Extranil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXTRANEAL

Composition:

Active substances: icodextrin; sodium chloride; calcium chloride dihydrate; magnesium chloride hexahydrate; sodium lactate solution;

1000 ml of solution contain: icodextrin 75 g; sodium chloride 5.4 g; calcium chloride dihydrate 0.257 g; magnesium chloride hexahydrate 0.051 g; sodium lactate solution 4.5 g;

Excipients: water for injections, concentrated hydrochloric acid or sodium hydroxide.

Pharmaceutical form. Solution for peritoneal dialysis.

Main physicochemical properties: clear, colorless to slightly yellowish solution.

Pharmacotherapeutic group. Agents for peritoneal dialysis. Isotonic solutions.

ATC code B05D A.

Pharmacological properties.

Pharmacodynamics.

Icodextrin is a glucose polymer derived from starch that acts as an osmotic agent when administered intraperitoneally for continuous ambulatory peritoneal dialysis (CAPD). The 7.5% solution is approximately iso-osmolar to serum, enabling ultrafiltration over a duration of up to 12 hours during CAPD. Compared to hyperosmolar glucose solutions, a reduced caloric load is observed.

The volume of ultrafiltrate produced is comparable to that achieved with 3.86% glucose solution for CAPD; however, blood glucose levels and insulin levels remain unchanged.

Ultrafiltration is maintained during episodes of peritonitis.

The recommended dosing regimen consists of one exchange every 24 hours as part of CAPD or automated peritoneal dialysis (APD).

Pharmacokinetics.

Blood levels of the carbohydrate polymer reach steady-state concentrations after 7–10 days of daily use for nocturnal dialysis. The polymer is hydrolyzed by amylase into smaller fragments, which are eliminated via peritoneal dialysis. The steady-state plasma concentration of glucose oligomers exceeding 9 glucose units (G9) is 1.8 mg/mL; an increase in serum maltose (G2) up to 1.1 mg/mL has been observed, but no significant changes in serum osmolality have been noted.

When the drug is used for prolonged daytime treatment in automated peritoneal dialysis (APD), maltose levels reached 1.4 mg/mL, yet without significant changes in serum osmolality.

The long-term effects of elevated plasma levels of maltose and icodextrin are unknown, but there is no evidence to suggest they are harmful.

Clinical characteristics.

Indications.

For continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) in the treatment of patients with chronic renal failure, especially those with low ultrafiltration levels when using glucose-based solutions.

Contraindications.

EXTRANIL should not be administered to patients with:

• hypersensitivity to any of the active or excipient substances;
• hypersensitivity to starch-based polymers (e.g. corn starch) and/or icodextrin;
• individual intolerance to maltose or isomaltose;
• glycogen storage disease;
• severe lactic acidosis;
• irreversible mechanical defects interfering with effective peritoneal dialysis (PD) or increasing the risk of infection;
• loss of peritoneal function or extensive adhesions preventing peritoneal function.

Interaction with other medicinal products and other types of interactions.

Interaction studies between EXTRANIL and other drugs have not been conducted. However, the blood concentration of drugs eliminated via dialysis may be reduced. Corrective therapy should be administered if necessary.

To avoid interference from maltose, blood glucose measurements should be performed using a glucose-specific method. When using EXTRANIL, methods based on glucose dehydrogenase-pyrroloquinoline quinone (GDH-PQQ) or glucose-dye-oxidoreductase should not be used. Furthermore, the use of certain blood glucose monitoring devices and test strips based on glucose dehydrogenase-flavin adenine dinucleotide (GDH-FAD) methods has led to falsely elevated glucose readings due to the presence of maltose (see section "Special precautions for use").

Special precautions for use.

Patients with diabetes mellitus often require additional insulin to maintain glycemic control during peritoneal dialysis. Switching from a glucose-based PD solution to EXTRANIL may necessitate adjustment of the usual insulin dose. Insulin may be administered intraperitoneally.

Blood glucose levels should be measured using a glucose-specific method to exclude interference from maltose. Methods based on glucose dehydrogenase-pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase (GDO) must not be used. Furthermore, the use of certain blood glucose monitoring devices and test strips based on glucose dehydrogenase-flavin adenine dinucleotide (GDH-FAD) may result in falsely elevated glucose readings due to the presence of maltose. In such cases, it is essential to contact the manufacturer(s) of the monitoring device or test strips to determine whether the presence of icodextrin or maltose affects glucose measurements or leads to falsely elevated glucose levels.

