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GAMMAGARD LIQUID Immune Globulin Intravenous (Human), 10% is a ready-for-use sterile, liquid preparation of highly purified and concentrated immunoglobulin G (IgG) antibodies. The distribution of the IgG subclasses is similar to that of normal plasma.1,2 The Fc and Fab functions are maintained in GAMMAGARD LIQUID. Pre-kallikrein activator activity is not detectable. GAMMAGARD LIQUID (immune globulin intravenous human 10%) contains 100 mg/mL protein. At least 98% of the protein is gammaglobulin, the average immunoglobulin A (IgA) concentration is 37µg/mL, and immunoglobulin M is present in trace amounts. GAMMAGARD LIQUID (immune globulin intravenous human 10%) contains a broad spectrum of IgG antibodies against bacterial and viral agents. Glycine (0.25M) serves as a stabilizing and buffering agent, and there are no added sugars, sodium or preservatives. The pH is 4.6 to 5.1. The osmolality is 240-300 mOsmol/kg, which is similar to physiological osmolality (285 to 295 mOsmol/kg).3
GAMMAGARD LIQUID is manufactured from large pools of human plasma. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of GAMMAGARD LIQUID (immune globulin intravenous human 10%) is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found negative. IgGs are purified from plasma pools using a modified Cohn-Oncley cold ethanol fractionation process, as well as cation and anion exchange chromatography.
To further improve the margin of safety, three dedicated, independent and effective virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely solvent/detergent (S/D) treatment,4,5 35 nm nanofiltration,6,7 and a low pH incubation at elevated temperature.8,9 The S/D process includes treatment with an organic mixture of tri-n-butyl phosphate, octoxynol 9 and polysorbate 80 at 18°C to 25°C for a minimum of 60 minutes. In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed under extreme conditions (e.g., at minimum S/D concentrations, incubation time and temperature for the S/D treatment). Virus clearance studies for GAMMAGARD LIQUID (immune globulin intravenous human 10%) performed in accordance with good laboratory practices (Table 1) have demonstrated that:
Table 1: Three Dedicated Independent Virus Inactivation/Removal Steps
Mean Log10 Reduction Factors a (RFs) For Each Virus and Manufacturing Step
| Virus type Family | Enveloped RNA | Enveloped DNA | Non-enveloped RNA | Non-enveloped DNA | |||
| Retroviridae | Flaviviridae | Herpesviridae | Picornaviridae | Parvoviridae | |||
| Virus | HIV-1 | BVDV | WNV | PRV | HAV | EMCV | MMV |
| SD treatment | > 4.5 | > 6.2 | n.a. | > 4.8 | n.d. | n.d. | n.d. |
| 35 nm nanofiltration | > 4.5 | > 5.1 | > 6.2 | > 5.6 | 5.7 | 1.4 | 2.0 |
| Low pH treatment | > 5.8 | > 5.5 | > 6.0 | > 6.5 | n.d.b | > 6.3 | 3.1 |
| Overall log reduction factor (ORF) | > 14.8 | > 16.8 | > 12.2 | > 16.9 | 5.7 b | > 7.7 | 5.1 |
| Abbreviations: HIV-1, Human Immunodeficiency Virus Type 1; BVDV, Bovine Viral Diarrhea Virus (model for Hepatitis C Virus and other lipid enveloped RNA viruses); WNV, West Nile Virus; PRV, Pseudorabies Virus (model for ipid enveloped DNA viruses, including Hepatitis B Virus); EMCV, Encephalomyocarditis Virus (model for non-lipid enveloped RNA viruses, including Hepatitis A virus [HAV]); MMV, Mice Minute Virus (model for non-lipid enveloped DNA viruses, including B19 virus [B19V]); n.d. (not done), n.a. (not applicable). a For the calculation of these RF data from virus clearance study reports, applicable manufacturing conditions were used. Log10 RFs on the order of 4 or more are considered effective for virus clearance in accordance with the Committee for Medicinal Products for Human Use (CHMP, formerly CPMP) guidelines. b No RF obtained due to immediate neutralization of HAV by the anti-HAV antibodies present in the product. |
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REFERENCES
1. Skvaril F. Qualitative and quantitative aspects of IgG subclasses in i.v. immunoglobulin preparations. In: Nydegger UE, ed. Immunotherapy. London: Academic Press; 1981:118-122.
