SIMDAX 2.5 MGML

Israel - English - Ministry of Health

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Active ingredient:
LEVOSIMENDAN
Available from:
BIOMED - JR LTD, ISRAEL
ATC code:
C01CX08
Pharmaceutical form:
CONCENTRATE FOR SOLUTION FOR INFUSION
Composition:
LEVOSIMENDAN 2.5 MG/ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
ORION CORPORATION ORION PHARMA,FINLAND
Therapeutic group:
LEVOSIMENDAN
Therapeutic area:
LEVOSIMENDAN
Therapeutic indications:
Therapeutic indications: Short-term treatment of acutely decompensated severe chronic heart failure.Simdax should only be used as add-on therapy in situations where conventional therapy with e.g. diuretics, ACE-inhibitors and digitalis is not sufficient and where there is a need for inotropic support.
Authorization number:
129 66 30801 00
Authorization date:
2013-12-31

1. NAME OF THE MEDICINAL PRODUCT

Simdax 2.5 mg/ml concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate contains 2.5 mg of levosimendan.

One 5 ml vial contains 12.5 mg of levosimendan.

For excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

The concentrate is a clear yellow or orange solution for dilution prior to

administration.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Simdax

indicated

short-term

treatment

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

Simdax is for in-hospital 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

Simdax is to be diluted prior to administration (see section 6.6).

The infusion is for intravenous use only and can be administered by the

peripheral or central route.

Posology

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 6-12 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 recommended 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.

response

deemed

excessive

(hypotension,

tachycardia),

rate

infusion

decreased

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.

recommended

duration

infusion

patients

with

acute

decompensation

severe

chronic

heart

failure

hours.

signs

development

tolerance

rebound

phenomena

have

been

observed

following

discontinuation

Simdax

infusion.

Haemodynamic effects persist for at least 24 hours and may be seen up

to 9 days after discontinuation of a 24-hour infusion (see section 4.4).

Experience of repeated administration of Simdax is limited. Experience

with concomitant use of vasoactive agents, including inotropic agents

(except digoxin), 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.

Monitoring 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.

Elderly

No dose adjustment is required for elderly patients.

Renal impairment

Simdax must be used with caution in patients with mild to moderate

renal impairment.

Simdax 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

Simdax must be used with caution in patients with mild to moderate

hepatic impairment although no dose adjustment appears necessary for

these patients.

Simdax should not be used in patients with severe hepatic impairment

(see sections 4.3, 4.4 and 5.2).

Children

Simdax should not be administered to children and adolescents under

18 years of age (see sections 4.4 and 5.2).

The following table provides detailed infusion rates for both the loading

and maintenance infusion doses of a 0.05 mg/ml preparation of Simdax

infusion:

Table 1.

Patient’s

weight

(kg)

Loading dose is given

as an infusion over

10 minutes with the

infusion rate (ml/h)

below

Continuous infusion rate (ml/h)

Loading

dose

6 mcg/kg

Loading

dose

12 mcg/kg

0.05

mcg/kg/

mcg/kg/

mcg/kg/

The following table provides detailed infusion rates for both the loading

and maintenance infusion doses for a 0.025 mg/ml preparation of

Simdax infusion:

Table 2.

Patient’s

weight

(kg)

Loading dose is given

as an infusion over 10

min with the infusion

rate (ml/h) below

Continuous infusion rate (ml/h)

Loading

dose

6 mcg/kg

Loading

dose

12 mcg/kg

0.05

mcg/kg/

mcg/kg/

mcg/kg/

4.3 Contraindications

Hypersensitivity to levosimendan or to any of the excipients listed in

section 6.1.

Severe

hypotension

tachycardia

(see

sections

5.1).

Significant mechanical obstructions affecting ventricular filling or outflow

or both. Severe renal impairment (creatinine clearance <30 ml/min) and

severe hepatic impairment. History of Torsades de Pointes.

4.4 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

PRESCRIBING INFORMATION

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 7-10 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. Non-invasive monitoring for at least 4-5 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 may be needed.

Simdax should be used cautiously in patients with mild to moderate renal

impairment. 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).

Simdax should be used cautiously in patients with mild to moderate

hepatic impairment. Impaired hepatic function may lead to prolonged

exposure

active

metabolites,

which

result

more

pronounced and prolonged haemodynamic effect (see section 5.2).

Simdax infusion may cause a decrease in serum potassium concentration.

