Cordarone X Intravenous, 150mg/3ml, Concentrate for solution for infusion or slow injection.

Each 3ml ampoule contains 150mg Amiodarone Hydrochloride (50mg/ml).

Excipients: Also contains benzyl alcohol 20mg/ml (60mg per 3ml ampoule).

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion or slow injection.

Colourless glass ampoule containing a clear, pale yellow solution.

Treatment should be initiated and normally monitored only under hospital or specialist supervision. Cordarone X Intravenous is indicated only for the treatment of severe rhythm disorders not responding to other therapies or when other treatments cannot be used.

Tachyarrhythmias associated with Wolff-Parkinson-White syndrome.

Atrial flutter and fibrillation when other drugs cannot be used.

All types of tachyarrhythmias including supraventricular, nodal and ventricular tachycardias, ventricular fibrillation, when other drugs cannot be used.

Intravenous Cordarone can be used where a rapid response is required or where oral administration is not possible.

Cordarone X Intravenous should only be used when facilities exist for cardiac monitoring, defibrillation and cardiac pacing.

Cordarone X Intravenous may be used prior to DC cardioversion.

The standard recommended dose is 5mg/kg bodyweight 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 infusions up to 1200mg, (approximately 15mg/kg bodyweight) in up to 500ml 5% dextrose per 24 hours, the rate of infusion being adjusted on the basis of clinical response. (see section 4.4).

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 Cordarone X Intravenous must be closely monitored, e.g., in an intensive care unit. (see section 4.4).

Cardiopulmonary rescusitation of shock resistant ventricular fibrillation: the recommended IV dose is 300mg (or 5mg/kg body-weight) diluted in 20ml 5% dextrose and rapidly injected. An additional 150mg (or 2.5mg/kg body-weight) IV dose may be considered if ventricular fibrillation persists.

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). Cordarone X Intravenous should then be phased out gradually.

Paediatric patients

The safety and efficacy of amiodarone in paediatric patients have not been established. It is not recommended for use in children and is contra-indicated for children under the age of 3 years (see section 4.3).

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. (see sections 4.3, 4.4 and 4.8).

See section 6.2 for information on incompatibilities.

Sinus bradycardia and sinoatrial heart block. In patients with severe conduction disturbances (high grade AV block, bifascicular or trifascicular block), or sinus node disease Cordarone X should only be used in conjunction with a pacemaker.

Evidence or history of thyroid dysfunction (see section 4.4).

Known hypersensitivity to iodine or to amiodarone, or to any of the excipients. (One ampoule contains approximately 56mg iodine).

The combination of Cordarone X with drugs which may induce torsades de pointes is contra-indicated (see section 4.5).

Severe respiratory failure, circulatory collapse, or severe arterial hypotension; hypotension, heart failure and cardiomyopathy are also contra-indications when using Cordarone X Intravenous as a bolus injection.

Due to the presence of benzyl alcohol, which has been associated with reports of fatal 'gasping syndrome' in neonates, Cordarone X Intravenous is contraindicated in infants or young children up to 3 years old. (One ampoule contains 60mg of benzyl alcohol)

Pregnancy, except in exceptional circumstances (see section 4.6)

Lactation (see section 4.6)

In the case of cardiopulmonary resuscitation of shock resistant ventricular fibrillation where all other alternative therapies have failed, please consult section 4.2 and 4.4.1.

4.4.1 Special Warnings

Specific to intravenous injection: see also contraindications 4.3

IV infusion is preferred to bolus due to the haemodynamic effects sometimes associated with rapid injection (see section 4.8). Circulatory collapse may be precipitated by too rapid administration or overdosage (atropine has been used successfully in such patients presenting bradycardia).

Intravenous infusion is preferable whenever possible.

Intravenous injection should be performed only in an emergency where alternative therapies have failed and only in an intensive care unit under continuous monitoring (ECG, blood pressure).

Dosage is 5mg/kg body-weight

Except in cardiopulmonary resuscitation of shock resistant ventricular fibrillation, amiodarone should be injected over a minimum of 3 minutes, and 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 (see section 4.2)

Paediatric patients:

The safety and efficacy of amiodarone in paediatric patients have not been established. Therefore its use in paediatric patients is not recommended.

