Cardilan Injection

SUMMARY OF PRODUCT CHARACTERISTICS 

1.  NAME OF THE MEDICINAL PRODUCT 

                                        CARDILAN

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
Active substance: 
                Potassium hydrogen aspartate hemihydrate 500 mg, 
                Magnesium hydrogen aspartate tetrahydrate 500 mg in 10  ml. 
                10 ml contains 108.5 mg of potassium, equivalent to 2.77 mmol. 
                10 ml containing 33.7 mg of magnesium, equivalent to 1.39 mmol. 
For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 
Solution for injection 
Clear, colorless or slightly yellow liquid.

4. CLINICAL PARTICULARS
4. 1 Therapeutic indications 
Cardilan is used in combination with cardiotonics in chronic conditions associated with cellular depletion of potassium ions, magnesium ions and to prevent their loss. 
It is used in digitalis intolerance or intoxication. 

4.2 Posology and method of administration 
a) Dosage for children: 
Administration of the product is not recommended in pediatrics. 
b) Dosage for adults: 
 1-2 ampoules of 10 ml, 1-2 times a day slowly, intravenously, better in microinfusion in 100 ml of 10% glucose solution or isotonic sodium chloride solution.  In urgent cases 4-5 ampoules in 500 ml of 10% glucose solution at 20 drops per minute may be administered.

4.3 Contraindications 
Cardilan is contraindicated in hyperkalaemia, hypermagnesemia, metabolic acidosis, in anuric phase of acute renal failure and in oliguric phase of chronic renal insufficiency.
In addition in Addison's disease and AV block of higher degree. 
 
4.4 Special warnings and precautions for use 
 Liver and kidney failure: in metabolic acidosis and in acute or chronic renal failure
 the product is not administered. 
The combination with potassium-sparing agents or with other drugs containing potassium is not recommended, due to the potentiation effect.  Concomitant use of these substances requires more frequent monitoring of potassium plasma levels. 

 4.5 Interactions with other medicinal products and other forms of interaction
Co-administration with dietary supplements, such as containing potassium or magnesium migt come into consideration, because it leads to additive effect . 
 Interactions with other drugs are not expected.  In eclampsia after suxamethonium coadministration or precisely after curare derivatives myorelaxants coadministration ,the neuromuscular blocking effect is potentiated. 

4.6 Pregnancy and lactation 
The same restrictions as for other supplements containing potassium or magnesium are valid.  Magnesium 
 at high doses is increasingly excreted into breast milk and may cause diarrhea in infants. 

4.7 Effects on ability to drive and use machines 
Cardilan has not been tested for potential reduction of attention when driving, but according to the mechanism of action of potassium and magnesium aspartate ,when used in recommended doses, side effects does not come into account.

4.8 Undesirable effects 
 In clinical controlled studies, phase  II.  and  III. , side effects as gastrointestinal discomfort - pressure in the epigastrium, diarrhea and nausea has been mostly observed.
 During the rapid intravenous injection symptomps of hyperkalemia nad hypermagnesemia may occur.  The long-term high doses might cause kidney damage. 

4.9. Overdose 
Is manifested as hyperkalemia nad hypermagnesemia . Particularly vulnerable are patients with disorders of the internal environment, dehydrated persons, patients with renal impairment and those suffering from cardiovascular disease. 
Symptoms of hyperkalemia: paresthesia of the extremities, muscle weakness, bradycardia, in the terminal phase of cardiac arrest or ventricular fibrillation.  ECG signs: PQ interval prolongation, QRS complex extension, high, sharp T waves. 
Symptoms of hypermagnesemia: nausea, vomiting, respiratory depression, muscle weakness, mental dullness, confusion, peripheral vasodilatation, hypotension, cardiac arrhythmias and cardiac arrest.  ECG signs: prolongation of AV conduction, QRS complex extension, elevated T waves. 
Treatment: Passage of potassium into cells is supported by intravenous administration of calcium ions in the form of gluconate or chloride (10-40 ml 10% solution).  Calcium antagonises some of the cardiovascular effects of potassium and some cardiovascular and neurological effects of magnesium ion. Excretion of potassium ions is increased by saluretics (furosemide, etacrynic acid).  In preserved renal function the diuresis is supported by iso-osmolar solutions.  In massive overdose hemodialysis or peritoneal dialysis may be performed. 

