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Gamunex®
Immune Globulin Intravenous (Human), 10%
Caprylate/Chromatography Purified
10% Liquid Preparation
WARNING: ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE
Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death. [24] Patients predisposed to acute renal failure include 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. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. GAMUNEX (immune globulin intravenous human 10%) does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer. (See DOSAGE AND ADMINISTRATION and WARNINGS and PRECAUTIONS for important information intended to reduce the risk of acute renal failure.)
Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified (GAMUNEX) is a ready-to-use sterile solution of human immune globulin protein for intravenous administration. GAMUNEX (immune globulin intravenous human 10%) 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 (immune globulin intravenous human 10%) 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 (immune globulin intravenous human 10%) doses of 1 g/kg correspond to a glycine dose of 0.15 g/kg. While toxic effects of glycine administration have been reported [12], the doses and rates of administration were 3 – 4 fold greater than those for GAMUNEX (immune globulin intravenous human 10%) . In another study it was demonstrated that intravenous bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects [13] 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 [14]. 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 (immune globulin intravenous human 10%) is 4.0 – 4.5. GAMUNEX (immune globulin intravenous human 10%) contains no preservative and is latex-free.
GAMUNEX 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 (immune globulin intravenous human 10%) is incubated in the final container (at the low pH of 4.0 – 4.3), for a minimum of 21 days at 23° to 27°C. The product is intended for intravenous administration.
The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: human immunodeficiency virus, type I (HIV-1) as the relevant virus for HIV-1 and HIV–2; bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; pseudorabies virus (PRV) as a model for large DNA viruses (e.g. herpes viruses); Reo virus type 3 (Reo) as a model for non-enveloped viruses and for its resistance to physical and chemical inactivation; hepatitis A virus (HAV) as relevant 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
| Process Step | Log10 Virus Reduction | |||||
| Enveloped Viruses | Non-enveloped Viruses | |||||
| HIV | PRV | BVDV | Reo | HAV | PPV | |
| Caprylate Precipitation/Depth Filtration | C/Ia | C/I | 2.7 | ≥ 3.5 | ≥ 3.6 | 4.0 |
| Caprylate Incubation | ≥ 4.5 | ≥ 4.6 | ≥ 4.5 | NAb | NA | NA |
| Depth Filtrationd | CAPc | 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 (21 days) | ≥ 6.5 | ≥ 4.3 | ≥ 5.1 | NA | NA | NA |
| Global Reduction | ≥ 14.0 | ≥ 12.2 | ≥ 16.3 | ≥ 7.5 | ≥ 5.0 | 8.2 |
| a 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. b Not Applicable – This step has no effect on non-enveloped viruses. c CAP - The presence of caprylate in the process at this step prevents detection of enveloped viruses, and their removal cannot be assessed. d Some mechanistic overlap occurs between depth filtration and other steps. Therefore, Talecris Biotherapeutics, Inc. has chosen to exclude this step from the global virus reduction calculations. |
||||||
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 [38-42 ].
Several of the individual production steps in the GAMUNEX (immune globulin intravenous human 10%) 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.
REFERENCE
12. Hahn, R.G., H.P. Stalberg, and S.A. Gustafsson, Intravenous infusion of irrigating fluids containing glycine or mannitol with and without ethanol. J Urol, 1989. 142(4): p. 1102-5.
13. Tai VM, M.E., Lee-Brotherton V, Manley JJ, Nestmann ER, Daniels JM. Safety Evaluation of Intravenous Glycine in Formulation Development. in J Pharm Pharmaceut Sci. 2000.
14. Traul, K.A., et al., Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol, 2000. 38(1): p. 79-98.
38. 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.
39. 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.
40. 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.
41. Cai K, Miller JL, Stenland, CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35.
42. 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.
Gamunex is an immune globulin intravenous (human) 10% liquid indicated for the treatment of:
GAMUNEX (immune globulin intravenous (human) 10%) 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 [16-23].
GAMUNEX (immune globulin intravenous (human) 10%) is indicated in Idiopathic Thrombocytopenic Purpura to rapidly raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo surgery [5-10].