Thus, low serum potassium concentrations should be corrected prior to

the administration of Simdax and serum potassium should be monitored

during treatment. As with other medicinal products for heart failure,

infusions of Simdax may be accompanied by decreases in haemoglobin

and haematocrit and caution should be exercised in patients with

ischaemic cardiovascular disease and concurrent anaemia.

Simdax infusion should be used cautiously in patients with tachycardia,

atrial

fibrillation

with

rapid

ventricular

response

potentially

life-

threatening arrhythmias.

Experience with repeated administration of Simdax is limited. Experience

with concomitant use of vasoactive agents, including inotropic agents

(except digoxin), is limited. Benefit and risk should be assessed for the

individual patient.

Simdax 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

information is available on the use of Simdax in the following disorders:

restrictive cardiomyopathy, hypertrophic cardiomyopathy, severe mitral

valve insufficiency, myocardial rupture, cardiac tamponade and right

ventricular infarction.

Simdax should not be administered to children as there is very limited

experience of use in children and adolescents under 18 years of age

(see section 5.2).

Limited experience is available on the use of Simdax in patients with

heart failure after surgery, and in severe heart failure in patients awaiting

heart transplantation.

4.5 Interaction with other medicinal products and other

forms of interaction

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 Simdax infusion. Simdax

infusion can be used in patients receiving beta-blocking agents without

loss

efficacy.

Co-administration

isosorbide

mononitrate

levosimendan in healthy volunteers resulted in significant potentiation of

the orthostatic hypotensive response.

4.6 Pregnancy and lactation

Pregnancy

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

Lactation

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 placebo-controlled clinical trials for ADHF (REVIVE programme), 53%

of patients experienced adverse reactions, the most frequent of which

were ventricular tachycardia, hypotension, and headache.

In a dobutamine-controlled clinical trial for ADHF (SURVIVE), 18% of

patients experienced adverse reactions, the most frequent of which

were ventricular tachycardia, atrial fibrillation, hypotension, ventricular

extrasystoles, tachycardia, and headache.

The following table describes

the adverse reactions observed in 1%

or greater of patients during REVIVE I, REVIVE II, SURVIVE, LIDO,

RUSSLAN, 300105, and 3001024 clinical trials. If the incidence of any

particular event in an individual trial was greater than that seen across

the other trials, then the higher incidence is reported in the table.

The events considered at least possibly related to levosimendan are

displayed by system organ class and frequency, using the following

convention: very common (≥ 1/10), common (≥ 1/100, < 1/10).

Table 3

Summary of Adverse Reactions

SURVIVE Clinical Study, REVIVE Programme,

and LIDO/RUSSLAN/300105/3001024 Clinical Studies combined

Body System

Frequency

Preferred Term

Metabolism and

nutrition disorders

Common

Hypokalaemia

Psychiatric disorders

Common

Insomnia

Nervous system

disorders

Very Common

Common

Headache

Dizziness

Cardiac disorders

Very Common

Common

Ventricular Tachycardia

Atrial Fibrillation

Tachycardia

Ventricular Extrasystoles

Cardiac Failure

Myocardial Ischaemia

Extrasystoles

Vascular disorders

Very Common

Hypotension

Gastrointestinal

disorders

Common

Nausea

Constipation

Diarrhoea

Vomiting

Investigations

Common

Haemoglobin Decreased

Post-marketing adverse reactions

In post-marketing experience, ventricular fibrillation has been reported

in patients being administered Simdax.

4.9 Overdose

Overdose of Simdax may induce hypotension and tachycardia. In

clinical trials with Simdax, 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

cardiac

filling

pressures

limit

response

Simdax 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 Simdax, continuous ECG

monitoring, repeated determinations of serum electrolytes and invasive

haemodynamic monitoring should be undertaken. Simdax 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic

group:

Other

cardiac

stimulants

(calcium

sensitisers), ATC code: C01CX08

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

after

authorisation

medicinal product is important. It allows continued monitoring of the

benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of

Health according to the National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formTy

pe=AdversEffectMedic@moh.gov.il

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 contractile 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

healthy

volunteers

patients

with

stable and unstable heart failure have shown a dose dependent effect

of levosimendan given intravenously as loading dose (3 micrograms/kg

to 24 micrograms/kg) and continuous infusion (0.05 to 0.2 microgram/

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 peripheral vascular

resistance.

