Levosimendan

Product Overview

Levosimendan is the representative of the calcium sensitizer class of inotropes — the (R)-(−)-biologically active enantiomer of racemic simendan — developed by Orion Pharma of Finland under the brand name Simdax.

Triple mechanism of action (which is why it is called an “inodilator”):

1. Positive inotropy (calcium sensitization): Selectively binds the N-terminal domain of cardiac troponin C (cTnC), stabilizing its calcium-bound conformation and prolonging the action of calcium on contractile proteins — the key point is that it enhances the sensitivity of contractile proteins to calcium rather than raising intracellular calcium concentration. It therefore increases myocardial contractility without increasing myocardial oxygen consumption and without impairing ventricular diastolic function — the core advantage distinguishing it from traditional inotropes (e.g., dobutamine, milrinone).
2. Vasodilation: Opens ATP-sensitive potassium channels (KATP) in vascular smooth muscle, dilating peripheral and coronary vessels and reducing preload and afterload.
3. Cardioprotection: Produces ischemic preconditioning-like protective effects by opening myocardial mitochondrial KATP channels; it also has phosphodiesterase (PDE) inhibitory activity.

Clinical value: In patients with decompensated heart failure, intravenous levosimendan increases cardiac output by approximately 30% and reduces pulmonary capillary wedge pressure and systemic vascular resistance by approximately 17%–29%. In large controlled trials, its overall hemodynamic response rate was significantly superior to placebo or dobutamine, with benefits also seen in mortality (vs placebo or dobutamine) and in the combined risk of worsening heart failure or death (vs dobutamine). Hemodynamic effects persist for at least 24 hours after discontinuation, with some effects lasting 9–10 days, and no tolerance or rebound has been observed after discontinuation.

Active metabolites: Levosimendan is metabolized via pathways including reduction by intestinal flora; the major metabolites OR-1855 and OR-1896 have long half-lives (approximately 70–80 hours), one of the reasons for its prolonged effect after discontinuation.

Technical Specifications

• Standards: CHP/USP/EP
• Specification: 0.99 (purity ≥99.0%, HPLC); reagent grade commonly 98.0%–99%, single impurity ≤0.2%, total impurities ≤0.5% (supplier internal control)
• CAS No.: 141505-33-1 (EINECS 663-528-6; UNII C6T4514L4E; MDL MFCD00867135)
• Molecular formula: C₁₄H₁₂N₆O
• Molecular weight: 280.28–280.29 (CAS and FDA GSRS report 280.29; Sigma/ChemicalBook report 280.28; calculated exact value 280.2847)
• Appearance: Yellow crystalline powder; some suppliers describe it as a light yellow to brown (sticky yellow/earthy yellow) powder or crystals
• Purity (HPLC): ≥ 99.0%
• Melting point: Approximately 205–219 °C (with decomposition). Sources differ: 216–219 °C (decomposes; ChemicalBook, InvivoChem, etc.); 205 °C (TCI reference value); 210–214 °C (Wujing database). Values vary considerably among sources and all note decomposition — refer to the actual COA and measurement method
• Specific optical rotation: [α]²⁰/D −600° to −650° (C=0.5, THF; TCI specification); reference value [α]D −627° (C=0.5, THF); other values under different conditions include α²⁵/D −566° (THF/methanol) and supplier internal control −548° to −582° — solvents and concentrations differ, so values are not directly comparable
• Chemical name: (R)-2-[[4-(1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]malononitrile; IUPAC: 2-[2-[4-[(4R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl]phenyl]hydrazinylidene]malononitrile
• Stereochemistry: Absolute configuration, (R)-enantiomer, 1 defined stereocenter
• Solubility: Freely soluble in DMSO (≥20 mg/mL; some suppliers record ≥50 mg/mL); soluble in THF; slightly soluble in methanol and ethanol; low solubility in water (some databases record “soluble”, others “water-soluble”; the actual formulation is an injection containing a solubilizer)
• Acidity coefficient (pKa): 6.3 (25 °C)
• Density: Approximately 1.33 g/cm³ (calculated)
• Storage conditions: Protected from light, sealed, refrigerated at 2–8 °C (some reference standards recommend freezing at −20 °C; powder stable 3 years at −20 °C, 2 years at 4 °C); formulations stored protected from light, tightly closed, at 2–8 °C

