ASCENIV

1 INDICATIONS AND USAGE ASCENIV (immune globulin intravenous, human – slra) is a 10% immune globulin liquid for intravenous injection, indicated for the treatment of primary humoral immunodeficiency (PI) in adults and adolescents (12 to 17 years of age). PI includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies (SCID). ASCENIV (immune globulin intravenous, human – slra) is a 10% immune globulin liquid for intravenous injection, indicated for the treatment of primary humoral immunodeficiency (PI) in adults and adolescents (12 to 17 years of age). [1]

2 DOSAGE AND ADMINISTRATION For intravenous use only. Dose Initial Infusion Rate Maintenance Infusion Rate (if tolerated) 300-800 mg/kg every 3- 4 weeks 0.5 mg/kg/min (0.005 mL/kg/min) for the first 15 minutes Increase gradually every 15 minutes (if tolerated) up to 8 mg/kg/min (0.08 mL/kg/min) Ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue ASCENIV if renal function deteriorates. [5.3] For patients at risk of renal dysfunction or thrombotic events, administer ASCENIV at the minimum infusion rate practicable. [5.2, 5.3] 2.1 Dose The recommended dose of ASCENIV for replacement therapy in primary humoral immunodeficiency (PI) is 300 to 800 mg/kg body weight administered every 3 to 4 weeks. The dose may be adjusted over time to achieve the desired trough levels and clinical response. ASCENIV 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, adjust the dose proportionally, targeting a trough of ≥ 600 mg/dL, based on the previous trough and the associated dose. For intravenous use only. Table 1 Dose Initial Infusion Rate Maintenance Infusion Rate (if tolerated) 300-800 mg/kg every 3-4 weeks 0.5 mg/kg/min (0.005 mL/kg/min) for the first 15 minutes Increase gradually every 15 minutes (if tolerated) up to 8 mg/kg/min (0.08 mL/kg/min) 2.2 Preparation and Handling ASCENIV is a clear to opalescent, colorless to pale yellow solution. Inspect visually for particulate matter and discoloration prior to administration. Do not use if the liquid is cloudy or turbid, or if it contains visible particulate matter. Allow refrigerated product to come to room temperature before use and maintain ASCENIV at room temperature during administration. DO NOT MICROWAVE. DO NOT SHAKE. DO NOT MIX with other IGIV products or other intravenous medications. DO NOT DILUTE. ASCENIV contains no preservatives. Each vial is for single use only. Do not reuse or save for future use. If large doses are required, several vials may be pooled using aseptic technique into sterile infusion bags and infused. 2.3 Administration Begin with an initial infusion rate of 0.5 mg/kg/min. If there are no adverse reactions, the infusion rate for subsequent infusions can be slowly increased to the maximum rate. 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 slower rate which 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 ASCENIV at the minimum infusion rate practicable, and consider discontinuation of administration if renal function deteriorates ( see Boxed Warning, Warnings and Precautions [5.2, 5.3] ).

4 CONTRAINDICATIONS ASCENIV is contraindicated in: patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. 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, 5.1]

5 WARNINGS AND PRECAUTIONS IgA-deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. Have medications such as epinephrine available to treat any acute severe hypersensitivity reactions. [4, 5.1] Thrombotic events have occurred in patients receiving IGIV treatments. Monitor patients with known risk factors for thrombotic events; consider baseline assessment of blood viscosity for patients at risk of hyperviscosity. [5.2, 5.4] In patients at risk of developing acute renal failure. monitor renal function, including blood urea nitrogen (BUN), serum creatinine, and urine output. [5.3, 5.9] Hyperproteinemia, increased serum viscosity, and hyponatremia or pseudohyponatremia can occur in patients receiving IGIV treatment. [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 IGIV treatment. 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 Hypersensitivity Severe hypersensitivity reactions may occur with IGIV products, including ASCENIV. In case of hypersensitivity, discontinue ASCENIV infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for treatment of acute hypersensitivity reactions. ASCENIV 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. ASCENIV is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications [4] ). 5.2 Thrombosis Thrombosis may occur following treatment with immune globulin products, including ASCENIV. 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 patients with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer ASCENIV 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] , Patient Counseling Information [17] ). 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 ASCENIV. 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 ASCENIV and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing ASCENIV (see Patient Counseling Information [17]). 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 ASCENIV at the minimum infusion rate practicable (see Dosage and Administration [2] ). 5.4 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV treatment, including ASCENIV. 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 with IGIV treatments, including ASCENIV. 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 may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. 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] ). 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. 5.6 Hemolysis IGIV products, including ASCENIV, 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 hemolysis. 10,11,12 Delayed hemolytic anemia can develop subsequent to IGIV treatment 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] ). If these are present after ASCENIV 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 ongoing hemolysis. 5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment, 14 including ASCENIV. 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] ). TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.8 Transmissible Infectious Agents Because ASCENIV is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. 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 ASCENIV, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information [17] ). 5.9 Monitoring Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients 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 ASCENIV 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 ASCENIV, 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 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 ASCENIV so that appropriate measures may be taken ( see Patient Counseling Information [17] ). 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]