If methods based on GDH-PQQ, GDO, or GDH-FAD are used, administration of EXTRANIL may lead to falsely elevated blood glucose readings, which in turn may result in administration of more insulin than required. Excessive insulin administration may cause hypoglycemia, leading to loss of consciousness, coma, neurological damage, and fatal outcomes. Additionally, falsely high blood glucose readings due to maltose interference may mask the presence of true hypoglycemia, which may progress untreated with corresponding consequences. Falsely elevated glucose levels may persist for up to two weeks after discontinuation of EXTRANIL (icodextrin) therapy when blood glucose is measured using GDH-PQQ, GDO, or GDH-FAD-based methods and test strips.

Since hospitals may use blood glucose monitoring systems based on GDH-PQQ, GDO, or GDH-FAD, it is important that physicians prescribing peritoneal dialysis with EXTRANIL (icodextrin) carefully review information about the blood glucose monitoring system used for such patients, including test strip specifications, to ensure compatibility with EXTRANIL (icodextrin).

To avoid inappropriate insulin administration, patients must be informed of the necessity to alert healthcare providers during hospitalization about their use of EXTRANIL.

Peritoneal dialysis should be performed with caution in patients with:

• Abdominal conditions including injury to the peritoneum and diaphragm due to surgery, congenital defects, or trauma—until full recovery; abdominal tumors, abdominal wall infection, hernias, fistulas, colostomy or ileostomy, frequent episodes of diverticulitis, inflammatory or ischemic bowel diseases, enlarged polycystic kidneys, and other conditions compromising the integrity of the abdominal wall, peritoneal surface, or intraperitoneal cavity;
• Other conditions including recent correction of aortic aneurysm and severe pulmonary diseases.

Encapsulating peritoneal sclerosis is a rare complication of peritoneal dialysis. Cases of encapsulating peritoneal sclerosis have been reported in patients undergoing peritoneal dialysis, including those treated with EXTRANIL. Rare fatal cases have also been reported.

Prior to and during treatment with lactate-based peritoneal dialysis solutions, patients with conditions predisposing to lactic acidosis (such as severe hypotension, sepsis, acute renal failure, inborn metabolic disorders, or treatment with certain drugs such as metformin and nucleoside/nucleotide reverse transcriptase inhibitors) should be carefully monitored for the development of lactic acidosis.

When prescribing the solution, potential interactions between all medications administered to the patient (for dialysis and treatment of other existing conditions) should be considered. Serum potassium levels should be closely monitored in patients receiving cardiac glycosides.

Peritoneal reactions, including abdominal pain and clouding of drained fluid with or without bacteria (septic peritonitis or aseptic peritonitis), have been associated with EXTRANIL (see section "Adverse reactions"). In the event of peritoneal reactions, the patient should retain the drained bag with icodextrin, including its batch number, and contact their physician for fluid analysis.

The drained fluid should be examined for the presence of fibrin or cloudiness, which may indicate possible infection or aseptic peritonitis. Patients should be informed that they must notify their physician if infection or aseptic peritonitis develops; appropriate microbiological samples should be collected for testing. Initiation of antibiotic therapy should be a clinical decision based on suspicion of infection. If other possible causes of fluid cloudiness are excluded, EXTRANIL should be discontinued until evaluation of this effect is completed. If the fluid clears again after discontinuation of EXTRANIL, the drug should not be reintroduced (or only under close supervision). If cloudiness reoccurs upon re-administration of EXTRANIL, the drug must not be prescribed again to this patient. Alternative therapy to PD should be initiated, and the patient should be closely monitored.

In cases of peritonitis, antibiotic selection and dosage should be based on pathogen identification and susceptibility testing of individual microorganisms, if possible. Pending identification results, broad-spectrum antibiotics should be initiated.

Serious hypersensitivity reactions to EXTRANIL, including toxic epidermal necrolysis, angioneurotic edema, erythema multiforme, and vasculitis, have been rarely reported. Anaphylactic/anaphylactoid reactions may occur. If any symptoms of hypersensitivity occur, administration must be stopped immediately, the solution drained from the peritoneal cavity, and appropriate treatment initiated according to clinical indications.

EXTRANIL is not recommended for treatment of patients with acute renal failure.

During peritoneal dialysis, loss of protein, amino acids, water-soluble vitamins, and other medications may occur, requiring appropriate supplementation.

Patients should avoid excessive or inadequate hydration. Enhanced ultrafiltration, especially in elderly patients, may lead to dehydration, resulting in hypotension or possibly neurological symptoms. Accurate fluid balance and body weight should be monitored.

Infusion of excessive volumes of EXTRANIL into the peritoneal cavity may cause abdominal distension, a sensation of fullness, and/or dyspnea.

Treatment of excessive EXTRANIL infusion consists of draining the volume present in the peritoneal cavity.

Like other PD solutions, EXTRANIL should be used with caution and only after careful assessment of potential benefits versus risks in patients with gastrointestinal or respiratory dysfunction or potassium deficiency.

