ALBUMINEX

6 ADVERSE REACTIONS The most common adverse reactions are rigors, hypotension/decreased BP, tachycardia/increased heart rate, pyrexia, feeling cold (chills), nausea, vomiting, dyspnea/bronchospasm, rash/pruritus. Stop the infusion if anaphylaxis, with or without shock is observed. To report SUSPECTED ADVERSE REACTIONS, contact BPL Inc. at 1-844-427-5872 or MedInfo@BPL-US.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 General In general, human albumin solutions are well-tolerated and no specific, clinically relevant alterations in organ function or coagulopathy have been substantiated. 26 The most common adverse reactions associated with infusion of human albumin solutions are rigors, hypotension/decreased BP, tachycardia/increased heart rate, pyrexia, feeling cold (chills), nausea, vomiting, dyspnea/bronchospasm, rash/pruritus. Reactions usually resolve when the infusion is slowed or stopped. Anaphylaxis, with or without shock, may occur and in this situation, stop the infusion. 6.2 Clinical Trials Experience No clinical studies were done using ALBUMINEX 5%.

4 CONTRAINDICATIONS ALBUMINEX 5% is contraindicated in patients with: Hypersensitivity to human albumin or any of the excipients Severe anemia or cardiac failure with normal or increased intravascular volume Hypersensitivity to human albumin or the excipients Severe anemia or cardiac failure with normal or increased intravascular volume

11 DESCRIPTION ALBUMINEX 5% is a sterile, ready-for-use, clear, slightly viscous, almost colorless, yellow, amber or slightly green aqueous solution of human albumin for single dose intravenous infusion. It is prepared from the pooled plasma of US donors in FDA-licensed facilities in the US. The product also contains 130-160 mmol/L of sodium, less than 200 micrograms/L of aluminum and is stabilized with caprylate (0.08 mmol/g albumin) and acetyltryptophanate (0.08 mmol/g albumin) but does not contain any preservative. 12.5 g (250 mL) of ALBUMINEX 5% is oncotically equivalent to 250 mL plasma. 25 g (500 mL) of ALBUMINEX 5% is oncotically equivalent to 500 mL plasma. The vials are closed with a synthetic rubber stopper. The stopper is not made with natural rubber latex. The viral risk from human plasma is minimized by the fractionation process and pasteurization of the albumin solution for 10 hours at 60 ° C (140 ° F) in its final container. These processes are effective for both enveloped and non-enveloped viruses. There have been no reports of virus transmission with products manufactured using this combination of processes. Typical reductions of experimental viral loads are shown in Table 1. Table 1: Virus Reduction for Albumin (Human) 5% Mean Reduction Factors (log 10 ) Enveloped Virus Enveloped Virus Enveloped Virus Enveloped Virus Non-Enveloped Virus Non-Enveloped Virus nd: not determined HIV-1: Human Immunodeficiency Virus Type 1 BVDV: Bovine Viral Diarrhoea Virus IBR: Infectious Bovine Rhinotracheitis HAV: Hepatitis A Virus CPV: Canine Parvovirus Manufacturing Step HIV-1 Sindbis BVDV IBR HAV CPV A+1 Precipitation nd 4.1 >3.4 3.4 3.4 3.7 Fraction IV Precipitation >4.6 >7.1 >4.2 >5.7 4.2 6.0 Pasteurization >6.7 >6.4 >4.2 >5.4 4.0 4.0 Overall >11.3 >13.5 >8.4 >11.1 8.2 10.0

