Levosimendan Waymade

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Levosimendan Waymade 2.5 mg/mL concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of concentrate contains: 2.5 mg of levosimendan.
A 5 mL vial contains 12.5 mg of levosimendan.
Excipient with known effect: ethanol
This medicinal product contains 785 mg/mL of ethanol (alcohol).
For a complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.
The concentrate is a yellow or orange transparent solution which must be diluted before administration.

4. CLINICAL INFORMATION

4.1 Therapeutic indications
Levosimendan Waymade is indicated for the short-term treatment of severe chronic heart failure in acute decompensated phase (severe chronic heart failure, ADHF), when conventional therapy is insufficient and when the use of an inotropic agent is considered appropriate (see section 5.1).
Levosimendan Waymade is indicated in adults.

4.2 Posology and method of administration
Levosimendan Waymade is for hospital use only. It must be administered in a hospital setting where adequate monitoring equipment and experience with inotropic agents are available.

Posology
The dose and duration of therapy should be individualized according to the patient's clinical condition and response to the drug.

Treatment should begin with a loading dose infusion of 6–12 mcg/kg administered over 10 minutes, followed by a continuous infusion of 0.1 mcg/kg/min (see section 5.1). The lower loading dose (6 micrograms/kg) is recommended for patients who are receiving concomitant intravenous vasodilators or inotropes, or both, at the start of the infusion. Higher loading doses within this range may produce a greater haemodynamic response but may also be associated with a transient increase in the incidence of adverse reactions. The patient's response should be evaluated during the loading infusion or within 30–60 minutes after any dosage adjustment, based on clinical response. If the response is excessive (hypotension, tachycardia), the infusion rate may be reduced to 0.05 mcg/kg/min or discontinued (see section 4.4).
If the initial dose is well tolerated and an increased haemodynamic effect is required, the infusion rate may be increased to 0.2 mcg/kg/min.

The recommended duration of infusion in patients with severe chronic heart failure in acute decompensated phase is 24 hours. No tolerance or rebound phenomena have been observed after discontinuation of levosimendan infusion. The haemodynamic effects of the drug persist for at least 24 hours and may be observed for up to 9 days after termination of a 24-hour infusion (see section 4.4).

Experience with repeated administrations of levosimendan is limited. Experience with concomitant use of vasoactive agents, including inotropic agents (except digoxin), is limited. In the REVIVE program, a lower loading dose (6 micrograms/kg) was administered with concomitant baseline infusion of vasoactive agents (see sections 4.4, 4.5 and 5.1).

Monitoring of treatment
In accordance with current medical practice, ECG, arterial blood pressure, heart rate and urine output should be monitored during treatment. Monitoring of these parameters is recommended for at least 3 days after the end of the infusion or until the patient is clinically stable (see section 4.4). Monitoring for at least 5 days is recommended in patients with mild to moderate hepatic or renal impairment.

Elderly
No dose adjustment is necessary in elderly patients.

Renal impairment
Levosimendan Waymade should be used with caution in patients with mild to moderate renal impairment. Levosimendan Waymade must not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) (see sections 4.3, 4.4 and 5.2).

Hepatic impairment
Levosimendan Waymade should be used with caution in patients with mild to moderate hepatic impairment, although no dose adjustment appears to be necessary in these patients. Levosimendan Waymade must not be administered to patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).

Paediatric population
Levosimendan Waymade must not be administered to children and adolescents under 18 years of age (see sections 4.4 and 5.2).

Method of administration
Levosimendan Waymade must be diluted before administration (see section 6.6).
The infusion is for intravenous use only and may be administered via either peripheral or central route.
The table below provides detailed information on infusion rates for both bolus and maintenance doses of a 0.05 mg/mL Levosimendan Waymade infusion preparation:

The following table provides detailed information on the infusion rate for both the bolus dose and the maintenance dose of a 0.025 mg/mL Levosimendan Waymade for infusion preparation:

4.3 Contraindications
Hypersensitivity to levosimendan or to any of the excipients listed in section 6.1.
Severe hypotension and tachycardia (see sections 4.4 and 5.1). Significant mechanical ventricular obstructions impairing filling or ejection or both. Severe renal impairment (creatinine clearance <30 mL/min) and severe hepatic impairment. History of torsades de pointes.

