Summary of Product Characteristics (SmPC) - Corhum solution for Cardioplegia
1 NAME OF THE MEDICINAL PRODUCT
Corhum solution for cardioplegia / organ preservation
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1000 ml solution contain:
g mmol
Sodium chloride 0.8766 15.0 Potassium chloride 0.6710 9.0 Magnesium chloride hexahdrate 0.8132 4.0 L-Histidine hydrochloride monohydrate 3.7733 18.0 L-Histidine 27.9289 180.0 Tryptophan 0.4085 2.0 Mannitol 5.4651 30.0 2-oxoglutaric acid 0.1461 1.0 Calcium chloride dihydrate 0.0022 0.015
Excipients with known effect 1000 ml Corhum solution for cardioplegia / organ preservation contains 15.0 mmol sodium and 9.0 mmol potassium.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Solution for cardioplegia / organ preservation
Clear, colorless to slightly straw-yellow solution
pH: 7.02 – 7.20 at 25°C.
Osmolality: 279-341 mOsmol/kg.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
- Cardioplegia during cardiac surgery
- protection of organs during operations in a bloodless field (heart, kidney, liver),
- preservation of organ transplants: perfusion and cold storage (heart, kidney, liver, pancreas)
4.2 Posology and method of administration
Adults
A. Cardioplegia
Perfusion volume
The perfusion rate is 1 ml / minute / gram heart weight. The normal weight of the heart accounts for approximately 0.5% of body weight in an adult, leading to a total volume of {Invented name} between 1.5 and 2 litres.
Temperature of the solution 6 °C – 10 °C in open heart procedure.
- Perfusion pressure (= pressure in the aortic root): in adults, initially 110 to 140 cm hydrostatic pressure, equivalent to 80 to 110 mmHg are used. The surgeon has to make sure, that the aortic valve is closing properly. After onset of cardiac arrest, the pressure is reduced by half to 50 – 70 cm hydrostatic pressure, equivalent to 40 – 50 mmHg. In case of severe coronary stenosis, a higher pressure should be used (approx. 50 mmHg).
- Perfusion time: Using this dosing and pressure regimen, the perfusion time must be 6 – 8 minutes in order to achieve myocardial homogeneous equilibration and this time should not be shorter under any circumstances.
- Perfusion technique:
After clamping the aorta and simultaneous “venting” of the left ventricle, the solution will be administered antegrade. Cardioplegic perfusion can be performed by either a roller pump with constant volume or by gravity (after cardiac arrest, the solution bag must be kept at 40-50 mmHg).
Administration guidelines for additional cardioplegic perfusion:
If cardioplegic reperfusions gets necessary, 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 coronary perfusion.
In most cases, the patient is placed in moderate systemic hypothermia. Usually, Corhum is given via the aortic root. In case of aortic insufficiency and of dissection of thoracic aortic surgery, the solution must be administered by selective coronary perfusion into the coronary ostia.
Due to a limited amount of clinical data a positive benefit/risk ratio for the use of Corhum in short surgery procedures (<90 minutes) has not been confirmed yet. Administration guidelines for retrograde perfusion on coronary sinus: Do not exceed 30 mmHg infusion pressure (usually about 250 ml/min) for a retrograde infusion of the same duration as an antegrade infusion (6-8 minutes minimum).
B. Hearth transplantation
Following cross-clamping of the ascending aorta, the heart is perfused for at least 6 minutes. This follows a perfusion rate of 1 ml/minute per gram of heart weight, up to a total amount of 3.5 litres or more for adults.
Perfusion pressure (= pressure in the aortic root):
In adults, initially 110 to 140 cm hydrostatic pressure, equivalent to 80 to 110 mmHg are used. The surgeon has to make sure, that the aortic valve is closing properly. After onset of cardiac arrest, the pressure is reduced by half to 50 – 70 cm hydrostatic pressure, equivalent to 40 – 50 mmHg. In case of severe coronary stenosis, a higher pressure should be used (approx. 50 mmHg).
Perfusion time:
Using this dosing and pressure regimen, the perfusion time must be 6 – 8 minutes in order to achieve myocardial homogeneous equilibration and this time should not be shorter under any circumstances.
Perfusion technique:
After clamping the aorta and simultaneous “venting” of the left ventricle, the solution will be administered antegrade. Cardioplegic perfusion can be performed by either a roller pump with constant volume or by gravity (after cardiac arrest, the solution bag must be kept at 40-50 mmHg).
If the heart perfused with {Invented name} is to be transplanted, in order to maintain protection, it must be stored and transported in cold Corhum at 2°C – 4°C. Protection can then be reliably achieved for up to five hours.
C. Kidney transplantation
The following general administration guidelines are recommended for the kidney: Temperature of the solution: 5°C – 8°C
Perfusion volume:
Perfusion with 1.5 ml {Invented name} per minute and gram of estimated kidney weight (the normal weight of the kidney in an adult is approximately 150 grams). Including 500 ml storage solution, this leads to a total volume of ca. 2.5 litres of Corhum per organ.