Applications

• Short-term treatment of acute decompensated heart failure (ADHF) (core indication): For the short-term treatment of acute decompensated heart failure in patients who respond inadequately to conventional therapy (diuretics, ACE inhibitors, digitalis) and require increased myocardial contractility. For use in hospitalized patients only, in medical facilities equipped with appropriate monitoring equipment and experienced in the use of inotropic agents
• Dosage and administration (Chinese package insert): Must be diluted before administration; for intravenous infusion only (peripheral or central vein). Initial loading dose 6–12 μg/kg infused over more than 10 minutes, followed by continuous infusion at 0.1 μg/(kg·min). For patients receiving concomitant vasodilators and/or inotropic agents, the recommended initial loading dose is 6 μg/kg. Observe the response closely during loading-dose administration and for the first 30–60 minutes of continuous infusion: if the response is excessive (hypotension, tachycardia), reduce the rate to 0.05 μg/(kg·min) or discontinue; if well tolerated and an enhanced hemodynamic effect is required, the rate may be increased to 0.2 μg/(kg·min). Continuous infusion in patients with severe chronic heart failure in the acute decompensated phase is usually 24 hours
• Preparation: 0.025 mg/mL infusion — 5 mL levosimendan injection + 500 mL 5% glucose injection; 0.05 mg/mL infusion — 10 mL levosimendan injection + 500 mL 5% glucose injection. Infuse separately after dilution; use within 24 hours of preparation
• Practical adjustment for hypotensive patients: The Chinese Guidelines for Emergency Diagnosis and Treatment of Acute Heart Failure (2026) recommend a standard regimen of a 12 μg/kg loading dose intravenously (>10 min) followed by 0.1–0.2 μg/(kg·min) maintained for 24 h; for patients with low baseline blood pressure, the maintenance dose may be given directly by intravenous drip for 24 h. International reviews likewise note that current practice often omits the loading dose to reduce hypotension risk; caution is advised and no loading dose should be given in patients with baseline systolic blood pressure <100 mmHg or diastolic blood pressure <60 mmHg; hypovolemia should be corrected before infusion
• Guideline recommendation level: The Chinese Guidelines for Emergency Diagnosis and Treatment of Acute Heart Failure (2026) recommend levosimendan for patients with tissue and organ hypoperfusion caused by left ventricular systolic dysfunction and reduced cardiac output (recommendation class Ⅱa, evidence level B), and recommend early initiation when low cardiac output or tissue hypoperfusion is present
• Investigational/extended applications: Intermittent (pulsed) repeat infusion regimens in patients with advanced heart failure (e.g., 6.25 mg every 2 weeks or 12.5 mg every 4 weeks); off-label uses such as cardiogenic shock and the perioperative period of cardiac surgery (marked as off-label indications in the Chinese package insert)
• Pharmacology and mechanism research: For in vitro and animal studies of troponin C calcium sensitization, KATP channels, PDE inhibition and ischemia-reperfusion protection
• Formulation and manufacturing: For formulation development of the injection (5 mL:12.5 mg, i.e., 2.5 mg/mL concentrate, requiring dilution before infusion); due to the API’s poor water solubility, the formulation must address solubilization and stability issues (the marketed formulation contains a solubilizer); suitable for analytical method development and validation, related-substance and enantiomeric purity control, stability studies, and GMP scale-up and CMO/CDMO contract manufacturing

Safety notice: This product is an active pharmaceutical ingredient (API) intended solely for legitimate industrial, research and pharmaceutical manufacturing use, and does not constitute end-user clinical or self-administration guidance. The finished product is a prescription drug, restricted to hospitalized patients under monitored conditions. Contraindications: Hypersensitivity to levosimendan or any excipient; mechanical obstructive diseases significantly affecting ventricular filling and/or ejection; severe hepatic impairment; severe renal impairment (creatinine clearance <30 mL/min); severe hypotension and tachycardia; history of torsades de pointes (TdP) ventricular tachycardia. The most common adverse reactions are headache, hypotension and ventricular tachycardia; common reactions include hypokalemia, insomnia, dizziness, tachycardia, ventricular premature beats, myocardial ischemia, nausea, constipation, diarrhea, vomiting and decreased hemoglobin. Overdose may cause hypotension and tachycardia; high doses (≥0.4 μg/(kg·min)) or infusion exceeding 24 hours may increase heart rate, sometimes with QTc interval prolongation. This product is GHS-classified as acute oral/dermal/inhalation toxicity (H301+H311+H331), skin irritation (H315) and serious eye irritation (H319); when handling, wear protective gloves, protective clothing and eye/face protection, and avoid dust inhalation.

Product information: please contact us. This information is for reference only.