CUSTODIOL SOLUTION FOR CARDIOPLEGIA AND ORGAN PRESERVATION

Introduction

Package Leaflet: Information for the Patient

Custodiol Solution for Cardioplegia and Organ Preservation

Read the entire package leaflet carefully before starting to use this medication, as it contains important information for you.

• Keep this package leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this package leaflet. See section 4.

Contents of the Package Leaflet

1. What is Custodiol and what is it used for
2. What you need to know before using Custodiol
3. How to use Custodiol
4. Possible side effects
   1. Storage of Custodiol

1. Contents of the Pack and Further Information

1. What is Custodiol and what is it used for

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

Custodiol is used:

• only during cardiac surgical interventions and organ harvesting for transplantation
• for induced and reversible cardiac arrest in open-heart surgical interventions (cardioplegia in cardiac surgery)
• for organ protection during interventions in a blood-free field (heart, kidney, liver)
• for the preservation of transplanted organs: perfusion and cold storage (heart, kidney, liver, pancreas)

2. What you need to know before using Custodiol

Custodiol should only be used intraoperatively.

Do not use Custodiol:

Warnings and Precautions

Children and Adolescents

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

Use of Custodiol with Other Medications

Tell your doctor if you are taking or have recently taken or might take any other medications.

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

• certain medications for treating heart failure (cardiac glycosides)
• diuretics (pills to make you urinate)
• medications for treating symptoms of angina pectoris (e.g. pain or pressure in the chest)
• medications used in situations where oxygen supply to the cardiac muscle is insufficient (such as nitrates, beta-blockers or calcium antagonists)
• medications that reduce blood pressure (such as beta-blockers or calcium channel blockers)

Pregnancy and Breastfeeding

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

Driving and Using Machines

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

Custodiol Contains Sodium

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

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 on a low-potassium diet.

3. How to Use Custodiol

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

If More Custodiol Has Been Used Than Prescribed

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

Note for the Doctor:You can find more information on overdose at the end of this package leaflet.

If you have any further questions on the use of this medication, ask your doctor or pharmacist.

4. Possible Side Effects

Like all medications, this medication can cause side effects, although not everybody gets them.

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

Systemic use of Custodiol may cause a temporary reduction in blood pressure during surgery.

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this package leaflet. You can also report side effects directly via the national reporting system, Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es

By reporting side effects, you can help provide more information on the safety of this medication.

5. Storage of Custodiol

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

Keep the bottle or plastic bag in the outer packaging to protect it from light.

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

Do not use this medication after the expiry date stated on the packaging after EXP. The expiry date is the last day of the month indicated.

Use only clear, colorless to pale yellow solutions, in undamaged containers. For single use only. Use immediately after opening. Discard any remaining solution.

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

After opening, the unused product must be diluted with water and disposed of down the drain.

6. Contents of the Pack and Further Information

Composition of Custodiol

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

Appearance and Packaging of the Product

Custodiol is a clear solution and is available in the following pack sizes:

Bottles of 500 ml

Bottles of 1,000 ml

Bags of 1,000 ml

Bags of 2,000 ml

Bags of 5,000 ml

10 bottles x 500 ml

6 bottles x 1,000 ml

6 bags x 1,000 ml

4 bags x 2,000 ml

2 bags x 5,000 ml

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

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: cardiolink@cardiolink.es

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 - info@koehler-chemie.de

This Medication is Authorized in the Member States of the European Economic Area Under the Following Names:

Austria Organosol Kardioplege Lösung / Organkonservierungslösung

Belgium Perisoc Solution de cardioplégie / preservation d'organe

Spain Custodiol Solución para cardioplejía y para conservación de órganos

France Perisoc Solution de cardioplégie / preservation d'organe

Italy Conasoc

Netherlands Cetomedic Solution for Cardioplegia / bewaaroplossing voor organen

Portugal Custodiol Solução para cardioplegia ou para conservação de órgãos

United Kingdom Custodiol Solution for Cardioplegia / Organ Preservation

Date of Last Revision of this Package Leaflet:February 2022.

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This information is intended only for healthcare professionals:

Overdose

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 after systemic application is recommended.

