PI: Intravenous (IV)
| Dose | Initial Infusion Rate | Maintenance Infusion Rate |
|---|---|---|
| 300 to 600 milligram (mg)/kg every 3 to 4 weeks based on clinical response | 0.5milliliter (mL)/kg/hr (0.8 mg/kg/min) for 30 minutes | Increase every 30minutes (if tolerated) up to 5 mL/kg/hr (8 mg/kg/min) |
Subcutaneous (SC)
| Dose | Initial Infusion Rate | Maintenance Infusion Rate |
|---|---|---|
| Initial Dose is 1.37 × previous intravenous dose divided by # of weeks between intravenous doses. Maintenance dose is based on clinical response and target IgG trough level. | 40 kg BW and greater: 30 mL/site at 20 mL/hr/site Under 40 kg BW: 20 mL/site at 15 mL/hr/site | 40 kg BW and greater: 30 mL/site at 20 to 30 mL/hr/site Under 40 kg BW: 20 mL/site at 15 to 20 mL/hr/site |
MMN: Intravenous (IV)
| Dose | Initial Infusion Rate | Maintenance Infusion Rate |
|---|---|---|
| Dose range 0.5 to 2.4 gram/kg/month based on clinical response | 0.5mL/kg/hr (0.8 mg/kg/min) | Infusion rate may be advanced if tolerated to 5.4 mL/kg/hr (9 mg/kg/min) |
CIDP: Intravenous (IV)
| Dose | Initial Infusion Rate | Maintenance Infusion Rate |
|---|---|---|
| Induction dose is 2 g/kg in divided doses over 2 to 5 consecutive days, followed by maintenance infusions. Maintenance dose is 1 g/kg in divided doses over 1 to 4 consecutive days, every 3 weeks. | 0.5 mL/kg/hr (0.8 mg/kg/min) | Infusion rate may be increased if tolerated up to 5.4 mL/kg/hr (9 mg/kg/min) |
GAMMAGARD LIQUID is indicated as replacement therapy for primary humoral immunodeficiency (PI) in adult and pediatric patients two years of age or older. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.1,2
GAMMAGARD LIQUID is indicated as a maintenance therapy to improve muscle strength and disability in adult patients with Multifocal Motor Neuropathy (MMN).
GAMMAGARD LIQUID is indicated as a therapy to improve neuromuscular disability and impairment in adult patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).
Limitation of Use
GAMMAGARD LIQUID has not been studied in immunoglobulin-naive patients with CIDP. GAMMAGARD LIQUID maintenance therapy in CIDP has not been studied for periods longer than 6 months. After responding during an initial treatment period, not all patients require indefinite maintenance therapy with GAMMAGARD LIQUID in order to remain free of CIDP symptoms. Individualize the duration of any treatment beyond 6 months based upon the patient’s response and demonstrated need for continued therapy.
Intravenous Administration (IV)
| Dose | Initial Infusion rate | Maintenance Infusion rate |
|---|---|---|
| 300 to 600 milligram (mg)/kg every 3 to 4 weeks based on clinical response | 0.5 milliliter (mL)/kg/hr (0.8mg/kg/min) for 30 minutes | Increase every 30 minutes (if tolerated) up to 5 mL/kg/hr (8mg/kg/min) |
Dose Adjustments
Adjust dose according to IgG levels and clinical response, as the frequency and dose of immune globulin may vary from patient to patient.
No randomized controlled clinical studies are available to determine an optimum trough serum IgG level for intravenous treatment. If a patient misses a dose, administer the missed dose as soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable.
Prior to switching from intravenous to subcutaneous treatment, obtain the patient's serum IgG trough level to guide subsequent dose adjustments. Start the initial subcutaneous dose approximately one week after the last intravenous infusion.
Dose Adjustments for Measles Exposure
If a patient has been exposed to measles, it may be prudent to administer an extra dose of GAMMAGARD LIQUID as soon as possible and within 6 days of exposure. A dose of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at least two weeks.
