SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Physioneal 35 Glucose 1.36% w/v / 13.6 mg/ml Clear-Flex, Solution for peritoneal dialysis.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Before mixing

1000 ml of electrolyte solution (large chamber "A") contains:
Active substances:
Glucose monohydrate	20.0 g
equivalent to Glucose anhydrous	18.2 g
Calcium chloride dihydrate	0.343 g
Magnesium chloride hexahydrate	0.068 g
1000 ml of buffer solution (small chamber "B") contains:
Active substances:
Sodium chloride	21.12 g
Sodium hydrogen carbonate	9.29 g
Sodium (S)-lactate solution
equivalent to sodium (S)-lactate	4.48 g

After mixing

1000 ml of the mixed solution contains:
Active substances:
Glucose monohydrate	15.0 g
equivalent to Glucose anhydrous	13.6 g
Sodium chloride	5.67 g
Calcium chloride dihydrate	0.257 g
Magnesium chloride hexahydrate	0.051 g
Sodium hydrogen carbonate	2.10 g
Sodium (S)-lactate solution equivalent to sodium (S)-lactate	1.12 g

1000 ml of final solution after mixing corresponds to 750 ml of solution A and 250 ml of solution B.

Composition of the final solution after mixing in mmol/l
Glucose anhydrous (C6H12O6)	75.5 mmol/l
Na+	132 mmol/l
Ca++	1.75 mmol/l
Mg++	0.25 mmol/l
Cl-	101 mmol/l
HCO3-	25 mmol/l
C3H5O3"	10 mmol/l

For the full list of excipients, see section 6.1.

The number ‘35’ in the name specifies the buffer concentration of the solution (10 mmol/l of lactate + 25 mmol/l of hydrogen carbonate = 35 mmol/l).

3    PHARMACEUTICAL FORM

Solution for peritoneal dialysis. Sterile, clear, colourless solution. The pH of the final solution is 7.4. Osmolarity: 345 mOsmol/l

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

PHYSIONEAL 35 is indicated whenever peritoneal dialysis is employed, including:

•    Acute and chronic renal failure;

•    Severe water retention;

•    Severe electrolyte imbalance;

•    Drug intoxication with dialysable substances, when a more adequate therapeutic alternative is not available.

PHYSIONEAL 35 hydrogen carbonate/lactate based peritoneal dialysis solutions with a physiological pH are particularly indicated in patients in whom solutions based on lactate buffer only, with a low pH, cause abdominal inflow pain or discomfort.

4.2    Posology and method of administration

Posology

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

To avoid the risk of severe dehydration, hypovolaemia and to minimise the loss of proteins, it is advisable to select the peritoneal dialysis solution with the lowest osmolarity consistent with fluid removal requirements for each exchange.

Adults

Patients on continuous ambulatory peritoneal dialysis (CAPD) typically perform 4 cycles per day (24 hours). Patients on automated peritoneal dialysis (APD) typically perform 4-5 cycles at night and up to 2 cycles during the day. The fill volume depends on body size, usually from 2.0 to 2.5 litres.

Elderly As for adults.

Paediatric population

The safety and efficacy of PHYSIONEAL 35 in paediatric patients have not been established. Therefore the clinical benefits of PHYSIONEAL 35 have to be balanced versus the risks of side effects in this patient category.

The use of PHYSIONEAL 35 in the Clear-Flex container is not recommended in children requiring a fill volume < 1600 ml due to the risk of not detecting a possible misinfusion (administration of the small chamber only). See section 4.4.

Method of administration

Precautions to be taken before handling or administering the medicinal product

•    PHYSIONEAL 35 is intended for intraperitoneal administration only. Not for intravenous administration.

•    Peritoneal dialysis solutions may be warmed 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, shows evidence of leakage between chambers or to the exterior, 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 peritonitis.

•    For single use only.

•    After removal of the overpouch, immediately open the long-seal (interchamber seal) to mix the two solutions and then open the short SafetyMoon seal (access seal) to allow administration of the mixed solution. The intraperitoneal solution must be infused within 24 hours after mixing.

•    For instructions on the use of the medicinal product see section 6.6 Special precautions for disposal and other handling.

4.3 Contraindications

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

PHYSIONEAL 35 should not be used in patients with:

•    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.

Special warnings and precautions for use

Use in patients with abdominal conditions

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 tumors, abdominal wall infection, hernias, fecal 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 intra-abdominal cavity

2)    other conditions including recent aortic graft replacement and severe pulmonary disease.