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

Dosage and Administration

• Cardioplegia:

- Perfusion volume:

• Open-heart procedures:

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

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

Perfusion pressure (= pressure at the aortic root):

In adults, an initial hydrostatic pressure of 110 to 140 cm is used, equivalent to 80 to 110 mmHg. 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 hydrostatic pressure of 50 to 70 cm, equivalent to 40 to 50 mmHg. In case of severe coronary stenosis, a higher pressure (approx. 50 mmHg) should be used.

Perfusion time:

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

Perfusion technique:

After aortic cross-clamping and simultaneous left ventricular aspiration, the solution is administered anterogradely. The 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 level of the heart).

Guidelines for administration of additional cardioplegic perfusions:

If further cardioplegic perfusions are necessary, the perfusion time should be 1 - 2 minutes (equivalent to 200 - 400 ml); 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 case of aortic insufficiency and thoracic aortic dissection surgery, the solution should be administered by selective coronary perfusion through the coronary orifices.

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).< p>

Guidelines for administration of retrograde perfusions in the coronary sinus

Do not exceed a perfusion pressure of 30 mmHg (normally around 250 ml/minute) in retrograde perfusions of the same duration as anterograde perfusions (6 - 8 minutes as a minimum).

• Heart Transplantation:

After cross-clamping of the ascending aorta, the heart is perfused for at least 6 minutes. This is done with a perfusion rate of 1 ml/minute/gram of heart weight, up to a total amount of 3.5 liters or more for adults.

Perfusion pressure (= pressure at the aortic root):

In adults, an initial hydrostatic pressure of 110 to 140 cm is used, equivalent to 80 to 110 mmHg. 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 hydrostatic pressure of 50 - 70 cm, equivalent to 40 - 50 mmHg. In case of severe coronary stenosis, a higher pressure (approx. 50 mmHg) should be used.

Perfusion time:

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

Perfusion technique:

After aortic cross-clamping and simultaneous left ventricular aspiration, the solution is administered anterogradely. The 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 level of the heart).

If the heart perfused with Custodiol is to be transplanted, it should be stored and transported in cold Custodiol at 2 - 4 °C to maintain protection. This allows for reliable protection for up to 5 hours.

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

Perfusion pressure (renal artery):

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

Perfusion time:

Using this dosing regimen and pressure, the perfusion time is 8 - 10 minutes. 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 a pronounced diuresis before the start of perfusion (using medications and/or patient hydration).

Custodiol is administered through the renal artery.

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

• 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 regimen and pressure, the perfusion time is 8 minutes (10 - 15 minutes).

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 - 200 ml of Custodiol solution/kg of body weight is required. With this "global protection", this corresponds to a perfusion volume of 8 - 12 liters of cold Custodiol solution in patients with an approximate weight of 70 - 80 kg.

If only the liver or part of it (e.g. in the case of a living donor) is to be harvested without other organs, the perfused volume is reduced accordingly.

Perfusion pressure:

Water column of 100 cm above the level of the liver.

Accompanying measures:

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

Additional measures for transplantation:

The bile ducts should be thoroughly flushed with a minimum of 100 ml of cold Custodiol, usually with the help of a small-caliber catheter.

Then, the surgically removed liver is packed or sent for transplantation immersed in cold Custodiol. The organ must be completely covered with cold Custodiol. A cold ischemia time of <10 hours is recommended.< p>

• Pancreas

The volume and perfusion time should be adjusted, with respect to the liver, to a much smaller graft, such as the pancreas. Optimal perfusion depends on careful cooling and exsanguination of the organ. This can be achieved with approximately 3 - 4 liters of Custodiol. Over-treatment and washing out of the graft should be avoided.

Preliminary investigations suggest that care should be taken not to excessively wash the pancreatic graft with any preservation solution, as this may cause edema and pancreatitis of the graft, and there appears to be a clear benefit in keeping the cold ischemia time as short as possible. A cold ischemia time of <10 hours is recommended.< p>

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

Pediatric Population:

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

Heart

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

The perfusion volume depends on the age of the child: 50 ml/kg (1st month of life), 30 ml/kg (2nd month - 1st year), 20 ml/kg (>1st year), while the perfusion time is 4 - 6 minutes in all cases. For example, an estimated heart weight of 50 g would require approximately 350 ml.