4.1. Therapeutic indications

PHYSIONEAL 40 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 40 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 40 in paediatric patients have not been established. Therefore the clinical benefits of PHYSIONEAL 40 have to be balanced versus the risks of side effects in this patient category.

The use of PHYSIONEAL 40 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 40 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 40 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.

4.4. 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 40 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), broadspectrum 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.

Secondary hyperparathyroidism

In patients with secondary hyperparathyroidism, the benefits and risks of the use of a solution with 1.25 mmol/l calcium, such as PHYSIONEAL 40, should be carefully considered as it might worsen hyperparathyroidism.

Overinfusion

Overinfusion of PHYSIONEAL 40 solutions into the peritoneal cavity may be characterized by abdominal distension/abdominal pain and/or shortness of breath.

Treatment of PHYSIONEAL 40 overinfusion is to drain the solution from the peritoneal cavity.

Use of higher glucose concentrations

Excessive use of PHYSIONEAL 40 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 40 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 40 in pregnant women.

PHYSIONEAL 40 is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether PHYSIONEAL 40 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 40 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 most commonly reported Adverse Reaction from the controlled clinical trials with PHYSIONEAL 40 was alkalosis, occurring in approximately 10 % of patients. In most cases, it was based on serum hydrogen carbonate values only and was usually not associated with clinical symptoms.

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 LYMPHATIC SYSTEM DISORDERS

Eosinophilia

Not known

METABOLISM AND NUTRITION DISORDERS

Alkalosis

Hypokalaemia

Fluid retention

Hypercalcaemia

Hypervolaemia

Anorexia

Dehydration

Hyperglycaemia

Lactic Acidosis

Common

Common

Common

Common

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

PSYCHIATRIC DISORDERS

Insomnia

Uncommon

NERVOUS SYSTEM DISORDERS

Dizziness

Headache

Uncommon

Uncommon

VASCULAR DISORDERS

Hypertension

Hypotension

Common

Uncommon

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS

Dyspnoea

Cough

Uncommon

Uncommon

GASTROINTESTINAL DISORDERS

Peritonitis

Peritoneal membrane failure

Abdominal pain

Dyspepsia

Flatulence

Nausea

Sclerosing encapsulating peritonitis

Cloudy peritoneal effluent

Common

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

Not known

Not known

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Angioedema

Rash

Not known

Not known

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Musculoskeletal pain

Not known

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Oedema

Asthenia

Chills

Facial oedema

Hernia

Malaise

Thirst

Pyrexia

Common

Common

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

Not known

INVESTIGATIONS

Weight increased

PCO2 increased

Common

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 40 and its treatment.