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  • Amiodacore Injection
    / Sanofi


    Active Ingredient
    Amiodarone HCl 150 mg / 3 ml

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Ampoule

    6 X 3 ml

    partial basket chart 31743 9477

    Dosage

    Amiodacore Injection should only be used when facilities exist for cardiac monitoring, defibrillation, and cardiac pacing. Amiodacore Injection may be used prior to DC cardioversion. The standard recommended dose is 5mg/kg body-weight given by intravenous infusion over a period of 20 minutes to 2 hours. This should be administered as a dilute solution in 250ml 5% dextrose. This may be followed by repeat infusion up to 1200mg (approximately 15mg/kg body-weight) in up to 500ml 5% dextrose per 24 hours, the rate of infusion being adjusted on the basis of clinical response. In extreme clinical emergency the drug may, at the discretion of the clinician, be given as a slow injection of 150-300mg in 10-20ml 5% dextrose over a minimum of 3 minutes. This should not be repeated for at least 15 minutes. Patients treated in this way with Amiodacore Injection must be closely monitored, e.g. in an intensive care unit.
    Changeover from Intravenous to Oral therapy: As soon as an adequate response has been obtained, oral therapy should be initiated concomitantly at the usual loading dose (i.e. 200mg three times a day). Amiodacore Injection should then be phased out gradually.
    Paediatric population: Due to the presence of benzyl alcohol, intravenous amiodarone is usually contraindicated in neonates and premature babies. No controlled paediatric studies have been undertaken. In published uncontrolled studies effective doses for children were: • Loading dose: 5mg/kg body- weight over 20 minutes to 2 hours • Maintenance dose: 10 to 15mg/kg/day from a few hours to several days. If needed, oral therapy may be initiated concomitantly. for full details see prescribing information.
    Elderly: As with all patients it is important that the minimum effective dose is used. Whilst there is no evidence that dosage requirements are different for this group of patients they may be more susceptible to bradycardia and conduction defects if too high a dose is employed. Particular attention should be paid to monitoring thyroid function.


    Indications

    Treatment should be initiated and normally monitored only under hospital or specialist supervision. This drug is indicated for Coronary insufficiency, arrhythmias resistant to other treatments, Wolff Parkinson White Syndrome. The drug can be used where a rapid response is required or where oral administration is not possible.
    See prescribing information for full details.


    Contra-Indications

    Sinus bradycardia and sino-atrial heart block. In patients with severe conduction disturbances (high grade AV block, bifascicular or trifascicular block) or sinus node disease, the drug should be used only in conjunction with a pacemaker.
    Evidence or history of thyroid dysfunction. Thyroid function tests should be performed where appropriate prior to therapy in all patients. Severe respiratory failure, circulatory collapse, or severe arterial hypotension; hypotension, heart failure and cardiomyopathy are also contra-indications when using this drug as a bolus injection. Known hypersensitivity to iodine or to amiodarone, or to any of the excipients. (One ampoule contains approximately 56 mg iodine). The combination of the drug with drugs which may induce torsades de pointes is contra-indicated. Due to the content of benzyl alcohol, the drug is contraindicated in newborns or premature neonates, infants and children up to 3 years old. Pregnancy – except in exceptional circumstances. Lactation. All these above contra-indications do not apply to the use of amiodarone for cardiopulmonary resuscitation of shock resistant ventricular fibrillation.
    See prescribing information for full details.


