Levosimendan STADA: Uses, Dosage & Side Effects

What Is Levosimendan STADA and What Is It Used For?

Levosimendan STADA contains the active substance levosimendan, which belongs to a pharmacological class known as calcium sensitizers or inodilators. It is supplied as a concentrate for solution for infusion at a strength of 2.5 mg/ml, which must be diluted before administration as a continuous intravenous infusion. Levosimendan represents a fundamentally different approach to treating acute heart failure compared with traditional inotropic agents such as dobutamine and milrinone, because it enhances cardiac contractility without substantially increasing myocardial oxygen consumption.

The mechanism of action of levosimendan is dual and complementary. The primary inotropic effect is achieved through calcium sensitization: levosimendan binds to cardiac troponin C (cTnC) in a calcium-dependent manner, stabilizing the calcium-troponin C complex and thereby increasing the sensitivity of the contractile apparatus to intracellular calcium. This enhances the force of cardiac muscle contraction during systole without altering the calcium concentration within the cardiomyocyte. During diastole, when intracellular calcium levels fall, levosimendan dissociates from troponin C, allowing normal myocardial relaxation. This calcium-dependent binding and unbinding is a crucial feature because it means that levosimendan enhances systolic contraction without impairing diastolic relaxation – a significant advantage over traditional inotropes that increase intracellular calcium levels and can impair relaxation and increase arrhythmia risk.

The second major mechanism involves the opening of ATP-sensitive potassium (K_ATP) channels. In vascular smooth muscle cells, levosimendan opens sarcolemmal K_ATP channels, causing hyperpolarization of the cell membrane and relaxation of vascular smooth muscle. This leads to arterial and venous vasodilation, which reduces both preload and afterload on the heart. The net hemodynamic effect is a reduction in pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance (SVR), combined with an increase in cardiac output. Additionally, levosimendan opens mitochondrial K_ATP channels in cardiomyocytes, which has been shown to confer cardioprotective and anti-ischemic effects in experimental models by preserving mitochondrial membrane potential and reducing apoptosis.

The clinical consequence of these combined mechanisms is improved hemodynamic function: increased cardiac output, reduced filling pressures, improved organ perfusion, and relief of heart failure symptoms such as breathlessness and fluid retention. Patients typically experience a noticeable improvement in symptoms within hours of starting the infusion. Furthermore, levosimendan achieves these hemodynamic improvements with either a neutral or slightly reduced myocardial oxygen consumption, in contrast to catecholamine-based inotropes (dobutamine, dopamine) which increase myocardial oxygen demand and have been associated with increased mortality in some studies.

Levosimendan STADA is indicated for the short-term treatment of acute decompensated chronic heart failure (ADHF) in situations where conventional therapy with diuretics, angiotensin-converting enzyme (ACE) inhibitors, and/or cardiac glycosides (digoxin) is considered insufficient, and where inotropic support is clinically judged to be appropriate. Typical clinical scenarios include:

• Acute decompensation of chronic heart failure: Patients with worsening symptoms of chronic heart failure (typically NYHA class III–IV) who present with signs of low cardiac output and congestion despite optimal medical therapy.
• Cardiogenic shock: In some clinical settings, levosimendan is used as part of the management of cardiogenic shock, either alone or in combination with other vasoactive agents, although evidence in this specific population is limited.
• Post-cardiac surgery: Levosimendan has been investigated and used in patients with low cardiac output syndrome following cardiac surgery, although this represents an off-label use in some jurisdictions.
• Advanced heart failure: Repetitive or intermittent levosimendan infusions have been studied in patients with advanced heart failure as a bridge to transplantation or destination therapy, particularly in Europe.

A distinctive pharmacokinetic feature of levosimendan is the formation of an active metabolite, OR-1896. After intravenous administration, levosimendan is extensively metabolized, primarily by conjugation with glutathione in the intestinal wall and liver, forming an intermediate metabolite (OR-1855) that is then acetylated to OR-1896. This active metabolite has a similar pharmacological profile to the parent compound but possesses a much longer elimination half-life of approximately 75 to 80 hours. As a result, the hemodynamic benefits of a single 24-hour levosimendan infusion can persist for 7 to 9 days after discontinuation, which is unique among inotropic agents and provides continued clinical benefit beyond the infusion period.

