SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

GLUCOTHERA 1.4% w/v, solution for peritoneal dialysis.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

GLUCOTHERA is delivered in a double chambered bag.

One chamber contains an alkaline lactate solution, the other chamber contains an acidic glucose-based electrolyte solution. Mixing of these two solutions provides a neutral, ready-to-use solution for peritoneal dialysis.

Before Reconstitution

1 litre of acidic glucose based electrolyte solution contains:

	Amount (mg/ml)
Glucose, anhydrous	28.0
(as glucose monohydrate)	(30.8)
Calcium chloride dihydrate	0.38
Magnesium chloride hexahydrate	0.20
1 litre of alkaline lactate solution contains:
	Amount (mg/ml)
Sodium chloride	11.10 mg
Sodium (S)-lactate	7.85 mg (as 15.69 mg sodium lactate solution)
After Reconstitution
1 litre of the neutral ready-to-use	solution contains:
	Amount (mg/ml)
Glucose, anhydrous	14.0
(as glucose monohydrate)	(15.4)
Sodium chloride	5.6
Sodium (S)-lactate	3.9 (as 7.8 mg sodium (S)-lactate solution)
Calcium chloride dihydrate	0.2
Magnesium chloride hexahydrate	0.1

Glucose	77.7
Na+	131.9
Ca++	1.3
Mg++	0.5
Cl-	99.0
Lactate	35.0

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for peritoneal dialysis.

Each of the solutions are clear and colourless before and after reconstitution. The pH of the solution after reconstitution is approximately 7.0.

The theoretical osmolarity (mOsm/l) is: 347

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

GLUCOTHERA is indicated for peritoneal dialysis in patients with end-stage chronic renal failure.

GLUCOTHERA has a physiological pH and is therefore particularly indicated in patients in whom solutions with a lower pH cause abdominal inflow pain or discomfort.

GLUCOTHERA must be used with caution in children as the currently available data in the paediatric population are too limited to confirm its efficacy and safety profile.

4.2 Posology and method of administration

Posology

Peritoneal dialysis is a long-term therapy involving repeated administrations of single peritoneal solutions. The mode of therapy, frequency of treatment, exchange volume, duration of dwell and length of dialysis has to be tailored to patient need and must be established by the physician.

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. Patients on incremental peritoneal dialysis perform different schedules established by the physician.

The usual volume per cycle depends on the patient’s body weight and typically ranges from 2000 ml to 2500 ml.

In patients with large body surface area, an increased fill volume may be infused. In these patients, a volume of 2500 ml to 3000 ml per cycle may be used when tolerated.

If pain due to abdominal distension occurs at the start of peritoneal dialysis, the volume infused may be temporarily reduced to 500-1500 ml per exchange.

To avoid the risk of dehydration or 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 cycle.

GLUCOTHERA is available in different glucose concentrations that used can be used sequentially depending on the osmotic pressure required.

Adjustment of the dosage, volume and number of exchanges will be necessary for individual patients.

If an exchange has been forgotten, the dwell times of the next bags may be reduced to achieve the total amount of dialysis solution required per day (e.g. 4 x 2000 ml).

Older people

No special dosage adjustments are necessary for elderly patients. See also section 4.4.

Paediatric population

The safety and efficacy of GLUCOTHERA in children and adolescents have not been established.

If used in these patients CAPD is not recommended due to the risk of administering too much drug; dosing must be undertaken using a suitable APD machine, where the volume administered is strictly controlled. The solution volume per exchange must be tailored according to age, height and body weight (body surface area). The usual fill volume is 800 to 1400 ml/m² (approximately 30-40 ml/kg of body weight).

Method of administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Glucothera is a sterile, free from bacterial endotoxins solution, indicated for intraperitoneal administration only.

Aseptic measures must be used wherever practical throughout the peritoneal dialysis procedure in order to reduce the risk of infection.

Solutions must be warmed to body temperature to enhance patient comfort.

Peritoneal dialysis manoeuvres require particular care and awareness. For these reasons the exchange must be performed by health care professionals or by patients who have been properly trained prior to home use.

Peritoneal dialysis must be continued for as long as renal function substitution therapy is required.

