Biphozyl

Patient Information Leaflet: Information for the User

Biphozyl, solution for haemodialysis/haemofiltration
Combination product
Please read all of this leaflet carefully before using this medicine, because it contains
important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor, pharmacist or nurse.
• If you experience any side effects, including any side effects not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Leaflet Contents

1. What Biphozyl is and what it is used for
2. Important information before using Biphozyl
3. How to use Biphozyl
4. Possible side effects
5. How to store Biphozyl
6. Contents of the pack and other information

1. What Biphozyl is and what it is used for

Biphozyl is a solution for dialysis therapy (haemofiltration, haemodialysis and haemodiafiltration) used to remove metabolic waste products from the blood when the kidneys are not functioning properly. This medicine is used in hospital settings as part of intensive therapy using continuous renal replacement therapy (CRRT). Specifically, this medicine is used in critically ill patients with acute kidney injury, in whom:

• blood potassium levels are normal,
• blood pH is normal,
• blood phosphate levels are normal,
• blood calcium levels are high (hypercalcaemia).

This medicine may also be used:

• when other sources of bicarbonates are available or when the extracorporeal circuit is anticoagulated with citrate,
• in cases of poisoning with drugs or substances that are dialysable or filterable.

2. Important information before using Biphozyl

Do not use Biphozyl if:

• you are allergic to one of the active substances or to any of the other ingredients of this medicine (listed in section 6),
• you have low levels of calcium in the blood (hypocalcaemia),
• you have high levels of potassium in the blood (hyperkalaemia),
• you have high levels of phosphate in the blood (hyperphosphataemia).

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Warnings and precautions
Warnings
Before starting treatment with Biphozyl, discuss this with your doctor, pharmacist, or nurse.
Biphozyl must not be used in patients with high levels of potassium in the blood. The patient's potassium level will be monitored regularly before and during treatment.
Since Biphozyl contains potassium, high levels of potassium in the blood may occur temporarily after starting treatment. The doctor will reduce the infusion rate until the appropriate potassium level is achieved. If normal levels are not restored, the doctor will have to discontinue administration of the medicine immediately. A potassium-free solution may be administered temporarily to restore appropriate potassium levels.
Since Biphozyl contains phosphates, high levels of phosphate in the blood may occur temporarily after starting treatment. The doctor will reduce the infusion rate until the appropriate phosphate level is achieved. If normal levels are not restored, the doctor will have to discontinue administration of the medicine immediately.
Since Biphozyl does not contain glucose, low blood glucose levels may occur during treatment. Blood glucose levels will be monitored regularly. If low blood glucose levels occur, the doctor may administer a glucose-containing solution. Other corrective measures may also be necessary to maintain appropriate blood glucose levels.
For patients receiving Biphozyl, the doctor will regularly monitor electrolytes and blood acidity/alkalinity (acid-base balance). Biphozyl contains dihydrogen phosphate, a weak acid, which may affect the patient's acid-base balance. If during Biphozyl therapy the plasma bicarbonate concentration decreases or this condition worsens, the doctor will reduce the infusion rate. If normal status is not restored, the doctor will have to discontinue administration of the medicine immediately.
Strictly follow the instructions for use.
Before use, mix together the solutions contained in the two chambers.
Use exclusively with a dialysis machine for continuous renal replacement therapy (CRRT).
Use only if the outer packaging and the solution bag are undamaged.
All seals must be intact. Using a contaminated solution may lead to sepsis and shock.
Use only with appropriate extracorporeal devices for extrarenal replacement therapy.
Precautions
This medicine does not contain calcium and may cause hypocalcaemia. Calcium infusion may be necessary.
To increase patient comfort, Biphozyl may be warmed to +37°C. Warming the solution before use should be performed before reconstitution and only using a dry heat source. Do not warm the solutions in water or in a microwave oven. Before administration, visually inspect Biphozyl for the presence of particulate matter and discoloration. Do not administer if the solution is not clear or if the seal is damaged.
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During the procedure, the doctor will closely monitor the patient's hemodynamic status, fluid balance, and electrolyte and acid-base balance, including volumes of fluids administered (intravenous infusions) and removed (urine output), even those not directly related to CRRT.
The medicine contains bicarbonate in an amount corresponding to the lower limit of the normal blood concentration range. This amount is appropriate when citrate anticoagulation is used, since citrate is metabolized to bicarbonate, or when normal pH values are restored. Assessment of the need for buffering substances based on repeated measurements of blood acidity/alkalinity and overall therapy analysis is essential. Administration of a solution with a higher bicarbonate content may be necessary.
In case of excessive fluid volume in the body (hypervolemia), the net ultrafiltration rate in the CRRT machine may be increased and/or the infusion rate of fluids other than replacement fluid and/or dialysate may be decreased.
In case of insufficient fluid volume in the body (hypovolemia), the net ultrafiltration rate in the CRRT machine may be decreased and/or the infusion rate of fluids other than replacement fluid and/or dialysate may be increased.
Children
No specific adverse effects are expected when this medicine is used in children.
Elderly patients
No specific adverse effects are expected when this medicine is used in elderly patients.
Biphozyl with other medicines
Inform your doctor, pharmacist, or nurse about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take. This includes medicines obtained without a prescription. This is because the levels of other medicines may be reduced due to removal by dialysis. The doctor will decide whether any dosage adjustments of the patient's medicines are necessary.
In particular, inform the doctor about the use of:

• Additional sources of phosphates (e.g. parenteral nutrition fluids), as they may increase the risk of high phosphate levels in the blood ( hyperphosphataemia ).
• Sodium bicarbonate, as it may increase the risk of excessive bicarbonate levels in the patient's blood ( metabolic alkalosis ).
• Citrate as an anticoagulant, as it may reduce calcium levels in plasma.

Pregnancy, breastfeeding and fertility
Pregnancy and breastfeeding:
There are no documented clinical data on the use of this medicine during pregnancy and lactation. This medicine should be administered to women during pregnancy and lactation only if clearly needed.
Fertility:
No effect of the medicine on fertility is expected, since sodium, potassium, magnesium, chlorides, dihydrogen phosphates and bicarbonates are normal components of the body.
Driving and operating machinery
It is unknown whether this medicine affects the ability to drive and operate machinery.
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3. How to use Biphozyl

Intravenous administration and use in hemodialysis. This medicinal product is intended for use in
hospitals and must be administered exclusively by healthcare professionals. The volume administered, and
thus the dose of the medicine, depends on the patient's condition. The dose volume will be determined by the
physician. This medicine should always be used exactly as directed by the physician, pharmacist, or nurse. In
case of doubt, consult the physician, pharmacist, or nurse.
The physician is responsible for determining the compatibility of additional medicinal products with this
medicine by checking the solution for possible changes in colour and/or precipitation. Before adding another
medicinal product, its solubility and stability in this medicine should be verified.
Dosage
Flow rate range when used as a substitution fluid in hemofiltration and hemodiafiltration:
Adults: 500–3000 ml/hour.
Children < 18 years: 1000 to 4000 ml/hour/1.73 m²
Flow rate range when used as a dialysate in continuous hemodialysis and continuous hemodiafiltration:
Adults: 500–2500 ml/hour.
Children < 18 years: 1000 to 4000 ml/hour/1.73 m²
In adolescents (12–18 years) if the calculated paediatric dose exceeds the maximum adult dose, the adult
recommended dose should be applied.
Instructions for use
This medicine will be administered to the patient in a hospital setting. The physician is familiar with the method of administration. Instructions for use are provided at the end of this leaflet.
Use of a higher than recommended dose of Biphozyl
If the patient feels unwell after receiving a dose of Biphozyl higher than recommended in this package leaflet or prescribed by the physician, seek immediate medical advice from a physician or nurse.
Symptoms of overdose include fatigue, oedema, or dyspnoea.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
Your doctor or nurse will regularly perform blood tests and monitor your clinical condition
to detect any potential adverse reactions. The use of this solution
may cause the following reactions (occurring at an unknown frequency, i.e. frequency cannot be
determined from available data):