Encapsulating Peritoneal Sclerosis (EPS)

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 PHYSIONEAL 35 as part of their PD therapy.

Peritonitis

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), broad-spectrum antibiotics may be indicated.

Hypersensitivity

Solutions containing glucose derived from hydrolysed maize starch should be used with caution in patients with a known allergy to maize or maize products. Hypersensitivity reactions such as those due to a corn (maize) starch allergy, including anaphylactic/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. Appropriate therapeutic countermeasures must be instituted as clinically indicated.

Use in patients with elevated lactate levels

Patients with elevated lactate levels should use lactate-containing peritoneal dialysis solutions with caution. It is recommended that patients with conditions known to increase the risk of lactic acidosis [e.g., severe hypotension, sepsis, 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.

General monitoring

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.

An accurate fluid balance record must be kept and the body weight of the patient must carefully be monitored to avoid over- or underhydration with severe consequences including congestive heart failure, volume depletion and shock.

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

Serum electrolyte concentrations (particularly hydrogen carbonate, potassium, magnesium, calcium and phosphate), blood chemistry (including parathyroid hormone and lipid parameters) and haematological parameters should be monitored periodically.

Metabolic alkalosis

In patients with plasma hydrogen carbonate level above 30 mmol/l, the risk of possible metabolic alkalosis should be weighed against the benefits of treatment with this product.

Overinfusion

Overinfusion of PHYSIONEAL 35 solutions into the peritoneal cavity may be characterized by abdominal distension/abdominal pain and/or shortness of breath.

Treatment of PHYSIONEAL 35 overinfusion is to drain the solution from the peritoneal cavity.

Use of higher glucose concentrations

Excessive use of PHYSIONEAL 35 peritoneal dialysis solution with a higher dextrose (glucose) during a peritoneal dialysis treatment may result in excessive removal of water from the patient. See section 4.9.

Addition of potassium

Potassium is omitted from PHYSIONEAL 35 solutions due to the risk of hyperkalemia.

In situations in which 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 and should be made after careful evaluation of serum and total body potassium, only under the direction of a physician.

Use in diabetic patients

In patients with diabetes, blood glucose levels should be monitored and the dosage of insulin or other treatment for hyperglycaemia should be adjusted.

Improper administration

Improper clamping or priming sequence may result in infusion of air into the peritoneal cavity, which may result in abdominal pain and/or peritonitis.

Patients must be instructed to open both the long and the short seals prior to infusion. If only the short SafetyMoon seal opens, infusion of the unmixed solution can cause abdominal pain, hypernatremia and severe metabolic alkalosis. In case of infusion of unmixed solution, the patient should immediately drain the solution and use a newly mixed bag.

Paediatric population

Safety and efficacy in paediatric patients have not been established.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

•    Blood concentration of dialysable medicinal product may be reduced during dialysis. A possible compensation for losses must be taken into consideration.

•    Plasma levels of potassium in patients using cardiac glycosides must be carefully monitored as there is a risk of digitalis intoxication. Potassium supplements may be necessary.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of PHYSIONEAL 35 in pregnant women.

PHYSIONEAL 35 is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether PHYSIONEAL 35 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 PHYSIONEAL 35 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

Adverse reactions (occurring in 1% of patients or more) from the clinical trials and post marketing are listed below.

The adverse drug reactions listed in this section are given following the recommended frequency convention: 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), not known (cannot be estimated from the available data)

System Organ Class	Preferred Term	Frequency
BLOOD AND	Eosinophilia	Not known
LYMPHATIC SYSTEM
DISORDERS
METABOLISM AND	Hypokalaemia	Common
NUTRITION	Fluid retention	Common
DISORDERS	Hypercalcaemia	Common
	Hypervolaemia	Uncommon
	Anorexia	Uncommon
	Dehydration	Uncommon
	Hyperglycaemia	Uncommon
	Lactic Acidosis	Uncommon
PSYCHIATRIC	Insomnia	Uncommon
DISORDERS
NERVOUS SYSTEM	Dizziness	Uncommon
DISORDERS	Headache	Uncommon
VASCULAR	Hypertension	Common
DISORDERS	Hypotension	Uncommon
RESPIRATORY,	Dyspnoea	Uncommon
THORACIC, AND	Cough	Uncommon
MEDIASTINAL
DISORDERS
GASTROINTESTINAL	Peritonitis	Common
DISORDERS	Peritoneal membrane failure	Uncommon
	Abdominal pain	Uncommon
	Dyspepsia	Uncommon
	Flatulence	Uncommon
	Nausea	Uncommon
	Sclerosing encapsulating	Not known
	peritonitis
	Cloudy peritoneal effluent	Not known
SKIN AND	Angioedema	Not known
SUBCUTANEOUS	Rash	Not known
TISSUE DISORDERS
MUSCULOSKELETAL	Musculoskeletal pain	Not known
AND CONNECTIVE
TISSUE DISORDERS