4.4 Special warnings and precautions for use
As an initial haemodynamic effect, a decrease in both systolic and diastolic arterial pressure may occur; therefore, levosimendan must be used with caution in patients with low baseline systolic and diastolic blood pressure or in those at risk of hypotensive episodes. More conservative dosage regimens are recommended for these patients. The physician must adjust the dosage and duration of treatment according to the patient's condition and response (see sections 4.2, 4.5 and 5.1).

Severe hypovolaemia must be corrected prior to the intravenous infusion of levosimendan.
If excessive changes in arterial pressure or heart rate occur, the infusion rate should be reduced or the infusion stopped.

The exact duration of all haemodynamic effects has not been established; however, haemodynamic effects generally last for 7–10 days. This is partly due to the presence of active metabolites, which reach their peak plasma concentrations approximately 48 hours after the end of the infusion. Non-invasive monitoring is recommended for at least 4–5 days after the end of the infusion. Monitoring should continue until the decrease in arterial pressure has reached its nadir and begins to rise again. Monitoring may last longer than 5 days if there are any signs of ongoing blood pressure reduction, but may be shorter than 5 days if the patient is clinically stable. An extended monitoring period may be necessary in patients with mild to moderate hepatic or renal impairment.

Levosimendan Waymade must be administered with caution in patients with mild to moderate renal impairment. Limited data are available regarding the elimination of active metabolites in patients with impaired renal function. Impaired renal function may lead to increased concentrations of active metabolites, which may cause a more pronounced and prolonged haemodynamic effect (see section 5.2).

Levosimendan Waymade must be administered with caution in patients with mild to moderate hepatic impairment. Impaired hepatic function may lead to prolonged exposure to active metabolites, which may cause a more pronounced and prolonged haemodynamic effect (see section 5.2). Levosimendan Waymade infusion may cause a decrease in serum potassium concentrations. Therefore, hypokalaemia must be corrected prior to administration of Levosimendan Waymade, and serum potassium levels should be monitored during therapy. As with other drugs for heart failure, infusions of Levosimendan Waymade may be associated with decreases in haemoglobin and haematocrit levels, and caution should be exercised in patients with concomitant cardiovascular ischaemia and anaemia.

Levosimendan Waymade infusion must be administered with caution in patients with tachycardia, atrial fibrillation with rapid ventricular response, or potentially life-threatening arrhythmias.

Experience with repeated administration of levosimendan is limited. Experience with concomitant administration of vasoactive agents, including inotropic agents (except digoxin), is limited. The benefit-risk balance should be evaluated for each individual patient.

Levosimendan Waymade must be administered with caution and under strict electrocardiographic monitoring in patients with ongoing coronary ischaemia, long QTc intervals regardless of cause, and when administered concomitantly with drugs that prolong the QTc interval (see section 4.9).

The use of levosimendan in cardiogenic shock has not been studied. Information on the use of levosimendan in the following conditions is not available: restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade, and right ventricular infarction.

Levosimendan Waymade must not be administered to children, as experience with the use of levosimendan in children and adolescents under 18 years of age is very limited (see section 5.2).

Limited experience is available on the use of levosimendan in severe heart failure in patients awaiting heart transplantation.

This medicinal product contains 3.925 mg of alcohol (anhydrous ethanol) in each 5 mL vial, equivalent to approximately 98% of the volume. The amount of alcohol in a 5 mL vial of this medicinal product is equivalent to 99.2 mL of beer or 41.3 mL of wine.

Harmful for individuals suffering from alcoholism.

This should be taken into account in pregnant or breastfeeding women, children, and high-risk patient groups such as patients with liver disease or epilepsy. The amount of alcohol present in this medicinal product may alter the effects of other medicinal products.

Since this medicinal product is usually administered slowly over 24 hours, the effects of alcohol may be reduced.

4.5 Interactions with other medicinal products and other forms of interaction
As per current medical practice, levosimendan should be used with caution when administered concomitantly with other intravenous vasoactive medicinal products, as this may increase the potential risk of hypotension (see section 4.4).

