Label: information for the user

Biphozyl solution for hemodialysis/hemofiltration

Magnesium chloride (hexahydrate), sodium chloride, sodium bicarbonate, potassium chloride, disodium hydrogen phosphate (dihydrate)

Read this label carefully before starting to use this medication, as it contains important information for you.

• Keep this label, as you may need to refer to it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this label. See section 4.

This medication is a solution for the treatment of dialysis (hemofiltration, hemodialysis, and hemodiafiltration) that is used to eliminate waste products from the blood when the kidneys do not function. This medication is used in hospitals during intensive care treatment with continuous renal replacement therapy (CRRT). This medication is used specifically to treat critically ill patients with acute kidney injury who present:

• normal potassium levels in the blood (normokalemia)
• normal pH levels in the blood
• normal phosphate levels in the blood (normophosphatemia)
• high calcium levels in the blood (hypercalcemia)

This medication may also be used:

• when other sources of bicarbonate are available or when the extracorporeal circuit is anticoagulated with citrate

in cases of intoxication with dialyzable or filterable substances.

No use Biphozyl in case of:

• allergy to any of the active principles or to any of the other components of this medication (listed in section 6)
• low calcium concentration in the blood (hypocalcemia)
• high potassium concentration in the blood (hyperkalemia)
• high phosphate concentration in the blood (hyperphosphatemia)

Warnings and precautions

Warnings

Consult your doctor, pharmacist, or nurse before starting to use Biphozyl.

Biphozyl should not be used in patients with high potassium levels in the blood. Regular monitoring of potassium levels in the blood before and during treatment will be performed.

Biphozyl contains potassium, which may cause high potassium levels in the blood after starting treatment. In this case, your doctor will reduce the infusion rate and ensure that the desired potassium level is reached. If this condition does not improve, your doctor will have to discontinue administration immediately. A potassium-free solution may be used temporarily to restore potassium levels in the blood.

Biphozyl contains phosphate, which may cause high phosphate levels in the blood after starting treatment. In this case, your doctor will reduce the infusion rate and ensure that the desired phosphate level is reached. If this condition does not improve, your doctor will have to discontinue administration immediately.

Biphozyl does not contain glucose, which may cause a decrease in blood glucose levels during treatment. Regular monitoring of blood glucose levels will be performed. If a decrease in blood glucose levels occurs, your doctor may use a glucose solution. Other corrective measures may be necessary to maintain the desired blood glucose level.

Your doctor will periodically monitor the patient's hemodynamic state, as well as the balance of fluids and acid-base and electrolyte balance, including all fluid inputs (intravenous infusion) and outputs (diuresis), even those not directly related to the TCRR treatment.

This medication has a bicarbonate content whose concentration is at the lower end of the normal concentration range in the blood. This is appropriate when using citrate anticoagulation, as citrate is metabolized to bicarbonate, or once normal pH values are restored. It is mandatory to perform an evaluation of the need for a buffer by repeated measurement of the blood acid-base value and review of the general therapy. A solution with a higher bicarbonate content may be necessary.

In case of an abnormally high volume of fluid in the body (hypervolemia), the prescribed net ultrafiltration rate for the TCRR device may be increased and/or the administration rate of solutions apart from the substitution fluid and/or dialysis fluid may be reduced.

In case of an abnormally low volume of fluid in the body (hypovolemia), the prescribed net ultrafiltration rate for the TCRR device may be reduced and/or the administration rate of solutions apart from the substitution fluid and/or dialysis fluid may be increased.

Children

No specific adverse effects are anticipated in children during the use of this medication.

Older adults

No specific adverse effects are anticipated in older adults during the use of this medication.

Use of Biphozyl with other medications

Inform your doctor, pharmacist, or nurse if you are taking, have taken recently, or may need to take any other medication. This is because the concentration of other medications may be reduced during treatment with dialysis. Your doctor will decide if it is necessary to modify the dose of the medications you are taking.

Particularly, inform your doctor if you are taking any of the following:

• phosphate supplements (e.g. nutritional liquids), which may increase the risk of high phosphate levels in the blood (hyperphosphatemia).
• sodium bicarbonate, which may increase the risk of excessive bicarbonate in the blood (metabolic alkalosis).
• citrate used as an anticoagulant, which may reduce calcium levels in the plasma.

Pregnancy, breastfeeding, and fertility

Pregnancy and breastfeeding:

No clinical data are available on the use of this medication during pregnancy and breastfeeding.

This medication should only be administered to pregnant women and breastfeeding women if it is clearly necessary.

Fertility:

No effect on fertility is anticipated, as sodium, potassium, magnesium, chloride, hydrogen phosphate, and bicarbonate are normal components of the body.

Driving and operating machinery

The effect of this medication on the ability to drive or operate machinery is unknown.

