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Indications/Uses
Tablet: Prevention of recurrence of: Life-threatening ventricular tachycardia; the treatment should be instituted in a hospital setting under monitoring; Documented, symptomatic and incapacitating ventricular tachycardia; Documented, supraventricular tachycardia in patients refractory to therapy or in whom other treatments are contraindicated; Ventricular fibrillation.
Treatment of supraventricular tachycardia: Slowing or reduction in atrial fibrillation or atrial flutter.
Amiodarone can be used in patients with coronary artery disease and/or impaired left ventricular function (see Pharmacology: Pharmacodynamics under Actions).
Injection: Serious arrhythmias when treatment via the oral route is not appropriate, particularly: atrial arrhythmia, with ventricular tachycardia; tachyarrhythmias associated with Wolf-Parkinson-White syndrome; documented and symptomatic and incapacitating ventricular arrhythmia.
Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest.
Treatment of supraventricular tachycardia: Slowing or reduction in atrial fibrillation or atrial flutter.
Amiodarone can be used in patients with coronary artery disease and/or impaired left ventricular function (see Pharmacology: Pharmacodynamics under Actions).
Injection: Serious arrhythmias when treatment via the oral route is not appropriate, particularly: atrial arrhythmia, with ventricular tachycardia; tachyarrhythmias associated with Wolf-Parkinson-White syndrome; documented and symptomatic and incapacitating ventricular arrhythmia.
Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest.
Dosage/Direction for Use
Tablet: Dosage: Loading dose: The usual dosage regimen is 3 tablets per day, for 8 to 10 days. In some cases, the patient may require higher loading doses (4 to 5 tablets per day), always for short periods and under electrocardiographic monitoring.
Maintenance dose: Use the minimum effective dose, which will depend on the patient, and ranges from ½ tablet per day (1 tablet every 2 days) to 2 tablets daily.
Pediatric population: The safety and efficacy of amiodarone in children have not been established. See Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions for currently available data.
Method of administration: Oral route.
Injection: For reasons related to the formulation of the 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 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 Precautions).
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 route: Loading dose: on average 5 mg/kg in glucose solution, preferably using an electric syringe, administered over 20 to 2 hours and repeated 2 or 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 dose: 10 to 20 mg/kg/day (on average 600 to 800 mg/24 h, up to 1.2 g/24 h) in 250 mL glucose solution, over a few days.
Changeover to oral therapy (3 tablets per day) should be initiated 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.
The initial intravenous dose is 300 mg (or 5 mg/kg) diluted in 20 ml 5% glucose given as a rapid injection.
An additional dose of 150 mg (or 2.5 mg/kg) IV may be considered if ventricular fibrillation persists.
Do not add any other products in the syringe.
Paediatric population: The safety and efficacy of amiodarone in children have not been established.
See Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions for currently available data.
As this medicinal product contains benzyl alcohol, it is contraindicated in premature and full-term infants and in children aged less than 3 years (see Contraindications and Precautions).
Maintenance dose: Use the minimum effective dose, which will depend on the patient, and ranges from ½ tablet per day (1 tablet every 2 days) to 2 tablets daily.
Pediatric population: The safety and efficacy of amiodarone in children have not been established. See Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions for currently available data.
Method of administration: Oral route.
Injection: For reasons related to the formulation of the 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 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 Precautions).
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 route: Loading dose: on average 5 mg/kg in glucose solution, preferably using an electric syringe, administered over 20 to 2 hours and repeated 2 or 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 dose: 10 to 20 mg/kg/day (on average 600 to 800 mg/24 h, up to 1.2 g/24 h) in 250 mL glucose solution, over a few days.
Changeover to oral therapy (3 tablets per day) should be initiated 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.
The initial intravenous dose is 300 mg (or 5 mg/kg) diluted in 20 ml 5% glucose given as a rapid injection.
An additional dose of 150 mg (or 2.5 mg/kg) IV may be considered if ventricular fibrillation persists.
Do not add any other products in the syringe.
Paediatric population: The safety and efficacy of amiodarone in children have not been established.
See Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions for currently available data.
As this medicinal product contains benzyl alcohol, it is contraindicated in premature and full-term infants and in children aged less than 3 years (see Contraindications and Precautions).
Overdosage
Treatment must be symptomatic.
Due to the pharmacokinetics of the drug, prolonged surveillance of the patient, particularly cardiac status, is recommended.
Tablet: There is little information available regarding acute overdose with oral amiodarone. A few cases of sinus bradycardia, ventricular arrhythmias, particularly torsades de pointes, and hepatic impairment have been reported.
Injection: There is no information regarding overdosage with intravenous amiodarone.
Due to the pharmacokinetics of the drug, prolonged surveillance of the patient, particularly cardiac status, is recommended.
Tablet: There is little information available regarding acute overdose with oral amiodarone. A few cases of sinus bradycardia, ventricular arrhythmias, particularly torsades de pointes, and hepatic impairment have been reported.
Injection: There is no information regarding overdosage with intravenous amiodarone.
Administration
May be taken with or without food.
Contraindications
This medicinal product is contraindicated in the following situations: Sinus bradycardia and sinoatrial heart block in unpaced patients; Sinus node disease in unpaced patients (risk of sinus arrest); high-degree atrioventricular conduction disorders in unpaced patients; hyperthyroidism because of possible exacerbation by amiodarone; Known hypersensitivity to iodine, amiodarone or to one of the excipients; 2nd and 3rd trimesters of pregnancy; breast-feeding women; Use in combination with: torsadogenic medicinal products (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, dolasetron IV, domperidone, dronedarone, erythromycin IV, levofloxacin, mequitazine, mizolastine, moxifloxacin, prucalopride, spiramycin IV, toremifene, vincamine IV (see Interactions), Telaprevir, Cobicistat.
Injection: Circulatory collapse; Severe hypotension; Premature neonates, full-term newborns and children aged less than 3 years, as the medicinal product contains benzyl alcohol.
These contraindications do not apply to the use of amiodarone to resuscitate patients experiencing cardiac arrest where a defibrillator has not worked to stop ventricular fibrillation.
Injection: Circulatory collapse; Severe hypotension; Premature neonates, full-term newborns and children aged less than 3 years, as the medicinal product contains benzyl alcohol.
These contraindications do not apply to the use of amiodarone to resuscitate patients experiencing cardiac arrest where a defibrillator has not worked to stop ventricular fibrillation.
Special Precautions
Electrolyte disturbances, particularly hypokalemia: it is important to consider any situations in which the patient may be at risk for hypokalemia, as hypokalemia can promote proarrhythmic effects.
Hypokalemia should be corrected before initiation of amiodarone therapy.
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 Adverse Reactions). 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.
Drug interactions: Concomitant administration of amiodarone with the following medicinal products is not recommended: 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), stimulant laxatives, methadone or fingolimod (see Interactions).
Tablet: Special warnings: Cardiac disorders: An ECG must be performed before starting treatment.
In the elderly, heart rate may decrease markedly.
Amiodarone induces ECG changes. These "Amidarone Hydrochloride (Cordarone)-induced" changes consist of QT interval prolongation as a result of prolonged repolarization, possibly with the development of a U wave. These changes are a sign of therapeutic impregnation and do not reflect toxicity.
Occurrence of 2nd or 3rd degree atrioventricular block, sinoatrial block, or bifascicular block must lead to treatment discontinuation. 1st degree atrioventricular block calls for increased monitoring.
Cases of new arrhythmias or worsening of treated arrhythmias have been reported (see Adverse Reactions).
Such a proarrhythmic effect may occur especially if there are factors that promote QT interval prolongation, such as certain drug combinations and/or hypokalemia (see Interactions and Adverse Reactions). The risk of drug-induced torsades de pointes seems lower with amiodarone than other anti-arrhythmic agents causing the same degree of QT interval prolongation.
Thyroid disorders: This medicinal product contains iodine, which interferes with certain thyroid function tests (radioactive iodine uptake, PBI); however, thyroid function tests remain interpretable (T3, T4, USTSH).
Amiodarone can cause thyroid disorders, particularly in patients with a history of thyroid dysfunction. Assay of TSH is recommended in all patients before starting treatment, then regularly throughout treatment and several months after treatment discontinuation, and if there is clinical suspicion of dysthyroidism (see Adverse Reactions).
Pulmonary disorders: The onset of dyspnea or non-productive cough, whether isolated or associated with deterioration of general health status, should suggest pulmonary toxicity, such as interstitial pneumonitis, and requires chest X-Ray (see Adverse Reactions).
Liver disorders: Monitoring of liver function is recommended at the start of treatment, then regularly throughout amiodarone treatment (see Adverse Reactions).
Neuromuscular disorders: Amiodarone can cause peripheral sensorimotor or mixed neuropathy and myopathy (see Adverse Reactions).
