QIVIGY kthm

1 INDICATIONS AND USAGE QIVIGY (immune globulin intravenous, human-kthm) 10% solution is indicated for the treatment of adults with Primary Humoral Immunodeficiency (PI). This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. QIVIGY (immune globulin intravenous, human-kthm) 10% solution is indicated for treatment of adults with primary humoral immunodeficiency (PI). ( 1 )

2 DOSAGE AND ADMINISTRATION Intravenous Administration Only. Dose Infusion number Initial Infusion Rate Maintenance Infusion Rate (as tolerated) 300 - 800 mg/kg every 3-4 weeks For the 1 st infusion 1 mg/kg/min (0.01 mL/kg/min) for 30 minutes Increase every 30 minutes to a maximum of 8 mg/kg/min (0.08 mL/kg/min) 300 - 800 mg/kg every 3-4 weeks From the 2 nd infusion 2 mg/kg/min (0.02 mL/kg/min) for 15 minutes Increase every 15 minutes to a maximum of 8 mg/kg/min (0.08 mL/kg/min) 2.1 Recommended Dosage Table 1. Recommended Dosage for QIVIGY Dose Infusion number Initial Infusion Rate Maintenance Infusion Rate (as tolerated) 300 - 800 mg/kg every 3-4 weeks For the 1 st infusion 1 mg/kg/min (0.01 mL/kg/min) for 30 minutes Increase every 30 minutes to a maximum of 8 mg/kg/min (0.08 mL/kg/min) 300 - 800 mg/kg every 3-4 weeks From the 2 nd infusion 2 mg/kg/min (0.02 mL/kg/min) for 15 minutes Increase every 15 minutes to a maximum of 8 mg/kg/min (0.08 mL/kg/min) Adjust frequency and dosage overtime to achieve target serum IgG levels and clinical response. If a patient misses a dose, administer the missed dose as soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable. In patients judged to have a potential increased risk for developing acute renal failure or thrombosis, QIVIGY should be administered at the minimum rate of infusion and dose practicable. In case of renal impairment, IGIV discontinuation should be considered [see Administration and Warnings and Precautions (2.3 , 5.3) ]. Measles pre-/post exposure prophylaxis Post-exposure prophylaxis If a patient has been exposed to measles, a dose of 400 mg/kg (4 mL/kg) of QIVIGY should be administered as soon as possible after exposure. Pre-exposure prophylaxis If a patient routinely receives a dose of less than 400 mg/kg of QIVIGY every 3 to 4 weeks (less than 4 mL/kg) and is at risk of measles exposure (i.e. traveling to a measles endemic area), administer a dose of at least 400 mg/kg (4 mL/kg) just prior to the expected measles exposure. 2.2 Preparation and Handling QIVIGY is a clear or slightly opalescent and colorless or pale-yellow solution. Inspect QIVIGY visually for particulate matter and discoloration prior to administration, whenever the solution and container permit. Do not use if the solution is cloudy, turbid, or if it contains particulate matter or deposits. Do not shake. Do not dilute. QIVIGY should be brought to room temperature before use (up to 25 °C [77 °F]). Keep the vial in the outer carton. If the packaging shows any signs of tampering, do not use the product and notify Kedrion Biopharma Inc. immediately at 1-855-3KDRION (1-855-353-7466). The QIVIGY vial is for single use only. Any vial that has been opened must be used immediately. QIVIGY contains no preservative. For administration of large doses, pool multiple vials using aseptic technique Infuse QIVIGY using a separate infusion line. At the end of the infusion flush tubing with saline solution or Dextrose 5% in water (D5W) to ensure that the entire dose is administered. Do not mix QIVIGY with other IGIV products or other intravenous medications (including normal saline) Do not use after expiration date. Record the batch number every time QIVIGY is administered to a patient. Dispose partially used or unused product or waste material in accordance with local requirements. 2.3 Administration Intravenous administration only . Hydrate the patient adequately prior to the initiation of infusion. Infuse QIVIGY intravenously using an intravenous infusion set. See Table 1 for recommended infusion rates. Monitor patient vital signs throughout the infusion. The rate of infusion can be related to certain severe adverse drug reactions. Slow or stop infusion if adverse reactions occur. If symptoms subside promptly, resume infusion at a lower rate as tolerated by the patient. The observation time of patients after QIVIGY administration may vary. If the patient (a) has not received QIVIGY or another IgG product, (b) is switched from an alternative IGIV product or (c) has had a long interval since the previous infusion, prolong the observation time for adverse reactions after QIVIGY infusion. Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients at risk of renal dysfunction or thrombosis, administer QIVIGY at the minimum dose and infusion rate practicable and discontinue QIVIGY if renal function deteriorates [see Boxed Warning , Warnings and Precautions (5.2 , 5.3) ] .

