levosimendan
simdax® is indicated for the short-term treatment of acutely decompensated severe chronic heartfailure (adhf) in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate.
important safety information
" simdax is contraindicated in patients with:
- a known 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
- a history of torsades de pointes
" caution is advised 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 prior to levosimendan infusion. if excessive changes in blood pressure or heart rate are observed, the rate of infusion should be reduced or the infusion discontinued.
" 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 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 infusion may cause a decrease in serum potassium concentration. 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 underclose 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 shocknhas 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.
" the most frequent adverse events with simdax are ventricular tachycardia, atrial fibrillation, hypotension, ventricular extrasystoles, tachycardia and headache.
" other common (< 1/10, > 1/100) adverse events include hypokalaemia, insomnia, dizziness, cardiac failure, myocardial ischaemia, extrasystoles, nausea, constipation, diarrhoea, vomiting and haemoglobin decreased.
pharmacokinetics:
levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. it increases cardiac contractility and induces vasodilatation. the pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. the short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite or-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (new york heart association functional class iii-iv). although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (or-1855). this metabolite is further metabolised by acetylation to n-acetylated conjugate (or-1896). the circulating metabolites or-1855 and or-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. the haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme n-acetyltransferase-2, which is responsible for the metabolism of or-1855 to or-1896, is polymorphically distributed in the population. levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. it also improves indices of diastolic function and seems to improve the function of stunned myocardium. despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. an increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. levosimendan reduces plasma brain natriuretic peptide (bnp) and n-terminal pro-bnp (nt-probnp) levels substantially, and a decrease in plasma endothelin-1 has been observed. levosimendan also exerts beneficial effects on proinflammatory cytokines and apoptosis mediators. the effects of a 24-hour levosimendan infusion on filling pressure, ventricular function and bnp, as well as nt-probnp, last for at least 7 days.
levosimendan is a calcium sensitiser that can be administered intravenously (iv) to patients with acute decompensated congestive heart failure (chf). at therapeutic dosages levosimendan enhances myocardial contractility without increasing oxygen requirements, and causes coronary and systemic vasodilation.
in clinical trials levosimendan has been shown to reduce the risk of worsening chf or death compared with dobutamine and placebo in patients with decompensated chf. the drug is well tolerated, does not appear to be proarrhythmic, has minimal potential for interactions with other drugs, and does not reduce short-or long-term (30-day) survival.
thus, unlike some other agents administered to improve contractility in decompensated heart failure, iv levosimendan appears to offer therapeutic benefits without risk of arrhythmogenesis and/or uncertain impacts on survival.
introduction
one strategy used in the management of congestive heart failure (chf) is to increase myocardial contractility. established positive inotropic agents achieve this by increasing intracellular concentrations of free calcium. however, this action markedly increases myocardial energy consumption, which may contribute to the risk of arrhythmias seen with some inotropic agents.[1]
levosimendan is one of a new class of heterogeneous agents, the calcium sensitisers. the drug works via a dual mechanism of action which enhances cardiac contractility and vasodilatation without affecting intracellular free calcium, and so should have reduced proarrhythmic potential. it can be administered intravenously (iv) which makes it a therapeutic option for acute decompensated chf.[1] decompensated chf has been defined as sustained deterioration of at least one new york heart association functional class, usually associated with objective evidence of volume overload (e.g. neck vein distension, rales, oedema)
levosimendan is a calcium sensitiser - it increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. levosimendan exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin c in a calcium-dependent manner. it also has a vasodilatory effect, by opening adenosine triphosphate (atp)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation. the combined inotropic and vasodilatory actions result in an increased force of contraction, decreased preload and decreased afterload. moreover, by opening also the mitochondrial (atp)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect
levosimendan is 98% bound to plasma proteins
and completely metabolized prior to excretion.
approxi-mately 5% of a dose is converted in the
intestines, and then to a highly-active metabolite
with an elimination half-life of 75-80 h (compared to
1 hour elimination half-life for levosimendan itself).
this metabolite reaches a peak plasma concentration
about 2 days after the termination of the infusion and
exhibits haemodynamic effects similar to those of
levosimendan. because of the long half-life of the
active metabolite, these effects last for up to 7 to 9
days after discontinuation of a 24-hour infusion of
levosimendan.