• changes in blood electrolyte concentrations (electrolyte imbalance), such as low calcium levels (hypocalcemia), high potassium levels (hyperkalemia), and high phosphate levels (hyperphosphatemia);
• decreased plasma bicarbonate concentration (metabolic acidosis).

Dialysis treatment may also cause certain adverse reactions, such as:

• excessive (hypervolemia) or insufficient (hypovolemia) fluid volume in the body;
• low blood pressure;

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• nausea, vomiting;
• muscle cramps.

Reporting of adverse reactions
If any adverse symptoms occur, including any adverse symptoms not listed
in this leaflet, inform your doctor, pharmacist, or nurse.
Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
By reporting adverse reactions, additional information on the safety of this medicine can be collected.

5. How to store Biphozyl

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and packaging.
The expiry date refers to the last day of the stated month.
No special storage instructions apply.
Do not freeze.
It has been demonstrated that, during use, the reconstituted solution remains chemically and physically stable for 24 hours at +22°C. If the solution is not used immediately, it is the user's responsibility to determine the conditions and duration of storage prior to use; however, the storage period should not exceed 24 hours, including the duration of administration.
The solution may be disposed of into the sewage system without hazard to the natural environment.
Do not use this medicine if damage to the product or the presence of particulate matter in the solution is observed. All seals must be intact.

6. Contents of the pack and other information

What Biphozyl contains
Before reconstitution
Small chamber A (250 ml):
Magnesium chloride hexahydrate 3.05 g/l
Large chamber B (4750 ml):
Sodium chloride 7.01 g/l
Sodium bicarbonate 2.12 g/l
Potassium chloride 0.314 g/l
Disodium phosphate dihydrate 0.187 g/l
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After reconstitution
ready-to-use solution, A+B:
Active substances mmol/l mEq/l
Sodium cations, Na 140 140
Potassium cations, K 4 4
Magnesium cations, Mg 0.75 1.5
Chloride anions, Cl 122 122
Hydrogen phosphate anions, HPO 1 2
Bicarbonate anions, HCO 22 22
Theoretical osmolarity: 290 mOsm/l
pH = 7.0–8.0
Other ingredients are:
Hydrochloric acid, diluted (for pH adjustment) E 507
Water for injections
Carbon dioxide (for pH adjustment) E 290
What Biphozyl looks like and contents of the pack
This medicine is a solution for haemodialysis/haemofiltration supplied in a dual-chamber bag made
of multilayer film containing polyolefins and elastomers. The final solution is obtained by opening the frangible seal and mixing the solutions contained in the large and small chambers. The solution is clear and colourless.
Each bag contains 5000 ml of solution and is wrapped in transparent film.
Each carton contains two bags and one patient leaflet.
Marketing Authorisation 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 medicinal product is authorised for marketing in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom (Northern Ireland): BIPHOZYL
Bulgaria: BIPHOZYL (Bifhozyl)

Information intended exclusively for healthcare professionals:

Dosage
The volume and rate of administration of the medicinal product Biphozyl depend on blood phosphate and other electrolyte concentrations, acid-base balance, fluid balance, and the patient's overall clinical condition. The volume of replacement solution and/or dialysate to be administered will also depend on the desired intensity of treatment (dose).
The method of administration (dose, infusion rate, and total volume) of the medicinal product Biphozyl must be determined solely by a physician experienced in intensive care and continuous renal replacement therapy (CRRT).