4.3 Contraindications

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

•    Documented loss of peritoneal    function,

•    Extensive adhesions or lesions    that compromise peritoneal function.

•    Abdominal conditions including disruption of the peritoneal membrane and diaphragm by surgery, from congenital anomalies or trauma until healing is complete, abdominal tumours, hernias, large polycystic kidneys, or other conditions that compromise the integrity of the abdominal wall, abdominal surface, intra-abdominal cavity or peritoneopleural communication.

•    Abdominal wall infection, faecal fistula, colostomy, ileostomy or nephrostomy, frequent episodes of diverticulitis, inflammatory or ischemic bowel disease or other conditions involving acute or chronic abdominal infections.

•    Severe pulmonary diseases.

•    Pulmonary diseases, especially    pneumonia.

•    Sepsis.

•    Lactic acidosis.

•    Cachexia and extreme weight loss, particularly when adequate nutrition is impossible.

•    In rare cases of uraemia which can no longer be managed by peritoneal dialysis.

•    Extreme hyperlipidaemia.

•    In patients who are physically or mentally incapable of performing peritoneal dialysis as instructed by the physician.

4.4 Special warnings and precautions for use

Warnings

Excessive use of GLUCOTHERA with a high glucose (dextrose) content during a peritoneal dialysis treatment may result in excessive removal of water from the patient.

Patients with elevated lactate levels or inadequate lactate metabolism must 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. acute renal failure, liver cirrhosis, 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.

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

When prescribing the solution to be used for an individual patient, consideration must be given to the potential interaction between the dialysis treatment and therapy directed at other existing illnesses. Serum potassium levels must be monitored carefully in patients treated with cardiac glycosides (see section 4.5).

If peritonitis occurs, the choice and dosage of antibiotics must 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.

Encapsulating Peritoneal Sclerosis (EPS) is considered a known, rare complication of peritoneal dialysis therapy. This has been reported in patients using peritoneal dialysis solutions as part of their PD therapy.

The transport characteristics of the peritoneal membrane may change during longterm peritoneal dialysis primarily indicated by a loss of ultrafiltration. In severe cases peritoneal dialysis must be stopped and haemodialysis started.

Over-infusion of GLUCOTHERA into the peritoneal cavity may be characterised by abdominal distension/abdominal pain and/or shortness of breath. In case of overinfusion of GLUCOTHERA the solution must be drained from the peritoneal cavity.

Precautions

Serum electrolyte concentrations (particularly potassium, magnesium and calcium), blood chemistry (including parathyroid hormone) and haematological parameters must be monitored periodically.

In case of hypocalcaemia, therapy must include an adequate treatment including calcium supply.

In case of hypokalemia, oral potassium supply may be required. The addition of potassium chloride to the dialysis solution (up to a concentration of 4 mEq/l) may be considered in case of severe hypokalemia, after careful evaluation of serum and total body potassium and only under the direction of a physician.

Protein, amino acids, water soluble vitamins and other medicines may be lost during peritoneal dialysis and may require replacement (see section 4.5).

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

Elderly patients

No special warnings or precautions for use are necessary for elderly patients.

It is however advisable to investigate the possible presence of abdominal hernias before opting for peritoneal dialysis, due to the high prevalence of hernia in elderly patients.

Paediatric population

Safety and efficacy of GLUCOTHERA in children and adolescents have not been established.

4.5 Interaction with other medicinal products and other forms of interaction

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

A reduction of the serum potassium level can increase the frequency of digitalis-associated adverse reactions. Potassium levels must be monitored and supplements may be required (see section 4.4).

Concomitant use of diuretic agents may help maintain residual diuresis however it may cause water and electrolyte imbalances.

The possibility of hypercalcaemia should be considered on concomitant administration of calcium compounds or Vitamin D.

Daily dose of insulin or oral hypoglycaemic medicinal products in diabetic patients must be adjusted to take account of the increased glucose load.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of peritoneal dialysis in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

GLUCOTHERA is not recommended during pregnancy.

Breastfeeding

There is insufficient information on the effects of GLUCOTHERA in newborns/infants.

GLUCOTHERA should not be used during breast-feeding.

Fertility

Fertility is markedly reduced in dialysis patients.