Eye disorders: If blurred vision or decreased vision occurs, a complete ophthalmologic examination, including funduscopy, must be promptly performed. Neuropathy or optic neuritis induced by amiodarone requires treatment discontinuation due to the potential risk of progression to blindness (see Adverse Reactions).
Severe skin reactions: Life-threatening or even fatal cutaneous reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. Should signs or symptoms occur, amiodarone treatment should be discontinued immediately.
Severe Bradycardia and conduction disorders: Cases of severe potentially life-threatening bradycardia and conduction disorders have been observed when amiodarone is used in combination with sofosbuvir in combination with another antiviral (DAA) acting directly on the hepatitis C virus (HCV), such as daclatasvir, simeprevir, or ledipasvir.
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 initiation of anti-HCV treatment.
Amiodarone should be only used in patients treated with medicines containing sofosbuvir if they are intolerant or contraindicated to other antiarrhythmic drugs.
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, following which 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 previously should also be performed in patients who have stopped amiodarone within the last few months and who are to start treatment with medicines containing sofosbuvir alone or in combination with other DAAs.
All patients who currently or have recently used amiodarone in combination with medicines containing sofosbuvir should be warned of the symptoms of bradycardia and conduction disturbances, and they should be advised of the need for urgent medical attention if they experience these symptoms.
Drug interactions: Use in combination (see Interactions): beta-blockers other than sotalol (contraindicated combination) and esmolol (combination requiring strict precautions for use), verapamil and diltiazem, should only be considered for the prevention of life-threatening ventricular arrhythmias.
Excipients: This medicinal product contains lactose. It is not recommended in patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases).
Precautions for use: The adverse effects mentioned as follows are usually related to drug overload; they can be avoided or their severity minimized by carefully selecting the minimum maintenance dose.
Patients should be advised to avoid exposure to sun and to use protective protection during treatment.
In children, the safety and efficacy of amiodarone have not been evaluated by controlled clinical studies.
Due to the possible increase in the defibrillation threshold and/or pacing threshold in patients with an implantable cardiac defibrillator or a pacemaker, the threshold should be checked before and several times after amiodarone treatment initiation and whenever doses are adjusted.
Anaesthesia: Before surgery, the anesthesiologist should be informed that the patient is on amiodarone. The adverse effects of chronic amiodarone therapy are likely to add to the hemodynamic risk associated with general or local anesthesia. These effects include in particular bradycardia, hypotension, reduced cardiac output and conduction disorders. Furthermore, some cases of acute respiratory distress syndrome have been observed immediately after surgery in patients treated with amiodarone. These patients should be closely monitored when mechanically ventilated (see Adverse Reactions).
Injection: 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, as 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 Adverse Reactions).
Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest: Administration via the peripheral venous route is generally not recommended due to the 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 arterial blood pressure and ECG should be instituted as soon as possible.
Do not add any other products in the syringe.
If amiodarone treatment must be pursued, the drug should be administered as an infusion via the central venous route, with continuous monitoring of arterial blood pressure and ECG.
Cardiac disorders: Cases of new arrhythmias or worsening of treated arrhythmias have been reported (see Adverse Reactions).
The proarrhythmic effect of amiodarone may occur especially if there are factors that promote QT interval prolongation, such as certain drug combinations and hypokalemia (see Interactions and Adverse Reactions). The risk of drug-induced torsades de pointes seems lower with amiodarone compared with other anti-arrhythmic agents in patients with the same degree of QT interval prolongation.
Severe skin disorders: Life-threatening or even fatal cutaneous reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. If patients experience signs or symptoms indicative of these conditions (e.g. progressive skin rash with blisters or mucosal lesions), amiodarone treatment should be discontinued immediately.
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 following that 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 previously 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 amiodarone injection. The onset of dyspnea or non-productive cough, whether isolated, or associated with deterioration of general health status, should suggest pulmonary toxicity, such as interstitial pneumonitis, and requires chest X-ray (see Adverse Reactions). 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, sometimes fatal, hepatocellular failure may occur within 24 hours following the start of treatment with amiodarone injection. Monitoring of liver function is recommended at the start of treatment, then regularly throughout amiodarone treatment (see Adverse Reactions).
Excipients: This medicinal product contains 60 mg of benzyl alcohol per 3 ml ampoule. Benzyl alcohol may cause toxic or anaphylactoid reactions in infants and children up to 3 years of age.
Administration of medicinal products containing benzyl alcohol in premature and full-term newborns has been associated with fatal cases of gasping syndrome (symptoms include sudden onset of gasping syndrome, hypotension, bradycardia and cardiovascular collapse.
Precautions for Use: Amiodarone should only be administered in a specialized hospital setting under continuous monitoring (ECG, BP), except in emergency situations.
Anesthesia: Before surgery, the anesthesiologist should be informed that the patient is on amiodarone.
The adverse effects of chronic amiodarone therapy are likely to add to the hemodynamic risk associated with general or local anesthesia. These effects include in particular bradycardia, hypotension, reduced cardiac output and conduction disorders.
Combination of amiodarone (see Interactions) 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.
Hypokalemia should be corrected before initiation of amiodarone therapy.
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 Adverse Reactions). 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.
Drug interactions: Concomitant administration of amiodarone with the following medicinal products is not recommended: 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), stimulant laxatives, methadone or fingolimod (see Interactions).
Tablet: Special warnings: Cardiac disorders: An ECG must be performed before starting treatment.
In the elderly, heart rate may decrease markedly.
Amiodarone induces ECG changes. These "Amidarone Hydrochloride (Cordarone)-induced" changes consist of QT interval prolongation as a result of prolonged repolarization, possibly with the development of a U wave. These changes are a sign of therapeutic impregnation and do not reflect toxicity.
Occurrence of 2nd or 3rd degree atrioventricular block, sinoatrial block, or bifascicular block must lead to treatment discontinuation. 1st degree atrioventricular block calls for increased monitoring.
Cases of new arrhythmias or worsening of treated arrhythmias have been reported (see Adverse Reactions).
Such a proarrhythmic effect may occur especially if there are factors that promote QT interval prolongation, such as certain drug combinations and/or hypokalemia (see Interactions and Adverse Reactions). The risk of drug-induced torsades de pointes seems lower with amiodarone than other anti-arrhythmic agents causing the same degree of QT interval prolongation.
Thyroid disorders: This medicinal product contains iodine, which interferes with certain thyroid function tests (radioactive iodine uptake, PBI); however, thyroid function tests remain interpretable (T3, T4, USTSH).
Amiodarone can cause thyroid disorders, particularly in patients with a history of thyroid dysfunction. Assay of TSH is recommended in all patients before starting treatment, then regularly throughout treatment and several months after treatment discontinuation, and if there is clinical suspicion of dysthyroidism (see Adverse Reactions).
Pulmonary disorders: The onset of dyspnea or non-productive cough, whether isolated or associated with deterioration of general health status, should suggest pulmonary toxicity, such as interstitial pneumonitis, and requires chest X-Ray (see Adverse Reactions).
Liver disorders: Monitoring of liver function is recommended at the start of treatment, then regularly throughout amiodarone treatment (see Adverse Reactions).
Neuromuscular disorders: Amiodarone can cause peripheral sensorimotor or mixed neuropathy and myopathy (see Adverse Reactions).
Eye disorders: If blurred vision or decreased vision occurs, a complete ophthalmologic examination, including funduscopy, must be promptly performed. Neuropathy or optic neuritis induced by amiodarone requires treatment discontinuation due to the potential risk of progression to blindness (see Adverse Reactions).
Severe skin reactions: Life-threatening or even fatal cutaneous reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. Should signs or symptoms occur, amiodarone treatment should be discontinued immediately.
Severe Bradycardia and conduction disorders: Cases of severe potentially life-threatening bradycardia and conduction disorders have been observed when amiodarone is used in combination with sofosbuvir in combination with another antiviral (DAA) acting directly on the hepatitis C virus (HCV), such as daclatasvir, simeprevir, or ledipasvir.
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 initiation of anti-HCV treatment.
Amiodarone should be only used in patients treated with medicines containing sofosbuvir if they are intolerant or contraindicated to other antiarrhythmic drugs.
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, following which 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 previously should also be performed in patients who have stopped amiodarone within the last few months and who are to start treatment with medicines containing sofosbuvir alone or in combination with other DAAs.
All patients who currently or have recently used amiodarone in combination with medicines containing sofosbuvir should be warned of the symptoms of bradycardia and conduction disturbances, and they should be advised of the need for urgent medical attention if they experience these symptoms.
Drug interactions: Use in combination (see Interactions): beta-blockers other than sotalol (contraindicated combination) and esmolol (combination requiring strict precautions for use), verapamil and diltiazem, should only be considered for the prevention of life-threatening ventricular arrhythmias.
