Regiocit

Package leaflet: Information for the user

Regiocit solution for hemofiltration

Citrate, sodium, chloride
Read this leaflet carefully before 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 this leaflet:

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

1. What this medicine 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, particularly when the standard medicine given to prevent blood clotting (heparin) is not suitable. Citrate achieves anticoagulation by binding to calcium in the blood.

2. What you need to know before using this medicine

Do not use this medicine if:

• You are allergic to the active substances or to any of the other ingredients (listed in section 6)
• You have severely impaired liver function
• You have severely reduced blood flow to the muscles

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using this medicine.
This medicine is not intended for direct intravenous infusion. It must only be used with a machine capable of performing continuous renal replacement therapy (CRRT), a type of dialysis specifically reserved for critically ill patients with kidney failure. The CRRT machine must be suitable for anticoagulation with citrate.
Regiocit may be warmed to 37°C to improve patient comfort. The solution must be heated before use using only dry heat. Solutions must not be heated in water or in a microwave oven. Before administration, Regiocit must be inspected for the presence of particulate matter and any discoloration. Do not administer if the solution is not clear and free of visible particles, or if the seal is broken.
If the outer packaging or the solution bag is damaged, the solution may be contaminated and must not be used.
In addition to this medicine, the treatment involves the infusion of other 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 as necessary.
Regiocit does not contain calcium. Use of Regiocit may lead to low blood calcium levels (hypocalcemia). Regiocit does not contain magnesium. Use of Regiocit may lead to 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 must be monitored regularly.
Regiocit does not contain potassium. Serum potassium concentration must be monitored before and during treatment.
Your doctor must pay particular attention to the citrate infusion rate. Excessive citrate can cause low blood calcium levels and elevated blood pH, which may lead to neurological and cardiac complications. Elevated blood pH can be corrected by adjusting dialysis settings and administering 0.9% sodium chloride solution after the filter, or by modifying the CRRT solution composition. Low blood calcium levels can be treated with calcium infusion.
Your doctor must pay special attention if you have liver impairment or develop hepatic shock. Citrate metabolism may be significantly reduced, leading to citrate accumulation accompanied by low blood pH. Your doctor will decide whether treatment needs to be adjusted. If the total-to-ionized calcium ratio increases above 2.3, the citrate buffer must be reduced or discontinued.
If Regiocit is administered to patients with hepatic impairment, it is important to frequently monitor pH, electrolytes, the ratio of total to ionized calcium, and systemic ionized calcium to prevent electrolyte and/or acid-base imbalances. Do not use Regiocit in cases of severe hepatic impairment.
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 administration rate of fluids other than replacement fluid and/or dialysate may be decreased.
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 administration rate of fluids other than replacement fluid and/or dialysate may be increased.
Regiocit is hypoosmolar/hypotonic compared to standard CRRT replacement fluids and must be used with caution in patients with brain injury, cerebral edema, or increased intracranial pressure.
Strictly follow the instructions for use. Incorrect use of venous access or other limitations in fluid flow may cause an unintended decrease in patient weight and trigger machine alarms. Continuing treatment without resolving the underlying cause may result in patient injury or death.

Other medicines and Regiocit
Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take any other medicines, including those available without a prescription. This precaution is necessary because the concentrations of other medicines may decrease during dialysis treatment. Your doctor will decide whether dosage adjustments are needed.
In particular, inform your doctor if you are taking medicines containing any of the following substances:

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

Pregnancy, breastfeeding, and fertility
Fertility:
No effects on fertility are 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 be administered to pregnant and breastfeeding women only if strictly necessary.

Driving and using machines
This medicine is not known to affect the ability to drive or use machinery.

3. How to use this medicine

For intravenous use. This medicine must be used in a hospital setting and must be administered exclusively by medical personnel. The volume used, and therefore the dose of the medicine, will depend on the patient's condition. The dose volume will be determined by the physician.
Recommended flow rates for this medicine in adult and adolescent patients:

• In continuous veno-venous haemofiltration: 1–2.5 l/hour with a blood flow rate between 100 and 200 ml/min.
• In continuous veno-venous haemodiafiltration: 1–2 l/hour with a blood flow rate between 100 and 200 ml/min.

Use in the elderly:
The recommended flow rates are the same as those for adult and adolescent patients.
Use in children:
In neonates and children (from 0 to 23 months of age), Regiocit should be used at a dose of 3 mmol of citrate per liter of blood flow in continuous veno-venous haemofiltration or haemodiafiltration. In children (from 2 to 11 years of age), the dosage should be adjusted according to both the patient's weight and the 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 to you in a hospital. The doctor will know how to use Regiocit.

