Levosimendan for Injection 12.5mg

  1. Name of the medicinal product

Levosimendan 12.5mg powder for solution for infusion.
Levosimendan 25mg powder for solution for infusion

  1. Qualitative and quantitative composition

Each ml contains 2.5mg of levosimendan.

One 5 ml vial contains 12.5mg of levosimendan.
One 10 ml vial contains 25mg of levosimendan.

For a full list of excipients, see section 6.1.

  1. Pharmaceutical form

Lyophilized Powder for solution for infusion.

  1. Clinical particulars

4.1       Therapeutic indications

Levosimendan is indicated for the short­term treatment of  acutely  decompensated severe chronic heart failure (ADHF) in situations where conventional therapy is  not sufficient, and in cases where inotropic support  is  considered  appropriate (see section 5.1.).

4.2       Posology and method of administration

Levosimendan is for in­hospital use only. It should be administered in a hospital setting where adequate monitoring facilities and expertise with  the  use  of  inotropic agents are available.

Method of administration

Levosimendan is to be diluted prior to administration (see section 6.6).The infusion is for intravenous use only and can be administered by the peri­ pheral or central route.


The dose and duration of treatment should be individualised according to the patient’s clinical condition and response.

The treatment should be initiated with a loading  dose  of  6­12  microgram/kg infused over 10 minutes followed by a continuous infusion of 0.1  microgram/kg/   min (see section 5.1). The lower loading  dose  of  6  microgram/kg  is  recommen­ ded for  patients  on  concomitant  intravenous  vasodilators  or  inotropes  or  both at the start of  the  infusion.  Higher  loading  doses  within  this  range  will  produce a stronger haemodynamic response but may be associated with a  transient increased incidence of adverse reactions. The response of the patient should be assessed with the loading dose or within  30  to  60  minutes  of  dose  adjustment and as clinically indicated If the response is deemed excessive (hypotension, tachycardia), the rate of the infusion  may  be  decreased  to  0.05  microgram/ kg/min or discontinued (see section 4.4). If the initial dose is tolerated and an increased haemodynamic effect is required, the rate of the infusion  can  be increased to 0.2 microgram/kg/min.

The recommended duration of infusion in patients with acute decompensation  of severe chronic heart failure is 24 hours. No signs of development of tolerance or rebound phenomena have been observed following discontinuation of   Levosimendan infusion. Haemodynamic effects persist for at least 24 hours and may    be seen up to 9 days after discontinuation of a 24­hour infusion (see section  4.4).

Experience of repeated administration of Levosimendan is limited. Experience with concomitant use of vasoactive  agents,  including  inotropic  agents  (except  di­ goxin) is limited In the REVIVE programme, a lower loading dose (6 micrograms/    kg) was administered with baseline concomitant vasoactive  agents  (see  sections 4.4, 4.5 and 5.1).

Monitoring of treatment

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


No dose adjustment is required for elderly patients.

Renal impairment

Levosimendan must be used with caution in patients with mild to moderate renal im­ pairment. Levosimendan should 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 must be used with caution in patients with mild to moderate hepatic impairment although no dose adjustment appears necessary for these patients. Levosimendan should not be used in patients with severe hepatic impairment (see sec­   tion 4.3, 4.4 and 5.2).


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

4.3       Contraindications

Hypersensitivity to levosimendan or to any of the excipients.

Severe hypotension and tachycardia (see sections 4.4 and 5.1). Significant mechanical obstructions affecting ventricular filling or outflow or both. Severe renal impairment (creatinine clearance <30 ml/min) and severe hepatic impair­ ment. History of Torsades de Pointes.

4.5 Special warnings and special precautions for use

An initial haemodynamic effect of levosimendan may be a decrease in systolic and diastolic blood pressure, therefore, levosimendan should be used with caution in patients with low baseline systolic or diastolic blood pressure or   those at risk for a hypotensive episode. More conservative dosing regimens are recommended for these patients. Physicians should tailor the dose and duration of therapy to the condition and response of the patient (see sections 4.2, 4.5  and 5.1).