    Special Precautions

    The drug contains benzyl alcohol (20 mg/ml).Benzyl alcohol may cause toxic reactions and allergic reactions in infants and children up to 3 years old. The administration of medications containing benzyl alcohol to newborns or premature neonates has been associated with a fatal “Gasping Syndrome” (symptoms include a striking onset of gasping syndrome, hypotension, bradycardia and cardio-vascular collapse). As benzyl alcohol may cross the placenta, solution for injection should be used with caution in pregnancy. The drug should only be used in a special care unit under continuous monitoring (ECG and blood pressure). IV infusion is preferred to bolus due to the haemodynamic effects sometimes associated with rapid injection. Circulatory collapse may be precipitated by too rapid administration or overdose (atropine has been used successfully in such patients presenting with bradycardia). Repeated or continuous infusion via peripheral veins may lead to injection site reactions. When repeated or continuous infusion is anticipated, administration by a central venous catheter is recommended. Dosage is approximately 5 mg/kg body-weight. Except for cases of cardio- pulmonary resuscitation of shock resistant ventricular fibrillation, amiodarone should be injected over a minimum period of 3 minutes. Intravenous injection should not be repeated less than 15 minutes following the first injection even if the latter was only 1 ampoule (possible irreversible collapse). Do not mix other preparations in the same syringe. Do not inject other preparations in the same line. If amiodarone should be continued, this should be via intravenous infusion. When given by infusion the drug may reduce drop size and, if appropriate, adjustments should be made to the rate of infusion. Anaesthesia: Before surgery, the anaesthetist should be informed that the patient is taking amiodarone.
    Cardiac disorders: Caution should be exercised in patients with hypotension and decompensated cardiomyopathy and severe heart failure. Amiodarone has a low pro-arrhythmic effect. Onsets of new arrhythmias or worsening of treated arrhythmias, sometimes fatal, have been reported. It is important, but difficult to differentiate a lack of efficacy of the drug from a proarrhythmic effect, whether or not this is associated with a worsening of the cardiac condition. Proarrhythmic effects generally occur in the context of QT prolonging factors such as drug interactions and/or electrolytic disorders. Despite QT interval prolongation, amiodarone exhibits a low torsadogenic activity. Too high a dosage may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm, particularly in elderly patients or during digitalis therapy. In these circumstances, treatment with the drug should be withdrawn. If necessary beta-adrenostimulants or glucagon may be given. Because of the long half-life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered. The pharmacological action of amiodarone induces ECG changes: QT prolongation (related to prolonged repolarisation) with the possible development of U-waves and deformed T-waves; these changes do not reflect toxicity.
    Endocrine disorders: Amiodarone IV may induce hyperthyroidism, particularly in patients with a personal history of thyroid disorders or patients who are taking/have previously taken oral amiodarone. Serum usTSH level should be measured when thyroid dysfunction is suspected. Amiodarone contains iodine and thus may interfere with radio-iodine uptake. However, thyroid function tests (free-T3, free-T4, usTSH) remain interpretable. Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, free-T3 being slightly decreased or even normal) in clinically euthyroid patients. There is no reason in such cases to discontinue amiodarone treatment if there is no clinical or further biological (usTSH) evidence of thyroid disease.
    Respiratory, thoracic and mediastinal disorders: Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity such as interstitial pneumonitis. Very rare cases of interstitial pneumonitis have been reported with intravenous amiodarone. When the diagnosis is suspected, a chest X-ray should be performed. Amiodarone therapy should be re-evaluated since interstitial pneumonitis is generally reversible following early withdrawal of amiodarone, and corticosteroid therapy should be considered. Clinical symptoms often resolve within a few weeks followed by slower radiological and lung function improvement. Some patients can deteriorate despite discontinuing the drug. Fatal cases of pulmonary toxicity have been reported. Very rare cases of severe respiratory complications, sometimes fatal, have been observed usually in the period immediately following surgery (adult acute respiratory distress syndrome); a possible interaction with a high oxygen concentration may be implicated.
    Hepato-biliary disorders: Severe hepatocellular insufficiency may occur within the first 24 hours of IV amiodarone, and may sometimes be fatal. Close monitoring of transaminases is therefore recommended as soon as amiodarone is started.
    Drug interactions: Concomitant use of amiodarone with the following drugs is not recommended; beta-blockers, heart rate lowering calcium channel inhibitors (verapamil, diltiazem), stimulant laxative agents which may cause hypokalaemia. Increased plasma levels of flecainide have been reported with co-administration of amiodarone. The flecainide dose should be reduced accordingly and the patient closely monitored. Severe bradycardia and heart block have been reported in patients taking amiodarone and Harvoni (Sofosbuvir /Ledipasvir combination), or amiodarone and a combination of Sovaldi (Sofosbuvir) and Daklinza (daclatasvir dihydrochloride). Of 8 cases reviewed up to April 2015, one case resulted in fatal cardiac arrest and two required pacemaker intervention. Onset of bradycardia was within 24 hours of initiating hepatitis C treatment in 6 cases and within 2 to 12 days in the other 2 cases. Rechallenge in the context of continued amiodarone treatment resulted in recurrence of symptomatic bradycardia in 2 cases. Recurrence was also seen on rechallenge with the antivirals 8 days after stopping amiodarone, but not 8 weeks after stopping. Amiodarone should only be initiated in patients treated with Harvoni, or Sovaldi plus Daklinza, if other antiarrhythmics are contra-indicated or not tolerated. If concomitant use with amiodarone is unavoidable, patients should be closely monitored, particularly during the first weeks of treatment. Those at high risk of bradyarrhythmia should be monitored in an appropriate clinical setting for 48 hours after starting concomitant treatment.
    Severe bullous reactions: Life-threatening or even fatal cutaneous reactions Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN). If symptoms or signs of SJS, TEN (e.g.progressive skin rash often with blisters or mucosal lesions) are present amiodarone treatment should be discontinued immediately.