GAMUNEX (immune globulin intravenous (human) 10%) is indicated for the treatment of CIDP to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapse.
GAMUNEX (immune globulin intravenous (human) 10%) consists of 9%–11% protein in 0.16–0.24 M glycine. The buffering capacity of GAMUNEX (immune globulin intravenous (human) 10%) 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 [15]. Thus, the acid load delivered with a dose of 1 g/kg of GAMUNEX (immune globulin intravenous (human) 10%) would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.
As there are significant differences in the half-life of IgG among patients with primary immunodeficiencies, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response.
The dose of GAMUNEX (immune globulin intravenous (human) 10%) for replacement therapy in primary immune deficiency diseases is 300 to 600 mg/kg body weight (3-6 mL/kg) administered every 3 to 4 weeks. The dosage may be adjusted over time to achieve the desired trough levels and clinical responses.
GAMUNEX (immune globulin intravenous (human) 10%) 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 (immune globulin intravenous (human) 10%) , 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. [11] The high dose regimen (1 g/kg × 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.
GAMUNEX (immune globulin intravenous (human) 10%) 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 (immune globulin intravenous (human) 10%) 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.
GAMUNEX (immune globulin intravenous (human) 10%) should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid and/or if discoloration is observed.
Only administer intravenously. GAMUNEX (immune globulin intravenous (human) 10%) should be at room temperature during administration.
Only 18 gauge needles should be used to penetrate the stopper for dispensing product from the 10 mL vial; 16 gauge needles or dispensing pins should only be used with 25 mL vial sizes and larger. Needles or dispensing pins should only be inserted once and be within the stopper area delineated by the raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the ring.
| GAMUNEX vial size | Gauge of needle to penetrate stopper |
| 10 mL | 18 gauge |
| 25, 50, 100, 200 mL | 16 gauge |
Any vial that has been opened should be used promptly. Partially used vials should be discarded.
If dilution is required, GAMUNEX (immune globulin intravenous (human) 10%) may be diluted with 5% dextrose in water (D5/W).
It is recommended that GAMUNEX (immune globulin intravenous (human) 10%) should initially be infused at a rate of 0.01 mL/kg per minute (1 mg/kg per minute) for the first 30 minutes. If well-tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg per minute).
| 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 |
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; discontinue GAMUNEX (immune globulin intravenous (human) 10%) if renal function deteriorates.
For patients at risk of renal dysfunction or thromboembolic events, administer GAMUNEX (immune globulin intravenous (human) 10%) at the minimum infusion rate practicable.
GAMUNEX (immune globulin intravenous (human) 10%) is not compatible with saline. If dilution is required, GAMUNEX (immune globulin intravenous (human) 10%) may be diluted with 5% dextrose in water (D5/W). No other drug interactions or compatibilities have been evaluated.
GAMUNEX (immune globulin intravenous (human) 10%) may be stored for 36 months at 2-8ºC (36-46ºF) from the date of manufacture AND product may be stored at temperatures not to exceed 25ºC (77º F) for up to 6 months any time during the 36 month shelf life , after which the product must be immediately discarded.
Do not freeze. Frozen product should not be used. Do not use after expiration date
GAMUNEX (immune globulin intravenous (human) 10%) is supplied in 1.0 g, 2.5 g, 5 g, 10 g, or 20 g single use bottles.
GAMUNEX (immune globulin intravenous (human) 10%) 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 (immune globulin intravenous (human) 10%) are latex-free. GAMUNEX (immune globulin intravenous (human) 10%) is supplied in the following sizes:
| NDC Number | Size | Grams Protein |
| 13533-645-12 | 10 mL | 1.0 |
| 13533-645-15 | 25 mL | 2.5 |
| 13533-645-20 | 50 mL | 5.0 |
| 13533-645-71 | 100 mL | 10.0 |
| 13533-645-24 | 200 mL | 20.0 |
GAMUNEX (immune globulin intravenous (human) 10%) may be stored for 36 months at 2 - 8°C (36 - 46°F), AND product may be stored at temperatures not to exceed 25°C (77°F) for up to 6 months anytime during the 36 month shelf life, after which the product must be immediately used or discarded. Do not freeze. Do not use after expiration date.
