BIPHOZYL SOLUTION FOR HEMODIALYSIS/HEMOFILTRATION

2. What you need to know before you use Biphozyl

Do not use Biphozyl if:

• you are allergic to any of the active substances or to any of the other ingredients of this medicine (listed in section 6)
• you have a low calcium level in the blood (hypocalcaemia)
• you have a high potassium level in the blood (hyperpotasemia)
• you have a high phosphate level in the blood (hyperphosphataemia)

Warnings and precautions

Warnings

Consult your doctor, pharmacist or nurse before you start using Biphozyl.

Biphozyl should not be used in patients with a high potassium level in the blood. Your potassium level in the blood will be regularly monitored before and during treatment.

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

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

The doctor will periodically monitor the electrolytes and acid-base parameters in the blood of patients treated with Biphozyl. Biphozyl contains bicarbonate, a weak acid that may affect your acid-base balance. If a reduction in plasma bicarbonate or worsening occurs during treatment with Biphozyl, the doctor will reduce the perfusion rate. If this condition does not improve, the doctor will have to discontinue administration immediately.

Instructions for use must be strictly followed.

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

Use only with a CRRT dialysis device.

Use only if the packaging and the solution bag are in perfect condition. All seals must be intact. The use of a contaminated solution can cause sepsis and shock.

Use the product only with suitable extracorporeal renal replacement equipment.

Precautions

This medicine does not contain calcium and may cause hypocalcaemia. Calcium perfusion may be necessary.

To increase patient comfort, Biphozyl can be warmed up to 37°C. Pre-warming before use of the solution should be done before reconstitution using only dry heat. The solutions should not be heated in water or in a microwave oven. Before administration, it should be visually checked that Biphozyl does not contain particles or has lost its original colour. Do not administer the solution unless it is transparent and the seal is intact.

The doctor will carefully monitor the patient's haemodynamic status, as well as fluid and acid-base and electrolyte balance, including all fluid inputs (intravenous perfusion) and outputs (diuresis), even those not directly related to CRRT treatment.

This medicine has a bicarbonate content whose concentration is at the lower end of the normal concentration range in the blood. This is suitable when citrate anticoagulation is used, as citrate is metabolised to bicarbonate, or once normal pH values are restored. It is mandatory to perform a buffer needs assessment by repeatedly measuring the acid-base value of the blood and reviewing the therapy in general. A solution with a higher bicarbonate content may be necessary.

In case of abnormally high fluid volume in the body (hypervolaemia), the prescribed net ultrafiltration rate for the CRRT device can be increased and/or the administration rate of solutions other than replacement fluid and/or dialysis fluid can be reduced.

In case of abnormally low fluid volume in the body (hypovolaemia), the prescribed net ultrafiltration rate for the CRRT device can be reduced and/or the administration rate of solutions other than replacement fluid and/or dialysis fluid can be increased.

Children

No specific adverse effects are expected in children during the use of this medicine.

Elderly

No specific adverse effects are expected in elderly patients during the use of this medicine.

Using Biphozyl with other medicines

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

In particular, tell 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 (hyperphosphataemia).
• Sodium bicarbonate, which may increase the risk of excess bicarbonate in the blood (metabolic alkalosis).
• Citrate used as an anticoagulant, which may reduce calcium levels in the plasma.

Pregnancy, breast-feeding and fertility

Pregnancy and breast-feeding:

There are no clinical data on the use of this medicine during pregnancy and breast-feeding.

This medicine should only be administered to pregnant and breast-feeding women if clearly necessary.

Fertility:

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

Driving and using machines

It is not known whether this medicine affects the ability to drive or use machines.

3. How to use Biphozyl

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

Follow exactly the administration instructions of this medicine given by your doctor, pharmacist or nurse. If you are in doubt, consult your doctor, pharmacist or nurse again.

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

Posology

The flow rate range when used as a replacement solution in haemofiltration and haemodiafiltration is:

Adults: 500 - 3000 ml/h

Children <18 years of age: 1000 to 4000 ml h 1.73 m2< p>

The flow rate range when used as dialysis fluid in continuous haemodialysis and continuous haemodiafiltration is:

Adults: 500 - 2500 ml/h

Children <18 years of age: 1000 to 4000 ml h 1.73 m2< p>

In adolescents (12 to 18 years), when the calculated paediatric dose exceeds the maximum dose for adults, the recommended dose for adults should be used.

Instructions for use

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

To see the instructions for use, refer to the end of this leaflet.

If you use more Biphozyl than you should

Contact your doctor or nurse immediately if you have used a larger amount of this medicine than recommended in this leaflet or prescribed by your doctor and you feel unwell.

