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human immunoglobulin g injection
FULL PRESCRIBING INFORMATION
WARNING: RENAL DYSFUNCTION AND ACUTE RENAL FAILURE
1 INDICATIONS AND USAGE
GAMUNEX-C is an immune globulin injection (human) 10% liquid that is indicated for the treatment of:
1.1 Primary Humoral Immunodeficiency (PI)
GAMUNEX-C 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)
GAMUNEX-C 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].
2 DOSAGE AND ADMINISTRATION
GAMUNEX-C consists of 9%–11% protein in 0.16–0.24 M glycine. The buffering capacity of GAMUNEX-C 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 GAMUNEX-C would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.
2.1 Preparation and Handling
2.2 Treatment of Primary Humoral Immunodeficiency
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.
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 thrombotic events, administer GAMUNEX-C at the minimum infusion rate practicable. (see Warnings and Precautions [5.2,5.5])
If a patient routinely receives a dose of less than 400 mg/kg of GAMUNEX-C 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.
Establish the initial weekly dose of GAMUNEX-C 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 GAMUNEX-C, convert the weekly 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
Initial SC dose = 1.37 × previous IGIV dose (in grams)
To convert the GAMUNEX-C dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 10.
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.
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 GAMUNEX-C from another Immune Globulin Subcutaneous (IGSC) product have not been studied. If a patient on GAMUNEX-C 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 Treatment of Idiopathic Thrombocytopenic Purpura
DO NOT ADMINISTER SUBCUTANEOUSLY (see Warnings and Precautions [5.3])
GAMUNEX-C may be administered at a total dose of 2 g/kg, divided in two doses of 1 g/kg (10 mL/kg) given on two consecutive days or into five doses of 0.4 g/kg (4 mL/kg) given on five consecutive days. If after administration of the first of two daily 1 g/kg (10 mL/kg) doses, an adequate increase in the platelet count is observed at 24 hours, the second dose of 1g/kg (10 mL/kg) body weight may be withheld.
Forty-eight ITP subjects were treated with 2 g/kg GAMUNEX-C, 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 thrombotic events, GAMUNEX-C should be administered at the minimum infusion rate practicable (see Warnings and Precautions [5.2,5.5]).
2.4 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
GAMUNEX-C may be initially administered as a total loading dose of 2 g/kg (20 mL/kg) given in divided doses over two to four consecutive days. GAMUNEX-C 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 thrombotic events, GAMUNEX-C should be administered at the minimum infusion rate practicable. (see Warnings and Precautions [5.2,5.5])
Administer intravenously for treatment of PI, ITP and CIDP.
GAMUNEX-C may also be administered subcutaneously for the treatment of PI.
GAMUNEX-C should be at room temperature during administration.
GAMUNEX-C should be inspected 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.
Only 18 gauge needles should be used to penetrate the stopper for dispensing product from the 10 mL vial; 16 gauge needles or dispensing pins should only be used with 25 mL vial sizes and larger. Needles or dispensing pins should only be inserted once and be within the stopper area delineated by the raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the ring.
Any vial that has been opened should be used promptly. Partially used vials should be discarded.
If dilution is required, GAMUNEX-C may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline.
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.
Rate of Administration
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.
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 thromboembolic events, administer GAMUNEX-C at the minimum infusion rate practicable and discontinue GAMUNEX-C if renal function deteriorates.
Subcutaneous for PI only
For PI, it is recommended that GAMUNEX-C 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.
Incompatibilities with Saline
GAMUNEX-C is not compatible with saline. If dilution is required GAMUNEX-C may be diluted with 5% dextrose in water (D5/W). No other drug interactions or compatibilities have been evaluated.
3 DOSAGE FORMS AND STRENGTHS
GAMUNEX-C is supplied in 1 g, 2.5 g, 5 g, 10 g, or 20 g single use bottles.
4.1 Hypersensitivity reaction to immune globulins
GAMUNEX-C is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.
