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IcodextrinEXTRANEAL (icodextrin) Peritoneal Dialysis Solution DESCRIPTIONEXTRANEAL (icodextrin) Peritoneal Dialysis Solution is a peritoneal dialysis solution containing the colloid osmotic agent icodextrin. Icodextrin is a starch-derived, water-soluble glucose polymer linked by alpha (1-4) and less than 10% alpha (1-6) glucosidic bonds with a weight-average molecular weight between 13,000 and 19,000 Daltons and a number-average molecular weight between 5,000 and 6,500 Daltons.
EXTRANEAL is available for intraperitoneal administration only as a sterile, nonpyrogenic, clear solution in 1.5 L, 2.0 L and 2.5 L AMBU-FLEX III and ULTRABAG containers. The container systems are composed of polyvinyl chloride. 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 Absorption Absorption of icodextrin from the peritoneal cavity follows zero-order kinetics consistent with convective transport via peritoneal lymphatic pathways. In a single-dose pharmacokinetic study using EXTRANEAL, a median of 40% (60 g) of the instilled icodextrin was absorbed from the peritoneal solution during a 12-hour dwell. Plasma levels of icodextrin rose during the dwell and declined after the dwell was drained. Peak plasma levels of icodextrin plus its metabolites (median Cpeak 2.2g/L) were observed at the end of the long dwell exchange (median Tmax = 13 hours). Plasma levels return to baseline values within 7 days following cessation of icodextrin administration. At steady-state, the mean plasma level of icodextrin plus its metabolites was about 5 g/L. In multidose studies, steady-state levels of icodextrin were achieved within one week. Metabolism Icodextrin is metabolized by alpha-amylase into oligosaccharides with a lower degree of polymerization (DP), including maltose (DP2), maltotriose (DP3), maltotetraose (DP4), and higher molecular weight species. In a single dose study, DP2, DP3 and DP4 showed a progressive rise in plasma concentrations with a profile similar to that for total icodextrin, with peak values reached by the end of the dwell and declining thereafter. Only very small increases in blood levels of larger polymers were observed. Steady-state plasma levels of icodextrin metabolites were achieved within one week and stable plasma levels were observed during long-term administration. Some degree of metabolism of icodextrin occurs intraperitoneally with a progressive rise in the concentration of the smaller polymers in the dialysate during the 12-hour dwell. Elimination Icodextrin undergoes renal elimination in direct proportion to the level of residual renal function. Diffusion of the smaller icodextrin metabolites from plasma into the peritoneal cavity is also possible after systemic absorption and metabolism of icodextrin. Special Populations Geriatrics The influence of age on the pharmacokinetics of icodextrin and its metabolites was not assessed. Gender and Race The influence of gender and race on the pharmacokinetics of icodextrin and its metabolites was not assessed. Clinical Studies EXTRANEAL has demonstrated efficacy as a peritoneal dialysis solution in clinical trials of approximately 400 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. There is no information on how creatinine and urea nitrogen clearances on EXTRANEAL compare with 4.25% dextrose. Effects were generally similar in CAPD and APD. 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. Mean creatinine and urea nitrogen clearances were also greater with EXTRANEAL. 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. Long-term Use Survival was examined in all controlled clinical studies, including those described above and a 12-month study (n=287) and a 2-year study (n=38). There were a total of 26 deaths in 366 patients on EXTRANEAL (7%) and 20 deaths in 285 patients receiving dextrose (7%). 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. EXTRANEAL 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 chronic renal failure. (See CLINICAL PHARMACOLOGY, Clinical Studies) EXTRANEAL is intended for intraperitoneal administration only. It should be administered only 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. Patients should be carefully monitored to avoid under- or over-hydration. An accurate fluid balance record must be kept and the patient’s body weight monitored to avoid potentially severe consequences including congestive heart failure, volume depletion, and hypovolemic shock. Aseptic technique should be used throughout the peritoneal dialysis procedure. To reduce possible discomfort during administration, solutions may be warmed prior to use. (See DOSAGE AND ADMINISTRATION, Directions for Use). EXTRANEAL should be administered over a period of 10-20 minutes at a rate that is comfortable for the patient. Do not use EXTRANEALif it is cloudy or discolored, if it contains particulate matter, or if the container is leaky. Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness, which may indicate the presence of an infection. Addition of Potassium 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. The decision to add potassium chloride should be made by the physician after careful evaluation of serum potassium. Addition of Insulin Addition of insulin to EXTRANEAL was evaluated in 6 insulin-dependent diabetic patients undergoing CAPD for end stage renal disease. No interference of EXTRANEAL with insulin absorption from the peritoneal cavity or with insulin’s ability to control blood glucose was observed. (See PRECAUTIONS, Drug /Laboratory Test Interactions). Appropriate monitoring of blood glucose should be performed when initiating EXTRANEAL in diabetic patients and insulin dosage adjusted if needed (See PRECAUTIONS). Addition of Heparin No human drug interaction studies with heparin were conducted. In vitro studies demonstrated no evidence of incompatibility of heparin with EXTRANEAL. Addition of Antibiotics No formal clinical drug interaction studies have been performed. In vitro compatibility studies with EXTRANEAL and the following antibiotics have demonstrated no effects with regard to minimum inhibitory concentration (MIC): vancomycin, cefazolin, ampicillin, ampicillin/flucoxacillin, ceftazidime, gentamicin, and amphotericin. Patients undergoing peritoneal dialysis should be under careful supervision of a 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. Directions for Use For complete CAPD and APD system preparation, see directions accompanying ancillary equipment. Aseptic technique should be used. Warming For patient comfort, EXTRANEAL can be warmed to 37°C (98°F). Only dry heat should be used. It is best to warm solutions within the overwrap using a heating pad. Do not immerse EXTRANEAL in water for warming. Do not use a microwave oven to warm EXTRANEAL. Heating above 40°C (104°F) may be detrimental to the solution. 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 Inspect the container for signs of leakage and check for minute leaks by squeezing the container firmly. Adding Medications Some drug additives may be incompatible with EXTRANEAL. See DOSAGE AND ADMINISTRATION section for additional information. If the re-sealable rubber plug on the medication port is missing or partly removed, do not use the product if medication is to be added.