2 DOSAGE AND ADMINISTRATION For intravenous administration only. For intravenous use only. ALBUMINEX 5% may be diluted with 0.9% saline or 5% dextrose (glucose). Dosage and infusion rate should be adjusted to the patient's individual requirements. Indication Dose Hypovolemia Adults: Initial dose of 25 g (including renal dialysis). For acute liver failure: initial dose of 12 to 25 g. ( 2.1 ) Prevention of central volume depletion after paracentesis due to cirrhotic ascites Adults: 8 g for every 1000 mL of ascitic fluid removed. ( 2.1 ) Hypoalbuminemia including from burns Adults: 50 to 75 g For pre- and post-operative hypoproteinemia: 50 to 75 g. For burn therapy after the first 24 h: initial dose of 25 g and dose adjustment to maintain plasma protein concentration of 2.5 g per 100 mL. Third space protein loss due to infection: initial dose of 50 to 100 g. ( 2.1 ) Acute nephrosis Adults: 25 g together with diuretic once a day for 7-10 days. ( 2.1 ) Adult respiratory distress syndrome (ARDS) Adults: 25 g over 30 minutes and repeated at 8 hours for 3 days, if necessary. ( 2.1 ) Cardiopulmonary bypass procedures Adults: Initial dose of 25 g. ( 2.1 ) 2.1 Dosage The concentration of ALBUMINEX 5% used, its dosage, and infusion rate should be adjusted to the patient's individual requirements and clinical indication. Indication Dose Hypovolemia Hypovolemia Adults: Initial dose of 25 g. If hemodynamic stability is not achieved within 15 to 30 minutes, an additional dose may be given. For acute liver failure: initial dose of 12 to 25 g. An infusion rate of 1-2 mL per minute is usually indicated. For renal dialysis; the initial dose should not exceed 25 g and patients should be carefully observed for signs of fluid overload. Prevention of central volume depletion after paracentesis due to cirrhotic ascites Adults: 8 g for every 1000 mL of ascitic fluid removed. Hypoalbuminemia including from burns Adults: 50 to 75 g For pre- and post-operative hypoproteinemia: 50 to 75 g. In burns, therapy usually starts with administration of large volumes of crystalloid solution to maintain plasma volume. After 24 hours: initial dose of 25 g and dose adjustment to maintain plasma protein concentration of 2.5 g per 100 mL or a serum protein concentration of 5.2 g per 100 mL. Third space protein loss due to infection or burns: initial dose of 50 to 100 g. An infusion rate of 1-2 mL per minute is usually indicated in the absence of shock. Treatment should always be guided by hemodynamic response. Acute nephrosis Adults: 25 g together with diuretic once a day for 7-10 days Adult respiratory distress syndrome (ARDS) Adults: 25 g over 30 minutes and repeated at 8 hours for 3 days, if necessary. Cardiopulmonary bypass procedures Adults: Initial dose of 25 g. Additional amounts may be administered as clinically indicated. 2.3 Administration Visually inspect the solution for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there are any particulates seen or if the solution is discolored. If a large volume is infused, ensure that the vial is at room temperature before infusion. Do not dilute with Sterile Water for Injection as hemolysis may occur. ALBUMINEX 5% may be diluted with 0.9% saline or 5% dextrose. Begin the infusion within 4 hours of piercing the vial stopper (the product does not contain any preservative). Adjust the rate of infusion according to the individual patient's hemodynamic and other physiological responses, using appropriate clinical monitoring.

1 INDICATIONS AND USAGE ALBUMINEX 5% is a 5% albumin solution indicated for adults and children: Hypovolemia ( 1.1 ) Ascites ( 1.2 ) Hypoalbuminemia including from burns ( 1.3 ) Acute Nephrosis ( 1.4 ) Acute Respiratory Distress Syndrome (ARDS) ( 1.5 ) Cardiopulmonary Bypass ( 1.6 ) 1.1 Hypovolemia ALBUMINEX 5% is indicated for restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated, and use of a colloid is appropriate e.g. hypovolemia following shock due to trauma or sepsis, in surgical patients and in other similar conditions with volume deficiency when restoration and maintenance of circulating blood volume is required in both adult and pediatric patients. In pediatric patients to reverse hypovolemia and achieve normal capillary refill time. 1, 2, 3, 4, 5, 6, 7, 8 1.2 Ascites ALBUMINEX 5% is indicated for prevention of central volume depletion and maintenance of cardiovascular function after large volume parencentesis in patients with liver cirrhosis or other chronic liver disease in adults and children. 9, 10, 11, 12 ALBUMINEX 5% infusion plus administration of vasoactive drugs is indicated in the treatment of type I hepatorenal syndrome. 6 For patients with spontaneous bacterial peritonitis, ALBUMINEX 5% is indicated as adjuvant treatment to antibiotic therapy. 9, 10, 13 1.3 Hypoalbuminemia including from burns ALBUMINEX 5% is indicated in patients with severe burn injury (> 20% total body surface area), but not until at least 12 to 24 hours after the burn, in order to correct protein loss, decrease overall fluid requirements, decrease systemic edema and stabilize cardiovascular hemodynamics without fluid overload (initial resuscitation should be with crystalloids). 8, 14 ALBUMINEX 5% is also indicated in patients with pre- or post-operative hypoproteinemia and for third space protein loss due to infection or burns. 1.4 Acute Nephrosis ALBUMINEX 5% is indicated in patients with acute nephrosis in combination with loop diuretics to reinforce the diuretic therapeutic effect, which is reduced by hypoalbuminemia, and for the correction of reduced oncotic pressure. 15, 16 1.5 Acute Respiratory Distress Syndrome (ARDS) ALBUMINEX 5% is indicated in conjunction with diuretics to correct fluid volume overload associated with ARDS. 17, 18, 19 1.6 Cardiopulmonary Bypass ALBUMINEX 5% is indicated in cardiopulmonary bypass procedures as part of the priming fluids to passivate the synthetic surfaces of the extracorporeal circuit and maintain the patient's colloid oncotic pressure. 20, 21, 22, 23, 24, 25