No pharmacokinetic interactions have been observed in patients treated with an infusion of digoxin and levosimendan. Levosimendan Waymade infusion can be administered to patients receiving beta-blockers without loss of efficacy. Concomitant administration of isosorbide mononitrate and levosimendan in healthy volunteers resulted in a significant potentiation of the orthostatic hypotension response.

Levosimendan has been shown to be an inhibitor of CYP2C8 in vitro, and therefore, an increase in exposure to concomitantly administered drugs that are primarily metabolised by CYP2C8 cannot be excluded. Therefore, whenever possible, co-administration of levosimendan with sensitive CYP2C8 substrates such as loperamide, pioglitazone, repaglinide, and enzalutamide should be avoided.

4.6 Fertility, pregnancy and lactation
Pregnancy
There is no experience with the use of levosimendan in pregnant women.
Animal studies have revealed reproductive toxicity (see section 5.3). Consequently, levosimendan should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the foetus.

Breastfeeding
Post-marketing data in breastfeeding women indicate that the active metabolites of levosimendan, OR-1896 and OR-1855, are excreted in breast milk and have been detected in milk for at least 14 days after initiation of a 24-hour levosimendan infusion. Women receiving levosimendan must not breastfeed in order to avoid potential cardiovascular adverse events in the newborn.

Fertility
Animal studies have shown reproductive toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines
Not applicable.

4.8 Undesirable effects
During placebo-controlled clinical trials in ADHF (REVIVE programme), 53% of patients reported adverse reactions, the most frequent of which were ventricular tachycardia, hypotension, and headache.

During a clinical trial in ADHF (SURVIVE), controlled against dobutamine, 18% of patients reported adverse reactions, the most frequent of which were ventricular tachycardia, atrial fibrillation, hypotension, ventricular extrasystoles, tachycardia, and headache.

The table below describes adverse reactions observed in 1% or more of patients during the clinical trials REVIVE I, REVIVE II, SURVIVE, LIDO, RUSSLAN, 300105 and 3001024. When, in a single study, a particular event occurred at a higher incidence than observed across other studies, the highest incidence is reported in the table.

Events considered at least potentially related to levosimendan are listed by system organ class and frequency, using the following convention: very common (≥ 1/10), common (≥ 1/100, < 1/10).

Summary of Adverse Reactions
SURVIVE clinical study, REVIVE programme, and combination of clinical studies LIDO/RUSSLAN/300105/3001024

Post-marketing Adverse Reactions
During post-marketing experience, ventricular fibrillation has been reported in patients receiving
levosimendan.

Reporting of Suspected Adverse Reactions
Reporting suspected adverse reactions occurring after marketing authorization of the medicinal product is important, as it allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system at the following website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

4.9 Overdose
Excessive doses of Levosimendan Waymade infusion may cause hypotension and tachycardia. In clinical studies with levosimendan, hypotension has been successfully managed using vasopressor agents (e.g. dopamine in patients with congestive heart failure or noradrenaline in patients undergoing cardiac surgery). Excessive reduction in cardiac filling pressure may limit the response to Levosimendan Waymade and can be treated with parenteral fluids. High doses (equal to or greater than 0.4 mcg/kg/min) and infusions lasting longer than 24 hours increase heart rate and are sometimes associated with QTc interval prolongation. In case of Levosimendan Waymade overdose, continuous ECG monitoring, repeated measurements of serum electrolytes, and invasive hemodynamic monitoring should be performed. Overdose of levosimendan leads to increased plasma concentrations of the active metabolite, potentially enhancing and prolonging the effect on heart rate, thus requiring a correspondingly extended observation period.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties
Pharmacotherapeutic category: Other cardiac stimulants (calcium sensitizers), ATC code: C01CX08
Pharmacodynamic effects
Levosimendan enhances calcium sensitivity of contractile proteins by binding to cardiac troponin C in a calcium-dependent manner. Levosimendan increases contractile force without impairing ventricular relaxation. In addition, levosimendan opens ATP-dependent potassium channels in vascular smooth muscle, thereby inducing vasodilation of systemic and coronary resistance vessels and systemic venous capacitance vessels. Levosimendan is a selective inhibitor of phosphodiesterase III in vitro. The relevance of this property at therapeutic concentrations is unclear. In patients with heart failure, the positive inotropic and vasodilatory actions of levosimendan result in increased contractility and reductions in both preload and afterload, without adversely affecting diastolic function. Levosimendan has been shown to activate myocardium following PTCA or thrombolysis.
Hemodynamic studies conducted in healthy volunteers and in patients with stable and unstable heart failure have demonstrated a dose-dependent effect of intravenous levosimendan administered as a bolus infusion (from 3 micrograms/kg to 24 micrograms/kg) and as continuous infusion (from 0.05 to 0.2 micrograms/kg per minute). Compared to placebo, levosimendan increased cardiac output, left ventricular ejection fraction, and heart rate, and reduced systolic and diastolic arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and systemic vascular resistance.
Levosimendan increases coronary blood flow in patients undergoing coronary surgery and improves myocardial perfusion in patients with heart failure. These benefits are achieved without a significant increase in myocardial oxygen consumption. Treatment with levosimendan infusion produces significant reductions in endothelin-1 levels in patients with congestive heart failure. It does not increase plasma catecholamine levels at the recommended infusion rate.