Levosimendan was first approved in the European Union in 2000 and is now available in over 60 countries worldwide. It is approved under various brand names, including Simdax (the originator product by Orion Corporation) and generic formulations such as Levosimendan STADA. While levosimendan is widely used in Europe, Asia, and South America, it has not received FDA approval in the United States, although it has been used in clinical trials and is available through expanded access programs in select clinical situations.

What Should You Know Before Taking Levosimendan STADA?

Contraindications

Levosimendan STADA is contraindicated in a number of clinical situations where administration could be harmful or where the drug's hemodynamic effects would be inappropriate. Understanding these contraindications is essential for safe use. The following are absolute contraindications to levosimendan administration:

• Hypersensitivity: Known allergy to levosimendan or to any of the excipients in the formulation.
• Severe hypotension and tachycardia: Patients with systolic blood pressure below 85 mmHg or severe tachycardia (heart rate above 120 beats per minute at rest) should not receive levosimendan, as the drug's vasodilatory effects may worsen hypotension and the sympathetic activation response may exacerbate tachycardia.
• Mechanical obstruction: Significant mechanical obstruction affecting ventricular filling or outflow, or both. This includes conditions such as severe aortic stenosis, hypertrophic obstructive cardiomyopathy (HOCM), and severe mitral stenosis, where increased contractility and vasodilation could be hazardous.
• Severe renal impairment: Patients with severe renal impairment (creatinine clearance <30 ml/min) should not receive levosimendan due to reduced clearance of the active metabolite OR-1896.
• Severe hepatic impairment: Levosimendan is extensively metabolized by the liver, and severe hepatic impairment can lead to unpredictable drug levels and increased risk of adverse effects.
• History of torsades de pointes: Patients with a documented history of torsades de pointes, a potentially life-threatening ventricular arrhythmia, should not receive levosimendan.

Warnings and Precautions

Several important precautions should be observed when using levosimendan. Healthcare professionals administering this medication should be aware of the following:

• Hypotension: Levosimendan causes dose-dependent vasodilation and can reduce blood pressure significantly. The infusion rate should be reduced or the infusion temporarily stopped if excessive hypotension develops. A loading dose is more likely to cause hypotension and may be omitted in patients with low baseline blood pressure (systolic 85–100 mmHg).
• Hypokalemia: Levosimendan may reduce serum potassium levels. Potassium levels should be monitored and corrected before and during administration, as hypokalemia increases the risk of cardiac arrhythmias. A minimum serum potassium of 3.5 mmol/L is recommended before starting the infusion.
• Cardiac arrhythmias: Levosimendan may precipitate or worsen atrial fibrillation, ventricular tachycardia, or ventricular extrasystoles. Patients should be on continuous ECG monitoring throughout the infusion and for at least 3 days afterward.
• Anemia and low hemoglobin: The hemoglobin level should be assessed before treatment. The vasodilatory effects of levosimendan may be poorly tolerated in patients with significant anemia, as the reduced oxygen-carrying capacity combined with decreased vascular resistance may compromise tissue oxygenation.
• Renal function: While mild to moderate renal impairment does not require dose adjustment of the parent drug, the active metabolite OR-1896 is partially eliminated renally. Patients with impaired renal function should be monitored closely for prolonged hemodynamic effects.
• Concurrent inotropes: The safety and efficacy of levosimendan administered concurrently with other intravenous inotropic or vasodilatory agents (other than digoxin) have not been sufficiently studied. If combination therapy is necessary, close hemodynamic monitoring is essential.

Pregnancy and Breastfeeding

Levosimendan should not be used during pregnancy unless the clinical condition of the woman requires treatment with levosimendan and the potential benefit to the mother justifies the potential risk to the fetus. There are no adequate data from the use of levosimendan in pregnant women. Animal studies have shown reproductive toxicity at doses substantially higher than those used clinically, but the relevance of these findings to humans is uncertain. Women of childbearing potential should use effective contraception during and for at least 14 days after treatment with levosimendan, to account for the prolonged activity of the OR-1896 metabolite.

