6 ADVERSE REACTIONS

PI: Intravenous: The most common adverse reactions observed at a rate ≥ 5% in subjects with intravenous treatment in the clinical trials were cough increased, rhinitis, pharyngitis, headache, asthma, nausea, fever, diarrhea, and sinusitis.

PI: Subcutaneous: The most common adverse reactions observed at a rate ≥ 5% of subjects with subcutaneous treatment in the clinical trials were local infusion site reactions, fatigue, headache, upper respiratory tract infection, arthralgia, diarrhea, nausea, sinusitis, bronchitis, depression, allergic dermatitis, erythema, migraine, myalgia, viral infection, and pyrexia.

ITP: The most common adverse reactions observed at a rate ≥ 5% in subjects in the clinical trials were headache, ecchymosis, vomiting, fever, nausea, rash, abdominal pain, back pain and dyspepsia.

CIDP: The most common adverse reactions observed at a rate ≥ 5% in subjects in the clinical trial were headache, pyrexia, hypertension, chills, rash, nausea, arthralgia, and asthenia.

6.1 Clinical Trials Experience

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

PI: Intravenous Administration

The most serious adverse event observed in clinical study subjects receiving GAMMAKED IV for PI was an exacerbation of autoimmune pure red cell aplasia in one subject.

In four different clinical trials to study PI, out of 157 subjects treated with GAMMAKED, 4 subjects discontinued due to the following adverse events: Coombs negative hypochromic anemia, autoimmune pure red cell aplasia, arthralgia/hyperhidrosis/fatigue/myalgia/nausea and migraine.

In a study of 87 subjects, 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion, such as diphenhydramine and acetaminophen.

Table 2 lists the adverse reactions reported by at least 5% of subjects during the 9-month treatment.

Table 2: Adverse Reactions Occurring in ≥ 5% of Subjects
* An adverse reaction is an adverse event that meets any of the following 3 criteria: (a) that began during or within 72 hours of the end of product infusion, (b) that was considered at least possibly related by either the investigator or the applicant, and/or (c) whose causality assessment by the investigator was missing or indeterminate.
	GAMMAKED™	GAMIMUNE® N, 10%
	No. of subjects: 87	No. of subjects: 85
	No. of subjects with adverse reaction	No. of subjects with adverse reaction
Adverse Reactions	(percentage of all subjects)	(percentage of all subjects)
Cough increased	27 (31.0%)	25 (29.4%)
Rhinitis	21 (24.1%)	24 (28.2%)
Headache	13 (14.9%)	17 (20.0%)
Pharyngitis	14 (16.1%)	16 (18.8%)
Asthma	13 (14.9%)	10 (11.8%)
Fever	6 (6.9%)	10 (11.8%)
Nausea	10 (11.5%)	9 (10.6%)
Diarrhea	6 (6.9%)	9 (10.6%)
Sinusitis	5 (5.7%)	6 (7.1%)

Table 3 lists the frequency of adverse reactions (as defined for Table 2), which were reported by at least 5% of subjects.

Table 3: Adverse Reactions Frequency
	GAMMAKED™	GAMIMUNE® N, 10%
	No. of infusions: 825	No. of infusions: 865
Adverse Reactions	Number (percentage of all infusions)	Number (percentage of all infusions)
Cough increased	40 (4.8%)	47 (5.4%)
Rhinitis	34 (4.1%)	44 (5.1%)
Headache	17 (2.1%)	24 (2.8%)
Pharyngitis	20 (2.4%)	24 (2.8%)
Fever	8 (1.0%)	20 (2.3%)
Asthma	17 (2.1%)	12 (1.4%)
Diarrhea	10 (1.2%)	10 (1.2%)
Nausea	10 (1.2%)	10 (1.2%)
Sinusitis	6 (0.7%)	7 (0.8%)

The mean number of adverse reactions per infusion that occurred during or within 72 hours of the end of product infusion was 0.33 for the GAMMAKED and 0.39 for the GAMIMUNE® N, 10% [Immune Globulin Intravenous (Human), 10%] treatment group.