5 WARNINGS AND PRECAUTIONS
Severe hypersensitivity reactions may occur with IGIV products, including GAMUNEX-C. In case of hypersensitivity, discontinue GAMUNEX-C infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reaction.
GAMUNEX-C 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 )
5.2 Renal Failure
Assure that patients are not volume depleted prior to the initiation of the infusion of GAMUNEX-C. 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 GAMUNEX-C and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of GAMUNEX-C. (see Patient Counseling Information ) 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 GAMUNEX-C 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 Hematoma Formation
Do not administer GAMUNEX-C subcutaneously in patients with ITP because of the risk of hematoma formation.
5.4 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia
Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV treatment, including GAMUNEX-C. 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 thromboembolic events. 
5.5 Thrombotic Events
Thrombotic events have been reported following IGIV treatment and may occur in patients receiving IGIV treatment, including GAMUNEX-C. [9-11] Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization and/or known or suspected hyperviscosity. 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 judged to be at risk of developing thrombotic events, administer GAMUNEX-C at the minimum rate of infusion practicable. (see Dosage and Administration [2.5])
5.6 Aseptic Meningitis Syndrome (AMS)
AMS may occur infrequently with IGIV treatment, including GAMUNEX-C. 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.
IGIV products, including GAMUNEX-C, 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. Monitor patients for clinical signs and symptoms of hemolysis.  (see Patient Counseling Information ) If signs and/or symptoms of hemolysis are present after GAMUNEX-C infusion, perform appropriate confirmatory laboratory testing.
5.8 Transfusion-related Acute Lung Injury (TRALI)
Noncardiogenic pulmonary edema may occur in patients following treatment with IGIV products, including GAMUNEX-C.  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 ) 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.
5.9 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.
5.10 Transmissible Infectious Agents
Because GAMUNEX-C 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 GAMUNEX-C. 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 Talecris Biotherapeutics, Inc. [1-800-520-2807]
5.11 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. Patients with known renal dysfunction or renal failure, including patients with pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or those receiving nephrotoxic agents, should be clinically assessed and monitored (BUN, creatinine), as appropriate, during therapy with GAMUNEX-C.
Consider baseline assessment of blood viscosity in patients at risk for hypervisocosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.
6 ADVERSE REACTIONS
The most common adverse reactions observed at a rate ≥5% in subjects treated with IV GAMUNEX-C for PI were headache, cough, injection site reaction, nausea, pharyngitis and urticaria.
The most common adverse reactions observed at a rate ≥5% of subjects treated with SC GAMUNEX-C for PI were infusion site reactions, headache, fatigue, arthralgia and pyrexia.
The most common adverse reactions observed at a rate ≥5% in subjects treated with GAMUNEX-C for ITP were headache, vomiting, fever, nausea, back pain and rash.
The most common adverse reactions observed at a rate ≥5% in subjects with GAMUNEX-C for CIDP 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.
Treatment of Primary Humoral Immunodeficiency by the Intravenous Route
The most serious adverse event observed in clinical study subjects receiving GAMUNEX-C 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 GAMUNEX-C, 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 3 lists the adverse reactions reported by at least 5% of subjects during the 9-month treatment.
Table 4 lists the frequency of adverse reactions, which were reported by at least 5% of subjects, and their relationship to infusions administered.
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 GAMUNEX-C and GAMIMUNE®N, Immune Globulin Intravenous (Human), 10%, treatment groups.
In all three trials in primary humoral immundeficiencies, 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 GAMUNEX-C, 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 GAMUNEX-C 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.
Treatment of Primary Humoral Immunodeficiency by the Subcutaneous Route (SC 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 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.
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 GAMUNEX-C 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%.
Treatment of Idiopathic Thrombocytopenic Purpura
In two different clinical trials to study ITP, out of 76 subjects treated with GAMUNEX-C, 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 GAMUNEX-C. The death was judged to be unrelated to GAMUNEX-C.
No pre-medication with corticosteroids was permitted by the protocol. Twelve (12) 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 GAMUNEX-C, 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 8 lists the adverse reactions reported by at least 5% of subjects during the 3-month efficacy and safety study.