Severe hypovolaemia should be corrected prior to levosimendan infusion. If excessive changes in blood pressure or heart rate are observed, the rate of infusion should be reduced or the infusion discontinued.

The exact duration of all haemodynamic effects has not been determined, however, the haemodynamic effects, generally last for 7­10 days. This is partly due to the presence of active metabolites, which reach their maximum plasma concentrations about 48 hours after the infusion has been stopped. Non­inva­ sive monitoring for at least 4­5 days after the end of infusion is recommended. Monitoring is recommended to continue until the blood pressure reduction   has reached its maximum and the blood pressure starts to increase again, and may need to be longer than 5 days if there are any signs of continuing blood pressure decrease, but can be shorter than 5 days if the patient is clinically stable. In patients with mild to moderate renal or mild to moderate hepatic impairment an extended period of monitoring maybe needed.

Levosimendan should be used cautiously in patients with mild to moderate renal im­ pairment. Limited data on the elimination of the active metabolites are available      in patients with impaired renal function. Impaired renal function may lead to increased concentrations of the active metabolites, which may result in a more pronounced and prolonged haemodynamic effect (see section 5.2).

Levosimendan should be used cautiously in patients with mild to moderate hepatic impairment. Impaired hepatic function may lead to prolonged exposure to the active metabolites, which may result in a more pronounced and prolonged haemodynamic effect (see section 5.2).

Levosimendan infusion may cause a decrease in serum potassium concentration. Thus, low serum potassium concentrations should be corrected prior to the adminis­ tration of Levosimendan and serum potassium should be monitored during treatment. As with other medicinal products for heart failure, infusions of Levosimendan may be accompanied by decreases in haemoglobin and haematocrit and caution should be exercised in patients with ischaemic cardiovascular disease and concurrent anaemia.

Levosimendan infusion should be used cautiously in patients with tachycardia atrial fibrillation with rapid ventricular response or potentially life­threatening arrhythmias.

Experience with repeated administration of Levosimendan is limited. Experience with concomitant use of vasoactive agents, including inotropic agents  (except  di­ goxin), is limited. Benefit and risk should be assessed for the individual patient.

Levosimendan should be used cautiously and under close ECG monitoring in patients with ongoing coronary ischaemia, long QTc  interval regardless of aetiology,    or when given concomitantly with medicinal products that prolong the QTc interval (see section 4.9).

The use of levosimendan in cardiogenic shock has not been studied. No infor­ mation is available on the use of Levosimendan in the following disorders: restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral valve insufficiency, myocardial rupture, cardiac tamponade, and right ventricular infarction

Levosimendan should not be administered to children as there  is  very  limited  expe­ rience of use in children and adolescent under 18 years of age (see section 5.2).

Limited experience is available on the use  of  Levosimendan  in  patients  with  heart failure after surgery, and insevere heart failure in patients awaiting heart trans­ plantation.

4.5       Interaction with other medicinal products and other forms of inte‑ raction

Consistent with current medical practice, levosimendan should  be  used  with caution when used with other intravenous vasoactive medicinal products due to        a potentially increased risk of hypotension (see section 4.4).

No pharmacokinetic interactions have been observed in a population analysis of patients receiving digoxin and Levosimendan infusion. Levosimendan infusion can be used in patients receiving beta­blocking agents without loss of efficacy. Co­administra­ tion of isosorbide mononitrate and levosimendan in healthy volunteers resulted in significant potentiation of the orthostatic hypotensive response.

4.6       Pregnancy and lactation


There is no experience of using levosimendan in pregnant women. Animal studies have shown toxic effects on reproduction (see section 5.3). Therefore, levosimendan should be used in pregnant women only if the benefits for the mother outweigh the possible risks to the foetus.


It is not known whether levosimendan is excreted in human milk. Studies in    rats have shown excretion of levosimendan in breast milk, therefore women receiving levosimendan should not breastfeed.

