PHOXILIUM 1.2 MMOL/L PHOSPHATE SOLUTION FOR HAEMODIALYSIS/ HAEMOFILTRATION - summary of medicine characteristics

PHOXILIUM 1.2 mmol/l phosphate Solution for haemodialysis/ haemofiltration

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Phoxilium is presented in a two-compartment bag. The final reconstituted solution is obtained after breaking the frangible pin or the peel seal and mixing both solutions.

1000 ml of solution in the small compartment (A) contains:

Calcium chloride, 2 H2O           3.68 g

Magnesium chloride, 6 H2O        2.44 g

1000 ml of solution in the large compartment (B) contains:

Sodium chloride                         ­6.44 g

Sodium hydrogen carbonate        2.92 g

Potassium chloride                       ­0.314 g

Disodium phosphate, 2 H2O        0.225 g

1000 ml of the reconstituted solution contains:

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for haemodialysis/ haemofiltration.

Clear and colourless solutions.

Theoretical osmolarity: 293 mOsm/l

pH of the reconstituted solution: 7.0 – 8.5

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Phoxilium is used for CRRT (continuous renal replacement therapy) in critically ill patients with ARF (acute renal failure) when pH and kalaemia have been restored to normal and when the patients need phosphate supplementation for loss of phosphate in the ultrafiltrate or to the dialysate during CRRT.

Phoxilium may also be used in cases of drug poisoning or intoxications when the poisons are dialysable or pass through the membrane.

Phoxilium is indicated for use in patients with normal kalaemia and normal or hypophosphataemia.

4.2 Posology and method of administration

Posology:

The volume and rate at which Phoxilium is administered depends on the blood concentration of phosphate and other electrolytes, acid-base balance, fluid balance and overall clinical condition of the patient. The volume of replacement solution and/or dialysate to be administered will also depend on the desired intensity (dose) of the treatment. Administration (dose, infusion rate and cumulative volume) of Phoxilium should only be established by a physician experienced in critical care medicine and CRRT (Continuous Renal Replacement Therapy).

The dose volume is therefore at the discretion and prescription of the responsible physician.

The range of flow rates for the replacement solution in haemofiltration and haemodiafiltra­tion are:

Adult: 500 – 3000 ml/hour

The range of flow rates for the dialysate in continuous haemodialysis and continuous haemodiafiltra­tion are:

Adult: 500 – 2500 ml/hour

Commonly used combined total flow rates for CRRT (dialysate and replacement solutions) in adults are approximately 2000 to 2500 ml/h which correspond to a daily fluid volume of approximately 48 to 60 l.

Paediatric population:

In children from neonates to adolescents to 18 years, the range of flow rates used as substitution solution in haemofiltration and haemodiafiltration and as dialysis solution (dialysate) in continuous haemodialysis and continuous haemodiafiltration are 1000 to 4000 ml/h/1.73 m2.

For adolescents (12–18 years), the adult dose recommendation should be used when the paediatric dose is calculated to exceed the maximum adult dose.

Method of administration:

Intravenous use and for haemodialysis.

Phoxilium, when used as a replacement solution is administered into the extracorporeal circuit before (pre-dilution) or after the haemofilter or haemodiafilter (post-dilution).

Phoxilium, when used as a dialysate, it is administered in the dialysate compartment of the extracorporeal filter separated from the blood flow by a semipermeable membrane.

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

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Solution dependent contraindications

Hyperkalaemia

Metabolic alkalosis

Hyperphosphataemia

Haemofiltration/- dialysis dependent contraindications

Renal failure with pronounced hypercatabolism, if the uraemic symptoms cannot be corrected with haemofiltration or haemodiafiltration,

Insufficient arterial pressure in the vascular access,

Systemic anticoagulation if there is a high risk of haemorrhage.

4.4 Special warnings and precautions for use

The solution shall be used only by, or under the direction of, a physician competent in CRRT treatments using haemofiltration, haemodiafiltration and haemodialysis.

Warnings:

Phoxilium should not be used in patients with hyperkalemia (see section 4.3). The serum potassium concentration must be monitored before and during haemofiltration and/or haemodialysis.

Because Phoxilium is a potassium-containing solution, hyperkalaemia may occur transiently after treatment is initiated. Decrease the infusion rate and confirm that the desired potassium concentration is achieved. If hyperkalaemia does not resolve, stop administration promptly.

If hyperkalaemia develops when Phoxilium is used as a dialysate, administration of a potassium-free dialysate may be necessary to increase the rate of potassium removal.

Because Phoxilium is a phosphate-containing solution, hyperphosphatemia may occur transiently after treatment is initiated. Decrease the infusion rate and confirm that the desired phosphate concentration is achieved. If hyperphosphatemia does not resolve, stop administration promptly (See Section 4.3 Contraindi­cation).

Electrolyte and blood acid/base parameters should be monitored regularly in patients treated with Phoxilium. Phoxilium contains hydrogen phosphate, a weak acid that can influence the patient’s acid/base balance. If metabolic acidosis develops or worsens during therapy with Phoxilium, the infusion rate may need to be decreased or its administration stopped.

Because Phoxilium contains no glucose, administration may lead to hypoglycaemia. Blood glucose levels should be monitored regularly in diabetic patients (including careful consideration of patients receiving insulin or other glucose lowering medications), but also considered in non-diabetic patients, e.g. risk for silent hypoglycemia during the procedure. If hypoglycaemia develops, use of a glucose-containing solution should be considered. Other corrective measures may be necessary to maintain desired glycaemic control.

The instructions for use (see section 6.6) must be strictly followed.

The solutions in the two compartments must be mixed before use.