7 DRUG INTERACTIONS Do not mix ALBUMINEX 5% with blood, blood components, protein hydrolysates, alcoholic solutions or other medicinal products. Although it is not usually necessary to dilute Albuminex 5%, if it should be necessary, it may be diluted with 0.9% saline or 5% dextrose. However, it can be administered, via a separate IV line, concomitantly with other parenterals.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Human albumin accounts for more than half of the total protein in the plasma and represents about 10% of protein synthesis activity by the liver. The primary physiological function of albumin results from its contribution to plasma colloid oncotic pressure and transport function. Albumin stabilizes circulating blood volume and is a carrier of hormones, enzymes, medicinal products and toxins. Other physiological functions include antioxidant properties, free radical scavenging, and capillary membrane integrity. 12.3 Pharmacokinetics Albumin is distributed throughout the extracellular space and more than 60% of the body albumin pool is located in the extravascular fluid compartment. Albumin has a circulating life span of 15-20 days, with a turnover of approximately 15 g per day. The balance between synthesis and breakdown is normally achieved by feedback regulation. Elimination is predominantly intracellular and due to lysosome proteases. In healthy subjects, less than 10% of infused albumin leaves the intravascular compartment during the first 2 hours following infusion. There is considerable individual variation in the effect of albumin on plasma volume. In some patients, the plasma volume can remain elevated for several hours. In critically ill patients, however, albumin can leak out of the vascular space in substantial amounts at an unpredictable rate.

12.1 Mechanism of Action Human albumin accounts for more than half of the total protein in the plasma and represents about 10% of protein synthesis activity by the liver. The primary physiological function of albumin results from its contribution to plasma colloid oncotic pressure and transport function. Albumin stabilizes circulating blood volume and is a carrier of hormones, enzymes, medicinal products and toxins. Other physiological functions include antioxidant properties, free radical scavenging, and capillary membrane integrity.

12.3 Pharmacokinetics Albumin is distributed throughout the extracellular space and more than 60% of the body albumin pool is located in the extravascular fluid compartment. Albumin has a circulating life span of 15-20 days, with a turnover of approximately 15 g per day. The balance between synthesis and breakdown is normally achieved by feedback regulation. Elimination is predominantly intracellular and due to lysosome proteases. In healthy subjects, less than 10% of infused albumin leaves the intravascular compartment during the first 2 hours following infusion. There is considerable individual variation in the effect of albumin on plasma volume. In some patients, the plasma volume can remain elevated for several hours. In critically ill patients, however, albumin can leak out of the vascular space in substantial amounts at an unpredictable rate.

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3 DOSAGE FORMS AND STRENGTHS ALBUMINEX 5% is a sterile, aqueous solution of human albumin (5% w/v i.e. 5 g/dL) for intravenous administration available as: 250 mL (12.5 g) single dose vial 500 mL (25 g) single dose vial ALBUMINEX 5% is a solution for infusion: ALBUMINEX 5% contains 5 g per dL of human albumin in 250 mL (12.5 g) and 500 mL (25 g) glass vials

ALBUMINEX Albumin Human Albumin Human Albumin Human Sodium Chloride Sodium Hydroxide Caprylic Acid Sodium acetyltryptophanate

