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Gamunex (Immune Globulin Intravenous Human) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

GENERAL

Increases in creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following infusion with Immune Globulin Intravenous (Human) products, predominantly with products containing sucrose as stabilizer. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment29. GAMUNEX®, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer. In the studies undertaken to date with GAMUNEX®, no increase in creatinine and blood urea nitrogen was observed.

Although not necessarily observed for GAMUNEX®, adverse effects similar to those previously reported with administration of intravenous and intramuscular immunoglobulin products may occur. Potential reactions, therefore, may include pyrexia, rigors, dyspnea, cyanosis, hypoxemia, bronchospasm, hepatic dysfunction, leukopenia, pancytopenia, tremor, erythema multiforme, epidermolysis, back pain, abdominal pain, pulmonary edema, seizures, hypotension, thrombosis, transfusion related acute lung injury (TRALI).

True anaphylactic reactions to GAMUNEX® may occur in recipients with documented prior histories of severe allergic reactions to intramuscular immunoglobulin, but some subjects may tolerate cautiously administered intravenous immunoglobulin without adverse effects30, 31. Very rarely an anaphylactoid reaction may occur in subjects with no prior history of severe allergic reactions to either intramuscular or intravenous immunoglobulin.31

LABORATORY ABNORMALITIES

During the course of the clinical program, ALT and AST elevations, similar to those reported for other IGIV products32, 33, were identified in some subjects. For ALT, in the primary humoral immunodeficiency (PI) study (100175) treatment emergent elevations above the upper limit of normal were transient and observed among 14/80 (18%) of subjects in the GAMUNEX® group versus 5/88 (6%) of subjects in the GAMIMUNE® N group (p = 0.026). In the ITP study which employed a higher dose per infusion, but a maximum of only two infusions, the reverse finding was observed among 3/44 (7%) of subjects in the GAMUNEX® group versus 8/43 (19%) of subjects in the GAMIMUNE® N group (p = 0.118). 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® may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4 class. Direct antiglobin 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. GAMUNEX® does not contain irregular antibodies to Rhesus antigens or other non-ABO RBC antigens. Hemolytic events were not detected in association with positive DAT findings in clinical trials. 1, 3, 4, 11, 34

PRIMARY HUMORAL IMMUNODEFICIENCIES (PI)

In three randomized clinical trials, 119 subjects with primary humoral immunodeficiencies were exposed to 939 infusions with GAMUNEX®, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified. The rates of discontinuation from controlled clinical trials of GAMUNEX® due to adverse events were comparable to those of the GAMIMUNE® N, Immune Globulin Intravenous (Human), treatment group. For the Primary Humoral Immunodeficiency studies, 2 subjects (1.4%) treated with GAMUNEX® discontinued due to adverse events (Coombs negative hypochromic anemia, autoimmune pure red cell aplasia). Both events were considered unrelated to study drug as per the investigator.

Two pharmacokinetic trials were carried out in 18-20 subjects each with primary humoral immunodeficiencies, who received 100-600 mg/kg GAMUNEX® or GAMIMUNE® N, 10% for three infusions on a 3 or 4 week infusion interval and then crossed over to three infusions of the alternate product (studies 100152, 100174). In a third trial investigating therapeutic equivalence, 172 subjects were randomized to GAMUNEX® or GAMIMUNE® N for a nine-month double-blinded treatment with either of the two products at a dose between 200 and 600 mg/kg on a 3 or 4 week infusion interval (study 100175). In this trial, only 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, reported by at least 15% of subjects during the 9-month treatment are given in the table below.

Subjects with At Least One Adverse Event Irrespective of Causality (Study 100175)
Adverse Event GAMUNEX®
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%)
Heachache 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 severity of the adverse events across the treatment groups is displayed below.