2. French M. Serum IgG subclasses in normal adults. Monogr Allergy. 1986;19:100-107.
3. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Appendix: Abbreviations and Measurements. Drug Information Handbook. Lexi-Comp; 1999:1254.
4. Horowitz B, Prince AM, Hamman J, Watklevicz C. Viral safety of solvent/detergent-treated blood products. Blood Coagul Fibrinolysis. 1994;5 Suppl 3:S21-S28.
5. Kreil TR, Berting A, Kistner O, Kindermann J. West Nile virus and the safety of plasma derivatives: verification of high safety margins, and the validity of predictions based on model virus data. Transfusion. 2003;43:1023-1028.
6. Hamamoto Y, Harada S, Kobayashi S, et al. A novel method for removal of human immunodeficiency virus: filtration with porous polymeric membranes. Vox Sang. 1989;56:230-236.
7. Yuasa T, Ishikawa G, Manabe S, Sekiguchi S, Takeuchi K, Miyamura T. The particle size of hepatitis C virus estimated by filtration through microporous regenerated cellulose fibre. J Gen Virol. 1991 ;72 (Pt 8):2021 -2024.
8. Kempf C, Jentsch P, Poirier B, et al. Virus inactivation during production of intravenous immunoglobulin. Transfusion. 1991;31:423-427.
9. Louie RE, Galloway CJ, Dumas ML, Wong MF, Mitra G. Inactivation of hepatitis C virus in low pH intravenous immunoglobulin. Biologicals. 1994;22:13-19.
Intravenous administration:
The serious adverse reaction (AR) seen during intravenous treatment in the clinical studies for PI was aseptic meningitis. The most common adverse reactions for PI (observed in ≥5% of subjects) were headache, fatigue, pyrexia, nausea, chills, rigors, pain in extremity, diarrhea, migraine, dizziness, vomiting, cough, urticaria, asthma, pharyngolaryngeal pain, rash, arthralgia, myalgia, oedema peripheral, pruritus, and cardiac murmur.
Subcutaneous Administration:
No serious adverse reactions were observed during the clinical study of subcutaneous treatment. The most common adverse reactions during subcutaneous treatment (observed in ≥5% of PI subjects) were infusion site (local) event, headache, fatigue, heart rate increased, pyrexia, abdominal pain upper, nausea, vomiting, asthma, blood pressure systolic increased, diarrhea, ear pain, aphthous stomatitis, migraine, oropharyngeal pain, and pain in extremity.
The serious adverse reactions in the clinical study for MMN were pulmonary embolism and blurred vision. The most common adverse reactions for MMN (observed in ≥5% of subjects) were headache, chest discomfort, muscle spasms, muscular weakness, nausea, oropharyngeal pain, and pain in extremity.
The most common adverse reactions observed in ≥5% of clinical study subjects receiving GAMMAGARD LIQUID for CIDP were headache, pyrexia, anemia, leukopenia, neutropenia, illness, blood creatinine increased, dizziness, migraine, somnolence, tremor, nasal dryness, abdominal pain upper, vomiting, chills, nasopharyngitis, and pain in extremity.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
The safety of GAMMAGARD LIQUID intravenous infusion was evaluated in 61 subjects.
Fifteen adverse reactions in 8 subjects were serious. Of these, two episodes of aseptic meningitis in one subject were deemed possibly related to infusion of GAMMAGARD LIQUID.
There were 400 non-serious adverse reactions. Of these, 217 were rated as mild (transient discomfort that resolves spontaneously or with minimal intervention), 164 were rated as moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 19 were rated as severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae). All of the severe non-serious adverse experiences were transient, did not lead to hospitalization, and resolved without complication. One subject withdrew from the study due to a non-serious adverse experience (papular rash).
Adverse reactions with a frequency of ≥5% (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 8.