Cordarone X IV ampoules contain benzyl alcohol. There have been reports of fatal 'gasping syndrome' in neonates (children less than one month of age) following the administration of intravenous solutions containing this preservative. Symptoms include a striking onset of gasping syndrome, hypotension, bradycardia, and cardiovascular collapse (see section 4.3).

Cardiac disorders:

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 drug interactions and / or electrolytic disorders (see sections 4.5. and 4.8).

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, Cordarone X treatment 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.

Pulmonary disorders:

Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity such as intertitial 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-eva luated since interstitial pneumonitis is generally reversible following early withdrawal of amiodarone, and corticosteroid therapy should be considered (see section 4.8). Clinical symptoms often resolve within a few weeks followed by slower radiological and lung function improvement. Some patients can deteriorate despite discontinuing Cordarone X. 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 (see sections 4.5 and 4.8).

Liver disorders (see section 4.8)

Close monitoring of liver function tests (transaminases) is recommended as soon as amiodarone is started and regularly during treatment. Acute liver disorders (including severe hepatocellular insufficiency or hepatic failure, sometimes fatal) and chronic liver disorders may occur with oral and intravenous forms within the first 24 hours of IV amiodarone. Therefore amiodarone dose should be reduced or the treatment discontinued if the transaminases increase exceeds three times the normal range.

Clinical and biological signs of chronic liver disorders due to oral amiodarone may be minimal (hepatomegaly, transaminases, increased up to 5 times the normal range) and reversible after treatment withdrawal, however fatal cases have been reported.

Thyroid dysfunction

Thyroid function tests should be performed where appropriate prior to therapy in all patients (see section 4.3).

Hyperthyroidism may occur during amiodarone treatment or up to several months after discontinuation. Severe cases with clinical presentation of tyrotoxicosis, and sometimes fatal require emergency therapeutical management

Drug interactions (see section 4.5)

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.

Caution should be exercised in patients with hypotension, decompensated cardiomyopathy and severe heart failure (also see section 4.3).

Cordarone X Intravenous should only be used in a special care unit under continuous monitoring (ECG and blood pressure).

Repeated or continuous infusion via the peripheral veins may lead to injection site reactions (see section 4.8). When repeated or continuous infusion is anticipated, administration by a central venous catheter is recommended.

When given by infusion Cordarone X 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 (see section 4.5).

Some of the more important drugs that interact with amiodarone include warfarin, digoxin, phenytoin and any drug which prolongs the QT interval.

Amiodarone raises the plasma concentrations of oral anticoagulants (warfarin) and phenytoin by inhibition of CYP 2C9. The dose of warfarin should be reduced accordingly. More frequent monitoring of prothrombin time both during and after amiodarone treatment is recommended. Phenytoin dosage should be reduced if signs of overdosage appear, and plasma levels may be measured.

Administration of Cordarone X to a patient already receiving digoxin will bring about an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with high digoxin levels. Clinical, ECG, and biological monitoring is recommended and digoxin dosage usually has to be reduced. A synergistic effect on heart rate and atrioventricular conduction is also possible.

Combined therapy with the following drugs which prolong the QT interval is contra-indicated (see section 4.3) due to the increased risk of torsades de pointes; for example:

• Class Ia anti-arrhythmic drugs e.g. quinidine, procainamide, disopyramide, bepridil

• Class III anti-arrhythmic drugs e.g. sotalol, bretylium

• intravenous erythromycin, co-trimoxazole or pentamidine injection (when parenterally administered), as there is an increased risk of potentially lethal “torsades de pointes”, vincamine, some neuroleptic agents, cisapride

• some anti-psychotics e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, amisulpiride 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.

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.

Combined therapy with the following drugs is not recommended:

• beta blockers and certain calcium channel inhibitors (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction slowing effects may occur.

• 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 cause hypokalaemia and/or hypomagnesaemia, e.g. diuretics, systemic corticosteroids, tetracosactride, intravenous amphotericin.

Grapefruit juice inhibits cytochrome P450 3A4 and may increase the plasma concentration of amiodarone. Grapefruit juice should be avoided during treatment with oral amiodarone.

