Gamunex

SIDE EFFECTS

Adverse Drug Reaction Overview

The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for PI was an exacerbation of autoimmune pure red cell aplasia in one subject.

The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for ITP was myocarditis in one subject that occurred 50 days post study drug infusion and was not considered drug related.

The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for CIDP was pulmonary embolism (PE) in one subject with a history of PE.

The most common drug related adverse reactions observed at a rate >5% in subjects with PI were headache, cough, injection site reaction, nausea, pharyngitis and urticaria.

The most common drug related adverse reactions observed at a rate >5% in subjects with ITP were headache, vomiting, fever, nausea, back pain and rash.

The most common drug related adverse reactions observed at a rate >5% in subjects with CIDP were headache, fever, chills and hypertension

Clinical Trials Adverse Drug Reactions

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

Adverse events similar to those previously reported with the administration of intravenous and intramuscular immunoglobulin products may occur. Cases of reversible aseptic meningitis, migraine, isolated cases of reversible hemolytic anemia and reversible increases in liver function tests have been observed with GAMUNEX (immune globulin intravenous (human) 10%) . Immediate anaphylactic reactions can possibly occur (<0.01%). Epinephrine should be available for treatment of any acute anaphylactoid reaction. (see WARNINGS and PRECAUTIONS)

Treatment of Primary Humoral Immunodeficiency

The following table shows the number of subjects treated with GAMUNEX (immune globulin intravenous (human) 10%) in clinical trials to study PI, and the reason for discontinuation due to adverse events:

Table 1: Reasons for Discontinuation Due to Adverse Events: All PI Studies

In study 100175, 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion. Generally, diphenhydramine and acetaminophen were used.

Any adverse events in trial 100175, irrespective of the causality assessment, are given in the following table.

Table 2: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100175)

The subset of drug related adverse events in trial 100175 reported by at least 5% of subjects during the 9-month treatment are given in the following table.

Table 3: Subjects with At Least One Drug Related Adverse Event (Study 100175)

Adverse events, which were reported by at least 5% of subjects, were also analyzed by frequency and in relation to infusions administered. The analysis is displayed in the following table.

Table 4: Adverse Event Frequency (Study 100175)

The mean number of adverse events per infusion that occurred during or on the same day as an infusion was 0.21 in both the GAMUNEX (immune globulin intravenous (human) 10%) and GAMIMUNE N treatment groups.

In all three trials in primary humoral immundeficiencies, the maximum infusion rate was 0.08 mL/kg/min (8 mg/kg/min). The infusion rate was reduced for 11 of 222 exposed subjects (7 GAMUNEX (immune globulin intravenous (human) 10%) , 4 GAMIMUNE N) at 17 occasions. In most instances, mild to moderate hives/urticaria, itching, pain or reaction at infusion site, anxiety or headache was the main reason. There was one case of severe chills. There were no anaphylactic or anaphylactoid reactions to GAMUNEX (immune globulin intravenous (human) 10%) or GAMIMUNE N.

In trial 100175, serum samples were drawn to monitor the viral safety at baseline and one week after the first infusion (for parvovirus B19), eight weeks after first and fifth infusion, and 16 weeks after the first and fifth infusion of IGIV (for hepatitis C) and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, Polymerase Chain Reaction (PCR), and serological testing. There were no treatment emergent findings of viral transmission for either GAMUNEX (immune globulin intravenous (human) 10%) , or GAMIMUNE N. [1, 3, 4]

Treatment of Idiopathic Thrombocytopenic Purpura

The following table shows the number of subjects treated with GAMUNEX (immune globulin intravenous (human) 10%) in clinical trials to study ITP, and the reason for discontinuation due to adverse events:

Table 5: Reasons for Discontinuation Due to Adverse Events: All ITP Studies

One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX (immune globulin intravenous (human) 10%) . The death was judged to be unrelated to GAMUNEX (immune globulin intravenous (human) 10%) .

No pre-medication with corticosteroids was permitted by the protocol. Twelve (12) ITP subjects treated in each treatment group were pretreated with medication prior to infusion. Generally, diphenhydramine and/or acetaminophen were used. More than 90% of the observed drug related adverse events were of mild to moderate severity and of transient nature.

