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141505-33-1 Levisimendan FDA Approval Calcium Sensitizer Increasing Cardiac Contractility

5ml:12.5mg/vial

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Description

141505-33-1 Levisimendan FDA Approval Calcium Sensitizer Increasing Cardiac Contractility

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We can supply Levisimendan Injection, 5 ml : 12.5 mg / vial

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Levsimendan is indicated for the short-term treatment of acutely decompensated severe chronic heartfailure (ADHF) in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate.

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Important safety information

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Levsimendan is contraindicated in patients with:
- A known hypersensitivity to levosimendan or to any of the excipients
- Severe hypotension and tachycardia
- Significant mechanical obstructions affecting ventricular filling or outflow or both
- Severe renal impairment (creatinine clearance <30 ml/min) and severe hepatic impairment
- A history of torsades de pointes

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Caution is advised 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.

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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.

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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.

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Levsimendan 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.

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Levsimendan 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.

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Levsimendan infusion should be used cautiously in patients with tachycardia, atrial fibrillation with rapid ventricular response or potentially life-threatening arrhythmias.

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Experience with repeated administration of Simdax is limited.

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Experience with concomitant use of vaso-active agents, including inotropic agents (except digoxin), is limited. Benefit and risk should be assessed for the individual patient.

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Levsimendan should be used cautiously and underclose 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.

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The use of levosimendan in cardiogenic shocknhas 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.

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Levsimendan should not be administered to children as there is very limited experience of use in children and adolescents under 18 years of age.

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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.

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The most frequent adverse events with Simdax are ventricular tachycardia, atrial fibrillation, hypotension, ventricular extrasystoles, tachycardia and headache.

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Other common (< 1/10, > 1/100) adverse events include hypokalaemia, insomnia, dizziness, cardiac failure, myocardial ischaemia, extrasystoles, nausea, constipation, diarrhoea, vomiting and haemoglobin decreased


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Characteristics

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1. Name of the medicinal Product 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. One 10 ml vial contains 25 mg of levosimendan. For a full list of excipients,


3. PharmaceutiCal form Concentrate for solution for infusion. The concentrate is a clear yellow or orange solution for dilution prior to administration.

we can supply both the finished products( in vials ) and the raw material powder.

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Mechanism of action

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Levosimendan is a calcium sensitizer — it increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C in a calcium-dependent manner.

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It also has avasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreased preload and decreased afterload. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.

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Clinical use

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Indications

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Levosimendan is indicated for inotropic support in acutely-decompensated severe congestive heart failure.


Some of the Phase III studies in the extensive clinical program were the trials LIDO (200 patients), RUSSLAN (500), CASINO (250), REVIVE-I (100), REVIVE-II (600) and SURVIVE (1350). In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind studies.


In the SURVIVE study, despite a reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days. However, the drug was proven to be superior to dobutamine for treating patients with a history of CHF or those on beta-blocker therapy when they are hospitalized with acute decompensations.


In a meta-analysis of randomized controlled studies by Landoni et al. levosimendan is shown to reduce mortality and hospitalization.

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Licensing status

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The Orion Corporation originally developed levosimendan and applied for a new drug application in 1998 in the U.S. However the Food and Drug Administration (FDA) requested further trials be conducted and Orion withdrew the application in November 1999. Initially, Orion obtained the approval to market the drug in Sweden in 2000.Since then 60 countries worldwide have approved the drug but it remains unapproved in North America, where it is currently in Phase III development by Tenax Therapeutics for reduction in morbidity and mortality of cardiac surgery patients at risk of low cardiac output syndrome.

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Contraindications

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The use of levosimendan is contraindicated in patients with moderate-to-severe kidney impairment, severe liverimpairment, severe ventricular filling or outflow obstruction, very low blood pressure and fast heart rate, and/or history of the abnormal heart rhythm torsades de pointes (Rossi, 2006).

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Adverse effects

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Common adverse drug reactions (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, arrhythmias (atrial fibrillation,extrasystoles, atrial tachycardia, ventricular tachycardia), myocardial ischaemia, hypokalaemia and/or nausea (Rossi, 2006).

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Formulations

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Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted with glucose 5% solution before infusion.

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