4.7       Effects on ability to drive and use machines

Not applicable

4.8       Undesirable effects

In placebo­controlled clinical trials for ADHF (REVIVE programme), 53% of patients experienced adverse reactions, the most frequent of which were ventri­ cular tachycardia, hypotension, and headache.

In a dobutamine­controlled clinical trial for ADHF (SURVIVE), 18% of patients experienced adverse reactions, the most frequent of which were ventricular tachycardia, atrial fibrillation, hypotension, ventricular extrasystoles, tachycar­ dia, and headache.

Post-marketing adverse reactions:

In post­marketing experience, ventricular fibrillation has been reported in patients being administered Levosimendan.

4.9       Overdose

Overdose of Levosimendan may induce hypotension  and  tachycardia.  In  clinical  trials with Levosimendan, hypotension has been successfully treated with vasopressors (e.g. dopamine in patients with congestive heart failure and adrenaline in patients following cardiac surgery). Excessive decreases in  cardiac  filling  pressures  may limit the response to Levosimendan and can be  treated  with  parenteral  fluids.  High doses (at or above 0.4 microgram/kg/min) and infusions over 24 hours increase    the heart rate and are sometimes associated with  prolongation  of  the  QTc interval. In the event of an overdose of Levosimendan, continuous ECG monitoring, repeated determinations of serum electrolytes and invasive haemodynamic monitoring should be undertaken. Levosimendan overdose leads to increased plasma concentrations of the active metabolite, which may lead to a more pronounced   and prolonged effect on heart rate requiring a corresponding extension of the observation period.

  1. Pharmacological properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Other cardiac stimulants (calcium sensitisers), ATC code: C01CX08

Pharmacodynamic effects

Levosimendan enhances the calcium sensitivity of contractile proteins by binding to cardiac troponin C in a calcium­dependent manner. Levosimendan increases the contraction force but does not impair ventricular relaxation. In addition, levosimendan opens ATP­sensitive potassium channels in vascular smooth muscle, thus inducing vasodilatation of systemic and coronary arterial resistance vessels and systemic venous capacitance vessels. Levosimendan

is a selective phosphodiesterase III inhibitor in vitro. The relevance of this at therapeutic concentrations is unclear. In patients with heart failure, the positive inotropic and vasodilatory actions of levosimendan result in an increased cont­ ractile force, and a reduction in both preload and afterload, without adversely affecting diastolic function. Levosimendan activates stunned myocardium in patients after PTCA or thrombolysis. Haemodynamic studies in healthy volunteers and in patients with stable and unstable heart failure have shown a dose­dependent effect of levosimendan given intravenously as loading dose (3 micrograms/kg to 24 micrograms/kg) and continuous infusion (0.05 to 0.2 micrograms/kg per minute). Compared with placebo, levosimendan increased cardiac output, stroke volume, ejection fraction, and heart rate and reduced systolic blood pressure, diastolic blood pressure, pulmonary capillary wedge pressure, right atrial pressure, and peri­ pheral vascular resistance.

Levosimendan infusion increases coronary blood flow in patients recovering from co­ ronary 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 significantly decreases circulating levels of endothelin­1 in patients with congestive heart failure. It does not increase plasma catecholamine levels at recommended infusion rates.

Clinical Trials

Levosimendan has been evaluated in clinical trials involving over 2800  heart  failure patients. The efficacy and safety of Levosimendan for the treatment of  ADHF  were assessed in the following randomised, double­blind, multi­national clinical trials:

REVIVE Programme


In a double­blind, placebo­controlled pilot study in 100 patients with ADHF who received a 24 hour infusion of Levosimendan, a beneficial response as measured by the clinical composite endpoint over placebo plus standard of care was observed in the Levosimendan­treated patients.


A double­blind, placebo­controlled pivotal study in 600 patients who were administered a 10 minute loading dose of 6­12 microgram/kg followed by a protocol­specified stepped titration of levosimendan to 0.05­0.2 microgram/kg/ minute for up to 24 hours that provided a benefit in clinical status in patients with ADHF who remained dyspnoeic after intravenous diuretic therapy.

