in 1 VIAL, GLASS; Combination Product Type = C112160
    3 NDC:76125-900-50 1 in 1 CARTON
    3 NDC:76125-900-51 50 mL in 1 VIAL, GLASS; Combination Product Type = C112160
    4 NDC:76125-900-10 1 in 1 CARTON
    4 NDC:76125-900-11 100 mL in 1 VIAL, GLASS; Combination Product Type = C112160
    5 NDC:76125-900-20 1 in 1 CARTON
    5 NDC:76125-900-21 200 mL in 1 VIAL, GLASS; Combination Product Type = C112160
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA125046 10/13/2010
    Labeler - KEDRION BIOPHARMA, INC (967820825)
    Establishment
    Name Address ID/FEI Business Operations
    Grifols Therapeutics Inc. 611019113 MANUFACTURE(76125-900)
    Close