ASCENIV

1 INDICATIONS AND USAGE ASCENIV is indicated for the treatment of primary humoral immunodeficiency (PI) in adults and pediatric patients 2 years of age and older. 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 pediatric patients 2 years of age and older.

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) 2.1 Dose For intravenous use only. Table 1: Recommended Dosage for ASCENIV 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) Adjust the dose over time to achieve the desired trough levels and clinical response. Measles pre-/post exposure prophylaxis Post-exposure prophylaxis If a patient has been exposed to measles, a dose of 400 mg/kg of ASCENIV should be administered as soon as possible after exposure. Pre-exposure prophylaxis If a patient routinely receives a dose of less than 530 mg/kg of ASCENIV every 3 to 4 weeks and is at risk of measles exposure (e.g., traveling to a measles endemic area), administer a dose of at least 530 mg/kg prior to the expected measles exposure. 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. [see Warnings and Precautions (5.1)] 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 IgA ≤ 200 micrograms per milliliter (see Description [11] ). Patients with known antibodies to IgA may have a greater risk of developing 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. 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] ). 5.3 Renal Injury Renal injury including acute renal dysfunction, acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering ASCENIV. 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)] . The risk of renal dysfunction and acute renal failure is greater in products that contain sucrose, though may still occur in products without sucrose. ASCENIV does not contain sucrose. Conduct 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. If renal function deteriorates, consider discontinuing ASCENIV [see Dosage and Administration (2)] . 5.4 Hyperproteinemia, Hyperviscosity, and Hyponatremia Hyperproteinemia, hyperviscosity, 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. 5.5 Aseptic Meningitis Syndrome Aseptic meningitis syndrome (AMS) may occur with IGIV treatments, including ASCENIV. The risk of AMS may be higher with high doses (≥2g/kg) and/or rapid infusion of IGIV. AMS usually begins within several hours to 2 days following IGIV treatment and is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. 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. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. 5.6 Hemolysis Hemolysis may occur after administration of IGIV products, including ASCENIV due to the presence of 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 test and hemolysis. Delayed hemolytic anemia can develop after IGIV treatment due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported. The risk factors for hemolysis include high doses (e.g., ≥ 2 g/kg) given either as a single administration or divided over several days, non-O blood group, and an underlying inflammatory disease condition. Monitor patients for clinical signs and symptoms of hemolysis. 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 Transfusion-Related Acute Lung Injury (TRALI) may occur in patients following IGIV treatment, 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, immediatly stop ASCENIV infusion, and perform appropriate tests for the presence of anti-neutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in both the product and the patient’s serum. Manage patients using oxygen therapy with adequate ventilatory support as appropriate. 5.8 Transmissible Infectious Agents There is risk of transmitting infectious agents including viruses, the variant Creutzfeldt-Jakob disease (vCJD) and the Creutzfeldt-Jakob disease (CJD) agent with ASCENIV administration because it is manufactured using human blood. The risk of infectious agent transmission is minimized by plasma donor screening, donation testing, and manufacturing steps proven to inactivate and remove bloodborne pathogens. All infections suspected to have been transmitted by ASCENIV should be reported by the physician or other healthcare provider to ADMA Biologics at (1-800-458-4244) . 5.9 Monitoring Laboratory Tests Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of ASCENIV and at appropriate intervals thereafter. 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 because of the potentially increased risk of thrombosis. 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 and anti-HLA 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. Inform the immunizing physician of recent therapy with ASCENIV so that appropriate measures may be taken. 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 (≥5% of study patients) 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. The safety data described in this section reflects exposure to ASCENIV in two clinical studies (Study 1 and Study 2) as described below. Study 1 In Study 1, 59 patients with PI received a total of 793 infusions of ASCENIV at a median dose of 505 mg/kg (range 284 to 1008 mg/kg) every 3 weeks or 4 weeks for up to 12 months (mean 346 days; range 36 to 385 days). Of the 793 infusions administered during this trial, 7 (11.9%) patients received premedication prior to 7 (0.9%) infusions [see Clinical Studies (14)] . The most common adverse reactions occurring in ≥5% of patients in Study 1 are presented in Table 2. Table 2: Adverse Reactions in ≥ 5% of Patients in Study 1 Adverse Reactions* Number (%) of Patients (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) Epistaxis 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) *Adverse reactions were defined as events occurring within 72 hours after the end of an ASCENIV infusion Study 2 (Pediatric Study) In Study 2, 16 pediatric patients with PI aged 2 to 11 years received 91 infusions of ASCENIV at a median dose of 541 mg/kg (range 300-800 mg/kg) every 3 or 4 weeks for approximately 5 months. The most common adverse reactions in Study 2 are presented in Table 3 below. Table 3: Adverse Reactions in Study 2 Adverse Reactions* Number (%) of Patients (N=16) Number (%) of Infusions (N=91) Chest Pain 1 (6) 1 (1) Epistaxis 1 (6) 1 (1) Fatigue 1 (6) 1 (1) Hypersensitivity 1 (6) 1 (1) Diarrhea 1 (6) 1 (1) Headache** 4 (25) 5 (5) Otitis** 2 (13) 2 (2) Viral Rash 1 (6) 1 (1) Vomiting 1 (6) 1 (1) Nausea 3 (19) 4 (4) *Adverse reactions were defined as events occurring within 72 hours after the end of an ASCENIV infusion **Includes multiple related terms. 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, thoracic and mediastinal disorders: Apnea, Acute Respiratory Distress Syndrome (ARDS), cyanosis, dyspnea, bronchospasm. Cardiac disorders: Cardiac arrest, vascular collapse, hypotension. Nervous system disorder: Coma, loss of consciousness, seizures, tremor. Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis. Blood and lymphatic system disorders: Pancytopenia, leukopenia. General disorders and administration site conditions: Pyrexia, rigors. Gastrointestinal disorders: 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. 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.