Regiocit

Package leaflet: Information for the user

Regiocit, solution for hemofiltration
Citrate, sodium, chloride ions
Please read carefully all the information in this leaflet before use, as it contains
important information for the patient.

• Keep this leaflet so that you can read it again if necessary.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• If the patient experiences any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet

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

1. What Regiocit is and what it is used for

This medicine is a solution for hemofiltration, used to prevent blood clotting during continuous
renal replacement therapy (CRRT), a type of dialysis procedure. The medicine is used in critically ill patients, particularly when the use of the drug usually employed to prevent blood clotting (heparin) is inappropriate. Citrate ions provide an anticoagulant effect by binding calcium present in the blood.

2. Important information before using Regiocit

Do not use this medicine if:

• you are allergic to the active substances or to any of the other ingredients of this medicine (listed in section 6),
• you have severe liver dysfunction,
• you have severe impairment of blood flow in the muscles.

Warnings and precautions
Before starting treatment with this medicine, discuss it with your doctor, pharmacist, or nurse.
This medicine is not intended for direct intravenous infusion. It must be used only with a device enabling continuous renal replacement therapy (CRRT), a type of dialysis used in critically ill patients with kidney failure. The CRRT device must be compatible with citrate ions as an anticoagulant.
Regiocit may be warmed to 37°C to increase patient comfort. Warming the solution prior to administration must be performed using only a dry heat source. Do not warm the solution in water or in a microwave oven. Before administration, visually inspect Regiocit for the presence of particulate matter and discoloration. Use only if the solution is clear, free from visible particles, and the seal is intact.
If the protective cover or the solution bag is damaged, the solution may be contaminated and must not be used. Treatment also includes administration of intravenous fluids other than this medicine. To ensure compatibility, adjustments to the composition or infusion rate of these fluids may be necessary.
Your doctor will closely monitor your hemodynamic status, fluid balance, glucose levels, electrolyte balance, and acid-base balance before and during the procedure.
Sodium, magnesium, potassium, phosphate, and calcium levels will be closely monitored.
If necessary, appropriate treatment adjustments will be made.
Regiocit does not contain calcium. Treatment with Regiocit may lead to low blood calcium levels (hypocalcemia).
Regiocit does not contain magnesium. Treatment with Regiocit may cause low blood magnesium levels (hypomagnesemia). Blood magnesium levels will be closely monitored and magnesium infusion may be required.
Regiocit does not contain glucose. Administration of Regiocit may lead to low blood glucose levels (hypoglycemia). Blood glucose levels should be monitored regularly.
Regiocit does not contain potassium. Serum potassium levels must be monitored before and during treatment.
Your doctor will pay special attention to the infusion rate of citrate ions. Excessive citrate ion infusion may reduce blood calcium levels and increase blood pH, potentially leading to neurological and cardiac complications.
Elevated blood pH can be corrected by adjusting dialysis settings, infusing 0.9% sodium chloride solution post-filter, or changing the composition of the continuous renal replacement therapy (CRRT) solution. Low calcium levels can be corrected with calcium ion infusion.
Your doctor should pay particular attention to patients with liver dysfunction or shock.
In these patients, metabolism of citrate may be significantly reduced, leading to citrate accumulation and associated decrease in blood pH. Your doctor will decide whether changes in treatment are needed. If the ratio of total calcium to ionized calcium exceeds 2.3, the infusion rate of citrate buffer should be reduced or discontinued.
When using Regiocit in patients with impaired liver function, frequent monitoring of pH, electrolytes, the ratio of total to ionized calcium, and systemic ionized calcium is essential to avoid disturbances in electrolyte and/or acid-base balance. This medicine must not be used in patients with severe liver dysfunction.
In case of abnormally high fluid volume in the body (hypervolemia), the prescribed net ultrafiltration rate for the CRRT device may be increased and/or the infusion rate of fluids other than replacement fluid and/or dialysate may be reduced.
In case of abnormally low fluid volume in the body (hypovolemia), the prescribed net ultrafiltration rate for the CRRT device may be decreased and/or the infusion rate of fluids other than replacement fluid and/or dialysate may be increased.
Regiocit is hypo-osmolar/hypotonic compared to standard CRRT replacement fluids, and caution should be exercised when administering it to patients with traumatic brain injury, cerebral edema, or increased intracranial pressure.
Strictly follow the instructions for use. Incorrect use of access ports or other devices limiting fluid flow may lead to incorrect patient weight loss and device alarms. Continuing treatment without correcting the cause of these events may result in patient injury or death.

Regiocit and other medicines
Inform your doctor, pharmacist, or nurse about all medicines you are currently taking or have recently taken, including over-the-counter medicines. This is because dialysis therapy may reduce the concentrations of other medicines. Your treating doctor will decide whether dosage adjustments of your other medicines are necessary.
In particular, inform your doctor if you are taking medicines containing any of the following:

• vitamin D and other calcium-containing medicines, or medicines containing calcium chloride or calcium gluconate, as these may increase the risk of high blood calcium levels (hypercalcemia) and may reduce anticoagulant efficacy;
• sodium bicarbonate, as it may increase blood bicarbonate levels.