Severity of Adverse Events Irrespective of Causality (Study 100175)
GAMUNEX®
No. events with
severity statement: 968
GAMIMUNE® N
No. events with
severity statement: 1083
Mild 558 (58%) 751 (69%)
Moderate 329 (34%) 259 (24%)
Severe 81 (8%) 73 (7%)

The subset of drug related adverse events in trial 100175 reported by at least 3% of subjects during the 9-month treatment are given in the table below.

Subjects with At Least One Drug Related Adverse Event (Study 100175)
Drug Related
Adverse Event
GAMUNEX®
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%)
Asthma 3 (3%) 0 (0%)
Asthenia 3 (3%) 2 (2%)
Fever 1 (1%) 6 (7%)

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 below.

Adverse Event Frequency (Study 100175)
Adverse Event     GAMUNEX®
No. of infusions: 825
No. of AE
(percentage of all infusions)
GAMIMUNE® N
No. of infusions: 865
No. of AE
(percentage of all infusions)
Cough increased All 154 (18.7%) 148 (17.1%)
Drug related 14 (1.7%) 11 (1.3%)
Pharyngitis All 96 (11.6%) 99 (11.4%)
Drug related 7 (0.8%) 9 (1.0%)
Headache All 57 (6.9%) 69 (8.0%)
Drug related 7 (0.8%) 11 (1.3%)
Fever All 41 (5.0%) 65 (7.5%)
Drug related 1 (0.1%) 9 (1.0%)
Nausea All 31 (3.8%) 43 (5.0%)
Drug related 4 (0.5%) 4 (0.5%)
Urticaria All 5 (0.6%) 8 (0.9%)
Drug related 4 (0.5%) 5 (0.6%)

The mean number of adverse events per infusion that occurred during or on the same day as an infusion was 0.21 in both the GAMUNEX® and GAMIMUNE® N treatment groups.

In all three trials in primary humoral immunodeficiencies, the maximum infusion rate was 0.08 mL/kg/min (8 mg/kg/min). The actual infusion rate was reduced for 11 of 222 exposed subjects (7 GAMUNEX®, 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® 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®, or GAMIMUNE® N.1, 3, 4

IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)

Two randomized clinical trials in acute or chronic ITP were conducted with GAMUNEX®. Seventy-six subjects with acute or chronic ITP were exposed to 170 infusions with GAMUNEX® (study 100176 and 100213). The rates of discontinuation from controlled clinical trials of GAMUNEX® due to adverse events were comparable to those of the GAMIMUNE® N treatment group. Altogether, 2 subjects (3%) treated with GAMUNEX® discontinued due to adverse events (headache, fever, vomiting, hives).

Study 100176 was a randomized double-blind therapeutic equivalence study, where 97 ITP subjects with acute or chronic ITP were randomized to a single dose of 2 g/kg of GAMUNEX® or GAMIMUNE® N. The total dose was divided into two 1 g/kg doses given on two consecutive days at a maximum infusion rate of 0.08 mL/kg/min. 48 subjects were exposed to 95 infusions with GAMUNEX®. One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX®. The death was unrelated to GAMUNEX®.

As expected, the adverse event rate of IGIV in this ITP trial was higher than observed in the replacement therapy for Primary Humoral Immunodeficiencies (PI), but was within the range reported earlier for IGIV35. It should be noted that the dose per infusion is 2-2.5 fold higher than in Primary Humoral Immunodeficiency and that the total dose was given on two consecutive days. Administration of other IGIV product(s) at 1g/kg/day for 2 consecutive days has been associated with a higher adverse event rate than when the same total dose of product(s) was administered over a 5 day period5. Finally, no pre-medication with corticosteroids was permitted by the protocol. Only 12 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.

Any adverse events in trial 100176, irrespective of the causality assessment, reported by at least 15% of subjects during the 3-month trial are given in the table below.