Use of a contaminated solution may cause sepsis and shock

Do not administer the solution unless it is clear. Aseptic technique must be used during connection / disconnection of the line sets to the Phoxilium container.

Use only with an appropriate extracorporal renal replacement equipment.

Special precautions for use:

Phoxilium may be warmed to 37 °C to enhance patient comfort. Warming of the solution prior to use should be done before reconstitution with dry heat only. Solutions should not be heated in water or in a microwave oven. Phoxilium should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless the solution is clear and the seal is intact.

Haemodynamic status, fluid balance, electrolyte and acid-base balance shall be closely monitored throughout the procedure including all fluid inputs and outputs, even those not directly related to CRRT.

In case of hypervolaemia, the net ultrafiltration rate prescribed for the CRRT device can be increased and/or the rate of administration of solutions other than replacement fluid and/or dialysate can be reduced.

In case of hypovolaemia, the net ultrafiltration rate prescribed for the CRRT device can be reduced and/or the rate of administration of solutions other than replacement fluid and/or dialysate can be increased.

4.5 Interaction with other medicinal products and other forms of interaction

The blood concentration of filterable/di­alysable drugs may be reduced during treatment due to their removal by the haemodialyser, haemofilter or haemodiafilter. Corresponding corrective therapy should be instituted if necessary to establish the correct doses for drugs removed during the treatment.

Interactions with other medications can be avoided by correct dosage of the solution for haemofiltration and haemodialysis.

The following are examples of potential drug interactions with Phoxilium:

Additional sources of phosphate (e.g., hyperalimentation fluid) may influence serum phosphate concentration and may increase the risk of hyperphosphatemia,

Vitamin D and other vitamin D analogues, as well as medicinal products containing calcium (e.g. calcium chloride or calcium gluconate used for maintenance of calcium homeostasis in CRRT patients receiving citrate anticoagulation) can increase the risk of hypercalcaemia,

Additional sodium bicarbonate (or buffer source) contained in the CRRT fluids or in other fluids may increase the risk of metabolic alkalosis.

When citrate is used as an anticoagulant, it contributes to the overall buffer load and can reduce plasma calcium levels.

4.6 Fertility, pregnancy and lactation

Fertility

No effects on fertility are anticipated, since calcium, sodium, potassium, magnesium, chloride, hydrogen phosphate and hydrogen carbonate are normal constituents of the body.

Pregnancy and lactation

There are no documented clinical data on the use of Phoxilium during pregnancy and lactation. Phoxilium should only be administered to pregnant and lactating women if clearly needed.

4.7 Effects on ability to drive and use machines

Not relevant

4.8 Undesirable effects

Undesirable effects can result from the solution used or the treatment.

Bicarbonate-buffered haemofiltration and haemodialysis solutions are generally well tolerated.

The following undesirable effects have been reported from post-marketing experience. The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies cannot be estimated from the available data.

* undesirable effects related generally to dialysis treatments.

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

Overdose with Phoxilium should not occur if the procedure is carried out correctly and the fluid balance, electrolyte and acid-base balance of the patient is carefully monitored by trained medical personnel.

However, Phoxilium overdose can lead to severe clinical conditions, such as congestive heart failure, electrolyte or acid-base disturbances.

If hypervolaemia or hypovolaemia occur, instruction for handling of hypervolaemia or hypovolaemia in section 4.4 must be strictly followed.

If metabolic acidosis and/or hyperphosphatemia occur, stop administration promptly.

There is no specific antidote for overdose. The risk can be minimized by close monitoring during treatment (see section 4.3 and 4.4).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hemofiltrates.

ATC code: B05ZB

Phoxilium, solution for haemofiltration and haemodialysis, is pharmacologically inactive. The sodium, calcium, magnesium, potassium, phosphate and chloride ions are present at concentrations similar to physiological concentrations in normal plasma.

Phoxilium is used to replace water and electrolytes removed during haemofiltration and haemodiafiltration or to serve as a suitable dialysate for use during continuous haemodiafiltration or continuous haemodialysis.

Hydrogen carbonate is used as an alkalising buffer.

5.2 Pharmacokinetic properties

Not relevant.

The active ingredients in Phoxilium are pharmacologically inactive and are present at concentrations similar to physiological plasma concentrations.

5.3 Preclinical safety data

No relevant data from preclinical findings. The active ingredients are pharmacologically inactive and are present at concentrations similar to physiological plasma levels.

6.1 List of excipients

Small compartment A: Water for injections

Hydrochloric acid (for pH adjustment)

Large compartment B: Water for injections

Carbon dioxide (for pH adjustment)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3

18 months

After reconstitution:

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at 22oC. If not used immediately in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours including the duration of the treatment.

6.4 Special precautions for storage

Store between +4 °C – +30°C. Do not refrigerate or freeze.

For the storage condition of the reconstituted solution, see section 6.3.

6.5 Nature and contents of container

The container made in polyvinyl chloride (PVC) or polyolefin is a two-compartment bag. The 5000 ml bag is comprised of a small compartment (250 ml) and a large compartment (4750 ml). The two compartments are separated by a frangible pin or a peel seal.

The large compartment B is fitted with an injection connector (or spike connector) made of polycarbonate (PC), which is closed with a rubber disc covered by a cap as well as a luer connector (PC) with a frangible pin (PC) or a valve made of silicone rubber for the connection of the bag with a suitable replacement solution line or dialysis line.

The bag is over wrapped with a transparent overwrap made of a multilayer polymer film.

Each two-compartment bag contains 5000 ml.

Package size: 2 × 5000 ml in a box.

6.6 Special precautions for disposal