Clinical studies in patients with acute heart failure
Levosimendan has been evaluated in clinical trials involving 2,800 patients with heart failure. The efficacy and safety of levosimendan in the treatment of ADHF were assessed in the following multinational, randomized, double-blind clinical trials:

REVIVE Program
REVIVE I
In a double-blind, placebo-controlled pilot study involving 100 patients with ADHF who received a 24-hour infusion of levosimendan, a benefit was observed in patients treated with levosimendan compared to placebo plus standard therapy, as measured by a composite clinical endpoint.
REVIVE II
A pivotal double-blind, placebo-controlled study in 600 patients who received a 10-minute bolus infusion of 6–12 micrograms/kg followed by a gradual, protocol-specified titration of levosimendan up to 0.05–0.2 micrograms/kg/min for up to 24 hours demonstrated clinical benefit in patients with ADHF who remained dyspneic despite intravenous diuretic therapy.
The REVIVE clinical program was designed to compare the efficacy of levosimendan plus standard therapy versus placebo plus standard therapy in the treatment of ADHF.
Inclusion criteria included hospitalization for ADHF, left ventricular ejection fraction ≤35% within the previous 12 months, and dyspnea at rest. All background therapies were permitted except intravenous milrinone. Exclusion criteria included severe ventricular outflow tract obstruction, cardiogenic shock, systolic blood pressure ≤90 mmHg or heart rate ≥120 beats per minute (persisting for at least five minutes), or requirement for mechanical ventilation.
Primary endpoint results showed a significantly higher proportion of patients classified as improved and a lower proportion as worsened (p=0.015), as measured by a composite clinical endpoint reflecting recognized clinical benefits at three time points: six hours, 24 hours, and five days. B-type natriuretic peptide decreased significantly compared to placebo and standard therapy at 24 hours and over five days (p=0.001).
At 90 days, the levosimendan treatment group showed a slightly higher mortality rate, although not statistically significant, compared to the control group (15% vs 12%). Post-hoc analyses identified baseline systolic blood pressure <100 mmHg or baseline diastolic blood pressure <60 mmHg as risk factors for increased mortality.

SURVIVE
A multicenter, double-blind, double-dummy, parallel-group study comparing levosimendan with dobutamine evaluated 180-day all-cause mortality in 1,327 patients with ADHF requiring additional therapy due to inadequate response to intravenous diuretics or vasodilators. The patient population was generally similar to that in REVIVE II, but included patients without a prior history of heart failure (e.g., acute myocardial infarction), as well as those requiring mechanical ventilation. Approximately 90% of patients were enrolled due to dyspnea at rest.
Results from the SURVIVE study showed no statistically significant difference between levosimendan and dobutamine in 180-day all-cause mortality (Hazard ratio=0.91 (95% CI [0.74, 1.13], p=0.401). However, there was a numerical advantage in favor of levosimendan for mortality at day 5 (4% levosimendan vs 6% dobutamine). This benefit persisted through 31 days (12% levosimendan vs 14% dobutamine) and was more pronounced in patients receiving background beta-blocker therapy. In both treatment groups, patients with low baseline blood pressure had higher mortality rates compared to those with higher baseline blood pressure.