Excipients: This medicinal product contains lactose. It is not recommended in patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases).
Precautions for use: The adverse effects mentioned as follows are usually related to drug overload; they can be avoided or their severity minimized by carefully selecting the minimum maintenance dose.
Patients should be advised to avoid exposure to sun and to use protective protection during treatment.
In children, the safety and efficacy of amiodarone have not been evaluated by controlled clinical studies.
Due to the possible increase in the defibrillation threshold and/or pacing threshold in patients with an implantable cardiac defibrillator or a pacemaker, the threshold should be checked before and several times after amiodarone treatment initiation and whenever doses are adjusted.
Anaesthesia: Before surgery, the anesthesiologist should be informed that the patient is on amiodarone. The adverse effects of chronic amiodarone therapy are likely to add to the hemodynamic risk associated with general or local anesthesia. These effects include in particular bradycardia, hypotension, reduced cardiac output and conduction disorders. Furthermore, some cases of acute respiratory distress syndrome have been observed immediately after surgery in patients treated with amiodarone. These patients should be closely monitored when mechanically ventilated (see Adverse Reactions).
Injection: 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, as 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 Adverse Reactions).
Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest: Administration via the peripheral venous route is generally not recommended due to the 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 arterial blood pressure and ECG should be instituted as soon as possible.
Do not add any other products in the syringe.
If amiodarone treatment must be pursued, the drug should be administered as an infusion via the central venous route, with continuous monitoring of arterial blood pressure and ECG.
Cardiac disorders: Cases of new arrhythmias or worsening of treated arrhythmias have been reported (see Adverse Reactions).
The proarrhythmic effect of amiodarone may occur especially if there are factors that promote QT interval prolongation, such as certain drug combinations and hypokalemia (see Interactions and Adverse Reactions). The risk of drug-induced torsades de pointes seems lower with amiodarone compared with other anti-arrhythmic agents in patients with the same degree of QT interval prolongation.
Severe skin disorders: Life-threatening or even fatal cutaneous reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. If patients experience signs or symptoms indicative of these conditions (e.g. progressive skin rash with blisters or mucosal lesions), amiodarone treatment should be discontinued immediately.
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 following that 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 previously 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 amiodarone injection. The onset of dyspnea or non-productive cough, whether isolated, or associated with deterioration of general health status, should suggest pulmonary toxicity, such as interstitial pneumonitis, and requires chest X-ray (see Adverse Reactions). 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, sometimes fatal, hepatocellular failure may occur within 24 hours following the start of treatment with amiodarone injection. Monitoring of liver function is recommended at the start of treatment, then regularly throughout amiodarone treatment (see Adverse Reactions).
Excipients: This medicinal product contains 60 mg of benzyl alcohol per 3 ml ampoule. Benzyl alcohol may cause toxic or anaphylactoid reactions in infants and children up to 3 years of age.
Administration of medicinal products containing benzyl alcohol in premature and full-term newborns has been associated with fatal cases of gasping syndrome (symptoms include sudden onset of gasping syndrome, hypotension, bradycardia and cardiovascular collapse.
Precautions for Use: Amiodarone should only be administered in a specialized hospital setting under continuous monitoring (ECG, BP), except in emergency situations.
Anesthesia: Before surgery, the anesthesiologist should be informed that the patient is on amiodarone.
The adverse effects of chronic amiodarone therapy are likely to add to the hemodynamic risk associated with general or local anesthesia. These effects include in particular bradycardia, hypotension, reduced cardiac output and conduction disorders.
Combination of amiodarone (see Interactions) 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.
Use In Pregnancy & Lactation
Pregnancy: Animal studies have not demonstrated any teratogenic effects, therefore no malformative effects are expected in humans. To date, substances causing 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 fetal thyroid gland begins to bind iodine from week 14 of amenorrhea, no effects on the fetal thyroid gland are expected if the drug has been administered before then.
Iodine overload with use of amiodarone beyond this period may cause fetal hypothyroidism which can be seen in laboratory tests or can even manifest clinically as goiter.
Consequently, use of this medicinal product is contraindicated from the 2nd trimester of pregnancy.
Injection: As benzyl alcohol crosses the placental barrier, solutions for injection should be used with caution in pregnant women.
Lactation: 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.
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 fetal thyroid gland begins to bind iodine from week 14 of amenorrhea, no effects on the fetal thyroid gland are expected if the drug has been administered before then.
Iodine overload with use of amiodarone beyond this period may cause fetal hypothyroidism which can be seen in laboratory tests or can even manifest clinically as goiter.
Consequently, use of this medicinal product is contraindicated from the 2nd trimester of pregnancy.
Injection: As benzyl alcohol crosses the placental barrier, solutions for injection should be used with caution in pregnant women.
Lactation: 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.
Adverse Reactions
Tablet: The adverse effects 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 available data).
Eye disorders: Very common: Corneal micro-deposits, in almost all adults, usually limited to the area under the pupil and not requiring treatment discontinuation. Exceptionally they may be associated with colored halos in dazzling light or blurred vision.
Corneal micro-deposits consist of complex lipid deposits and are always entirely reversible following discontinuation of treatment.
Very rare: Optic neuropathy (optic neuritis) with blurred, reduced vision and papillary edema on fundoscopy, possibly progressing to more or less severe reduction in visual acuity. A causal relationship to amiodarone has not been established to date. In the absence of any other obvious cause, amiodarone treatment discontinuation is nevertheless recommended.
Skin and subcutaneous tissue disorders: Very common: Photosensitivity. Patients are advised to avoid exposure to sun (and ultraviolet rays in general) during treatment.
Common: Lilac or slate-grey colored pigmentation of the skin occurring at high daily dosages prescribed for a long period of time; such pigmentations slowly disappear following treatment discontinuation (10 to 24 months).
Very rare: Erythema during radiotherapy, Skin rashes, usually non-specific, Exfoliative dermatitis, although a causal relationship to the drug is not clearly established, Alopecia.
Not known: Eczema, Severe, sometimes fatal, cutaneous reactions such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, Bullous dermatitis, DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).
Endocrine disorders: Thyroid disorders: Very common: 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: Hypothyroidism is typically characterized 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. It is essential to discontinue amiodarone treatment, which is usually sufficient to trigger clinical recovery within 3 to 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.
Other endocrine disorders: Very rare cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion), particularly when amiodarone is used in combination with medicinal products that may induce hyponatremia. See also "Investigations" as follows.
Respiratory, thoracic and mediastinal disorders: Common: Cases of diffuse interstitial or alveolar pneumonitis and bronchiolitis obliterans organizing pneumonia (BOOP), sometimes fatal, have been reported. The onset of effort dyspnea or dry cough - either isolated or associated with a deterioration in general condition (fatigue, weight loss, febricula) - requires radiological control and, if necessary, treatment discontinuation. These types of pneumonitis can progress to pulmonary fibrosis.
Early discontinuation of amiodarone-associated or not with corticosteroid therapy - leads to regression of the disorders. Clinical signs usually disappear within 3 or 4 weeks. Radiological and functional improvement is usually slower (several months).
A few cases of pleurisy, generally associated with interstitial pneumonitis, have been reported.
Very rare: Bronchospasm, particularly in asthmatic patients.
Acute respiratory distress syndrome, occasionally with fatal outcome, occurring sometimes immediately after surgery (a possible interaction with high oxygen doses has been suggested) (see Precautions).
Not known (cannot be estimated from the available data): Cases of pulmonary hemorrhage, sometimes revealed by hemoptysis, have been reported. These pulmonary effects often occur along with amiodarone-induced pneumonitis.
Nervous system disorders: Common: Tremor or other extrapyramidal symptoms, sleep disorders, including nightmares, Peripheral sensorimotor or mixed neuropathy.
Uncommon: Myopathy.
Peripheral sensorimotor or mixed neuropathy or myopathy may occur after just a few months of treatment, but sometimes after several years. These disorders are generally reversible on treatment discontinuation. However, recovery may be incomplete, very slow and occur only several months after treatment discontinuation.
Very rare: Cerebellar ataxia, Benign intracranial hypertension, headache. The onset of isolated headaches requires investigation for an underlying disease.
Not known: Syndrome parkinsonism, parosmia.
Hepatobiliary disorders: Cases of liver damage, diagnosed based on elevated serum transaminases, have been reported as follows: Very common: Generally moderate, isolated elevation in transaminases (1.5 to 3 times normal range) resolving after dose reduction, or even spontaneously.
Common: Acute liver damage with high serum transaminases and/or jaundice, sometimes with fatal outcome, requiring treatment discontinuation.
Very rare: Chronic liver damage during prolonged treatment.
Histological findings are consistent with pseudoalcoholic 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 damage 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, the course was irreversible.
Cardiac disorders: Common: Generally moderate, dose-dependent bradycardia.