Perfusion pressure (renal artery):
120 to 140 cm water column 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 and pressure regimen, the perfusion time is 8 – 10 minutes. This time is necessary in order to achieve homogeneous equilibration of the extracellular space of the kidney (including the interstitium and tubular system), and this time must not be shorter under any circumstances.
Accompanying measures:
In order to derive maximum benefit from the protective efficiency of Corhum in the kidney, it is important to ensure pronounced diuresis prior to the start of perfusion (pharmacologically and/or hydration of the patient).
Corhum is given via the Arteria renalis.
If the kidney perfused with {Invented name} is to be transplanted, in order to maintain protection it must be stored and transported in cold Corhum at 2°C – 4°C. Protection can then be reliably achieved for 48 hours.
D. Liver transplantation
The following general administration guidelines are recommended for the liver: Temperature of the solution: 5°C – 8°C
Perfusion time:
Using this dosing and pressure regimen, the perfusion time is 8 minutes (10-15 minutes).
Perfusion volume:
If the liver, pancreas and kidneys are to be protected all together in a so-called donor organism, a perfusion quantity of 150 – 200 ml {Invented name}/kg body weight is necessary. With this "overall protection", this is equivalent to a perfusion quantity of cold Corhum -solution of 8 – 12 l in patients weighing approximately 70 – 80 kg. If only the liver or a part of the liver (e.g. in the case of live donation) is being removed without other organs, the perfused volume is reduced accordingly.
Perfusion pressure:
100 cm water column above the level of the liver.
Accompanying measures:
In an organ donor, the blood must be heparinised prior to the start of perfusion. The bile ducts should be abundantly rinsed with a minimum of 100 ml cold Corhum inside or outside the body - usually with the aid of a small-calibre catheter. The surgically removed liver is then packed or sent for transplantation immersed in cold Corhum. The organ must be fully covered by cold Corhum. A cold ischaemia time <10 hours is advised.
E. Pancreas
Perfusion volume and time should be adjusted from the liver to the much smaller graft, which is the pancreas. Optimal perfusion depends on a thorough cooling and exsanguination of the organ. This can be achieved with approximately 3-4 liters of {Invented name}. Overtreatment and reflushing of the graft should be avoided.
Previous research suggests that care must be taken not to overflush the pancreas allograft with any preservation solution as this may lead to allograft oedema and pancreatitis and there seems to be a clear benefit to maintaining as brief a cold ischaemia time as possible. A cold ischaemia time <10 hours is advised. With higher flush volumes (>5 l) and longer ischaemic times (>12 h), there may be a risk of allograft pancreatitis.
Paediatric population
There is only a limited amount of data regarding the use in children and adolescents.
Heart
Perfusion pressure: In neonates and infants, initially 110 to 120 cm water column above the level of the heart, equivalent to 80 to 90 mmHg; after the onset of cardiac arrest, reduction to 40 to 50 cm water column, equivalent to 30 to 40 mmHg. In patients with severe coronary sclerosis, higher pressures over a longer period of time should be maintained. The right atrium should be opened and the cardioplegia completely aspirated outside the bypass circuit to avoid haemodilution.
The perfusion volume depends on the age of the children: 50 ml/kg (first month of life), 30 ml/kg (2nd month-1st year), 20 ml/kg (>1st year), while perfusion time is 4-6 minutes in all cases.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Only colorless to slightly straw-yellow solutions from intact containers should be used. Yellow colored solutions that are due to the presence of tryptophan degradation products should not be used.
Corhum will be taken out of the refrigerator just before use.
Corhum is not intended for intravenous or intra-arterial administration. Corhum is not suitable for replenishment of circulatory volume or for replacement of amino acids or electrolytes.
As a precaution, in the event of an emergency operation on the heart during pregnancy, the cardioplegic solution must be aspirated from the right atrium and ventricle after completion of the operation.
Depending on the nature of the surgical operation, the technique employed, the duration of the operation and the weight of the patient, up to 3 liters of cardioplegic solution may enter the systemic circulation. This can result in some lowering of serum levels of calcium and sodium. In such cases appropriate laboratory checks must therefore be performed.
Inactivation of the heart accounts for its susceptibility to distension. Thus, relaxation of the left ventricle must take place when inducing cardioplegia and is important to ensure adequate ventricular drainage. The recommended perfusion volumes and pressures should not be exceeded. Special caution is required for the hearts of children and infants. For details regarding perfusion volumes, perfusion times and perfusion technique please refer to the recommendations given in section 4.2.
Because the sodium concentration in Corhum is lower than in blood, administration of Corhum may cause hyponatraemia. It is important to note that this hyponatremia does not modify blood osmolarity because Corhum has an osmolarity close to that of blood. Therefore, no deleterious consequences are expected in the patient from the decreased sodium level caused by Corhum administration.
In order to mitigate the haemodilution consequences associated with the use of Corhum in cardiac surgery, it is recommended to use hemofiltration during CEC.
In case of improper permanent perfusion with insufficiently cooled cardioplegic solution (>20°C and >15 minutes), a so-called calcium paradox can be initiated, which occurs after reconnection to the circulation as destruction of the cardiac muscle cells. This risk does not apply to solutions with a sodium content of <20 mmol/l, if the calcium content is >10 µmol/l and the solution is cold, i.e. <15°C and perfused continuously for a limited period of time i.e. no longer than 20 minutes.
