1 INDICATIONS AND USAGE BIVIGAM is an Immune Globulin Intravenous (Human), 10% Liquid, indicated for the treatment of adults and pediatric patients 2 years of age and older with primary humoral immunodeficiency (PI).

[1] 1.1 Primary Humoral Immunodeficiency BIVIGAM is an Immune Globulin Intravenous (Human), 10% Liquid, indicated for the treatment of adults and pediatric patients 2 years of age and older with primary humoral immunodeficiency (PI).

This includes, but is not limited to, the humoral immune defect in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

6 ADVERSE REACTIONS Serious adverse reactions observed in clinical trial subjects receiving BIVIGAM were vomiting and dehydration in one subject.

The most common adverse reactions to BIVIGAM (reported in ≥5% of clinical study subjects) were headache, fatigue, infusion site reaction, nausea, sinusitis, blood pressure increased, diarrhea, dizziness, and lethargy.

The most common adverse reactions to BIVIGAM (reported in ≥5% of clinical study subjects) were headache, fatigue, infusion site reaction, nausea, sinusitis, blood pressure increased, diarrhea, dizziness, and lethargy.

[6] To report SUSPECTED ADVERSE REACTIONS, contact ADMA Biologics at (800) 458-4244 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice.

In a multicenter, open-label, non-randomized clinical trial, 63 subjects with PI, on regular IGIV replacement therapy, received doses of BIVIGAM ranging from 254 to 1029 mg/kg (median dose 462.8 mg/kg) every 3 weeks or 4 weeks for up to 12 months (mean 317.3 days; range 66 – 386 days) ( see Clinical Studies [ 14 ] ).

The use of pre-medication was discouraged; however, if subjects required pre-medication (antipyretic, antihistamine, or antiemetic agent) for recurrent reactions to immune globulins, they were allowed to continue those medications for this trial.

Of the 746 infusions administered, 41 (65%) subjects received premedication prior to 415 (56%) infusions.

Fifty-nine subjects (94%) had an adverse reaction at some time during the study.

The proportion of subjects who had at least one adverse reaction was the same for both the 3- and 4-week cycles.

The most common adverse reactions observed in this clinical trial were headache (32 subjects, 51%), sinusitis (24 subjects, 38%), fatigue (18 subjects, 29%), upper respiratory tract infection (16 subjects, 25%), diarrhea (13 subjects, 21%), cough (14 subjects, 22%), bronchitis (12 subjects, 19%), pyrexia (12 subjects, 19%), and nausea (9 subjects, 14%).

Adverse reactions (ARs) are those occurring during or within 72 hours after the end of an infusion.

In this study, the upper bound of the 1-sided 95% confidence interval for the proportion of BIVIGAM infusions with one or more temporally associated adverse reactions was 31%.

The total number of adverse reactions was 431 (a rate of 0.58 ARs per infusion).

Table 2: Adverse Reactions (ARs) (within 72 hours after the end of a BIVIGAM infusion) in ≥5% of Subjects ARs No.

Subjects Reporting ARs (% of Subjects) [n=63] No.

Infusions With ARs (% of Infusions) [n=746] Headache 27 (43%) 115 (15.4%) Fatigue 15 (24%) 59 (7.9%) Infusion Site Reaction 5 (8%) 5 (0.7%) Nausea 5 (8%) 8 (1.1%) Sinusitis 5 (8%) 5 (0.7%) Blood Pressure Increased 4 (6%) 5 (0.7%) Diarrhea 4 (6%) 4 (0.5%) Dizziness 4 (6%) 4 (0.5%) Lethargy 4 (6%) 4 (0.5%) Back Pain 3 (5%) 3 (0.4%) Blood Pressure Diastolic Decreased 3 (5%) 5 (0.7%) Fibromyalgia a 3 (5%) 17 (2.3%) Migraine 3 (5%) 8 (1.1%) Myalgia 3 (5%) 4 (0.5%) Pharyngolaryngeal Pain 3 (5%) 3 (0.4%) a Symptoms occurring under pre-existing fibromyalgia Seven subjects (11.1%) experienced 11 serious ARs.

Two of these were related serious ARs (vomiting and dehydration) that occurred in one subject.

One subject withdrew from the study due to ARs related to BIVIGAM (lethargy, headache, tachycardia and pruritus).

All 63 subjects enrolled in this study had a negative direct antiglobulin (Coombs’) test at baseline.

During the study, no subjects showed clinical evidence of hemolytic anemia.

No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM.

During the clinical trial no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).

There was a single positive finding for parvovirus (B19 virus) during the study.

This subject came in contact with acute B19 virus from working at a school, greeting children, where a child was reported to have symptomatic Fifth's disease.

There was no cluster (no other cases in other subjects) of B19 virus transmission with the IGIV batch concerned.

Pediatric Only Study In a prospective, open-label, single-arm, multi-center study, 16 children and adolescents with PI received doses of BIVIGAM ranging from 300 to 800 mg/kg every 3-weeks (±7 days) days (actual doses ranged from 350 mg/kg to 1077 mg/kg) or 4-weeks (±7 days) (actual doses ranged from 312 mg/kg to 693 mg/kg), for up to 5 months.

In this study, four subjects (25.0%) experienced a total of 9 adverse reactions.

Adverse reactions (ARs) are those occurring during or within 72 hours after the end of an infusion.

All ARs were of mild (3 events) or moderate severity (6 events).

No infusion site reactions occurred during the study.

No deaths and no treatment-related SAEs occurred during the study.

Seven of the 96 (7.3%) BIVIGAM infusions administered were temporally associated with an adverse reaction.

Two infusions were associated with more than one AR.

Table 3: Adverse Reactions (ARs) within 72 hours after the end of a BIVIGAM Infusion Adverse Reaction (AR) Number of Subjects Reporting AR (n=16) % of Subjects Reporting AR (n=16) Number of Infusions with AR (n=96) % of Infusions with AR (n=96) Fatigue 1 6 2 2 Headache 3 19 5 5 Nausea 1 6 1 1 Rash 1 6 1 1 6.2 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.

The following adverse reactions have been identified and reported during the post-approval use of IGIV products: Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Associated Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm.

Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension.

Neurological: Coma, loss of consciousness, seizures, 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.