Uncommon: Conduction disorders (sinoatrial block, atrioventricular block of varying degrees).
Very rare: Marked bradycardia and, more exceptionally, sinus arrest, reported in certain cases (sinus dysfunction, elderly patients).
Not known: Torsades de pointes (see Precautions and Interactions).
Gastrointestinal disorders: Very common: Mild gastrointestinal disorders (nausea, vomiting, dysgeusia), usually occurring during initial treatment and resolving on dose reduction.
Not known: Pancreatitis/acute pancreatitis, dry mouth, constipation.
Breast and reproductive system disorders: Very rare: Epididymitis. A causal relationship with the medicinal product has apparently not been established.
Not known: Loss of libido.
Vascular disorders: Very rare: Vasculitis.
Investigations: Rare: Rare cases of hyponatremia, suggestive of SIADH.
Very rare: Renal impairment with increased serum creatinine.
Blood and lymphatic system disorders: Very rare: Thrombocytopenia.
Not known: Neutropenia, agranulocytosis.
Immune system disorders: Not known: Cases of angioedema and/or urticaria have been reported.
Anaphylactic/anaphylactoid reaction, and even shock.
General disorders: Not known: Granuloma, essentially bone marrow granuloma, have been reported.
Metabolism and nutrition disorders: Not known: Decreased appetite.
Psychiatric disorders: Not known: Confusional state, delirium, hallucination.
Musculoskeletal and connective tissue disorders: Not known: Lupus syndrome.
Injury, poisoning and procedural complications: Not known: Potentially fatal primary graft dysfunction post cardiac transplant (see Precautions).
Injection: The adverse effects are presented by organ class and according to frequency, as follows: Very common (≥10%); common (≥1%, <10%); uncommon (≥0.1%, <1%); rare (≥0.01%, <0.1%); very rare (<0.01%), unknown (cannot be estimated from available data).
Cardiac disorders: Common: Bradycardia.
Very rare: Marked bradycardia and, more exceptionally, sinus arrest, reported in certain cases, particular in elderly patients, Proarrhythmic effect.
Not known: Torsades de pointes (see Precautions and Interactions).
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, reactions at the injection site, such as pain, erythema, edema, necrosis, extravasation, infiltration, inflammation, phlebitis and cellulitis.
Hepato-biliary disorders: Cases of liver damage, diagnosed based on elevated serum transaminases, have been reported, as follows: Very rare: Generally moderate, isolated elevation in transaminases (1.5 to 3 times normal range) resolving after dose reduction, or even spontaneously; Acute liver damage with high serum transaminases and/or jaundice, sometimes with fatal outcome, requiring treatment discontinuation.
Chronic liver damage during prolonged treatment (via the oral route). Histological findings are consistent with pseudoalcoholic 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 damage 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 reported cases, the course was irreversible.
Immune system disorders: Very rare: Anaphylactic shock.
Not known: Cases of angioedema 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 characterized 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 intracranial hypertension (pseudotumor cerebri).
Respiratory, thoracic and mediastinal disorders: Very rare: Acute respiratory distress syndrome, generally associated with interstitial pneumonitis, occasionally with fatal outcome, occurring sometimes 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 Precautions).
Bronchospasm and/or apnea in the event of severe respiratory failure, particularly in asthmatic patients.
Skin and subcutaneous tissue disorders: Very rare: Sweating, alopecia.
Not known: Eczema. Severe, sometimes fatal, cutaneous reactions such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome. Bullous dermatitis. DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).
Vascular disorders: Common: Generally moderate and transient fall in blood pressure. Cases of severe hypotension or collapse have been reported, particularly after overdose if the drug is injected too rapidly.
Very rare: Hot flushes.
Musculoskeletal and connective tissue disorders: Not known: Lower back pain, back pain.
Hematological and lymphatic system disorders: Not known: Neutropenia, agranulocytosis.
Psychiatric disorders: Not known: Confusional state, delusion, hallucination.
Reproductive system and breast disorders: Not known: Loss of libido.
Injury, poisoning and procedural complications: Not known: Potentially fatal primary graft dysfunction post cardiac transplant (see Precautions).
Eye disorders: Very common: Corneal micro-deposits, in almost all adults, usually limited to the area under the pupil and not requiring treatment discontinuation. Exceptionally they may be associated with colored halos in dazzling light or blurred vision.
Corneal micro-deposits consist of complex lipid deposits and are always entirely reversible following discontinuation of treatment.
Very rare: Optic neuropathy (optic neuritis) with blurred, reduced vision and papillary edema on fundoscopy, possibly progressing to more or less severe reduction in visual acuity. A causal relationship to amiodarone has not been established to date. In the absence of any other obvious cause, amiodarone treatment discontinuation is nevertheless recommended.
Skin and subcutaneous tissue disorders: Very common: Photosensitivity. Patients are advised to avoid exposure to sun (and ultraviolet rays in general) during treatment.
Common: Lilac or slate-grey colored pigmentation of the skin occurring at high daily dosages prescribed for a long period of time; such pigmentations slowly disappear following treatment discontinuation (10 to 24 months).
Very rare: Erythema during radiotherapy, Skin rashes, usually non-specific, Exfoliative dermatitis, although a causal relationship to the drug is not clearly established, Alopecia.
Not known: Eczema, Severe, sometimes fatal, cutaneous reactions such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, Bullous dermatitis, DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).
Endocrine disorders: Thyroid disorders: Very common: 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: Hypothyroidism is typically characterized 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. It is essential to discontinue amiodarone treatment, which is usually sufficient to trigger clinical recovery within 3 to 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.
Other endocrine disorders: Very rare cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion), particularly when amiodarone is used in combination with medicinal products that may induce hyponatremia. See also "Investigations" as follows.
Respiratory, thoracic and mediastinal disorders: Common: Cases of diffuse interstitial or alveolar pneumonitis and bronchiolitis obliterans organizing pneumonia (BOOP), sometimes fatal, have been reported. The onset of effort dyspnea or dry cough - either isolated or associated with a deterioration in general condition (fatigue, weight loss, febricula) - requires radiological control and, if necessary, treatment discontinuation. These types of pneumonitis can progress to pulmonary fibrosis.
Early discontinuation of amiodarone-associated or not with corticosteroid therapy - leads to regression of the disorders. Clinical signs usually disappear within 3 or 4 weeks. Radiological and functional improvement is usually slower (several months).
A few cases of pleurisy, generally associated with interstitial pneumonitis, have been reported.
Very rare: Bronchospasm, particularly in asthmatic patients.
Acute respiratory distress syndrome, occasionally with fatal outcome, occurring sometimes immediately after surgery (a possible interaction with high oxygen doses has been suggested) (see Precautions).
Not known (cannot be estimated from the available data): Cases of pulmonary hemorrhage, sometimes revealed by hemoptysis, have been reported. These pulmonary effects often occur along with amiodarone-induced pneumonitis.
Nervous system disorders: Common: Tremor or other extrapyramidal symptoms, sleep disorders, including nightmares, Peripheral sensorimotor or mixed neuropathy.
Uncommon: Myopathy.
Peripheral sensorimotor or mixed neuropathy or myopathy may occur after just a few months of treatment, but sometimes after several years. These disorders are generally reversible on treatment discontinuation. However, recovery may be incomplete, very slow and occur only several months after treatment discontinuation.
Very rare: Cerebellar ataxia, Benign intracranial hypertension, headache. The onset of isolated headaches requires investigation for an underlying disease.
Not known: Syndrome parkinsonism, parosmia.
Hepatobiliary disorders: Cases of liver damage, diagnosed based on elevated serum transaminases, have been reported as follows: Very common: Generally moderate, isolated elevation in transaminases (1.5 to 3 times normal range) resolving after dose reduction, or even spontaneously.
Common: Acute liver damage with high serum transaminases and/or jaundice, sometimes with fatal outcome, requiring treatment discontinuation.
Very rare: Chronic liver damage during prolonged treatment.
Histological findings are consistent with pseudoalcoholic 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 damage 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, the course was irreversible.
Cardiac disorders: Common: Generally moderate, dose-dependent bradycardia.
Uncommon: Conduction disorders (sinoatrial block, atrioventricular block of varying degrees).
Very rare: Marked bradycardia and, more exceptionally, sinus arrest, reported in certain cases (sinus dysfunction, elderly patients).
Not known: Torsades de pointes (see Precautions and Interactions).
Gastrointestinal disorders: Very common: Mild gastrointestinal disorders (nausea, vomiting, dysgeusia), usually occurring during initial treatment and resolving on dose reduction.
Not known: Pancreatitis/acute pancreatitis, dry mouth, constipation.
Breast and reproductive system disorders: Very rare: Epididymitis. A causal relationship with the medicinal product has apparently not been established.
Not known: Loss of libido.