It is not known whether levosimendan or its metabolites are excreted in human breast milk. A risk to the breastfed infant cannot be excluded. Breastfeeding should be discontinued during and for at least 14 days after treatment with levosimendan. The decision to discontinue breastfeeding or to withhold levosimendan therapy should take into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Driving and Operating Machinery

Given that levosimendan is administered exclusively in the hospital setting to patients with acute decompensated heart failure, the question of driving and operating machinery is generally not relevant during treatment. However, patients should be aware that hypotension, dizziness, and headache are common side effects, and they should not drive or operate machinery until they have fully recovered and feel well enough to do so. Healthcare providers should advise patients accordingly upon discharge.

How Does Levosimendan STADA Interact with Other Drugs?

Drug interactions with levosimendan are primarily pharmacodynamic rather than pharmacokinetic. Because levosimendan is metabolized primarily through conjugation with glutathione and subsequent acetylation (rather than through cytochrome P450 enzymes), it has a low potential for traditional drug-drug interactions involving CYP enzyme induction or inhibition. However, its potent hemodynamic effects mean that additive or synergistic interactions with other cardiovascular agents are clinically important.

Clinical experience and pharmacological studies have identified the following interaction profiles:

One of the most clinically important findings regarding levosimendan's drug interactions is its preserved efficacy in patients receiving beta-blocker therapy. In the LIDO (Levosimendan Infusion versus Dobutamine) trial, levosimendan demonstrated superior hemodynamic improvement compared with dobutamine, and this benefit was maintained regardless of whether patients were on concurrent beta-blocker therapy. This is because levosimendan's mechanism of action (calcium sensitization) does not depend on beta-adrenergic receptor stimulation, unlike dobutamine. This makes levosimendan particularly valuable in clinical practice, given that beta-blockers are a cornerstone of chronic heart failure treatment and a large proportion of patients presenting with acute decompensation will be receiving these medications.

The interaction with isosorbide mononitrate was specifically studied in a pharmacodynamic interaction trial. Co-administration of levosimendan with isosorbide mononitrate led to a significant enhancement of the orthostatic hypotensive response. While both drugs are vasodilators, their combined use may result in clinically significant drops in blood pressure, particularly when the patient assumes an upright position. If nitrates are required during levosimendan infusion, careful blood pressure monitoring and dose titration are essential.

Regarding the combination with other intravenous inotropes, the safety and efficacy data are limited. Although levosimendan and dobutamine have different mechanisms of action and could theoretically be complementary, the combination has not been extensively studied in controlled trials. If sequential or overlapping use is considered, careful hemodynamic monitoring with invasive methods (such as pulmonary artery catheterization) is advisable. The combination of levosimendan with milrinone (a phosphodiesterase III inhibitor) carries a particularly high risk of hypotension and tachycardia due to overlapping vasodilatory mechanisms.

What Is the Correct Dosage of Levosimendan STADA?

Levosimendan STADA must be diluted before administration. The 2.5 mg/ml concentrate is diluted with 5% glucose (dextrose) solution to achieve a final concentration suitable for continuous intravenous infusion. A 5 ml vial containing 12.5 mg of levosimendan is typically diluted in 500 ml of 5% glucose to achieve a final concentration of approximately 0.025 mg/ml (25 mcg/ml). The diluted solution should be used within 24 hours. The solution should be clear and yellow; do not use if it is discolored or contains particulate matter.

Adults

Treatment with levosimendan begins in a hospital or intensive care unit under continuous hemodynamic monitoring. The dosing consists of an optional loading dose followed by a continuous maintenance infusion:

The decision to administer a loading dose depends on the clinical situation. In patients with relatively preserved blood pressure (systolic >100 mmHg), a loading dose of 6–12 mcg/kg infused over 10 minutes may be used to achieve rapid hemodynamic improvement. However, the loading dose is associated with a higher incidence of hypotension and should be omitted or reduced in patients with low baseline blood pressure (systolic 85–100 mmHg), those already receiving other vasodilators, or patients at increased risk of hypotension. In many clinical centers, particularly in the critical care setting, the loading dose is routinely omitted to minimize the risk of hypotension, and treatment is initiated directly with the continuous maintenance infusion.