Subjects with At Least One Adverse Event Irrespective of Causality (Study 100176)
Adverse Event GAMUNEX®
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%)

The severity of the adverse events across the treatment groups is displayed below:

Severity of Adverse Events Irrespective of Causality (Study 100176)
GAMUNEX®
No. events with
severity statement: 418
GAMIMUNE® N
No. events with
severity statement: 444
Mild 307 (73%) 326 (73%)
Moderate 97 (23%) 96 (22%)
Severe 14 (3%) 22 (5%)

The subset of drug related adverse events in trial 100176 reported by at least 3% of subjects during the 3-month trial are given in the table below.

Subjects with At Least One Drug Related Adverse Event (Study 100176)
Drug Related Adverse Event GAMUNEX®
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%)
Asthenia 2 (4%) 3 (6%)
Abdominal Pain 2 (4%) 2 (4%)
Pruritus 2 (4%) 0 (0%)
Arthralgia 2 (4%) 0 (0%)
Dizziness 1 (2%) 3 (6%)
Neck Pain 0 (0%) 2 (4%)

The actual infusion rate was reduced for only 4 of the 97 exposed subjects (1 GAMUNEX®, 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® or GAMIMUNE® N.

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, serum samples were drawn to monitor the viral safety of the ITP subjects. 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®, or GAMIMUNE® N11.

Although the incidences of abnormal hematocrit, hemoglobin, RBC and glucose were twice as high in the GAMUNEX® group, the actual mean changes from baseline in these parameters were not different between study drugs and the magnitudes of these mean changes were small and clinically insignificant. These changes were attributed to pre-existing differences at baseline for the hematology parameters, which continued through the study with no incremental effect carried forward. For glucose, confounding variables such as non-fasting samples further suggest the finding to be by random chance.



REPORTS OF SUSPECTED GAMUNEX SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Gamunex. The information is not vetted and should not be considered as verified clinical evidence.

Possible Gamunex side effects / adverse reactions in 4 month old female

Reported by a physician from Canada on 2011-10-05

Patient: 4 month old female weighing 6.0 kg (13.2 pounds)

Reactions: Anti-Erythrocyte Antibody Positive, Haemolytic Anaemia

Adverse event resulted in: hospitalization

Suspect drug(s):
Igivnex
    Indication: Kawasaki's Disease
    Start date: 2011-07-24
    End date: 2011-07-24

Gamunex
    Indication: Kawasaki's Disease
    Start date: 2011-07-24
    End date: 2011-07-24

Gammagard Liquid
    Start date: 2011-07-27
    End date: 2011-07-27

Gammagard Liquid
    Indication: Kawasaki's Disease
    Start date: 2011-07-27
    End date: 2011-07-27

Other drugs received by patient: Potassium Chloride; Ceftriaxone; Aspirin; Acetaminophen



Possible Gamunex side effects / adverse reactions in 56 year old female

Reported by a individual with unspecified qualification from United States on 2011-10-14

Patient: 56 year old female

Reactions: Eye Swelling, Malignant Melanoma, Psoriasis, Infusion Related Reaction

Suspect drug(s):
Gamunex
    Indication: Immunodeficiency Common Variable

Hizentra
    Indication: Immunodeficiency Common Variable
    Start date: 2011-01-01
    End date: 2011-06-01



Possible Gamunex side effects / adverse reactions in 64 year old male

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-20

Patient: 64 year old male weighing 113.9 kg (250.5 pounds)

Reactions: Jugular Vein Thrombosis

Suspect drug(s):
Gamunex
    Dosage: 400 mg/kg;qm;iv
    Indication: Autoimmune Neuropathy
    Start date: 2011-05-11

Privigen
    Dosage: 400 mg/kg;qm;iv
    Indication: Autoimmune Neuropathy
    Start date: 2011-08-01
    End date: 2011-08-03

Other drugs received by patient: Zovirax /00587301/; Clonazepam; Ambien; Multi-Vitamins; Omeprazole; Isosorbide Dinitrate; Effexor XR; Indapamide; Flomax



See index of all Gamunex side effect reports >>

Drug label data at the top of this Page last updated: 2006-06-02

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