Vascular disorders: Very rare: Vasculitis.
Investigations: Rare: Rare cases of hyponatremia, suggestive of SIADH.
Very rare: Renal impairment with increased serum creatinine.
Blood and lymphatic system disorders: Very rare: Thrombocytopenia.
Not known: Neutropenia, agranulocytosis.
Immune system disorders: Not known: Cases of angioedema and/or urticaria have been reported.
Anaphylactic/anaphylactoid reaction, and even shock.
General disorders: Not known: Granuloma, essentially bone marrow granuloma, have been reported.
Metabolism and nutrition disorders: Not known: Decreased appetite.
Psychiatric disorders: Not known: Confusional state, delirium, hallucination.
Musculoskeletal and connective tissue disorders: Not known: Lupus syndrome.
Injury, poisoning and procedural complications: Not known: Potentially fatal primary graft dysfunction post cardiac transplant (see Precautions).
Injection: The adverse effects are presented by organ class and according to frequency, as follows: Very common (≥10%); common (≥1%, <10%); uncommon (≥0.1%, <1%); rare (≥0.01%, <0.1%); very rare (<0.01%), unknown (cannot be estimated from available data).
Cardiac disorders: Common: Bradycardia.
Very rare: Marked bradycardia and, more exceptionally, sinus arrest, reported in certain cases, particular in elderly patients, Proarrhythmic effect.
Not known: Torsades de pointes (see Precautions and Interactions).
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, reactions at the injection site, such as pain, erythema, edema, necrosis, extravasation, infiltration, inflammation, phlebitis and cellulitis.
Hepato-biliary disorders: Cases of liver damage, diagnosed based on elevated serum transaminases, have been reported, as follows: Very rare: Generally moderate, isolated elevation in transaminases (1.5 to 3 times normal range) resolving after dose reduction, or even spontaneously; Acute liver damage with high serum transaminases and/or jaundice, sometimes with fatal outcome, requiring treatment discontinuation.
Chronic liver damage during prolonged treatment (via the oral route). Histological findings are consistent with pseudoalcoholic 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 damage 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 reported cases, the course was irreversible.
Immune system disorders: Very rare: Anaphylactic shock.
Not known: Cases of angioedema 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 characterized 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 intracranial hypertension (pseudotumor cerebri).
Respiratory, thoracic and mediastinal disorders: Very rare: Acute respiratory distress syndrome, generally associated with interstitial pneumonitis, occasionally with fatal outcome, occurring sometimes 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 Precautions).
Bronchospasm and/or apnea in the event of severe respiratory failure, particularly in asthmatic patients.
Skin and subcutaneous tissue disorders: Very rare: Sweating, alopecia.
Not known: Eczema. Severe, sometimes fatal, cutaneous reactions such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome. Bullous dermatitis. DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).
Vascular disorders: Common: Generally moderate and transient fall in blood pressure. Cases of severe hypotension or collapse have been reported, particularly after overdose if the drug is injected too rapidly.
Very rare: Hot flushes.
Musculoskeletal and connective tissue disorders: Not known: Lower back pain, back pain.
Hematological and lymphatic system disorders: Not known: Neutropenia, agranulocytosis.
Psychiatric disorders: Not known: Confusional state, delusion, hallucination.
Reproductive system and breast disorders: Not known: Loss of libido.
Injury, poisoning and procedural complications: Not known: Potentially fatal primary graft dysfunction post cardiac transplant (see Precautions).
Drug Interactions
Antiarrhythmics: Many antiarrhythmic agents have depressant effects on cardiac automaticity, conduction and contractility.
Combined use of antiarrhythmic agents from different classes can be beneficial, but this therapeutic approach often proves problematic, and requires ECG and close clinical monitoring. Combined use of antiarrhythmic agents which induce torsades de pointes (amiodarone, disopyramide, quinidines, sotalol, etc.) is contraindicated.
Combined use of antiarrhythmic agents from the same class is not recommended, except in exceptional cases, due to the higher risk of adverse cardiac 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.
Medicinal products that may induce torsades de pointes: This serious arrhythmia can be induced by a number of medicinal products, regardless of whether they are antiarrhythmics. Hypokalemia (see Hypokalemic agents as follows) is a predisposing factor, as is bradycardia (see Bradycardia-inducing agents as follows) and a congenital or acquired pre-existing QT interval prolongation.
These medicinal products include class Ia and III antiarrhythmic agents and certain neuroleptics.
For dolasetron, erythromycin, spiramycin, and vincamine, this interaction only occurs with IV forms.
In general, using two torsadogenic drugs concomitantly 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 torsadogenic medicinal products. This concerns methadone, antiparasitic drugs (halofantrine, lumefantrine, pentamidine) and neuroleptics.
Bradycardia-inducing agents: Numerous medicinal products can induce bradycardia, particularly class Ia antiarrhythmic agents, beta-blockers, 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.
Given the long-acting effect of amiodarone, these interactions may be observed for several months after treatment discontinuation.
Effect of other medicinal products on amiodarone: CYP3A4 inhibitors and CYP2C8 inhibitors may potentially inhibit amiodarone metabolism and therefore increase exposure.
CYP3A4 inhibitors (e.g. grapefruit juice and certain medicinal products) should preferably not be used during amiodarone treatment.
Contraindicated combinations: Medicinal products that may induce torsades de pointes (apart from antiparasitic agents, neuroleptics and methadone, see Inadvisable combinations as follows); class Ia 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: Increased risk of ventricular arrhythmias, particularly torsades de pointes.
Telaprevir: Cardiac automaticity and conduction disorders with risk of excessive bradycardia.
Cobicistat: 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 as follows).
CYP3A4 substrates: Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of CYP3A4 substrates, potentially increasing the toxicity of these substrates.
Ciclosporin: Increase in blood ciclosporin concentrations, due to reduced liver metabolism, with a risk of nephrotoxic effects.
Assay of blood ciclosporin concentrations, monitoring of renal function and ciclosporin dose adjustment during amiodarone treatment should be performed.
Diltiazem injection: Risk of bradycardia and atrioventricular heart block.
If this combination cannot be avoided, close clinical supervision and continuous ECG monitoring should be performed.
Fingolimod: Potentiation of the bradycardia-inducing effects with potentially 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: 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 torsades de pointes (halofantrine, lumefantrine, pentamidine): Increased risk of ventricular arrhythmias, particularly torsades de pointes.
Discontinue one of the two treatments, if possible. If the combination cannot be avoided, monitor QT before instituting treatment and monitor ECG.
Neuroleptics that may induce torsades de pointes (amisulpride, chlorpromazine, cyamemazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sultopride, tiapride, zuclopenthixol): Increased risk of ventricular arrhythmias, particularly torsades de pointes.
Methadone: Increased risk of ventricular rhythm disorders, especially torsades de pointes.
Fluoroquinolones other than levofloxacin and moxifloxacin (contraindicated combinations): Increased risk of ventricular rhythm disorders, especially torsades de pointes.
Stimulant laxatives: Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalemia is a predisposing factor).
Correct any hypokalemia before administering the medicinal product and carry out ECG and clinical monitoring, together with electrolyte monitoring.
Fidaxomicine: Increased plasma fidaxomicine concentrations.
Combinations requiring precautions for use: P-glycoprotein substrates: Amiodarone is a P-glycoprotein (P-gp) inhibitor. Coadministration with P-gp substrates may lead to increased exposure of these substrates.
Digitalis drugs: Suppressed automaticity (excessive bradycardia) and atrioventricular conduction disorders.
If digoxin is used, blood digoxin levels can be increased due to reduced digoxin clearance, requiring ECG and clinical monitoring.
If necessary, blood digoxin levels should be monitored and the digoxin dose adjusted.
Dabigatran: 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 increases plasma concentrations of CYP2C9 substrates such as vitamin K antagonists and phenytoin.
Vitamin K antagonists: Increased vitamin K antagonist effect and increased risk of bleeding.
INR should be monitored more frequently. The vitamin K agonist dose should be adjusted during treatment with amiodarone and for 8 days after treatment discontinuation.
Phenytoin (and, by extrapolation, fosphenytoin): Increase in plasma phenytoin concentrations with signs of overdose, particularly neurological signs (decreased liver metabolism of phenytoin).
Clinical monitoring and monitoring of plasma phenytoin concentrations should be performed and, if necessary, the phenytoin dose should be adjusted.
CYP2D6 substrates: Flecainide: Amiodarone increases plasma concentrations of flecainide by inhibiting cytochrome CYP2D6. The flecainide dose should be adjusted.
CYP3A4 substrates: Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of substrates of this cytochrome, potentially increasing the toxicity of these substrates.
Statins (simvastatin, atorvastatin, lovastatin): The risk of muscle toxicity (e.g., rhabdomyolysis) is increased by concomitant administration of amiodarone as statins can be metabolized by CYP3A4. Use of another statin not affected by this type of interaction is recommended.