Table 8: Adverse Reactions Occurring in ≥5% of Subjects with PI (Intravenous Administration)
| Events | By Infusion N (%) (N=1812 Infusions) |
By Subject N (%) (N=61 Subjects) |
| Headache | 94 (5.2%) | 29 (47.5%) |
| Fatigue | 33 (1.8%) | 14 (23.0%) |
| Pyrexia | 28 (1.5%) | 17 (27.9%) |
| Nausea | 17 (0.9%) | 11 (18.0%) |
| Chills | 14 (0.8%) | 8 (13.1%) |
| Rigors | 14 (0.8%) | 8 (13.1%) |
| Pain in extremity | 13 (0.7%) | 7 (11.5%) |
| Diarrhea | 12 (0.7%) | 9 (14.8%) |
| Migraine | 12 (0.7%) | 4 (6.6%) |
| Dizziness | 11 (0.6%) | 8 (13.1%) |
| Vomiting | 11 (0.6%) | 9 (14.8%) |
| Cough | 9 (0.5%) | 8 (13.1%) |
| Urticaria | 9 (0.5%) | 5 (8.2%) |
| Asthma | 7 (0.4%) | 6 (9.8%) |
| Pharyngolaryngeal pain | 7 (0.4%) | 5 (8.2%) |
| Rash | 6 (0.3%) | 4 (6.6%) |
| Arthralgia | 5 (0.3%) | 4 (6.6%) |
| Myalgia | 5 (0.3%) | 5 (8.2%) |
| Oedema peripheral | 5 (0.3%) | 5 (8.2%) |
| Pruritus | 5 (0.3%) | 4 (6.6%) |
| Cardiac murmur | 4 (0.2%) | 4 (6.6%) |
Pooled analysis of 4 short term clinical studies with 106 subjects (total of 854 infusions) showed no differences in the safety profile of GAMMAGARD LIQUID. These short-term studies were designed to stabilize the immune globulin treatment or as a safety follow-up study. They were not designed to study the safety, efficacy and tolerability of GAMMAGARD LIQUID. No additional adverse reactions were reported during the study periods.
The safety of GAMMAGARD LIQUID in subcutaneous infusion was evaluated in 47 subjects.
Adverse reactions with a frequency of ≥5% (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 9.
Table 9: Adverse Reactions Occurring in ≥5% of Subjects with PI (Subcutaneous Administration)
| Events | By Infusion N (%) (N=2294 infusions) |
By Subject N (%) (N=47 Subjects) |
| Infusion site (local) event | 55 (2.4%) | 21 (44.7%) |
| Headache | 31 (1.4%) | 19 (40.4%) |
| Fatigue | 11 (0.5%) | 7 (14.9%) |
| Heart rate increased | 11 (0.5%) | 3 (6.4%) |
| Pyrexia | 11 (0.5%) | 9 (19.1%) |
| Abdominal pain upper | 9 (0.4%) | 5 (10.6%) |
| Nausea | 7 (0.3%) | 3 (6.4%) |
| Vomiting | 7 (0.3%) | 5 (10.6%) |
| Asthma | 6 (0.3%) | 4 (8.5%) |
| Blood pressure systolic increased | 6 (0.3%) | 3 (6.4%) |
| Diarrhea | 5 (0.2%) | 3 (6.4%) |
| Ear pain | 4 (0.2%) | 3 (6.4%) |
| Aphthous stomatitis | 3 (0.1%) | 3 (6.4%) |
| Migraine | 3 (0.1%) | 3 (6.4%) |
| Oropharyngeal pain | 3 (0.1%) | 3 (6.4%) |
| Pain in extremity | 3 (0.1%) | 3 (6.4%) |
Of the 348 non-serious adverse reactions, 228 were rated as mild (transient discomfort that resolves spontaneously or with minimal intervention), 112 were rated as moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 8 were rated as severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae). Neither of the severe adverse reactions required hospitalization or resulted in sequelae.
Local Adverse Reactions:
Local adverse reactions reported as mild (transient discomfort that resolves spontaneously or with minimal intervention) were rash, erythema, edema, hemorrhage, and irritation. Local adverse reactions reported as mild or moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae) were pain, hematoma, pruritus, and swelling.
One subject withdrew from the study after 10 treatments with GAMMAGARD LIQUID subcutaneous infusion (2.5 months) due to increased fatigue and malaise.