If a patient is at risk of future measles exposure and receives a dose of less than 530 mg/kg every 3 to 4 weeks, the dose should be increased to at least 530 mg/kg. This should provide a serum level of 240 mIU/mL of measles antibodies for at least 22 days after infusion.
Subcutaneous Administration (SC)
| Dose | Initial Infusion rate | Maintenance Infusion rate |
|---|---|---|
| Initial dose is 1.37 × previous intravenous dose divided by # of weeks between intravenous doses. Maintenance dose is based on clinical response and target IgG trough level. | 40 kg BW and greater: 30 mL/site at 20 mL/hr/site. Under 40 kg BW: 20 mL/site at 15 mL/hr/site. | 40 kg BW and greater: 30 mL/site at 20 to 30 mL/hr/site. Under 40 kg BW: 20 mL/site at 15 to 20 mL/hr/site. |
Dose Adjustments
Based on the results of clinical studies, the expected increase in serum IgG trough level during weekly subcutaneous treatment at the dose adjusted to provide a comparable AUC, is approximately 281 mg/dL higher than the last IgG trough level during prior stable intravenous treatment. To calculate the target trough IgG level for subcutaneous treatment, add 281 mg/dL to the IgG trough level obtained after the last intravenous treatment.
To guide dose adjustment, calculate the difference between the patient's target serum IgG trough level and the IgG trough level during subcutaneous treatment. Find this difference in the columns of Table 3 and the corresponding amount (in mL) by which to increase (or decrease) the weekly dose based on the patient's body weight. If the difference between measured and target trough levels is less than 100 mg/dL then no adjustment is necessary. However, the patient's clinical response should be the primary consideration in dose adjustment.
| ||||
Difference between Measured and Target IgG Trough Levels | ||||
Body Weight | 100 mg/dL | 200 mg/dL | 300 mg/dL | 400 mg/dL |
10 kg | 2 mL | 4 mL | 6 mL | 8 mL |
20 kg | 4 mL | 8 mL | 11 mL | 15 mL |
30 kg | 6 mL | 11 mL | 17 mL | 23 mL |
40 kg | 8 mL | 15 mL | 23 mL | 30 mL |
50 kg | 9 mL | 19 mL | 28 mL | 38 mL |
60 kg | 11 mL | 23 mL | 34 mL | 45 mL |
70 kg | 13 mL | 26 mL | 40 mL | 53 mL |
80 kg | 15 mL | 30 mL | 45 mL | 60 mL |
90 kg | 17 mL | 34 mL | 51 mL | 68 mL |
100 kg | 19 mL | 38 mL | 57 mL | 75 mL |
110 kg | 21 mL | 42 mL | 62 mL | 83 mL |
120 kg | 23 mL | 45 mL | 68 mL | 91 mL |
130 kg | 25 mL | 49 mL | 74 mL | 98 mL |
140 kg | 26 mL | 53 mL | 79 mL | 106 mL |
Example 1: A patient with a body weight of 80 kg has a measured IgG trough level of 800 mg/dL and the target trough level is 1000 mg/dL. The desired target trough level difference is 200 mg/dL (1000 mg/dL minus 800 mg/dL). The weekly dose of GAMMAGARD LIQUID should be increased by 30 mL (3.0 gm).
Example 2: A patient with a body weight of 60 kg has a measured IgG trough of 1000 mg/dL and the target trough level is 800 mg/dL. The desired target trough level difference is 200 mg/dL (800 mg/dL minus 1000 mg/dL). The weekly dose of GAMMAGARD LIQUID should be decreased by 23 mL (2.3 gm).