    Side Effects

    The most common side effects are: Bradycardia, Injection site reactions, Decrease in blood pressure.
    Cardiac disorders: Common: bradycardia, generally moderate.
    General disorders and administration site conditions: 
    Common: injection site reactions such as pain, erythema, oedema, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes.
    Vascular disorders
    : Common: decrease in blood pressure, usually moderate and transient. Cases of hypotension or collapse have been reported following overdose or a too rapid injection.
    See prescribing information for full details.


    Drug interactions

    Concomitant use of amiodarone with the following drugs is not recommended; beta- blockers, heart rate lowering calcium channel inhibitors (verapamil, diltiazem), stimulant laxative agents which may cause hypokalaemia. Increased plasma levels of flecainide have been reported with co-administration of amiodarone. The flecainide dose should be reduced accordingly and the patient closely monitored.
    Pharmacodynamic interactions: Drugs inducing Torsade de Pointes or prolonging QT:  Drugs inducing Torsade de Pointes Combined therapy with drugs that may induce “torsade de pointes” is contra-indicated: • antiarrhythmic agents such as Class Ia, sotalol, bepridil, • non-antiarrhythmic agents such as vincamine, some neuroleptic agents, cisapride, erythromycin IV, pentamidine (when parenterally administrated), as there is an increased risk of potentially lethal “ torsade de pointes.
    Drugs prolonging QT Co-administration of amiodarone with drugs known to prolong the QT interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase and patients should be monitored for QT prolongation. Combined therapy with the following drugs which prolong the QT interval is contra- indicated due to the increased risk of torsades de pointes; for example:
    Class Ia anti-arrhythmic drugs e.g. quinidine, procainamide, disopyramide • Class III anti-arrhythmic drugs e.g. sotalol, bretylium • intravenous erythromycin, co-trimoxazole or pentamidine injection • some anti-psychotics e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, amisulpride and sertindole • lithium and tricyclic anti-depressants e.g. doxepin, maprotiline, amitriptyline • certain antihistamines e.g. terfenadine, astemizole, mizolastine • anti-malarials e.g. quinine, mefloquine, chloroquine, halofantrine. • Moxifloxacin Fluoroquinolones: There have been rare reports of QTc interval prolongation, with or without torsades de pointes, in patients taking amiodarone with fluoroquinolones. Concomitant use of amiodarone with fluoroquinolones should be avoided (concomitant use with moxifloxacin is contra-indicated, see above).
    Drugs lowering heart rate or causing automaticity or conduction disorders Combined therapy with these drugs is not recommended. Beta blockers and certain calcium channel inhibitors (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction slowing effects may occur.
     Agents which may induce hypokalaemia: Combined therapy with the following drugs is not recommended: Stimulant laxatives, which may cause hypokalaemia thus increasing the risk of torsades de pointes; other types of laxatives should be used. Caution should be exercised over combined therapy with the following drugs which may also cause hypokalaemia and/or hypomagnesaemia, e.g. diuretics, systemic corticosteroids, tetracosactide, intravenous amphotericin. In cases of hypokalaemia, corrective action should be taken and QT interval monitored. In case of torsades de pointes antiarrhythmic agents should not be given; pacing may be instituted and IV magnesium may be used.
    General anaesthesia: Caution is advised in patients undergoing general anaesthesia, or receiving high dose oxygen therapy.
    Potentially severe complications have been reported in patients taking amiodarone undergoing general anaesthesia: bradycardia unresponsive to atropine, hypotension, disturbances of conduction, decreased cardiac output. Very rare cases of severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal, have been observed usually in the period immediately following surgery. A possible interaction with a high oxygen concentration may be implicated.
    Effect of Amiodacore injection on other medical products Amiodarone and/or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein and may increase exposure of their substrates. Due to the long half life of amiodarone, interactions may be observed for several months after discontinuation of amiodarone.