The overall rate of local adverse reactions (excluding infections) during subcutaneous treatment was 2.4% per infusion. In subcutaneous naïve subjects, the incidence of local adverse reactions (N=1757 infusions) was 2.8% (2.2% mild and 0.6% moderate with no severe adverse reactions). In the subjects who were subcutaneous experienced (N=537 infusions), the incidence of local adverse reactions was 1.1% (1.1% mild, and no moderate or severe adverse reactions).
After all subcutaneous doses were adjusted, only one subject did not reach the maximum rate allowed in the protocol for one or more infusions, 20 mL/site/hour if weight was below 40 kg and 30/mL/hour for weight 40 kg and greater. Overall, 70% (31 of 44) of subjects opted for the highest rate for all infusions. No subject limited the infusion rate due to an adverse reaction. Median duration of each weekly infusion was 1.2 hours (range: 0.8-2.3 hours). The rate set on the pump was the rate per site multiplied by the number of sites, with no maximum.
During subcutaneous treatment, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. The proportion of subjects who experienced local adverse reactions (excluding infections) was highest immediately following the switch from intravenous to subcutaneous treatment in all age groups. The rate of local adverse reactions per infusion immediately after switching from intravenous to subcutaneous treatment was 4.9% (29/595), decreasing to 1.5% (8/538) by the end of the study and to 1.1% (10/893) in the Study Extension. There was a decrease of local adverse reactions over subsequent subcutaneous infusions.
Eight (17%) subjects experienced a local adverse reaction during the first infusion, but that decreased to 1 (2.2%) for subsequent infusions, ranging from 0 to 4 (8.7%) during the first year of subcutaneous treatment. No subject reported a local adverse reaction from week 53 to end of study at week 68.
Analysis of a short-term follow-up safety study of 10 subjects who were treated with subcutaneous administration of GAMMAGARD LIQUID (total of 218 infusions) showed no differences in the safety profile. The follow-up safety study was not designed to study the safety, efficacy and tolerability of GAMMAGARD LIQUID and no additional adverse reactions were reported during the study period.
The safety of GAMMAGARD LIQUID was evaluated in 44 subjects with MMN who received a total of 983 infusions. Two serious adverse reactions, pulmonary embolism and blurred vision, occurred.
In the study, among the 317 non-serious adverse reactions, 176 were considered ARs. Of these, 126 were mild (transient discomfort that resolves spontaneously or with minimal intervention), 37 were moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae) and 13 were severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae).
Adverse reactions with a frequency ≥5% (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 10.
Table 10: Adverse Reactions Occurring in ≥5% of MMN Subjects
|
Events |
GAMMAGARD LIQUID |
Placebo |
||
|
By Infusion |
By Subject |
By Infusion |
By Subject |
|
|
Headache |
28 (2.85%) |
14 (31.82%) |
3 (2.33%) |
2 (4.65%) |
|
Chest Discomfort |
3 (0.31%) |
3 (6.82%) |
0 (0.00%) |
0 (0.00%) |
|
Muscle Spasms |
3 (0.31%) |
3 (6.82%) |
0 (0.00%) |
0 (0.00%) |
|
Muscular weakness |
4 (0.41%) |
3 (6.82%) |
1 (0.78%) |
1 (2.33%) |
|
Nausea |
28 (2.85%) |
3 (6.82%) |
2 (1.55%) |
1 (2.33%) |
|
Oropharyngeal pain |
4 (0.41%) |
3 (6.82%) |
0 (0.00%) |
0 (0.00%) |
|
Pain in extremity |
4 (0.41%) |
3 (6.82%) |
1 (0.78%) |
1 (2.33%) |
The safety of GAMMAGARD LIQUID was evaluated in a clinical study of 20 adult subjects with CIDP. A total of 389 infusions of GAMMAGARD LIQUID were administered during the study.
Fourteen out of the 20 subjects reported 60 adverse events; 9 experienced mild events (transient discomfort that resolves spontaneously or with minimal intervention), 3 had moderate events (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 2 experienced severe events (marked impairment of function or can lead to a temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae). There were 39 ARs in 13 subjects (65%), and 31 related to GAMMAGARD LIQUID in 11 subjects (55%). One subject (5%) experienced one severe AR (headache) related to GAMMAGARD LIQUID. No AR resulted in early discontinuation or death, and no serious AR was reported.
Adverse reactions with a frequency ≥5% (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 11.