Symptoms of overdose are fatigue, oedema and dyspnoea (difficulty breathing).

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Your doctor or nurse will regularly monitor your blood tests and clinical status to detect side effects. The use of this solution may cause the following side effects:

• Changes in salt concentrations in the blood (electrolyte imbalances) such as: low calcium levels (hypocalcaemia), high potassium levels (hyperpotasemia) and high phosphate levels (hyperphosphataemia).
• Reduction of bicarbonate concentration in plasma (metabolic acidosis)

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

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

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist or nurse, even if it is possible side effects not listed in this leaflet.

You can also report side effects directly to the Spanish Medicines Agency: www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storing Biphozyl

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

Do not use this medicine after the expiry date which is stated on the label and on the carton. The expiry date is the last day of the month stated.

No special storage conditions are required.

Do not freeze.

Chemical and physical stability of the reconstituted solution has been demonstrated for 24 hours at +22°C. If not used immediately, storage times 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 harm to the environment.

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

6. Container Contents and Additional Information

Biphozyl Composition

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 chloride 7.01 g/l

Sodium bicarbonate 2.12 g/l

Potassium chloride 0.314 g/l

Disodium hydrogen phosphate (dihydrate) 0.187 g/l

The active principles after reconstitution are:

Reconstituted solution, A+B:

Active principles mmol/l mEq/l

Sodium, Na+ 140 140

Potassium, K+ 4 4

Magnesium, Mg2+ 0.75 1.5

Chloride, Cl- 122 122

Hydrogen phosphate, HPO4 2- 1 2

Bicarbonate, HCO3- 22 22

Theoretical osmolality: 290 mOsm/l

pH = 7.0 – 8.0

The other components are:

Diluted hydrochloric acid (for pH adjustment) E 507

Water for injectable preparations

Carbon dioxide (for pH adjustment) E 290

Product Appearance and Container Contents

This medication is a solution for hemodialysis/hemofiltration packaged in a two-compartment bag made of a multilayer film containing elastomers and polyolefins. The final reconstituted solution is obtained after breaking 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 medication is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under 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 (БИПХОЗИЛ).

You can request more information about this medication 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

Date of the last revision of this leaflet:April 2019

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This information is intended only 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 overall clinical condition. The volume of the substitution solution and/or dialysis fluid to be administered will also depend on the intensity (dose) of the desired treatment. The administration schedule (dose, perfusion rate, and cumulative volume) of Biphozyl should only be determined by a physician with experience in intensive medicine and CRRT (continuous renal replacement therapy).

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

hemodiafiltration is:

Adults: 500 - 3000 ml/h

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

Adults: 500 - 2500 ml/h

The total combined flow rate commonly used for CRRT (dialysis fluid and substitution solutions) in adults is approximately 2000 ml/h to 2500 ml/h, which corresponds to a daily fluid volume of approximately 48 to 60 L.

Pediatric population

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

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

Elderly

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

Overdose symptoms

Overdose of Biphozyl can cause serious clinical situations, such as congestive heart failure or alterations in electrolyte or acid-base balance.

Overdose treatment

• Hyperolemia or hypovolemia:

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

• Metabolic acidosis

In case of metabolic acidosis and/or hyperphosphatemia derived from an overdose, suspend administration immediately. There is no specific antidote for overdose. The risk can be minimized if closely monitored 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 must be transparent and colorless.

Aseptic technique should be used throughout the administration process to the patient.

Use only 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 found, discard the solution immediately as its sterility cannot be guaranteed.

The large compartment has an injection port through which necessary medications can be added once the solution is reconstituted. It is the physician's responsibility to judge the compatibility of the added medication with the Biphozyl solution 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 range of Biphozyl is suitable (the pH range of the reconstituted solution is 7.0–8.0).

Additives may not be compatible. The instructions for use of the medication to be added should be consulted.

Mix the solution well after introducing any additive. 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 the two 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 fully open (see figure II below).

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

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

IVaIf the luer connector is used, remove the cap by twisting and pulling it, and connect the male luer of the dialysis fluid or substitution line to the female luer connector of the bag by a push-and-twist movement. Ensure that the connection is properly placed and tightened. The connector is now open. Check that the fluid circulates freely (see figure IV.a below).

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

IVbIf the injection connector (or spike connector) is used, remove the cap beforehand by lifting it. The injection port can be disinfected. Then, insert the spike through the rubber wall. Check that the fluid circulates freely (see figure IV.b below).

The reconstituted solution is for single use. Unused solution should be discarded. The solution can be discarded with wastewater without causing any harm to the environment.