Intravenous Administration (IV)
| Dose | Initial Infusion rate | Maintenance Infusion rate |
|---|---|---|
| Dose range 0.5 to 2.4 gram/kg/month based on clinical response | 0.5 mL/kg/hr (0.8 mg/kg/min) | Infusion rate may be increased if tolerated up to 5.4 mL/kg/hr (9 mg/kg/min) |
Dose Adjustments
The dose may need to be adjusted to achieve the desired clinical response. In the clinical study, the dose ranged between 0.5 to 2.4 grams/kg/month. While receiving GAMMAGARD LIQUID, 9% of subjects in the clinical study experienced neurological decompensation that required an increase in dose. In order to avoid worsening of muscle weakness in patients, dose adjustment may be necessary.
Intravenous Administration (IV)
| Dose | Initial Infusion rate | Maintenance Infusion rate |
|---|---|---|
| Induction dose is 2 g/kg in divided doses over 2 to 5 consecutive days, followed by maintenance infusions. Maintenance dose is 1 g/kg in divided doses over 1 to 4 consecutive days, every 3 weeks. | 0.5 mL/kg/hr (0.8 mg/kg/min) | Infusion rate may be increased if tolerated up to 5.4 mL/kg/hr (9 mg/kg/min) |
Dose Adjustments
The induction dose is 2 g/kg divided over 2 to 5 consecutive days, followed by 1 g/kg maintenance doses divided over 1 to 4 days consecutive days, every 3 weeks. The maintenance dose level and dosing interval of GAMMAGARD LIQUID treatment may be adjusted according to the clinical response.
The recommended initial infusion rate is 0.5 mL/kg/hr (0.8 mg/kg/min). If the infusion is well tolerated, the rate may be gradually increased to a maximum of 5.4 mL/kg/hr (9 mg/kg/min). [see Administration (2.5)].
For patients at risk of renal dysfunction or thromboembolic events, do not exceed the recommended dose. Infuse at the minimum intravenous infusion rate practicable [see Warnings and Precautions (5.2, 5.4) and Use In Specific Populations (8.5)].
Intravenous administration
PI | MMN | CIDP | |
Initial | 0.5 mL/kg/hr | Increasing rates of infusion starting at 0.5 mL/kg/h (0.8 mg/kg/min) | 0.5 mL/kg/hr (0.8 mg/kg/min) |
Subsequent | Increase every 30 minutes (if tolerated) up to 5 mL/kg/hr (8 mg/kg/min) | Increasing to a maximum rate of 5.4 mL/kg/hr if tolerated (9 mg/kg/min) | Increase to a maximum rate of 5.4 mL/kg/hr if tolerated (9 mg/kg/min) |
Monitor patient vital signs throughout the infusion. Certain adverse reactions (ARs) such as headaches, flushing, and changes in pulse rate and blood pressure may be related to the rate of infusion. Slow or stop infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that does not result in recurrence of the symptoms.
Adverse reactions may occur more frequently in patients receiving immune globulin for the first time, upon switching brands or if there has been a long interval since the previous infusion.2 In such cases, start at lower infusion rates and gradually increase as tolerated.
Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients over 65 years of age or judged to be at risk for renal dysfunction or thrombotic events, administer GAMMAGARD LIQUID at the minimum infusion rate practicable. In such cases, the maximal rate should be less than 3.3 mg/kg/min (<2 mL/kg/hr); consider discontinuation of administration if renal function deteriorates [see Warnings and Precautions (5.2, 5.4) and Use In Specific Populations (8.5)].
Subcutaneous administration for PI
40 kg BW and greater | Under 40 kg BW | |
Initial | 30 mL/site at a rate of 20 mL/hr/site | 20 mL/site at a rate of 15 mL/hr/site |
Maintenance | 30 mL/site at a rate of 20 to 30 mL/hr/site | 20 mL/site at a rate of 15 to 20 mL/hr/site |
Selection of Infusion Site: Suggested areas for subcutaneous infusion of GAMMAGARD LIQUID are abdomen, thighs, upper arms, or lower back. Infusion sites should be at least two inches apart, avoiding bony prominences. Rotate sites each week.
Volume per Site: The weekly dose (mL) should be divided by 30 or 20, based on patient weight above, to determine the number of sites required. Simultaneous subcutaneous infusion at multiple sites can be facilitated by use of a multi-needle administration set.
