REGIOCIT SOLUTION FOR HEMOFILTRATION

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Regiocit solution for haemofiltration

Citrate, sodium and chloride

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the leaflet

1. What Regiocit is and what it is used for
2. What you need to know before you use 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 and prevents blood clotting during continuous renal replacement therapy (CRRT), which is a form of dialysis treatment. This medicine is used in critically ill patients, especially when the standard medicine used to prevent blood clotting (heparin) is unsuitable. Citrate provides an anticoagulant effect by binding to calcium in the blood.

2. What you need to know before using Regiocit

Do not use this medicine if:

• You are allergic to the active substances or to any of the other components (listed in section 6)
• You have severe hepatic insufficiency
• You have severe reduction in blood flow to the muscles

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting treatment with Regiocit.

This medicinal product is not intended for direct intravenous infusion. It must be used exclusively with a machine capable of performing continuous renal replacement therapy (CRRT), which is a specific type of dialysis for critically ill patients with renal failure. The CRRT device must be suitable for citrate anticoagulation.

Regiocit should be warmed to 37 °C to improve patient well-being. Warming of the solution prior to use must be performed using dry heat only. Solutions must not be warmed in water or in a microwave. Regiocit must be visually inspected to ensure there are no particles or changes in color before administration. Do not administer unless the solution is clear, free of particles, and the seal is intact.

If the packaging or solution bag is damaged, the solution may be contaminated and must not be used. In addition to this medicine, the treatment includes other infused fluids. The composition or rate of administration of these other fluids may need to be adjusted to be compatible with this medicine. Your doctor will closely monitor your hemodynamic status, fluid balance, glucose levels, and electrolyte and acid-base balance before and during treatment. Levels of sodium, magnesium, potassium, phosphate, and calcium will be closely monitored.

Adjustments to therapy may be made if necessary.

Regiocit does not contain calcium. The use of Regiocit may cause low levels of calcium in the blood (hypocalcemia).

Regiocit does not contain magnesium. The use of Regiocit may cause low levels of magnesium in the blood (hypomagnesemia). Blood magnesium levels will be closely monitored and magnesium infusion may be required.

Regiocit does not contain glucose. Administration of Regiocit may cause low blood glucose levels (hypoglycemia). Blood glucose levels must be monitored regularly.

Regiocit does not contain potassium. Serum potassium concentration must be monitored before and during treatment.

Your doctor will pay special attention to the citrate infusion rate. High citrate levels reduce blood calcium and increase blood pH, which may lead to neurological and cardiac complications. Elevated blood pH can be corrected by adjusting dialysis parameters, infusing 0.9% sodium chloride solution post-filter, or changing the composition of the CRRT solution. Low blood calcium levels can be treated by calcium infusion. Special attention from your doctor is required if you have hepatic shock or hepatic insufficiency. Citrate metabolism may be significantly reduced, leading to citrate accumulation accompanied by low blood pH. Your doctor will decide whether treatment adjustments are needed. If the total calcium/ionized calcium ratio increases above 2.3, the citrate buffer should be reduced or stopped.

If Regiocit is administered to patients with hepatic insufficiency, it is important to frequently monitor pH, electrolytes, the total/ionized calcium ratio, and systemic ionized calcium to avoid acid-base and hydroelectrolytic imbalances. Do not use if you have severe hepatic insufficiency.

In case of abnormally high fluid volumes 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 or dialysis fluid may be reduced.

In case of abnormally low fluid volumes in the body (hypovolemia), the prescribed net ultrafiltration rate for the CRRT device should be decreased and/or the infusion rate of fluids other than replacement or dialysis fluid may be increased.

Regiocit is hypo-osmolar/hypotonic compared to the replacement fluids commonly used in CRRT and should be used with caution in patients with traumatic brain injury, cerebral edema, or elevated intracranial pressure.

The instructions for use must be strictly followed. Incorrect use of access ports or any other restriction affecting fluid flow could result in incorrect patient weight loss and trigger machine alarms. Continuing treatment without resolving the cause of the alarm may result in patient injury or even death.

Use of Regiocit with other medicines

Inform your doctor, pharmacist, or nurse if you are taking, or have recently taken, any other medicines, including those obtained without a prescription. This is because the concentration of other medicines may be reduced during dialysis treatment. Your doctor will decide whether the doses of your medicines need to be adjusted.

In particular, inform your doctor if you are using any medical product containing any of the following components:

• Vitamin D or other medicines containing calcium, and medicines containing calcium chloride or calcium gluconate, as they may increase the risk of high calcium levels in the blood (hypercalcemia), which may reduce the anticoagulant effect.
• Sodium bicarbonate, as it may increase blood bicarbonate levels.

Pregnancy, breastfeeding, and fertility

Fertility:

No effect on fertility is expected, as sodium, chloride, and citrate are normal components of the body.