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 GAMUNEX®-C, Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified or GAMIMUNE® N, Immune Globulin Intravenous (Human), 10%.
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
In the CIDP efficacy and safety study, 113 subjects were exposed to GAMUNEX-C and 95 were exposed to Placebo. (see Clinical Studies [14.3]) As a result of the study design, the drug exposure with GAMUNEX-C was almost twice that of Placebo, with 1096 GAMUNEX-C 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 10 shows adverse events reported by at least 5% of subjects in any treatment group irrespective of causality.
The most common adverse reactions with GAMUNEX-C were headache and pyrexia. Table 11 lists adverse reactions reported by at least 5% of subjects in any treatment group.
The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX-C for CIDP was pulmonary embolism (PE) in one subject with a history of PE.
During the course of the clinical program, ALT and AST elevations were identified in some subjects.
Elevations of ALT and AST were generally mild (<3 times upper limit of normal), transient, and were not associated with obvious symptoms of liver dysfunction.
GAMUNEX-C 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.
GAMUNEX-C Postmarketing Experience
The following adverse reactions have been identified and reported during the post marketing use of GAMUNEX-C:
The following adverse reactions have been identified and reported during the overall post marketing use of IGIV products :
7 DRUG INTERACTIONS
GAMUNEX-C may be diluted with 5% dextrose in water (D5/W). Admixtures of GAMUNEX-C with other drugs and intravenous solutions have not been evaluated. It is recommended that GAMUNEX-C 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 GAMUNEX-C with D5/W.
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 GAMUNEX-C so that appropriate measures may be taken. (see Patient Counseling Information )
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C. Animal reproduction studies have not been conducted with GAMUNEX-C. It is not known whether GAMUNEX-C can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMUNEX-C 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]
8.4 Pediatric Use
Treatment of Primary Humoral Immunodeficiency
GAMUNEX-C was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI subjects exposed to GAMUNEX-C 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.
SC GAMUNEX-C 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 ) Efficacy and safety in pediatric patients using the SC route of administration have not been established.
Treatment of Idiopathic Thrombocytopenic Purpura
For treatment of ITP, GAMUNEX-C must be administered by the intravenous route.
GAMUNEX-C was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of the acute ITP subjects exposed to GAMUNEX-C 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 GAMUNEX-C. The death was judged to be unrelated to GAMUNEX-C.
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
The safety and effectiveness of GAMUNEX-C has not been established in pediatric subjects with CIDP.
8.5 Geriatric Use
Use caution when administering GAMUNEX-C to patients age 65 and over who are judged to be at increased risk for developing thromboembolic events or renal insufficiency. (see Boxed Warning, Warnings and Precautions [5.2]) Do not exceed recommended doses, and administer GAMUNEX-C at the minimum infusion rate practicable. Clinical studies of GAMUNEX-C did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
GAMUNEX-C is a ready-to-use sterile solution of human immune globulin protein for intravenous and subcutaneous (PI indication only) administration. GAMUNEX-C consists of 9%–11% protein in 0.16–0.24 M glycine. Not less than 98% of the protein has the electrophoretic mobility of gamma globulin. GAMUNEX-C 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. GAMUNEX-C 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 GAMUNEX-C. In another study it was demonstrated that intravenous bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects.  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.  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 GAMUNEX-C is 4.0 – 4.5. GAMUNEX-C contains no preservative and is latex-free.
GAMUNEX-C 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. GAMUNEX-C 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); Reo virus type 3 (Reo) as a model for non-enveloped viruses and for its resistance to physical and chemical inactivation; hepatitis A virus (HAV) as relevant 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.
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 GAMUNEX-C 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Treatment of Primary Humoral Immunodeficiency
GAMUNEX-C 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.
Treatment of Idiopathic Thrombocytopenic Purpura
The mechanism of action of high doses of immunoglobulins in the treatment of ITP has not been fully elucidated.
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
The precise mechanism of action in CIDP has not been fully elucidated.