Table 11: Adverse Reactions Occurring in ≥5% of CIDP Subjects
| Events | By Infusion N (%) (N=389 Infusions) |
By Subject N (%) (N=20 Subjects) |
| Headache | 20 (5.1%) | 8 (40.0%) |
| Pyrexia | 3 (0.8%) | 2 (10.0%) |
| Abdominal pain upper | 1 (0.3%) | 1 (5.0%) |
| Anemia | 1 (0.3%) | 1 (5.0%) |
| Blood creatinine increased | 1 (0.3%) | 1 (5.0%) |
| Chills | 2 (0.5%) | 1 (5.0%) |
| Dizziness | 1 (0.3%) | 1 (5.0%) |
| Illness | 1 (0.3%) | 1 (5.0%) |
| Leukopenia | 1 (0.3%) | 1 (5.0%) |
| Migraine | 1 (0.3%) | 1 (5.0%) |
| Nasal Dryness | 1 (0.3%) | 1 (5.0%) |
| Nasopharyngitis | 1 (0.3%) | 1 (5.0%) |
| Neutropenia | 1 (0.3%) | 1 (5.0%) |
| Pain in extremity | 1 (0.3%) | 1 (5.0%) |
| Somnolence | 1 (0.3%) | 1 (5.0%) |
| Tremor | 1 (0.3%) | 1 (5.0%) |
| Vomiting | 1 (0.3%) | 1 (5.0%) |
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.
Intravenous Adverse Reactions
Blood and Lymphatic System Disorders: Hemolysis
Immune System Disorders: Anaphylactic shock
Nervous System Disorders: Cerebral vascular accident, transient ischemic attack, tremor
Cardiac Disorders: Myocardial infarction
Vascular Disorders: Deep vein thrombosis, hypotension
Respiratory, Thoracic and Mediastinal Disorders: Pulmonary embolism, pulmonary edema
Skin and Subcutaneous Tissue Disorders: Hyperhidrosis
General Disorders and Administration-Site Conditions: Chest pain
Investigations: Coombs direct test positive, oxygen saturation decreased
Injury, Poisoning and Procedural Complications: Transfusion-related acute lung injury
Subcutaneous Adverse Reactions
Immune System Disorders: Hypersensitive
Musculoskeletal and Connective Tissue Disorders: Myalgia
General Disorders and Administration-Site Conditions: Chills
In addition to the adverse reactions listed above, the following reactions have been identified for immune globulin products administered intravenously:
Renal and Urinary Disorders: Osmotic nephropathy
Respiratory, Thoracic and Mediastinal Disorders: Cyanosis, hypoxemia, bronchospasm, apnea, Acute Respiratory Distress Syndrome (ARDS)
Integumentary: Bullous dermatitis, epidermolysis, erythema multiforme, Stevens-Johnson Syndrome
Vascular Disorders: Cardiac arrest, vascular collapse
Nervous System Disorders: Coma, seizures, loss of consciousness
Blood and Lymphatic System Disorders: Pancytopenia
Gastrointestinal: Hepatic dysfunction
The adverse reactions listed below have been identified and reported with the use of another immune globulin products administered subcutaneously:
Immune System Disorders: Anaphylactic reaction
Nervous System Disorders: Paresthesia, tremor
Cardiac Disorders: Tachycardia
Vascular Disorders: Hypotension
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, laryngospasm
General Disorders and Administration-Site Conditions: Chest discomfort, injection site reaction (including induration, warmth)
Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as mumps, rubella and varicella for up to 6 months, and for a year or more to measles (rubeola). Inform the immunizing physician of recent therapy with GAMMAGARD LIQUID so that appropriate precautions can be taken [see Patient Counseling Information (17)].
Included as part of the PRECAUTIONS section.
Severe hypersensitivity reactions may occur, even in patients who had tolerated previous treatment with human normal immune globulin. In case of hypersensitivity, discontinue GAMMAGARD LIQUID infusion immediately and institute appropriate treatment.
GAMMAGARD LIQUID contains trace amount of IgA (average concentration of 37 μg/mL). Patients with antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. GAMMAGARD LIQUID is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction [see Contraindications (4.1)].
Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death may occur upon use of IGIV treatment, especially those containing sucrose3. Acute renal dysfunction/failure has been reported in association with infusions of GAMMAGARD LIQUID. Assure that patients are not volume depleted prior to the initiation of infusion of GAMMAGARD LIQUID. In patients who are at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs, etc.), administer GAMMAGARD LIQUID intravenously at the minimum rate of infusion practicable (not exceeding 3.3 mg IgG/kg/min (<2 mL/kg/hr) [see Dosage and Administration (2.5)].
Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of GAMMAGARD LIQUID and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of GAMMAGARD LIQUID [see Dosage and Administration (2.5)].
Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving GAMMAGARD LIQUID. It is critical to distinguish true hyponatremia from pseudohyponatremia that is temporally or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap. Treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a predisposition to thromboembolic events.4
Thrombosis may occur following treatment with immune globulin products, including GAMMAGARD LIQUID. Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.
Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer GAMMAGARD LIQUID at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity [see Boxed Warning,Dosage and Administration (2.5),Patient Counseling Information (17)].
AMS may occur with immune globulin treatment, including GAMMAGARD LIQUID, administered intravenously or subcutaneously. AMS may occur more frequently in female patients. Discontinuation of immune globulin treatment has resulted in remission of AMS within several days without sequelae.
The syndrome usually begins within several hours to two days following immune globulin treatment.
AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting [see Patient Counseling Information (17)]. Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred milligram/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.
GAMMAGARD LIQUID, contains blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBC) with immune globulin. This may cause a positive direct antiglobulin test [DAT (Coomb’s test)].5,6 Delayed hemolytic anemia can develop subsequent to GAMMAGARD LIQUID therapy due to enhanced RBC sequestration; acute hemolysis, consistent with intravascular hemolysis, has been reported [see Adverse Reactions (6)].5-8
The following risk factors may be related to the development of hemolysis: high doses (e.g., ≥2 grams/kg, single administration or divided over several days) and non-O blood group.5 Underlying inflammatory state in an individual patient may increase the risk of hemolysis,5 but its role is uncertain.8,9
Monitor patients for clinical signs and symptoms of hemolysis particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform additional confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis [see Warnings and Precautions (5.9)].
Non-cardiogenic pulmonary edema (TRALI) has been reported in patients following treatment with IGIV products, including GAMMAGARD LIQUID. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment.
Monitor patients for pulmonary adverse reactions [see Patient Counseling Information (17)]. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.
Because GAMMAGARD LIQUID is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease agent. This also applies to unknown or emerging viruses and other pathogens. No confirmed cases of viral transmission or vCJD have been associated with GAMMAGARD LIQUID.
All infections thought by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) (in the U.S.).
After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield false positive serological testing results, with the potential for misleading interpretation.
Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.
Administration of immune globulin products, including GAMMAGARD LIQUID, can lead to false positive readings in assays that depend on detection of beta-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product.
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of GAMMAGARD LIQUID or its effect on fertility.
An in vitro mutagenicity test was performed with GAMMAGARD LIQUID. No evidence of mutagenicity was observed.
In single-dose toxicity studies GAMMAGARD LIQUID revealed no adverse effects at doses of 5000 mg/kg or 2000 mg/kg in mice and rats, respectively. Repeat-dose toxicity studies were not conducted.
With intravenous administration, overdose of GAMMAGARD LIQUID may lead to fluid overload and hyperviscosity. Patients at risk of complications of fluid overload and hyperviscosity include elderly patients and those with cardiac or renal impairment.
GAMMAGARD LIQUID is contraindicated in patients who have a history of anaphylactic or severe systemic hypersensitivity reactions to administration of human immune globulin.
GAMMAGARD LIQUID is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity. Anaphylaxis has been reported with intravenous use of GAMMAGARD LIQUID and is theoretically possible following subcutaneous administration [see Warnings and Precautions (5.1)].
GAMMAGARD LIQUID supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. GAMMAGARD LIQUID also contains a spectrum of antibodies capable of interacting with and altering the activity of cells of the immune system as well as antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies and the mechanism of action of IgG in GAMMAGARD LIQUID have not been fully elucidated.
The mechanism of action of immunoglobulins in the treatment of CIDP in adults has not been fully elucidated but may include immunomodulatory effects.