Pregnancy and breastfeeding:

There are no documented clinical data on the use of this medicine during pregnancy and breastfeeding.

This medicine should only be administered to pregnant or breastfeeding women if clearly necessary.

Driving and use of machines

It is unknown whether this medicine affects your ability to drive or use machines.

3. How to use Regiocit

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

The recommended flow rates for this medicine in adults and adolescents are:

• In continuous veno-venous hemofiltration

• 1–2.5 l/h with a blood flow rate between 100 and 200 ml/min.

• In continuous veno-venous hemodiafiltration

• 1–2 l/h with a blood flow rate between 100 and 200 ml/min.

Use in elderly patients:

The recommended flow rates are the same as those indicated for adults and adolescents.

Use in children:

In neonates and young children (aged between 0 and 23 months), Regiocit must be limited to a dose of 3 mmol of citrate per liter of blood flow in continuous veno-venous hemofiltration or hemodiafiltration. In children (aged between 2 and 11 years), the dose must be adjusted according to the patient's weight and blood flow rate.

Hepatic impairment or hepatic shock:

In these conditions, the initial dose of citrate must be reduced.

Instructions for use

Regiocit will be administered in a hospital setting, and the physician will know how to use the product.

For instructions on use, refer to the end section of this leaflet.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them. Your doctor or nurse will regularly monitor your blood to detect possible adverse effects. Use of this solution may cause the following adverse effects:

Frequent: may affect up to 1 in 10 people

• Acid-base imbalance in blood
• Imbalances in blood electrolyte levels (for example, decreased blood levels of calcium, sodium, magnesium, potassium, and/or phosphate, or increased blood calcium levels)

Not known: frequency cannot be estimated from available data

• Fluid imbalance in blood (dehydration, fluid retention in the body)

• Decreased blood pressure*

• Nausea*, vomiting*

• Cramps*

• Adverse effects related to dialysis treatment rather than this medicine.

Reporting of 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 leaflet.

You may also report them directly via the Spanish System for Pharmacovigilance of Human Medicines: www.notificaRAM.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Regiocit

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

No special storage conditions are required.

Do not freeze.

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

Do not use this medicine if you notice any damage to the product or particles in the solution.

The solution may be disposed of via wastewater without any harmful effect on the environment.

6. Contents of the pack and other information

Composition of this medicinal product

Composition:

Sodium chloride 5.03 g/l
Sodium citrate 5.29 g/l

The active substances are:

Sodium, Na+ 140 mmol/l
Chloride, Cl- 86 mmol/l
Citrate, C6H5O73- 18 mmol/l

Theoretical osmolarity: 244 mOsm/l
pH ≈ 7.4

Other components are:

Dilute hydrochloric acid (for pH adjustment) E507
Water for injections

Appearance of the product and contents of the container

This medicinal product is a clear, colourless solution for haemofiltration, contained in a single-compartment bag made from a multilayer film containing elastomers and polyolefins. The solution is sterile and free from bacterial endotoxins. Each bag contains 5000 ml of solution and is individually wrapped in a transparent film. Each carton contains two bags and a package leaflet.

Marketing Authorization Holder

Vantive Belgium SRL
Boulevard d'Angleterre 2
1420 Braine-l'Alleud
Belgium

Manufacturers

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 regarding this medicinal product, please contact the local representative of the Marketing Authorization Holder:

Vantive Health, S.L.
Polígono Industrial Sector 14. Pouet de Camilo, 2
46394 Valencia, Spain

This medicinal product is authorised in the European Economic Area (EEA) Member States and 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): Regiocit

Bulgaria: Regiocit (????????)

Date of the most recent review of this leaflet: September 2019

This information is intended for healthcare professionals only:

Dosage

The administration rate of Regiocit depends on the target citrate dose and the prescribed blood flow rate (BF). The prescription of Regiocit must take into account the effluent flow rate and other therapeutic fluids, the patient's fluid removal requirements, additional fluid inputs and outputs, and the desired acid-base and hydroelectrolytic balance. The prescription of Regiocit and its administration regimen (dose, infusion rate, and cumulative volume) must be determined solely by a physician experienced in intensive care medicine and CRRT (Continuous Renal Replacement Therapy).

The pre-filter infusion rate of Regiocit must be prescribed and adjusted according to blood flow to achieve a target blood citrate concentration of 3 to 4 mmol/l of blood.

The prescription of Regiocit must take into account the effluent flow rate and other therapeutic fluids, the patient's fluid removal requirements, additional fluid inputs and outputs, and the desired acid-base and hydroelectrolytic balance.

The anticoagulation flow rate in the extracorporeal circuit must be adjusted to achieve a post-filter ionised calcium concentration in the range of 0.25 to 0.35 mmol/l. The patient's systemic ionised calcium concentration must be maintained within the normal physiological range by adjusting supplemental calcium administration.