Simdax infusion increases coronary blood flow in patients recovering

from 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 Simdax

infusion significantly decreases circulating levels of endothelin-1 in

patients with congestive heart failure. It does not increase plasma

catecholamine levels at recommended infusion rates.

Clinical Trials

Simdax has been evaluated in clinical trials involving over 2800 heart

failure patients. The efficacy and safety of Simdax for the treatment of

ADHF were assessed in the following randomised, double-blind, multi-

national clinical trials:

REVIVE Programme

REVIVE I

In a double-blind, placebo-controlled pilot study in 100 patients with

ADHF who received a 24 hour infusion of Simdax, a beneficial response

as measured by the clinical composite endpoint over placebo plus

standard of care was observed in the Simdax-treated patients.

REVIVE II

A double-blind, placebo-controlled pivotal study in 600 patients who

were administered a 10 minute loading dose of 6-12 microgram/kg

followed by a protocol-specified stepped titration of levosimendan to

0.05-0.2 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.

REVIVE

clinical

programme

designed

compare

effectiveness of levosimendan plus standard-of-care to placebo plus

standard-of-care 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 intravenous 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.

results

primary

endpoint

demonstrated

that

greater

proportion of patients were categorised as improved with a smaller

proportion of patients categorised as worsened (p-value=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.

B-type natriuretic peptide was significantly reduced vs. placebo and

standard of care at 24 hours and through five days (p-value=0.001).

The Simdax 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.

SURVIVE

double-blind,

double-dummy,

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

intravenous

diuretics

vasodilators.

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 patients requiring

mechanical ventilation. Approximately 90% of patients entered the trial

due to dyspnoea at rest.

The results of SURVIVE did not demonstrate a statistically significant

difference

between

levosimendan

dobutamine

all-cause

mortality at 180 days {Hazard Ratio = 0.91 (95% CI [0.74, 1.13]

p-value

0.401)}.

However,

there

numerical

advantage

mortality

levosimendan

dobutamine)

levosimendan.

This

advantage

persisted

through

31-day

period

(12%

levosimendan

dobutamine)

most

prominent in those individuals who received baseline beta-blocker

therapy. In both treatment groups, patients with low baseline blood

pressure experienced higher rates of mortality than did those with higher

baseline blood pressure.

LIDO

Levosimendan has been shown to lead to dose-dependent increases in

cardiac output and stroke volume as well as dose-dependent decrease

in pulmonary capillary wedge pressure, mean arterial pressure and total

peripheral resistance.

double-blind

multicentre

trial,

patients

with

severe

output heart failure (ejection fraction ≤0.35, cardiac index <2.5 l/min/

, pulmonary capillary wedge pressure (PCWP) >15 mmHg) and

in need of inotropic support received levosimendan (loading dose 24

microgram/kg over 10 minutes followed by a continuous infusion of

0.1-0.2

microgram/kg/min)

dobutamine

(5-10

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 simultaneous 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). Sixty-eight 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. All-cause 31-

day mortality was 7.8% for levosimendan and 17% for dobutamine

treated patients.

RUSSLAN

In a further double-blind multicentre trial carried out primarily to evaluate

safety,

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 RUSSLAN trials.

5.2 Pharmacokinetic properties

General

The pharmacokinetics of levosimendan are linear in the therapeutic dose

range 0.05-0.2 microgram/kg/min.

Distribution

The volume of distribution of levosimendan (V

) is approximately

0.2 l/kg. Levosimendan is 97-98% bound to plasma proteins, primarily

to albumin. For OR-1855 and OR-1896, the mean protein binding values

were 39% and 42%, respectively in patients.

Metabolism

Levosimendan is completely metabolised and negligible amounts of

unchanged parent drug are excreted in urine and faeces. Levosimendan

primarily

metabolised

conjugation

cyclic

N-acetylated

cysteinylglycine and cysteine conjugates. Approximately 5% of the dose

is metabolised in the intestine by reduction to aminophenylpyridazinone

(OR-1855),

which

after

re-absorption

metabolised

N-acetyl-

transferase to the active metabolite OR-1896. The acetylation level

is genetically determined. In rapid acetylators, the concentrations of

the metabolite OR-1896 are slightly higher than in slow acetylators.

However, this has no implication for the clinical haemodynamic effect

at recommended doses.

systemic

circulation

only

significant

detectable

metabolites

following

levosimendan

administration

OR-1855

OR-1896.