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.

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.

Flecainide

Possible increase of flecainide plasma levels; dosage of flecainide by inhibition of CYP 2D6; the dosage of flecainide should be adjusted.

Drugs metabolised by cytochrome P450 3A4

When such 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: combination with amiodarone may increase ciclosporin plasma levels. Dosage should be adjusted.

• Fentanyl: combination with amiodarone may enhance the pharmacologic effects of fentanyl and increase the risk of its toxicity.

• Statins: The risk of muscular toxicity is increased by concomitant administration of amiodarone with statins metabolized by CYP3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolized by CYP3A4 when given with amiodarone.

• Other drugs metabolised by CYP 3A4: lidocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine.

Interaction with substrates of other CYP 450 isoenzymes

In vitro studies show that amiodarone also has the potential to inhibit CYP 1A2, CYP 2C19 and CYP 2D6 through its main metabolite. When co-administered, amiodarone would be expected to increase the plasma concentration of drugs whose metabolism is dependent upon CYP 1A2, CYP 2C19 and CYP 2D6.

In view of its effect on the foetal thyroid gland, amiodarone is contraindicated during pregnancy, except in exceptional circumstances.

Amiodarone is excreted in the breast milk in significant quantities and breast-feeding is contraindicated.

Not relevant.

The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention: very common (>= 10%), common (>= 1% and < 10%); uncommon (>= 0.1% and < 1%); rare (>= 0.01% and < 0.1%), very rare (< 0.01%).

Cardiac disorders:

• Common: bradycardia, generally moderate.

• Very rare:

- marked bradycardia, sinus arrest requiring discontinuation of amiodarone, especially in patients with sinus node dysfunction and/or in elderly patients

- onset or worsening of arrhythmia, sometimes followed by cardiac arrest (see sections 4.4 and 4.5.).

Gastrointestinal disorders:

• Very rare: nausea.

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.

Hepatobiliary disorders:

• Very rare:

- isolated increase in serum transaminases, which is usually moderate (1.5 to 3 times normal range) at the beginning of therapy. They may return to normal with dose reduction or even spontaneously.

- acute liver disorders with high serum transaminases and/or jaundice, including hepatic failure, sometimes fatal (see section 4.4).

Immune system disorders:

• Very rare: anaphylactic shock.

• Angioneurotic oedema (Quincke's oedema)

(Frequency not known)

Nervous system disorders:

• Very rare: benign intra-cranial hypertension (pseudo tumor cerebri), headache.

Respiratory, thoracic and mediastinal disorders:

• Very rare:

- interstitial pneumonitis (see section 4.4)

- severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal (see sections 4.4 and 4.5)

- bronchospasm and/or apnoea in case of severe respiratory failure, and especially in asthmatic patients.

Skin and subcutaneous tissue disorders:

• Very rare: sweating.

• Frequency not known:

- urticaria.

Vascular disorders:

• Common: decrease in blood pressure, usually moderate and transient. Cases of severe hypotension or collapse have been reported following overdosage or a too rapid injection.

• Very rare: hot flushes.

There is no information regarding overdosage with intravenous amiodarone.

Little information is available regarding acute overdosage with 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 or its metabolites are dialysable.

ATC code: C01BD01

Cordarone is a product for the treatment of tachyarrhythmias and has complex pharmacological actions. Its effects are anti adrenergic (partial alpha and beta blockers). It has haemodynamic effects (increased blood flow and systemic / coronary vasodilation). The drug reduces myocardial oxygen consumption and has been shown to have a sparing effect on rat myocardial ATP utilisation, with decreased oxidative processes. Amiodarone inhibits the metabolic and biochemical effects of catecholamines on the heart and inhibits Na⁺ and K⁺ activated ATP-ase.

The safety and efficacy of amiodarone IV in patients with out-of hospital cardiac arrest due to shock resistant ventricular fibrillation have been eva luated in two double-blind studies: the ARREST study, a comparison of amiodarone to placebo, and the ALIVE study, a comparison of amiodarone to lidocaine. The primary endpoint of the both studies was survival to the hospital admission.

