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Levosimendan


Brand Names: International
  • Daxim (CL, VE)
  • Simdak (IS, SI, SK)
  • Simdax (AE, AR, AT, BG, BR, CR, CY, CZ, DK, DO, ES, FI, GR, GT, HN, HR, HU, IL, IT, JO, KW, LB, MX, NI, NO, NZ, PA, PE, PL, PT, QA, RO, RU, SE, SG, SV, TH, TR, UY)
  • Simenda (IN)
  • Symdaks (UA)
International Nonproprietary Names (INN)
  • Levosimendan [English]
  • Levosimendanum [Latin]
  • Levosimendán [Spanish]
  • Lévosimendan [French]
  • Левосимендан [Russian]
  • ليفوسيماندان [Arabic]
  • 左西孟旦 [Chinese]
Brazilian Nonproprietary Names (DCB)
  • Levosimendana
Anatomic Therapeutic Chemical (ATC) Classification
  • C01CX08
Pharmacologic Category
  • Cardiac Troponin C Calcium Sensitizer
  • Inotrope
Dosing: Adult
Acute decompensated heart failure (ADHF): IV: Initial: 6 to 12 mcg/kg infused over 10 minutes. Maintenance: 0.1 mcg/kg/minute by continuous infusion. Note: ESC heart failure guidelines recommend against administration of initial bolus dose in patients with systolic BP <90 mm Hg (Ponikowski 2016).
Dosage adjustments with concomitant medication (initial dose): Concomitant IV vasodilator or inotropic agents: Reduce initial infusion dose to 6 mcg/kg over 10 minutes.
Dosage adjustments (maintenance infusion):
If significant hypotension or tachycardia occur: Decrease infusion rate to 0.05 mcg/kg/minute or discontinue.
If inadequate response: May increase infusion up to 0.2 mcg/kg/minute.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Renal Impairment: Adult
CrCl ≥30 mL/minute: There are no dosage adjustments provided in manufacturer’s labeling; use with caution.
CrCl <30 mL/minute: Use is contraindicated.
Dosing: Hepatic Impairment: Adult
Mild to moderate impairment: No dosage adjustment necessary; use with caution.
Severe impairment: Use is contraindicated.

