Prospect: information for the user

Regiocit solution for hemofiltration

Citrate, sodium and chloride

Read this prospect carefully before starting to use this medication, because it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this prospect. See section 4.

This medication is a solution for hemofiltration and prevents blood coagulation during continuous renal replacement therapy (CRRT), which is a form of dialysis treatment. This medication is used in critically ill patients, especially those for whom the usual medication used to prevent blood coagulation (heparin) is inadequate. Citrate provides an anticoagulant effect by binding to calcium in the blood.

Do not use this medication in the following cases:

Allergy to the active ingredients or to any of the other components (listed in section 6) Severe liver insufficiency

Severe reduction in blood flow to the muscles

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Regiocit.

This medication has not been designed for use in direct intravenous perfusion. 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 insufficiency. The CRRT device must be suitable for anticoagulation with citrate.

Regiocit must be warmed to 37°C to improve patient well-being. The warming of the solution before use must be done only with dry heat. Solutions must not be warmed in water or in the microwave. Regiocit must be visually inspected to check that it does not contain particles or color changes before administration. Do not administer unless the solution is transparent, no particles are observed, and the seal is intact.

If the packaging or the solution bag is damaged, the solution may be contaminated and must not be used. In addition to this medication, the treatment includes other liquids that are perfused. The composition or the rate of administration of these other liquids may need to be adjusted to be compatible with this medication. Your doctor will closely monitor your hemodynamic state, fluid balance, glucose level, and acid-base balance before and during treatment. Sodium, magnesium, potassium, phosphate, and calcium levels will be closely monitored.

If necessary, adjustments will be made to the therapy.

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

Regiocit does not contain magnesium. The use of Regiocit may produce low levels of magnesium in the blood (hypomagnesemia). Magnesium levels in blood will be closely monitored, and it may be necessary to perfuse magnesium.

Regiocit does not contain glucose. The administration of Regiocit may produce low levels of glucose in the blood (hypoglycemia). Blood glucose levels must be regularly monitored.

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

Your doctor will pay special attention to the perfusion rate of citrate. A high amount of citrate reduces calcium levels in the blood and increases blood pH, which may lead to neurological and cardiac complications. Elevated blood pH can be corrected by adjusting dialysis parameters and by perfusing a 0.9% sodium chloride solution post-filter or by changing the composition of the CRRT solution. Low calcium levels in the blood can be treated by perfusing calcium. Your doctor will require special attention if you have hepatic shock or liver insufficiency. You may have a marked reduction in citrate metabolism due to citrate accumulation accompanied by low blood pH. Your doctor will decide if the treatment needs to be adjusted. If the total/ionized calcium ratio increases above 2.3, the citrate tampon must be reduced or stopped.

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

In case of presenting abnormally high volumes of fluid in the body (hypervolemia), the prescribed net ultrafiltration rate for the CRRT device may be increased, and/or the rate of administration of solutions other than substitution and/or dialysis fluid may be reduced.

In case of presenting abnormally low volumes of fluid in the body (hypovolemia), the prescribed net ultrafiltration rate for the CRRT device must be decreased, and/or the rate of administration of solutions other than substitution and/or dialysis fluid may be increased.

Regiocit is hypotonic/hyposmolar compared to the substitution fluids used in CRRT and must be used with caution in patients with traumatic brain injury, cerebral edema, or elevated intracranial pressure.

Follow the usage instructions strictly. The incorrect use of access ports or any other restriction affecting the fluid flow may cause incorrect weight loss in the patient and activate the machine alarm. Continuing treatment without resolving the cause of the alarm may cause patient injury or even death.

Use of Regiocit with other medications

Inform your doctor, pharmacist, or nurse if you are taking or have recently taken other medications, including those purchased without a prescription. This is because the concentration of other medications may be reduced during treatment with dialysis. Your doctor will decide if it is necessary to modify the dose of medications you take.

Particularly, inform your doctor if you are using any medicinal product containing any of the following components:

• Vitamin D or other medications containing calcium, as they may increase the risk of elevated calcium levels in the blood (hypercalcemia) that may lead to a reduction in anticoagulant effect.
• Sodium bicarbonate, as it may increase blood bicarbonate levels.

Pregnancy, breastfeeding, and fertility

Fertility:

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

Pregnancy and breastfeeding:

No clinical data are documented on the use of this medication during pregnancy and breastfeeding.

This medication should only be administered to pregnant women and breastfeeding women if it is clearly necessary.

Driving and operating machines

The effect of this medication on your ability to drive or operate machines is unknown.

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

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

• In continuous veno-venous hemofiltration

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

• In continuous veno-venous hemodiafiltration

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

Use in elderly individuals:

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

Use in children:

In the case of neonates and small children (ages 0-23 months), Regiocit should have a maximum dose of 3 mmol of citrate per liter of blood flow in continuous hemofiltration or hemodiafiltration. In the case of children (ages 2-11 years), the dose should be adjusted according to the patient's weight and blood flow.

Liver insufficiency or hepatic shock:

With these conditions, the initial dose of citrate should be reduced.

Usage instructions

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

To view the usage instructions, consult the final part of this prospectus.

Like all medications, this medication may produce adverse effects, although not all people will experience them. Your doctor or nurse will regularly monitor your blood to detect possible adverse effects. The use of this solution may cause the following adverse effects:

Frequent: may affect 1 in 10 people

• Acid-base imbalance in blood
• Electrolyte level imbalances in blood (for example, a decrease in blood levels of calcium, sodium, magnesium, potassium, and/or phosphate, or an increase in blood calcium levels)

Not known: the frequency cannot be estimated from available data

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

* Adverse effects related to dialysis treatment rather than this medication.

