Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: Pharmacy Retailing (NZ) Limited, trading as Healthcare Logistics, 58 Richard Pearse Drive, Airport Oaks, Auckland, New Zealand
Hypersensitivity to Simdax or to any of the excipients.
Severe hypotension and tachycardia (see section 5.1, Pharmacodynamics; section 4.4, Special warnings and precautions for use). 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.
A haemodynamic effect of Simdax, which may be more pronounced in the beginning of therapy, may be a decrease in systolic and diastolic blood pressure, therefore, Simdax 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 section 5.1, Pharmacodynamics; section 4.2, Dose and method of administration – Dosing Schedule; section 4.5, Interaction with other medicines and other forms of interaction).
As excessive decrease in cardiac filling pressure may limit the response to Simdax, severe hypovolaemia should be corrected prior to Simdax infusion by administration of parenteral fluids. If excessive changes in blood pressure or heart rate are observed, the rate of infusion should be reduced or the infusion discontinued.
Haemodynamically favourable effects on cardiac output and pulmonary capillary wedge pressure persist for at least 24 hours after discontinuation of (a 24-hour) infusion. The exact duration of all haemodynamic effects has not been determined, however, the effects on blood pressure generally last for 3-4 days and the effects on heart rate for 7-9 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. Interactions with the elimination of the active metabolites could lead to more pronounced and prolonged haemodynamic effects. Non-invasive monitoring for at least 3 days after the end of infusion or until the patient is clinically stable is recommended. In patients with mild to moderate renal or mild to moderate hepatic impairment monitoring is recommended for at least 5 days (see section 5.2, Pharmacokinetics).
Simdax should be used cautiously in patients with mild to moderate renal or mild to moderate hepatic impairment. Only limited data are available in patients with impaired renal function. Impaired hepatic or renal function may lead to increased concentrations of the metabolite, which may result in more pronounced and prolonged haemodynamic effects.
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 or 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. Consistent with current medical practice, Simdax should be used with caution when used with other intravenous vasoactive medicinal products due to a potentially increased risk of hypotension.
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, Overdose).
The use of Simdax 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 using Simdax in children and adolescents under 18 years of age (see section 5.2, Pharmacokinetics).
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.
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 decreased the number of corpora lutea, implantations and 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.
In vitro studies utilizing human liver microsomes have shown that levosimendan is unlikely to cause significant drug-drug interactions with agents metabolised by cytochrome P450 (CYP) enzymes due to its apparent low affinity to various CYP-isoforms (see section 5.2, Pharmacokinetics).
A possible interaction between the active metabolites OR-1855 and OR-1896 and other drugs with hemodynamic effects could lead to more pronounced and prolonged haemodynamic effects. The duration of this effect could be longer than the 7-9 days normally seen after a Simdax infusion.
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 of efficacy. Co-administration of isosorbide mononitrate and levosimendan in healthy volunteers resulted in significant potentiation of the orthostatic hypotensive response. Concomitant captopril treatment did not affect the pharmacokinetics or hemodynamics of Simdax. No pharmacokinetic or pharmacodynamic interactions were observed between Simdax and alcohol.
No data available.
There is no experience of using Simdax in pregnant women. Animal studies have shown toxic effects on reproduction (see section 4.4, Special warnings and precautions for use: Carcinogenesis, Mutagenesis and Impairment of Fertility). Therefore, Simdax 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 Simdax is excreted in human milk, therefore, women receiving Simdax should not breastfeed.
No data available.
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 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:
Common: Hypokalaemia
Common: Insomnia
Very Common: Headache
Common: Dizziness
Very Common: Ventricular Tachycardia
Common: Myocardial Ischemia, Cardiac failure, Atrial fibrillation, Tachycardia, Ventricular extrasystoles, Extrasystoles
Very Common: Hypotension
Common: Diarrhoea, Vomiting, Nausea, Constipation
Common: Haemoglobin Decreased
In post-marketing experience, ventricular fibrillation has been reported in patients being administered Simdax.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/
No data available.
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