System Organ Class	Preferred Term	Frequency
GENERAL	Oedema	Common
DISORDERS AND	Asthenia	Common
ADMINISTRATION	Chills	Uncommon
SITE CONDITIONS	Facial oedema	Uncommon
	Hernia	Uncommon
	Malaise	Uncommon
	Thirst	Uncommon
	Pyrexia	Not known
INVESTIGATIONS	Weight increased	Common
	PCO2 increased	Uncommon

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

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 the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Possible consequences of overdose include hypervolaemia, hypovolaemia, electrolyte disturbances or (in diabetic patients) hyperglycaemia. See section 4.4.

Management of overdose

Hypervolaemia may be managed by using hypertonic peritoneal dialysis solutions and fluid restriction.

Hypovolaemia may be managed by fluid replacement either orally or intravenously, depending on the degree of dehydration.

Electrolyte disturbances shall be managed according to the specific electrolyte disturbance verified by blood test. The most probable disturbance, hypokalaemia, may be managed by the oral ingestion of potassium or by the addition of potassium chloride in the peritoneal dialysis solution prescribed by the treating physician.

Hyperglycaemia (in diabetic patients) shall be managed by adjusting the insulin dose according to the insulin scheme prescribed by the treating physician.

See section 4.4 for information on overinfusion of Physioneal 35 and its treatment.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Peritoneal Dialytics, Hypertonic solutions ATC code: B05DB

Mechanism of action

For patients with renal failure, peritoneal dialysis is a procedure for removing toxic substances produced by nitrogen metabolism and normally excreted by the kidneys, and for aiding the regulation of fluid and electrolyte as well as acid base balances.

This procedure is accomplished by administering peritoneal dialysis fluid through a catheter into the peritoneal cavity.

Pharmacodynamic effects

Glucose produces a solution hyperosmolar to the plasma, creating an osmotic gradient which facilitates fluid removal from the plasma to the solution. Transfer of substances between the patient's peritoneal capillaries and the dialysis fluid is made across the peritoneal membrane according to the principles of osmosis and diffusion. After dwell time, the solution is saturated with toxic substances and must be changed. With the exception of lactate, present as a hydrogen carbonate precursor, electrolyte concentrations in the fluid have been formulated in an attempt to normalise plasma electrolyte concentrations. Nitrogenous waste products, present in high concentration in the blood, cross the peritoneal membrane into the dialysis fluid.

Clinical efficacy and safety

More than 30% of the patients in the clinical trials were older than 65. The evaluation of the results obtained for this group does not show any difference to the rest of the patients.

In vitro and ex vivo studies have shown evidence of improved biocompatibility indicators of PHYSIONEAL 35 in comparison with standard lactate buffered solution. In addition, clinical studies in limited numbers of patients with abdominal inflow pain have confirmed some symptomatic benefit. To date, however, there are no data available which indicate that clinical complications overall are reduced or that regular use of such solutions might translate into meaningful benefits over the longer-term.

5.2 Pharmacokinetic properties

Intraperitoneally administered glucose, electrolytes and water are absorbed into the blood and metabolised by the usual pathways.

Glucose is metabolised (1 g of glucose = 4 kilocalories or 17 kilojoules) into CO₂ and H2O.

5.3 Preclinical safety data

No non-clinical studies have been performed with PHYSIONEAL 35.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hydrochloric acid dilute (pH adjuster) Sodium hydroxide (pH adjuster) Water for Injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Shelf life as packaged for sale:

2 years.

Shelf life after mixing:

The product, once removed from its overpouch and mixed, should be used within 24 hours.

6.4 Special precautions for storage

Do not store below 4°C.

6.5 Nature and contents of container

The Physioneal 35 solution is stored inside a two-chamber bag made of a coextruded film (Clear-Flex film) of Polypropylene, Polyamide and a blend of Polypropylene, SEBS and Polyethylene.