Following intravenous infusion, IGIV products show a biphasic decay curve. The initial (α) phase is characterized by an immediate post-infusion peak in serum IgG and is followed by rapid decay due to equilibration between the plasma and extravascular fluid compartments. The second (β) phase is characterized by a slower and constant rate of decay. The commonly cited “normal” half-life of 18 to
25 days is based on studies in which tiny quantities of radiolabeled IgG are injected into healthy individuals. When radiolabeled IgG was injected into patients with hypogammaglobulinemia or agammaglobulinemia, highly variable half-lives ranging from 12 to 40 days were observed. In other radiolabeled studies, high serum concentrations of IgG and hypermetabolism associated with fever and infection have been seen to coincide with a shortened IgG half-life.
In contrast, pharmacokinetic studies in immunodeficient patients are based on the decline of IgG concentrations following infusion of large quantities of immune globulin. In such studies, investigators have reported uniformly prolonged half-lives of 26 to 35 days. Pharmacokinetic parameters for GAMMAGARD LIQUID were determined from total IgG levels following the fourth infusion in subjects with primary humoral immunodeficiency (N=61) treated intravenously with the product every 3 or 4 weeks according to the regimen used prior to entering the study. Of these, 57 had sufficient pharmacokinetic data to be included in the dataset. The median weight-adjusted dose per subject was 455mg/kg/4 weeks with a range
of 262 to 710. Pharmacokinetic parameters are presented in Table 13.
Table 13: Summary of Intravenous Pharmacokinetic Parameters in 57 Subjects
| Parameter | Median | 95% Confidence Interval |
| Dose of IgG (milligram/kg/4 weeks) | 455 | Range: 262-710 |
| Elimination Half-Life (T ½ days) | 35 | (31, 42) |
| AUC0-21d (milligram·days/dL) | 29139 | (27494, 30490) |
| Cmax (Peak, milligram/dL) | 2050 | (1980, 2200) |
| Cmin (Trough, milligram/dL) | 1030 | (939, 1110) |
| Incremental recovery (milligram/dL)/(milligram/kg) | 2.3 | (2.2, 2.6) |
|
Abbreviations: AUC=area under the curve, Cmax=maximum concentration, Cmin=minimum concentration. |
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Median IgG trough levels were maintained between 960 to 1120mg/dL. These dosing regimens-maintained serum trough IgG levels generally considered adequate to prevent bacterial infections. The elimination half-life of GAMMAGARD LIQUID (35 days) was similar to that reported for other IGIV products.
Pharmacokinetic (PK) parameters of subcutaneously administered GAMMAGARD LIQUID were evaluated in subjects with primary immunodeficiency (PI) who were 12 years and older during a clinical study [see Clinical Studies (14)].
Subjects were treated intravenously for 12 weeks with GAMMAGARD LIQUID and then switched to weekly subcutaneous GAMMAGARD LIQUID infusions. Initially, all subjects were treated for a minimum of 12 weeks at a subcutaneous dose that was 130% of the intravenous dose. A comparison of the area under the curve (AUC) for intravenous and subcutaneous infusions done on the first 15 adult subjects determined that the subcutaneous dose required to provide an exposure from subcutaneous administration that was not inferior to the exposure from intravenous administration was 137% of the intravenous dose. Subsequently, all subjects were treated with this dose for 6 weeks after which the dose was individualized for all subjects using IgG trough levels, as described below. After a minimum of 8 weeks at this subcutaneous dose, a PK evaluation was conducted on subjects 12 years of age or older (N=32).
The mean adjusted dose at the end of the study was 137.3% (125.7 to 150.8) of the intravenous dose for subjects 12 years and older, and 141.0% (100.5 to 160.0) for subjects under the age of 12. Thus, a significant dosing difference was not required for children. At this dose adjustment, the geometric mean ratio of the AUC for subcutaneous vs. intravenous GAMMAGARD LIQUID administration was 95.2% (90% confidence limit: 92.3 to 98.2). The peak IgG level occurred 2.9 (1.2 to 3.2) days after subcutaneous administration.