Pregnancy, breastfeeding, and fertility
Fertility:
Affect on fertility is not expected, as sodium, chloride, and citrate occur naturally in the body.
Pregnancy and breastfeeding:
There are no documented clinical data on the use of this medicine during pregnancy and breastfeeding. This medicine should be administered to pregnant and breastfeeding women only if clearly needed.

Driving and using machines
It is unknown whether this medicine affects the ability to drive and use machines.

3. How to use Regiocit

For intravenous use. This medicine is intended for use in hospitals and must be administered only by healthcare professionals. The volume used, and thus the dose of the medicine, depends on the patient's condition. The dose volume will be determined by the attending physician. Recommended flow rates in adult and adolescent patients:

• In continuous veno-venous hemofiltration at 1–2.5 l/hour with a blood flow rate of 100 to 200 ml/min.
• In continuous veno-venous hemodiafiltration at 1–2 l/hour with a blood flow rate of 100 to 200 ml/min.

Use in elderly patients:
The recommended flow rates are the same as in adult and adolescent patients.

Use in children:
In neonates and young children (from birth to 23 months of age), the target dose of Regiocit should be 3 mmol of citrate ions per liter of blood flowing through continuous veno-venous hemofiltration or hemodiafiltration. In children (from 2 to 11 years of age), the dose should be adjusted according to the patient's body weight and blood flow rate.

Hepatic impairment or shock:
In cases of hepatic impairment or shock, the initial dose of citrate ions should be reduced.

Instructions for use
Regiocit will be administered to the patient in a hospital setting. The physician is familiar with the method of administering Regiocit. Instructions for use are provided at the end of this leaflet.

4. Possible adverse reactions

Like all medicines, this product may cause adverse reactions, although not everyone experiences them.
Your doctor or nurse will regularly monitor your blood parameters to detect any potential adverse reactions.
The use of this solution may cause the following adverse reactions:
Common: may affect up to 1 in 10 people

• disturbance of blood acid-base balance,
• disturbance of electrolyte concentrations in blood (e.g. decreased levels of calcium, sodium, magnesium, potassium and (or) phosphate in blood or increased calcium levels in blood).

Unknown frequency: cannot be estimated from available data

• disturbances in body fluid balance (dehydration, fluid retention);
• low blood pressure*;
• nausea*, vomiting*;
• muscle cramps*.

* Adverse reactions more likely related to dialysis therapy than to the medicinal product itself.
Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions 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.
Reporting adverse reactions helps to provide more information on the safety of this medicine.

5. How to store Regiocit

Keep the medicine out of sight and reach of children.
No special storage instructions apply.
Do not freeze.
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.
Do not use this medicine if you notice any damage to the product or the presence of solid particles in the solution.
The solution may be poured into the sewage system without causing harm to the natural environment.

6. Contents of the pack and other information

What Regiocit contains
Composition:
Sodium chloride 5.03 g/l
Sodium citrate 5.29 g/l

The active substances of the medicinal product are:
Sodium cations, Na 140 mmol/l
Chloride anions, Cl 86 mmol/l
Citrate anions, C\ H\ O 18 mmol/l
Theoretical osmolarity: 244 mOsm/l
pH ≈ 7.4

The other ingredients are:
Dilute hydrochloric acid (for pH adjustment) E 507
Water for injections

What Regiocit looks like and contents of the pack
This medicinal product is a clear, colourless solution for haemofiltration contained in a single-compartment bag made of multilayer film containing polyolefins and elastomers. The solution is sterile and free from bacterial endotoxins. Each bag contains 5000 ml of solution and is enclosed in a transparent protective bag. 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
or
Vantive Manufacturing Limited,
Moneen Road,
Castlebar
County Mayo
F23 XR63
Ireland

For further information, please contact the local representative of the Marketing Authorisation Holder.

This medicinal product is authorised in 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, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom (Northern Ireland): Regiocit
Bulgaria: Regiocit (Региоцит)

Information intended exclusively for healthcare professionals:

Dosing
The infusion rate of Regiocit depends on the target citrate dose and the prescribed blood flow rate (BFR). When prescribing Regiocit, consideration must be given to the effluent fluid flow rate and other therapeutic fluids, fluid removal requirements, input and removal of additional fluids, and desired acid-base and electrolyte balance. Regiocit should be prescribed, and its mode of administration (dose, infusion rate, and total volume) should be determined solely by a physician experienced in intensive care and continuous renal replacement therapy (CRRT).

The infusion rate of Regiocit pre-filter relative to the blood flow rate should be established and adjusted to achieve a target blood citrate concentration of 3 to 4 mmol/L. When prescribing Regiocit, the effluent fluid flow rate and other therapeutic fluids, patient fluid removal requirements, input and removal of additional fluids, and desired acid-base and electrolyte balance must be considered.