For intravenous use and use in hemodialysis. This medication will be used in hospitals and administered exclusively by medical professionals. The volume used and, therefore, the dose of this medication will depend on the patient's condition. The doctor must determine the volume of the dose.

Follow exactly the administration instructions for this medication indicated by your doctor, pharmacist, or nurse. In case of doubt, consult your doctor, pharmacist, or nurse again.

It is the doctor's responsibility to determine the compatibility of an additional medication with this medication by checking for a possible color change and/or precipitation. Before adding a medication, check that it is soluble and stable in this medication.

Dosage

The flow rate interval when used as a substitution solution in hemofiltration and hemodiafiltration is:

Adults:500 - 3000 ml/h

Children <18>1000 to 4000 ml/h/1.73 m2

The flow rate interval when used as a dialysis fluid in continuous hemodialysis and continuous hemodiafiltration are:

Adults:500 - 2500 ml/h

Children <18>1000 to 4000 ml/h/1.73 m2

In adolescents (12 to 18 years old), when it is calculated that the pediatric dose exceeds the maximum adult dose, the recommended adult dose should be used.

Usage Instructions

This medication will be administered in a hospital setting and the doctor will know how to use the product.

To view the usage instructions, consult the end of this prospectus.

If you use more Biphozyl than you should

Immediately contact your doctor or nurse if you have used a quantity of this medication greater than the recommended in this prospectus or as prescribed by your doctor and feel unwell.

The symptoms of overdose are fatigue, edema, and dyspnea (difficulty breathing).

Like all medications, this medication may produce adverse effects, although not everyone will experience them. Your doctor or nurse will regularly monitor your blood tests and clinical status to detect adverse effects. The use of this solution may cause the following adverse effects:

• Changes in blood electrolyte concentrations (electrolyte imbalances) such as: low calcium concentration (hypocalcemia), high potassium concentration (hyperkalemia), and high phosphate concentration (hyperphosphatemia).
• Reduction in plasma bicarbonate concentration (metabolic acidosis)

There are also some adverse effects that may be due to dialysis treatment, for example:

• Abnormally high (hypervolemia) or low (hypovolemia) fluid volume in the body
• Decrease in blood pressure
• Nausea, vomiting
• Muscle cramps

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this prospectus.

You can also report them directly through the Spanish System for Pharmacovigilance of Medicinal Products for Human Use:www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the label and on the packaging. The expiration date is the last day of the month indicated.

No special storage conditions are required.

Do not freeze.

Chemical and physical stability has been demonstrated during the use of the reconstituted solution for 24 hours at +22°C. If not used immediately, storage periods and conditions before use are the responsibility of the user and should not exceed 24 hours, including the duration of treatment.

The solution can be disposed of with wastewater without causing any harm to the environment.

Do not use this medication if you observe damage to the product or particles in the solution. All seals must be intact.

Composition of Biphozyl

The active principles before reconstitution are:

In the small compartment, A (250 ml):

Magnesium chloride (hexahydrate)3.05 g/l

In the large compartment, B (4750 ml):

Sodium chloride7.01 g/l

Sodium bicarbonate2.12 g/l

Potassium chloride0.314 g/l

Dihydrated disodium hydrogen phosphate0.187 g/l

The active principles after reconstitution are:

Reconstituted solution, A+B:

Active principlesmmol/lmEq/l

Sodium, Na+140140

Potassium, K+44

Magnesium, Mg2+0.751.5

Chloride, Cl-122122

Dihydrogen phosphate, HPO42-12

Bicarbonate, HCO3-2222

Theoretical osmolarity: 290 mOsm/l

pH = 7.0 – 8.0

The other components are:

Diluted hydrochloric acid (for pH adjustment) E 507

Water for injection

Carbon dioxide (for pH adjustment) E 290

Aspect of the product and content of the package

This medicine is a solution for hemodialysis/hemofiltration packaged in a bicompartimental bag made of a multi-layer film containing elastomers and polyolefins. The final reconstituted solution is obtained after opening the hermetic seal and mixing the solutions from the small and large compartments. The solution is transparent and colorless.

Each bag contains 5000 ml of solution and the bag is wrapped in a transparent film.

Each box contains two bags and a leaflet.

Marketing authorization holder

Vantive Belgium SRL

Boulevard d´Angleterre 2

1420 Braine-l´Alleud

Belgium

Manufacturer

Bieffe Medital S.P.A.

Via Stelvio, 94

23035 Sondalo (SO)

Italy

This medicine is authorized in the member states of the European Economic Area and in the United Kingdom (Northern Ireland) with the following names:Germany, Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Slovakia, Slovenia, Spain, Estonia, Finland, France, Greece, Netherlands, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Norway, Poland, Portugal, Romania, Sweden,United Kingdom (Northern Ireland): BIPHOZYL. Bulgaria: BIPHOZYL (???????).

