6 ADVERSE REACTIONS

Serious adverse reactions (ARs) observed in clinical trial subjects with primary humoral immunodeficiency (PI) were thrombosis and chest pain. The one event of thrombosis (1 subject, 2%) was reported in an adult who also had a diagnosis of antiphospholipid syndrome which results in increased clotting tendency [see Warnings and Precautions (5.2)].

Serious ARs observed in clinical trial subjects with immune thrombocytopenic purpura (ITP) were headache, vomiting and dehydration. In addition following a review of the data, 4 subjects (11%) were considered to have experienced asymptomatic suspected treatment-emergent hemolysis [see Clinical Trials Experience (6.1)].

The following potential serious ARs are described above and/or elsewhere in the labeling:

Thrombotic Events [see Warnings and Precautions (5.2)]
Hemolysis [see Warnings and Precautions (5.6)]

The most common ARs observed in the PI clinical trials were headache (29 subjects, 39%), pyrexia (11 subjects, 15%), nasal congestion/edema (10 subjects, 13%), fatigue (9 subjects, 12%), nausea (7 subjects, 9%), hypertension (6 subjects, 8%), rash (6 subjects, 8%), hypotension (5 subjects, 7%), infusion site reactions (5 subjects, 7%), vomiting (5 subjects, 7%), myalgia (4 subjects, 5%), chills (4 subjects, 5%), tachycardia (4 subjects, 5%), chest pain/discomfort (4 subjects, 5%), pain (4 subjects, 5%), dizziness (4 subjects, 5%), malaise (4 subjects, 5%), dysuria (4 subjects, 5%), and dry skin (4 subjects, 5%).

The most common ARs observed in the chronic ITP clinical trial were headache (12 subjects, 34%), vomiting (8 subjects, 23%), nausea (5 subjects, 14%), pyrexia (5 subjects, 14%), pruritus (2 subjects, 6%) and arthralgia (2 subjects, 6%).

6.1 Clinical Trials Experience

As clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Primary Humoral Immunodeficiency Study

In a multicenter, open-label, non-randomized clinical trial, 50 subjects with primary humoral immunodeficiency received doses of GAMMAPLEX 5% ranging from 279 to 799 mg/kg every 21 days (mean dose 465 mg/kg) or 28 days (mean dose 458 mg/kg), for up to 12 months [see Clinical Studies (14.1)].

Twenty-four subjects (48%) had an AR at some time during the clinical trial that was considered product-related. Of these 24 subjects, three had ARs that were considered definitely related to GAMMAPLEX 5% including headache, pyrexia, tachycardia, chest discomfort, and hypertension. More subjects with the 21-day infusion cycle had at least one AR (14 of 22 subjects, 64%) than subjects with the 28-day infusion cycle (10 of 28 subjects, 36%). The total number of ARs during infusion or within 72 hours of infusion was 237 (a rate of 0.34 ARs per infusion), reflecting that some subjects experienced more than one AR during the observation period. The percentage of GAMMAPLEX 5% infusions with one or more ARs within 72 hours of infusion was 21%. The upper bound of the 1-sided 95% confidence interval for this percentage was 24%, which was below the pre-specified upper limit of 40% for this safety endpoint.

The most common ARs observed in this clinical trial were headache (18 subjects, 36%), fatigue (6 subjects, 12%), nausea (6 subjects, 12%), pyrexia (6 subjects, 12%), pain (4 subjects, 8%), hypertension (3 subjects, 6%), chills (3 subjects, 6%), myalgia (3 subjects, 6%) and vomiting (3 subjects, 6%). Two subjects experienced serious ARs (thrombosis and chest pain).

Forty-seven of the 50 subjects enrolled in this clinical trial had a negative direct antiglobulin test (DAT) at baseline. Of these 47 subjects, 4 (9%) developed a positive DAT at some time during the clinical trial. However, no subjects showed evidence of hemolytic anemia.

There was no evidence of transmission of hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or parvovirus B19 during this clinical trial.