BLA125644

ALBUMINEX

Albumin Human

64208-2510

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 500 mL Vial Label NDC 64208-2510-6 Albumin (Human) - kjda ALBUMINEX ® 5% 25 g 500 mL solution for infusion For intravenous use only. See package insert for directions for use and product dosage information. Do not use if turbid. Do not begin administration 4 hours after the vial has been pierced. Rx only ACAUS2L Distributor: BPL USA, Inc., 302 E. Pettigrew Street, Suite C-190, Durham, NC 27701, USA Manufactured by: Bio Products Laboratory Ltd., Elstree, Borehamwood, WD6 3BX. U.K. U.S. License No. 1811 PRINCIPAL DISPLAY PANEL - 500 mL Vial Label

Manufactured by: Bio Products Laboratory Ltd., Elstree, WD6 3BX. United Kingdom U.S. Distributor: Bio Products Laboratory USA Inc., 302 East Pettigrew Street, Suite C-190, Durham, NC 27701 USA U.S. Licence No:1811 ALBUMINEX ® is a registered trademark of Bio Products Laboratory Ltd.

17 PATIENT COUNSELING INFORMATION Ensure that patients to be treated with ALBUMINEX 5% are informed of the potential risks and benefits of its use for their clinical condition [see Warnings and Precautions (5) ] . Check that they are not known to be allergic to the product or its excipients [see Contraindications (4) and Description (11) ] . Make them aware of the symptoms of anaphylaxis [see Hypersensitivity (5.1) ] . Make them aware of the symptoms of potential circulatory overload [see Hypervolemia (5.2) ] . Inform patients that because ALBUMINEX 5% is derived from human blood plasma it may contain infectious agents that cause disease (e.g. viruses and, theoretically CJD agent) although the risk of infection from ALBUMINEX 5% has been reduced by the procedures used in donor selection and during manufacture [see Infectious Diseases (5.6) and Description (11) ] .

15 REFERENCES 1. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;3650:2247-2256 2. Bunn F, Trivedi D, Ashraf S. Colloid solutions for fluid resuscitation. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD001319. DOI: 10.1002/14651858.CD001319.pub3 3. Powell-Tuck J, Gosling P, Lobo DN, et al. British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients. BAPEN; 2011. Available from: http://www.bapen.org.uk/pdfs/bapen_pubs/giftasup.pdf (Guideline Ref ID GIFTASUP2011) 4. Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med 2014;161(5):347-355 5. Wiedermann CJ, Joannidis M. Albumin replacement in severe sepsis or septic shock. N Engl J Med 2014;371:83-84 6. Akech S, Gwer S, Idro R, et al. Volume expansion with albumin compared to gelofusine in children with severe malaria: results of a controlled trial. PLoS Clin Trials 2006; 5:0001-0011 7. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Critical Care Medicine, 2013; 41(2):580–637 8. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systemic Reviews 2013, Issue 2.Art. No.CD000567. DOI:10.1002/14651858.CD000567.pub6. 9. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. The American Association for the Study of Liver Diseases 2012. http://www.aasld.org/publications/practice-guidelines-0 [accessed 15 April 2016] 10. EASL clinical practise guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010; 53: 397–417 11. Bernardi M, Carceni P, Navickis RJ, et al. Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials. Hepatology 2012;55:1172-1181 12. Sarma MS, Yachha SK, Bhatia V, et al. Safety, complications and outcome of large volume paracentesis with or without albumin therapy in children with severe ascites due to liver disease. J Hepatol 2015:63;1126-1132 13. Wiest R, Krag A, Gerbes A. Spontaneous Bacterial Peritonitis. Recent Guidelines and Beyond. Gut 2012; 61(2):297-310 14. Pham TN, Cancio LC, Gibran NS. American Burn Association Practice Guidelines Burn Shock Resuscitation. J Burn Care Res 2008; 29(1):257-266 15. Bircan Z, Kervancioglu M. Does albumin and furosemide therapy affect plasma volume in nephrotic children? Pediatr Nephrol 2001;16:497-499 16. Dharmaraj R, Hari P, Bagga A. Randomized cross-over trial comparing albumin and frusemide infusions in nephrotic syndrome. Pediatr Nephrol 2009; 24(4):775-782 17. Martin GS, Moss M, Wheeler AP, et al. A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med 2005;33(8):1681-1687 18. Uhlig C, Pedro L, Silva PL, et al. Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care 2014, 18:R10 http://ccforum.com/content/18/1/R10 [accessed 02 November 2016] 19. Quinlan GJ, Mumby S, Martin GS, et al. Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury. Crit Care Med 2004;32:755–759 20. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg 2001;72(2):527-534 21. Golab HD, Scohy TV, de Jong PL, et al. Relevance of colloid oncotic pressure regulation during neonatal and infant cardiopulmonary bypass: a prospective randomized study. Eur J Cardio-Thor Surg 2011; 39(6):886-891 22. Hanart C, Khalife M, De Villé A, et al. Perioperative volume replacement in children undergoing cardiac surgery: Albumin versus hydroxyethyl starch 130/0.4. Crit Care Med 2009;37 (2): 696-701 DOI: 10.1097/CCM.0b013e3181958c81 23. Loeffelbein F, Zirell U, Benk C, et al. High colloid oncotic pressure priming of cardiopulmonary bypass in neonates and infants: implications on haemofiltration, weight gain and renal function. Eur J Cardio-Thor Surg 2008; 34(3):648-652 24. Oliver WC Jr, Beynen FM, Nuttall GA, et al. Blood loss in infants and children for open heart operations: albumin 5% versus fresh-frozen plasma in the prime. Ann Thor Surg 2003;75(5):1506-1512 25. Yu K, Liu Y, Hei F, et al. Effect of different albumin concentrations in extracorporeal circuit prime on perioperative fluid status in young children. ASAIO Journal 2008; 54(5):463-466 26. German Medical Association. Cross-Sectional Guidelines for Therapy with Blood Components and Plasma Derivatives. 4th revised and updated edition 2014. http://www.bundesaerztekammer.de/aerzte/medizin-ethik/wissenschaftlicher-beirat/veroeffentlichungen/haemotherapie-transfusionsmedizin/english/ [accessed 15 April 2016]