See the instructions for use at the end of this leaflet.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Your blood will be regularly monitored by a doctor or nurse to detect possible side effects.
The use of this solution may cause:
Common: may affect up to 1 in 10 people

• Acid/base imbalance in the blood
• Electrolyte imbalances in the blood (e.g. sudden drop in blood levels of calcium, sodium, magnesium, potassium and/or phosphate, or increased blood calcium levels)

Not known: frequency cannot be estimated from the available data

• Fluid imbalance in the body (dehydration, fluid retention in the body)
• Reduction in blood pressure*
• Nausea*, vomiting*
• Cramps*

*Side effects related more to dialysis treatment than to this medicine.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, tell your doctor, pharmacist or nurse.
You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store this medicine

Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage conditions.
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 that month.
Do not use this medicine if you notice any damage to the product or visible particles in the solution.
The solution may be disposed of via wastewater without harming the environment.

6. Package contents and other information

What this medicinal product contains
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, C H O 18 mmol/l
Theoretical osmolarity: 244 mOsm/l
pH ≈ 7.4
The other components are:
Dilute hydrochloric acid (for pH adjustment) E 507
Water for injections

Description of the medicinal product and contents of the pack
This medicinal product is a clear, colourless solution for hemofiltration, packed in a single-compartment bag made from a 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 overwrap. Each carton contains two bags and a package leaflet.

Marketing Authorization Holder
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 about this medicinal product, please contact the local representative of the Marketing Authorization Holder.

The following information is intended exclusively for physicians or healthcare professionals:

Dosage
The rate at which Regiocit is administered depends on the intended citrate dose and blood flow rate. The prescription of Regiocit must take into account the effluent flow rates and other therapeutic fluids, the patient's fluid removal requirements, inputs and outputs of other fluids, and the desired acid-base and electrolyte balance. Regiocit must be prescribed and its administration (dose, infusion rate, and cumulative volume) must be determined only by a physician experienced in intensive care medicine and continuous renal replacement therapy (CRRT).

The pre-filter infusion rate of Regiocit should be prescribed and adjusted according to the blood flow rate to achieve a target blood citrate concentration of 3–4 mmol/l. The prescription of Regiocit must consider the effluent flow rates and other therapeutic fluids, the patient's fluid removal needs, inputs and outputs of other fluids, and the desired acid-base and electrolyte balance.

The flow rate for anticoagulation of the extracorporeal circuit must be titrated to achieve a post-filter ionized calcium concentration between 0.25 and 0.35 mmol/l. The patient's systemic ionized calcium concentration must be maintained within the normal physiological range by adjusting calcium supplementation.

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

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

Monitoring of post-filter blood ionized calcium (iCa), systemic blood iCa, and total blood calcium, together with monitoring of other laboratory and clinical parameters, is essential to achieve an appropriate Regiocit dosage based on the desired level of anticoagulation (see section 4.4).

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

Regiocit flow rates in adults and adolescents:

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

Paediatric population:
In neonates and children (0 to 23 months of age), Regiocit should be used at a dose of 3 mmol citrate per litre of blood flow in continuous veno-venous hemofiltration or hemodiafiltration. In children (2 to 11 years of age), the dosage should be adjusted according to both the patient's body weight and blood flow rate.

Special populations:
No specific dose adjustment is required in elderly patients compared to adults.

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

Overdose
Unintentional administration of excessive volumes of replacement fluid solution may lead to overdose, potentially resulting in a life-threatening condition for the patient. Pulmonary oedema and congestive heart failure due to fluid overload, as well as hypocalcaemia and metabolic alkalosis due to citrate overload relative to blood flow, may occur. This imbalance must be corrected immediately by stopping the replacement fluid infusion and administering intravenous calcium. Careful calcium supplementation can reverse the effects of overdose. The risk can be minimized by careful monitoring during treatment.

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

Regiocit should therefore be reduced or discontinued.

To correct metabolic acidosis, bicarbonate reinfusion is required. Continuous renal replacement therapy may be continued without anticoagulation, or alternative anticoagulation methods should be considered.

Preparation and/or handling
The solution may be disposed of into the wastewater system without causing environmental harm.

The following instructions for use must be followed:

An aseptic technique must be used throughout handling and administration to the patient.

Remove the outer wrapper from the bag immediately before use. Use only if the outer wrapper is undamaged, all seals are intact, and the solution is clear. Press the bag firmly to check for leaks. If leakage is detected, discard the solution immediately, as sterility can no longer be assured. The solution must be used immediately after opening to avoid microbiological contamination.

I. If using the luer connector, twist and remove the cap. Connect the male luer lock of the pre-blood pump line to the female luer connector on the bag by pushing and rotating. Ensure the connection is fully secured and firmly attached. 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 automatically and solution flow will stop. The luer is a needle-free, disinfectable connector.

II. If using the injection port (or spike connector), remove the snap cap. The injection port is disinfectable. Insert the spike through the rubber septum. Check that fluid flows freely (see figure II below).

Before adding any substance or medicinal product, verify that it is soluble and stable in Regiocit and that the product's pH range is appropriate. Additives known or determined to be incompatible must not be added. Consult the instructions for use of the medicinal product to be added and other relevant literature.

Do not use if, after addition, a change in colour or the presence of precipitates, insoluble complexes or crystals is observed.

Mix the solution thoroughly after additives have been introduced. The addition and mixing of additives must always be performed before connecting the solution bag to the extracorporeal circuit.

The solution is for single use only. Discard any unused portion.