SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Extraneal Clear-Flex Solution for peritoneal dialysis

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

A sterile peritoneal dialysis fluid containing Icodextrin at a concentration of 7.5% w/v in an electrolyte solution.

Icodextrin    75.0 g/l

Sodium chloride    5.4 g/l

Sodium (S)-lactate solution equivalent to sodium (S)-lactate    4.5 g/l

Calcium chloride    0.257 g/l

Magnesium chloride    0.051 g/l

Theoretical osmolarity 284 (milliosmoles per litre) Theoretical osmolality 301 (milliosmoles per kg)

Contents per 1000 ml electrolyte solution:

1 33 mmol/l 1.75 mmol/l 0.25 mmol/l 96 mmol/l 40 mmol/l

pH = 5,0 to 6,0

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for peritoneal dialysis.

Extraneal Clear-Flex is a sterile, clear, colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Extraneal Clear-Flex is recommended as a once daily replacement for a single glucose

exchange as part of an automated peritoneal dialysis (APD) regimen for the treatment of chronic renal failure, particularly for patients who have lost ultrafiltration on glucose solutions, because it can extend time on APD therapy in such patients.

4.2 Posology and method of administration

Posology:

Extraneal Clear-Flex is recommended for use in APD for the long daytime dwell.

•    The mode of therapy, frequency of treatment, exchange volume, duration of dwell and length of dialysis should be initiated and supervised by the physician.

Adults:

By intraperitoneal administration limited to a single exchange in each 24 hour-period, as part of an APD regimen.

The volume to be instilled should be given over a period of approximately 10 to 20 minutes at a rate, which the patient finds comfortable. For adult patients of normal body size the instilled volume should not exceed 2.0 L. For larger patients (more than 70-75 kg), a fill volume of 2.5 L may be used.

If the instilled volume causes discomfort due to abdominal tension the instilled volume should be reduced. The recommended dwell time is between 14-16 hours in APD.

Older people As for adults.

Paediatric population

The safety and efficacy of Extraneal in children aged less than 18 years has not been established. No data are available.

Method of administration:

Precautions to be taken before handling or administering the medicinal product

•    Extraneal Clear-Flex is intended for intraperitoneal administration only. Not for intravenous injection.

•    Peritoneal dialysis solutions may be warmed in the overpouch to 37 °C to enhance patient comfort. However, only dry heat (for example, heating pad, warming plate) should be used. Solutions should not be heated in water or in a microwave oven due to the potential for patient injury or discomfort.

•    Aseptic technique should be employed throughout the peritoneal dialysis procedure.

•    Do not administer if the solution is discoloured, cloudy, contains particulate matter or shows evidence of leakage, or if seals are not intact.

•    The drained fluid should be inspected for the presence of fibrin or cloudiness, which may indicate the presence of infection or aseptic peritonitis (see Section 4.4).

•    For single use only

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Extraneal Clear-Flex should not be used in patients with:

• a known allergy to starch based polymers/or icodextrin maltose or

isomaltose intolerance

•    glycogen storage disease

•    pre-existing severe lactic acidosis

•    uncorrectable mechanical defects that prevent effective PD or increase the risk of infection

•    documented loss of peritoneal function or extensive adhesions that compromise peritoneal function.

4.4 Special warnings and precautions for use

-    Patients with diabetes mellitus often need additional insulin in order to maintain glycaemic control during Peritoneal Dialysis (PD). Transfer from glucose based PD solution to Extraneal Clear-Flex may necessitate an adjustment of the usual insulin dosage. Initial results show that insulin is minimally absorbed from Extraneal in Clear-Flex bags compared with PVC bags, so dosage adjustments may be also necessary and special attention is advised in this situation. Insulin can be administered intraperitoneally.

-    Blood glucose measurement must be done with a glucose specific method to prevent maltose interference. Glucose dehydrogenase pyrroloquinolinequinone (GDH- PQQ) or glucose-dye-oxidoreductase (GDO)-based methods should not be used. Also, the use of some glucose monitors and test strips using glucose dehydrogenase flavin-adenine dinucleotide (GDH-FAD) methodology has resulted in falsely elevated glucose readings due to the presence of maltose. 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.

