EXTRANEAL

1 INDICATIONS AND USAGE EXTRANEAL (icodextrin) is indicated for a single daily exchange for the long (8- to 16- hour) dwell during continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for the management of kidney failure in patients requiring long-term kidney replacement therapy. EXTRANEAL is also indicated to improve (compared to 4.25% dextrose) long-dwell ultrafiltration and clearance of creatinine and urea nitrogen in patients with high average or greater transport characteristics, as defined using the peritoneal equilibration test (PET) [see Clinical Pharmacology ( 12 ), Clinical Studies ( 14 )]. • For a single daily exchange for the long (8- to 16- hour) dwell during continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for the management of kidney failure in patients requiring long-term kidney replacement therapy. ( 1 ) • To improve (compared to 4.25% dextrose) long-dwell ultrafiltration and clearance of creatinine and urea nitrogen in patients with high average or greater transport characteristics, as defined using the peritoneal equilibration test (PET). ( 1 )

2 DOSAGE AND ADMINISTRATION For intraperitoneal administration only. Not for intravenous or intra-arterial administration. Administer as a single daily peritoneal dialysis (PD) exchange for the long dwell. Dosage should be individualized by the prescribing physician experienced in the treatment of kidney failure in patients requiring long-term kidney replacement therapy with PD. ( 2.1 ) 2.1 Basic Dosing Information EXTRANEAL is intended for intraperitoneal administration only. Not for intravenous or intra-arterial administration. Administer as a single daily exchange for the long dwell in continuous ambulatory peritoneal dialysis or automated peritoneal dialysis. The recommended dwell time is 8 to 16 hours. Administer over a period of 10 to 20 minutes at a rate that is comfortable for the patient. The mode of therapy, frequency of treatment, exchange volume, duration of dwell, and length of dialysis should be initiated and supervised by the prescribing physician experienced in the treatment of kidney failure in patients requiring long-term kidney replacement therapy with peritoneal dialysis. It is recommended that patients being placed on peritoneal dialysis should be appropriately trained in a program that is under supervision of a physician. 2.2 Directions for Use For complete CAPD and APD system preparation, see directions accompanying ancillary equipment. Aseptic technique should be used throughout the peritoneal dialysis procedure. For single-dose only. Storage Store in moisture barrier overwrap and in carton until ready to use [see How Supplied/Storage and Handling ( 16 )] . Warming For patient comfort, EXTRANEAL can be warmed to 37°C (98.6°F). Only dry heat should be used (e.g., heating pad, warming plate). Do not immerse EXTRANEAL in water for warming. Do not use a microwave oven to warm EXTRANEAL. Do not heat above 40°C (104°F). To Open To open, tear the overwrap down at the slit and remove the solution container. Some opacity of the plastic, due to moisture absorption during the sterilization process, may be observed. This does not affect the solution quality or