Keep this leaflet. You may need to read it again.
If you have any questions, consult your doctor.
If you experience any adverse reactions, including those not listed in this leaflet, consult your doctor or nurse. See section 4.

Contents of this leaflet:

What Custodiol is and what it is used for
What you need to know before using Custodiol
How to use Custodiol
Possible side effects
How to store Custodiol
Contents of the pack and other information

1. What Custodiol is and what it is used for

Custodiol is an aqueous solution containing a mixture of electrolytes and amino acids.
Custodiol is used:

only during heart surgery and in the context of organ harvesting for transplantation
for induced and reversible cardiac arrest during open-heart surgical procedures (cardioplegia in cardiac surgery)
for organ protection during bloodless surgical procedures (heart, kidney, liver)
for organ transplant preservation: perfusion and cold storage (heart, kidney, liver, pancreas)

2. What you need to know before using Custodiol

Custodiol must only be used during surgical procedures.
Do not use Custodiol:

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

Warnings and precautions
Children and adolescents
There is limited data available on the use of Custodiol in children and adolescents.
Other medicines and Custodiol
Inform your doctor if you are currently taking or using, have recently taken or used, or might take or use any other medicines.
No interactions are known with the following medicines, which are mainly used during, but often also before and after surgery:

certain medicines for the treatment of heart failure (cardiac glycosides)
tablets that increase urine excretion (diuretics)
medicines for the treatment of angina pectoris symptoms (e.g. chest pain or tightness)
medicines used in conditions of insufficient oxygen supply to the heart muscle (such as nitrates, beta-blockers or calcium antagonists)
medicines that lower blood pressure (e.g. beta-blockers or calcium channel blockers).

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or are breastfeeding, consult your doctor before using this medicine.
Driving and using machines
Custodiol does not affect the ability to drive vehicles or operate machinery.
Custodiol contains sodium
Custodiol contains 15.0 mmol of sodium per 1000 ml. This should be taken into consideration in patients on a low-sodium diet.
Custodiol contains 10.0 mmol of potassium per 1000 ml. This should be taken into consideration in patients with impaired renal function or in patients on a low-potassium diet.

3. How to use Organosol

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

If more Custodiol has been used than prescribed
Absorption of large amounts of Custodiol into the circulation may lead to volume overload and electrolyte imbalances (too low levels of calcium or sodium in the blood or too high levels of magnesium and potassium in the blood). In such cases, the doctor will perform periodic blood tests.
Note for the physician: further information on overdose is provided at the end of this leaflet.

If you have any doubts about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody experiences them.
Side effects with unknown frequency (cannot be estimated from the available data):
Systemic use of Custodiol may lead to a temporary reduction in blood pressure during surgery.
Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, please inform your doctor or nurse. You may also report side effects directly via the website:
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 Custodiol

Store in a refrigerator (2 °C – 8 °C).
Keep the vial or plastic bag in the outer packaging to protect the medicine from light.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp". The expiry date refers to the last day of that month.
Use only clear solutions, from colourless to pale yellow, in undamaged containers.
For single use only. After opening, use immediately. Discard any remaining solution.
Do not use this medicine if the solution is excessively yellow.
After opening, dilute any remaining medicinal solution with water and discard it.

6. Package Contents and Other Information

What Custodiol Contains

The active substances are sodium chloride, potassium chloride, magnesium chloride hexahydrate, histidine, histidine hydrochloride monohydrate, tryptophan, mannitol, calcium chloride dihydrate, and α-ketoglutaric acid.
The other excipients are water for injections and potassium hydroxide (to adjust pH).

