Prospect: information for the patient

Custodiol Solution for cardioplegia and for organ preservation

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 doubts, consult your doctor.
• If you experience adverse effects, consult your doctor or nurse, even if they are not listed in this prospect. See section 4.

1.What is Custodiol and how it is used

2.What you need to know before starting to use Custodiol

3.How to use Custodiol

4.Possible adverse effects

1. Conservation of Custodiol

6. Contents of the package and additional information

Custodiol is an aqueous solution with a mixture of electrolytes and amino acids.

Custodiol is used:

-only during cardiac surgical interventions and organ extraction for transplantation

-in induced and reversible cardiac standstill during open-heart surgical interventions (cardioplegia in cardiac surgical interventions)

-for organ protection during bloodless surgical interventions (heart, kidney, liver)

-for organ transplant preservation: perfusion and cold storage (heart, kidney, liver, pancreas)

Custodiol should only be used intraoperatively.

Do not use Custodiol:

- if you are allergic to the active ingredients or to any of the other components of this medication (listed in section 6).

Warnings and precautions

Children and adolescents

There is limited information available on the use in children and adolescents.

Using Custodiol with other medications

Inform your doctor if you are taking or using, have taken or used recently, or may need to take or use any other medication.

No interactions are known with the following medications that are used especially during and also frequently before and after the procedure:

- certain medications for treating heart failure (cardiac glycosides)

- tablets to urinate (diuretics)

- medications for treating angina symptoms (e.g., chest pain or pressure).

- medications used in situations where oxygen supply to the heart muscle is insufficient (such as nitrates, beta-blockers, or calcium channel blockers)

- medications that lower blood pressure (such as, e.g., beta-blockers or calcium channel blockers).

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor before using this medication.

Driving and operating machines

Custodiol has no influence on the ability to drive and operate machines.

Custodiol contains sodium

Custodiol contains 15.0 mmol of sodium per 1,000 ml, which should be taken into account in patients with low-sodium diets.

Custodiol contains 10.0 mmol of potassium per 1,000 ml, which should be taken into account in patients with renal insufficiency or in patients with low-potassium diets.

The treatment regimen and dosage must be determined by a specialist. Custodiol should only be administered by healthcare professionals, i.e., by a doctor or a nurse. Consult the posological recommendations in the detailed information for healthcare professionals at the end of this leaflet.

If more Custodiol than prescribed has been used

The transfer of large quantities of Custodiol to the systemic circulation may cause a volume overload and electrolyte disturbances (serum levels of calcium or sodium too low or magnesium or potassium too high). In this case, your doctor will perform periodic blood tests.

Note for the doctor:You can find more information about overdose at the end of this leaflet.

If you have any other questions about the use of this medication, ask your doctor or nurse.

Like all medications, this medication may produce adverse effects, although not all people will experience them.

Adverse effects of unknown frequency (cannot be estimated from available data):

The systemic use of Custodiol may cause a temporary reduction in blood pressure during the surgical procedure.

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or nurse,even if it is about possible adverse effects that do not appear in this prospectus. You can also report them directly through the national notification system Spanish System of Pharmacovigilance of Medicinal Products for Human Use:www.notificaRAM.es

By reporting adverse effects, you can contribute to providing more information about the safety of this medication.

Store in the refrigerator (between 2°C and 8°C).

Store the bottle or plastic bag in the outer packaging to protect them from light.

Keep this medication out of sight and reach of children.

Do not use this medication after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Use only transparent, colorless to pale yellow solutions in undamaged containers. For single use only. Once opened, use immediately. Discard any remaining solution.

Do not use this medication if the solution has an excessively yellow color.

After opening, unused product must be diluted with water and discarded through the drain.

Composition of Custodiol

• The active principles are sodium chloride, potassium chloride, magnesium chloride hexahydrate, histidine, monohydrate histidine chloride, tryptophan, mannitol, dihydrate calcium chloride, and alpha-cetoglutaric acid.
• The other excipients are water for injection and potassium hydroxide (for pH adjustment).

Aspect of the product and contents of the package

Custodiol is a transparent solution and is available in the following package sizes:

500 ml bottles

1,000 ml bottles

1,000 ml bags

2,000 ml bags

5,000 ml bags

10 x 500 ml bottles

6 x 1,000 ml bottles

6 x 1,000 ml bags

4 x 2,000 ml bags

2 x 5,000 ml bags

It may only be marketed in some package sizes.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

DR. FRANZ KÖHLER CHEMIE GMBH

Werner-von-Siemens-Str. 14-28

64625 Bensheim

Germany

Local Representative

Cardiolink S.L.