safety and may often leave a slight amount of moisture within the overwrap. Inspect for Container Integrity and Solution Appearance Do not use EXTRANEAL if it is cloudy or discolored, if it contains particulate matter, or if the container is leaking. Inspect the patient connector to ensure the pull ring is attached. Do not use if pull ring is not attached to the connector. Inspect the EXTRANEAL container for signs of leakage and check for minute leaks by squeezing the container firmly. If the container has frangible(s), inspect that they are positioned correctly and are not broken. Do not use EXTRANEAL if the frangible(s) are broken or leaks are suspected as sterility may be impaired. For EXTRANEAL in ULTRABAG, inspect the tubing and drain container for presence of solution. Small droplets are acceptable, but if solution flows past the frangible prior to use, do not use and discard the units. Adding Medications The decision to add medication should be made by the physician after careful evaluation of the patient [see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] . If the re-sealable rubber plug on the medication port is missing or partly removed, do not use the product. To add a medication: 1. Put on mask. Clean and/or disinfect hands. 2. Prepare medication port site using aseptic technique. 3. Using a syringe with a 1-inch long, 25- to 19-gauge needle, puncture the medication port and inject additive. 4. Reposition container with container ports up and evacuate medication port by squeezing and tapping it. 5. Mix solution and additive thoroughly. Preparation for Administration 1. Put on mask. Clean and/or disinfect hands. 2. Place EXTRANEAL on work surface. 3. For ULTRABAG system for manual exchanges, uncoil tubing and drain bag. Ensure the patient transfer set is closed. Break the connector (Y-set) frangible. 4. Remove pull ring from connector of solution container. If continuous fluid flow from connector is observed, discard solution container. Once the pull ring has been removed, do not reuse the solution or container. 5. Immediately attach the solution container to patient connector (transfer set) or appropriate peritoneal dialysis set. 6. For AMBU-FLEX II, continue with therapy set-up as instructed in user manual or directions accompanying tubing sets for automated peritoneal dialysis. 7. For ULTRABAG, follow the below steps: • Clamp solution line and then break frangible near solution bag. Hang solution container and place the drainage container below the level of the abdomen. • Open transfer set to drain the solution from abdomen. If drainage cannot be established, contact your clinician. When drainage complete, close transfer set. • Remove clamp from solution line and flush new solution to flow into the drainage container for 5 seconds to prime the line. Clamp drain line after flush complete. • Open transfer set to fill. When fill complete, close transfer set and clamp solution line. • Put on mask. Clean and/or disinfect hands. • Disconnect ULTRABAG from transfer set and apply MINICAP. Completion of Therapy 1. Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness, which may indicate the presence of peritonitis. 2. Discard unused portion.