In all three trials in primary humoral immunodeficiencies, 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 GAMMAKED, 4 GAMIMUNE N, 10%) 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 GAMMAKED or GAMIMUNE N, 10% in clinical trials.

In the IV efficacy and safety study, serum samples were drawn to monitor the virus safety at baseline and one week after the first infusion of IGIV (for parvovirus B19), eight weeks after first and fifth infusion of IGIV (for hepatitis C, hepatitis B, and HIV-1), 16 weeks after the first and fifth infusion of IGIV (for hepatitis C) and at any time of premature discontinuation of the study (for hepatitis C, hepatitis B, HIV-1, and parvovirus B19). 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 related emergent findings of virus transmission for either GAMMAKED or GAMIMUNE N, 10%.

PI: Subcutaneous Administration (PK and Safety Studies)

Adverse reactions were divided into 2 types: 1) Local infusion site reactions, and 2) Non-infusion site adverse reactions. Table 4 lists those adverse reactions (as defined for Table 2) occurring in ≥ 2% of infusions during the SC phase of two pharmacokinetic (PK) crossover and safety trials, one in adults and adolescents and the other in children and adolescents. [see Clinical Pharmacology (12.3)]

Table 4: Most Frequent Adverse Reactions (≥ 2% of infusions) by Infusion in the SC Phase
* For each trial, rate is calculated by the total number of events divided by the number of infusions received (725 for the adult and adolescent trial and 121 for the children / adolescent trial). † All local infusion site reactions were a priori considered drug-related. ‡ At each level of summation (Preferred Term), local infusion site reactions are counted only once if they occur at the same infusion visit. Mild – usually transient in nature and generally not interfering with normal activities Moderate – sufficiently discomforting to interfere with normal activities Severe – prevents normal activities
Adverse Reactions	Number (Rate*)
Adverse Reactions	Adult, Adolescent (Study 060001)	Child, Adolescent (Study T5004-401)
Non-infusion Site Adverse Reactions
Headache	25 (0.03)	1 (0.01)
Abdominal Pain	1 (<0.01)	2 (0.02)
Local Infusion Site Reactions†,‡
Mild	389 (0.54)	56 (0.46)
Moderate	29 (0.04)	4 (0.03)
Severe	9 (0.01)	1 (0.01)

Table 5 lists the adverse reactions occurring in ≥ 5% of subjects and the frequency of adverse reactions (as defined for Table 2) per infusion.

Table 5: Most Frequent Adverse Reactions (≥ 5% of subjects) by Subject and Infusion in the SC Phase
* For each trial, rate is calculated by the total number of events divided by the number of infusions received (725 for the adult and adolescent trial and 121 for the children / adolescent trial). † All local infusion site reactions were a priori considered drug-related ‡ At each level of summation (Preferred Term), infusion site reactions are counted only once if they occur at the same infusion visit.
Adverse Reaction	Adult, Adolescent (Study 060001)		Child, Adolescent (Study T5004-401)
Adverse Reaction	No. of Subjects n=32 (%)	No. of Adverse Reactions (Rate*)	No. of Subjects n=11 (%)	No. of Adverse Reactions (Rate*)
Local Infusion Site Reaction†,‡	24 (75.0%)	427 (0.59)	11 (100%)	61 (0.50)
Fatigue	5 (15.6%)	6 (0.01)	0	0
Headache	4 (12.5%)	25 (0.03)	1 (9.1%)	1 (0.01)
Upper respiratory tract infection	4 (12.5%)	5 (0.01)	1 (9.1%)	1 (0.01)
Arthralgia	3 (9.4%)	6 (0.01)	0	0
Diarrhea	3 (9.4%)	6 (0.01)	0	0
Nausea	3 (9.4%)	4 (0.01)	0	0
Sinusitis	3 (9.4%)	4 (0.01)	0	0
Abdominal pain	1 (3.1%)	1 (<0.01)	1 (9.1%)	2 (0.02)
Abdominal pain upper	0	0	1 (9.1%)	1 (0.01)
Autoimmune thyroiditis	0	0	1 (9.1%)	1 (0.01)
Drug hypersensitivity	0	0	1 (9.1%)	1 (0.01)
Influenza	0	0	1 (9.1%)	1 (0.01)
Oropharyngeal pain	0	0	1 (9.1%)	1 (0.01)
Skin chapped	0	0	1 (9.1%)	1 (0.01)
Viral upper respiratory tract infection	0	0	1 (9.1%)	1 (0.01)
Wheezing	1 (3.1%)	1 (<0.01)	1 (9.1%)	1 (0.01)
Bronchitis	2 (6.3%)	2 (<0.01)	0	0
Depression	2 (6.3%)	2 (<0.01)	0	0
Dermatitis allergic	2 (6.3%)	2 (<0.01)	0	0
Erythema	2 (6.3%)	2 (<0.01)	0	0
Migraine	2 (6.3%)	2 (<0.01)	0	0
Myalgia	2 (6.3%)	2 (<0.01)	0	0
Pyrexia	2 (6.3%)	2 (<0.01)	0	0
Viral infection	2 (6.3%)	2 (<0.01)	0	0

