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5 ml X 2.5 mg/ml
The dose and duration of treatment should be individualised according to the patient’s clinical condition and response. The treatment should be initiated with a loading dose of 6-12 microgram kg infused over 10 minutes followed by a continuous infusion of 0.1 microgram/kg/min. The lower loading dose of 6 microgram/kg is recommended for patients on concomitant intravenous vasodilators or inotropes or both at the start of the infusion. Higher loading doses within this range will produce a stronger haemodynamic response but may be associated with a transient increased incidence of adverse reactions. The response of the patient should be assessed with the loading dose or within 30 to 60 minutes of dose adjustment and as clinically indicated. If the response is deemed excessive (hypotension tachycardia), the rate of the infusion may be decreased to 0.05 microgram/kg/min or discontinued. If the initial dose is tolerated and an increased haemodynamic effect is required, the rate of the infusion can be increased to 0.2 microgram/kg/min.
The recommended duration of infusion in patients with acute decompensation of severe chronic heart failure is 24 hours. No signs of development of tolerance or rebound phenomena have been observed following discontinuation of Simdax infusion.
Haemodynamic effects persist for at least 24 hours and may be seen up to 9 days after discontinuation of a 24-hour infusion.
Experience of repeated administration of Simdax is limited.
Experience with concomitant use of vasoactive agents, including inotropic agents except digoxin, is limited. In the REVIVE programme, a lower loading dose (6 micrograms/kg) was administered with baseline concomitant vasoactive agents.
For full details see prescribing information.
Short-term treatment of acutely decompensated severe chronic heart failure. Simdax should only be used as add-on therapy in situations where conventional therapy with e.g. diuretics, ACE-inhibitors and digitalis is not sufficient and where there is no need for inotropic support.
Hypersensitivity to levosimendan or to any of the excipients.
Severe hypotension and tachycardia.
Significant mechanical obstructions affecting ventricular filling or outflow or both. Severe renal impairment (creatinine clearance <30 ml/min) and severe hepatic impairment. History of Torsades de Pointes.
An initial haemodynamic effect of levosimendan may be a decrease in systolic and diastolic blood pressure, therefore, levosimendan should be used with caution in patients with low baseline systolic or diastolic blood pressure or those at risk for a hypotensive episode. More conservative dosing regimens are recommended for these patients. Physicians should tailor the dose and duration of therapy to the condition and response of the patient.
Severe hypovolaemia should be corrected priorto levosimendan infusion.
If excessive changes in blood pressure or heart rate are observed, the rate of infusion should be reduced or the infusion discontinued.
The exact duration of all haemodynamic effects has not been determined, however, the haemodynamic effects generally last for 7-10 days. This is partly due to the presence of active metabolites, which reach their maximum plasma concentrations about 48 hours after the infusion has been stopped. Non-invasive monitoring for at least 4-5 days after the end of infusion is recommended. Monitoring is recommended to continue until the blood pressure reduction has reached its maximum and the blood pressure starts to increase again, and may need to be longer than 5 days if there are any signs of continuing blood pressure decrease, but can be shorter than 5 days if the patient is clinically stable. In patients with mild to moderate renal or mild to moderate hepatic impairment an extended period of monitoring may be needed.
Simdax should be used cautiously in patients with mild to moderate renal impairment. Limited data on the elimination of the active metabolites are available in patients with impaired renal function. Impaired renal function may lead to increased concentrations of the active metabolites, which may result in a more pronounced and prolonged haemodynamic effect.
Simdax should be used cautiously in patients with mild to moderate hepatic impairment. Impaired hepatic function may lead to prolonged exposure to the active metabolites, which may result in a more pronounced and prolonged haemodynamic effect.
Simdax infusionmay cause adecrease inserumpotassiumconcentration.
Thus, low serum potassium concentrations should be corrected prior to the administration of Simdax and serum potassium should be monitored during treatment. As with other medicinal products for heart failure, infusions of Simdax may be accompanied by decreases in haemoglobin and haematocrit and caution should be exercised in patients with ischaemic cardiovascular disease and concurrent anaemia.
Simdax infusion should be used cautiously in patients with tachycardia, atrial fibrillation with rapid ventricular response or potentially lifethreatening arrhythmias.
Experience with repeated administration of Simdax is limited. Experience with concomitant use of vasoactive agents, including inotropic agents (except digoxin), is limited. Benefit and risk should be assessed for the individual patient.
Simdax should be used cautiously and under close ECG monitoring in patients with ongoing coronary ischaemia, long QTc interval regardless of aetiology, or when given concomitantly with medicinal products that prolong the QTc interval.
The use of levosimendan in cardiogenic shock has not been studied. No information is available on the use of Simdax in the following disorders: restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade and right ventricular infarction.
Simdax should not be administered to children as there is very limited experience of use in children and adolescents under 18 years of age.
Limited experience is available on the use of Simdax in patients with heart failure after surgery, and in severe heart failure in patients awaiting heart transplantation.
In placebo-controlled clinical trials for ADHF (REVIVE programme), 53% of patients experienced adverse reactions, the most frequent of which were ventricular tachycardia, hypotension, and headache.
In a dobutamine-controlled clinical trial for ADHF (SURVIVE), 18% of patients experienced adverse reactions, the most frequent of which were ventricular tachycardia, atrial fibrillation, hypotension, ventricular extrasystoles, tachycardia, and headache.
See prescribing information for full details.
Consistent with current medical practice, levosimendan should be used with caution when used with other intravenous vasoactive medicinal products due to a potentially increased risk of hypotension.
No pharmacokinetic interactions have been observed in a population analysis of patients receiving digoxin and Simdax infusion. Simdax infusion can be used in patients receiving beta-blocking agents without loss of efficacy. Co-administration of isosorbide mononitrate and levosimendan in healthy volunteers resulted in significant potentiation of the orthostatic hypotensive response.
Pregnancy and Lactation
Pregnancy: There is no experience of using levosimendan in pregnant women.
Animal studies have shown toxic effects on reproduction. Therefore, levosimendan should be used in pregnant women only if the benefits for the mother outweigh the possible risks to the foetus.
Lactation: It is not known whether levosimendan is excreted in human milk. Studies in rats have shown excretion of levosimendan in breast milk, therefore
women receiving levosimendan should not breastfeed.
Overdose of Simdax may induce hypotension and tachycardia. In clinical trials with Simdax, hypotension has been successfully treated with vasopressors (e.g. dopamine in patients with congestive heart failure and adrenaline in patients following cardiac surgery). Excessive decreases in cardiac filling pressures may limit the response to Simdax and can be treated with parenteral fluids. High doses (at or above 0.4 microgram/kg/min) and infusions over 24 hours increase the heart rate and are sometimes associated with prolongation of the QTc interval. In the event of an overdose of Simdax, continuous ECG monitoring, repeated determinations of serum electrolytes and invasive haemodynamic monitoring should be undertaken. Simdax overdose leads to increased plasma concentrations of the active metabolite, which may lead to a more pronounced and prolonged effect on heart rate requiring a corresponding extension of the observation period.