REFERENCES
5. Blanchette, V.S., M.A. Kirby, and C. Turner, Role of intravenous immunoglobulin G in autoimmune hematologic disorders. Semin Hematol, 1992. 29(3 Suppl 2): p. 72-82.
6. Lazarus, A.H., J. Freedman, and J.W. Semple, Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP): mechanisms of action. Transfus Sci, 1998. 19(3): p. 289-94.
7. Semple, J.W., A.H. Lazarus, and J. Freedman, The cellular immunology associated with autoimmune thrombocytopenic purpura: an update. Transfus Sci, 1998. 19(3): p. 245-51.
8. Imbach, P.A., Harmful and beneficial antibodies in immune thrombocytopenic purpura. Clin Exp Immunol, 1994. 97(Suppl 1): p. 25-30.
9. Bussel, J.B., Fc receptor blockade and immune thrombocytopenic purpura. Semin Hematol, 2000. 37(3): p. 261-6.
10. Imbach, P., et al., Immunthrombocytopenic purpura as a model for pathogenesis and treatment of autoimmunity. Eur J Pediatr, 1995. 154(9 Suppl 4): p. S60-4.
11. Cyrus P, F.G., Kelleher J, Schwartz L,, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety, and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2000. Report on file.
15. Guyton, A., Textbook of Medical Physiology. 5th Edition. 1976, Philadelphia: W.B. Saunders. 499-500.
16. Ammann, A.J., et al., Use of intravenous gamma-globulin in antibody immunodeficiency: results of a multicenter controlled trial. Clin Immunol Immunopathol, 1982. 22(1): p. 60-7.
17. Buckley, R.H. and R.I. Schiff, The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med, 1991. 325(2): p. 110-7.
18. Cunningham-Rundles, C. and C. Bodian, Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol, 1999. 92(1): p. 34-48.
19. Nolte, M.T., et al., Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol, 1979. 36(2): p. 237-43.
20. 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.
21. Roifman, C.M., H. Levison, and E.W. Gelfand, High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet, 1987. 1(8541): p. 1075-7.
22. Sorensen, R.U. and S.H. Polmar, Efficacy and safety of high-dose intravenous immune globulin therapy for antibody deficiency syndromes. Am J Med, 1984. 76(3A): p. 83-90.
23. Stephan, J.L., et al., Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr, 1993. 123(4): p. 564-72.
24. Cayco, A.V., M.A. Perazella, and J.P. Hayslett, Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol, 1997. 8(11): p. 1788-94.
Manufactured by: Talecris Biotherapeutics, Inc. Research Triangle Park, NC 27709 USA. September 2008. FDA Rev date: 9/12/2008
The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for PI was an exacerbation of autoimmune pure red cell aplasia in one subject.
The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for ITP was myocarditis in one subject that occurred 50 days post study drug infusion and was not considered drug related.
The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for CIDP was pulmonary embolism (PE) in one subject with a history of PE.
The most common drug related adverse reactions observed at a rate >5% in subjects with PI were headache, cough, injection site reaction, nausea, pharyngitis and urticaria.
The most common drug related adverse reactions observed at a rate >5% in subjects with ITP were headache, vomiting, fever, nausea, back pain and rash.
The most common drug related adverse reactions observed at a rate >5% in subjects with CIDP were headache, fever, chills and hypertension
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.