LIDO
Levosimendan produced dose-dependent increases in cardiac output and systolic ventricular output and dose-dependent reductions in pulmonary capillary wedge pressure, mean arterial pressure, and total peripheral resistance.
In a multicenter, double-blind study, 203 patients with heart failure and very low output (ejection fraction ≤0.35, cardiac index <2.5 L/min/m², pulmonary capillary wedge pressure [PCWP] >15 mmHg), requiring inotropic support, received levosimendan (loading dose 24 mcg/kg over 10 minutes followed by continuous infusion of 0.1–0.2 mcg/kg/min) or dobutamine (5–10 mcg/kg/min) for 24 hours. The etiology of heart failure was ischemic in 47% of patients; 45% had idiopathic dilated cardiomyopathy. Seventy-six percent of patients had dyspnea at rest. Key exclusion criteria included systolic blood pressure <90 mmHg and heart rate >120 beats per minute. Primary endpoints were an increase in cardiac output ≥30% and a simultaneous decrease in PCWP ≥25% at 24 hours. This was achieved in 28% of patients treated with levosimendan compared to 15% with dobutamine (p=0.025). Sixty-eight percent of symptomatic patients showed improvement in dyspnea signs after levosimendan treatment, compared to 59% after dobutamine. Improvement in fatigue signs was observed in 63% and 47% of patients after levosimendan and dobutamine, respectively. All-cause mortality at day 31 was 7.8% in levosimendan-treated patients and 17% in dobutamine-treated patients.

RUSSLAN
In a subsequent multicenter, double-blind study primarily designed to assess safety, 504 patients with acute unstable heart failure following acute myocardial infarction requiring inotropic support were treated with levosimendan and placebo for 6 hours. No significant differences in the incidence of hypotension and ischemia were observed between treatment groups.
A retrospective analysis of the LIDO and RUSSLAN studies showed no adverse effects on survival up to six months.

Clinical studies in cardiac surgery
Two of the largest placebo-controlled studies are described below.

LEVO CTS
In a double-blind, placebo-controlled study involving 882 patients undergoing cardiac surgery, levosimendan (0.2 µg/kg/min for 60 min, followed by 0.1 µg/kg/min for 23 h) was administered at induction of anesthesia in patients with preoperative left ventricular ejection fraction ≤35%. The study did not meet its primary composite endpoints.
The four-component primary endpoint (death up to day 30, renal replacement therapy up to day 30, perioperative myocardial infarction up to day 5, or use of mechanical cardiac assist device up to day 5) occurred in 24.5% of patients in the levosimendan group and 24.5% in the placebo group (adjusted OR, 1.00; 99% CI, 0.66–1.54). The two-component primary endpoint (death up to day 30 or use of mechanical cardiac assist device up to day 5) occurred in 13.1% of patients in the levosimendan group and 11.4% in the placebo group (adjusted odds ratio, 1.18; 96% CI, 0.76–1.82). At day 90, deaths occurred in 4.7% of patients in the levosimendan group and 7.1% in the placebo group (hazard ratio, 0.64; 95% CI, 0.37–1.13).
Hypotension was reported in 36% of patients in the levosimendan group and 33% in the placebo group. Atrial fibrillation was reported in 38% of patients in the levosimendan group and 33% in the placebo group.

LICORN
In an independent, multicenter, randomized, double-blind, placebo-controlled clinical study involving 336 adult patients with LVEF ≤40% scheduled for coronary artery bypass grafting (with or without valve surgery), levosimendan infusion at 0.1 μg/kg/min (without a loading dose) was administered for 24 hours after induction of anesthesia. The primary outcome was a composite of catecholamine infusion beyond 48 hours, need for mechanical circulatory support postoperatively, or need for renal replacement therapy. The primary endpoint occurred in 52% of levosimendan-treated patients and 61% of placebo-treated patients (absolute risk difference, −7%; 95% CI, −17% to 3%). The estimated 10% risk reduction was primarily related to reduced need for catecholamine infusion at 48 hours. Mortality at day 180 was 8% in the levosimendan group and 10% in the placebo group. Hypotension was reported in 57% of patients in the levosimendan group and 48% in the placebo group. Atrial fibrillation was reported in 50% of patients in the levosimendan group and 40% in the placebo group.