Other drugs metabolized by CYP3A4 (lidocaine, tacrolimus, sildenafil, midazolam, dihydroergotamine, ergotamine, colchicine, triazolam): Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of these molecules, potentially increasing the toxicity of these substances.
Lidocaine: Risk of increased lidocaine plasma 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: 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): Automaticity and conduction disorders (suppression of sympathetic compensation mechanisms).
ECG and clinical monitoring should be performed.
Beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol): Automaticity and cardiac conduction disorders with risk of excessive bradycardia.
Increased risk of ventricular arrhythmias, particularly torsades de pointes. Regular clinical and ECG monitoring should be performed.
Esmolol: Contractility, automaticity and conduction disorders (suppressed compensatory sympathetic mechanisms).
ECG and clinical monitoring should be performed.
Oral diltiazem: Risk of bradycardia or atrioventricular heart block, particularly in the elderly.
ECG and clinical monitoring should be performed.
Oral verapamil: Risk of bradycardia or atrioventricular heart block, particularly in the elderly. ECG and clinical monitoring should be performed.
Some macrolides (azithromycin, clarithromycin, roxithromycin): Increased risk of ventricular rhythm disorders, especially torsades de pointes.
ECG and clinical monitoring should be performed during combined treatment with amiodarone.
Hypokalemic agents: hypokalemic diuretics (alone or in combination), amphotericin B (IV route), glucocorticoids (systemic route), tetracosactide: Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalemia is a predisposing factor).
Correct any hypokalemia before administering the medicinal product and carry out ECG and clinical monitoring, together with electrolyte monitoring.
Bradycardic agents: Increased risk of ventricular arrhythmias, particularly torsades de pointes.
ECG and clinical monitoring should be performed.
Orlistat: Risk of decreased plasma concentrations of amiodarone and its active metabolite.
Clinical monitoring and, if necessary, ECG monitoring should be performed.
Tamsulosin: Risk of increased tamsulosin-induced adverse effects due to inhibition of its hepatic metabolism.
Clinical monitoring should be performed and the tamsulosin dose adjusted during treatment with the enzyme inhibitor and after its discontinuation, if necessary.
Voriconazole: Increased risk of ventricular arrhythmias, particularly torsades de pointes, as amiodarone metabolism may be decreased.
Clinical and ECG monitoring should be performed and the amiodarone dose adjusted if necessary.
Combinations to be taken into account: Pilocarpine: There is a risk of excessive bradycardia (cumulative bradycardia-inducing effects).
Combined use of antiarrhythmic agents from different classes can be beneficial, but this therapeutic approach often proves problematic, and requires ECG and close clinical monitoring. Combined use of antiarrhythmic agents which induce torsades de pointes (amiodarone, disopyramide, quinidines, sotalol, etc.) is contraindicated.
Combined use of antiarrhythmic agents from the same class is not recommended, except in exceptional cases, due to the higher risk of adverse cardiac 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.
Medicinal products that may induce torsades de pointes: This serious arrhythmia can be induced by a number of medicinal products, regardless of whether they are antiarrhythmics. Hypokalemia (see Hypokalemic agents as follows) is a predisposing factor, as is bradycardia (see Bradycardia-inducing agents as follows) and a congenital or acquired pre-existing QT interval prolongation.
These medicinal products include class Ia and III antiarrhythmic agents and certain neuroleptics.
For dolasetron, erythromycin, spiramycin, and vincamine, this interaction only occurs with IV forms.
In general, using two torsadogenic drugs concomitantly 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 torsadogenic medicinal products. This concerns methadone, antiparasitic drugs (halofantrine, lumefantrine, pentamidine) and neuroleptics.
Bradycardia-inducing agents: Numerous medicinal products can induce bradycardia, particularly class Ia antiarrhythmic agents, beta-blockers, 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.
Given the long-acting effect of amiodarone, these interactions may be observed for several months after treatment discontinuation.
Effect of other medicinal products on amiodarone: CYP3A4 inhibitors and CYP2C8 inhibitors may potentially inhibit amiodarone metabolism and therefore increase exposure.
CYP3A4 inhibitors (e.g. grapefruit juice and certain medicinal products) should preferably not be used during amiodarone treatment.
Contraindicated combinations: Medicinal products that may induce torsades de pointes (apart from antiparasitic agents, neuroleptics and methadone, see Inadvisable combinations as follows); class Ia 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: Increased risk of ventricular arrhythmias, particularly torsades de pointes.
Telaprevir: Cardiac automaticity and conduction disorders with risk of excessive bradycardia.
Cobicistat: 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 as follows).
CYP3A4 substrates: Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of CYP3A4 substrates, potentially increasing the toxicity of these substrates.
Ciclosporin: Increase in blood ciclosporin concentrations, due to reduced liver metabolism, with a risk of nephrotoxic effects.
Assay of blood ciclosporin concentrations, monitoring of renal function and ciclosporin dose adjustment during amiodarone treatment should be performed.
Diltiazem injection: Risk of bradycardia and atrioventricular heart block.
If this combination cannot be avoided, close clinical supervision and continuous ECG monitoring should be performed.
Fingolimod: Potentiation of the bradycardia-inducing effects with potentially 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: 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 torsades de pointes (halofantrine, lumefantrine, pentamidine): Increased risk of ventricular arrhythmias, particularly torsades de pointes.
Discontinue one of the two treatments, if possible. If the combination cannot be avoided, monitor QT before instituting treatment and monitor ECG.
Neuroleptics that may induce torsades de pointes (amisulpride, chlorpromazine, cyamemazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sultopride, tiapride, zuclopenthixol): Increased risk of ventricular arrhythmias, particularly torsades de pointes.
Methadone: Increased risk of ventricular rhythm disorders, especially torsades de pointes.
Fluoroquinolones other than levofloxacin and moxifloxacin (contraindicated combinations): Increased risk of ventricular rhythm disorders, especially torsades de pointes.
Stimulant laxatives: Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalemia is a predisposing factor).
Correct any hypokalemia before administering the medicinal product and carry out ECG and clinical monitoring, together with electrolyte monitoring.
Fidaxomicine: Increased plasma fidaxomicine concentrations.
Combinations requiring precautions for use: P-glycoprotein substrates: Amiodarone is a P-glycoprotein (P-gp) inhibitor. Coadministration with P-gp substrates may lead to increased exposure of these substrates.
Digitalis drugs: Suppressed automaticity (excessive bradycardia) and atrioventricular conduction disorders.
If digoxin is used, blood digoxin levels can be increased due to reduced digoxin clearance, requiring ECG and clinical monitoring.
If necessary, blood digoxin levels should be monitored and the digoxin dose adjusted.
Dabigatran: 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 increases plasma concentrations of CYP2C9 substrates such as vitamin K antagonists and phenytoin.
Vitamin K antagonists: Increased vitamin K antagonist effect and increased risk of bleeding.
INR should be monitored more frequently. The vitamin K agonist dose should be adjusted during treatment with amiodarone and for 8 days after treatment discontinuation.
Phenytoin (and, by extrapolation, fosphenytoin): Increase in plasma phenytoin concentrations with signs of overdose, particularly neurological signs (decreased liver metabolism of phenytoin).
Clinical monitoring and monitoring of plasma phenytoin concentrations should be performed and, if necessary, the phenytoin dose should be adjusted.
CYP2D6 substrates: Flecainide: Amiodarone increases plasma concentrations of flecainide by inhibiting cytochrome CYP2D6. The flecainide dose should be adjusted.
CYP3A4 substrates: Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of substrates of this cytochrome, potentially increasing the toxicity of these substrates.
Statins (simvastatin, atorvastatin, lovastatin): The risk of muscle toxicity (e.g., rhabdomyolysis) is increased by concomitant administration of amiodarone as statins can be metabolized by CYP3A4. Use of another statin not affected by this type of interaction is recommended.
Other drugs metabolized by CYP3A4 (lidocaine, tacrolimus, sildenafil, midazolam, dihydroergotamine, ergotamine, colchicine, triazolam): Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of these molecules, potentially increasing the toxicity of these substances.
Lidocaine: Risk of increased lidocaine plasma 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: 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): Automaticity and conduction disorders (suppression of sympathetic compensation mechanisms).
ECG and clinical monitoring should be performed.
Beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol): Automaticity and cardiac conduction disorders with risk of excessive bradycardia.
Increased risk of ventricular arrhythmias, particularly torsades de pointes. Regular clinical and ECG monitoring should be performed.
Esmolol: Contractility, automaticity and conduction disorders (suppressed compensatory sympathetic mechanisms).
ECG and clinical monitoring should be performed.
Oral diltiazem: Risk of bradycardia or atrioventricular heart block, particularly in the elderly.
