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 10-20 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 end-stage renal disease 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.

4.1 Allergy to Cornstarch or Icodextrin

EXTRANEAL is contraindicated in patients with a known allergy to cornstarch or icodextrin.

4.2 Metabolic Diseases

EXTRANEAL is contraindicated in patients with maltose or isomaltose intolerance and in patients with glycogen storage disease.

4.3 Severe Lactic Acidosis

EXTRANEAL is contraindicated in patients with severe lactic acidosis. 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.

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 Baxter 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. 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 (4.3)].

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.

6.1 Clinical Trials Experience

EXTRANEAL was originally studied in controlled clinical trials of 493 patients with end-stage renal disease 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.

Adverse events related to EXTRANEAL use or in conjunction with performing the peritoneal dialysis procedure include:

Reported with an incidence of > 5% and at least as common on dextrose control included asthenia, exit site infection, infection, back pain, hypotension, diarrhea, vomiting, anemia, peripheral edema, hypokalemia, hyperphosphatemia, hypoproteinemia, hypervolemia, arthralgia, dizziness, dyspnea, pruritis.

Reported with an incidence of < 5%: pain on infusion, abdominal enlargement, cloudy effluent, ultrafiltration decrease, postural hypotension, heart failure, hyponatremia, hypochloremia, hypercalcemia, hypoglycemia, alkaline phosphatase increase, SGPT increase, SGOT increase, cramping, confusion, lung edema, facial edema, exfoliative dermatitis, eczema, vesicobullous rash, maculopapular rash, erythema multiforme.

EXTRANEAL was additionally studied in a subpopulation of 92 high average/high transporter APD patients in a two-week controlled clinical trial where patients received a single daily exchange of EXTRANEAL (n=47) or dextrose control (n=45) for the long dwell (14 ± 2 hours). Consistent with the data reported in the original trials of EXTRANEAL, rash was the most frequently occurring event.

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

8.3 Nursing Mothers

It is not known whether icodextrin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when EXTRANEAL is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

No formal studies were specifically carried out in the geriatric population. However, 140 of the patients in clinical studies of EXTRANEAL were age 65 or older, with 28 of the patients age 75 or older. No overall differences in safety or effectiveness were observed between these patients and patients under age 65. Although clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

12.1 Mechanism of Action

EXTRANEAL is an isosmotic peritoneal dialysis solution containing glucose polymers (icodextrin) as the primary osmotic agent. Icodextrin functions as a colloid osmotic agent to achieve ultrafiltration during long peritoneal dialysis dwells. Icodextrin acts in the peritoneal cavity by exerting osmotic pressure across small intercellular pores resulting in transcapillary ultrafiltration throughout the dwell. Like other peritoneal dialysis solutions, EXTRANEAL also contains electrolytes to help normalize electrolyte balance and lactate to help normalize acid-base status.

12.2 Pharmacodynamics

EXTRANEAL results in a reduction in the absorbed caloric (carbohydrate) load compared to 4.25% hyperosmolar glucose solutions. Additionally, EXTRANEAL results in an increased ultrafiltration volume per gram of absorbed carbohydrate compared to hyperosmolar glucose solutions.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Icodextrin did not demonstrate evidence of genotoxicity potential in in vitro bacterial cell reverse mutation assay (Ames test); in vitro mammalian cell chromosomal aberration assay (CHO cell assay); and in the in vivo micronucleus assay in mice. Long-term animal studies to evaluate the carcinogenic potential of EXTRANEAL or icodextrin have not been conducted. Icodextrin is derived from maltodextrin, a common food ingredient.

A fertility study in rats where males and females were treated for four and two weeks, respectively, prior to mating and until day 17 of gestation at up to 1.5 g/kg/day (1/3 the human exposure on a mg/m2 basis) revealed slightly low epididymal weights in parental males in the high dose group as compared to Control. Toxicological significance of this finding was not evident as no other reproductive organs were affected and all males were of proven fertility. The study demonstrated no effects of treatment with icodextrin on mating performance, fertility, litter response, embryo-fetal survival, or fetal growth and development.

14.1 Ultrafiltration, Urea and Creatinine Clearance

In the active-controlled trials of one to six months in duration, described below, EXTRANEAL used once-daily for the long dwell in either continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) therapy resulted in higher net ultrafiltration than 1.5% and 2.5% dextrose solutions, and higher creatinine and urea nitrogen clearances than 2.5% dextrose. Net ultrafiltration was similar to 4.25% dextrose across all patients in these studies. Effects were generally similar in CAPD and APD.

In an additional randomized, multicenter, active-controlled two-week study in high average/high transporter APD patients, EXTRANEAL used once daily for the long dwell produced higher net ultrafiltration compared to 4.25% dextrose. Mean creatinine and urea nitrogen clearances were also greater with EXTRANEAL and ultrafiltration efficiency was improved.

In 175 CAPD patients randomized to EXTRANEAL (N=90) or 2.5% dextrose solution (N=85) for the 8-15 hour overnight dwell for one month, mean net ultrafiltration for the overnight dwell was significantly greater in the EXTRANEAL group at weeks 2 and 4 (Figure 1). Mean creatinine and urea nitrogen clearances were also greater with EXTRANEAL (Figure 1).

Figure 1 - Mean Net Ultrafiltration, Mean Creatinine and Urea Nitrogen Clearance for the Overnight Dwell

In another study of 39 APD patients randomized to EXTRANEAL or 2.5% dextrose solution for the long, daytime dwell (10-17 hours) for three months, the net ultrafiltration reported during the treatment period was (mean ± SD) 278 ± 192 mL for the EXTRANEAL group and -138 ± 352 mL for the dextrose group (p<0.001). Mean creatinine and urea nitrogen clearances were significantly greater for EXTRANEAL than 2.5% dextrose at weeks 6 and 12 (p<0.001).

In a six-month study in CAPD patients comparing EXTRANEAL (n=28) with 4.25% dextrose (n=31), net ultrafiltration achieved during an 8-hour dwell averaged 510 mL for EXTRANEAL and 556 mL for 4.25% dextrose. For 12-hour dwells, net ultrafiltration averaged 575 mL for EXTRANEAL (n=29) and 476 mL for 4.25% dextrose (n=31). There was no significant difference between the two groups with respect to ultrafiltration.

In a two week study in high average/high transporter APD patients (4-hour D/P creatinine ratio >0.70 and a 4-hour D/D0 ratio <0.34, as defined by the peritoneal equilibration test (PET)), comparing EXTRANEAL (n=47) to 4.25% dextrose (n=45), after adjusting for baseline, the mean net ultrafiltration achieved during a 14 ± 2 hour dwell was significantly greater in the EXTRANEAL group than the 4.25% dextrose group at weeks 1 and 2 (p<0.001, see Figure 2). Consistent with increases in net ultrafiltration, there were also significantly greater creatinine and urea nitrogen clearances and ultrafiltration efficiency in the EXTRANEAL group (p<0.001, see Figure 2).

Figure 2 – Mean Net Ultrafiltration, Creatinine and Urea Nitrogen Clearances and Ultrafiltration Efficiency for the Long Dwell in High Average/High Transporter Patients

14.2 Peritoneal Membrane Transport Characteristics

After one year of treatment with EXTRANEAL during the long dwell exchange, there were no differences in membrane transport characteristics for urea and creatinine. The mass transfer area coefficients (MTAC) for urea, creatinine, and glucose at one year were not different in patients receiving treatment with EXTRANEAL or 2.5% dextrose solution for the long dwell.