5.2 Pharmacokinetic Properties
General
The pharmacokinetics of levosimendan are linear within the therapeutic dose range of 0.05–0.2 mcg/kg/min.

Distribution
The volume of distribution of levosimendan (Vss) is approximately 0.2 L/kg. Levosimendan is 97–98% bound to plasma proteins, primarily albumin. In patients, the mean plasma protein binding of metabolites OR-1855 and OR-1896 is approximately 39% and 42%, respectively.

Biotransformation
Levosimendan is completely metabolized, and only negligible amounts of unchanged drug are excreted in urine and feces. Levosimendan is primarily metabolized via conjugation to cyclic cysteinylglycine or N-acetylated cysteine conjugate. Approximately 5% of the dose is metabolized in the intestine by reduction to aminophenylpyridazinone (OR-1855), which after reabsorption is metabolized by N-acetyltransferase to the active metabolite OR-1896. The acetylation rate is genetically determined. In fast acetylators, concentrations of the metabolite OR-1896 are slightly higher than in slow acetylators. However, this has no implications for the clinical hemodynamic effect at recommended doses.
Following administration of levosimendan, the only metabolites significantly detected in systemic circulation are OR-1855 and OR-1896. In vivo, these metabolites reach equilibrium as a result of acetylation and deacetylation metabolic pathways regulated by the polymorphic enzyme N-acetyltransferase 2. In slow acetylators, the metabolite OR-1855 predominates, whereas in fast acetylators, OR-1896 predominates. The sum of exposures to the two metabolites is similar between slow and fast acetylators, and there are no differences in hemodynamic effects between the two groups. The prolonged hemodynamic effects (lasting up to 7–9 days after discontinuation of a 24-hour levosimendan infusion) are attributed to these metabolites.
Several in vitro studies have shown that levosimendan, OR-1855, and OR-1896 do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at concentrations achieved with recommended dosing. Furthermore, levosimendan does not inhibit CYP1A1, and neither OR-1855 nor OR-1896 inhibit CYP2C8 or CYP2C9. Levosimendan has been shown to be an inhibitor of CYP2C8 in vitro (see section 4.5). Results from human interaction studies between levosimendan and warfarin, felodipine, and itraconazole have confirmed that levosimendan does not inhibit CYP3A4 or CYP2C9, and that levosimendan metabolism is not affected by CYP3A inhibitors.

Elimination
The clearance of levosimendan is 3.0 mL/min/kg, and its half-life is approximately 1 hour. Fifty-four percent of the dose is excreted in urine and 44% in feces. More than 95% of the dose is excreted within one week. An irrelevant amount (<0.05% of the dose) of unchanged levosimendan is excreted in urine. The metabolites OR-1855 and OR-1896 are formed and eliminated slowly. Peak plasma concentration is reached two days after the end of infusion. The half-life of the metabolites is approximately 75–80 hours. The active metabolites of levosimendan, OR-1855 and OR-1896, undergo conjugation or renal filtration and are primarily excreted in urine.

Special Populations
Children:
Levosimendan should not be administered to children (see section 4.4).
Limited data indicate that the pharmacokinetics of levosimendan after a single dose in children (age 3 months – 6 years) are similar to those in adults. The pharmacokinetics of the active metabolite have not been studied in children.

Renal impairment:
The pharmacokinetics of levosimendan have been studied in subjects with various degrees of renal impairment without heart failure. Exposure to levosimendan was similar in subjects with mild to moderate renal impairment and in those undergoing hemodialysis, while exposure may be slightly lower in subjects with severe renal impairment.
Compared to healthy volunteers, the unbound fraction of levosimendan appeared slightly increased, and AUCs of the metabolites (OR-1855 and OR-1896) were up to 170% higher in subjects with severe renal impairment and in patients undergoing hemodialysis. The effects of mild to moderate renal impairment on the pharmacokinetics of OR-1855 and OR-1896 are expected to be less pronounced than those of severe renal impairment.
Levosimendan is not dialyzable, whereas OR-1855 and OR-1896 are. Dialysis clearances are low (approximately 8–23 mL/min), and the net effect of a 4-hour dialysis session on overall exposure to these metabolites is minimal.