4 CONTRAINDICATIONS EXTRANEAL is contraindicated in patients with: • known hypersensitivity to icodextrin [see Warnings and Precautions ( 5.3 )] • maltose or isomaltose intolerance • glycogen storage disease • severe lactic acidosis, as EXTRANEAL contains lactate which may contribute to worsening acidosis if conversion to bicarbonate is impaired and may be associated with hyperventilation, lethargy, hypotension or irregular heart rhythms. • Known hypersensitivity to icodextrin • Maltose or isomaltose intolerance • Glycogen storage disease • Pre-existing severe lactic acidosis

5 WARNINGS AND PRECAUTIONS • Use glucose-specific glucose monitoring systems when measuring blood glucose ( 5.1 ) • Encapsulating peritoneal sclerosis (5.2 ) • Peritonitis: Initiate appropriate antimicrobial therapy. ( 5.2 ) • Hypersensitivity reactions: Serious reactions have been reported. Discontinue use of EXTRANEAL if serious reaction is suspected. ( 5.3 ) • Monitor for lactic acidosis in patients at risk ( 5.4 ) • Monitor for electrolyte, fluid, and nutrition imbalances ( 5.6 ) 5.1 Unrecognized Hypoglycemia Resulting from Drug-Device Interaction When measuring blood glucose levels in patients using EXTRANEAL (icodextrin) Peritoneal Dialysis Solution, do not use blood glucose monitoring devices using glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ)-, glucose-dye-oxidoreductase (GDO)-, and some glucose dehydrogenase flavin-adenine dinucleotide (GDH-FAD)-based methods because these systems may result in falsely elevated glucose readings (due to the presence of maltose). Falsely elevated glucose readings have led patients or health care providers to withhold treatment of hypoglycemia or to administer insulin inappropriately leading to unrecognized hypoglycemia. Falsely elevated glucose levels may be measured up to two weeks following cessation of EXTRANEAL (icodextrin) therapy when GDH-PQQ, GDO, and GDH-FAD-based blood glucose monitors and test strips are used. Additionally, other glucose-measuring technologies, such as continuous glucose monitoring systems, may or may not be compatible with EXTRANEAL. Always contact the device manufacturer for current information regarding compatibility and intended use of the device in the dialysis patient population. For additional information, please contact the Vantive Renal Clinical Help Line 1-888-RENAL-HELP or visit www.glucosesafety.com . 5.2 Peritonitis and Encapsulating Peritoneal Sclerosis Infectious and aseptic peritonitis has been associated with EXTRANEAL use. Following EXTRANEAL use, inspect the drained fluid for the presence of fibrin or cloudiness, which may indicate the presence of peritonitis. Improper clamping or priming sequence may result in infusion of air into the peritoneal cavity, which may result in abdominal pain and/or peritonitis. If peritonitis occurs, treat with appropriate therapy. Encapsulating peritoneal sclerosis (EPS), sometimes fatal, is a complication of peritoneal dialysis therapy and has been reported in patients using EXTRANEAL. 5.3 Hypersensitivity Reactions Serious hypersensitivity reactions to EXTRANEAL have been reported such as toxic epidermal necrolysis, angioedema, serum sickness, erythema multiforme and vasculitis [ see Adverse Reactions ( 6.1 , 6.2 ) ]. Anaphylactic or anaphylactoid reactions may occur. Stop the infusion immediately and drain the solution from the peritoneal cavity if any signs or symptoms of a suspected hypersensitivity reaction develop [see Contraindications ( 4 )] . Institute appropriate therapeutic countermeasures as clinically indicated. 5.4 Lactic Acidosis Monitor patients with conditions known to increase the risk of lactic acidosis [e.g., severe hypotension or sepsis that can be associated with acute renal failure, inborn errors of metabolism, treatment with drugs such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)] for lactic acidosis before the start of treatment and during treatment with EXTRANEAL [see Contraindications ( 4 )]. 5.5 Overinfusion Overinfusion of peritoneal dialysis solution volume into the peritoneal cavity may be characterized by abdominal distention, feeling of fullness and/or shortness of breath. Drain the peritoneal dialysis solution from the peritoneal cavity to treat overinfusion. 5.6 Electrolyte, Fluid, and Nutrition Imbalances Peritoneal dialysis may affect a patient’s protein, water-soluble vitamin, potassium, sodium, chloride, bicarbonate, and magnesium levels and volume status [see Adverse Reactions ( 6 )] . Monitor electrolytes and blood chemistry periodically and take appropriate clinical action. Potassium is omitted from EXTRANEAL solutions because dialysis may be performed to correct hyperkalemia. In situations where there is a normal serum potassium level or hypokalemia, the addition of potassium chloride (up to a concentration of 4 mEq/L) may be indicated to prevent severe hypokalemia. Monitor fluid status to avoid hyper- or hypovolemia and potentially severe consequences including congestive heart failure, volume depletion, and hypovolemic shock.

7 DRUG INTERACTIONS As with other dialysis solutions, blood concentrations of dialyzable drugs may be reduced by dialysis. Dosage adjustment of concomitant medications may be necessary. In patients using cardiac glycosides (digoxin and others), plasma levels of calcium, potassium and magnesium must be carefully monitored [see Warnings and Precautions ( 5.6 )]. Insulin: Patients with insulin-dependent diabetes may require modification of insulin dosage following initiation of treatment with EXTRANEAL. Monitor blood glucose and adjust insulin, if needed [see Warnings and Precautions ( 5.1 )] .