Table 2: Adverse Reactions (ARs*) Occurring in >5% of Subjects with PI†
Adverse Reactions	Subjects (%)	Infusions (%)
PI studies	PI [n=75]	PI [n=1071]
Headache	29 (39%)	74 (6.9%)
Sinusitis	14 (19%)	17 (1.6%)
Pyrexia	11 (15%)	13 (1.2%)
Nasal congestion/edema	10 (13%)	8 (0.7%)
Fatigue	9 (12%)	13 (1.2%)
Nausea	7 (9%)	8 (0.7%)
Hypertension	6 (8%)	8 (0.7%)
Upper respiratory tract infection	6 (8%)	8 (0.7%)
Rash	6 (8%)	6 (0.6%)
Hypotension	5 (7%)	11 (1.0%)
Infusion site reaction	5 (7%)	6 (0.6%)
Vomiting	5 (7%)	4 (0.4%)
Myalgia	4 (5%)	15 (1.4%)
Chills	4 (5%)	9 (0.8%)
Tachycardia	4 (5%)	6 (0.6%)
Rhinitis	4 (5%)	6 (0.6%)
Chest pain/discomfort	4 (5%)	5 (0.5%)
Pain	4 (5%)	5 (0.5%)
Dizziness/vertigo	4 (5%)	4 (0.4%)
Malaise/asthenia/lethargy	4 (5%)	4 (0.4%)
Dysuria/cystitis/UTI	4 (5%)	4 (0.4%)
Dry skin/eczema	4 (5%)	4 (0.4%)
Bronchitis	4 (5%)	4 (0.4%)

Table 3: ARs* in >5% of Pediatric Subjects with PI†
Adverse Reactions PI Pediatric	Subjects (%)	Infusions (%)
Adverse Reactions PI Pediatric	PI [n=25]	PI [n=368]
* Adverse Reactions (ARs) are defined as treatment emergent adverse events which met any of the following criteria: (a) adverse events which began during an infusion of GAMMAPLEX 5% or within 72 hours of the end of an infusion, (b) adverse events considered by the investigator or sponsor to have been possibly, probably, or definitely related to administration of GAMMAPLEX 5%, (c) adverse events for which the investigator's causality assessment was either missing or indeterminate. † ARs are presented for the PI studies if occurred in >5% of subjects. ARs seen in the pediatric study are presented in a separate table if occurred in >5% of pediatric subjects and were not reported in the major effectiveness study.
Dyspnea	2 (8%)	2 (0.5%)
Otitis media acute	2 (8%)	2 (0.5%)
Tonsillar disorder	2 (8%)	2 (0.5%)

Pediatric Primary Humoral Immunodeficiency Study

In a multicenter, open-label, non-randomized clinical trial, 25 children and adolescents with primary humoral immunodeficiency received doses of GAMMAPLEX 5% ranging from 300 to 800 mg/kg every 21 days (mean dose 545 mg/kg) or 28 days (mean dose 521 mg/kg), for up to 12 months [see Clinical Studies (14.1)].

Fourteen subjects (56%) had an AR at some time during the clinical trial that was considered product-related. Of these 14 subjects, two had ARs that were considered definitely related to GAMMAPLEX 5% including headache, fatigue and myalgia. Seven subjects with the 21-day infusion cycle had at least one AR (7 of 14 subjects, 50%), as did seven subjects with the 28-day infusion cycle (7 of 11 subjects, 64%).

Chronic Immune Thrombocytopenic Purpura Study

In a multicenter, open-label, non-randomized clinical trial, 35 subjects with chronic immune thrombocytopenic purpura were treated with a nominal dose of 1,000 mg/kg on each of two consecutive days (total dose 2,000 mg/kg). Doses of GAMMAPLEX 5% ranged from 482 to 1149 mg/kg on an infusion day. The median total dose per subject was 2035 mg/kg. Pre-medication with antihistamine or analgesic drugs was permitted if required, but corticosteroids were not permitted prior to infusion as pre-medication. Ten subjects received corticosteroids for ITP during the trial and one additional subject received corticosteroids as pre-medication in violation of the protocol. All 35 subjects received at least one infusion of clinical trial drug, and all but one subject completed the first course of treatment.