Description of the Appearance of Custodiol and Contents of the Package
Custodiol is a clear solution available in the following pack sizes:
500 ml bottles
1000 ml bottles
1000 ml bags
2000 ml bags
5000 ml bags
10 x 500 ml bottles
6 x 1000 ml bottles
6 x 1000 ml bags
4 x 2000 ml bags
2 x 5000 ml bags
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
DR. FRANZ KÖHLER CHEMIE GMBH
Werner-von-Siemens-Str. 14-28, 64625 Bensheim
Germany
Tel.: 06251 1083-0 - Fax: 06251 1083-146
Email: [email protected]

Manufacturer
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 European Economic Area member states under the following names:
Austria Organosol Kardioplege Lösung / Organkonservierungslösung
Belgium Perisoc Solution de cardioplégie / preservation d'organe
Spain Perisoc Solución para cardioplegia y para conservación de órganos
France Perisoc Solution de cardioplégie / preservation d'organe
Italy Custodiol
Netherlands Cetomedic oplossing voor cardioplegie / bewaaroplossing voor organen
Portugal Organosol Solução para cardioplegia ou para conservação de órgãos
United Kingdom Perisoc Solution for Cardioplegia / Organ Preservation

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

Overdose
Large volumes of Custodiol entering the systemic circulation may lead to volume overload and electrolyte imbalances (hypocalcemia, hyponatremia, hypermagnesemia, hyperkalemia). Regular monitoring of serum electrolytes is recommended after systemic administration.
Complete inactivation renders the myocardium susceptible to dilation. Therefore, adequate ventricular drainage must be ensured. Do not exceed the recommended perfusion volumes and pressures. Particular caution is required for hearts of children and infants.

Dosage and Method of Administration
A. Cardioplegia
Perfusion volume:

Open-heart procedures: Solution temperature 6 °C – 10 °C for open-heart procedures
Perfusion rate is 1 ml/minute/gram of cardiac weight. Normal heart weight corresponds to approximately 0.5% of adult body weight, resulting in a total Custodiol volume between 1.5 and 2 liters.

Perfusion pressure (= pressure in the aortic root):
In adults, initially use 110–140 cm hydrostatic pressure, equivalent to 80–110 mmHg. The surgeon must ensure proper closure of the aortic valve. After cardiac arrest, reduce pressure by half to 50–70 cm hydrostatic pressure, equivalent to 40–50 mmHg. In cases of severe coronary stenosis, use higher pressure (approximately 50 mmHg).

Perfusion time:
With this dosage and pressure regimen, a perfusion time of 6–8 minutes is required for homogeneous myocardial equilibration and must not be shortened under any circumstances.

Custodiol Perfusion Technique:
Following aortic clamping and simultaneous "drainage" of the left ventricle, administer the solution antegrade. Cardioplegic perfusion can be performed using a roller pump with constant volume or by gravity (after cardiac arrest, the solution bag should be kept 40–50 cm above heart level).

Guidelines for Additional Cardioplegic Perfusion:
If additional cardioplegic perfusions are required, perfusion time should be 1–2 minutes (equivalent to 200–400 ml); perfusion pressure should correspond to the pressure used in the last minute of the initial cardioplegic coronary perfusion.

In most cases, moderate systemic hypothermia should be induced.
Normally, Custodiol is administered via the aortic root. In cases of aortic insufficiency or surgery for thoracic aortic dissection, the solution must be administered via selective coronary perfusion into the coronary ostia.

Due to limited clinical data, a positive benefit-risk ratio has not yet been confirmed for the use of Custodiol in short surgical procedures (<90 minutes).

Guidelines for Retrograde Perfusion into the Coronary Sinus
Do not exceed an infusion pressure of 30 mmHg (normally about 250 ml/min) for retrograde infusion of the same duration as antegrade infusion (at least 6–8 minutes).

B. Heart Transplantation
After cross-clamping the ascending aorta, perfuse the heart for at least 6 minutes. This corresponds to a perfusion rate of 1 ml/minute per gram of cardiac weight, up to a total of 3.5 liters or more in adults.

Perfusion pressure (= pressure in the aortic root):
In adults, initially use 110–140 cm hydrostatic pressure, equivalent to 80–110 mmHg. The surgeon must ensure proper closure of the aortic valve. After cardiac arrest, reduce pressure to 50–70 cm hydrostatic pressure, equivalent to 40–50 mmHg. In cases of severe coronary stenosis, maintain higher pressure (approximately 50 mmHg).

Perfusion time:
With this dosage and pressure regimen, a perfusion time of 6–8 minutes is required for homogeneous myocardial equilibration and must not be shortened under any circumstances.

Perfusion Technique:
Following aortic clamping and simultaneous "drainage" of the left ventricle, administer the solution antegrade. Cardioplegic perfusion can be performed using a roller pump with constant volume or by gravity (after cardiac arrest, the solution bag should be kept 40–50 cm above heart level).