6 ADVERSE REACTIONS The most common adverse reaction (incidence > 5%) was rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vantive US Healthcare LLC at 1-855-857-0003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience EXTRANEAL was originally studied in controlled clinical trials of 493 patients with kidney failure in patients requiring long-term kidney replacement therapy who received a single daily exchange of EXTRANEAL for the long dwell (8-to 16- hours). There were 215 patients exposed for at least 6 months and 155 patients exposed for at least one year. The population was 18-83 years of age, 56% male and 44% female, 73% Caucasian, 18% Black, 4% Asian, 3% Hispanic, and it included patients with the following comorbid conditions: 27% diabetes, 49% hypertension and 23% hypertensive nephropathy. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Rash was the most frequently occurring EXTRANEAL-related adverse reaction (5.5%, EXTRANEAL; 1.7% Control). Seven patients on EXTRANEAL discontinued treatment due to rash, and one patient on EXTRANEAL discontinued due to exfoliative dermatitis. The rash typically appeared within the first three weeks of treatment and resolved with treatment discontinuation or, in some patients, with continued treatment. Table 1 shows the adverse events reported in these clinical studies regardless of causality, occurring in ≥ 5% of patients and more common on EXTRANEAL than control. Table 1 - Adverse Experiences in ≥5% of Patients and More Common on EXTRANEAL EXTRANEAL Control N = 493 N = 347 Peritonitis 26% 25% Upper respiratory infection 15% 13% Hypertension 13% 8% Rash 10% 5% Headache 9% 7% Abdominal Pain 8% 6% Flu syndrome 7% 6% Nausea 7% 5% Cough increase 7% 4% Edema 6% 5% Accidental injury 6% 4% Chest pain 5% 4% Dyspepsia 5% 4% Hyperglycemia 5% 4% Clinical Laboratory Findings An increase in mean serum alkaline phosphatase has been observed in clinical studies of ESRD patients receiving EXTRANEAL. No associated increases in other liver chemistry tests were observed. Serum alkaline phosphatase levels did not show progressive increase over a 12-month study period. Levels returned to normal approximately two weeks after discontinuation of EXTRANEAL. Decreases in serum sodium and chloride have been observed in patients using EXTRANEAL. The mean change in serum sodium from baseline to the last study visit was -2.8 mmol/L for patients on EXTRANEAL and -0.3 mmol/L for patients on control solution. Four EXTRANEAL patients and two control patients developed serum sodium < 125 mmol/L. The mean change in serum chloride from baseline to last study visit was -2 mmol/L for EXTRANEAL patients and + 0.6 mmol/L for control patients. Similar changes in serum chemistries were observed in an additional clinical study in a subpopulation of high average/high transporter patients. The declines in serum sodium and chloride may be related to dilution resulting from the presence of icodextrin metabolites in plasma. An apparent decrease in serum amylase activity has been observed in patients administered EXTRANEAL. Investigations indicate that icodextrin and its metabolites interfere with enzymatic-based amylase assays, resulting in inaccurately low values. This should be taken into account when evaluating serum amylase levels for diagnosis or monitoring of pancreatitis in patients using EXTRANEAL. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of EXTRANEAL, or in conjunction with performing the peritoneal dialysis procedure. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. INFECTIONS AND INFESTATIONS: Fungal peritonitis, Peritonitis bacterial, Catheter related infection BLOOD AND LYMPHATIC SYSTEM DISORDERS: Thrombocytopenia, Leukopenia, Leukocytosis IMMUNE SYSTEM DISORDERS: Vasculitis, Serum sickness, Hypersensitivity METABOLISM AND NUTRITION DISORDERS: Hypoglycemic shock, Dehydration NERVOUS SYSTEM DISORDERS: Hypoglycemic coma, Burning sensation EYE DISORDERS: Vision blurred RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Bronchospasm, Stridor GASTROINTESTINAL DISORDERS: Encapsulating peritoneal sclerosis, Aseptic peritonitis, Ileus, Ascites, Inguinal hernia SKIN AND SUBCUTANEOUS DISORDERS: Toxic epidermal necrolysis, Angioedema, Urticaria generalized, Prurigo, Dermatitis (including bullous, allergic and contact), Erythema, Onychomadesis, Dry skin, Skin chapped, Blister MUSCULOSKELETAL, CONNECTIVE TISSUE DISORDERS: Musculoskeletal pain REPRODUCTIVE SYSTEM AND BREAST DISORDERS: Penile edema, Scrotal edema GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS: Pyrexia, Chills, Malaise, Catheter site erythema, Catheter site inflammation, Infusion related reaction (including Infusion site pain, Instillation site pain) INVESTIGATIONS: Liver function test abnormal, Urine output decreased

8.1 Pregnancy Risk Summary EXTRANEAL is a pharmacologically inactive solution. While there are no adequate and well controlled studies in pregnant women, appropriate administration of EXTRANEAL with monitoring of hematology, blood chemistry, and fluid status is not expected to cause fetal harm. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.