The anticoagulant flow rate in the extracorporeal circuit should be gradually increased to achieve a post-filter ionized calcium concentration between 0.25 and 0.35 mmol/L. Systemic ionized calcium concentration should be maintained within normal physiological ranges by appropriate calcium supplementation.

Additionally, citrate acts as a buffer source (due to its conversion to bicarbonate). The Regiocit infusion rate must account for buffer delivery from other sources (e.g., dialysate and/or substitution fluid). Regiocit must be used in conjunction with a dialysate/substitution fluid containing an appropriate bicarbonate concentration.

A separate calcium infusion is always required. Calcium infusion should be adjusted or discontinued according to physician instructions if anticoagulation is stopped.

Monitoring of post-filter ionized calcium (iCa), systemic iCa, and total blood calcium levels, in conjunction with other laboratory and clinical parameters, is essential for determining the appropriate Regiocit dosing based on the desired level of anticoagulation.

Sodium, magnesium, potassium, and phosphate levels should be monitored regularly and supplemented as needed.

Regiocit infusion rates in adults and adolescents:

• Continuous veno-venous hemofiltration (CVVH): 1–2.5 L/hour with a blood flow rate of 100–200 mL/min;
• Continuous veno-venous hemodiafiltration (CVVHDF): 1–2 L/hour with a blood flow rate of 100–200 mL/min.

Children and adolescents:
In neonates and small children (from birth to 23 months of age), the target dose of Regiocit should be 3 mmol of citrate ions per liter of blood processed during continuous veno-venous hemofiltration or hemodiafiltration. In children (aged 2 to 11 years), the dose should be adjusted according to body weight and blood flow rate.

Special patient groups:
No specific dosage adjustment is required in elderly patients compared to adult dosing.

Hepatic impairment or shock:
Dose reduction may be necessary in patients with mild to moderate hepatic impairment (e.g., Child-Pugh score ≤12).
In patients with hepatic dysfunction (e.g., cirrhosis), the initial citrate dose should be reduced due to the risk of inadequate metabolism. Frequent monitoring for citrate accumulation is recommended. Regiocit must not be administered to patients with severe hepatic impairment or shock with muscular hypoperfusion (e.g., septic shock, lactic acidosis) due to reduced citrate metabolism.

Overdose
Inappropriate administration of excessive volumes of substitution fluid may lead to overdose, which can be life-threatening. Overdose may result in pulmonary edema and congestive heart failure due to fluid overload, as well as hypocalcemia and metabolic alkalosis due to citrate excess relative to blood flow. These disturbances should be promptly corrected by discontinuing the substitution fluid and administering intravenous calcium. Careful calcium supplementation may reverse the effects of overdose. Risk can be minimized through strict monitoring during treatment.

In patients with impaired citrate metabolism (liver failure or shock), overdose may manifest as citrate accumulation, metabolic acidosis, systemic hypercalcemia with total calcium, hypocalcemia with low ionized calcium, and an increased ratio of total calcium to ionized calcium.

Administration of Regiocit should be discontinued or reduced.
To correct metabolic alkalosis, bicarbonate supplementation should be provided. Continuous renal replacement therapy may be continued without anticoagulation, or alternative anticoagulation methods may be considered.

Preparation and (or) administration
The solution may be safely disposed of into the sewage system without harm to the natural environment.

Follow the instructions below for administration:
Throughout the entire process of preparation and administration to the patient, aseptic technique must be used.
Remove the product from its protective packaging immediately before use. Use only if the protective packaging is intact, all seals are undamaged, and the solution is clear and transparent. Squeeze the bag firmly to check for leaks. If leakage is detected, discard the solution immediately, as sterility cannot be assured. The solution should be used promptly after opening the packaging to avoid microbiological contamination.

I. When using Luer-type connectors, unscrew and remove the cap. Connect the male Luer-lock connector on the pre-pump arterial line to the female Luer connector on the bag by pressing and twisting. Ensure connectors are fully seated and securely tightened. The connector is now open. Confirm free flow of fluid (see Figure I below).

When the pre-pump arterial line is disconnected from the Luer connector, the connector will close automatically, stopping solution flow. The Luer connector is needle-free and can be disinfected with antiseptic agents.

II. When using an injection port (or spike connector), remove the sliding cap. The injection port can be disinfected with antiseptic agents. Insert the spike through the rubber septum. Confirm free flow of fluid (see Figure II below).

Before adding any substance or drug, ensure compatibility—solubility and stability in Regiocit—and that the pH range is suitable. Do not add components known or confirmed to be incompatible.

Consult the instructions for use of the added drug and other relevant literature. Do not use if color change or precipitation occurs after addition, or if insoluble complexes or crystals are observed. After adding components, mix the solution thoroughly. Additional components must always be introduced and mixed before connecting the solution bag to the extracorporeal circuit.

The solution is intended for single use only. Any unused solution should be discarded.