Rate of Infusion for Patients 40 kg and greater (88 lbs): If multiple sites are used, the rate set on the pump should be the rate per site multiplied by the number of sites (e.g., 30 mL x 4 sites = 120 mL/hr). The number of simultaneous sites should be limited to 8, or maximum infusion rate of 240 mL/hr.
Rate of Infusion for Patients under 40 kg (88 lbs): If multiple sites are used, the rate set on the pump should be the rate per site multiplied by the number of sites (e.g., 20 mL x 3 sites = 60 mL/hr). The number of simultaneous sites should be limited to 8, or maximum infusion rate of 160 mL/hr.
Instructions for Subcutaneous Administration: Instruct patients to observe the following procedures:
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GAMMAGARD LIQUID is an aqueous solution containing 10% IgG (100 mg/mL).
Risk Summary
Animal reproduction studies have not been conducted with GAMMAGARD LIQUID. It is not known whether GAMMAGARD LIQUID can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. GAMMAGARD LIQUID should be given to a pregnant woman only if clearly indicated.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Risk Summary
There is no information regarding the presence of GAMMAGARD LIQUID in human milk, its effects on the breastfed infant or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GAMMAGARD LIQUID and any potential adverse effects on the breastfed infant from GAMMAGARD LIQUID or from the underlying maternal condition.
Treatment of Primary Immunodeficiency (PI)
GAMMAGARD LIQUID administered intravenously was evaluated in 15 pediatric subjects with PI (7 subjects aged 2 to <12 years and 8 subjects aged 12 to <16 years) in a multicenter clinical study. GAMMAGARD LIQUID administered subcutaneously was evaluated in 18 pediatric subjects with PI (14 subjects aged 2 to <12 years and 4 subject aged 12 to <16 years) in another multicenter clinical study. The safety and efficacy profiles were similar to adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.
Safety and efficacy of GAMMAGARD LIQUID in pediatric patients below the age of 2 have not been established.
Treatment of Multifocal Motor Neuropathy (MMN) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Safety and effectiveness in pediatric patients with MMN and CIDP have not been established.
Treatment of Primary Immunodeficiency (PI)
Limited information is available for the geriatric use of GAMMAGARD LIQUID. GAMMAGARD LIQUID administered intravenously and subcutaneously was evaluated in two PI studies with a total of 8 subjects over the age of 65 years. No differences in safety or efficacy were observed for this group. Monitor patients who are at an increased risk for developing renal failure or thrombotic events. Do not exceed the recommended dose. Infuse at the minimum intravenous infusion rate practicable [see Boxed Warning, Warnings and Precautions (5.2, 5.4) and Dosage and Administration (2.5)].
Treatment of Multifocal Motor Neuropathy (MMN)
GAMMAGARD LIQUID was administered intravenously for treatment of MMN in 5 subjects aged 65 years and above. There was an insufficient number of subjects aged 65 years and above to determine whether they respond differently from younger subjects [see Boxed Warning, Warnings and Precautions (5.2, 5.4) and Dosage and Administration (2.5)].
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
GAMMAGARD LIQUID was administered intravenously for the treatment of CIDP in 5 subjects aged 65 years and above and 15 subjects aged below 65 years. There was an insufficient number of subjects aged 65 years and above to determine whether they respond differently from younger subjects. [see Boxed Warning, Warnings and Precautions (5.2, 5.4) and Dosage and Administration (2.5)].
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)].
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.
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)].
GAMMAGARD LIQUID 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. The Fc and Fab functions are maintained in GAMMAGARD LIQUID. Pre-kallikrein activator activity is not detectable. GAMMAGARD LIQUID contains 100 mg/mL protein. At least 98% of the protein is immune globulin, the average immunoglobulin A (IgA) concentration is 37 µg/mL, and immunoglobulin M is present in trace amounts. GAMMAGARD LIQUID contains a broad spectrum of IgG antibodies against bacterial and viral agents. Glycine (0.25M) serves as a stabilizing and buffering agent. There are no added sugars, sodium or preservatives. The pH is 4.6 to 5.1. The osmolality is 240 to 300 mOsmol/kg, which is similar to physiological osmolality (285 to 295 mOsmol/kg).