Adverse events similar to those previously reported with the administration of intravenous and intramuscular immunoglobulin products may occur. Cases of reversible aseptic meningitis, migraine, isolated cases of reversible hemolytic anemia and reversible increases in liver function tests have been observed with GAMUNEX (immune globulin intravenous (human) 10%) . Immediate anaphylactic reactions can possibly occur (<0.01%). Epinephrine should be available for treatment of any acute anaphylactoid reaction. (see WARNINGS and PRECAUTIONS)
The following table shows the number of subjects treated with GAMUNEX (immune globulin intravenous (human) 10%) in clinical trials to study PI, and the reason for discontinuation due to adverse events:
Table 1: Reasons for Discontinuation Due to Adverse Events:
All PI Studies
| Study Number | Number of Subjects Treated with GAMUNEX | Number of Subjects Discontinued Due to Adverse Events | Adverse Event |
| 100152 | 18 | 0 | ----- |
| 100174 | 20 | 1 | Coombs negative hypochromic anemia* |
| 100175 | 87 | 1 | Autoimmune pure red cell aplasia* |
| * Both events were considered unrelated to study drug as per the investigator. | |||
In study 100175, 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion. Generally, diphenhydramine and acetaminophen were used.
Any adverse events in trial 100175, irrespective of the causality assessment, are given in the following table.
Table 2: Subjects with At Least One Adverse Event Irrespective
of Causality (Study 100175)
| Adverse Event | GAMUNEX (immune globulin intravenous (human) 10%) No. of subjects: 87 No of subjects with AE (percentage of all subjects) |
GAMIMUNE N No. of subjects: 85 No of subjects with AE (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%) |
The subset of drug related adverse events in trial 100175 reported by at least 5% of subjects during the 9-month treatment are given in the following table.
Table 3: Subjects with At Least One Drug Related Adverse
Event (Study 100175)
| Drug Related Adverse Event | GAMUNEX (immune globulin intravenous (human) 10%) No. of subjects: 87 No. of subjects with drug related AE (percentage of all subjects) |
GAMIMUNE N No. of subjects: 85 No. of subjects with drug related AE (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%) |
Adverse events, which were reported by at least 5% of subjects, were also analyzed by frequency and in relation to infusions administered. The analysis is displayed in the following table.
Table 4: Adverse Event Frequency (Study 100175)
| Adverse Event | GAMUNEX (immune globulin intravenous (human) 10%) No. of infusions: 825 Number of AE (percentageof all infusions) |
GAMIMUNE N No. of infusions: 865 Number of AE (percentageof 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 events per infusion that occurred during or on the same day as an infusion was 0.21 in both the GAMUNEX (immune globulin intravenous (human) 10%) and GAMIMUNE N 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 (immune globulin intravenous (human) 10%) , 4 GAMIMUNE N) at 17 occasions. In most instances, mild to moderate hives/urticaria, itching, pain or reaction at infusion site, anxiety or headache was the main reason. There was one case of severe chills. There were no anaphylactic or anaphylactoid reactions to GAMUNEX (immune globulin intravenous (human) 10%) or GAMIMUNE N.
In trial 100175, serum samples were drawn to monitor the viral safety at baseline and one week after the first infusion (for parvovirus B19), eight weeks after first and fifth infusion, and 16 weeks after the first and fifth infusion of IGIV (for hepatitis C) and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, Polymerase Chain Reaction (PCR), and serological testing. There were no treatment emergent findings of viral transmission for either GAMUNEX (immune globulin intravenous (human) 10%) , or GAMIMUNE N. [1, 3, 4]
The following table shows the number of subjects treated with GAMUNEX (immune globulin intravenous (human) 10%) in clinical trials to study ITP, and the reason for discontinuation due to adverse events:
Table 5: Reasons for Discontinuation Due to Adverse Events:
All ITP Studies
| Study Number | Number of Subjects Treated with GAMUNEX | Number of Subjects Discontinued Due to Adverse Events | Adverse Event |
| 100213 | 28 | 1 | Hives |
| 100176 | 48 | 1 | Headache, Fever, Vomiting |
One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX (immune globulin intravenous (human) 10%) . The death was judged to be unrelated to GAMUNEX (immune globulin intravenous (human) 10%) .
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 (immune globulin intravenous (human) 10%) , 3 GAMIMUNE N) on 4 occasions. Mild to moderate headache, nausea, and fever were the reported reasons. There were no anaphylactic or anaphylactoid reactions to GAMUNEX (immune globulin intravenous (human) 10%) or GAMIMUNE N.
Any adverse events in trial 100176, irrespective of the causality assessment, reported by at least 5% of subjects during the 3-month trial are given in the following table.