Reporting 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 prospectus.

You can also report them directly through the Spanish System for Pharmacovigilance of Medicinal Products for Human Use:www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

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

No special storage conditions are required.

Do not freeze.

Do not use this medication after the expiration date shown on the label and the packaging. The expiration date is the last day of the month indicated.

Do not use this medication if you observe damage to the product or particles in the solution.

The solution can be disposed of with wastewater without causing any harm to the environment.

Composition of this medication

Composition:

Sodium chloride5.03 g/l

Sodium citrate5.29 g/l

The active principles are:

Sodium, Na+140 mmol/l

Chloride, Cl-86 mmol/l

Citrate, C6H5O73-18 mmol/l

Theoretical osmolality: 244 mOsm/l

pH≈7.4

The other components are:

Diluted hydrochloric acid (for pH adjustment) E507

Water for injection

Appearance of the product and contents of the package

This medication is a transparent and colorless solution for hemofiltration packaged in a single-compartment bag made of a multi-layer film containing elastomers and polyolefins. The solution is sterile and free of bacterial endotoxins. Each bag contains 5000 ml of solution and the bag is wrapped in a transparent film. Each box contains two bags and a leaflet.

Holder of the marketing authorization

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

Ó

Vantive Manufacturing Limited

Moneen Road,

Castlebar

County Mayo

F23 XR63

Ireland

You can request more information about this medication by contacting the local representative of the marketing authorization holder

Vantive Health, S.L.

Polígono Industrial Sector 14. Pouet de Camilo, 2

46394 Valencia Spain

This medication is authorized in the member states of the European Economic Area and in the United Kingdom (Northern Ireland)with 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 (????????)

Last review date of this leaflet: September 2019

This information is intended solely for healthcare professionals:

Dosage

The administration rate of Regiocit depends on the target citrate concentration and the prescribed blood flow (FS). The prescription of Regiocit should take into account the effluent flow and other therapeutic liquids, the patient's fluid extraction requirements, additional fluid inputs and the desired acid-base and electrolyte balance. The prescription of Regiocit and its administration schedule (dose, infusion rate and cumulative volume) should only be determined by an experienced intensive care physician and renal replacement therapy (RRT) specialist.

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

The prescription of Regiocit should take into account the effluent flow and other therapeutic liquids, the patient's fluid extraction requirements, additional fluid inputs and the desired acid-base and electrolyte balance.

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

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

A separate calcium infusion is always required. Adjust or stop the calcium infusion in accordance with the physician's prescription when anticoagulation is stopped.

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

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

Infusion rates for Regiocit in adults and adolescents:

• In continuous veno-venous hemofiltration

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

• In continuous veno-venous hemodiafiltration

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

Pediatric population:

In the case of neonates and small children (ages 0-23 months), Regiocit should have a maximum dose of 3 mmol of citrate per liter of blood flow in continuous hemofiltration or hemodiafiltration. In the case of children (ages 2-11 years), the dose should be adjusted according to the patient's weight and blood flow.

Special populations:

In the elderly population, there is no specific dose modification compared to adults.

Liver insufficiency or hepatic shock:

In patients with mild or moderate liver insufficiency (e.g., Child-Pugh ≤12), it may be necessary to reduce the dose. In the case of liver insufficiency (including, for example, cirrhosis), the initial citrate dose should be reduced, as metabolism may be inadequate. It is recommended to monitor citrate accumulation frequently. Regiocit should not be administered to patients with severely reduced liver function or hepatic shock with muscle hypoperfusion (e.g., conditions such as septic shock and lactic acidosis) due to reduced citrate metabolism.

Overdose

The administration of excessively high volumes of replacement solution can cause an overdose, which can potentially be fatal for the patient. This can result in pulmonary edema and congestive heart failure related to fluid overload and hypocalcemia and metabolic alkalosis due to citrate overload in relation to blood flow. This condition should be corrected immediately by stopping or reducing the amount of replacement solution and administering intravenous calcium. Supplemental calcium administration with caution may reverse the effects of the overdose. The risk can be minimized with close monitoring during treatment.

In patients with deteriorated citrate metabolism (liver insufficiency or hepatic shock)the overdose may present as citrate accumulation,metabolic acidosis, hypercalcemia total systemic and hypocalcemiaof ionized calcium, along with an increase in the ratio of total calcium to ionized calcium.

The administration of Regiocit should therefore be reduced or stopped.

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

Preparation and handling

The solution can be disposed of with wastewater without causing any harm to the environment.

The following instructions should be followed:

Aseptic technique should be used throughout the manipulation and administration process to the patient. Remove the wrapping covering the bag immediately before use. Only use if the wrapping is not damaged, the seal is intact and the solution is transparent. Tighten the bag firmly to ensure there are no leaks. If a leak is observed, discard the solution immediately, as its sterility cannot be guaranteed. The solution should be used immediately after opening to prevent microbiological contamination.

I. If the Luer connector is used, remove the plug by turning and pulling. Connect the male Luer lock connector of the blood pump line to the female Luer connector of the bag through a pressure and turning movement. Ensure the connection is properly placed and tightened. Now the connector is open. Check that the liquid flows freely. (See Figure I below).

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

II. If the injection connector (or spike connector) is used, remove the plug by lifting it first. The injection port is a port that can be disinfected with a swab. Introduce the needle through the rubber wall afterwards. Check that the liquid flows freely. (See Figure II below).

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

Consult 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 color and/or precipitation, insoluble complexes or crystals.

Mix the solution thoroughly after adding the additives. The introduction and mixing of additives should always be done before connecting the solution bag to the extracorporeal circuit.

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