Treatment of serious rhythm disorders when oral treatment cannot be used, i.e.:

•         Atrial arrhythmias with ventricular tachycardia.

•         Tachycardias associated with Wolff-Parkinson-White syndrome.

•         Documented, symptomatic and incapacitating ventricular arrhythmias.

Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest.

For reasons related to the pharmaceutical form of the medicinal product, concentrations used must not be less than the equivalent of 2 ampoules per 500 mL. Use only isotonic glucose solution as the infusion vehicle. Do not add any other products to the infusion vehicle.

Amiodarone must be administered via the central venous route, except during cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest, in which case the peripheral route may be used if the central venous route is not available (see section 4.4 “Special warnings and precautions for use”).

Serious arrhythmias when treatment via the oral route is not appropriate, except during cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest:

Infusion via the central venous route 

•         Loading dose: The usual loading dose is 5 mg/kg in glucose solution, preferably using an electric syringe, administered over a period of between 20 to 120 minutes. This may be repeated 2 to 3 times per 24-hour period.

The effect of the medicinal product is of short duration, therefore making it necessary to continue administration by infusion.

•         Maintenance dosage: 10 to 20 mg/kg/24 hours (usually 600 to 800 mg and up to 1200 mg/24 hours) in 250 mL glucose solution over several days.

The relay to oral administration (3 tablets per day) should be started from the first day of infusion. Dosage may be increased to 4 or even 5 tablets per day.

Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest.

When administering the medicinal product in this situation, use of a central venous catheter is recommended if immediately available; otherwise, administration may be performed via the peripheral venous route, using the largest possible peripheral vein with the highest possible blood flow.

•         A first intravenous dose of 300 mg (or 5 mg/kg) diluted in 20 mL of 5% glucose solution is administered via bolus injection.

•         An additional 150 mg (or 2.5 mg/kg) IV dose may be considered if the ventricular fibrillation persists.

•         Do not mix other preparations in the same syringe.

Paediatric population 

The safety and efficacy of amiodarone in children have not been established.

Currently available data are described in section 5.1 and 5.2. 

 

As this medicinal product contains benzyl alcohol, caution should be exercised when administering amiodarone intravenously to neonates and children under 3 years of age (see section 4.4).

This medicinal product is contraindicated in the following situations: • sinus bradycardia and sinoatrial block, unless a pacemaker is fitted, • sick sinus syndrome (risk of sinus arrest), unless a pacemaker is fitted, • severe atrioventricular conduction disorders, unless a pacemaker is fitted, • hyperthyroidism because of possible exacerbation by amiodarone, • known hypersensitivity to iodine or to amiodarone or to any of the excipients, • circulatory collapse, • severe arterial hypotension, • 2nd and 3rd trimesters of pregnancy, • lactation, • use in combination with: o drugs which may induce torsades de pointes (excluding antiparasitic drugs, neuroleptics, and methadone):  class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide),  class III antiarrhythmics (sotalol, dofetilide, ibutilide),  other medicinal products such as: arsenic compounds, bepridil, cisapride, citalopram, escitalopram, diphemanil, domperidone, dolasetron IV, dronedarone, erythromycin IV, levofloxacin, mequitazine, mizolastine, moxifloxacin, prucalopride, spiramycin IV, toremifene, vincamine IV (see section 4.5), o telaprevir, o cobicistat. The above contraindications do not apply when amiodarone is used in the emergency treatment of cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest.

Route of administration

Infusion via the central venous route: serious arrhythmias when treatment via the oral route is not appropriate, except during cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest.

Amiodarone injection must be administered via the central venous route. Administration via the peripheral venous route may lead to injection site reactions, such as local venous irritation. Amiodarone injection must be used exclusively as an infusion.

Even a very slow direct intravenous injection may exacerbate hypotension, heart failure or severe respiratory failure (see section 4.8).

Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest. 

•         Administration via the peripheral venous route is generally not advised because of hemodynamic risks (severe hypotension, circulatory collapse). The central venous route should be used for infusion whenever possible.

•         Use of a central venous catheter is recommended if immediately available; otherwise, administration may be performed via the peripheral venous route, using the largest possible peripheral vein with the highest possible blood flow.