6 ADVERSE REACTIONS The most common adverse reactions to ASCENIV (reported in ≥5% of clinical study subjects) were headache, sinusitis, diarrhea, gastroenteritis viral, nasopharyngitis, upper respiratory tract infection, bronchitis, and nausea. The most common adverse reactions to ASCENIV (≥5% of study subjects) were headache, sinusitis, diarrhea, gastroenteritis viral, nasopharyngitis, upper respiratory tract infection, bronchitis, and nausea. [6] To report SUSPECTED ADVERSE REACTIONS, contact ADMA Biologics at (1-800-458-4244) 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, 59 subjects with PI, on regular IGIV replacement therapy, received doses of ASCENIV ranging from 284 to 1008 mg/kg (mean dose 505 mg/kg) every 3 weeks or 4 weeks for up to 12 months (mean 346 days; range 36 to 385 days) (see Clinical Studies [14] ). The use of pre-medication was discouraged; however, if after two infusions of ASCENIV subjects required pre-medication (antipyretic, antihistamine, or antiemetic agent) for recurrent reactions, they could continue those medications for the duration of the trial. Of the 793 infusions administered during this trial, only 7 (11.9%) subjects received premedication prior to 7 (0.9%) infusions. Fifty-eight subjects (98%) had an adverse reaction during the study. The proportion of subjects who had at least one adverse reaction was similar for both the 3- and 4-week cycles. The most common adverse reactions observed in this clinical trial were headache (22 subjects, 37%), sinusitis (16 subjects, 27%), diarrhea (14 subjects, 23%), gastroenteritis viral (13 subjects, 22%), nasopharyngitis (13 subjects, 22%), upper respiratory tract infection (13 subjects, 22%), bronchitis (12 subjects, 20%), nausea (12 subjects, 20%), and acute sinusitis (11 subjects, 19%). Adverse reactions (ARs) occurring during or within 72 hours after the end of an infusion are presented in Table 2 . In this study, the upper bound of the 1-sided 95% confidence interval for the proportion of ASCENIV infusions with one or more temporally associated adverse reactions was 16.4%. The total number of adverse reactions was 158 (a rate of 0.20 ARs per infusion). Table 2: Adverse Reactions (ARs) (within 72 hours after the end of an ASCENIV infusion) in ≥ 5% of Subjects Preferred Term (MedDRA v16.0) Number (%) of Subjects (N=59) Number (%) of Infusions (N=793) Headache 14 (24) 21 (2.6) Sinusitis 6 (10) 7 (0.9) Nausea 5 (9) 5 (0.6) Acute sinusitis 4 (7) 4 (0.5) Fatigue 4 (7) 9 (1.1) Muscle spasms 4 (7) 4 (0.5) Bronchitis 3 (5) 3 (0.4) Diarrhea 3 (5) 3 (0.4) Nose Bleed 3 (5) 4 (0.5) Muscle Pain 3 (5) 5 (0.6) Oropharyngeal pain 3 (5) 3 (0.4) Pain in extremity 3 (5) 3 (0.4) Itching 3 (5) 3 (0.4) 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), cyanosis, dyspnea, bronchospasm. Cardiovascular: Cardiac arrest, vascular collapse, hypotension. Neurological: Coma, loss of consciousness, seizures, tremor. Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis. Hematologic: Pancytopenia, leukopenia. General/Body as a Whole: Pyrexia, rigors. Gastrointestinal: Hepatic dysfunction, abdominal pain.

8.1 Pregnancy Risk Summary No human data are available to indicate the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with ASCENIV. It is not known whether ASCENIV 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. 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. ASCENIV should be given to pregnant women only if clearly needed. 17,18