The REVIVE clinical programme was designed to compare the effectiveness of levosimendan plus standard­of­care to placebo plus standard­of­care in the treatment of ADHF.

Inclusion criteria included patients  hospitalised  with  ADHF,  left  ventricular ejection fraction less than or equal to 35% within the previous 12 months, and dyspnoea at rest. All baseline therapies were allowed, with the exception of in­ travenous milrinone. Exclusion criteria included severe obstruction of ventricular outflow tracts, cardiogenic shock, a systolic blood pressure of ≤ 90 mmHg or

a heart rate ≥ 120 beats per minute (persistent for at least five minutes), or a requirement for mechanical ventilation.

The results of the primary endpoint demonstrated that a greater proportion of patients were categorised as improved with a smaller proportion of patients categorised as worsened (p­value 0.015) as measured by a clinical composite endpoint reflecting sustained benefits to clinical status over three time points: six hours, 24 hours and five days. B­type natriuretic peptide was significantly reduced vs. placebo and standard of care at 24 hours and through five days (p­value=0.001).

The Levosimendan group had a slightly higher, although not statistically significant, death rate compared with the control group at 90 days (15% vs. 12%).  Post  hoc analyses identified systolic blood pressure < 100 mmHg or diastolic blood pressure < 60 mmHg at baseline as factors increasing the mortality risk.


A double­blind, double­dummy, parallel group, multicentre study comparing levosimendan vs. dobutamine evaluated 180 day mortality in 1327 patients with ADHF who required additional therapy after an inadequate response to intra­ venous diuretics or vasodilators. The patient population was generally similar to the patients in the REVIVE II study. However, patients without a previous history of heart failure were included (e.g., acute myocardial infarction), as were pa­ tients requiring mechanical ventilation. Approximately 90% of patients entered the trial due to dyspnoea at rest.

The results of SUVIVE did not demonstrate a statistically significant difference between levosimendan and dobutamine in all­cause mortality at 180 days

{Hazard Ratio = 0.91 (95% CI [0.74, 1.13]  p­value  0.401)}.  However,  there was a numerical advantage in mortality at Day 5 (4% levosimendan vs. 6% dobutamine) for levosimendan. This advantage persisted through the 31­day period (12% levosimendan vs. 14% dobutamine) and was most prominent in

those individuals who received baseline beta­blocker therapy. In both treatment groups, patients with low baseline blood pressure experienced higher rates of mortality than did those with higher baseline blood pressure.


Levosimendan has been shown to lead to dose­dependent increases in cardiac output and stroke volume as well as dose­dependent decrease in pulmonary capillary wedge pressure, mean arterial pressure and total peripheral resistance.

In a double­blind multicentre trial, 203 patients with  severe  low  output  heart failure (ejection fraction ≤  0.35,  cardiac  index  <2.5  l/min/m2,  pulmonary  capil­ lary wedge pressure (PCWP)>15 mmHg) and in  need  of  inotropic  support  re­ ceived levosimendan  (loading  dose  24  microgram/kg  over  10  minutes  followed by a continuous infusion of 0.1­0.2 microgram/kg/min) or dobutamine (5­10 microgram/kg/min) for 24 hours. The aetiology of heart failure was ischaemic in   47% of the patients; 45% had idiopathic dilative cardiomyopathy. 76 % of the patients had dyspnoea at rest. Major exclusion criteria included systolic blood pressure below 90 mmHg and heart  rate  above  120  beats  per  minute.  The primary endpoint was an increase in cardiac  output  by  ≥  30%  and  a  simulta­ neous decrease of PCWP by ≥ 25% at 24 hours. This was reached in 28% of levosimendan treated patients compared with  15%  after  dobutamine  treatment (p= 0.025). Sixty­eight percent of symptomatic patients had an improvement

in  their  dyspnoea  scores  after  levosimendan  treatment,  compared  with 59%

after  dobutamine  treatment.  Improvement  in  fatigue  scores  were  63%  and 47% after levosimendan and dobutamine  treatment,  respectively.  All­cause 31­day mortality was 7.8% for levosimendan and 17% for dobutamine treated patients.