GAMMAGARD LIQUID is manufactured from large pools of human plasma. IgG preparations are purified from plasma pools using a modified Cohn-Oncley cold ethanol fractionation process, as well as cation and anion exchange chromatography.
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 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 to be negative.
To further improve the margin of safety, validated virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely solvent/detergent (S/D) treatment,10 35 nm nanofiltration, and a low pH incubation at elevated temperature (30 C to 32 C). 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. S/D treatment inactivates the lipid-enveloped viruses investigated to below detection limits within minutes.12
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, 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 performed in accordance with good laboratory practices are summarized in Table 12.
| 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 lipid 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). | |||||||
| |||||||
Virus type | Enveloped RNA | Enveloped DNA | Non-enveloped | Non-enveloped | |||
Family | 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. † | >6.3 | 3.1 |
Overall log reduction factor (ORF) | >14.8 | >16.8 | >12.2 | >16.9 | 5.7 † | >7.7 | 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.
Treatment of Primary Immunodeficiency (Intravenous)
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.
| Abbreviations: AUC=area under the curve, Cmax=maximum concentration Cmin=minimum concentration. | ||
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) |
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.
Treatment of Primary Immunodeficiency (Subcutaneous)
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).
| Subcutaneous Administration | Intravenous Administration | ||
|---|---|---|---|
| Number of Subjects | 32 | 32 | |
| |||
| Dose * (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 † (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 | |
Treatment of Multifocal Motor Neuropathy (Intravenous)
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.
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (Intravenous)
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.
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.
Treatment of Primary Immunodeficiency (Intravenous)
Intravenous use of GAMMAGARD LIQUID is supported by a study in subjects (N=61) who were treated with 300 to 600 mg/kg every 21 to 28 days for 12 months. The age range of subjects was 6 to 72 years, with 54% female and 46% male, and 93% Caucasian, 5% African American, and 2% Asian. Three subjects were excluded from the per-protocol analysis due to non-study product related reasons. The annualized rate of prespecified acute serious bacterial infections, i.e., the mean number of prespecified acute serious bacterial infections per subject per year, was studied (see Table 15).
| |
Number of Events | |
Validated Infections * | |
Bacteremia / Sepsis | 0 |
Bacterial Meningitis | 0 |
Osteomyelitis / Septic Arthritis | 0 |
Bacterial Pneumonia | 0 |
Visceral Abscess | 0 |
Total | 0 |
Hospitalizations Secondary to Infection | 0 |
Mean Number of Validated Infections per Subject per Year | 0 |
p-value † | p < 0.0001 |
95% Confidence Interval † | (0.000, 0.064) |
The annualized rate of other prespecified validated bacterial infections (see Table 16), and the number of hospitalizations secondary to all validated infectious complications also were studied (see Table 15 and Table 16).
| |
Number of Events | |
Validated Infections * | |
Urinary Tract Infection | 1 |
Gastroenteritis | 1 |
Lower Respiratory Tract Infection: Tracheobronchitis, Bronchiolitis (Without Evidence of Pneumonia) | 0 |
Lower Respiratory Tract Infection: | 0 |
Otitis Media | 2 |
Total | 4 |
Hospitalizations Secondary to Infection | 0 |
Mean Number of Validated Infections per Subject per Year | 0.07 |
95% Confidence Interval | (0.018, 0.168) |
None of the 61 treated subjects was positive for HCV, HIV-1, and HIV-2 and HBV prior to study entry and none converted from negative to positive during the 12-month period.