4 CONTRAINDICATIONS QIVIGY is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. QIVIGY is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity [see Warnings and Precautions (5.1) ] . Patients with history of anaphylactic or severe systemic reactions to human immune globulins. ( 4 ) IgA deficient patients with antibodies against IgA and a history of hypersensitivity. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: In case of a severe hypersensitivity reaction, discontinue QIVIGY infusion, and manage as appropriate. IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. ( 5.1 ) Thrombotic events: Monitor patients with known risk factors for thrombotic events; consider baseline assessment of blood viscosity for patients at risk of hyperviscosity. ( 5.2 ) Hyperproteinemia, hyperviscosity, hyponatremia, or pseudohyponatremia may occur in patients receiving IGIV therapy. ( 5.4 ) Renal Injury: Ensure patients are not volume depleted before administering QIVIGY. Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output in patients receiving QIVIGY prior to initial infusion and at appropriate intervals thereafter. ( 5.3 ) Aseptic Meningitis Syndrome (AMS) may occur, more frequently in association with high doses of IGIV or rapid infusion. ( 5.5 ) Hemolysis: Risk factors include high doses and non-O blood group. Monitor patients for hemolysis and hemolytic anemia. ( 5.6 ) Transfusion-related acute lung injury (TRALI): Monitor patients for symptoms of TRALI and manage using oxygen therapy with adequate ventilatory support as appropriate. ( 5.7 ) Transmission of infectious agents: QIVIGY is made from human plasma and may carry a risk of transmitting infectious agents. ( 5.8 ) 5.1 Hypersensitivity Severe hypersensitivity reactions, including anaphylaxis, may occur with QIVIGY [see Adverse Reactions (6) ] In case of hypersensitivity, discontinue QIVIGY infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. QIVIGY contains IgA (≤ 50 mg/L) [see Description (11) ] . Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. QIVIGY is contraindicated in IgA deficient patients with antibodies against IgA and patients with a history of hypersensitivity reaction [see Contraindications (4) ] . 5.2 Thrombosis Thrombosis may occur following treatment with immune globulin products, including QIVIGY. 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, high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer QIVIGY at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis [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 after treatment with immune globulin products including QIVIGY. Ensure that patients are not volume depleted prior to the initiation of the infusion of QIVIGY. For patients judged to be at risk for 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 drugs, or age over 65 years), administer QIVIGY 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. QIVIGY does not contain sucrose. Conduct periodic monitoring of renal function and urine output 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 QIVIGY and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing QIVIGY [see Dosage and Administration (2) ]. 5.4 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia Hyperproteinemia, hyperviscosity, and hyponatremia may occur in patients receiving immune globulin treatment, including QIVIGY. 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 thromboembolic events. 5.5 Aseptic Meningitis Syndrome Aseptic meningitis syndrome (AMS) may occur in patients following immune globulin treatment, including QIVIGY. The risk of AMS may be higher with high doses (2 g/kg) and/or rapid infusion of immune globulin products. AMS usually begins within several hours to two days following immune globulin treatment and is characterized by the following symptoms and signs: 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 symptoms and signs of AMS, including CSF studies, to rule out other causes of meningitis. Discontinuation of immune globulin treatment has resulted in remission of AMS within several days without sequelae. 5.6 Hemolysis Hemolysis may occur after administration of immune globulin products, including QIVIGY due to the presence of blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immune globulin, causing a positive direct antiglobulin test and hemolysis. Delayed hemolytic anemia can develop after immune globulin 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. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 hours and again 7 to 10 days post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit are observed after QIVIGY infusion, perform confirmatory laboratory testing. 5.7 Transfusion-related Acute Lung Injury Transfusion-Related Acute Lung Injury (TRALI) may occur in patients following immune globulin treatment, including QIVIGY. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours after treatment. Monitor patients for pulmonary adverse reactions. If TRALI is suspected, immediately stop QIVIGY infusion, and perform appropriate tests for the presence of anti-neutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in both the product and patient's serum. Manage patients using oxygen therapy with adequate ventilatory support as appropriate. 5.8 Transmissible Infectious Agents There is risk of transmission of infectious disease or agents including viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and the Creutzfeldt-Jakob disease agent with QIVIGY 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. Any infection suspected to have been transmitted by this product should be reported by the physician or other healthcare provider to Kedrion Biopharma Inc. at 1-855-3KDRION (1-855-353-7466) . 5.9 Monitoring Laboratory Tests Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of QIVIGY and at appropriate intervals thereafter [see Warnings and Precautions (5.3) ]. 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 [see Warnings and Precautions (5.2) ]. If signs and/or symptoms of hemolysis are present after an infusion of QIVIGY, perform appropriate laboratory testing for confirmation [see Warnings and Precautions (5.6) ]. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and the patient's serum [see Warnings and Precautions (5.7) ]. 5.10 Interference with Laboratory Tests After the administration of immune globulin, the transitory rise of the various passively transferred antibodies in the patients' blood may result in misleading positive results in serological testing. Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies for example the direct or indirect antiglobulin test (Coombs test).