Córcega 270, 3º-2ª

08008 Barcelona

Spain

Tel: +34 932 370 274

email: [email protected]

Responsible for manufacturing

DR. FRANZ KÖHLER CHEMIE GMBH

Werner-von-Siemens-Str. 14-28, 64625 Bensheim

Germany

Tel.: 06251 1083-0 - Fax: 06251 1083-146

www.koehler-chemie.de -[email protected]

This medicinal product is authorized in the Member States of the European Economic Area with the following names:

AustriaOrganosol Kardioplege Lösung / Organkonservierungslösung

BelgiumPerisoc Solution de cardioplégie / preservation d'organe

SpainCustodiol Solución para cardioplejía y para conservación de órganos

FrancePerisoc Solution de cardioplégie / preservation d'organe

ItalyConasoc

NetherlandsCetomedic Solution for Cardioplegia / bewaaroplossing voor organen

PortugalCustodiol Solução para cardioplegia ou para conservação de órgãos

United KingdomCustodiol Solution for Cardioplegia / Organ Preservation

Last review date of this leaflet:February 2022.

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This information is intended solely for doctors and healthcare professionals:

Overdose

The transfer of large volumes of Custodiol to the systemic circulation may cause volume overload and electrolyte disturbances (hypocalcemia, hyponatremia, hypermagnesemia, hyperkalemia). Periodic monitoring of serum electrolytes is recommended after systemic application.

The complete inactivation makes the myocardium prone to distension. Therefore, it is essential to ensure adequate ventricular drainage. The recommended volumes and pressures of perfusion should not be exceeded. Special caution should be exercised in children's and infants' hearts.

Dosage and administration

A.Cardioplegia:

-Perfusion volume:

• Open-heart procedures:

Temperature of the solution between 6°C and 10°C in open-heart procedures

The perfusion rate is 1ml/min/gram of cardiac weight. The normal cardiac weight corresponds to approximately 0.5% of the body weight in an adult, resulting in a total volume of Custodiol between 1.5 and 2liters.

Perfusion pressure (=pressure in the aortic root):

In adults, an initial pressure of 110 to 140cm, equivalent to 80 to 110mmHg, is used. The surgeon must ensure that the aortic valve is closing properly. After the onset of cardiac arrest, the pressure is reduced to half, i.e., to a pressure of 50 to 70cm, equivalent to 40 to 50mmHg. In cases of severe coronary stenosis, a higher pressure (approximately 50mmHg) should be used.

Perfusion time:

Using this dosing and pressure regimen, the perfusion time should be 6‑8minutes to achieve a homogeneous myocardial equilibrium and should not be shorter under any circumstances.

Perfusion technique:

After aortic pinching and simultaneous ventricular aspiration, the solution is administered anterogradely. Cardioplegic perfusion can be administered using a roller pump with constant volume or by gravity (after cardiac arrest, the bag with the solution should be kept 40‑50 cm above the heart level).

Additional guidelines for administering cardioplegic perfusions:

If it is necessary to administer additional cardioplegic perfusions, the perfusion time should be 1‑2minutes (equivalent to 200‑400ml); the perfusion pressure should correspond to the pressure in the last minute of the initial cardioplegic perfusion.

In most cases, the patient is subjected to moderate systemic hypothermia.

Custodiol is usually administered through the aortic root. In cases of aortic insufficiency and thoracic aortic dissection surgery, the solution should be administered via selective coronary perfusion through the coronary orifices.

Due to limited clinical data, the relationship between benefit and risk has not been confirmed for the use of Custodiol in short surgical procedures (<90minutes).

Perfusion guidelines for retrograde perfusion in the coronary sinus

Do not exceed a perfusion pressure of 30mmHg (usually 250ml/min) in retrograde perfusions of the same duration as anterograde perfusions (6‑8minutes as a minimum).

B.Heart transplantation:

After transverse pinching of the ascending aorta, the heart is perfused for at least 6minutes. This is done at a perfusion rate of 1ml/min/gram of cardiac weight, up to a total volume of 3.5liters or more for adults.

Perfusion pressure (=pressure in the aortic root):

In adults, an initial pressure of 110 to 140cm, equivalent to 80 to 110mmHg, is used. The surgeon must ensure that the aortic valve is closing properly. After the onset of cardiac arrest, the pressure is reduced to half, i.e., to a pressure of 50‑70cm, equivalent to 40‑50mmHg. In cases of severe coronary stenosis, a higher pressure (approximately 50mmHg) should be used.