Table 6: Subjects with At Least One Adverse Event Irrespective
of Causality (Study 100176)
| Adverse Event | GAMUNEX (immune globulin intravenous (human) 10%) No. of subjects: 48 No of subjects with AE (percentage of all subjects) |
GAMIMUNE N No. of subjects: 49 No of subjects with AE (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%) |
The subset of drug related adverse events in trial 100176 reported by at least 5% of subjects during the 3-month trial are given in the following table.
Table 7: Subjects with At Least One Drug Related Adverse
Event (Study 100176)
| Drug Related Adverse Event | GAMUNEX (immune globulin intravenous (human) 10%) No. of subjects: 48 No. of subjects with drug related AE (percentage of all subjects) |
GAMIMUNE N No. of subjects: 49 No. of subjects with drug related AE (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 GAMUNEX (immune globulin intravenous (human) 10%) , or GAMIMUNE N [11].
In study 100538, 113 subjects were exposed to GAMUNEX and 95 were exposed to Placebo (See Clinical Studies). As a result of the study design, the drug exposure with GAMUNEX (immune globulin intravenous (human) 10%) was almost twice that of Placebo, with 1096 GAMUNEX (immune globulin intravenous (human) 10%) 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.
The following table shows the numbers of subjects per treatment group in the CIDP clinical trial, and the reason for discontinuation due to adverse events:
Table 8: Reasons for Discontinuation Due to Adverse Events:
CIDP
| Number of Subjects | Number of Subjects Discontinued due to Adverse Events | Adverse Event | |
| GAMUNEX | 113 | 3 (2.7%) | Urticaria, Dyspnea, Bronchopneumonia |
| Placebo | 95 | 2 (2.1%) | Cerebrovascular Accident, Deep Vein Thrombosis |
Adverse events reported by at least 5% of subjects in any treatment group irrespective of causality are shown in the following table.
Table 9: Subjects with At Least One Adverse Event Irrespective
of Causality (Study 100538)
| MedDRA Preferred Term a | GAMUNEX No. of subjects: 113 |
Placebo No. of subjects: 95 |
||||
| No. of Subjects (%) | No. of Adverse Events | Incidence density b | No. of Subjects (%) | No. of Adverse Events | Incidence density b | |
| 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 |
| a Reported in ≥ 5% of subjects in any treatment group
irrespective of causality. b Calculated by the total number of adverse events divided by the number of infusions received (1096 for GAMUNEX (immune globulin intravenous (human) 10%) and 575 for Placebo) |
||||||
Drug-related adverse events reported by at least 5% of subjects in any treatment group are reported in the following table. The most common drug-related events with GAMUNEX (immune globulin intravenous (human) 10%) were headache and pyrexia:
Table 10: Subjects with At Least 1 Drug Related Adverse Event
(Study 100538)
| MedDRA Preferred term a | GAMUNEX No. of subjects:113 |
Placebo No. of subjects: 95 |
||||
| No. of Subjects (%) | No. of Adverse Events | Incidence density b | No. of Subjects (%) | No. of Adverse Events | Incidence density b | |
| Any drug-related adverse event | 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 |
| a Reported in ≥ 5% of subjects in any treatment group. b Calculated by the total number of adverse events divided by the number of infusions received (1096 for GAMUNEX (immune globulin intravenous (human) 10%) and 575 for Placebo). |
||||||
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 (immune globulin intravenous (human) 10%) class. may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4
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.[1, 3, 4, 11, 36]
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
The following adverse reactions have been identified and reported during the post marketing use of GAMUNEX (immune globulin intravenous (human) 10%) :
The following adverse reactions have been identified and reported during the post marketing use of IGIV products [37]:
GAMUNEX (immune globulin intravenous (human) 10%) may be diluted with 5% dextrose in water (D5/W). Admixtures of GAMUNEX (immune globulin intravenous (human) 10%) with other drugs and intravenous solutions have not been evaluated. It is recommended that GAMUNEX (immune globulin intravenous (human) 10%) 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 (immune globulin intravenous (human) 10%) with 5% dextrose in water. Various passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing.