7 DRUG INTERACTION The passive transfer of antibodies may: Interfere with the response to live virus vaccines, such as measles, rubella, mumps and varicella. ( 7 ) Result in misleading positive results in serological testing. ( 5.9 , 7 ) 7.1 Effect of QIVIGY on Live attenuated virus vaccines Immune globulin administration may transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps, rubella, s 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 QIVIGY so that appropriate measures may be taken. 7.2 Effect of QIVIGY on Serological Testing Passive transmission of antibodies through immune globulin administration may interfere with some serological testing [see Warnings and Precautions (5.10) ]. 7.3 Effect of Loop diuretics on QIVIGY The use of loop diuretics should be avoided. Concomitant use of loop diuretics with IGIV may contribute to an increased blood viscosity and subsequently increase the risk of thromboembolic events.

6 ADVERSE REACTIONS The most common adverse reactions observed in ≥ 5% of patients were headache, fatigue, nausea, infusion-related reaction, Coombs direct test positive, sinusitis, dizziness and diarrhea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Kedrion Biopharma Inc. at 1-855-3KDRION (1-855-353-7466) or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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. The safety data described in this section reflects exposure to QIVIGY in one clinical study. A total of 47 patients with PI received intravenous infusion of QIVIGY at a dose range of 266 to 826 mg/kg every 3 or 4 weeks for up to 12 months [see Clinical Studies (14) ] . A total of 643 infusions of QIVIGY were administered, 136 in the every 3-week schedule and 507 in the 4-week schedule. During the study, 4 out of 47 (9%) patients received premedication. The most common product-related adverse events observed in ≥ 5% of clinical study patients with PI were headache, infusion-related reaction, Coombs direct test positive, fatigue, and nausea. Table 2 lists the most common adverse reactions reported in ≥5% of patients. Table 2: Adverse Reactions Adverse reactions were defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period. Occurring in ≥ 5% of Patients Adverse Reaction By Patients n (%) [n = 47] By Infusions n (%) [n = 643] Headache 14 (30) 26 (4) Fatigue 7 (15) 10 (2) Nausea 6 (13) 6 (<1) Infusion-related Reaction 5 (11) 7 (1) Coombs Direct Test Positive 5 (11) 8 (1) Sinusitis 3 (6) 3 (<1) Dizziness 3 (6) 3 (<1) Diarrhea 3 (6) 4 (<1) 6.2 Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug 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-Related Acute Lung Injury (TRALI), respiratory failure, hypoxemia, pulmonary edema, dyspnea, wheezing, cough, bronchospasm, pulmonary embolism. Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension, phlebitis, pallor, angina, tachycardia, bradycardia, palpitations, myocardial infarction, cyanosis. Neurological: Coma, loss of consciousness, seizures, (acute) encephalopathy, tremor, aseptic meningitis syndrome, migraine, speech disorder, paresthesia, hypoesthesia, photophobia. Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis, eczema, erythematous rash, dermatitis, pruritus, alopecia, urticaria. Gastrointestinal: Hepatic dysfunction, abdominal pain, diarrhea. Renal: Acute renal failure, osmotic nephropathy, renal pain. Hematologic: Pancytopenia, leukopenia, hemolysis. Musculoskeletal: Musculoskeletal pain, muscle spasm, arthralgia, myalgia, muscle stiffness. General disorders and administration site conditions: Pyrexia, rigors, injection-site reactions, chills, flushing, lethargy, malaise, burning sensation. Psychiatric disorders: Confusion, anxiety, agitation, nervousness. Metabolic and nutritional: Fluid overload, (pseudo) hyponatremia. Immune system disorders: Hypersensitivity (e.g. anaphylaxis, allergic reaction), angioedema. Investigations: Falsely elevated erythrocyte sedimentation rate, positive direct antiglobulin (Coombs') test, increased hepatic enzymes.

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 QIVIGY. It is not known whether QIVIGY can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation. QIVIGY should be given to pregnant women only if clearly needed. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 - 4% and 15 - 20%, respectively.