5. PHARMACOLOGICAL PROPERTIES 
5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: Cardiac drug
ATC code: A12BA 
Mechanism of effect 
Cardilan is a two component product containing organically bound potassium and magnesium.  Potassium as an essential, especially intracellularly bound element, plays a key role in maintaining transmembrane potential, which is the basis for muscle function, especially the myocardium. 
 Magnesium is one of the biogenic elements.  It plays a key role in the function of vital enzyme systems that are involved primarily in neurotransmission, such as ATPase.  Magnesium has an inhibitory effect on the CNS, reduces the release of acetylcholine from the endings. It prolongs myocardial refractory period and finally increases myocardial electrical stability and thus has a some cardioprotective effect. 

In experimental conditions during myocardial ischemia the potentiating effect of potassium and magnesium aspartate on the membrane repolarization and a positive influence on the development of postinfarct phase have been proved. It is probably based on inhibition of potassium leakage from asphyctic cells, preventive administration of potassium and magnesium aspartate reduces mortality in rats exposed to hypoxia and increases heart survival  in vitro. 
Controlled clinical trials have shown a good tolerability of the product and the expected results to increase the glycoside cardiotonic drugs tolerance in the prevention of arrhythmias. 
Administration of the analogous products containing magnesium is good in the prevention and treatment of complex arrhythmias during myocardial ischemia and myocardial infarction. 

 5.2 Pharmacokinetic properties 
 Pharmacokinetics of a mixture of magnesium and potassium aspartate after intravenous administration corresponds to kinetics of both ions.  In the case of potassium the specific mechanism of absorption and distribution is not known.  Potassium is predominantly excreted by the kidneys and 10% by the intestinal mucosa.  Excretion is markedly reduced in renal insufficiency, which increases the toxicity of potassium salts in those patients. 
Adrenaline and beta-2-agonists transfer via beta-effect potassium into cells and it may lead to hypokalemia.  Insulin increases intracellular uptake of potassium by cells and therefore with concomitantly administered insulin, higher potassium supplementation is necessary.
Different salts of magnesium have a different process of absorption , except of sulfate, chloride and aspartate, that are absorbed well. One third of plasma magnesium is protein bound. The main body of elimination is the kidney, therefore, in renal insufficiency and current magnesium supplementation the risk of accumulation may be increased. 

5.3 Preclinical safety data
Basic acute toxicity data was gathered in the evaluation of LD 50 after oral administration in rats and mice.  Lethality was observed in the dose of 2000 mg / kg of body weight, which is the limit of determination.  Neither parenteral application has been tested nor subchronic and chronic toxicity.  In this type of potassium and magnesium organotoxic significant effects or other adverse effects of the type of idiosyncratic reaction are not expected.
 Mutagenic or carcinogenic activity of potassium or magnesium compounds has not been proved so far. 
 There are the results of controlled clinical trials with analogous products, which demonstrate the good tolerance and perceived effectiveness. 

6. PHARMACEUTICAL PARTICULARS 
6.1 List of excipients 
Water for injection 

6.2 Incompatibilities 
None known.

6.3 Shelf life 
3 years

6.4 Special precautions for storage 
Store at 10-25 ° C. 

6.5 Nature and contents of container 
Clear glass with a label, insert a PVC box 
Package size: 10 ampoules of 10 ml 

6.6 Special precautions for disposal
No special requirements.

7. MARKETING AUTHORISATION HOLDER 
BB Pharma Pod Višňovkou 1662/21, 140 00 Prague 4, Czech Republic
8. MARKETING AUTHORISATION NUMBER(S) 
41/798/92-S/C 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 December 18th, 1992 / June 24th, 1998
10.DATE OF REVISION OF THE TEXT
December 28th, 2005