•         Supervision in an intensive care unit with continuous monitoring of blood pressure and ECG should be instituted as soon as possible.

•         Do not mix other preparations in the same syringe.

•         If amiodarone treatment should be continued, this should be via an infusion via the central venous route, with continuous monitoring of arterial blood pressure and ECG.

Drug interactions 

Concomitant use of amiodarone is not recommended with the following drugs: ciclosporin, diltiazem (by injection) or verapamil (by injection), certain antiparasitic agents (halofantrine, lumefantrine and pentamidine), certain neuroleptics (amisulpride, chlorpromazine, cyamemazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sultopride, tiapride, zuclopenthixol), fluoroquinolones (other than levofloxacin and moxifloxacin), stimulating laxative agents, methadone or fingolimod (see section 4.5).

Cardiac disorders 

•         Onset of new arrhythmias or worsening of treated arrhythmias have been reported (see section 4.8).

•         Proarrhythmic effects generally occur in the context of QT prolonging factors such as drug interactions and/or hypokalaemia (see sections 4.5 and 4.8). The risk of drug-induced torsades de pointes seems lower with amiodarone than with other antiarrhythmic agents causing the same degree of QT prolongation.

Severe skin disorders

Life-threatening or even fatal cutaneous reactions such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) may occur. 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.

Eye disorders 

If blurred or decreased vision occurs, complete ophthalmologic examination including fundoscopy should be promptly performed. The onset of optic neuropathy and/or optic neuritis requires amiodarone withdrawal due to the potential progression to blindness (see section 4.8).

Severe bradycardia and conduction disorders

Cases of severe, potentially life-threatening bradycardia and conduction disorders have been observed with medicinal products containing sofosbuvir in combination with amiodarone.

Bradycardia has usually occurred within a few hours to a few days, but cases with a longer time to onset have been observed, mostly up to 2 weeks after the initiation of anti-HCV treatment.

Amiodarone should only be used in patients treated with medicinal products containing sofosbuvir in case of intolerance or contraindication to other antiarrhythmics.

If concomitant use of amiodarone is deemed necessary, it is recommended that patients undergo inpatient cardiac monitoring for the first 48 hours of co-administration, and subsequently outpatient monitoring or heart rate self-monitoring should be performed daily for at least the first 2 weeks of treatment.

In view of the long half-life of amiodarone, cardiac monitoring as described above should also be performed in patients who have stopped amiodarone in the last few months and who are to start treatment with medicinal products containing sofosbuvir.

All patients who are currently using or have recently used amiodarone in combination with medicinal products containing sofosbuvir should be warned of the symptoms of bradycardia and conduction disorders, and they should be advised of the need for urgent medical attention if they experience these symptoms.

Pulmonary disorders

A few cases of interstitial pneumonitis have been reported with intravenous amiodarone. Onset of dyspnoea or non-productive cough, whether isolated or associated with deterioration of general health status, may be related to pulmonary toxicity such as interstitial pneumonitis, and a chest X-ray should be performed (see section 4.8).

Furthermore, some cases of acute respiratory distress syndrome have been observed immediately after surgery in patients treated with amiodarone. Close monitoring of these patients during artificial ventilation is therefore recommended.

Liver disorders 

Severe hepatocellular insufficiency, sometimes fatal, may occur within the first 24 hours of IV amiodarone. Close monitoring of liver function tests is recommended as soon as amiodarone is started and regularly during treatment (see section 4.8).

Related to the excipients: 

This medicinal product contains 60 mg of benzyl alcohol in each 3 mL ampoule. 

Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse effects and death in neonates (“gasping syndrome”). The minimum amount of benzyl alcohol at which toxicity may occur is not known. Increased risk due to accumulation in young children.

High volumes of benzyl alcohol should be used with caution and only if necessary, especially in subjects with liver or kidney impairment, and during pregnancy and breast-feeding, because of the risk of accumulation and toxicity (metabolic acidosis).

For effects concerning pregnancy and lactation, see section 4.6.