Immunoglobulins are fractionated blood products made from pooled human plasma. Immunoglobulins are endogenous proteins produced by B lymphocyte cells. The main component of GAMUNEX-C 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.
Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX-C in 38 subjects with Primary Humoral Immunodeficiencies given 3 infusions 3 or 4 weeks apart of test product at a dose of 100-600 mg/kg body weight per infusion. One trial compared the pharmacokinetic characteristics of GAMUNEX-C to GAMIMUNE N, 10% and the other trial compared the pharmacokinetics of GAMUNEX-C (10% strength) with a 5% concentration of this product. The ratio of the geometric least square means for dose-normalized IgG peak levels of GAMUNEX-C and GAMIMUNE N, 10% was 0.996. The corresponding value for the dose-normalized area under the curve (AUC) of IgG levels was 0.990. The results of both PK parameters were within the pre-established limits of 0.080 and 1.25. Similar results were obtained in the comparison of GAMUNEX-C 10% to a 5% concentration of GAMUNEX-C.
The main pharmacokinetic parameters of GAMUNEX-C, measured as total IgG in study 100152 are displayed below:
The two pharmacokinetic trials with GAMUNEX-C 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 GAMUNEX-C treatment group and 8.2 ± 2.0 mg/mL for the GAMIMUNE N, 10% control group.
Treatment of Primary Humoral Immunodeficiency by the Subcutaneous (SC) Route
In a single sequence, open-label, crossover trial, the pharmacokinetics, safety, and tolerability of SC administered GAMUNEX-C in subjects with PI were evaluated. A total of 32 and 26 subjects received GAMUNEX-C as IV or SC for PK study, respectively. Subjects received GAMUNEX-C 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.
The mean trough concentration ( mean Ctrough) of plasma total IgG following IV and SC administration are presented in Table 15.
In contrast to plasma total IgG levels observed with monthly IV GAMUNEX-C treatment (rapid peaks followed by a slow decline), the plasma IgG levels in subjects receiving weekly SC GAMUNEX-C therapy were relatively stable (Figure 7).
14 CLINICAL STUDIES
14.1 Treatment of Primary Humoral Immunodeficiency by the Intravenous (IV) Route
In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies GAMUNEX-C 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.
The annual rate of validated infections (Number of Infection/year/subject) was 0.18 in the group treated with GAMUNEX-C 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).
14.2 Treatment of Idiopathic Thrombocytopenic Purpura
A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to prove the hypothesis that GAMUNEX-C 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.
GAMUNEX-C was demonstrated to be at least as effective as GAMIMUNE N, 10% in the treatment of adults and children with acute or chronic ITP.
A trial was conducted to evaluate the clinical response to rapid infusion of GAMUNEX-C in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMUNEX-C on three occasions for treatment of relapses. The infusion rate was randomly assigned to 0.08, 0.11, or 0.14 mL/kg/min (8, 11 or 14 mg/kg/min). Pre-medication with corticosteroids to alleviate infusion-related intolerability was not permitted. Pre-treatment with antihistamines, anti-pyretics and analgesics was permitted. The average dose was approximately 1 g/kg body weight at all three prescribed rates of infusion (0.08, 0.11 and 0.14 mL/kg/min). All patients were administered each of the three planned infusions except seven subjects. Based on 21 patients per treatment group, the a posteriori power to detect twice as many drug-related adverse events between groups was 23%. Of the seven subjects that did not complete the study, five did not require additional treatment, one withdrew because he refused to participate without concomitant medication (prednisone) and one experienced an adverse event (hives); however, this was at the lowest dose rate level (0.08 mL/kg/min).
14.3 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
A multi-center, randomized, double-blind, Placebo-controlled trial (The Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMUNEX-C.  This study included two separately randomized periods to assess whether GAMUNEX-C was more effective than Placebo for the treatment of CIDP (assessed in the Efficacy Period for up to 24 weeks) and whether long-term administration of GAMUNEX-C could maintain long-term benefit (assessed in the 24 week Randomized Withdrawal Period).