In the ARREST study, 504 patients with out-of hospital cardiac arrest resulting from ventricular fibrillation or pulseless ventricular tachycardia resistant to three or more defibrillation shocks and epinephrine, were randomised to amiodarone 300mg diluted in 20 ml 5 % dextrose rapidly injected into a peripheral vein (246 patients) or to placebo (258 patients). Of the 197 patients (39 %) who survived to be admitted to the hospital, amiodarone significantly increased the chances to be resuscitated and admitted to the hospital: 44 % in the amiodarone group and 34 % in the placebo group respectively, p = 0.03. After adjustment for other independent predictors of outcome, the adjusted odds ratio for survival to admission to the hospital in the amiodarone group as compared with the placebo group was 1.6 (95 % confidence interval, 1.1 to 2.4; p = 0.02). More patients in the amiodarone group than in the placebo group had hypotension (59 % versus 25 %, p = 0.04) or bradycardia (41 % versus 25 %, p = 0.004).

In the ALIVE study, 347 patients with ventricular fibrillation resistant to three defibrillation shocks, epinephrine, and a further defibrillation shock, or with recurrence of ventricular fibrillation after initially successful debrillation, were randomised to receive amiodarone (5 mg per kilogram of estimated body-weight diluted in 30 ml 5 % dextrose) and lidocaine matching placebo, or lidocaine (1.5 mg per kilogram at a concentration of 10 mg per milliliter) and amiodarone matching placebo containing the same diluent (polysorbate 80). Of the 347 patients enrolled, amiodarone significantly increased the chances to be resuscitated and admitted to the hospital: 22.8 % in the amiodarone group (41 patients of 180) and 12 % in the lidocaine group (20 patients of 167), p = 0.009.

After adjustment for other factors that may influence the likelihood of survival, the adjusted odds ratio for survival to hospital admission in recipients of amiodarone as compared with recipients of lidocaine was 2.49 (95 percent confidence interval, 1.28 to 4.85; P=0.007). There were no differences between the treatment groups in the proportions of patients who needed treatment of bradycardia with atropine or pressor treatment with dopamine or in the proportions receiving open-label lidocaine. The proportion of patients in whom asystole occurred following defibrillation shock after administration of the initial study drug was significantly higher in the lidocaine group (28.9 %) than in the amiodarone group (18.4 %), p = 0.04.

Pharmacokinetics of amiodarone are unusual and complex, and have not been completely elucidated. Absorption following oral administration is variable and may be prolonged, with enterohepatic cycling. The major metabolite is desethylamiodarone. Amiodarone is highly protein bound (> 95%). Renal excretion is minimal and faecal excretion is the major route. A study in both healthy volunteers and patients after intravenous administration of amiodarone reported that the calculated volumes of distribution and total blood clearance using a two-compartment open model were similar for both groups. Elimination of amiodarone after intravenous injection appeared to be biexponential with a distribution phase lasting about 4 hours. The very high volume of distribution combined with a relatively low apparent volume for the central compartment suggests extensive tissue distribution. A bolus IV injection of 400mg gave a terminal T½ of approx 11 hours.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Benzyl alcohol

Polysorbate 80

Water for injections

Cordarone X Intravenous is incompatible with saline and should be administered solely in 5% dextrose solution. Solutions containing less than 2 ampoules Cordarone X Intravenous in 500ml dextrose 5% are unstable and should not be used.

The use of administration equipment or devices containing plasticizers such as DEHP (di-2-ethylhexylphthalate) in the presence of amiodarone may result in leaching out of DEHP. In order to minimise patients exposure to DEHP, the final amiodarone dilution for infusion should preferably be administered through non DEHP-containing sets.

Unopened: 2 years.

Once opened: Discard any unused portion immediately after opening.

Once diluted: Use immediately and discard any unused portion.

Do not store above 25 °C.

Keep the ampoules in the outer carton.

Clear, type I glass ampoules containing 3ml solution.

Each carton contains ten glass ampoules.

Refer to 4.2 above.

sanofi-aventis Ireland Ltd

Citywest Business Campus

Dublin 24

Ireland

PA 540/142/3

24^th August 1997/24^th August 2007.

March 2011