Precautions for use 

•         Electrolyte disorders, particularly hypokalaemia: it is important to consider any situations in which the patient may be at risk for hypokalaemia, as hypokalaemia can promote proarrhythmic effects. Hypokalaemia should be corrected before initiation of amiodarone therapy.

•         Intravenous amiodarone should only be used in a special care unit under continuous monitoring (ECG, blood pressure), except in emergency situations.

Anaesthesia

Before surgery, the anaesthetist should be informed that the patient is taking amiodarone.

The adverse effects of chronic amiodarone therapy are likely to add to the haemodynamic risk associated with general or local anaesthesia. These effects include in particular bradycardia, hypotension, reduced cardiac output and conduction disorders.

Combination of amiodarone (see section 4.5) with beta-blockers other than sotalol (contraindicated combination) and esmolol (combination requiring precautions for use), verapamil and diltiazem should only be considered in the prevention of life-threatening ventricular arrhythmias and during cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest.

Transplantation

In retrospective studies, amiodarone use in the transplant recipient prior to heart transplant has been associated with an increased risk of primary graft dysfunction (PGD).

PGD is a life-threatening complication of heart transplantation that presents as left, right or biventricular dysfunction occurring within the first 24 hours of transplant surgery for which there is no identifiable secondary cause (see section 4.8). Severe PGD may be irreversible.

For patients who are on the heart transplant waiting list, consideration should be given to use an alternative antiarrhythmic drug as early as possible before transplant.

Antiarrhythmics 

Many antiarrhythmics have depressant effects on cardiac automaticity, conduction and contractility.

Combined use of antiarrhythmics of different classes can have a beneficial therapeutic effect, but is most often problematic, and requires close clinical and ECG monitoring. Combined therapy of antiarrhythmic agents that may induce torsades de pointes (amiodarone, disopyramide, quinidines, sotalol, etc.) is contraindicated.

Combined use of antiarrhythmics of the same class is not recommended, except in very rare cases, due to the higher risk of cardiac adverse effects.

Use of amiodarone in combination with medicinal products that have negative inotropic properties, that induce bradycardia and/or slow atrioventricular conduction is problematic, and requires clinical and ECG monitoring.

Drugs inducing torsades de pointes 

This serious cardiac rhythm disorder can be caused by a number of antiarrhythmic and non-antiarrhythmic agents. Hypokalaemia (see “Hypokalaemia-inducing agents”) is a predisposing factor, as is bradycardia (see “Bradycardia-inducing agents”) or congenital or acquired pre-existing QT prolongation.

The drugs involved are in particular class Ia and III antiarrhythmics and some neuroleptic agents.

For dolasetron, erythromycin, spiramycin, and vincamine, this interaction only occurs with IV forms.

Combined therapy with drugs that may induce torsades de pointes is contraindicated.

However, this does not apply to some of these agents which are considered absolutely necessary and, instead of being contraindicated, are simply not recommended in combination with other drugs inducing torsades de pointes. These include: 

•             methadone, 

•             antiparasitic agents (halofantrine, lumefantrine, pentamidine), •    and neuroleptic agents.

Bradycardia-inducing agents 

Numerous medicinal products can induce bradycardia, particularly class Ia antiarrhythmic agents, betablockers, some class III antiarrhythmic agents, some calcium antagonists, digitalis drugs, pilocarpine and anticholinesterase agents.

Effect of amiodarone on other medicinal 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.

Effect of other products on amiodarone 

CYP3A4 inhibitors and CYP2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure.

It is recommended to avoid CYP3A4 inhibitors (e.g. grapefruit juice and certain medicinal products) during treatment with amiodarone.

Contraindicated combinations 

+ Torsades de pointes-inducing drugs (excluding antiparasitic agents, neuroleptics and methadone, see “Inadvisable combinations”):

•             class la antiarrhythmics (quinidine, hydroquinidine, disopyramide),

•             class III antiarrhythmics (dofetilide, ibutilide, sotalol),

•             other medicinal products, such as: arsenic compounds, bepridil, cisapride, citalopram, escitalopram, diphemanil, dolasetron IV, domperidone, dronedarone, erythromycin IV, levofloxacin, mequitazine, mizolastine, moxifloxacin, prucalopride, spiramycin IV, toremifene, vincamine IV.