On the upper chamber an injection site is welded for drug admixture to the glucose with electrolytes solution. On the lower chamber a valve system is welded for connection to a suitable administration set allowing dialysis operations.

The lineo connector that may equip the Y transfer line of the twin bag, contains 10.5% of Povidone iodine ointment

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

Container volumes after reconstitution: 1500 ml (1125 ml of solution A and 375 ml of solution B), 2000 ml (1500 ml of solution A and 500 ml of solution B), 2500 ml (1875 ml of solution A and 625 ml of solution B), 3000 ml (2250 ml of solution A and 750 ml of solution B), 4500 ml (3375 ml of solution A and 1125 ml of solution B), 5000 ml (3750 ml of solution A and 1250 ml of solution B).

The single bag is a two-chamber bag (large chamber "A" and small chamber "B", see section 2) to be used in Automated Peritoneal Dialysis. The twin bag is a two-chamber bag (large chamber "A" and small chamber "B", see section 2) with an

integrated disconnect system plus an empty drain bag to be used in Continuous

Ambulatory Peritoneal Dialysis

Not all pack sizes may be marketed:

1.5 l	5 units per box	two-chamber single bag
Luer connector 1.5 l Luer connector	6 units per box	two-chamber single bag
1.5 l	5 units per box	two-chamber twin bag Luer
connector 1.5 l connector	6 units per box	two-chamber twin bag Luer
1.5 l	5 units per box	two-chamber twin bag Lineo
connector 1.5 l connector	6 units per box	two chamber twin bag Lineo
2.0 l	4 units per box	two-chamber single bag Luer
connector 2.0 l	5 units per box	two-chamber single bag
Luer connector 2.0 l	4 units per box	two-chamber twin bag Luer
connector 2.0 l	5 units per box	two-chamber twin bag Luer
connector 2.0 l	4 units per box	two-chamber twin bag Lineo
connector 2.0 l connector	5 units per box	two-chamber twin bag Lineo
2.5 l	3 units per box	two-chamber single bag
Luer connector 2.5 l Luer connector	4 units per box	two-chamber single bag
2.5 l	3 units per box	two-chamber twin bag Luer
connector 2.5 l	4 units per box	two-chamber twin bag Luer
connector 2.5 l	3 units per box	two-chamber twin bag Lineo
connector 2.5 l connector	4 units per box	two-chamber twin bag Lineo
3.0 l	3 units per box	two-chamber single bag
Luer connector 3.0 l connector	3 units per box	two-chamber twin bag Luer
3.0 l	3 units per box	two-chamber twin bag Lineo

connector

4.5 l    2 units per box    two-chamber single bag

Luer connector

5.0 l    2 units per box    two-chamber single bag

Luer connector

2 units per box single two-chamber bag Luer connector + HomeChoice APD set with Lineo connector

5.0 l 2 units per boxsingle two-chamber bag Luer connector + HomeChoice

APD set with Luer connector + clamshell and minicap

6.6 Special precautions for disposal

For details on the conditions of administration see section 4.2.

•    Detailed instruction on the Peritoneal Dialysis exchange procedure is given to patients by means of training, in a specialised training centre, prior to home use.

•    After removal of the overpouch, immediately open the long-seal (interchamber seal) to mix the two solutions and then open the short Safety Moon seal (access seal) to allow administration of the mixed solution. The intraperitoneal solution must be infused within 24 hours after mixing. See section 4.2.

•    Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C for: cefazolin (750 mg/l), heparin (2500 IU/L), low molecular weight heparin (Innohep 2500 IU/L), netilmycin (60 mg/l) and vancomycin (1000 mg/l).

•    Chemical and physical in-use stability has been demonstrated for 6 hours at 25°C for insulin (Actrapid 4 IU/L, 10 IU/L, 20 IU/L and 40 IU/L).

•    Gentamicin (60 mg/l) and tobramycin (60 mg/l) can be added if the solution is used immediately after drug addition.

•    Drugs should be added through the medication site in the larger chamber before opening the interchamber peel-seal. Drug compatibility must be checked before admixture and the pH and salts of the solution must be taken into account. The product should be used immediately after any drug addition.

•    Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

•    The solution is free from bacterial endotoxins.

7    MARKETING AUTHORISATION HOLDER

Baxter Healthcare Ltd.

Caxton Way

Thetford Norfolk IP24 3SE United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00116/0408

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 5 October 2007 Date of latest renewal: 23 October 2008

10 DATE OF REVISION OF THE TEXT

16/06/2016