The maintenance infusion rate is titrated based on the patient's hemodynamic response. Clinical endpoints that guide dose titration include:

• Blood pressure: Target an adequate mean arterial pressure (MAP >65 mmHg). Reduce the infusion rate if systolic blood pressure drops below 85 mmHg.
• Heart rate: Monitor for excessive tachycardia. If heart rate exceeds 120 bpm or increases by more than 20% from baseline, consider dose reduction.
• Urine output: Improving urine output is a positive indicator of improved renal perfusion and cardiac output.
• Symptoms: Relief of dyspnea, reduction of peripheral edema, and improvement in general well-being.
• Invasive monitoring: If available, improvements in cardiac index (CI), reduction in pulmonary capillary wedge pressure (PCWP), and decrease in systemic vascular resistance (SVR) guide optimal dosing.

The recommended maximum duration of a single infusion is 24 hours. Extending the infusion beyond 24 hours has not been shown to provide additional benefit and may increase the risk of adverse effects. After stopping the infusion, hemodynamic monitoring should continue for at least 3 days (and ideally up to 5 days in patients with renal impairment), as the active metabolite OR-1896 continues to exert hemodynamic effects.

Children

Levosimendan has not been approved for use in children. Limited published data on pediatric use exist, primarily in the context of pediatric cardiac surgery and congenital heart disease. Any use in pediatric patients is off-label and should only be considered in specialized centers with appropriate expertise. Dosing in children, when used off-label, has generally followed similar weight-based calculations as in adults, but safety and efficacy data are insufficient to make formal recommendations.

Elderly Patients

No specific dose adjustment is required for elderly patients based on age alone. However, elderly patients are more likely to have reduced renal and hepatic function, lower baseline blood pressure, and a higher prevalence of comorbidities that may affect tolerability. In practice, many clinicians opt to omit the loading dose and start with a lower maintenance infusion rate (0.05 mcg/kg/min) in elderly patients, titrating upward cautiously based on hemodynamic response and tolerability.

Repeat Administration

The concept of a missed dose does not apply in the conventional sense, as levosimendan is a single-course intravenous infusion administered in a hospital setting. However, the question of repeat administration is clinically relevant, particularly in patients with advanced chronic heart failure who may experience recurrent decompensations. Several studies have investigated intermittent or repetitive levosimendan infusions (typically every 2–4 weeks) in patients with advanced heart failure. The LevoRep and LION-HEART trials have provided evidence that repetitive levosimendan infusions can reduce hospitalizations and improve quality of life in selected patients with advanced heart failure. However, this approach remains investigational in many jurisdictions and should be decided on a case-by-case basis by the treating heart failure specialist.

Overdose

Overdose with levosimendan may result in excessive hypotension, tachycardia, and cardiac arrhythmias. There is no specific antidote for levosimendan. Management of overdose is supportive and should include:

• Immediate discontinuation of the infusion
• Continuous ECG and hemodynamic monitoring
• Intravenous fluid resuscitation for hypotension
• Vasopressor support (norepinephrine, phenylephrine) if hypotension persists despite fluids
• Antiarrhythmic therapy as indicated by the specific arrhythmia
• Correction of electrolyte imbalances, particularly hypokalemia
• Prolonged monitoring for at least 5 days due to the long-acting metabolite OR-1896

Levosimendan is not removed by hemodialysis due to its high plasma protein binding (approximately 97–98%).

What Are the Side Effects of Levosimendan STADA?

Like all medicines, levosimendan can cause side effects, although not everyone will experience them. The side effects reflect the drug's pharmacological profile as a potent inodilator and are largely predictable from its hemodynamic actions. Most adverse effects are dose-dependent and can be managed by reducing the infusion rate or temporarily stopping the infusion. The following classification is based on data from clinical trials and post-marketing surveillance.

It is important to note that many patients receiving levosimendan have severe underlying heart failure and comorbidities, which makes it challenging to distinguish drug-related side effects from manifestations of the underlying disease. Clinical trials have shown that the overall adverse event rate with levosimendan is broadly similar to that of comparator treatments (dobutamine, placebo), with the notable exception of hypotension and headache being more common with levosimendan.

Hypotension is the most common and clinically significant side effect. In clinical trials, hypotension requiring dose reduction or discontinuation occurred in approximately 5–8% of patients. The risk of hypotension is highest during or shortly after the loading dose and can be minimized by omitting the loading dose, using a lower starting infusion rate, and ensuring adequate volume status before initiating therapy. Patients who are volume-depleted or who have low baseline blood pressure are at greatest risk.