There is an increased risk of ventricular arrhythmias, especially torsades de pointes.

+ Telaprevir

Automaticity and cardiac conduction disorders may occur with a risk of excessive bradycardia.

+ Cobicistat

There is a risk of increased amiodarone-induced adverse effects due to decreased metabolism.

Inadvisable combinations 

+ Sofosbuvir

Co-administration of amiodarone with treatments containing sofosbuvir may result in severe symptomatic bradycardia. Use only if no alternative treatment is available. Close monitoring is recommended when these medicinal products are co-administered (see section 4.4).

+ CYP3A4 substrates

When CYP3A4 substrates are co-administered with amiodarone, an inhibitor of CYP3A4, their plasma concentrations may increase, which may lead to a possible increase in their toxicity.

 

Cyclosporin

There is an increase in blood cyclosporin levels, due to reduced liver metabolism, with a risk of nephrotoxic effects.

Assay of blood cyclosporin levels, monitoring of renal function and cyclosporin dose adjustment during amiodarone treatment should be performed.

+ Diltiazem injection

There is a risk of bradycardia and atrioventricular heart block.

If this combination cannot be avoided, close clinical supervision and continuous ECG monitoring should be performed.

+ Fingolimod

The bradycardia-inducing effects may be potentiated, and may have a fatal outcome. This is particularly true for beta-blockers which inhibit adrenergic compensation mechanisms.

Clinical supervision and continuous ECG monitoring for 24 hours following the first dose should be performed.

+ Verapamil injection

There is a risk of bradycardia and atrioventricular heart block.

If this combination cannot be avoided, close clinical supervision and continuous ECG monitoring should be performed.

+ Antiparasitics that may induce torsade de pointes (halofantrine, lumefantrine, pentamidine) There is an increased risk of ventricular arrhythmias, especially torsades de pointes.

If possible, one of the two treatments should be discontinued. If coadministration cannot be avoided, a preliminary QT examination should be carried out and ECG monitoring performed.

+ Neuroleptics inducing torsade de pointes (amisulpride, chlorpromazine, cyamemazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sultopride, tiapride, zuclopenthixol)

There is an increased risk of ventricular arrhythmias, especially torsades de pointes.

+ Methadone

There is an increased risk of ventricular arrhythmias, especially torsades de pointes.

+ Fluoroquinolones other than levofloxacin and moxifloxacin (contraindicated combinations) There is an increased risk of ventricular arrhythmias, especially torsades de pointes. + Stimulating laxatives

There is an increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalaemia is a predisposing factor).

Any existing hypokalaemia should be corrected before administration, and clinical, electrolyte and ECG monitoring implemented.

+ Fidaxomicin

Increased plasma fidaxomicin concentrations may occur.

Combinations requiring precautions for use 

+ P-gp substrates

Amiodarone is a P-gp inhibitor. Coadministration with P-gp substrates is expected to result in an increase of their exposure. + Digitalis

Disturbances in automaticity (excessive bradycardia) and atrioventricular conduction may occur.

If digoxin is used, an increase in plasma digoxin concentrations is possible due to the decrease in digoxin clearance.

Clinical monitoring and ECG should be carried out. It may be necessary to monitor plasma digoxin concentrations and adjust dosage of digitalis treatment.

Dabigatran

There is an increase in plasma dabigatran concentrations, with a higher risk of bleeding.

If dabigatran is used postoperatively, clinical monitoring should be performed and, if necessary, the dabigatran dose should be adjusted, without exceeding 150 mg/day.

+ CYP2C9 substrates

Amiodarone raises the concentrations of CYP2C9 substrates such as vitamin K antagonists and phenytoin.

+ Vitamin K antagonists

There is an increase in vitamin K antagonist effects and an increased risk of bleeding.

It is necessary to monitor INR more regularly. The vitamin K antagonist dose should be adjusted during treatment with amiodarone and for 8 days after treatment discontinuation.

+ Phenytoin (and, by extrapolation, fosphenytoin)

The combination of phenytoin with amiodarone may lead to phenytoin overdose, resulting in neurological signs (decreased liver metabolism of phenytoin).