Flow rate range when used as replacement fluid in hemofiltration and hemodiafiltration:
Adults: 500–3000 mL/hour

Flow rate range when used as dialysate in continuous hemodialysis and continuous hemodiafiltration:
Adults: 500–2500 mL/hour

In adults, a total flow rate during CRRT (dialysate and replacement fluids) of approximately 2000 to 2500 mL/hour is commonly used, corresponding to a daily fluid volume ranging from about 48 to 60 L.

Children and adolescents
In children, from neonates to adolescents up to 18 years of age, the flow rate range when used as replacement fluid in hemofiltration and hemodiafiltration, or as dialysis solution (dialysate) in continuous hemodialysis and continuous hemodiafiltration, is 1000 to 4000 mL/hour/1.73 m².
If the calculated pediatric dose exceeds the maximum adult dose in adolescents (12–18 years), the recommended adult dose should be applied.

Elderly patients
Adults over 65 years of age: clinical trial data and clinical experience indicate that use of the product in elderly patients does not affect safety or efficacy.

Overdose
Symptoms of overdose
Overdose of the medicinal product Biphozyl may lead to severe clinical manifestations such as congestive heart failure, electrolyte disturbances, or acid-base imbalances.

Management in case of overdose

• Hypervolemia/hypovolemia: In case of hypervolemia or hypovolemia, strictly follow the management instructions provided in section 2 Warnings.
• Metabolic acidosis: If metabolic acidosis and/or hyperphosphatemia occurs as a result of overdose, administration of the product should be immediately discontinued. There is no specific antidote for overdose of this product. However, the risk can be minimized by close monitoring during treatment.

Preparation and/or use
The solution from the small chamber is added to the solution in the large chamber by opening the peelable seal immediately before use. The reconstituted solution should be clear and colorless.
Throughout the entire administration process of the medicinal product to the patient, aseptic technique must be used.
Use only if the outer protective packaging is undamaged, all seals are intact, the peelable seal is not damaged, and the solution is clear. Squeeze the bag firmly to check for leaks. If leakage is observed, the solution must be immediately discarded, as sterility cannot be guaranteed.

The large chamber is equipped with an injection port, which allows the addition of other necessary medicinal products after reconstitution of the solution. The user is responsible for verifying compatibility of the added medicinal product with Biphozyl by checking for any color change and/or precipitation, presence of insoluble complexes, or crystals. Before adding any medicinal product, ensure that it is soluble and stable in Biphozyl and that the pH range of Biphozyl is suitable (the pH of the reconstituted solution ranges from 7.0 to 8.0). Additional components may be incompatible with the solution. Refer to the instructions for use of the added medicinal product.
After adding additional components, thoroughly mix the solution. The addition and mixing of supplementary components must always be performed before connecting the solution bag to the extracorporeal circuit.

I Open the seal by holding the small chamber with both hands and squeezing until a split forms in the peelable seal between the two chambers (see Figure I below).
II Squeeze the large chamber with both hands until the peelable seal between the two chambers is completely opened (see Figure II below).
III Mix the solution thoroughly by gently agitating the bag. The solution is now ready for use, and the bag may be hung on the device stand (see Figure III below).
IV The dialysis line drain or the replacement fluid line drain can be connected to either of the two access ports.
IV.a When using luer connectors, remove the cap by twisting and pulling, then connect the male luer lock connector on the dialysis line or replacement fluid line to the female luer connector on the bag by pushing and twisting. Ensure that the connectors are fully seated, then tighten. The connector is now open. Confirm that fluid flows freely (see Figure IV.a below).
When the dialysis line or replacement fluid line drain is disconnected from the luer connector, the connector will close automatically, stopping the flow of solution. The luer port is needle-free and can be wiped with disinfectants.
IV.b When using an injection (or spike) connector, first remove the sliding cap. The injection port can be wiped with disinfectants. Insert the spike through the rubber septum. Ensure that fluid flows freely (see Figure IV.b below).

The reconstituted solution is intended for single use only. Any unused solution should be discarded. The solution may be disposed of via the sewer system without harm to the natural environment.
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