Hepatic impairment:
In subjects with mild to moderate cirrhosis, no differences in pharmacokinetics or plasma protein binding of levosimendan were observed compared to healthy subjects. The pharmacokinetics of levosimendan, OR-1855, and OR-1896 were similar between healthy volunteers and subjects with moderate hepatic impairment (Child-Pugh Class B), except for longer elimination half-lives of OR-1855 and OR-1896 in subjects with moderate hepatic impairment.
Population analysis did not show effects attributable to age, ethnicity, or gender on the pharmacokinetics of levosimendan. However, the same analysis revealed that volume of distribution and total clearance are weight-dependent.

5.3 Preclinical Safety Data
Conventional studies on general toxicity and genotoxicity revealed no particular risks for humans with short-term use.
In animal studies, levosimendan was not teratogenic but caused a generalized reduction in fetal ossification in rats and rabbits, with abnormal development of the supraoccipital bone in rabbits. When administered before and during early stages of pregnancy, levosimendan reduced fertility (reduced number of corpora lutea and implantations) and showed developmental toxicity (reduced litter size and increased number of early resorptions and post-implantation losses) in female rats.
These effects were observed at clinically relevant doses.
In animal studies, levosimendan was excreted in breast milk.

6. PHARMACEUTICAL INFORMATION

6.1 List of excipients
Povidone
Citric acid
Ethanol, anhydrous

6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products or diluents except those
mentioned in section 6.6.

6.3 Shelf life
Unopened vial
24 months

After dilution
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.
From a microbiological standpoint, the product should be used immediately. If not used immediately,
storage conditions and duration prior to use are the responsibility of the user and should normally not
exceed 24 hours between 2°C and 8°C, unless dilution has been carried out under well-controlled and
validated aseptic conditions. Storage and duration of use after dilution must never exceed 24 hours.

6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze.
The colour of the concentrate may turn slightly orange during storage, but this does not imply a loss of
efficacy: the medicinal product may therefore be used up to the expiry date indicated, provided storage
instructions are followed.
For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container
Clear type I glass vial with chlorobutyl rubber stopper and aluminium flip-off seal.
Pack sizes:

• 1, 4, 10 vials of 5 mL

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and handling
Levosimendan Waymade 2.5 mg/mL concentrate for solution for infusion is intended for single use only.
Levosimendan Waymade 2.5 mg/mL concentrate for solution for infusion must not be diluted to a concentration higher than 0.05 mg/mL as specified below, otherwise opalescence and precipitation may occur.
As with all parenteral medicinal products, visually inspect the diluted solution for particulate matter and discoloration prior to administration.

To prepare an infusion of 0.025 mg/mL, mix 5 mL of Levosimendan Waymade 2.5 mg/mL concentrate for solution for infusion with 500 mL of 5% glucose solution.
To prepare an infusion of 0.05 mg/mL, mix 10 mL of Levosimendan Waymade 2.5 mg/mL concentrate for solution for infusion with 500 mL of 5% glucose solution.

The following medicinal products may be administered simultaneously with Levosimendan Waymade by intravenous route:

• Furosemide 10 mg/mL
• Digoxin 0.25 mg/mL
• Glycerol trinitrate 0.1 mg/mL

Any unused medicinal product or waste material derived from this medicinal product must be disposed of in accordance with local regulations.

7. MARKETING AUTHORISATION HOLDER

Waymade B.V.
Herikerbergweg 88,
1101CM Amsterdam,
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

051156014 - “2.5 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION” 1
5 ML GLASS VIAL
051156026 - “2.5 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION” 4
5 ML GLASS VIALS
051156038 - “2.5 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION” 10
5 ML GLASS VIALS

9. DATE OF FIRST AUTHORISATION/DATE OF RECENT AUTHORISATION RENEWAL

Date of first authorisation:
Date of most recent renewal:

10. DATE OF TEXT REVISION