There were no serious bacterial infections in the SC phase of the PK and safety trials.

Local Infusion Site Reactions

Local infusion site reactions with SC GAMMAKED consisted of erythema, pain and swelling. One child discontinued due to infusion site pain. The majority of local infusion site reactions resolved within 3 days. The number of subjects experiencing an infusion site reaction and the number of infusion site reactions decreased over time as subjects received continued weekly SC infusions. At the beginning of the SC phase (week 1) in the adult and adolescent trial, a rate of approximately 1 infusion site reaction per infusion was reported, whereas at the end of the study (week 24) this rate was reduced to 0.5 infusion site reactions per infusion, a reduction of 50%. In the children and adolescent trial, the rate of local infusion site reactions decreased from week 1 for all age groups by the end of the study.

ITP

In two different clinical trials to study ITP, out of 76 subjects treated with GAMMAKED, 2 subjects discontinued due to the following adverse reactions: Hives and Headache/Fever/Vomiting.

One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMMAKED. The death was judged to be unrelated to GAMMAKED.

No pre-medication with corticosteroids was permitted by the protocol. Twelve 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 GAMMAKED™, 3 GAMIMUNE N, 10%) on 4 occasions. Mild to moderate headache, nausea, and fever were the reported reasons.

Table 6 lists the adverse reactions (as defined for Table 2) reported by at least 5% of subjects during the 3-month efficacy and safety study.

Table 6: Adverse Reactions Occurring in ≥ 5% of Subjects
	GAMMAKED™	GAMIMUNE® N, 10%
	No. of subjects: 48	No. of subjects: 49
Adverse Reaction	Number (percentage of all subjects)	Number (percentage of all subjects)
Headache	25 (52.1%)	26 (53.1%)
Vomiting	6 (12.5%)	8 (16.3%)
Ecchymosis	7 (14.6%)	2 (4.1%)
Fever	6 (12.5%)	6 (12.2%)
Nausea	6 (12.5%)	5 (10.2%)
Rash	4 (8.3%)	0
Abdominal pain	3 (6.3%)	3 (6.1%)
Back pain	3 (6.3%)	2 (4.1%)
Dyspepsia	3 (6.3%)	0
Asthenia	2 (4.2%)	3 (6.1%)
Dizziness	2 (4.2%)	3 (6.1%)

Serum samples were drawn to monitor the virus 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 virus transmission for either GAMMAKED or GAMIMUNE N, 10%.

CIDP

In the CIDP efficacy and safety study, 113 subjects were exposed to GAMMAKED and 95 were exposed to Placebo. [see Clinical Studies (14)] As a result of the study design, the drug exposure with GAMMAKED was almost twice that of Placebo, with 1096 GAMMAKED 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.

Table 7 shows the numbers of subjects per treatment group in the CIDP clinical trial, and the reason for discontinuation due to adverse events.