Pharmacokinetic parameters of GAMMAGARD LIQUID administered intravenously versus subcutaneously in the clinical study are shown in Table 14. The mean peak IgG level was lower (1393 ± 289 mg/dL) during subcutaneous treatment than with intravenous treatment (2240 ± 536 mg/dL), consistent with lower weekly doses compared with doses administered every 3 or 4 weeks intravenously. In contrast, the mean trough level was higher when GAMMAGARD LIQUID was given subcutaneously (1202 ± 282 mg/dL) than when it was given intravenously (1050 ± 260 mg/dL), a result of both higher monthly dose and more frequent dosing. The median IgG trough level during intravenous treatment in this clinical study, 1010 mg/dL (95% CI: 940 to 1240), was similar to the median IgG trough level of 1030 mg/dL (95% CI: 939 to 1110) during intravenous treatment as shown in Table 13. By contrast, the median IgG trough level during subcutaneous treatment was higher, at 1260 mg/dL (95% CI: 1060 to 1400).
Table 14: Pharmacokinetic Parameters of Subcutaneously Administered GAMMAGARD LIQUID Compared With GAMMAGARD LIQUID Administered Intravenously
| Subcutaneous Administration | Intravenous Administration | |||
| Number of Subjects | 32 | 32 | ||
| Dose a (milligram/kg) | ||||
| Mean ± SD | 182.6 ± 48.4 | 133.2 ± 36.9 | ||
| Range (min to max) | 94.2 to 293.8 | 62.7 to 195.4 | ||
| IgG Peak Levels (milligram/dL) | ||||
| Mean ± SD | 1393 ± 289 | 2240 ± 536 | ||
| Range (min to max) | 734 to 1900 | 1130 to 3610 | ||
| IgG Trough Levels (milligram/dL) | ||||
| Mean ± SD | 1202 ± 282 | 1050 ± 260 | ||
| Range (min to max) | 621 to 1700 | 532 to 1460 | ||
| AUC b(days*milligram/dL) | ||||
| Mean ± SD | 9176 ± 1928 | 9958 ± 2274 | ||
| Range (min to max) | 4695 to 12468 | 5097 to 13831 | ||
| Clearance [mL/kg/day] | ||||
| Mean ± SD | 2.023 ± 0.528 | 1.355 ± 0.316 | ||
| Range (min to max) | 1.225 to 3.747 | 0.880 to 2.340 | ||
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a Weekly equivalent dose |
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No full pharmacokinetic study was conducted in subjects with MMN. However, trough levels of IgG were measured in this population (n = 44; five 12 week study parts). The median serum trough level of total IgG over all study parts regardless of dosing intervals and length of infusion cycles, was 1640 (95% confidence interval: 1570 to 1710) mg/dL. During placebo administration, the median trough level was 1235 (95% CI: 1060 to 1360) mg/dL. The relationship between serum IgG concentration and efficacy was not assessed.
The full pharmacokinetic profile of GAMMAGARD LIQUID was not evaluated but serum trough IgG levels were measured in subjects with CIDP following administrations of GAMMAGARD LIQUID in the clinical study [see Clinical Studies (14)]. In 16 subjects who had previously received placebo in a preceding study and started administration of GAMMAGARD LIQUID after relapse, the median (range, number of subjects) serum trough IgG levels at baseline, Week 13, and Week 25 were 1220 (449 to 2220, N=16) mg/dL, 1810 (590 to 3200, N=13) mg/dL, and 1615 (712 to 3480, N=14) mg/dL, respectively.
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients to immediately report the following signs and symptoms to their healthcare provider:
Prior to starting GAMMAGARD LIQUID ask about a history of IgA deficiency, allergic reactions to immune globulin or other blood products. Patients with a history of allergic reactions should not be treated subcutaneously at home until several treatments have been administered and tolerated under medical supervision.
Inform patients that GAMMAGARD LIQUID is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the vCJD agent). The risk of GAMMAGARD LIQUID transmitting an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing. Patients should report any symptoms that concern them which might be caused by virus infections [see Warnings andPrecautions (5.8)].
Inform patients that GAMMAGARD LIQUID can interfere with their immune response to live viral vaccines such as measles, mumps, rubella and varicella, and instruct patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations [see Drug Interactions (7)].
Self-administration – If self-administration is deemed to be appropriate by the physician, clear instructions and training on subcutaneous infusion should be given to the patient/caregiver, and the demonstration of their ability to independently administer subcutaneous infusions should be documented.