Twenty-four subjects (69%) reported at least one AR (103 in total); the most commonly reported being headache (12 subjects, 34%), vomiting (8 subjects, 23%), nausea (5 subjects, 14%), pyrexia (5 subjects, 14%), pruritus (2 subjects, 6%), dehydration (2 subjects, 6%) and arthralgia (2 subjects, 6%). Three subjects experienced a total of five serious ARs. Of the five serious ARs, one subject had three concurrently (vomiting, dehydration and headache) and two subjects each had one serious AR (headache). One of these latter two subjects discontinued from the clinical trial because of the severe headache. Table 4 lists the ARs in more than 5% of subjects.

Based on a review of clinical and laboratory data, 4/35 subjects (11%) with drops in hemoglobin exceeding 2 g/dL following administration of GAMMAPLEX 5% were considered to have experienced suspected treatment-emergent hemolysis. Milder treatment-emergent hemolysis could not be excluded for an additional 7 subjects, giving a total of 11 of 35 subjects (31%) for whom hemolysis could not be excluded (not including an additional two subjects who lacked follow-up testing for hemolysis, so their hemolysis status was considered unassessable). Data for two subjects were consistent with possible intravascular hemolysis, including one subject who may also have had an element of extravascular hemolysis. Nine of the possible hemolysis cases were mild and appeared consistent with possible extravascular hemolysis.

There was no evidence of transmission of HBV, HCV, HIV and parvovirus B19 during this clinical trial.

Table 4: Adverse Reactions (ARs*) Occurring in >5% of Subjects with ITP
Adverse Reactions	Subjects (%)	Infusions (%)
Adverse Reactions	ITP [n=35]	ITP [n=94]
* Adverse Reactions (ARs) are defined as treatment emergent adverse events which met any of the following criteria: (a) adverse events which began during an infusion of GAMMAPLEX 5% or within 72 hours of the end of an infusion, (b) adverse events considered by the investigator or sponsor to have been possibly, probably, or definitely related to administration of GAMMAPLEX 5%, (c) adverse events for which the investigator's causality assessment was either missing or indeterminate.
Headache	12 (34%)	15 (16%)
Vomiting	8 (23%)	9 (9.6%)
Nausea	5 (14%)	5 (5.3%)
Pyrexia	5 (14%)	7 (7.4%)
Pain	2 (6%)	2 (2.1%)
Abdominal pain upper	2 (6%)	2 (2.1%)
Gastritis	2 (6%)	2 (2.1%)
Contusion	2 (6%)	2 (2.1%)
Arthralgia	2 (6%)	2 (2.1%)
Cough	2 (6%)	2 (2.1%)
Anemia	2 (6%)	1 (1.1%)
Ecchymosis	2 (6%)	3 (3.2%)
Pruritus	2 (6%)	2 (2.1%)
Dehydration	2 (6%)	2 (2.1%)
Hypertension	2 (6%)	1 (1.1%)
Neck pain	2 (6%)	1 (1.1%)

6.2 Postmarketing Experience

As adverse reactions are voluntarily reported post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

In addition to the adverse reactions identified in clinical studies [see Adverse Reactions (6.1)], the following adverse reactions have been identified during postmarketing use of GAMMAPLEX 5%:

Infusion reactions: Dizziness
Respiratory: Pulmonary embolism, dyspnea, respiratory distress
Cardiovascular: Myocardial infarction, other thromboembolic event
Neurological: Migraine, aseptic meningitis
Integumentary: Rash, urticaria
Musculoskeletal: Musculoskeletal pain

The following adverse reactions have been identified during postmarketing use of intravenous immune globulins9:

Infusion reactions: Hypersensitivity (e.g. anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure
Renal: Acute renal dysfunction/failure, osmotic nephropathy
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, tremor, aseptic meningitis syndrome
Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g. bullous dermatitis)
Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test
Gastrointestinal: Hepatic dysfunction, abdominal pain
General/Body as a Whole: Pyrexia, rigors