If the heart perfused with Custodiol is intended for transplantation, it must be stored and transported in cold Custodiol at 2 °C–4 °C to maintain protection. This provides effective protective effects for at least five hours.

C. Kidney Transplantation
For the kidney, the following general usage guidelines are recommended:
Solution temperature: 5 °C – 8 °C
Perfusion volume:
Perfuse with 1.5 ml of Custodiol per minute per gram of estimated kidney weight (normal adult kidney weight is approximately 150 grams). Including 500 ml of preservation solution, a total volume of approximately 2.5 liters of Custodiol per organ is obtained.

Perfusion pressure (renal artery):
120–140 cm water column above kidney level, equivalent to approximately 90–110 mmHg at the tip of the perfusion catheter in the renal artery.

Perfusion time:
Using this dosage and pressure regimen, perfusion time is 8–10 minutes. This duration is necessary to ensure homogeneous equilibration of the kidney's extracellular space (including interstitial tissues and renal tubular system) and must not be reduced under any circumstances.

Concomitant measures:
To achieve maximum benefit from Custodiol's protective effect in the kidney, it is important to ensure pronounced diuresis before starting perfusion (pharmacologically and/or by patient hydration).

Custodiol is administered through the renal artery.
If the kidney perfused with Custodiol is intended for transplantation, it must be stored and transported in cold Custodiol at 2 °C–4 °C to maintain protective effects. This provides effective protection for up to 48 hours.

D. Liver Transplantation
For the liver, the following general usage guidelines are recommended:
Solution temperature: 5 °C – 8 °C
Perfusion time:
With this dosage and pressure regimen, perfusion time is 8 minutes (10–15 minutes).

Perfusion volume:
If simultaneously protecting liver, pancreas, and kidney in a so-called multi-organ donor, a perfusion volume of 150–200 ml of Custodiol solution/kg body weight is required. With this "general protection," this corresponds to a perfusion volume of cold Custodiol solution of 8–12 liters in patients weighing approximately 70–80 kg.

For surgical removal of the liver or part of the liver (e.g., in living donors) without other organs, the perfusion volume should be reduced accordingly.

Perfusion pressure:
100 cm water column above liver level.

Concomitant measures:
In the organ donor, blood must be heparinized before starting perfusion.

Additionally, for transplantation:
Bile ducts must be abundantly flushed with at least 100 ml of cold Custodiol, either in situ or ex situ—usually with the aid of a small-caliber catheter.

The surgically removed liver is packaged or shipped for transplantation immersed in cold Custodiol. The organ must be completely covered with cold Custodiol. A cold ischemia time <10 hours is recommended.

E. Pancreas
The volume and duration of perfusion used for the liver must be adapted for the pancreas, a much smaller organ. Optimal perfusion depends on careful cooling and blood removal from the organ, achieved using approximately 3–4 liters of Custodiol. Avoid excessive treatment and additional irrigation of the organ.

Previous research data suggest that care must be taken not to over-irrigate pancreatic allografts with any preservation solution, as this may induce edema and allograft pancreatitis; there also appears to be a clear benefit in keeping cold ischemia time as short as possible. A cold ischemia time <10 hours is recommended.

With larger irrigation volumes (>5 liters) and longer ischemia times (>12 hours), there may be a risk of allograft pancreatitis.

Paediatric Population
Only limited data are available regarding use in children and adolescents.

Heart

Perfusion pressure: in neonates and infants, initially 110–120 cm water column above heart level, equivalent to 80–90 mmHg; after cardiac arrest, reduce pressure to 40–50 cm water column, equivalent to 30–40 mmHg. In patients with severe coronary sclerosis, maintain higher pressure for a longer period. Open the right atrium and completely aspirate the cardioplegic solution from the bypass circuit to avoid hemodilution.

Perfusion volume depends on the child's age: 50 ml/kg (first month of life), 30 ml/kg (2nd month–1st year), 20 ml/kg (>1st year), with a perfusion time of 4–6 minutes in all cases. For example, with an estimated heart weight of 50 g, approximately 350 ml are required.