Preparation for Administration
EXTRANEAL (icodextrin) Peritoneal Dialysis Solution is available in the following containers and fill volumes:
Each 100 mL of EXTRANEAL contains 7.5 grams of icodextrin in an electrolyte solution with 40 mEq/L lactate. Store at 20–25°C (68–77°F). Excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature]. Store in moisture barrier overwrap in carton until ready to use. Protect from freezing. BAXTER, EXTRANEAL, ULTRABAG, and AMBU-FLEX are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Deerfield, IL 60015 USA Printed in USA, ©Copyright 2001, Baxter Healthcare Corporation. All rights reserved., 07-19-35-560 2003/01
Adverse reactions reported with an incidence of > 5% and at least as common on dextrose control included pain, asthenia, exit site infection, infection, back pain, hypotension, diarrhea, vomiting, nausea/vomiting, anemia, peripheral edema, hypokalemia, hyperphosphatemia, hypoproteinemia, hypervolemia, arthralgia, dizziness, dyspnea, skin disorder, pruritis. Additional adverse events occurring at an incidence of < 5% and that may or may not have been related to EXTRANEAL include: 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. All reported events are included in the list except those already listed in Table 1 or the following two paragraphs, those not plausibly associated with EXTRANEAL, and those that were associated with the condition being treated or related to the dialysis procedure. Peritoneal Dialysis-Related Adverse events common to the peritoneal dialysis, including peritonitis, infection around the catheter, fluid and electrolyte imbalance, and pain, were observed at a similar frequency with EXTRANEAL and Controls (See PRECAUTIONS). Changes in Alkaline Phosphatase and Serum Electrolytes 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 declines in serum sodium and chloride may be related to dilution resulting from the presence of icodextrin metabolites in plasma. Although these decreases have been small and clinically unimportant, monitoring of patients’ serum electrolyte levels as part of routine blood chemistry testing is recommended. DRUG ABUSE AND DEPENDENCE There has been no observed potential of drug abuse or dependence with EXTRANEAL. General No clinical drug interaction studies were performed. No evaluation of EXTRANEAL’s effects on the cytochrome P450 system was conducted. 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. Insulin A clinical study in 6 insulin-dependent diabetic patients demonstrated no effect of EXTRANEAL on insulin absorption from the peritoneal cavity or on insulin’s ability to control blood glucose when insulin was administered intraperitoneally with EXTRANEAL. However, appropriate monitoring (See PRECAUTIONS, Drug/Laboratory Test Interactions) of blood glucose should be performed when initiating EXTRANEAL in diabetic patients and insulin dosage should be adjusted if needed (See PRECAUTIONS). Heparin No human drug interaction studies with heparin were conducted. In vitro studies demonstrated no evidence of incompatibility of heparin with EXTRANEAL. Antibiotics No human drug interaction studies with antibiotics were conducted. In vitro studies evaluating the minimum inhibitory concentration (MIC) of vancomycin, cefazolin, ampicillin, ampicillin/flucoxacillin, ceftazidime, gentamicin, and amphotericin demonstrated no evidence of incompatibility of these antibiotics with EXTRANEAL. (See DOSAGE AND ADMINISTRATION) Not for intravenous injection. Blood glucose measurement in patients receiving EXTRANEAL must be done with a glucose-specific method (monitor and test strips) to avoid interference by maltose, released from EXTRANEAL. Glucose dehydrogenase pyrroloquinolinequinone (GDH PQQ)-based methods must not be used. The manufacturer(s) of the monitor and test strips should be contacted to determine if icodextrin or maltose causes interference or falsely elevated glucose results. 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. General Peritoneal Dialysis-Related All peritoneal dialysis solutions, including EXTRANEAL, should be used with caution in patients with a history of abdominal surgery within 30 days of commencement of therapy, abdominal fistulae, tumors, open wounds, hernia or other conditions which compromise the integrity of the abdominal wall, abdominal surface or intra-abdominal cavity. Caution should also be used in patients with conditions that preclude normal nutrition, patients with impaired respiratory function, and patients with potassium deficiency. Aseptic technique should be employed throughout the peritoneal dialysis procedure to reduce the possibility of infection. If peritonitis occurs, the choice and dosage of antibiotics should be based upon the results of culture and sensitivity of the isolated organisms. Prior to identification of involved organisms, broad-spectrum antibiotics may be indicated. Need for Trained Physician Treatment should be initiated and monitored under the supervision of a physician knowledgeable in the management of patients