Table 7: Reasons for Discontinuation Due to Adverse Events
Number of Subjects		Number of Subjects Discontinued due to Adverse Events	Adverse Event
GAMMAKED™	113	3 (2.7%)	Urticaria, Dyspnea, Bronchopneumonia
Placebo	95	2 (2.1%)	Cerebrovascular Accident, Deep Vein Thrombosis

The most common adverse reactions with GAMMAKED were headache and pyrexia. Table 8 lists adverse reactions (as defined for Table 2) reported by at least 5% of subjects in any treatment group.

Table 8: Adverse Reactions Occurring in ≥ 5% of Subjects
* Reported in ≥ 5% of subjects in any treatment group. † Calculated by the total number of adverse reactions divided by the number of infusions received (1096 for GAMMAKED and 575 for Placebo).
	GAMMAKED™ No. of subjects: 113			Placebo No. of subjects: 95
MedDRA Preferred Term*	No. of Subjects (%)	No. of Adverse Reactions	Incidence density †	No. of Subjects (%)	No. of Adverse Reactions	Incidence density†
Headache	35 (31.0%)	50	0.046	7 (7.4%)	9	0.016
Pyrexia	15 (13.3%)	27	0.025	0	0
Hypertension	10 (8.8%)	19	0.017	3 (3.2%)	3	0.005
Chills	9 (8.0%)	10	0.009	0	0
Nausea	7 (6.2%)	9	0.008	3 (3.2%)	3	0.005
Rash	7 (6.2%)	10	0.009	1 (1.1%)	1	0.002
Arthralgia	6 (5.3%)	7	0.006	0	0
Asthenia	6 (5.3%)	6	0.005	1 (1.1%)	2	0.003

The most serious adverse reaction observed in clinical study subjects receiving GAMMAKED for CIDP was pulmonary embolism (PE) in one subject with a history of PE.

Laboratory Abnormalities

During the course of the clinical program, ALT and AST elevations were identified in some subjects.

For ALT, in the IV PI study treatment emergent elevations above the upper limit of normal were transient and observed among 14/80 (18%) of subjects in the GAMMAKED group versus 5/88 (6%) of subjects in the GAMIMUNE N, 10% group (p = 0.026).
In the SC PI study treatment emergent laboratory abnormalities during the SC phase occurred in several subjects. Four subjects (4/32, 13%) had elevated Alkaline Phosphatase. One subject (1/32, 3%) had an elevated ALT and three subjects (3/32, 9%) had an elevated AST. No elevations were > 1.6 times the upper limit of normal.
In the ITP study which employed a higher dose per infusion, but a maximum of only two infusions, the reverse finding for elevation of ALT was observed among 3/44 (7%) of subjects in the GAMMAKED group versus 8/43 (19%) of subjects in the GAMIMUNE N, 10% group (p = 0.118).
In the CIDP study, 15/113 (13%) of subjects in the GAMMAKED 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.

GAMMAKED may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4 class. 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. There were 2 cases of hemolytic anemia across these clinical trials. One hemolytic event not associated with positive DAT findings was observed in the IV PI study in a woman with common variable immune deficiency and B12 deficiency (pernicious anemia) at a dose of (450 mg/kg). The other hemolytic event occurred in the CIDP study in a subject with positive DAT at a dose of 1g/kg.

6.2 Postmarketing Experience

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

The following adverse reactions have been identified during post-approval use of IGIV products,(8,20) including GAMMAKED:

Infusion Reactions: Hypersensitivity (e.g., anaphylaxis), tachycardia, malaise, flushing, or other skin reactions, chest discomfort, rigors, and
changes in blood pressure
Renal: Acute renal dysfunction/failure, osmotic nephropathy
Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, bronchospasm
Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
Neurological: Coma, loss of consciousness, seizures/convulsions, tremor, aseptic meningitis
Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
Hematologic: Pancytopenia, leukopenia, hemolysis, hemolytic anemia, positive direct antiglobulin (Coombs test)
General/Body as a Whole: Rigors
Gastrointestinal: Hepatic dysfunction