In the Efficacy Period, there was a requirement for Rescue (crossover) to the alternate study drug if the subject did not improve and maintain this improvement until the end of the 24 week treatment period. Subjects entering the Rescue phase followed the same dosing and schedule as in the Efficacy period. Any subject who was rescued (crossed over) and did not improve and maintain this improvement was withdrawn from the study.
Subjects who completed 24 weeks treatment in the Efficacy period or Rescue phase and responded to therapy were eligible for entry into a double-blind Randomized Withdrawal Period. Eligible subjects were re-randomized to GAMUNEX-C 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 GAMUNEX-C or equal volume of Placebo given over 2-4 consecutive days. All other infusions (including the first infusion of the Randomized Withdrawal Period) were given as maintenance doses of 1 g/kg bw (or equivalent volume of Placebo) every three weeks.
The Responder rates of the GAMUNEX-C 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).  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 GAMUNEX-C: 28 of 59 subjects (47.5%) responded to GAMUNEX-C compared with 13 of 58 subjects (22.4%) administered Placebo (25% difference; 95% CI 7%-43%; p=0.006). The study included both subjects who were IGIV naive and subjects who had previous IGIV experience. The outcome was influenced by the group of subjects who experienced prior therapy with IGIV, as shown by the outcomes table, below.
Time to relapse for the subset of 57 subjects who previously responded to GAMUNEX-C was evaluated: 31 were randomly reassigned to continue to receive GAMUNEX-C and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive GAMUNEX-C experienced a longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with GAMUNEX-C versus 45% with Placebo (hazard ratio, 0.19; 95% confidence interval, 0.05, 0.70).
The following table shows outcomes for the Rescue Phase (which are supportive data):
The following Kaplan-Meier curves show the outcomes for the Randomized Withdrawal Period:
16 HOW SUPPLIED/STORAGE AND HANDLING
GAMUNEX-C 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 GAMUNEX-C are latex-free. GAMUNEX-C is supplied in the following sizes:
Do not freeze
GAMUNEX-C 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.
17 PATIENT COUNSELING INFORMATION
Inform patients to immediately report the following signs and symptoms to their healthcare provider:
Inform patients that GAMUNEX-C is made from human plasma and may contain infectious agents that can cause disease. While the risk GAMUNEX-C 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 [5.10])
Inform patients that GAMUNEX-C 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 Interaction )
Home Treatment for Primary Humoral Immunodeficiency with Subcutaneous Infusion
Provide the patient with instructions on subcutaneous infusion for home treatment, if the physician believes that home administration is appropriate for the patient. Include 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, and measures to be taken in case of adverse reactions in the patient instructions.
Talecris Biotherapeutics, Inc.
Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified
Subcutaneous Infusion for Primary Humoral Immunodeficiency
Information for Patients
What is the most important information I should know about GAMUNEX-C?
What is GAMUNEX-C?
Who should NOT take GAMUNEX-C?
How should I take GAMUNEX-C?
Instructions for administering GAMUNEX-C are at the end of this patient package insert (see "Steps for Administration"). Only use GAMUNEX-C by yourself after you have been instructed by your doctor or healthcare professional.
What should I avoid while taking GAMUNEX-C?
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 GAMUNEX-C?
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.
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
Before Using GAMUNEX-C
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.
Solution for Infusion
1 Gram Protein in 10 ml
Gamunex-C may be stored for
The patient and physician should
FOR INTRAVENOUS OR SUBCUTANEOUS
Refer to package insert for dosage
Single Dose Vial
Do not use if turbid.
Discard unused portion. Do not store
Contains no preservative
Do not freeze.
Each milliliter (mL) contains approximately
If the shrink band is absent or shows
Not Returnable for Credit or
Talecris Biotherapeutics, Inc.
Talecris Biotherapeutics, Inc.
Gamunex-C, 1 g Protein in 10 mL
Revised: 10/2010 TALECRIS BIOTHERAPEUTICS, INC.
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2017
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