In a further double­blind multicentre trial carried out primarily to evaluate safety, 504 patients with decompensated heart failure after acute myocardial infarction who were assessed to require inotropic support were treated with levosimendan or placebo for 6 hours. There were no significant differences in the incidence of hypotension and ischaemia between the treatment groups.

No adverse effect on survival up to 6 months was observed in a retrospective analysis of the LIDO and RUSSLANtrials.

5.2       Pharmacokinetic properties


The pharmacokinetics of levosimendan are linear in the therapeutic dose range 0.05­0.2 microgram/kg/min.


The volume of distribution of levosimendan (Vss) is approximately 0.2 l/kg. Levosimendan is 97­98% bound to plasma proteins, primarily to albumin. For OR­1855 and OR­1896, the mean protein binding values were 39% and 42%, respectively in patients.


Levosimendan is completely metabolised and negligible amounts of unchanged parent drug are excreted in urine and faeces. Levosimendan is primarily meta­ bolised by conjugation to cyclic or N­acetylated cysteinylglycine and cysteine conjugates. Approximately 5 % of the dose is metabolised in the intestine by reduction to aminophenylpyridazinone (OR­1855), which after re­absorption is metabolised by N­acetyltransferase to the active metabolite OR­1896. The ace­ tylation level is genetically determined. In rapid acetylators, the concentrations of the metabolite OR­1896 are slightly higher than in slow acetylators. However, this has no implication for the clinical haemodynamic effect at recommended doses.

In systemic circulation the only significant detectable metabolites following levosimendan administration are OR­1855 and OR­1896. These  metabolites  in vivo reach  equilibrium  as  a  result  of  acetylation  and  de­acetylation  metabo­ lic pathways, which are governed by N­acetyl transferase­2, a polymorphic enzyme. In slow acetylators, the OR­1855 metabolite predominates, while in

rapid acetylators the OR­1896 metabolite predominates. The sum of exposures for the two metabolites is similar among slow and rapid acetylators, and there  is no difference in the haemodynamic effects between the two groups. The prolonged haemodynamic effects (lasting up to 7­9 days after discontinuation of a 24 hour Levosimendan infusion) are attributed to these metabolites.

In vitro studies have shown that levosimendan, OR­1855 and OR­1896 do not inhibit CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at

concentrations achieved by the recommended dosing. In addition levosimendan does not inhibit CYP1A1 and neither OR­1855 nor OR­1896 inhibit CYP2C9.

The results of drug interaction studies in humans with warfarin, felodipine, and itraconazole confirmed that levosimendan does not inhibit CYP3A4 or CYP2C9, and metabolism of levosimendan is not affected by CYP3A inhibitors.

Elimination and excretion

Clearance is about 3.0 ml/min/kg and the half­life about 1 hour. 54 % of the dose is excreted in urine and 44 % in faeces. More than 95 % of the dose

is excreted within one week. Negligible amounts (<0.05 % of the  dose)  are excreted as unchanged levosimendan in the urine. The circulating metabolites OR­1855 and OR­1896 are formed and eliminated slowly. Peak plasma concentration is reached about 2 days after termination of a levosimendan infusion. The half­lives of the metabolites are about 75­80 hours. Active metabolites of levosimendan, OR­1855 and OR­1896, undergo conjugation or renal filtration, and are excreted predominantly 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 month to 6 years) are similar to those in adults.

The pharmacokinetics of the active metabolite have not been investigated in


Renal impairment:

The pharmacokinetics of levosimendan  have  been  studied  in  subjects  with varying degrees  of  renal  impairment  who  did  not  have  heart  failure.  Exposure to levosimendan was similar in subjects with mild to moderate renal impairment  and in subjects undergoing haemodialysis, while the  exposure  to  levosimendan may be slightly lower in subjects with severe renal impairment.