Clinical monitoring should be undertaken and phenytoin dosage should be reduced as soon as overdose signs appear; phenytoin plasma levels should be determined.

+ CYP2D6 substrates

•      Flecainide

Amiodarone raises plasma concentrations of flecainide by inhibition of the cytochrome CYP2D6. Therefore, flecainide dosage should be adjusted.

+ CYP3A4 substrates

When such drugs are co-administered with amiodarone, an inhibitor of CYP3A4, this may result in a higher level of their plasma concentrations, which may lead to a possible increase in their toxicity. + Statins (simvastatin, atorvastatin, lovastatin)

The risk of muscular toxicity (e.g. rhabdomyolysis) is increased by concomitant administration of amiodarone with statins metabolised by CYP3A4. It is recommended to use a statin not metabolised by CYP3A4 when given with amiodarone.

+ Other drugs metabolised by CYP3A4 (sirolimus, sildenafil, midazolam, dihydroergotamine, ergotamine, colchicine, triazolam)

When such drugs are co-administered with amiodarone, an inhibitor of CYP3A4, this may result in a higher level of their plasma concentrations, which may lead to a possible increase in their toxicity.

+ Lidocaine

There is a risk of increased plasma lidocaine concentrations, potentially leading to neurological and cardiac adverse effects, due to decreased liver metabolism by amiodarone.

Clinical and ECG monitoring and, if necessary, monitoring of plasma lidocaine concentrations should be performed. If necessary, the lidocaine dose should be adjusted during treatment and after amiodarone discontinuation. + Tacrolimus

There is an increase in blood tacrolimus concentrations due to inhibition of its metabolism by amiodarone.

Assay of blood tacrolimus concentrations, monitoring of renal function and tacrolimus dose adjustment should be performed during combined treatment with amiodarone and after amiodarone discontinuation.

+ Beta-blockers (other than esmolol and sotalol)

Disturbances in cardiac automaticity and conduction (suppression of sympathetic compensation mechanisms) may occur.

Clinical monitoring and ECG should be carried out.

+ Beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol) 

Automaticity and cardiac conduction disorders may occur with a risk of excessive bradycardia.

There is an increased risk of ventricular arrhythmias, especially torsades de pointes. Regular clinical monitoring and ECG should be carried out.

Esmolol

Disturbances in contractility, cardiac automaticity and conduction (suppression of sympathetic compensatory mechanisms) may occur.

Clinical monitoring and ECG should be carried out.

+ Oral diltiazem

There is a risk of bradycardia or atrioventricular heart block, particularly in the elderly.

Clinical monitoring and ECG should be carried out.

+ Oral verapamil

There is a risk of bradycardia or atrioventricular heart block, particularly in the elderly. Clinical monitoring and ECG should be carried out.

+ Some macrolides (azithromycin, clarithromycin, roxithromycin)

There is an increased risk of ventricular arrhythmias, especially torsades de pointes.

Clinical monitoring and ECG are required during concomitant use.

+ Hypokalaemia-inducing agents: diuretics inducing hypokalaemia (either alone or combined), amphotericin B (IV), (systemic) glucocorticoids, tetracosactide

There is an increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalaemia is a predisposing factor).

Any existing hypokalaemia should be corrected before administration, and clinical, electrolyte and ECG monitoring implemented.

+ Bradycardia-inducing agents

There is an increased risk of ventricular arrhythmias, especially torsades de pointes.

Clinical monitoring and ECG should be carried out.

+ Orlistat

There is a risk of decreased plasma concentrations of amiodarone and its active metabolite.

Clinical monitoring and, if necessary, ECG should be carried out.

+ Tamsulosin

There is a risk of increased tamsulosin-induced adverse effects due to inhibition of its liver metabolism.

Clinical monitoring should be performed and the tamsulosin dose adjusted during treatment with the enzyme inhibitor and after its discontinuation, if necessary.

+ Voriconazole

There is an increased risk of ventricular arrhythmias, especially torsades de pointes, as amiodarone metabolism may be decreased.