Treatment of Primary Immunodeficiency (Subcutaneous)
A prospective, open-label, non-controlled, multicenter study was conducted in the U.S. to determine the efficacy, tolerability and PK of GAMMAGARD LIQUID subcutaneous infusion in adult and pediatric subjects (N=49) with PI. All subjects were treated for 12 weeks with GAMMAGARD LIQUID intravenous infusion every 3 or 4 weeks. Subjects who were on intravenous treatment prior to entering the study were switched to GAMMAGARD LIQUID at the same dose and frequency. Subjects who were receiving subcutaneous immune globulin were switched to GAMMAGARD LIQUID at the intravenous dose they had received prior to switching to subcutaneous treatment. A PK analysis was performed at the end of the intravenous period in all subjects aged 12 years and older.
One week after the last intravenous infusion, each subject began subcutaneous treatment with GAMMAGARD LIQUID at 130% of the weekly equivalent of the intravenous dose for a minimum of 12 weeks. PK data from the first 15 adult subjects were used to determine the dose required to ensure that the IgG exposure with subcutaneous treatment was not inferior to that with intravenous treatment. The median dose determined from these subjects was 137% of the intravenous dose, and subsequently all subjects were treated for a minimum of 6 weeks at this dose. After 6 subcutaneous infusions, a trough IgG level was obtained and used to individually adapt the subcutaneous dose of GAMMAGARD LIQUID to compensate for individual variation from the mean value of 137% [see Pharmacokinetics (12.3) and Dosage and Administration (2.1)].
All subjects received a minimum of 12 infusions at this individually adapted dose and continued to receive subcutaneous treatment with GAMMAGARD LIQUID until the last subject completed the study. Subjects (N=47) were treated with 2,294 subcutaneous infusions of GAMMAGARD LIQUID: 4 subjects treated for up to 29 weeks, 17 subjects for 30 to 52 weeks, and 26 subjects for 53 weeks or longer. Two subjects that completed the intravenous treatment part of the study did not continue to the subcutaneous treatment part of the study. The median duration of subcutaneous treatment was 379 days (range: 57 to 477 days).
Efficacy was determined throughout the entire subcutaneous phase. There were 31 adults aged 16 years or older, 4 adolescents aged 12 to <16 years, and 14 children aged 2 to <12 years. The volume of GAMMAGARD LIQUID infused was 30 mL per site for subjects weighing 40 kg and greater, and 20 mL per site for those weighing less than 40 kg. The total weekly dose was divided by those values to determine the number of sites.
Mean weekly subcutaneous doses ranged from 181.9 mg/kg to 190.7 mg/kg (at 130% to 137% of the intravenous dose). In the study, the number of infusion sites per infusion was dependent on the dose of IgG and ranged from 2 to 10. In 75% of infusions, the number of infusion sites was 5 or fewer.
There were 3 serious validated bacterial infections, all bacterial pneumonia. None of these subjects required hospitalization to treat their infection. The annual rate of acute serious bacterial infections while on GAMMAGARD LIQUID subcutaneous treatment was 0.067, with an upper 99% confidence limit of 0.133, which is lower than the minimal goal of achieving a rate of <1 bacterial infection per patient-year.
Table 17 presents a summary of infections and associated events for subjects during subcutaneous treatment with GAMMAGARD LIQUID. The annual rate of any infection in this study during subcutaneous treatment, including viral and fungal infections, was 4.1 infections per subject per year.
| |
Number of subjects (efficacy phase) Total number of subject years Annual rate of any infections | 47 44 4.1 (95% CI 3.2 to 5.1) infections/subject year |
Antibiotic use * (prophylaxis or treatment) | |
Number of subjects (%) Annual rate | 40 (85.1%) 50.2 (95% CI 33.4 to 71.9) days/subject year |
Days out of work/school/day care or unable to perform normal activities | |
Number of subjects (%) Annual rate | 25 (53.2%) 4.0 (95% CI 2.5 to 6.1) days/subject year |
Hospitalizations due to infections | |
Number of subjects (%) Annual rate | 0 (0.0%) 0.0 (95% CI 0.0 to 0.1) days/subject year |
Treatment of Multifocal Motor Neuropathy
A randomized, double-blind, placebo controlled, cross-over withdrawal study was conducted to evaluate the efficacy and safety/tolerability of GAMMAGARD LIQUID in adult subjects (N=44) with MMN.12 The study examined grip strength in the more affected hand11 (measured with dynamometer), and Guy's Neurological Disability Scale (GNDS) [upper limb part 6 subsection].13 Study subjects were on a regimen of licensed immunoglobulin (existing maintenance dose ranging from 0.5 to 2.0 grams/kg/month) prior to enrollment and thus, the results cannot be generalized to naïve patients.