ECG and clinical monitoring should be performed.
Oral verapamil: Risk of bradycardia or atrioventricular heart block, particularly in the elderly. ECG and clinical monitoring should be performed.
Some macrolides (azithromycin, clarithromycin, roxithromycin): Increased risk of ventricular rhythm disorders, especially torsades de pointes.
ECG and clinical monitoring should be performed during combined treatment with amiodarone.
Hypokalemic agents: hypokalemic diuretics (alone or in combination), amphotericin B (IV route), glucocorticoids (systemic route), tetracosactide: Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalemia is a predisposing factor).
Correct any hypokalemia before administering the medicinal product and carry out ECG and clinical monitoring, together with electrolyte monitoring.
Bradycardic agents: Increased risk of ventricular arrhythmias, particularly torsades de pointes.
ECG and clinical monitoring should be performed.
Orlistat: Risk of decreased plasma concentrations of amiodarone and its active metabolite.
Clinical monitoring and, if necessary, ECG monitoring should be performed.
Tamsulosin: Risk of increased tamsulosin-induced adverse effects due to inhibition of its hepatic metabolism.
Clinical monitoring should be performed and the tamsulosin dose adjusted during treatment with the enzyme inhibitor and after its discontinuation, if necessary.
Voriconazole: Increased risk of ventricular arrhythmias, particularly torsades de pointes, as amiodarone metabolism may be decreased.
Clinical and ECG monitoring should be performed and the amiodarone dose adjusted if necessary.
Combinations to be taken into account: Pilocarpine: There is a risk of excessive bradycardia (cumulative bradycardia-inducing effects).
Caution For Usage
Injection: Incompatibilities: Use of PVC equipment or medical devices plasticized with DEHP (di-2-ethylhexyl phthalate) with amiodarone solution for injection can cause leaching out of DEHP. To minimize patient exposure to DEHP, the final amiodarone dilution before infusion should preferably be performed using DEHP-free sets.
Preparation and Handling: Because of pharmaceutical characteristics, concentrations less than 600 mg/L should not be used. Only 5% dextrose solution should be used for dilution.
Do not mix with other preparations in infusion solution.
Special precautions for disposal and other handling: Use of PVC equipment or medical devices plasticized with DEHP (di-2-ethylhexyl phthalate) with amiodarone solution for injection can cause leaching out of DEHP. To minimize patient exposure to DEHP, the final amiodarone dilution before infusion should preferably be performed using DEHP-free equipment, such as equipment made of DEHP-free PVC, polyolefins (polyethylene, polypropylene) or glass.
Preparation and Handling: Because of pharmaceutical characteristics, concentrations less than 600 mg/L should not be used. Only 5% dextrose solution should be used for dilution.
Do not mix with other preparations in infusion solution.
Special precautions for disposal and other handling: Use of PVC equipment or medical devices plasticized with DEHP (di-2-ethylhexyl phthalate) with amiodarone solution for injection can cause leaching out of DEHP. To minimize patient exposure to DEHP, the final amiodarone dilution before infusion should preferably be performed using DEHP-free equipment, such as equipment made of DEHP-free PVC, polyolefins (polyethylene, polypropylene) or glass.
Storage
Protect from light.
Tablet: Store at temperatures not exceeding 30°C.
Injection: Store at temperatures not exceeding 25°C.
Tablet: Store at temperatures not exceeding 30°C.
Injection: Store at temperatures not exceeding 25°C.
Action
Pharmacotherapeutic group: Class III Antiarrhythmic. ATC code: C01BD01.
Pharmacology: Pharmacodynamics: Antiarrhythmic properties: Lengthening of phase 3 of the cardiac action potential mainly due to a decrease in potassium channels (Vaughan Williams class III).
Injection: This effect, which is isolated, is due to slowing of the potassium channel, with no change in the sodium or calcium channels.
Bradycardia-inducing effect by reducing sinus automaticity. This effect is not antagonized by atropine; Non-competitive alpha and beta-antiadrenergic antagonism; 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 on an atria, nodal tissues and ventricles; Slowing of conduction and prolongation of refractoriness in the accessory atrioventricular pathways; Absence of negative inotropic effects (injection).
Tablet: Other properties: Decreased oxygen consumption due to a moderate decrease in peripheral resistance and reduction in heart rate.
Increase in coronary blood flow due to a direct effect on the smooth muscles of the myocardial arteries and maintenance of cardiac output due to decreased pressure and peripheral resistance and absence of any negative inotropic effects.
Data from thirteen controlled, randomized, prospective studies including 6553 patients with a recent experience of myocardial infarction (78%) or chronic heart failure (22%) were included in a meta-analysis.
Mean follow-up ranged from 0.4 to 2.5 years. Mean daily maintenance dose ranged from 200 to 400 mg.
This meta-analysis demonstrated that amiodarone significantly reduced total deaths by 13% [95% CI: 0.78 - 0.99; p = 0.030] and arrhythmia-related deaths by 29% [95% CI: 0.59 - 0.85; p = 0.0003].
However, these results must be interpreted cautiously, taking into account the heterogeneity of the studies in terms of patient population, duration of follow-up, methodology and study results.
The percentage of treatment discontinuations was higher in the amiodarone group (41%) than in the placebo group (27%).
Seven percent of the patients on amiodarone developed hypothyroidism, versus 1% in the placebo group. Hyperthyroidism was diagnosed in 1.4% of patients taking amiodarone, versus 0.5% in the placebo group.
Interstitial pneumonitis occurred in 1.6% of patients receiving amiodarone, versus 0.5% in the placebo group.
Injection: Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest: The efficacy and safety of IV amiodarone in patients with out-of-hospital cardiac arrest due to shock-resistant ventricular fibrillation were evaluated in two double-blind studies: the ARREST study, which compared amiodarone with placebo, and the ALIVE study, which compared amiodarone to lidocaine. The primary endpoint of the both studies was the proportion of patients admitted alive to hospital.
In the ARREST study, 504 patients with out-of-hospital cardiac arrest as a result of ventricular fibrillation, or pulseless ventricular tachycardia refractory to 3 or more defibrillator shocks and epinephrine were randomized to 2 groups and given either 300 mg amiodarone diluted in 20 ml 5% glucose as a rapid injection into a peripheral vein (246 patients) or placebo (258 patients). In the 197 patients (39%) who were admitted alive to hospital, amiodarone significantly increased the probability of being resuscitated and admitted to hospital: 44% in the amiodarone group versus 34% in the placebo group (p = 0.03).
After adjustment for other predictors of outcome, the adjusted odds ratio for survival to hospital admission was 1.6 (95% CI, 1.1 to 2.4; p = 0.02) in the amiodarone group, compared with the placebo group. The incidence of hypotension (59% versus 48%, p = 0.04) or bradycardia (41% versus 25%, p = 0.004) was more common in patients receiving amiodarone than in those given placebo.
In the ALIVE study, 347 patients with ventricular fibrillation refractory to 3 defibrillator shocks, epinephrine and another defibrillator shock, or with recurrence of ventricular fibrillation after initially successful defibrillation, were randomized to receive either amiodarone (5 mg/kg of estimated body weight, diluted in 30 ml 5% glucose) and a lidocaine placebo, or lidocaine (1.5 mg/kg at a concentration of 10 mg/ml) and an amiodarone placebo containing the same solvent (polysorbate 80).
In the 347 patients included in the study, amiodarone significantly increased the probability of being resuscitated and admitted to hospital: 22.8% in the amiodarone group (41 out of 180 patients) versus 12% in the lidocaine group (20 patients of 167), p = 0.009. After adjustment for other factors likely to affect survival, the adjusted odds ratio for survival to hospital admission was 2.49 (95% CI, 1.28 to 4.85; p = 0.007) in the amiodarone group compared with the lidocaine group. There was no difference between the 2 treatment groups in the number of patients requiring management of bradycardia with atropine, or of blood pressure with dopamine, or in the number of patients given lidocaine (in addition to the study medication).
The proportions of patients with asystole after defibrillation and administration of the study medication 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 1118 children with various types of arrhythmia.
The following doses were used in pediatric clinical studies: Tablet: Loading dose: 10 to 20 mg/kg/day for 7 to 10 days (i.e. 500 mg/m2/day if dose is expressed as BSA).
Maintenance dose: the minimum effective dose should be used; based on individual response, this can range from 5 to 10 mg/kg/day (i.e. 250 mg/m2/day if dose is expressed as BSA).
Injection: 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.
Pharmacokinetics: Amiodarone is mainly metabolized 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.
Pediatric 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.
Tablet: Amiodarone is a compound with slow transit and high tissue affinity. Oral bioavailability ranges from 30% to 80% (mean: 50%), depending on individuals. After a single dose, peak plasma concentrations are reached in 3 to 7 hours. Therapeutic activity is obtained, on average, within one week (from a few days to two weeks).