Citrate also acts as a buffer source (through conversion to bicarbonate); the infusion rate of Regiocit must therefore be considered in relation to the buffer administration rate from other sources (e.g., dialysis fluid or replacement fluid). Regiocit must be used with a dialysis or replacement solution containing an appropriate bicarbonate concentration.

A separate calcium infusion is always required. Adjust or stop the calcium infusion according to the physician's prescription when anticoagulation is discontinued.

Monitoring of post-filter blood ionised calcium (Cai), systemic Cai, and total blood calcium levels, along with other clinical and laboratory parameters, is essential to determine the appropriate dose of Regiocit according to the desired anticoagulation levels (see section 4.4).

Plasma levels of sodium, magnesium, potassium, and phosphate must be monitored regularly, and supplementation administered if necessary.

Flow rates for Regiocit in adults and adolescents:

• In continuous veno-venous haemofiltration (CVVH):
  1–2.5 l/h with a blood flow rate between 100 and 200 ml/min.

• In continuous veno-venous haemodiafiltration (CVVHDF):
  1–2 l/h with a blood flow rate between 100 and 200 ml/min.

Paediatric population:

In neonates and young children (aged 0 to 23 months), Regiocit must not exceed a dose of 3 mmol of citrate per litre of blood flow in continuous veno-venous haemofiltration or haemodiafiltration. In children (aged 2 to 11 years), the dose must be adjusted according to the patient's body weight and blood flow rate.

Special populations:

In elderly patients, no specific dose adjustment is required compared to adults.

Hepatic impairment or hepatic shock:

In patients with mild to moderate hepatic impairment (e.g., Child-Pugh ≤12), dose reduction may be necessary. In cases of hepatic insufficiency (including, for example, liver cirrhosis), the initial citrate dose should be reduced, as metabolism may be inadequate. Frequent monitoring for citrate accumulation is recommended. Regiocit must not be administered to patients with severely reduced liver function or shock with muscular hypoperfusion (e.g., conditions such as septic shock and lactic acidosis) due to impaired citrate metabolism.

Overdose

Administration of excessively high volumes of replacement solution may lead to overdose, potentially resulting in life-threatening conditions for the patient. This may cause fluid overload-related pulmonary oedema and congestive heart failure, hypocalcaemia, and citrate-related metabolic alkalosis due to excessive citrate load relative to blood flow. This condition must be corrected immediately by stopping or reducing the amount of replacement solution and by intravenous administration of calcium. Cautious administration of supplemental calcium may reverse the effects of overdose. The risk can be minimized by close monitoring during treatment.

In patients with impaired citrate metabolism (hepatic insufficiency or hepatic shock), overdose may manifest as citrate accumulation, metabolic acidosis, systemic total hypercalcaemia and ionised hypocalcaemia, along with an increased total calcium/ionised calcium ratio.

Regiocit administration must therefore be reduced or discontinued.

To correct metabolic acidosis, sodium bicarbonate should be administered. Continuous renal replacement therapy may continue without anticoagulation, or alternative anticoagulation methods should be considered.

Preparation and handling

The solution may be disposed of via wastewater without causing harm to the environment.

The following instructions must be followed:

Aseptic technique must be used throughout the handling and administration process. Remove the overwrap immediately before use. Use only if the overwrap is undamaged, the seal is intact, and the solution is clear. Squeeze the bag firmly to ensure there are no leaks. If any leakage is observed, discard the solution immediately, as sterility cannot be guaranteed. The solution must be used immediately after opening to avoid microbiological contamination.

• If using the luer connector, remove the cap by twisting and pulling. Connect the male luer-lock connector of the pre-blood pump line to the female luer receptor on the bag by pushing and turning. Ensure the connection is secure and tight. The connector is now open. Check that fluid flows freely. (See Figure I below).

When the pre-blood pump line is disconnected from the luer connector, the connector will close and the solution will stop flowing. The luer is a needle-free port that can be disinfected with an alcohol-impregnated swab.

II. If using the spike connector (or spike port), first remove the cap by lifting it off. The spike port is a disinfectable port. Then insert the spike through the rubber membrane. Check that fluid flows freely. (See Figure II below).

Before adding any substance or medication, verify that it is soluble and stable in Regiocit and that the product's pH range is suitable. Do not add any additives known to be incompatible.

Refer to the instructions for use of the medication to be added and other relevant scientific publications.

After addition, do not use if there is a change in colour and/or formation of precipitates, insoluble complexes, or crystals.

Mix the solution thoroughly after adding additives. The addition and mixing of additives must always be completed before connecting the solution bag to the extracorporeal circuit.

The solution is for single use only. Any unused portion must be discarded.