-    If GDH-PQQ-, GDO- or GDH-FAD-based methods are used, using Extraneal Clear-Flex may cause a falsely high glucose reading, which could result in the administration of more insulin than needed. Administration of more insulin than needed has caused hypoglycaemia, which has resulted in loss of consciousness, coma, neurological damage and death. Additionally, falsely elevated blood glucose measurements due to maltose interference may mask true hypoglycaemia and allow it to go untreated with similar consequences. Falsely elevated glucose levels may be measured up to two weeks following cessation of Extraneal Clear-Flex (icodextrin) therapy when GDH-PQQ-, GDO- or GDH-FAD-based blood glucose monitors and test strips are used. Because GDH-PQQ-, GDO- or 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 Clear-Flex (icodextrin) carefully review the product information of the blood glucose testing system, including the information of test strips, to determine if the system is appropriate for use with Extraneal Clear-Flex (icodextrin).

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

-    Peritoneal dialysis should be done with caution in patients with: 1) abdominal conditions, including disruption of the peritoneal membrane and diaphragm by surgery, from congenital anomalies or trauma until healing is complete,

abdominal tumours, abdominal wall infection, hernias, faecal fistula, colostomy or iliostomy, frequent episodes of diverticulitis, inflammatory or ischemic bowel disease, large polycystic kidneys, or other conditions that compromise the integrity of the abdominal wall, abdominal surface, or intraabdominal cavity; and 2) other conditions including recent aortic graft replacement and severe pulmonary disease.

Encapsulating peritoneal sclerosis (EPS) is considered to be a known, rare complication of peritoneal dialysis therapy. EPS has been reported in patients using peritoneal dialysis solutions including some patients using Extraneal Clear-Flex as part of their PD therapy. Infrequently, fatal outcomes have been reported with Extraneal Clear-Flex.

-    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)) should 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.

-    Peritoneal reactions, including abdominal pain, cloudy effluents with or without bacteria (aseptic peritonitis) have been associated with Extraneal Clear-Flex (see section 4.8). In case of peritoneal reactions, the patient should keep the icodextrin drained fluid bag along with its batch number, and contact the medical team for analysis of the drained fluid bag.

The drained fluid should be inspected for the presence of fibrin or cloudiness, which may indicate the presence of infection or aseptic peritonitis. Patients should be asked to inform their physician if this occurs and appropriate microbiological samples should be drawn. The initiation of antibiotic treatment should be a clinical decision based on whether or not infection is suspected. If other possible reasons for cloudy fluid have been excluded, Extraneal Clear-Flex should be stopped and the result of this action evaluated. If Extraneal Clear-Flex is stopped and the fluid becomes clear afterwards, Extraneal Clear-Flex should not be reintroduced unless under close supervision. If by re-challenging with Extraneal Clear-Flex, the cloudy fluid recurs then this patient should not be prescribed Extraneal Clear-Flex again. Alternative peritoneal dialysis therapy should be initiated and the patient should be kept under close supervision.

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 identification of the involved organism(s), broadspectrum antibiotics may be indicated.

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

-    Extraneal Clear-Flex is not recommended in children or in patients with acute renal failure.

-    Protein, amino acids, water-soluble vitamins and other medicines may be lost during peritoneal dialysis and may require replacement.

-    Patients should be carefully monitored to avoid overhydration or underhydration. Enhanced ultra-filtration, particularly in elderly patients, may lead to dehydration, resulting in hypotension and possibly neurological symptoms. An accurate fluid balance record should be kept and the patient’s body weight monitored.

-    Overinfusion of an Extraneal Clear-Flex volume into the peritoneal cavity may be characterised by abdominal distension, feeling of fullness and/or shortness of breath.

-    Treatment of Extraneal Clear-Flex overinfusion is to drain Extraneal Clear-Flex from the peritoneal cavity.

-    In common with other peritoneal dialysis fluids, Icodextrin should be used with caution, after careful evaluation of its potential risks and benefits, in patients with conditions which preclude normal nutrition, with impaired respiratory function or with potassium deficiency.

-    Fluid, haematology, blood chemistry, and electrolyte concentrations should be monitored periodically, including magnesium and bicarbonate. If serum magnesium levels are low, oral magnesium supplements or peritoneal dialysis solutions containing higher magnesium concentrations may be used.

-    A decrease in the serum sodium and chloride level has been observed in some patients. Though these decreases have been regarded as clinically nonsignificant, it is recommended that serum electrolyte levels are monitored regularly.