Clinical monitoring and ECG should be carried out and the amiodarone dose adjusted if necessary. 

Combinations to be taken into account 

+ Pilocarpine

There is a risk of severe bradycardia (cumulative bradycardia-inducing effects).

Pregnancy

Animal studies have not demonstrated any teratogenic effects. Therefore, no malformative effects are expected in humans. To date, substances responsible for malformations in humans have been shown to be teratogenic in animals during well-conducted studies in two species.

There are not currently enough relevant clinical data to evaluate a possible teratogenic effect of amiodarone when administered during the first trimester of pregnancy.

Since the foetal thyroid gland begins to bind iodine from week 14 of pregnancy, no effects on the foetal thyroid gland are expected if the drug has been administered before then.

Iodine overload with the use of this medicinal product beyond this period may cause foetal hypothyroidism or even clinical foetal hypothyroidism (goiter).

 

Consequently, use of this medicinal product is contraindicated from the 2^nd trimester of pregnancy.

As benzyl alcohol crosses the placental barrier, high volumes should be used with caution and only if necessary because of the risk of accumulation and toxicity (metabolic acidosis).

Breast-feeding

Amiodarone and its metabolite, together with iodine, are excreted in breast milk at concentrations higher than those in maternal plasma. Due to the risk of hypothyroidism in the infant, breast-feeding is contraindicated during treatment with this medicinal product.

Not relevant.

The adverse reactions are presented by system organ class and according to frequency, as follows:

Very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%), not known (cannot be estimated from the available data).

Cardiac disorders:

Common:

Bradycardia.

Very rare: 

Marked bradycardia and, more exceptionally, sinus arrest, reported in certain cases, particularly in elderly patients.

Proarrhythmic effect.

Not known: 

Torsades de pointes (see sections 4.4 and 4.5).

Gastrointestinal disorders: 

Very common: 

Nausea.

Not known: 

Pancreatitis (acute pancreatitis).

General disorders and administration site conditions:

Common:  

Possible inflammatory reaction, such as local venous irritation when administered directly in a peripheral vein, injection site reactions such as pain, erythema, oedema, necrosis, extravasation, infiltration, inflammation, phlebitis and cellulitis.

Hepatobiliary disorders: 

Cases of liver damage have been reported. These are based on elevated serum transaminases. 

The frequency was as follows:

Very rare: 

Isolated increase in serum transaminases, which is usually moderate (1.5 to 3 times normal range). They may return to normal with dose reduction or even spontaneously.

Acute liver disorders with high serum transaminases and/or jaundice, sometimes fatal, requiring treatment discontinuation.

Chronic liver disease during prolonged treatment (via the oral route). Histological findings are consistent with pseudo-alcoholic hepatitis. Given the discreet nature of the clinical and laboratory evidence (inconstant hepatomegaly, elevated serum transaminases between 1.5 and 5 times normal range), regular monitoring of liver function is justified. The diagnosis of chronic hepatic disease should be considered if an elevation, even moderate, in blood transaminases occurs after more than 6 months of treatment. Clinical disorders and abnormal laboratory values usually resolve after treatment discontinuation, although in a few cases reported this was irreversible.

Immune system disorders: 

Very rare: 

Anaphylactic shock.

Not known: 

Angioneurotic oedema and/or urticaria have been reported.

Endocrine disorders: 

Very common

Thyroid disorders: In the absence of any clinical evidence of thyroid dysfunction, “dissociated” blood thyroid hormone levels (increased T4, normal or slightly lower T3) should not lead to treatment discontinuation.

Common

Thyroid disorders: Hypothyroidism is typically characterised by signs such as weight gain, sensitivity to cold, apathy, drowsiness; a clear increase in TSH confirms the diagnosis. After treatment discontinuation, normal thyroid function is gradually restored within 1 to 3 months; discontinuation is not mandatory: if amiodarone treatment is necessary, the drug may be continued in combination with thyroid hormone replacement therapy with L-thyroxine, using TSH to determine the dose.

Hyperthyroidism is more misleading, causing only a few symptoms (minor, unexplained weight loss, decreased antianginal and/or antiarrhythmic efficacy), manifesting as psychiatric symptoms in elderly subjects, or even as thyrotoxicosis.