Fluid and hematological parameters, blood counts, and electrolyte concentrations, including magnesium and bicarbonate, should be monitored periodically. If serum magnesium levels are low, oral magnesium supplements or peritoneal dialysis solutions containing higher magnesium concentrations may be prescribed.

Decreased serum sodium and chloride levels have been observed in some patients. Although these decreases were considered clinically insignificant, regular monitoring of serum electrolytes is recommended.

A decrease in serum amylase levels has also been observed as a general finding in patients undergoing long-term PD. This reduction has not been associated with adverse effects. However, it is unknown whether subnormal amylase levels may mask the rise in serum amylase typically seen in acute pancreatitis. During clinical trials, occasional increases in serum alkaline phosphatase of approximately 20 U/L were observed. Isolated cases of elevated alkaline phosphatase associated with increased serum glutamate oxaloacetate transaminase (SGOT) levels have also been reported.

Use during pregnancy or breastfeeding.

Pregnancy

There are insufficient or limited data on the use of EXTRANIL in pregnant women. Data from animal reproductive toxicity studies are inadequate. EXTRANIL is not recommended for use in pregnant women or women of childbearing potential who are not using contraception.

Breastfeeding

It is unknown whether EXTRANIL metabolites are excreted in human milk. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or discontinue EXTRANIL therapy should be based on an assessment of the benefit of breastfeeding to the child versus the benefit of therapy to the mother.

Fertility

There are no clinical data on fertility.

Ability to affect reaction speed when driving or operating machinery.

Patients with end-stage renal failure undergoing peritoneal dialysis may experience adverse effects that could impair their ability to drive or operate machinery.

Method of Administration and Dosage

Dosage

EXTRANIL is recommended to be used during the longest period of rest, i.e., in CAPD, usually at night, and in APD, during a prolonged daytime exchange. The type of therapy, frequency of treatment, exchange volume, dwell time between sessions, and duration of dialysis itself must be determined and monitored by a physician.

Adults

Peritoneal administration consists of one exchange every 24 hours as part of CAPD or APD.

The volume of the preparation to be instilled in patients with normal body size should not exceed 2 L. It is administered over approximately 10–20 minutes at a rate comfortable for the patient. Patients with body weight above 70–75 kg may be administered 2.5 L of solution. The administered volume should be reduced if the patient experiences abdominal discomfort (sense of fullness). The recommended dwell time in CAPD is 6–12 hours, and in APD, 14–16 hours. Drainage of fluid occurs by gravity at a rate comfortable for the patient.

Elderly Patients

Same as for adults.

Administration

EXTRANIL is intended for intraperitoneal use only and must not be administered intravenously.

The peritoneal dialysis solution should be warmed in its protective bag to a temperature of 37°C for patient comfort. Only dry heat (e.g., a heating pad or warming surface) should be used. Solutions must not be heated in water or in a microwave oven due to the risk of damage or patient discomfort.

The entire procedure must be performed under strict aseptic conditions. Do not use the solution if it is discolored, cloudy, contains foreign particles, or if the bag shows signs of leakage or if the packaging is damaged. The drained fluid should be examined for the presence of fibrin or cloudiness, which may indicate infection or aseptic peritonitis (see section "Special Warnings and Precautions").

For single use only.

Several antibiotics, including vancomycin, cefazolin, ampicillin/flucloxacillin, ceftazidime, gentamicin, amphotericin, and insulin, have shown no incompatibility with EXTRANIL. However, aminoglycosides should not be mixed with penicillins due to chemical incompatibility.

When mixed with other medicinal products, the preparation should be used immediately.

Any unused portions should be discarded.

Children

Safety and efficacy in children (under 18 years of age) have not been established. Data are lacking. EXTRANIL is not recommended for use in pediatric patients.

Overdose

There are no data regarding the effects of overdose. However, prolonged use of more than one bag of EXTRANIL per 24 hours may increase levels of carbohydrate metabolites and maltose. The clinical impact of such an increase is unknown, but an increase in plasma osmolality is possible.

Treatment may include peritoneal dialysis without icodextrin or hemodialysis.

Side effects

The adverse reactions listed below were reported during clinical trials and post-marketing use.

Skin reactions associated with the use of EXTRANIL, including rash and pruritus, were generally mild or moderate in severity. Occasionally, these rashes were accompanied by skin desquamation. If such reactions occur, EXTRANIL should be discontinued, at least temporarily, depending on the severity.

The frequency of adverse reactions is categorized as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon – fungal syndrome, furunculosis.

Blood and lymphatic system disorders: uncommon – anaemia, leukocytosis, eosinophilia; frequency not known – thrombocytopenia, leukopenia.

Immune system disorders: frequency not known – hypersensitivity**, vasculitis.