-    A decrease in serum amylase levels has also been noticed as a common finding in PD patients on long term treatment. The decrease has not been reported to be accompanied with any side effects. However, it is not known whether subnormal amylase level may mask the rise in serum amylase, commonly seen during acute pancreatitis. An increase in serum alkaline phosphatase of approximately 20 IU/L was seen during clinical trials. There were individual cases where increased alkaline phosphatase was associated with elevated SGOT- (ASAT-) levels.

4.5    Interaction with other medicinal products and other forms of interaction

No interaction studies have been conducted with Extraneal Clear-Flex. The blood concentrations of dialysable drugs may be reduced by dialysis. Corrective therapy should be instituted if necessary.

Blood glucose measurement must be done with a glucose-specific method to prevent maltose interference. Glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ)- or glucose-dye-oxidoreductase-based methods must not be used for glucose measurements. Also, the use of some glucose monitors and test strips using glucose dehydrogenase flavin-adenine dinucleotide (GDH-FAD) methodology has resulted in falsely elevated glucose readings due to the presence of maltose. (see section 4.4).

4.6    Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of Extraneal Clear-Flex in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

In pregnant women or women of childbearing potential the benefit/risk should be assessed before using the product (see section 4.4).

Breastfeeding

It is unknown whether Extraneal Clear-Flex metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Extraneal Clear-Flex therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no clinical data on fertility.

4.7    Effects on ability to drive and use machines

End stage renal disease (ESRD) patients undergoing peritoneal dialysis may experience undesirable effects, which could affect the ability to drive or use machines.

4.8    Undesirable effects

Undesirable effects which occurred in patients treated with Extraneal Clear-Flex from the clinical trials and post marketing are listed below.

Extraneal Clear-Flex associated skin reactions, including rash and pruritus, are generally mild or moderate in severity. Occasionally, these rashes have been associated with exfoliation. In the event of this occurring and depending on the severity, Extraneal Clear-Flex should be withdrawn at least temporarily.

Frequency is based upon the following scale: Very Common (>1/10); Common (>1/100-<1/10), Uncommon (>1/1,000-<1/100), Rare (>1/10,000-<1/1,000), Very Rare (<1/10,000), not known (cannot be estimated from the available data).

System Organ Class (SOC)	Preferred MedDRA Term	Frequency
INFECTIONS AND	Flu syndrome	Uncommon
INFESTATIONS	Furuncle	Uncommon
BLOOD AND LYMPHATIC	Anaemia	Uncommon
SYSTEM DISORDERS	Leukocytosis	Uncommon
	Eosinophilia	Uncommon
	Thrombocytopenia	Not known
	Leukopenia	Not known
IMMUNE SYSTEM DISORDERS	Vasculitis	Not known
	Hypersensitivity**	Not known
METABOLISM AND NUTRITION	Dehydration	Common
DISORDERS	Hypovolaemia	Common
	Hypoglycaemia	Uncommon
	Hyponatraemia	Uncommon
	Hyperglycaemia	Uncommon
	Hypervolaemia	Uncommon
	Anorexia	Uncommon
	Hypochloraemia	Uncommon
	Hypomagnesaemia	Uncommon
	Hypoproteinaemia	Uncommon
	Shock hypoglycaemia	Not known
	Fluid imbalance	Not known
PSYCHIATRIC DISORDERS	Thinking abnormal	Uncommon
	Anxiety	Uncommon
	Nervousness	Uncommon
NERVOUS SYSTEM DISORDERS	Dizziness	Common
	Headache	Common
	Hyperkinesia	Uncommon
	Paraesthesia	Uncommon
	Ageusia	Uncommon
	Hypoglycaemic coma	Not known
	Burning sensation	Not known
EYE DISORDERS	Vision blurred	Not known
EAR AND LABYRINTH	Tinnitus	Common
DISORDERS
CARDIAC DISORDERS	Cardiovascular disorder	Uncommon
	Tachycardia	Uncommon
VASCULAR DISORDERS	Hypotension	Common
	Hypertension	Common
	Orthostatic hypotension	Uncommon
RESPIRATORY, THORACIC, AND	Pulmonary oedema	Uncommon
MEDIASTINAL DISORDERS	Dyspnoea	Uncommon
	Cough	Uncommon