The infusion rate was reduced for 4 of the 97 exposed subjects (1 GAMUNEX (immune globulin intravenous (human) 10%) , 3 GAMIMUNE N) on 4 occasions. Mild to moderate headache, nausea, and fever were the reported reasons. There were no anaphylactic or anaphylactoid reactions to GAMUNEX (immune globulin intravenous (human) 10%) or GAMIMUNE N.

Any adverse events in trial 100176, irrespective of the causality assessment, reported by at least 5% of subjects during the 3-month trial are given in the following table.

Table 6: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100176)

The subset of drug related adverse events in trial 100176 reported by at least 5% of subjects during the 3-month trial are given in the following table.

Table 7: Subjects with At Least One Drug Related Adverse Event (Study 100176)

Serum samples were drawn to monitor the viral safety of the ITP subjects at baseline, nine days after the first infusion (for parvovirus B19), and 3 months after the first infusion of IGIV and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, PCR), and serological testing. There were no treatment related emergent findings of viral transmission for either GAMUNEX (immune globulin intravenous (human) 10%) , or GAMIMUNE N [11].

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

In study 100538, 113 subjects were exposed to GAMUNEX and 95 were exposed to Placebo (See Clinical Studies). As a result of the study design, the drug exposure with GAMUNEX (immune globulin intravenous (human) 10%) was almost twice that of Placebo, with 1096 GAMUNEX (immune globulin intravenous (human) 10%) infusions versus 575 Placebo infusions. Therefore, adverse reactions are reported per infusion (represented as frequency) to correct for differences in drug exposure between the 2 groups. The majority of loading-doses were administered over 2 days. The majority of maintenance-doses were administered over 1 day. Infusions were administered in the mean over 2.7 hours.

The following table shows the numbers of subjects per treatment group in the CIDP clinical trial, and the reason for discontinuation due to adverse events:

Table 8: Reasons for Discontinuation Due to Adverse Events: CIDP

Adverse events reported by at least 5% of subjects in any treatment group irrespective of causality are shown in the following table.

Table 9: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100538)

Drug-related adverse events reported by at least 5% of subjects in any treatment group are reported in the following table. The most common drug-related events with GAMUNEX (immune globulin intravenous (human) 10%) were headache and pyrexia:

Table 10: Subjects with At Least 1 Drug Related Adverse Event (Study 100538)

Laboratory Abnormalities

During the course of the clinical program, ALT and AST elevations 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 (immune globulin intravenous (human) 10%) 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 (immune globulin intravenous (human) 10%) group versus 8/43 (19%) of subjects in the GAMIMUNE N group (p = 0.118).
• In the CIDP study (100538), 15/113 (13%) of subjects in the GAMUNEX (immune globulin intravenous (human) 10%) group and 7/95 (7%) in the Placebo group (p=0.168) had a treatment emergent transient elevation of ALT.

Elevations of ALT and AST were generally mild (<3 times upper limit of normal), transient, and were not associated with obvious symptoms of liver dysfunction.

GAMUNEX (immune globulin intravenous (human) 10%) class. may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4

Direct antiglobulin tests (DAT or direct Coombs tests), which are carried out in some centers as a safety check prior to red blood cell transfusions, may become positive temporarily. Hemolytic events not associated with positive DAT findings were observed in clinical trials.[1, 3, 4, 11, 36]

Postmarketing Experience

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.

GAMUNEX (immune globulin intravenous (human) 10%) Postmarketing Experience

The following adverse reactions have been identified and reported during the post marketing use of GAMUNEX (immune globulin intravenous (human) 10%) :

• Hematologic:Hemolytic anemia
• Infections and Infestations: Aseptic meningitis

General

The following adverse reactions have been identified and reported during the post marketing use of IGIV products [37]:

• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
• Cardiovascular:Cardiac arrest, thromboembolism, vascular collapse, hypotension
• Neurological: Coma, loss of consciousness, seizures/convulsions, tremor
• Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
• Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs test)
• General/Body as a Whole: Pyrexia, rigors
• Musculoskeletal: Back pain
• Gastrointestinal:Hepatic dysfunction, abdominal pain

Read the entire FDA prescribing information for Gamunex (Immune Globulin Intravenous (Human) 10%)