These metabolites in vivo reach equilibrium as a result of acetylation and

de-acetylation metabolic pathways, which are governed by N-acetyl

transferase-2, a polymorphic enzyme. In slow acetylators, the OR-

1855 metabolite predominates, while in rapid acetylators the OR-1896

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 7-9 days after discontinuation of a

24 hour Simdax infusion) are attributed to these metabolites.

In vitro

studies have shown that levosimendan OR-1855 and OR-1896

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 OR-1855

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 OR-1855 and OR-1896 are formed and

eliminated

slowly.

Peak

plasma

concentration

reached

about

days after termination of a levosimendan infusion. The half-lives of the

metabolites are about 75-80 hours. Active metabolites of levosimendan,

OR-1855 and OR-1896, 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 months - 6 years) are similar to those

in adults. The pharmacokinetics of the active metabolite have not been

investigated in children.

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 (OR-

1855 and OR-1896) 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 OR-

1855 and OR-1896 are expected to be less than those of severe renal

impairment.

Levosimendan is not dialysable. While OR-1855 and OR-1896 are

dialysable, the dialysis clearances are low (approximately 8-23 ml/min)

and the net effect of a 4-hour dialysis session on the overall exposure to

these metobolites is small.

Hepatic impairment

differences

pharmacokinetics

protein

binding

levosimendan were found in subjects with mild or moderate cirrhosis

versus healthy subjects. The pharmacokinetics of levosimendan, OR-

1855 and OR-1896 are similar between healthy subjects and subjects

with

moderate

hepatic

impairment

(Child-Pugh

Class

with

exception that elimination half-lives of OR-1855 and OR-1896 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 generalised 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 developmental toxicity (decreased

pups per litter and increased the number of early resorptions and post-

implantation losses) in the female rat. The effects were seen at clinical

exposure levels.

In animal studies, levosimendan was excreted into maternal milk.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Povidone

Citric Acid, anhydrous

Ethanol, anhydrous

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products

or diluents except those stated in section 6.6.

6.3 Shelf life

The expiry date of the product is indicated on the packaging materials.

After dilution

Chemical and physical in-use 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, in-use storage times and conditions

prior to use are the responsibility of the user and would normally not be

longer than 24 hours at 2ºC to 8ºC, unless dilution has taken place in

controlled and validated aseptic conditions. Storage and in-use time

after dilution should never exceed 24 hours.

6.4 Special precautions for storage

Store at 2°C-8°C (in a refrigerator). 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.

6.5 Nature and contents of container

8 or 10 ml Type I glass vials

Chlorobutyl

bromobutyl

rubber

closure

with

fluoropolymer

coating

Pack sizes

1, 4, 10 vials of 5 ml

Not all pack sizes may be marketed.

6.6 Instructions for use and handling

Simdax 2.5 mg/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 0.025 mg/ml infusion, mix 5 ml of Simdax 2.5 mg/

ml concentrate for solution for infusion with 500 ml of 5% glucose

solution.

To prepare the 0.05 mg/ml infusion, mix 10 ml of Simdax 2.5 mg/

ml concentrate for solution for infusion with 500 ml of 5% glucose

solution.

The following medicinal products can be given simultaneously with

Simdax in connected intravenous lines:

Furosemide 10 mg/ml

Digoxin 0.25 mg/ml

Glyceryl trinitrate 0.1 mg/ml

7. Manufactured by

Orion Corporation Orion Pharma, Espoo, Finland

8. License Holder

Biomed-JR Ltd.

28 Hayasmin St., Tel-Mond 4061353

License number: 129 66 30801 00

The content of this leaflet was approved by the Ministry of Health

in April 2010.

DOR-Sim-SPC-0418-04

Pharmacodynamic effects

Levosimendan

enhances

calcium

sensitivity

contractile

proteins by binding to cardiac troponin C in a calcium-dependent

manner.

Levosimendan

increases

contraction

force

does

impair

ventricular

relaxation.

addition,

levosimendan

opens

ATP-sensitive potassium channels in vascular smooth muscle, thus

nor OR-1896 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 half-life about 1 hour. 54%

04

Product

Simdax

Size

150x405 mm

Product spec.

2.5 mg/ml

concentrate for solution for infusion

Font

(type

& min.

size /

language)

Color

Type

Date

09/05/2018

Artwork operator

Sima Agam_Oso Bayo Studio

Job no.

Physician leaflet

24525

black

Technical reference

Helvetica neue 6 p

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