The study comprised of five study periods, each lasting 12 weeks: 3 stabilization phases, one randomized withdrawal phase and one cross-over phase. Open-label GAMMAGARD LIQUID was administered at the beginning (study period 1) and at the end of the study (study period 5) for clinical stabilization, and between the double-blinded periods to prevent carry-over effect (study period 3). If, during either of the double-blinded treatment periods, the subject's upper limb function involving the affected muscles deteriorated such that the subject had difficulty completing daily activities or experienced a decline in grip strength of ≥50% in the more affected hand, the subject was switched directly to the next stabilization phase of open-label GAMMAGARD LIQUID ("accelerated switch") without breaking the blind.
All subjects were treated for 12 weeks with open-label GAMMAGARD LIQUID during initial stabilization (study period 1). Each subject was then randomized in a double-blind manner to continuation of GAMMAGARD LIQUID or withdrawal of GAMMAGARD LIQUID and replacement by placebo for 12 weeks (study period 2); subjects who did not tolerate treatment were immediately transitioned to open label GAMMAGARD LIQUID. After infusion of open-label GAMMAGARD LIQUID for 12 weeks (study period 3), subjects crossed-over to receive placebo or GAMMAGARD LIQUID for 12 weeks (study period 4). No subject was allowed to experience placebo more than one time during the study. At study end, subjects were treated with open-label GAMMAGARD LIQUID for 12 weeks (study period 5).
Overall, 69% (n=29) of subjects required an accelerated switch to open-label treatment with GAMMAGARD LIQUID during the placebo period due to functional deterioration, but did not switch when receiving GAMMAGARD LIQUID. The median number of treatment days using GAMMAGARD LIQUID was 84 and the median number of days using placebo was 28. One subject (2.4%) switched to open‑label treatment during blinded GAMMAGARD LIQUID cross-over period 1, but did not switch during placebo administration (p <0.001).
Forty-four subjects were evaluated to demonstrate effectiveness of GAMMAGARD LIQUID to improve or maintain muscle strength and functional ability in patients with MMN.
Statistical significance (p<0.001) favoring GAMMAGARD LIQUID over placebo was demonstrated by a substantially lower decline from baseline (22.30%; 95% CI: 9.92% to 34.67%) in mean grip strength in the more affected hand following treatment (see Table 18). The difference in relative change for GAMMAGARD LIQUID and placebo of 22.94% (95% CI: 10.69 to 35.19).
| |||||
Statistics | Sequence 1 | Sequence 2 | Difference | ||
GAMMAGARD LIQUID | Placebo | Placebo | GAMMAGARD LIQUID | (GAMMAGARD LIQUID - Placebo) | |
N | 22 | 22 | 19 | 20 * | 41 |
Mean (SD) | -16.36 (32.84) | -30.52 (29.68) | -29.19 | 1.46 | 22.30 |
Median | -3.90 | -27.00 | -25.03 | -0.11 | 26.6 |
Guy's Neurological Disability Scores (GNDS)12 for the upper limbs, reflecting both fine motor skills and proximal strength, showed a significant difference in efficacy between GAMMAGARD LIQUID and placebo at the 2.5% level in favor of GAMMAGARD LIQUID. GNDS is a patient orientated clinical disability scale designed for multiple sclerosis and is considered appropriate for other neurological disorders.