Perfusion time:

Using this dosing and pressure regimen, the perfusion time should be 6‑8minutes to achieve a homogeneous myocardial equilibrium and should not be shorter under any circumstances.

Perfusion technique:

After aortic pinching and simultaneous ventricular aspiration, the solution is administered anterogradely. Cardioplegic perfusion can be administered using a roller pump with constant volume or by gravity (after cardiac arrest, the bag with the solution should be kept 40‑50 cm above the heart level).

If the Custodiol-perfused heart is to be transplanted, it should be stored and transported in Custodiol cold at 2°C to 4°C to maintain protection. This allows for reliable protection for a maximum of five hours.

C.Kidney transplantation:

For the kidney, the following general guidelines for administration are recommended:

Temperature of the solution: between 5°C and 8°C

Perfusion volume:

Perfusion of 1.5ml of Custodiol per minute and gram of estimated kidney weight (the normal kidney weight in an adult is approximately 150grams). Including the 500ml conservation solution, this results in a total volume of approximately 2.5liters of Custodiol per organ.

Perfusion pressure (renal artery):

Column of 120 to 140cm of water above the kidney level, equivalent to approximately 90 to 110mmHg at the tip of the perfusion catheter in the renal artery.

Perfusion time:

Using this dosing and pressure regimen, the perfusion time is 8‑10minutes. This time is necessary to achieve a homogeneous equilibrium of the extracellular space of the kidney (including the interstitium and the tubular system) and should not be shorter under any circumstances.

Accompanying measures:

To obtain the maximum benefit of the protective efficacy of Custodiol in the kidney, it is essential to ensure pronounced diuresis before the onset of perfusion (using drugs and/or patient hydration).

Custodiol is administered through the renal artery.

If the Custodiol-perfused kidney is to be transplanted, it should be stored and transported in Custodiol cold at 2°C to 4°C to maintain protection. This allows for reliable protection for 48hours.

D.Liver transplantation:

For the liver, the following general guidelines for administration can be recommended:

Temperature of the solution: between 5°C and 8°C

Perfusion time:

Using this dosing and pressure regimen, the perfusion time is 8minutes (10‑15minutes).

Perfusion volume:

If it is necessary to protect the liver, pancreas, and kidneys simultaneously in a so-called organ donor, a perfusion volume of 150‑200ml of Custodiol/kg body weight is required. With this "global protection," this corresponds to a perfusion volume of 8‑12liters in patients with an approximate weight of 70‑80kg.

Perfusion pressure:

Column of water of 100cm above the liver level.

Accompanying measures:

In an organ donor, the blood should be heparinized before the onset of perfusion.

Additional measures for transplantation:

The bile ducts should be lavaged abundantly with a minimum of 100ml of cold Custodiol, either inside or outside the body, usually with the help of a small-caliber catheter.

Subsequently, the surgically removed liver should be packaged or sent for transplantation immersed in cold Custodiol. The organ should be completely covered with cold Custodiol. A cold ischemia time of <10hours is recommended.

E.Pancreas transplantation:

The perfusion volume and time should be adjusted, compared to the liver, to a much smaller-sized graft, such as the pancreas. The optimal perfusion depends on a meticulous cooling and exsanguination of the organ. This can be achieved with approximately 3‑4liters of Custodiol. Overperfusion and lavage of the graft should be avoided.

Previous investigations suggest that care should be taken not to excessively lavage the pancreas graft with any conservation solution, as this may cause edema and graft pancreatitis and appears to be a clear benefit of maintaining a cold ischemia time as short as possible. A cold ischemia time of <10hours is recommended.

With larger lavage volumes (>5liters) and longer cold ischemia times (>12h), there may be a risk of graft pancreatitis.

Pediatric population:

Only limited data are available on the use in children and adolescents.

Heart

-Perfusion pressure: in newborns and infants, an initial pressure of 110‑120cm of water above the heart level, equivalent to 80‑90mmHg; after the onset of cardiac arrest, reduction to a pressure of 40‑50cm of water, equivalent to 30‑40mmHg. In patients with severe coronary stenosis, higher pressures should be maintained for a longer period. The right atrium should be opened and the cardioplegia completely aspirated from the derivation circuit to avoid hemodilution.

The perfusion volume depends on the child's age: 50ml/kg (1stmonth of life), 30ml/kg (2ndmonth‑1styear), 20ml/kg (>1styear), while the perfusion time is4‑6minutes in all cases. For example, an estimated cardiac weight of 50g would require approximately 350ml.