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.

Pharmacokinetics of Icodextrin

Special Populations

Clinical Studies

Extraneal has demonstrated efficacy as a peritoneal dialysis solution in clinical trials of approximately 480 patients studied with end-stage renal disease (ESRD).

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 2).

Figure 1 - Mean Net Ultrafiltration for the Overnight Dwell

Figure 2 - 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 3). 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 3).

Figure 3 – Mean Net Ultrafiltration, Creatinine and Urea Nitrogen Clearances and Ultrafiltration Efficiency for the Long Dwell in High Average/High Transporter Patients

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.

Dangerous Drug-Device Interaction

(See BOXED WARNING)

Only use glucose-specific monitors and test strips to measure blood glucose levels in patients using Extraneal (icodextrin) Peritoneal Dialysis Solution. Blood glucose monitoring devices using glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase (GDO)-based methods must not be used. In addition, some blood glucose monitoring systems using glucose dehydrogenase flavin-adenine dinucleotide (GDH-FAD)-based methods must not be used. Use of GDH-PQQ, GDO, and GDH-FAD-based glucose monitors and test strips has resulted in falsely elevated glucose readings (due to the presence of maltose, see PRECAUTIONS/Drug/Laboratory Test Interactions). Falsely elevated glucose readings have led patients or health care providers to withhold treatment of hypoglycemia or to administer insulin inappropriately. Both of these situations have resulted in unrecognized hypoglycemia, which has led to loss of consciousness, coma, permanent neurological damage, and death. Plasma levels of Extraneal (icodextrin) and its metabolites return to baseline within approximately 14 days following cessation of Extraneal (icodextrin) administration. Therefore 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.

Because GDH-PQQ, GDO, and GDH-FAD-based blood glucose monitors may be used in hospital settings, it is important that the health care providers of peritoneal dialysis patients using Extraneal (icodextrin) carefully review the product information of the blood glucose testing system, including that of test strips, to determine if the system is appropriate for use with Extraneal (icodextrin).

To avoid improper insulin administration, educate patients to alert health care providers of this interaction whenever they are admitted to the hospital.

The manufacturer(s) of the monitor and test strips should be contacted to determine if icodextrin or maltose causes interference or falsely elevated glucose readings. For a list of toll free numbers for glucose monitor and test strip manufacturers, please contact the Baxter Renal Clinical Help Line 1-888-RENAL-HELP or visit www.glucosesafety.com.

Extraneal is intended for intraperitoneal administration only. Not for intravenous injection.

Encapsulating peritoneal sclerosis (EPS) is a known, rare complication of peritoneal dialysis therapy. EPS has been reported in patients using peritoneal dialysis solutions including Extraneal (icodextrin). Infrequent but fatal outcomes have been reported.

If peritonitis occurs, the choice and dosage of antibiotics should be based upon the results of identification and sensitivity studies of the isolated organism(s) when possible. Prior to the identification of the involved organism(s), broad-spectrum antibiotics may be indicated.

Rarely, serious hypersensitivity reactions to Extraneal have been reported such as toxic epidermal necrolysis, angioedema, serum sickness, erythema multiforme and leukocytoclastic vasculitis. If a serious reaction is suspected, discontinue Extraneal and institute appropriate treatment as clinically indicated.

Patients with severe lactic acidosis should not be treated with lactate-based peritoneal dialysis solutions (See CONTRAINDICATIONS). It is recommended that patients with conditions known to increase the risk of lactic acidosis [e.g., acute renal failure, inborn errors of metabolism, treatment with drugs such as metformin and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)] must be monitored for occurrence of lactic acidosis before the start of treatment and during treatment with lactate-based peritoneal dialysis solutions.

When prescribing the solution to be used for an individual patient, consideration should be given to the potential interaction between the dialysis treatment and therapy directed at other existing illnesses. Serum potassium levels should be monitored carefully in patients treated with cardiac glycosides. For example, rapid potassium removal may create arrhythmias in cardiac patients using digitalis or similar drugs; digitalis toxicity may be masked by hyperkalemia, hypermagnesemia, or hypocalcemia. Correction of electrolytes by dialysis may precipitate signs and symptoms of digitalis excess. Conversely, toxicity may occur at suboptimal dosages of digitalis if potassium is low or calcium high.