Metabolism and nutrition disorders: common – dehydration, hypovolemia; uncommon – hypoglycemia, hyponatremia, hyperglycemia, hypervolemia, anorexia, hypochloremia, hypomagnesemia, hypoproteinemia; frequency not known – hypoglycemic shock, fluid imbalance.

Psychiatric disorders: uncommon – abnormal thinking, excitement, restlessness, anxiety.

Nervous system disorders: common – dizziness, headache; uncommon – hyperkinesia, paresthesia, ageusia; frequency not known – hypoglycemic coma, burning sensation.

Eye disorders: frequency not known – blurred vision.

Ear and labyrinth disorders: common – tinnitus.

Cardiac disorders: uncommon – cardiovascular disorders, tachycardia.

Vascular disorders: common – arterial hypotension, arterial hypertension; uncommon – orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: uncommon – pulmonary edema, dyspnea, cough, hiccup; frequency not known – bronchospasm, stridor.

Gastrointestinal disorders: common – abdominal pain; uncommon – intestinal obstruction, peritonitis, bloody peritoneal exudate, diarrhea, gastric ulcer, gastritis, vomiting, constipation, dyspepsia, nausea, dry mouth, flatulence; frequency not known – ascites, inguinal hernia, abdominal discomfort, sclerosing encapsulating peritonitis.

Skin and subcutaneous tissue disorders: common – rash (including macular, papular, erythematous), pruritus, skin desquamation; uncommon – urticaria, bullous dermatitis, psoriasis, skin ulcers, eczema, nail disorders, dry skin, skin discoloration; frequency not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, generalized urticaria, toxic skin eruptions, periorbital edema, dermatitis (including allergic and contact dermatitis), erythema, blisters, skin fissures.

Musculoskeletal and connective tissue disorders: uncommon – bone pain, muscle spasms, myalgia, neck pain; frequency not known – arthralgia, back pain, musculoskeletal pain.

Renal and urinary disorders: uncommon – renal pain.

Reproductive system disorders: frequency not known – penile edema, scrotal edema.

General disorders and administration site conditions: common – peripheral edema, asthenia; uncommon – chest pain, facial swelling, edema, pain; frequency not known – fever, chills, malaise, erythema at catheter insertion site, inflammation at catheter site, infusion-related reactions (including pain at infusion site, pain at instillation site).

Investigations: uncommon – increased alanine aminotransferase and aspartate aminotransferase levels, increased alkaline phosphatase levels, changes in liver function tests, decreased or increased body weight.

Injury, poisoning and procedural complications: frequency not known – interaction with device material*.

* Icodextrin interacts with devices used to measure blood glucose levels (see section "Special precautions for use").

** Hypersensitivity-type reactions have been reported in patients receiving EXTRANIL, including bronchospasm, arterial hypotension, rash, pruritus, and urticaria.

Other adverse effects of peritoneal dialysis related to the procedure: fungal peritonitis, bacterial peritonitis, catheter insertion site infections, catheter-related infections, and complications associated with catheter insertion.

Enhanced ultrafiltration, particularly in elderly patients, may lead to dehydration, which in turn may result in arterial hypotension and possibly neurological symptoms.

Episodes of hypoglycemia in patients with diabetes mellitus.

Elevated serum alkaline phosphatase levels and electrolyte imbalances (e.g., hypokalemia, hypocalcemia, hypercalcemia).

Peritoneal reactions, including abdominal pain and cloudy peritoneal fluid with or without bacteria, aseptic peritonitis (see section "Special precautions for use").

Fatigue, frequently reported spontaneously and in publications as an adverse effect related to the procedure.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 30 °C. Do not freeze. Keep out of reach of children. Do not use if the solution is cloudy or the container is damaged.

The product is intended for single use only.

Any unused portions should be discarded.

Incompatibilities.

Not known.

Compatibility with other medicinal products should be verified before mixing. In addition, the pH level of the solution and the presence of salts should be taken into account.

Packaging.

2 L of solution in a plastic bag equipped with an injection port and connector, enclosed in a transparent plastic pouch. 5 units per cardboard box.

2 L of solution in a plastic bag equipped with an injection port and integrated via two tubing lines and a Y-connector with an empty plastic drainage bag, all enclosed in a transparent plastic pouch. 5 units per cardboard box.

2.5 L of solution in a plastic bag equipped with an injection port and connector, enclosed in a transparent plastic pouch. 4 units per cardboard box.

2.5 L of solution in a plastic bag equipped with an injection port and integrated via two tubing lines and a Y-connector with an empty plastic drainage bag, all enclosed in a transparent plastic pouch. 4 units per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Vantive Manufacturing Limited

Manufacturer's address and location of operations.

Moneen Road, Castlebar, Co. Mayo, F23 XR63, Ireland.