8.5 Geriatric Use No human or animal data. Use only if clearly needed.

8.4 Pediatric Use No human or animal data. Use only if clearly needed.

8.1 Pregnancy Risk Summary There are no data with ALBUMINEX 5% use in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted using ALBUMINEX 5%. It is not known whether ALBUMINEX 5% can cause fetal harm when administered to a pregnant woman or can affect fertility. ALBUMINEX 5% should be given to a pregnant woman 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no data with ALBUMINEX 5% use in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted using ALBUMINEX 5%. It is not known whether ALBUMINEX 5% can cause fetal harm when administered to a pregnant woman or can affect fertility. ALBUMINEX 5% should be given to a pregnant woman 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. 8.2 Lactation Risk Summary There is no information regarding the presence of ALBUMINEX 5% in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ALBUMINEX 5% and any potential adverse effects on the breast-fed infant from ALBUMINEX 5% or from the underlying maternal condition. 8.4 Pediatric Use No human or animal data. Use only if clearly needed. 8.5 Geriatric Use No human or animal data. Use only if clearly needed.

16 HOW SUPPLIED/STORAGE AND HANDLING How ALBUMINEX 5% is supplied ALBUMINEX 5%, 5 g/dL in clear Type II glass vials. Strength Grams and fill size NDC carton number NDC vial number 5% 12.5 g in 250 mL 64208-2510-1 64208-2510-2 5% 25 g in 500 mL 64208-2510-5 64208-2510-6 Not all pack sizes may be marketed. Storage and handling Do not store above 30 ° C (86 ° F). Keep the vial stored in the outer carton in order to protect from light. Do not freeze. Do not use ALBUMINEX 5% after the expiration date which is stated on the carton and label after "EXP." The expiration date refers to the last day of that month. ALBUMINEX 5% should be inspected visually for particulate matter and discoloration prior to administration. U.S. federal law prohibits dispensing without prescription.

Storage and handling Do not store above 30 ° C (86 ° F). Keep the vial stored in the outer carton in order to protect from light. Do not freeze. Do not use ALBUMINEX 5% after the expiration date which is stated on the carton and label after "EXP." The expiration date refers to the last day of that month. ALBUMINEX 5% should be inspected visually for particulate matter and discoloration prior to administration. U.S. federal law prohibits dispensing without prescription.