You can request more information about this medicine by contacting the local representative of the marketing authorization holder.

Vantive Health, S.L.

C/Pouet de Camilo, 2

46394 Ribarroja del Turia (Valencia)

Spain

Last review date of this leaflet:April 2019

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This information is intended solely for healthcare professionals:

Dosage

The volume and rate at which Biphozyl is administered depend on the concentration of phosphate and other electrolytes in the blood, acid-base balance, fluid balance, and the patient's general clinical condition. The volume of the substitution solution and/or dialysis fluid to be administered also depends on the intensity (dose) of the desired treatment. The administration schedule (dose, perfusion rate, and accumulated volume) of Biphozyl should only be determined by an experienced intensive care physician and renal replacement therapy (RRT) specialist.

The flow rate interval when used as a substitution solution in hemofiltration and

hemodiafiltration is:

Adults:500 - 3000 ml/h

The flow rate interval when used as a dialysis fluid in continuous hemodialysis and continuous hemodiafiltration is:

Adults:500 - 2500 ml/h

The total combined flow rate usually used for RRT (dialysis fluid and substitution solutions) in adults is approximately 2000 ml/h to 2500 ml/h, corresponding to an approximate daily fluid volume of 48 to 60 L.

Pediatric population

In the case of children, from neonates to adolescents up to 18 years, the flow rate interval when used as a substitution solution in hemofiltration and hemodiafiltration and as a dialysis solution (dialysis fluid) in continuous hemodialysis and continuous hemodiafiltration is between 1000 and 4000 ml/h/1.73 m2.

In adolescents (12 to 18 years), when the pediatric dose exceeds the adult maximum dose, the recommended adult dose should be used.

Older adults

Adults over 65 years: The evidence from studies and clinical experience suggests that use in the elderly population is not associated with differences in safety or efficacy.

Overdose

Symptoms of overdose

Biphozyl overdose can cause severe clinical situations, such as congestive heart failure or electrolyte or acid-base balance disturbances.

Treatment of overdose

• Hypervolemia or hypovolemia:

In case of hypervolemia or hypovolemia, follow the instructions for hypervolemia or hypovolemia management (section 2) carefully.

• Metabolic acidosis

In case of metabolic acidosis and/or hyperphosphatemia resulting from an overdose, discontinue administration immediately. There is no specific antidote for overdose. The risk can be minimized by closely monitoring the patient during treatment.

Preparation and/or handling

The solution from the small compartment is added to the solution from the large compartment after breaking the peelable seal and immediately before use.The reconstituted solution should be transparent and colorless.

Use aseptic technique throughout the administration process to the patient.

Only use if the packaging is intact, the seals are intact, the peelable seal is not broken, and the solution is transparent. Squeeze the bag to ensure there are no leaks. If a leak is detected, discard the solution immediately, as its sterility cannot be guaranteed.

The large compartment has an injection port through which the necessary medications can be added once the solution is reconstituted. It is the responsibility of the physician to judge the compatibility of the added medication with Biphozyl by checking for any possible color change and/or precipitation, insoluble complexes, or crystals. Before adding a medication, check that it is soluble and stable in this medication and that the pH interval of Biphozyl is suitable (the pH interval of the reconstituted solution is 7.0–8.0).

Admixtures may not be compatible.Consult the instructions for use of the medication to be added.

Mix the solution well after introducing any additives. The introduction and mixing of additives should always be done before connecting the solution bag to the extracorporeal circuit.

IBreak the seal by holding the small compartment between your hands and squeezing until an opening is made in the hermetic seal that separates the two compartments (see figure I below).

IIPress the large compartment with both hands until the hermetic seal between the two compartments is completely open (see figure II below).

IIIEnsure the solutions are mixed thoroughly by gently agitating the bag. The solution is now ready for use, and the bag can be hung on the equipment (see figure III below).

IVThe dialysis or substitution fluid line can be connected to either of the two access ports.

IVaIf a luer connector is used, remove the cap by turning and pulling it, and connect the male luer of the dialysis or substitution fluid line to the female luer of the bag by a pressure and twisting motion. Ensure the connection is properly placed and tightened. Now the connector is open. Check that the fluid flows freely (see figure IV.a below).

When the dialysis or substitution fluid line is disconnected from the luer connector, the connector will close, and the solution will stop flowing. The luer port is a disinfected port with an alcohol swab and without a needle.

IVbIf a needle connector (or spike connector) is used, remove the cap first. The injection port can be disinfected. Insert the needle through the rubber wall. Check that the fluid flows freely (see figure IV.b below).

The reconstituted solution is for single use only. Discard the solution that is not used. The solution can be disposed of with wastewater without causing any harm to the environment.