Levosimendan

Levosimendan

Clinical data
Trade names	Simdax
AHFS/Drugs.com	International Drug Names
Routes of administration	IV
ATC code	C01CX08 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	85% (oral)
Protein binding	97–98%
Metabolism	Extensive hepatic
Elimination half-life	~1 hour (levosimendan), 75–80 hours (metabolites)
Excretion	urine (54%), feces (44%)
Identifiers
IUPAC name 2-[[4-[(4R)-4-methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile
CAS Number	141505-33-1 Y
PubChem CID	3033825
DrugBank	DB00922 Y
ChemSpider	2298414 Y
UNII	C6T4514L4E
KEGG	D04720 Y
ChEBI	CHEBI:50567 Y
ChEMBL	ChEMBL313136 N
CompTox Dashboard (EPA)	DTXSID9046445
ECHA InfoCard	100.189.828
Chemical and physical data
Formula	C14H12N6O
Molar mass	280.28 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C2N/N=C(/c1ccc(N/N=C(\C#N)C#N)cc1)[C@H](C)C2
InChI InChI=1S/C14H12N6O/c1-9-6-13(21)19-20-14(9)10-2-4-11(5-3-10)17-18-12(7-15)8-16/h2-5,9,17H,6H2,1H3,(H,19,21)/t9-/m1/s1 Y Key:WHXMKTBCFHIYNQ-SECBINFHSA-N Y
NY (what is this?)  (verify)

Levosimendan (INN) /ˌliːvoʊsaɪˈmɛndən/ is a calcium sensitiser used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax (Orion Corporation).

Mechanism of action

Levosimendan is a calcium sensitizer — 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.

Clinical use

Indications

Levosimendan is indicated for inotropic support in acutely-decompensated severe congestive heart failure in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate.

Some of the Phase III studies in the extensive clinical program including the trials LIDO (200 patients), RUSSLAN (500), REVIVE-I (100), REVIVE-II (600) and SURVIVE (1350). In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind randomized studies.

In the SURVIVE study, despite a reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days. However, the drug was proven to be superior to dobutamine for treating patients with a history of CHF or those on beta-blocker therapy when they are hospitalized with acute decompensations.

Licensing status

The Orion Corporation originally developed levosimendan and applied for a new drug application in 1998 in the U.S. However the Food and Drug Administration (FDA) requested further trials be conducted and Orion withdrew the application in November 1999. Initially, Orion obtained the approval to market the drug in Sweden in 2000. Since then 60 countries worldwide have approved the drug but it remains unapproved in North America, where it is currently in Phase III development by Tenax Therapeutics for reduction in morbidity and mortality of cardiac surgery patients at risk of low cardiac output syndrome.

Contraindications

The use of levosimendan is contraindicated in patients with moderate-to-severe kidney impairment, severe liver impairment, severe ventricular filling or outflow obstruction, very low blood pressure and fast heart rate, and/or history of the abnormal heart rhythm torsades de pointes.

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, arrhythmias (atrial fibrillation, extrasystoles, atrial tachycardia, ventricular tachycardia), myocardial ischaemia, hypokalaemia and/or nausea (Rossi, 2006).

Formulations

Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted with glucose 5% solution before infusion.