Cardiac arrhythmias, particularly atrial fibrillation and ventricular tachycardia, are common in the population receiving levosimendan. It is often difficult to determine whether these arrhythmias are caused by the drug or are a manifestation of the underlying severe heart failure. In the SURVIVE (Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support) trial, which compared levosimendan with dobutamine in 1,327 patients, atrial fibrillation was more common in the levosimendan group (9.1% vs. 6.1%), while ventricular tachycardia occurred at similar rates in both groups.

Hypokalemia occurs because levosimendan activates K_ATP channels, which can lead to potassium shifts. Monitoring and maintaining adequate serum potassium levels (ideally above 4.0 mmol/L) is important to minimize the proarrhythmic risk, particularly in patients who are also receiving diuretics that cause potassium loss.

Headache is a common side effect related to the vasodilatory action of levosimendan and usually responds to standard analgesic therapy (paracetamol). It is generally mild to moderate and does not usually require discontinuation of the infusion.

How Should You Store Levosimendan STADA?

Proper storage of levosimendan STADA is essential to maintain the chemical stability and sterility of the product. The undiluted concentrate for solution for infusion (2.5 mg/ml) has specific storage requirements that must be adhered to at all times. Levosimendan is a photosensitive compound, meaning it can degrade when exposed to light, which is why protection from light is a key storage requirement.

The following storage conditions apply:

• Undiluted concentrate: Store in a refrigerator at 2–8 °C. Keep the vial in the outer carton in order to protect from light. Do not freeze. If accidentally frozen, the product should be discarded and not used.
• Diluted solution: After dilution in 5% glucose solution, the solution should be used within 24 hours when stored at room temperature (up to 25 °C). Chemical and physical in-use stability has been demonstrated for 24 hours at 25 °C. From a microbiological point of view, the diluted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the healthcare professional.
• Appearance: The concentrate is a clear, yellow or orange solution. Do not use if the solution is turbid, discolored (other than yellow/orange), or contains visible particles. Do not use the medicine after the expiry date which is stated on the carton and vial label.
• Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements for pharmaceutical waste. Do not dispose of through household waste or wastewater.

Healthcare facilities typically store levosimendan in dedicated medication refrigerators in cardiac care units, intensive care units, or pharmacy departments. The vials should be inspected before use for any signs of damage, leakage, or changes in the color or clarity of the solution. The expiry date should be checked before each use.

What Does Levosimendan STADA Contain?

Understanding the composition of Levosimendan STADA is important for healthcare professionals administering the medication, particularly regarding excipient content that may be relevant for patient safety. The full qualitative and quantitative composition is as follows:

Active substance: Each milliliter of concentrate for solution for infusion contains 2.5 mg of levosimendan. Each 5 ml vial contains 12.5 mg of levosimendan. Each 10 ml vial (where available) contains 25 mg of levosimendan.

Excipients (inactive ingredients):

• Povidone: A water-soluble polymer used as a solubilizer and stabilizer. It helps maintain the levosimendan in solution at the required concentration.
• Citric acid anhydrous: Used as a pH buffer to maintain the solution within the optimal pH range for stability and compatibility.
• Ethanol 96%: Used as a co-solvent to dissolve levosimendan, which has limited aqueous solubility. The ethanol content is important to consider in patients who are sensitive to alcohol, those with hepatic impairment, pregnant women, and patients taking metronidazole or disulfiram. A 5 ml vial may contain up to approximately 0.5 g of ethanol. After dilution in 500 ml of glucose solution, the final ethanol concentration is negligible.

The concentrate is a clear, yellow to orange solution with a pH of approximately 3.8–4.2. Levosimendan is chemically described as (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, with a molecular formula of C₁₄H₁₂N₆O and a molecular weight of 280.29 g/mol. The R-enantiomer (levosimendan) is the pharmacologically active form, while the S-enantiomer has no significant calcium-sensitizing activity.

For dilution, only 5% glucose (dextrose) solution is recommended as the diluent. Do not mix or co-infuse levosimendan with other medicinal products except for the recommended diluent. The compatibility of levosimendan with other intravenous solutions or medications in the same infusion line has not been established. A dedicated intravenous line or a dedicated lumen of a multi-lumen central venous catheter is recommended for administration.

References

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