Compared to healthy subjects, the unbound fraction of levosimendan appeared to be slightly increased, and AUCs of the metabolites (OR­1855 and OR­1896) were up to 170% higher in subjects with severe renal impairment and patients undergoing haemodialysis. The effects of mild and moderate renal impairment on the pharmacokinetics of OR­1855 and OR­1896 are expected to be less than those of severe renal impairment.

Levosimendan is not dialysable. While OR­1855 and OR­1896 are dialysable, the dialysis clearances are low (approximately 8­23 ml/min) and the net effect of a 4­hour dialysis session on the overall exposure to these metobolites is small.

Hepatic impairment:

No differences in the pharmacokinetics or protein binding of levosimendan were found in subjects with mild or moderate cirrhosis versus healthy subjects. The pharmacokinetics of levosimendan, OR­1855 and OR­1896 are similar bet­ ween healthy subjects and subjects with moderate hepatic impairment (Child­ Pugh Class B), with the exception that elimination half­lives of OR­1855 and OR­1896 are slightly prolonged in subjects with moderate hepatic impairment.

Population analysis has shown no effects of age, ethnic origin or gender on the pharmacokinetics of levosimendan. However, the same analysis revealed that volume of distribution and total clearance are dependent on weight.

5.3       Preclinical safety data

Conventional studies on general toxicity and genotoxicity revealed no special hazard for humans in short term use.

In animal studies, levosimendan was not  teratogenic,  but  it  caused  a  gene­ ralised reduction in the degree of ossification in rat and rabbit foetuses with anomalous development of the supraoccipital bone in the rabbit. When administered before and during early pregnancy, levosimendan reduced fertility (decreased the number of corpora lutea and implantations) and exhibited deve­ lopmental toxicity (decreased pups per litter and increased the number of early resorptions and post­implantation losses) in  the  female  rat.  The  effects  were seen at clinical exposure levels.

In animal studies, levosimendan was excreted into maternal milk.

  1. Pharmaceutical particulars

List of excipients

Povidone, Citric Acid, anhydrous Ethanol, anhydrous

6.1       Incompatibilities

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

6.2       Shelf‑life

3 years

After dilution

Chemical and physical in­use stability has been demonstrated for 24 hours at 25˚C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in­use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours  at 2 to 8˚C, unless dilution has taken place in controlled and validated aseptic

conditions. Storage and in­use time after dilution should never exceed 24 hours.

6.3       Special precautions for storage

Store in a refrigerator (2˚C­8˚C) Do not freeze.

The colour of the concentrate may turn to orange during storage, but there is        no loss of potency and the product may be used until the indicated expiry date        if storage instructions have been followed.

For storage conditions of the diluted medicinal product, see section 6.3.

6.4       Nature and content of container

  • 8 or 10 ml Type I glass vials
  • Chlorobutyl or bromobutyl rubber closure with fluoropolymer coating

Pack sizes

  • 1, 4, 10 vials of 5 ml
  • 1, 4, 10 vials of 10 ml

Not all pack sizes may be marketed.

6.5       Special precautions for disposal and other handling

Levosimendan 2.5mg/ml concentrate for solution for infusion is intended for single use only.

As for all parenteral medicinal products, inspect the diluted solution visually for particulate matter and discolouration prior to administration.

To prepare the 0.025mg/ml infusion, mix 5 ml of Levosimendan 2.5mg/ml concen­ trate for solution for infusion with 500 ml of 5 % glucose solution.

To prepare the 0.05mg/ml infusion, mix 10 ml of Levosimendan 2.5mg/ml concen­ trate for solution for infusion with 500 ml of 5% glucose solution.

The following medicinal products can be given simultaneously with Levosimendan in connected intravenous lines:

  • Furosemide 10mg/ml
  • Digoxin 0.25mg/ml
  • Glyceryl trinitrate 0.1mg/ml


  1. Manufactured in India by:
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
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