Immersion of a whole heart in cold Corhum, however, does not represent a risk in the sense of a calcium paradox even when used over hours - e. g. for the time interval between removal of the organ from the donor and transplantation into a recipient. Therefore, with proper application, a calcium paradox is virtually impossible even under extreme experimental conditions.
Reversal of cardioplegia occurs by re-opening the aorta. It is advisable to initially perfuse the myocardium, which is very flaccid as a result of the cardioplegia, with a low blood pressure (mean arterial pressure of 40 mmHg for approximately 2 minutes). As the activity of the myocardium increases, the perfusion pressure can be returned to normal. Cardiac activity frequently returns with a spontaneous rhythm, otherwise one defibrillation is generally sufficient.
Corhum contains 15.0 mmol sodium per 1000 ml, equivalent to 17% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Corhum contains 9.0 mmol potassium per 1000 ml. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.
This solution is not intended for use with a continuous perfusion machine.
4.5 Interaction with other medicinal products and other forms of interaction
Interactions with drugs such as glycosides, diuretics, nitro products, antihypertensives, beta-receptor blockers and calcium antagonists, which are frequently used perioperatively and in particular during surgery, are unknown.
4.6 Fertility, pregnancy and lactation
Pregnancy and breast-feeding
Corhum should be used during pregnancy and breast-feeding only after carefully assessing the benefit/risk ratio (see also section 4.4).
For safety reasons, in case of emergency surgery during pregnancy, the cardioplegic solution should be aspirated from the right ventricle of the heart after completing the operation.
Fertility
It is not known if the active ingredients of Corhum or its metabolites have any effect on fertility.
4.7 Effects on ability to drive and use machines
Corhum has no influence or a negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Cardiac/vascular disorders
Not known (frequency cannot be estimated from the available date) Therapeutic use of Corhum may reduce blood pressure, since during the solution storage L-histidine and 2-oxoglutaric acid may form a reaction product (micimopin) that blocks the angiotensin II receptors of the subtype 1, possibly lowering the blood pressure.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
The intake of large volumes of Corhum into the systemic circulation may lead to an excessive circulating volume with consequent electrolytic imbalance (hypocalcemia, hyponatremia, hypermagnesemia, hyperkalemia). An adequate monitoring of serum electrolytes is recommended.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Blood substitutes and perfusions solutions, i.v. solution additives, electrolyte solutions.. ATC-Code: B05XA16
The two main mechanisms of an organ-protective solution are:
- minimizing the energy requirement of the organ for the duration of ischemia through cell inactivation;
- optimization of anaerobic (glycolytic) energy production for the duration of ischemia by artificial buffering of the organ.
Activation of cells takes place through a depolarization of the outer membrane and an increase in the Ca2+ concentration in the cytoplasm. This intracellular increase in Ca2+ is partly due to the Ca2+ influx from the extracellular space.
Corhum causes the inactivation of the heart primarily due to the electrolytic composition. Reducing the sodium concentration to approximately cytoplasmic levels (around 15 mmol/l) and simultaneously lowering the calcium concentration to the level of a quiescent cell in the cytoplasm (<10 µmol/l) stabilizes the membrane potential of the cells near the normal resting potential and prevents the intracellular cell-activating sodium and calcium influx.
5.2 Pharmacokinetic properties
Biotransformation:
The degradation of 2-oxoglutaric acid takes place through the citric acid cycle, partially also through glutamine and glutamic acid.
L-histidine and Tryptophan are mainly metabolized in the liver, partially also excreted renally.
Mannitol is eliminated unchanged via the kidney.
5.3 Preclinical safety data
Preclinical data did not indicate toxic properties of Corhum
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injections
Potassium hydroxide (for pH adjustment)
Nitrogen
6.2 Incompatibilities
In the absence of further information this product must not be mixed with other medicinal products.
6.3 Shelf life
12 months at 2°C – 8°C.
For single use only. Use immediately after opening.
Unused solution must be discarded (see section 6.6).
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C) and keep bags in outer carton in order to protect from light.
Do not freeze.
6.5 Nature and contents of container
Corhum solution for cardioplegia is available in 1000 ml and 2000 ml bags (polyolefin/styrene block copolymer) with two tubings (polyolefin/styrene block copolymer) closed with a perforable stopper in polyisoprene with silicate filler and polycarbonate and a chlorobutyl injection stopper. The bags are packed inside polypropylene overbags to ensure outer sterility of the primary bag.
Carton box with 10 x 1000 ml bags
Carton box with 5 x 2000 ml bags
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Use only clear and colorless to slightly straw-yellow solutions from intact containers. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
S.A.L.F. SpA Laboratorio Farmacologico
Via G. Marconi, 2
24069 Cenate Sotto (Bergamo) - Italy
8 MARKETING AUTHORISATION NUMBER(S)
PL 29472/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/11/2023
10 DATE OF REVISION OF THE TEXT
18/02/2026