through its non-?-adrenergic actions, it allows
for interruption of catecholamine infusions, which
may mitigate the tolerance or tachyphylaxis
associated with these drugs, an approach that has
been reported in adult patients. finally, its inotropic
properties may be particularly desirable in children
who are receiving ?-blockers, for whom
catecholamines may provide only limited benefit.
dose:
the usual dosage of intravenous levosimendan used
in clinical trials of patients with heart failure is 6 to
12 ìg/kg loading dose over 10 minutes followed by
0.05 to 0.2 ìg/kg/min as a continuous infusion.
hemodynamic response is generally observed
within 5 minutes of commencement of infusion of
the loading dose. peak effects are observed within 10
to 30 minutes of infusion; duration of action of
levosimendan is about 75-78 hours to 1 week due to
active metabolites. no dosage adjustments are
required in patients with mild to moderate renal
failure and hepatic impair-ment. efficacy with once
a week administration makes it a promising drug.
the published trials so far have utilized intravenous
levosimendan. however, the agent is also well
absorbed orally and oral preparation is now
available.
side effects
levosimendan is well tolerated, with most adverse
events (e.g., headache, hypotension) being doserelated
and arising from the vasodilatory actions of
the drug. in order to avoid undue hypotension it may
be prudent to temporarily stop milrinone and other
vasodilators when administering this drug(2,3). the
other side effects that are forthcoming from trials
include prolongation of corrected qt interval and
rarely, ventricular tachycardia. nevertheless, it
should be avoided in patients with torsades or any
other abnormal rhythm.
evidence supporting use of levosimendan
a study in a pediatric cohort of children with severe
heart failure who were inotrope dependent
demonstrated that levosimendan can be safely
administered to infants and children with severe
heart failure(4). in this study, amongst children with
acute onset cardiac failure, levosimendan allowed
for substantial reduction in catecholamine infusions
and produced an objective improvement in myocardial
performance. the effects of levosimendan was
less favaourable in patients with end stage chronic
heart failure. in another study from australia, when
levosimendan was administered during cardiopulmonary
bypass in children with anticipated low
cardiac output, it demonstrated low arterial lactate
levels, trends toward improved hemodynamics, heart
rate reduction, an increase in mean blood pressure,
and reduced conventional inotrope use
a similar pharmokinetic profile of levosimendan
was demonstrated in children with
congenital heart disease, comparable to adults(6).
case reports of levosimendan in myocardial stunning
have been documented(7). levosimendan
seems to improve medium term survival in patients
failing to wean off cardiopulmonary bypass and
requiring cardiac assist devices as a bridge to
recovery(8). two large prospective trials- revive ii
(randomized multicenter evaluation of intravenous
levosimendan efficacy-ii) and survive (survival
of patients with acute heart failure in need of
intravenous inotropic support) evaluated the efficacy
of levosimendan in patients hospitalized for acute
decompensated heart failure (adhf) have
concluded that this novel inotropic agent does confer
early additional benefit in addition to standard
therapy(9,10). in the lido(levosimendan versus
dobutamine) study, levosimendan improved
hemodynamic performance and survival, compared
with dobutamine, in adults with severe heart
failure(11). in the randomized study on safety and
effectiveness of levosimendan in patients with left
ventricular failure after an acute myocardial infarct
(russlan), the drug showed outcome benefits in
comparison with dobutamine and placebo,
respectively(12). a comparative study, calcium
sensitizer or inotrope or none in low-output heart
failure (casino), suggested mortality benefits with
levosimendan over placebo and dobutamine(13). a
prospective randomized pilot study demonstrated
improved right ventricular performance in patients
with acute respiratory distress syndrome(ards) and
septic shock(14). the role of levosimendan in septic
myocardial dysfunction has been studied and found
to be beneficial(15). levosimendan also finds a place
in the management of septic shock in the latest
pediatric septic shock guidelines(16). it has been
recommended by the guidelines to use levosimendan
in refractory cold septic shock.
it has been also been reported that oral
levosimendan has favorable cardiac and hemodynamic
effects in patients with severe congestive
heart failure; these effects are similar to those seen
after intravenous dosing with levosimendan(17).
the 4-8 mg daily doses of oral levosimendan showed
moderate inotropic effects(18). both 6-h infusion
and a 2-mg single dose of levosimendan showed that
if has moderate inotropic and vasodilatory effects in
patient with severe congestive heart failure(19).
thus, oral levosimendan may be used as substitute
for intravenous inotropic support in end-stage heart
failure, as pilot results on the use of oral
levosimendan are encouraging.