    – PgP substrates Amiodarone is a P-gp inhibitor. Co administration with P-gp substrates is expected to result in an increase of their exposure. – Digitalis Disturbances in automaticity (excessive bradycardia) and atrioventricular conduction (synergistic action) may occur; in addition, an increase in plasma digoxin concentrations is possible due to the decrease in digoxin clearance. ECG, and digoxin plasma levels should be monitored, and patients should be observed for clinical signs of digitalis toxicity. It may be necessary to adjust dosage of digitalis treatment. – Dabigatran Caution should be exercised when amiodarone is co administered with dabigatran due to the risk of bleeding. It may be necessary to adjust the dosage of dabigatran as per its label.
    CYP 2C9 substrates Amiodarone raises the concentrations of CYP 2C9 substrates such as warfarin or phenytoin by inhibition of the cytochrome P450 2C9. – Warfarin The combination of warfarin with amiodarone may exacerbate the effect of the oral anticoagulant thus increasing the risk of bleeding. It is necessary to monitor prothrombin (INR) levels more regularly and to adjust oral doses of anticoagulant agents both during treatment with amiodarone and after discontinuation of amiodarone treatment.
    Phenytoin The combination of phenytoin with amiodarone may lead to phenytoin overdose, resulting in neurological signs. Clinical monitoring should be undertaken and phenytoin dosage should be reduced as soon as overdose signs appear; phenytoin plasma levels should be determined.
    CYP 2D6 substrates Flecainide Given that flecainide is mainly metabolized by CYP 2D6, by inhibiting this isoenzyme, amiodarone may increase flecainide plasma levels; it is advised to reduce the flecainide dose by 50% and to monitor the patient closely for adverse effects. Monitoring of flecainide plasma levels is strongly recommended in such circumstances.
    CYP P450 3A4 substrates When drugs are co-administered with amiodarone, an inhibitor of CYP 3A4, this may result in a higher level of their plasma concentrations, which may lead to a possible increase in their toxicity: – Ciclosporin: plasma levels of ciclosporin may increase as much as 2-fold when used in combination. A reduction in the dose of ciclosporin may be necessary to maintain the plasma concentration within the therapeutic range. – Statins: the risk of muscular toxicity is increased by concomitant administration of amiodarone with statins metabolized by CYP 3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolized by CYP 3A4 when given with amiodarone. – Other drugs metabolized by cytochrome P450 3A4: examples of such drugs are lidocaine, tacrolimus, sildenafil, fentanyl, midazolam, triazolam, dihydroergotamine, ergotamine and colchicine.
    Effect of other products on Amiodacore injection CYP3A4 inhibitors and CYP2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure. It is recommended to avoid CYP 3A4 inhibitors (e.g grapefruit juice and certain medicinal products) during treatment with amiodarone.
    See prescribing information for full details.


    Pregnancy and Lactation

    Pregnancy: There are insufficient data on the use of amiodarone during pregnancy in humans to judge any possible toxicity. However, in view of its effect on the foetal thyroid gland, amiodarone is contraindicated during pregnancy, except in exceptional circumstances.
    Lactation: Amiodarone is excreted into the breast milk in significant quantities and breast-feeding is contra-indicated.


    Overdose

    There is no information regarding overdose with intravenous amiodarone. Little information is available regarding acute overdose with oral amiodarone. Few cases of sinus bradycardia, heart block, attacks of ventricular tachycardia, torsades de pointes, circulatory failure and hepatic injury have been reported. In the event of overdose, treatment should be symptomatic, in addition to general supportive measures. The patient should be monitored and if bradycardia occurs beta- adrenostimulants or glucagon may be given. Spontaneously resolving attacks of ventricular tachycardia may also occur. Due to the pharmacokinetics of amiodarone, adequate and prolonged surveillance of the patient, particularly cardiac status, is recommended. Neither amiodarone nor its metabolites are dialysable.


    Manufacturer
    Sanofi Winthrop Industrie, France
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