The half-life of amiodarone is long, with high inter-individual variability (20 to 100 days). During the first days of treatment, the medicine accumulates in most of the body's tissues, particularly in adipose tissue. Elimination begins after a few days and the input/output ratio balances out after a period of a few months, depending on the individual.
These characteristics explain the use of loading doses aimed at rapidly achieving the level of tissue impregnation required for therapeutic activity.
Part of the iodine becomes detached from the compound and is recovered in the urine as iodide; this corresponds to 6 mg/24 hours for a daily dose of 200 mg of amiodarone. The rest of the compound, i.e. the largest proportion of iodine, is excreted in the feces after passing through the liver.
The negligible urinary elimination means that the medicine can be used at usual doses in patients with impaired kidney function.
After treatment discontinuation, excretion continues for several months. The persistence of remanent activity for 10 days to a month should be taken into account.
Injection: 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.
Toxicology: Preclinical Safety Data: In a 2-year carcinogenicity study in rats, amiodarone caused an increase in the number of thyroid follicular tumors (adenomas and/or carcinomas) in both sexes at clinically relevant exposures.
Since mutagenicity findings were negative, an epigenetic rather than genotoxic mechanism has been suggested to explain induction of this type of tumor.
Studies in mice did not show any carcinomas, but dose-dependent thyroid follicular hyperplasia was observed. These effects on the thyroid in rats and mice were probably due to the effects of amiodarone on the synthesis and/or release of thyroid hormones.
These findings have little relevance to humans.
Pharmacology: Pharmacodynamics: Antiarrhythmic properties: Lengthening of phase 3 of the cardiac action potential mainly due to a decrease in potassium channels (Vaughan Williams class III).
Injection: This effect, which is isolated, is due to slowing of the potassium channel, with no change in the sodium or calcium channels.
Bradycardia-inducing effect by reducing sinus automaticity. This effect is not antagonized by atropine; Non-competitive alpha and beta-antiadrenergic antagonism; 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 on an atria, nodal tissues and ventricles; Slowing of conduction and prolongation of refractoriness in the accessory atrioventricular pathways; Absence of negative inotropic effects (injection).
Tablet: Other properties: Decreased oxygen consumption due to a moderate decrease in peripheral resistance and reduction in heart rate.
Increase in coronary blood flow due to a direct effect on the smooth muscles of the myocardial arteries and maintenance of cardiac output due to decreased pressure and peripheral resistance and absence of any negative inotropic effects.
Data from thirteen controlled, randomized, prospective studies including 6553 patients with a recent experience of myocardial infarction (78%) or chronic heart failure (22%) were included in a meta-analysis.
Mean follow-up ranged from 0.4 to 2.5 years. Mean daily maintenance dose ranged from 200 to 400 mg.
This meta-analysis demonstrated that amiodarone significantly reduced total deaths by 13% [95% CI: 0.78 - 0.99; p = 0.030] and arrhythmia-related deaths by 29% [95% CI: 0.59 - 0.85; p = 0.0003].
However, these results must be interpreted cautiously, taking into account the heterogeneity of the studies in terms of patient population, duration of follow-up, methodology and study results.
The percentage of treatment discontinuations was higher in the amiodarone group (41%) than in the placebo group (27%).
Seven percent of the patients on amiodarone developed hypothyroidism, versus 1% in the placebo group. Hyperthyroidism was diagnosed in 1.4% of patients taking amiodarone, versus 0.5% in the placebo group.
Interstitial pneumonitis occurred in 1.6% of patients receiving amiodarone, versus 0.5% in the placebo group.
Injection: Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation in patients experiencing cardiac arrest: The efficacy and safety of IV amiodarone in patients with out-of-hospital cardiac arrest due to shock-resistant ventricular fibrillation were evaluated in two double-blind studies: the ARREST study, which compared amiodarone with placebo, and the ALIVE study, which compared amiodarone to lidocaine. The primary endpoint of the both studies was the proportion of patients admitted alive to hospital.
In the ARREST study, 504 patients with out-of-hospital cardiac arrest as a result of ventricular fibrillation, or pulseless ventricular tachycardia refractory to 3 or more defibrillator shocks and epinephrine were randomized to 2 groups and given either 300 mg amiodarone diluted in 20 ml 5% glucose as a rapid injection into a peripheral vein (246 patients) or placebo (258 patients). In the 197 patients (39%) who were admitted alive to hospital, amiodarone significantly increased the probability of being resuscitated and admitted to hospital: 44% in the amiodarone group versus 34% in the placebo group (p = 0.03).
After adjustment for other predictors of outcome, the adjusted odds ratio for survival to hospital admission was 1.6 (95% CI, 1.1 to 2.4; p = 0.02) in the amiodarone group, compared with the placebo group. The incidence of hypotension (59% versus 48%, p = 0.04) or bradycardia (41% versus 25%, p = 0.004) was more common in patients receiving amiodarone than in those given placebo.
In the ALIVE study, 347 patients with ventricular fibrillation refractory to 3 defibrillator shocks, epinephrine and another defibrillator shock, or with recurrence of ventricular fibrillation after initially successful defibrillation, were randomized to receive either amiodarone (5 mg/kg of estimated body weight, diluted in 30 ml 5% glucose) and a lidocaine placebo, or lidocaine (1.5 mg/kg at a concentration of 10 mg/ml) and an amiodarone placebo containing the same solvent (polysorbate 80).
In the 347 patients included in the study, amiodarone significantly increased the probability of being resuscitated and admitted to hospital: 22.8% in the amiodarone group (41 out of 180 patients) versus 12% in the lidocaine group (20 patients of 167), p = 0.009. After adjustment for other factors likely to affect survival, the adjusted odds ratio for survival to hospital admission was 2.49 (95% CI, 1.28 to 4.85; p = 0.007) in the amiodarone group compared with the lidocaine group. There was no difference between the 2 treatment groups in the number of patients requiring management of bradycardia with atropine, or of blood pressure with dopamine, or in the number of patients given lidocaine (in addition to the study medication).
The proportions of patients with asystole after defibrillation and administration of the study medication 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 1118 children with various types of arrhythmia.
The following doses were used in pediatric clinical studies: Tablet: Loading dose: 10 to 20 mg/kg/day for 7 to 10 days (i.e. 500 mg/m2/day if dose is expressed as BSA).
Maintenance dose: the minimum effective dose should be used; based on individual response, this can range from 5 to 10 mg/kg/day (i.e. 250 mg/m2/day if dose is expressed as BSA).
Injection: 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.
Pharmacokinetics: Amiodarone is mainly metabolized 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.
Pediatric 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.
Tablet: Amiodarone is a compound with slow transit and high tissue affinity. Oral bioavailability ranges from 30% to 80% (mean: 50%), depending on individuals. After a single dose, peak plasma concentrations are reached in 3 to 7 hours. Therapeutic activity is obtained, on average, within one week (from a few days to two weeks).
The half-life of amiodarone is long, with high inter-individual variability (20 to 100 days). During the first days of treatment, the medicine accumulates in most of the body's tissues, particularly in adipose tissue. Elimination begins after a few days and the input/output ratio balances out after a period of a few months, depending on the individual.
These characteristics explain the use of loading doses aimed at rapidly achieving the level of tissue impregnation required for therapeutic activity.
Part of the iodine becomes detached from the compound and is recovered in the urine as iodide; this corresponds to 6 mg/24 hours for a daily dose of 200 mg of amiodarone. The rest of the compound, i.e. the largest proportion of iodine, is excreted in the feces after passing through the liver.
The negligible urinary elimination means that the medicine can be used at usual doses in patients with impaired kidney function.
After treatment discontinuation, excretion continues for several months. The persistence of remanent activity for 10 days to a month should be taken into account.
Injection: 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.
Toxicology: Preclinical Safety Data: In a 2-year carcinogenicity study in rats, amiodarone caused an increase in the number of thyroid follicular tumors (adenomas and/or carcinomas) in both sexes at clinically relevant exposures.
Since mutagenicity findings were negative, an epigenetic rather than genotoxic mechanism has been suggested to explain induction of this type of tumor.
Studies in mice did not show any carcinomas, but dose-dependent thyroid follicular hyperplasia was observed. These effects on the thyroid in rats and mice were probably due to the effects of amiodarone on the synthesis and/or release of thyroid hormones.
These findings have little relevance to humans.
MedsGo Class
Cardiac Drugs
Features
Brand
Cordarone
Full Details
Dosage Strength
200 mg
Drug Ingredients
- Amiodarone
Drug Packaging
Tablet 30's
Generic Name
Amiodarone Hydrochloride
Dosage Form
Tablet
Registration Number
DRP-043
Drug Classification
Prescription Drug (RX)