Suppression of ultrasensitive TSH confirms the diagnosis. Amiodarone must be discontinued: this is usually enough to prompt clinical recovery within 3-4 weeks. In serious cases that may be fatal, appropriate treatment should be urgently instituted.

If thyrotoxicosis is a cause for concern, in itself or because of its effect on a precarious myocardial balance, direct corticosteroid therapy (1 mg/kg) over a sufficiently long period (3 months) may be recommended due to the inconsistent efficacy of synthetic antithyroid drugs. Cases of hyperthyroidism have been reported up to several months after discontinuing amiodarone.

Very rare: 

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Nervous system disorders: 

Very rare: 

Benign intra-cranial hypertension (pseudotumor cerebri).

Respiratory, thoracic and mediastinal disorders: 

Very rare: 

Interstitial pneumonitis or fibrosis, sometimes fatal.

Acute respiratory distress syndrome, generally associated with interstitial pneumonitis, sometimes fatal, possibly occurring immediately after surgery (a possible interaction with high oxygen doses has been suggested). Discontinuation of amiodarone should be considered, as well as the potential benefit of corticosteroid therapy (see section 4.4).

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

Skin and subcutaneous tissue disorders: 

Very rare: 

Sweating, alopecia.

Common: 

Eczema.

Not known: 

Severe skin reactions including toxic epidermal necrolysis/Stevens-Johnson syndrome, bullous dermatitis, and drug reaction with eosinophilia and systematic symptoms (DRESS syndrome).

Eye disorders: 

Not known: 

Optic neuropathy/neuritis that may progress to blindness.

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.

Musculoskeletal and connective tissue disorders: 

Not known: 

Lower back pain, back pain.

Blood and lymphatic system disorders: 

Not known: 

Neutropenia, agranulocytosis.

Psychiatric disorders:  Common:

Decreased libido.

Not known:

Delirium (including confusion), hallucinations.

Injury, poisoning and procedural complications:

Not known:  

Potentially fatal primary graft dysfunction post cardiac transplant (see section 4.4).

Reporting of suspected adverse reactions 

 

To report any side effect(s):

·       Saudi Arabia:

-        The National Pharmacovigilance and Drug Safety Centre (NPC)

·       SFDA call center : 19999

·       E-mail: npc.drug@sfda.gov.sa

·       Website: https://ade.sfda.gov.sa/

• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

 

Not much information is available regarding acute overdose with high oral doses of amiodarone. A few cases of sinus bradycardia, ventricular arrhythmias, particularly torsades de pointes, and hepatic impairment have been reported. Treatment should be symptomatic. Due to the pharmacokinetics of the drug, prolonged surveillance of the patient, particularly cardiac status, is recommended.

Neither amiodarone nor its metabolites are removed during dialysis.

Pharmacotherapeutic group: CLASS III ANTIARRHYTHMICS, ATC code: C01BD01 Antiarrhythmic properties: 

•         Lengthening of phase 3 of the cardiac action potential without modifying its height or rate of increase (Vaughan Williams class III). The isolated prolongation of phase 3 of the action potential is due to slowing of the potassium channel, with no change in the sodium or calcium channel,

•         Bradycardia-inducing effect by reducing sinus automaticity. This effect is not antagonised by atropine,

•         Non-competitive alpha and beta-antiadrenergic effect,

•         Slowing of sinoatrial, atrial and nodal conduction, which is more pronounced as heart rhythm becomes more rapid,

•         No changes in ventricular conduction,

•         Prolongation of refractoriness and decreased myocardial excitability in the atria, nodal tissues and ventricles,

•         Slowing of conduction and prolongation of refractoriness periods in the accessory atrioventricular pathways,

•         Absence of negative inotropic effects.

Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest. 

The safety and efficacy of amiodarone IV in patients with out-of-hospital cardiac arrest due to shock- (defibrillator) resistant ventricular fibrillation have been evaluated 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 both studies was survival to 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 300 mg diluted in 20 mL of 5% glucose solution rapidly injected into a peripheral vein (246 patients) or to placebo (258 patients). 