4.7 Effects on ability to drive and use machines

GLUCOTHERA has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Undesirable effects are ranked according to MedDRA System Organ Class (SOC) and to their frequency.

The frequency of occurrence of the adverse events is classified as follows: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 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 (SOC)	Adverse event	Frequency
Blood and Lymphatic System Disorders	Eosinophilia	Not known

System Organ Class (SOC)	Adverse event	Frequency
Metabolism and Nutritional	Alkalosis	Common
Disorders	Hypokalaemia	Common
	Fluid retention	Common
	Hypercalcaemia	Common
	Hypervolaemia	Uncommon
	Anorexia	Uncommon
	Dehydration	Uncommon
	Hyperglycaemia	Uncommon
	Lactic Acidosis	Uncommon
	Dyslipidaemia	Not known
Psychiatric Disorders	Insomnia	Uncommon
Nervous System Disorders	Dizziness	Uncommon
	Headache	Uncommon
Vascular Disorders	Hypertension	Common
	Hypotension	Uncommon
Respiratory, Thoracic, and	Dyspnoea	Uncommon
Mediastinal Disorders	Cough	Uncommon
Gastrointestinal Disorders	Peritonitis	Common
	Peritoneal membrane failure	Uncommon
	Abdominal pain	Uncommon
	Dyspepsia	Uncommon
	Flatulence	Uncommon
	Nausea	Uncommon
	Vomiting	Not known
	Diarrhoea	Not known
	Constipation	Not known
	Sclerosing encapsulating	Not known
	peritonitis Cloudy Peritoneal effluent	Not known

System Organ Class (SOC)	Adverse event	Frequency
Skin and Subcutaneous	Angioedema	Not known
Disorders	Rash	Not known
Musculoskeletal,	Musculoskeletal pain	Not known
Connective Tissue Disorders
General Disorders and	Oedema	Common
Administrative Site	Asthenia	Common
Conditions	Chills	Uncommon
	Facial oedema	Uncommon
	Hernia	Uncommon
	Malaise	Uncommon
	Thirst	Uncommon
	Pyrexia	Not known
Investigations	Weight increased	Common
	PCO2 increased	Uncommon

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

4.9 Overdose

Symptoms

Possible symptoms of overdose include hypervolaemia, hypovolaemia, electrolyte disturbances or, in diabetic patients, hyperglycaemia.

Management

Hypervolaemia may be treated 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 treated according to the specific electrolyte disturbance identified following 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 resolved by adjusting the insulin dose according to the insulin scheme prescribed by the physician.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Peritoneal Dialysis, 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, which induces an osmotic gradient that promotes 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 the dwell time, the solution contains toxic substances and must be replaced.

The electrolyte content of the solution is similar to that of the physiological serum, although it has been adapted (e.g. the potassium content) for use in uraemic patients to enable renal function substitution therapy by means of intraperitoneal substances and fluid exchange.

Calcium concentrations around 1.3 mmol/l help to remove small amounts of calcium from plasma.

Some substances which are normally eliminated through the urine (e.g. urea, creatinine, inorganic phosphate and uric acid) are removed from the body into the dialysis solution. The fluid balance can be maintained through the administration of solutions with different concentrations of glucose, (ultrafiltration).

Metabolic acidosis secondary to end-stage renal failure is counterbalanced by the presence in the solution of lactate which is metabolised to bicarbonate.

5.2 Pharmacokinetic properties

Absorption

Glucose in the dialysate is used as an osmotic agent. It is slowly absorbed, reducing the diffusion gradient between the dialysis solution and the extracellular fluid. Approximately 60% of the dialysate glucose is absorbed within four hours.

Biotransformation

Following absorption glucose is metabolised in order to maintain a stable plasma concentration.

The ultrafiltration is maximal at the beginning of the dwell time, reaching a peak after about two to three hours. Subsequently, there is a progressive loss of ultra-filtrate whose rate depends on the peritoneal permeability.

Lactate is rapidly metabolised to bicarbonate in patients with a normal hepatic function.