Antibodies in GAMUNEX (immune globulin intravenous (human) 10%) may interfere with the response to live viral vaccines such as measles, mumps and rubella. Physicians should be informed of recent therapy with IGIVs, so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration. (See Patient Counseling Information)
REFERENCES
1. Kelleher J, F.G., Cyrus P, Schwartz L,, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Immune Deficiency (PID), 2000. Report on file.
3. Bayever E, M.F., Sundaresan P, Collins S, Randomized, Double-Blind, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100152). MMRR-1512/1, 1999.
4. Lathia C, E.B., Sundaresan PR, Schwartz L, A Randomized, Open-Label, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 5% with IGIV-Chromatography 10% in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100174). 2000.
11. Cyrus P, F.G., Kelleher J, Schwartz L,, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety, and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2000. Report on file.
36. Kelleher J, S.L., IGIV-C 10% Rapid Infusion Trial in Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2001. Report on file.
37. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003; 17,241-251.
Included as part of the PRECAUTIONS section.
Severe hypersensitivity reactions may occur. In case of hypersensitivity, IGIV infusion should be immediately discontinued and appropriate treatment instituted. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction. (See Patient Counseling Information)
GAMUNEX (immune globulin intravenous (human) 10%) contains trace amounts of IgA (average 46 micrograms/mL). It is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity. (See Patient Counseling Information)
Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of GAMUNEX (immune globulin intravenous (human) 10%) and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. (See Patient Counseling Information) For patients judged to be at risk for developing renal dysfunction and/or at risk of developing thrombotic events, it may be prudent to reduce the amount of product infused per unit time by infusing GAMUNEX at a rate less than 8 mg IG/kg/min (0.08 mL/kg/min). (See Boxed Warning) (See DOSAGE AND ADMINISTRATION)
Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV therapy. The hyponatremia is likely to be a pseudohyponatremia as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap. Distinguishing true hyponatremia from pseudohyponatremia is clinically critical, as treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a disposition to thromboembolic events. [45]
Thrombotic events have been reported in association with IGIV [33,34,35]. Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.
An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. [25-27]The syndrome usually begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cu mm, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. It appears that patients with a history of migraine may be more susceptible. (See Patient Counseling Information)
Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.[28,29,30] Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis. [31] If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done. (See Patient Counseling Information)
There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV.[32] TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6 hrs after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.
IGIV recipients should be monitored for pulmonary adverse reactions (See Patient Counseling Information) If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum.
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.
Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1-800-520-2807]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient (See Patient Counseling Information)
If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done.
If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum.
Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.
Pregnancy Category C. Animal reproduction studies have not been conducted with GAMUNEX (immune globulin intravenous (human) 10%) . It is not known whether GAMUNEX (immune globulin intravenous (human) 10%) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMUNEX (immune globulin intravenous (human) 10%) should be given to a pregnant woman only if clearly needed.
GAMUNEX (immune globulin intravenous (human) 10%) has not been evaluated in nursing mothers.
GAMUNEX (immune globulin intravenous (human) 10%) was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI subjects (Study 100175) exposed to GAMUNEX (immune globulin intravenous (human) 10%) 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.
One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX (immune globulin intravenous (human) 10%) . The death was judged to be unrelated to GAMUNEX (immune globulin intravenous (human) 10%) .
GAMUNEX (immune globulin intravenous (human) 10%) was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of the acute ITP subjects (Study 100176) exposed to GAMUNEX (immune globulin intravenous (human) 10%) 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.
The safety and effectiveness of GAMUNEX (immune globulin intravenous (human) 10%) has not been established in pediatric subjects with CIDP.
Patients > 65 years of age may be at increased risk for developing certain adverse reactions such as thromboembolic events and acute renal failure. (See Boxed Warning, WARNINGS and PRECAUTIONS) Clinical studies of GAMUNEX (immune globulin intravenous (human) 10%) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Table 11: Clinical Studies of GAMUNEX (immune globulin intravenous (human) 10%) by Age Group
| Clinical Study | Indication | Number of Subjects | |
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