with renal failure. A patient’s volume status should be carefully monitored to avoid hyper- or hypovolemia and potentially severe consequences including congestive heart failure, volume depletion and hypovolemic shock. An accurate fluid balance record must be kept and the patient’s body weight monitored. Significant losses of protein, amino acids, and water-soluble vitamins may occur during peritoneal dialysis. The patient’s nutritional status should be monitored and replacement therapy should be provided as necessary. In patients with hypercalcemia, particularly in those on low-calcium peritoneal dialysis solutions, consideration should be given to the fact that EXTRANEAL is not provided in a low-calcium electrolyte solution. Solutions that are cloudy, contain particulate matter, or show evidence of leakage should not be used. Insulin-dependent diabetes mellitus Patients with insulin-dependent diabetes may require modification of insulin dosage following initiation of treatment with EXTRANEAL. Appropriate monitoring of blood glucose should be performed and insulin dosage adjusted if needed (See WARNINGS; PRECAUTIONS, Drug/Laboratory Test Interactions). Patients should be instructed not to use solutions if they are cloudy, discolored, contain visible particulate matter, or if they show evidence of leaking containers. Aseptic technique should be employed throughout the procedure. To reduce possible discomfort during administration, patients should be instructed that solutions may be warmed to 37°C (98°F) prior to use. Only dry heat should be used. It is best to warm solutions within the overwrap using a heating pad. To avoid contamination, solutions should not be immersed in water for warming. Do not use a microwave oven to warm EXTRANEAL. Heating the solution above 40°C (104°F) may be detrimental to the solution. (See DOSAGE AND ADMINISTRATION, Directions for Use). Because the use of EXTRANEAL interferes with glucose dehydrogenase pyrroloquinolinequinone (GDH PQQ)-based blood glucose measurements, diabetic patients should be instructed to use only glucose-specific glucose monitors and test strips. (See WARNINGS; PRECAUTIONS, Drug/Laboratory Test Interactions). Additional information for patients is provided at the end of the labeling. Laboratory Tests Serum Electrolytes 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 –2.0 mmol/L for EXTRANEAL patients and + 0.6 mmol/L for control patients. The declines in serum sodium and chloride may be related to dilution resulting from the presence of icodextrin metabolites in plasma. Although these decreases have been small and clinically unimportant, monitoring of the patients’ serum electrolyte levels as part of routine blood chemistry testing is recommended. EXTRANEAL does not contain potassium. Evaluation of serum potassium should be made prior to administering potassium chloride to the patient. Alkaline Phosphatase An increase in mean serum alkaline phosphatase has been observed in clinical studies of ESRD patients receiving EXTRANEAL. No associated increases in liver function tests were observed. Serum alkaline phosphatase levels did not show evidence of progressive increase over a 12-month study period. Levels returned to normal approximately two weeks after discontinuation of EXTRANEAL. There were individual cases where increased alkaline phosphatase was associated with elevated AST (SGOT), but neither elevation was considered causally related to treatment. Drug/Laboratory Test Interactions Blood Glucose Blood glucose measurement must be done with a glucose-specific method to prevent maltose interference with test results. Since falsely elevated glucose levels have been observed with blood glucose monitoring devices and test strips that use glucose dehydrogenase pyrroloquinolinequinone (GDH PQQ)-based methods, GDH PQQ-based methods should not be used to measure glucose levels in patients administered EXTRANEAL. (See WARNINGS). Serum Amylase An apparent decrease in serum amylase activity has been observed in patients administered EXTRANEAL. Preliminary 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. 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 rats. 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. Pregnancy Pregnancy Category C Complete animal reproduction studies including in utero embryofetal development at appreciable multiples of human exposure have not been conducted with EXTRANEAL or icodextrin. Thus it is not known whether icodextrin or EXTRANEAL solution can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. EXTRANEAL should only be utilized in pregnant women when the need outweighs the potential risks. 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. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use No formal studies were specifically carried out in the geriatric population. However, 123 of the patients in clinical studies of EXTRANEAL were age 65 or older, with 21 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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