BIVIGAM

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.

2 DOSAGE AND ADMINISTRATION For Intravenous Use Only Intravenous Use Only Indication Dose Initial Infusion Rate Maintenance Infusion Rate (if tolerated) PI 300-800 mg/kg every 3-4 weeks 0.5 mg/kg/min for first 10 minutes Increase every 20 minutes (if tolerated) by 0.8 mg/kg/min up to 6 mg/kg/min. Ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue BIVIGAM if renal function deteriorates. [5.3] For patients at risk of renal dysfunction or thrombotic events, administer BIVIGAM at the minimum infusion rate practicable. [5.1 , 5.3] 2.1 Preparation and Handling BIVIGAM is a clear or slightly opalescent, colorless to pale yellow solution. Inspect BIVIGAM visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or turbid, or contains particulate matter. Allow refrigerated product to come to room temperature before use. Do not freeze or heat. Do not use any solution that has been frozen or heated. DO NOT SHAKE. Do not mix BIVIGAM with other IGIV products or other intravenous medications. If large doses of BIVIGAM are to be administered, several vials may be pooled using aseptic technique into sterile infusion bags and infused. Do not dilute BIVIGAM. BIVIGAM contains no preservatives. BIVIGAM vial is for single use only. Any vial of BIVIGAM that has been entered should be used promptly and any unused portion should be discarded immediately. Do not reuse or save for future use. Maintain BIVIGAM at room temperature during administration. Do not use after expiration date. 2.2 Recommended Dose As there are significant differences in the half-life of IgG among patients with primary humoral immunodeficiency, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The recommended dose of BIVIGAM for replacement therapy in primary humoral immunodeficiency in adults and children 2 years of age and older, is 300 to 800 mg/kg body weight administered every 3 to 4 weeks. The dosage may be adjusted over time to achieve the desired trough levels and clinical response. BIVIGAM dose adjustments may be required in patients who fail to maintain trough total IgG concentrations of at least 500 mg/dL with a target of 600 mg/dL. Starting with the second infusion, the dose will be adjusted proportionally, targeting a trough of ≥ 600 mg/dL, based on the previous trough and the associated dose. 2.3 Administration It has been reported that the frequency of adverse drug reactions to IGIV increases with the infusion rate. Initial infusion rates should be slow. If there are no adverse drug reactions, the infusion rate for subsequent infusions can be slowly increased to the maximum rate. For patients experiencing adverse drug reactions, it is advisable to reduce the infusion rate in subsequent infusions. Table 1: Recommended Infusion Rates for BIVIGAM Indication Initial Infusion Rate (for first 10 minutes) Maintenance Infusion Rate (if tolerated) PI 0.5 mg/kg/min (0.005 mL/kg/min) Increase every 20 minutes (if tolerated) by 0.8 mg/kg/min up to 6 mg/kg/min. Monitor patient vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient. Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombotic events, administer BIVIGAM at the minimum infusion rate practicable, and consider discontinuation of administration if renal function deteriorates ( see Boxed Warning, Warnings and Precautions [5.1 , 5.3] ).

4 CONTRAINDICATIONS BIVIGAM is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. BIVIGAM is contraindicated in IgA deficiency patients with antibodies to IgA and a history of hypersensitivity. History of anaphylactic or severe systemic reactions to human immunoglobulin. [4] IgA deficient patients with antibodies to IgA and a history of hypersensitivity. [4 , 5.2]

5 WARNINGS AND PRECAUTIONS Thrombotic events have occurred in patients receiving IGIV therapy. Monitor patients with known risk factors for thrombotic events; consider baseline assessment of blood viscosity for those at risk of hyperviscosity. [5.1 , 5.4] IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. Have medications such as epinephrine available immediately to treat any acute severe hypersensitivity reactions. [4 , 5.2] Monitor renal function, including blood urea nitrogen (BUN), serum creatinine, and urine output in patients at risk of developing acute renal failure. [5.3 , 5.9] Hyperproteinemia, increased serum viscosity, and hyponatremia or pseudohyponatremia can occur in patients receiving IGIV therapy. [5.4] Aseptic meningitis syndrome (AMS) has been reported with IGIV treatments, especially with high doses or rapid infusion. [5.5] Hemolytic anemia can develop subsequent to treatment with IGIV products. Monitor patients for hemolysis and hemolytic anemia. [5.6] Monitor patients for pulmonary adverse reactions (Transfusion-related acute lung injury [TRALI]). If transfusion-related acute lung injury is suspected, test the product and patient for antineutrophil antibodies. [5.7] Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. [5.8] 5.1 Thrombosis Thrombosis may occur following treatment with immune globulin products (IGIV), including BIVIGAM. 4,5,6 Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer BIVIGAM at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity ( see Boxed Warning , Dosage and Administration [2.3] , Patient Counseling Information [17.2] ). 5.2 Hypersensitivity Severe hypersensitivity reactions may occur with IGIV products, including BIVIGAM. In case of hypersensitivity, discontinue BIVIGAM infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. BIVIGAM contains trace amounts of IgA (≤ 200 micrograms per milliliter) ( see Description [11] ). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. BIVIGAM is contraindicated in IgA deficient patients with antibodies against IgA and a history of hypersensitivity reaction ( see Contraindications [4] ). 5.3 Acute Renal Dysfunction and Acute Renal Failure Acute renal dysfunction/failure, osmotic nephrosis, and death 1,2 may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering BIVIGAM. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure 2 . Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing BIVIGAM ( see Patient Counseling Information [17.1] ). In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age of >65 years), administer BIVIGAM at the minimum infusion rate practicable ( see Dosage and Administration [2.3] ). 5.4 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy, including BIVIGAM. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events 3 . 5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with IGIV treatments including BIVIGAM. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. 7,8,9 AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting ( see Patient Counseling Information [17.3] ). Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. 5.6 Hemolysis IGIV products, including BIVIGAM, may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. 10,11,12 Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration, 13 and acute hemolysis, consistent with intravascular hemolysis, has been reported. Monitor patients for clinical signs and symptoms of hemolysis ( see Patient Counseling Information [17.4] ). If these are present after BIVIGAM infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. 5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment 14 including BIVIGAM. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum ( see Patient Counseling Information [17.5] ). TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.8 Transmissible Infectious Agents Because BIVIGAM is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to ADMA Biologics at 1-800-458-4244. Before prescribing BIVIGAM, the physician should discuss the risks and benefits of its use with the patient ( see Patient Counseling Information [17.6] ). 5.9 Monitoring Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis with IGIV treatment, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If signs and/or symptoms of hemolysis are present after an infusion of BIVIGAM, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. 5.10 Interference with Laboratory Tests After infusion of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.

7 DRUG INTERACTIONS Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines, such as measles, mumps, rubella, and varicella. [7] Passive transfer of antibodies may confound the results of serological testing. [5.10] 7.1 Live Virus Vaccines Immunoglobulin administration may transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps, rubella, and varicella because the continued presence of high levels of passively acquired antibody may interfere with an active antibody response. 15,16 The immunizing physician should be informed of recent therapy with BIVIGAM so that appropriate measures may be taken (see Patient Counseling Information [17.7] ).

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.

8.1 Pregnancy No human data are available to indicate the presence or absence of drug-associated risk. Animal reproductive studies have not been conducted with BIVIGAM. It is not known whether BIVIGAM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. BIVIGAM should be given to pregnant women only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.