Elimination

The transfer of calcium depends on the glucose concentration in the dialysis solution, the effluent volume and the serum ionised calcium. The higher the glucose concentration, effluent volume and serum calcium concentration, the higher is the calcium transfer from the patient to the dialysate.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydrogen carbonate

Sodium hydroxide and hydrochloric acid for pH adjustment 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

2 years.

The product must be used within 24 hours after removal from the overpouch and reconstitution.

6.4 Special precautions for storage

Do not refrigerate or freeze.

For storage conditions after reconstitution of the medicinal product see section 6.3.

6.5 Nature and contents of container

Double chambered bag which contains:

Alkaline lactate solution: Acid glucose-based electrolyte solution = 1:1

An injection site for the administration of other medicinal products is welded on the upper chamber (containing the glucose-based electrolyte solution). A valve system, for connection to a suitable administration set which allows the dialysis operations, is welded on the lower chamber.

Glucothera is packaged in a plastic container-closure system which consists of the following components and materials:

•    One pre-printed double chambered multi-layer co-extruded polyolefin plastic bag of 2500 ml (containing 2000 ml of solution) or 5000 ml (containing 5000 ml of solution);

•    Three multi-layer co-extruded polyolefin plastic port tubes;

•    One medication site (injection site) closure made of polycarbonate with a cap of polypropylene and a septum of polyisoprene.

•    One gamma sterilised access system (administration site closure) made of polycarbonate with a breakable membrane made in low density polyethylene (LDPE) placed at one end;

•    One Luer Lock closure made of polycarbonate and an outer cap of high density polyethylene (HDPE).

The double chambered bag is wrapped into a protective bag. These are made of multi-layer polyolefine foils, latex free.

Pack sizes:

• 4 double chambered bags containing 2000 ml of solution (1000 ml : 1000 ml)

• 2 double chambered bags containing 5000 ml of solution (2500 ml : 2500 ml)

Not all pack sizes may be marketed

6.6 Special precautions for disposal

The medicinal product is a sterile and free from bacterial endotoxins solution for single-patient use only.

Aseptic measures must be used wherever practical throughout the peritoneal dialysis procedure in order to reduce the risk of infection.

Do not remove the unit from the overwrap until ready to use. Do not use if the overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner double chambered bag maintains the sterility of the solution.

After removal of the overwrap, open the breakable seal that divides the chambers (interchamber seal) to mix the two solutions, by squeezing the two chambers together. Mix gently by pushing with both hands on the bag walls.

The solution must be administered within 24 hours after mixing (see also section 6.3).

Check for minute leaks by squeezing the inner double chambered bag firmly. If leaks are found, discard the solution as sterility may be impaired.

Do not administer if the solution is cloudy or contains particulate matter.

The solution must be warmed to body temperature to enhance the patient comfort. However, only dry heat (for example, heating pad, warming plate) must be used. Due to the potential for patient injury or discomfort, the solution must not be heated in water or in a microwave oven.

Do not reconnect partially used product.

Medicinal products such as antibiotics (cephalosporins, penicillins, aminoglycosides, fluoroquinolones, macrolides), insulin and heparin may be added to the solution for peritoneal dialysis through the injection site however precautions have to be taken to avoid any contamination. The proper dose must be prescribed by the physician.

Before administration, the compatibility of the solution for peritoneal dialysis with other medicinal products must be confirmed by checking the absence of any turbidity or particles. The product must be used immediately after any drug addition.

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

Only the following medicinal products may be added up to the mentioned concentration if indicated by the attending physician:

•    heparin 1000 I.U./l

•    insulin 20 I.U./l

•    vancomycin 1000 mg/l

•    teicoplanin 400 mg/l

•    cefazolin 500 mg/l

•    ceftazidime 250 mg/l

•    gentamicin 8 mg/l

After thorough mixing and checking for the absence of any turbidity or particles the peritoneal dialysis solution must be used immediately (no storage).

7 MARKETING AUTHORISATION HOLDER

Glomeria Therapeutics S.r.l.

Via P. U. Frasca, snc,

66100 Chieti Italy

Tel: +39 0871 562276

Fax: +39 0871 571902 E-mail: info@glomeria.com

8    MARKETING AUTHORISATION NUMBER(S)

PL 42388/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/02/2016

10    DATE OF REVISION OF THE TEXT

08/02/2016