Document: spc-doc_PL 00116-0315 change

• spc-doc_PL 00116-0315
• spc-doc_PL 00116-0411

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Physioneal 40 Glucose 1.36% w/v / 13.6 mg/ml Solution for peritoneal dialysis

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Before mixing

1000 ml of electrolyte solution (Small chamber "A")
Active substances:
Glucose monohydrate	41.25 g
Equivalent to Anhydrous glucose	37.5 g
Calcium chloride dihydrate	0.507 g
Magnesium chloride hexahydrate	0.140 g
1000 ml of buffer solution (Large chamber "B")
Active substances:
Sodium chloride	8.43 g
Sodium bicarbonate	3.29 g
Sodium (S)-lactate solution	2.63 g

After mixing

1000 ml of the mixed solution contains:
Active substances:
Glucose monohydrate	15.0 g
Equivalent to Anhydrous glucose	13.6 g
Sodium chloride	5.38 g
Calcium chloride dihydrate	0.184 g
Magnesium chloride hexahydrate	0.051 g
Sodium bicarbonate	2.10 g
Sodium (S)-lactate solution	1.68 g

1000 ml of final solution after mixing corresponds to 362.5 ml of solution A and 637.5 ml of solution B.

Composition of the final solution after mixing in mmol/l
Glucose anhydrous (C6Hi2O6)	75.5 mmol/l
Na+	132 mmol/l
Ca++	1.25 mmol/l
Mg++	0.25 mmol/l
Cl-	95 mmol/l

HCO3-	25 mmol/l
C3H5O3-	15 mmol/l

For the full list of excipients, see section 6.1.

The number ‘40’ in the name specifies the buffer concentration of the solution (15 mmol/l of lactate + 25 mmol/l of bicarbonate = 40 mmol/l).

3. PHARMACEUTICAL FORM

Solution for peritoneal dialysis.

Sterile, clear, colourless solution.

The pH of the final solution is 7.4.

4.    CLINICAL PARTICULARS

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 bicarbonate/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.

•    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.

•

• Paediatric population (patients from pre-term newborn infants to adolescents):

Paediatric patients have not been evaluated in clinical studies with PHYSIONEAL 40. Therefore the clinical benefits of PHYSIONEAL 40 have to be balanced versus the risks of side effects in this patient category. For pediatric patients >2 years old, 800 to 1400 mL/m2 per cycle up to a maximum amount of 2000 mL, as tolerated, has been recommended. Fill volumes of 200 to 1000 mL/m2 are recommended in children less than 2 years of age.

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.

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 break the interchamber frangible pin to mix the two solutions. Wait until the upper chamber has completely drained into the lower chamber. Mix gently by pushing with both hands on the lower chamber walls. The intraperitoneal solution must be infused within 24 hours after mixing.

•    For further information on the use of the medicinal product see section 6.6 Instructions for use and 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

•    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, 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

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 PHYSIONEAL 40 as part of their PD therapy.

•    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.

•    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 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.

•    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.

•    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.

•    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.

•    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.

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

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

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

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

•    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.

•    Potassium is omitted from PHYSIONEAL 40 solutions due to the risk of hyperkalaemia.

o In situations in which there is a normal serum potassium level or hypokalaemia, the addition of potassium chloride (up to a concentration of 4 mEq/l) may be indicated to prevent severe hypokalaemia and should be made after careful evaluation of serum and total body potassium, only under the direction of a physician.

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

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

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

Paediatric population

•    Safety and effectiveness in paediatric patients has not been established.

4.5 Interaction with other medicinal products and other forms of interaction

-    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 glucosides 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.

Breastfeeding

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 bicarbonate 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 available data).

System Organ Class	Preferred Term	Frequency
BLOOD AND	Eosinophilia	Not known
LYMPHATIC SYSTEM
DISORDERS
METABOLISM AND	Alkalosis	Common
NUTRITION	Hypokalaemia	Common
DISORDERS	Fluid retention	Common
	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
GENERAL	Oedema	Common
DISORDERS AND	Asthenia	Common
ADMINISTRATIVE	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. Refer to 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamics properties

Pharmacotherapeutic group: Peritoneal Dialytics ATC code: B05DB

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. 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 bicarbonate 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.

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 40 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

There are no preclinical data considered relevant to clinical safety beyond data included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Water for Injections.

Carbon dioxide (for pH adjustment).

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.

Store in the original package.

6.5 Nature and contents of container

The Physioneal 40 solution is hermetically sealed inside a two-chambered bag manufactured from medical grade plasticised PVC.

The upper chamber is fitted with an injection port for drug admixture to the glucose with electrolytes solution. The lower chamber is fitted with a port 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 sealed inside a transparent overpouch obtained by thermic fusion and made of multilayer copolymers.

Container volumes after reconstitution: 1500 ml (544 ml of solution A and 956 ml of solution B), 2000 ml (725 ml of solution A and 1275 ml of solution B), 2500 ml (906 ml of solution A and 1594 ml of solution B).

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

1.5    l 6 units per boxsingle two-chamber bag

1.5    l 5 units per boxsingle two-chamber bag

1.5    l 6 units per boxsingle two-chamber bag

1.5    l 5 units per boxtwin two-chamber bag

1.5    l 6 units per boxtwin two-chamber bag

boxtwin two-chamber bag boxtwin two chamber bag box twin two-chamber bag boxtwin two chamber bag

boxsingle two-chamber bag boxsingle two-chamber bag boxsingle two-chamber bag boxsingle two-chamber bag boxtwin two-chamber bag boxtwin two-chamber bag boxtwin two-chamber bag boxtwin two-chamber bag boxtwin two-chamber bag boxtwin two-chamber bag

boxsingle two-chamber bag boxsingle two-chamber bag boxsingle two-chamber bag boxsingle two-chamber bag boxtwin two-chamber bag boxtwin two-chamber bag boxtwin two-chamber bag boxtwin two-chamber bag box twin two-chamber bag boxtwin two-chamber bag

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 break the interchamber frangible pin to mix the two solutions. Wait until the upper chamber has completely drained into the lower chamber. Mix gently by pushing with both hands on the lower chamber walls. The intraperitoneal solution must be infused within 24 hours after mixing. Refer to section 4.2.

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

•    Drugs should be added through the medication port in the top chamber before breaking the interchamber frangible pin. 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.

•    Discard any unused remaining solution.

•    The solution is free from bacterial endotoxins.

7.    MARKETING AUTHORISATION HOLDER

Baxter Healthcare Ltd Caxton Way,

Thetford, Norfolk

8.    MARKETING AUTHORISATION NUMBER

PL 00116/0315

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/03/2008

10    DATE OF REVISION OF THE TEXT

09/01/2016