System Organ Class (SOC)	Preferred MedDRA Term	Frequency
	Hiccups	Uncommon
	Bronchospasm	Not known
GASTROINTESTINAL	Abdominal pain	Common
DISORDERS	Ileus	Uncommon
	Peritonitis	Uncommon
	Bloody peritoneal effluent	Uncommon
	Diarrhoea	Uncommon
	Gastric ulcer	Uncommon
	Gastritis	Uncommon
	Vomiting	Uncommon
	Constipation	Uncommon
	Dyspepsia	Uncommon
	Nausea	Uncommon
	Dry mouth	Uncommon
	Flatulence	Uncommon
	Ascites	Not known
	Inguinal hernia	Not known
	Abdominal discomfort	Not known
SKIN AND SUBCUTANEOUS	Rash (including macular, papular,	Common
TISSUE DISORDERS	erythematous)
	Pruritus	Common
	Skin exfoliation	Common
	Urticaria	Uncommon
	Dermatitis bullous	Uncommon
	Psoriasis	Uncommon
	Skin ulcer	Uncommon
	Eczema	Uncommon
	Nail disorder	Uncommon
	Dry skin	Uncommon
	Skin discolouration	Uncommon
	Toxic epidermal necrolysis	Not known
	Erythema multiform	Not known
	Angiodema	Not known
	Urticaria generalised	Not known
	Toxic skin eruption	Not known
	Periorbital oedema	Not known
	Dermatitis (including allergic and	Not known
	contact)
	Erythema	Not known
	Blister	Not known
MUSCULOSKELETAL AND	Bone pain	Uncommon
CONNECTIVE TISSUE	Muscle spasms	Uncommon
DISORDERS	Myalgia	Uncommon
	Neck pain	Uncommon
	Arthralgia	Not known
	Back pain	Not known
	Musculoskeletal pain	Not known
RENAL AND URINARY	Renal pain	Uncommon
DISORDERS

System Organ Class (SOC)	Preferred MedDRA Term	Frequency
GENERAL DISORDERS AND	Oedema peripheral	Common
ADMINISTRATIVE SITE	Asthenia	Common
CONDITIONS	Chest pain	Uncommon
	Face oedema	Uncommon
	Oedema	Uncommon
	Pain	Uncommon
	Pyrexia	Not known
	Chills	Not known
	Malaise	Not known
	Catheter site erythema	Not known
	Catheter site inflammation	Not known
	Infusion related reaction (including infusion site pain, instillation site pain)	Not known
INVESTIGATIONS	Alanine aminotransferase increased	Uncommon
	Aspartate aminotransferase increased	Uncommon
	Blood alkaline phosphatase increased	Uncommon
	Liver function test abnormal	Uncommon
	Weight decreased	Uncommon
	Weight increased	Uncommon
INJURY, POISONING, AND PROCEDURAL COMPLICATIONS	Device interaction*	Not known

*Icodextrin interferes with blood glucose measurement devices (see section 4.4).

** Hypersensitivity-type reactions have been reported in patients using Extraneal Clear-Flex including bronchospasm, hypotension, rash, pruritus and urticaria

Other undesirable effects of peritoneal dialysis related to the procedure: fungal peritonitis, bacterial peritonitis, catheter site infection, catheter related infection and catheter related complication.

Enhanced ultrafiltration, particularly in the elderly patients, may lead to dehydration, resulting in hypotension, dizziness and possibly neurological symptoms (see section 4.4).

Hypoglycaemic episodes in diabetic patients (see section 4.4).

Increase in serum alkaline phosphatases (see section 4.4) and electrolyte disturbances (e.g. hypokalaemia, hypocalcaemia and hypercalcaemia).

Peritoneal reactions, including abdominal pain, cloudy effluents with or without bacteria, aseptic peritonitis (see section 4.4).

Fatigue was often reported spontaneously and in literature as an undesirable effect related to the procedure.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product 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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No data are available on the effects of overdosage. However, continuous administration of more than one bag of Extraneal Clear-Flex in 24 hours would increase plasma levels of carbohydrate metabolites and maltose. The effects of such an increase are unknown but an increase in plasma osmolality may occur. Treatment could be managed by Icodextrin-free peritoneal dialysis or haemodialysis.

Refer to section 4.4 on overinfusion of Extraneal Clear-Flex and its treatment.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Peritoneal dialytics, Isotonic solutions, ATC code: B05DA

Icodextrin is a starch-derived glucose polymer which acts as an osmotic agent when administered intraperitoneally for the long peritoneal dialysis dwell. A 7.5 % solution is approximately iso-osmolar to serum but produces sustained ultrafiltration over a period up to 16 hours in APD. There is a reduction in calorie load compared to hyperosmolar glucose solutions.