Use: Labeled Indications
Note: Not approved in US and/or Canada
Acute decompensated heart failure: For the short-term treatment of patients with acute decompensated heart failure (ADHF) when conventional therapies are insufficient and inotropic support is appropriate
Clinical Practice Guidelines
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure, 2016
Administration: IV
Must be diluted prior to administration; may infuse IV in peripheral or central vein.
Storage/Stability
Store undiluted solution at 2°C to 8°C (36°F to 46°F). Do not freeze. Use immediately after dilution; stable for 24 hours at 25°C (77°F) in D5W.
Preparation for Administration
Final concentration (using 2.5 mg/mL concentrated solution):
0.025 mg/mL: Dilute 5 mL of the concentrated solution into 500 mL of D5W
0.05 mg/mL: Dilute 10 mL of the concentrated solution into 500 mL of D5W
Contraindications
Hypersensitivity to levosimendan or any component of the formulation; significant mechanical obstruction of ventricular filling and/or outflow; severe hypotension and tachycardia; severe renal impairment (CrCl <30 mL/minute); severe hepatic impairment; history of torsade de pointes
Warnings/Precautions
Concerns related to adverse events:
• Anemia: May decrease hemoglobin and hematocrit; in the REVIVE trials incidence of anemia was not significantly greater than placebo (Packer 2013); however, the manufacturer recommends using caution in patients with concurrent anemia and ischemic heart disease.
• Cardiac arrhythmias: Tachycardias (including atrial fibrillation, ventricular extrasystoles, and ventricular tachycardia) have been commonly reported with use; use caution in patients with preexisting tachycardia (eg, atrial fibrillation with rapid ventricular response or potentially life-threatening arrhythmias). Use is contraindicated in patients with severe tachycardia or a history of torsades de pointes.
• Hypokalemia: Some trials (eg, SURVIVE) reported significantly greater decreases in serum potassium in levosimendan-treated patients relative to an active comparator (Mebazaa 2007); however, the REVIVE trials did not show increased hypokalemia relative to placebo (Packer 2013). The manufacturer recommends correcting hypokalemia prior to initiation and monitoring serum potassium.
• Hypotension: Hypotension has been commonly reported with use; use caution in patients with low baseline systolic or diastolic blood pressure or on concurrent IV vasodilator or inotropic agents; dosage adjustments, including avoiding initial bolus infusion, may be required (Ponikowski 2016). As appropriate, correct hypovolemia prior to initiation. Use is contraindicated in patients with severe hypotension. In all patients, adjust dose or discontinue therapy if significant hypotension occurs. After completion of therapy, continue monitoring blood pressure since hemodynamic effects may be prolonged.
Disease-related concerns:
• Hepatic impairment: Use caution in patients with mild to moderate hepatic impairment; may lead to prolonged and pronounced hemodynamic effects due to increased concentrations of the active metabolites. Use is contraindicated in patients with severe hepatic impairment.
• Ischemic heart disease: Use caution in patients with ongoing myocardial ischemia; close ECG monitoring is recommended.
• QTc prolongation: Use caution in patients with QTc interval prolongation or in patients on concomitant QTc prolonging agents; close ECG monitoring is recommended.
• Renal impairment: Use caution in patients with mild to moderate renal impairment; may lead to prolonged and pronounced hemodynamic effects due to increased concentrations of the active metabolites. Use is contraindicated in patients with severe renal impairment (CrCl <30 mL/minute).
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Other warnings/precautions:
• Appropriate use: Has not been adequately studied in patients with restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade, and right ventricular infarction. Use is contraindicated in patients with significant mechanical obstruction of ventricular filling and/or outflow.
Pregnancy Considerations
Adverse events have been observed in animal reproduction studies. Heart failure in pregnant women should be treated according to guidelines; levosimendan can be used if an inotropic drug is needed (Regitz-Zagrosek [ESG/AEPC/DGesGM/ESC] 2011).
Breast-Feeding Considerations
It is not known if levosimendan is present in breast milk. Breast-feeding is not recommended by the manufacturer.
Adverse Reactions
>10%:
Cardiovascular: Hypotension, ventricular tachycardia
Central nervous system: Headache
1% to 10%:
Cardiovascular: Atrial fibrillation, cardiac failure, extrasystoles, myocardial ischemia, tachycardia, ventricular extrasystoles
Central nervous system: Dizziness, insomnia
Endocrine & metabolic: Hypokalemia
Gastrointestinal: Constipation, diarrhea, nausea, vomiting
Hematologic & oncologic: Hemoglobin decreased
<1%, postmarketing, and/or case reports: Ventricular fibrillation
Drug Interactions: Avoid Concomitant Use
Avoid concomitant use of Levosimendan with any of the following: Bromperidol
Drug Interactions: Decreased Effect
The levels/effects of Levosimendan may be decreased by: Bromperidol
Drug Interactions: Increased Effect/Toxicity
Levosimendan may increase the levels/effects of: Amifostine; Antipsychotic Agents (Second Generation [Atypical]); Bromperidol; DULoxetine; Hypotension-Associated Agents; Levodopa; Nitroprusside; Pholcodine; QTc-Prolonging Agents (Highest Risk); QTc-Prolonging Agents (Moderate Risk)
The levels/effects of Levosimendan may be increased by: Alfuzosin; Barbiturates; Benperidol; Blood Pressure Lowering Agents; Brimonidine (Topical); Diazoxide; Herbs (Hypotensive Properties); Lormetazepam; MiFEPRIStone; Molsidomine; Naftopidil; Nicergoline; Nicorandil; Obinutuzumab; Pentoxifylline; Phosphodiesterase 5 Inhibitors; Prostacyclin Analogues; Quinagolide
Drug Interactions: Metabolism/Transport Effects
None known.
Monitoring Parameters
Assess hemodynamic response immediately after loading dose and within 30 to 60 minutes of any dosage adjustment; serum potassium; blood pressure; heart rate; ECG; urine output. Due to prolonged effects of levosimendan metabolites, continue noninvasive monitoring for 4 to 5 days (or longer in patients with renal and/or hepatic impairment) after infusion is stopped.
Product Availability (US)
Not available in the US
Dosage Forms: International
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. Note: Availability of specific dosage forms may vary by country/region.
Solution, Intravenous: 2.5 mg/mL
Mechanism of Action
Sensitizes calcium-dependent troponin C in cardiac tissue, enhancing contractility. Opens ATP-sensitive potassium channels in vascular smooth muscle, inducing vasodilation. May additionally open ATP-sensitive potassium channels in cardiac mitochondria, suggested to confer anti-ischemic cardioprotection (Papp 2012). Increases cardiac output, stroke volume, ejection fraction, and heart rate; decreases blood pressure; decreases pulmonary capillary wedge pressure, right atrial pressure, and peripheral vascular resistance.
Pharmacodynamics/Kinetics
Onset of action: <5 minutes with bolus administration (Nieminen 2013)
Duration of action: Hemodynamic effects continue for up to 7 to 9 days after discontinuation of a 24-hour infusion.
Distribution: Vss: ~0.2 L/kg
Protein binding: Levosimendan: 97% to 98% (primarily to albumin); OR-1855: 39%; OR-1896: 42%
Metabolism: Completely metabolized (primarily by conjugation) into two active metabolites (OR-1855 and OR-1896)
Half-life elimination:
Levosimendan: ~1 hour
OR-1855 and OR-1896: 75 to 80 hours
Time to peak: OR-1855 and OR-1896: Peak plasma concentration occurs ~2 days after infusion is stopped
Excretion: Urine (54%; as metabolites); feces (44%)
Pharmacodynamics/Kinetics: Additional Considerations
Renal function impairment: AUC of active metabolites OR-1855 and OR-1896 is increased by 170% in patients with severe renal impairment and in patients on dialysis.
References: International
European Society of Gynecology (ESG); Association for European Paediatric Cardiology (AEPC); German Society for Gender Medicine (DGesGM), Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, et al; ESC Committee for Practice Guidelines. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(24):3147-3197.[PubMed 21873418]
Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007;297(17):1883-1891.[PubMed 17473298]
Nieminen MS, Fruhwald S, Heunks LM, et al. Levosimendan: current data, clinical use and future development. Heart Lung Vessel. 2013;5(4):227-245.[PubMed 24364017]
Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. J Am Coll Cardiol HF. 2013;1:103-111.
Papp Z, Édes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan [published online July 23, 2011]. Int J Cardiol. 2012;159(2):82-87.[PubMed 21784540]
Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(27):2129-2200.[PubMed 27206819]
Simdax (levosimendan) solution for infusion [Sweden summary of product characteristics]. Espoo, Finland: Orion Corporation; December 2016.

This monograph is adopted from Lexicomp, Nov. 8, 2018