As determined by GNDS scores for the upper limbs, 35.7% of subjects deteriorated while receiving placebo but not during treatment with GAMMAGARD LIQUID, whereas 11.9% of subjects deteriorated during GAMMAGARD LIQUID but not during the placebo period. This difference was statistically significant (p=0.021) (see Table 19). Overall, 4.8% of subjects showed deterioration with both placebo and GAMMAGARD LIQUID, while 47.6% showed no deterioration using either.
Deterioration on Placebo | 15 (35.7%) |
Deterioration on GAMMAGARD LIQUID | 5 (11.9%) |
Deterioration on both | 2 (4.8%) |
No deterioration | 20 (47.6%) |
When data from both treatment sequences were combined, a relative decline of ≥30% in grip strength in the more affected hand occurred in 42.9% of subjects during the placebo period, but not during treatment with GAMMAGARD LIQUID, whereas 4.8% of subjects experienced a ≥30% decline during treatment with GAMMAGARD LIQUID, but not during placebo. A relative decline of ≥30% in grip strength in the less affected hand occurred in 31.0% of subjects during the placebo period, but not during treatment with GAMMAGARD LIQUID. No subject experienced a ≥30% decline during treatment with GAMMAGARD LIQUID.
The Overall Disability Sum Score (ODSS) changed by -7.14% during placebo (indicating worsening of disability) and by -1.11% (indicating minimal change in disability) during treatment with GAMMAGARD LIQUID. For this specific analysis of ODSS, lower scores represented more disability.
With the dominant hand, subjects required 17% longer to complete the 9-hole peg test (a measure of dexterity) at the end of the placebo period, compared with baseline. By contrast, at the end of the GAMMAGARD LIQUID treatment period, subjects required 1.2% longer to complete the 9-hole peg test for the dominant hand compared with baseline. With the non-dominant hand, subjects required 33% longer to complete the 9-hole peg test at the end of the placebo period and 6.7% longer at the end of the GAMMAGARD LIQUID treatment period, compared with baseline.
Compared with baseline, assessment by subjects of physical functioning, as measured by visual analog scale (VAS) showed a mean change of 290% during placebo compared with baseline. Assessment by subjects of physical functioning showed a mean change of 73% during GAMMAGARD LIQUID treatment. Higher visual analog scale scores represent more severe disability.
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
In a prospective, open-label, single-arm, multicenter clinical study, a total of 18 subjects who developed a relapse in Epoch 1 and received GAMMAGARD LIQUID in Epoch 2 were included in efficacy analyses. GAMMAGARD LIQUID was administered at an induction dose of 2 g/kg body weight, followed by maintenance infusions at every 3 weeks for a period of 6 months. The dose of GAMMAGARD LIQUID treatment could be adjusted at the investigator's discretion. Adjustments to the dosing interval of every 3 weeks were not allowed. All subjects completed the study. All dosed subjects were analyzed for efficacy and safety.
Efficacy in Epoch 2 was based on responder rate, where a responder was defined as a subject who demonstrated an improvement of functional disability, indicated by at least a 1 point decrease in the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score at the completion of the IV treatment period (6 months) or the last study visit of the IV treatment period, relative to pre-IV treatment baseline. The responder rate was 94.4% (N=18, 95% CI: 74.2% to 99.0%). The adjusted INCAT score returned back to baseline values prior to joining the study in 17 of the 18 subjects (94.4%) at 6 months. All subjects (N=18) had improvement in functional ability. Functional ability was a composite measure based on meeting any of the following criteria: decrease of ≥1 point in the adjusted INCAT disability score, increase of ≥8 kPa in hand grip strength in the more affected hand, or increase of ≥4 points in raw summed RODs score.
The mean adjusted INCAT score showed an improvement by 2.1 points. Medical Research Council (MRC) sum score improved by a mean of 5.4 points. The mean change in centile Rasch-built Overall Disability Scale (RODS) score was 15.0 points. Grip strength improved by a mean of 13.8 kPa in the more affected hand and 9.8 kPa in the less affected hand.
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.