The volume of ultrafiltrate produced is comparable to that with 3.86 % glucose. Blood glucose and insulin levels remain unaffected.

Ultrafiltration is maintained during episodes of peritonitis.

The recommended posology is limited to a single exchange in each 24 hour-period, as part of an APD regimen.

5.2 Pharmacokinetic properties

Carbohydrate polymer levels in blood reach steady state after about 7-10 days when used on a daily basis for overnight dialysis. The polymer is hydrolysed by amylase to smaller fragments which are cleared by peritoneal dialysis. Steady state plasma levels of 1.8 mg/ml have been measured for oligomers of glucose units greater than 9 (G9) and there is a rise in serum maltose (G2) to

1.1 mg/ml but there is no significant change in serum osmolality. When used for the long day time dwell in APD maltose levels of 1.4 mg/ml have been measured but with no significant change in serum osmolality.

The long-term effects of raised plasma levels of maltose and glucose polymer are unknown, but there is no reason to suppose these to be harmful.

5.3 Preclinical safety data

Acute toxicity

Acute i.v. and i.p. studies in mice and rats have demonstrated no effects at doses up to 2000 mg/kg.

Subchronic toxicity

Twice daily i.p. administration of 20 % Icodextrin solution for 28 days to rats and dogs revealed no target organ or tissue toxicity. The major effect was upon the dynamics of fluid balance.

Mutagenic and tumorigenic potential

In vitro and in vivo studies on mutagenicity gave negative results. Carcinogenicity studies with the product are not feasible but carcinogenic effects are unlikely given the chemical nature of the molecule, its lack of pharmacological effect, lack of target organ toxicity and negative results in mutagenicity studies.

Reproductive toxicity

A reproduction toxicity study in rats demonstrated no effect on fertility or embryofetal development.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Water for Injections

Sodium hydroxide or Hydrochloric acid for pH adjustment

6.2    Incompatibilities

Drug compatibility must be checked before admixture (see section 6.3 for additional information on drug additives). In addition, the pH and salts of the solution must be taken into account. The product should be used immediately after any addition of medication.

Initial results show that insulin is minimally absorbed from Extraneal in Clear-Flex bags compared with PVC bags, so dosage adjustments may be necessary and special attention is advised in this situation.

6.3    Shelf life

2 years.

The product should be used immediately after the outer bag is removed. From a microbiological point of view, the product should be used immediately

unless the method for adding medication prevents the risk for microbial contamination. If it is not used immediately, the shelf life and conditions for use are the responsibility of the user.

Chemical and physical stability during use has been demonstrated for 24 hours at 25°C for: cefazolin (125 and 750 mg/L), ceftazidime (125 and 500 mg/L), aztreonam (250 and 1000 mg/L), fluconazole (40 and 80 mg/L), gentamicin (4 and 30 mg/L), low molecular weight heparin (2500 IU/L), high molecular weight heparin (2500 IU/L), tobramycin (4 and 30 mg/L) or vancomycin (25 and 1500 mg/L).

Aminoglycosides should not be mixed with penicillin because of chemical incompatibility.

The product should be used immediately after any addition of medication.

6.4    Special precautions for storage

Do not store below 4°C.

See section 6.3 and 6.6 for storage of product that has been opened or has had medications added to it, respectively.

6.5    Nature and contents of container

The fluid is hermetically sealed inside a bag manufactured of co-extruded film (Clear-Flex) of polypropylene, polyamide and a blend of polypropylene, SEBS and polyethylene. On the outer layer of the film, a valve system is welded at the bottom of the bag (luer connector) and an injection site in the middle of the bag.

The bag is overwrapped inside a transparent overpouch made of multilayer copolymers.

Pack sizes:

Extraneal Clear-Flex is registered in the following pack sizes:

2.5 l	1 unit/box	Single bag	Luer connector
2.5 l	3 units/box	Single bag	Luer connector
2.5 l	4 units/box	Single bag	Luer connector

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Detailed instructions about exchange procedures for peritoneal dialysis are given to the patients during training in a specialized centre before use in the home.

Discard any unused solution.

7 MARKETING AUTHORISATION HOLDER

Baxter Healthcare Limited

Caxton Way

Thetford

Norfolk

IP24 3SE

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00116/0657

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/05/2015

10 DATE OF REVISION OF THE TEXT

09/03/2016