Of the 197 patients (39%) who survived to be admitted to hospital, amiodarone significantly increased the chances to be resuscitated and admitted to the hospital: 44% in the amiodarone group versus 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 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 presented hypotension (59% versus 48%, 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 defibrillation, were randomised to receive amiodarone (5 mg per kilogram of estimated bodyweight diluted in 30 mL of 5% glucose solution) and lidocaine placebo, or lidocaine (1.5 mg per kilogram at a concentration of 10 mg per millilitre) and amiodarone placebo containing the same diluent (polysorbate 80).

Of the 347 patients enrolled, amiodarone significantly increased the chances to be resuscitated and admitted to 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% 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 for bradycardia with atropine or pressor treatment with dopamine or in the proportions receiving open-label lidocaine (in addition to the study medication).

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].

 

Paediatric population 

No controlled clinical studies have been conducted in children. In the published literature, the safety of amiodarone has been studied in 1 118 children with various types of arrhythmia.

The following doses were used in paediatric clinical studies:

•         loading dose: 5 mg/kg bodyweight over 20 minutes to 2 hours.

•         maintenance dose: 10 to 15 mg/kg/day over several hours to several days.

If necessary, initiate switch to oral amiodarone therapy at the usual loading dose, starting from the first day of infusion.

After amiodarone injection, plasma decay is very rapid while tissues become impregnated and receptor sites saturated by the drug; peak effects are observed after approximately 15 minutes and decline within 4 hours.

Amiodarone is mainly metabolised by cytochrome CYP3A4, and also by cytochrome CYP2C8. Amiodarone and its metabolite, desethylamiodarone, are potential in vitro inhibitors of cytochromes CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, CYP2B6 and CYP2C8. Amiodarone and desethylamiodarone can also inhibit transport proteins such as P-gp and organic cation transporter 2 (OCT2). One study showed a 1.1% increase in creatinine concentration (an OCT2 substrate).

In vivo data describe an interaction between amiodarone and CYP3A4, CYP2C9, CYP2D6 and P-gp substrates.

Paediatric population: 

No controlled clinical studies have been conducted in children.

Available literature data, which are limited, show no difference in pharmacokinetic parameters between adults and children.

In a 2-year carcinogenicity study in rats, amiodarone caused an increase in thyroid follicular tumours (adenomas and/or carcinomas) in both sexes at clinically relevant exposures.

Since mutagenicity findings were negative, an epigenetic rather than genotoxic mechanism is proposed for this type of tumour induction.

In mice, carcinomas were not observed, but a dose-dependent thyroid follicular hyperplasia was seen. These effects on the thyroid in rats and mice are most likely due to effects of amiodarone on the synthesis and/or release and turn-over of thyroid gland hormones. The relevance of these findings to humans is considered to be limited.

Polysorbate 80, benzyl alcohol, water for injection.

Use of PVC equipment or medical devices plasticised with DEHP (di-2-ethylhexyl phthalate) with amiodarone solution for injection can cause leaching out of DEHP. To minimise patient exposure to DEHP, the final amiodarone dilution before infusion should preferably be performed using DEHP-free sets.

As there are no incompatibility studies, this medicinal product should not be mixed with drugs other than those mentioned in section 6.6.

Two years. After opening the medicinal product should be used immediately.

Store  below 25°C.

3 ml in (glass) ampoules. Box of 6 ampoules.

Use of PVC equipment or medical devices plasticised with DEHP (di-2-ethylhexyl phthalate) with amiodarone solution for injection can cause leaching out of DEHP. To minimise patient exposure to DEHP, the final amiodarone dilution should preferably be performed prior to infusion using DEHP-free equipment, such as equipment made of DEHP-free PVC, polyolefins (polyethylene, polypropylene), glass etc.

The solution should normally be clear and transparent. Do not use any ampoules with crystals in the solution.

For reasons related to the pharmaceutical form of the medicinal product, concentrations used must not be less than the equivalent of 2 ampoules per 500 mL. Use only isotonic glucose solution as the infusion vehicle.

Do not add any other products to the infusion liquid. Any unused solution should be disposed of.