Levosimendan

Approved Indications:

• Acute Decompensated Heart Failure (ADHF):
  Indicated for short-term intravenous treatment of acutely decompensated severe chronic heart failure (NYHA Class III–IV) in adult patients who require inotropic support.

Clinically Accepted Off-Label Uses:

• Perioperative Support in Cardiac Surgery:
  Used to improve cardiac output in patients with impaired left ventricular function undergoing high-risk cardiac surgery.
• Weaning from Mechanical Circulatory Support (e.g., ECMO or LVAD):
  Used in patients with persistent myocardial dysfunction to facilitate discontinuation of extracorporeal support.
• Low Cardiac Output Syndrome (LCOS):
  Used in intensive care settings to manage LCOS unresponsive to conventional inotropes.
• Advanced Heart Failure with Hypotension:
  Considered when catecholamines are ineffective or contraindicated.

Adults:

• Loading Dose (optional):
  6–12 mcg/kg over 10 minutes. May be omitted in hypotensive patients.
• Maintenance Infusion:
  0.05 to 0.2 mcg/kg/min for 24 hours, adjusted based on clinical response and tolerability.

Pediatric (off-label):

• Infusion:
  0.05–0.2 mcg/kg/min (no loading dose typically used). Close monitoring required.

Elderly:

• Use with caution. Initiate at lower end of dosing range due to increased sensitivity to cardiovascular effects.

Renal Impairment:

• No dose adjustment required for mild to moderate impairment. Use with caution in severe renal dysfunction (GFR <30 mL/min/1.73 m²).

Hepatic Impairment:

• Use with caution in moderate to severe hepatic dysfunction. Clearance may be reduced.

Administration Instructions:

• Dilute before use in 5% dextrose. Infuse over 24 hours using an infusion pump.
• Continuous ECG and hemodynamic monitoring is recommended during administration.

Levosimendan enhances myocardial contractility by sensitizing cardiac troponin C to calcium, thereby increasing the strength of cardiac contraction without raising intracellular calcium concentrations. This calcium sensitization results in improved cardiac performance with reduced myocardial oxygen demand. Additionally, levosimendan activates ATP-sensitive potassium (K⁺) channels in vascular smooth muscle, causing vasodilation. The dual inotropic and vasodilatory effects improve cardiac output, reduce preload and afterload, and enhance tissue perfusion.

• Absorption: Not applicable (IV only)
• Distribution: Volume of distribution: ~0.2 L/kg; plasma protein binding: ~97–98%
• Metabolism: Extensively metabolized in the gut and liver to active metabolite OR-1896 and inactive forms
• Active Metabolite: OR-1896, responsible for prolonged hemodynamic effects
• Onset of Action: Within 5–15 minutes
• Peak Effect: 6–12 hours
• Half-life: Levosimendan: ~1 hour; OR-1896: 70–80 hours
• Excretion: Renal (~54%) and fecal (~44%)

• Pregnancy:
  Category C (US FDA – when applicable). Animal studies have shown adverse fetal effects. There are no adequate human studies. Use only if potential benefits justify the potential risks to the fetus.
• Lactation:
  Unknown whether levosimendan or its metabolites are excreted in human milk. Use caution if administered during breastfeeding. Monitor infant for potential adverse effects.

• Primary Class: Inotropic Agent
• Subclass: Calcium Sensitizer and KATP Channel Opener
• Type: Non-catecholaminergic inotrope

• Known hypersensitivity to levosimendan or any component of the formulation
• Severe hypotension (systolic blood pressure <85 mmHg)
• Significant mechanical obstruction affecting ventricular filling or outflow (e.g., severe aortic stenosis)
• Severe renal impairment requiring dialysis
• History of torsades de pointes or other significant ventricular arrhythmias

• Hypotension: Risk of excessive vasodilation; close blood pressure monitoring is essential.
• Arrhythmias: May cause or worsen tachyarrhythmias. Continuous ECG monitoring is recommended.
• Electrolyte Disturbances: Hypokalemia may increase the risk of arrhythmias. Correct electrolyte imbalances prior to use.
• Myocardial Ischemia: Use with caution in patients with recent or ongoing ischemia.
• Use in Critically Ill Patients: Benefit-risk assessment must be individualized, especially in multi-organ failure or shock states.
• Prolonged Hemodynamic Effects: Due to long-acting metabolite, effects may last several days after infusion has ended.

Common:

• Hypotension
• Headache
• Tachycardia
• Nausea
• Atrial fibrillation

Less Common or Serious:

• Ventricular arrhythmias (including ventricular tachycardia)
• QT interval prolongation
• Myocardial ischemia
• Hypokalemia
• Thrombocytopenia
• Allergic reactions (rash, urticaria, anaphylaxis – rare)

• Beta-blockers: May blunt inotropic response. Monitor hemodynamic effect closely.
• Nitrates or other vasodilators: May increase risk of hypotension when co-administered.
• Diuretics (especially loop): Risk of electrolyte disturbances such as hypokalemia.
• Antiarrhythmics (e.g., amiodarone): Additive proarrhythmic potential.
• Calcium channel blockers (e.g., verapamil, diltiazem): Enhanced risk of hypotension or bradycardia.

Enzyme Systems:
Levosimendan is not significantly metabolized by CYP450 enzymes. Its conversion to the active metabolite is mediated by intestinal bacteria and liver conjugation pathways.

• ESC 2023 Heart Failure Guidelines:
  Recommends levosimendan as an option for short-term support in decompensated heart failure when conventional therapy fails, particularly in patients not tolerating catecholamines.
• Cardiac Surgery Studies:
  Recent trials have demonstrated improved cardiac output and decreased ICU stay when used perioperatively in patients with poor left ventricular function.
• Recognition of Extended Action:
  Emphasis on the long half-life of the active metabolite OR-1896, which sustains effects beyond the infusion period.

• Storage Temperature:
  Store at 20°C to 25°C (68°F to 77°F).
  Excursions permitted to: 15°C–30°C
• Protection Requirements:
  Protect from light. Do not freeze.
• Handling Instructions:
• Use only clear solutions.
• Dilute with 5% dextrose before administration.
• After dilution, use within 24 hours when stored at room temperature.
• Do not use saline for dilution (precipitation risk).