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| نشرة الممارس الصحي | نشرة معلومات المريض بالعربية | نشرة معلومات المريض بالانجليزية | صور الدواء | بيانات الدواء |
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Prevention of recurrence of:
• life-threatening ventricular tachycardia; 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 Section 5.1).
Posology
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 1/2 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 Sections 5.1.
and 5.2. for currently available data.
Method of administration
Oral route.
Cardiac disorders:
• An ECG must be performed before starting treatment.
• In the elderly, heart rate may decrease markedly.
• Amiodarone induces ECG changes. These “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 Section 4.8).
• 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 Sections 4.5 and 4.8). The risk of drug-induced torsades de pointes seems lower with amiodarone than with 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 Section 4.8).
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 Section 4.8).
Liver disorders:
Monitoring of liver function is recommended at the start of treatment, then regularly throughout amiodarone treatment (see Section 4.8).
Neuromuscular disorders:
Amiodarone can cause peripheral sensorimotor or mixed neuropathy and myopathy (see Section
4.8).
Eye disorders:
If blurred vision or decreased vision occurs, a complete ophthalmological 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 Section 4.8).
Severe skin disorders.
Life-threatening or even fatal cutaneous reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. Should signs or symptoms indicative of these conditions (e.g. progressive skin rash with blisters or mucosal lesions) occur, amiodarone treatment should be discontinued immediately.
Severe bradycardia
Severe, potentially life-threatening bradycardia and severe conduction disorders have been reported when amiodarone is coadministered with an antiviral combination based on sofosbuvir and another direct-acting antiviral drug (DAA) for hepatitis C, such as daclatasvir, simeprevir or ledipasvir. As a result, coadministration with amiodarone is not recommended.
If concomitant use with amiodarone cannot be avoided, patients should be closely monitored on treatment initiation with sofosbuvir in combination with other DAAs. Appropriate, continuous monitoring should be performed in patients known to be at high risk for bradyarrhythmia for at least 48 hours after sofosbuvir treatment initiation.
Due to the long half-life of amiodarone, appropriate examination should also be carried out in patients who have discontinued the drug within the past few months prior to treatment with sofosbuvir alone or in combination with other DAAs.
Patients receiving these hepatitis C medicines concomitantly with amiodarone, with or without other medicines that lower heart rate, should be warned of the symptoms caused by bradycardia and severe conduction disorders and should be advised to seek medical advice if they experience them.
Drug interactions
Use in combination (see Section 4.5.) with:
• beta-blockers other than sotalol (contraindicated combination) and esmolol (combination requiring precautions for use),
• verapamil and diltiazem, should only be considered for the prevention of life-threatening ventricular arrhythmias.
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 Section 4.5).
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
• 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.
o Hypokalemia should be corrected before initiation of amiodarone therapy.
• The adverse effects mentioned below 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 or to use sun 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.
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.
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 Section 4.8).
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") is a predisposing factor, as is bradycardia (see "Bradycardia-inducing agents") 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”): + 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
Only in patients receiving dual therapy with daclatasvir/sofosbuvir or ledipasvir/sofosbuvir: Bradycardia, possibly symptomatic or even fatal.
If use in combination cannot be avoided, close clinical monitoring and ECG are required, particularly during the first few weeks of dual therapy.
+ 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 inbibition 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).
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 the use of this medicinal product beyond this period may cause fetal hypothyroidism or even clinical fetal hypothyroidism (goiter).
Consequently, use of this medicinal product is contraindicated from the 2nd trimester of pregnancy.
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, breastfeeding is contraindicated during treatment with this medicinal product.
Not applicable.
The adverse effects are presented by system 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%); not known (cannot be estimated from the 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 funduscopy, 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".
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 Section 4.4).
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 Sections 4.4 and 4.5). 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.
Reporting of suspected adverse reactions
To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o Toll free phone: 8002490000 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc |
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com
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. Treatment must be symptomatic. Due to the pharmacokinetics of the drug, prolonged surveillance of the patient, particularly cardiac status, is recommended. Amiodarone and its metabolites are not dialyzable.
Pharmacotherapeutic group: CLASS III ANTIARRHYTHMIC, ATC code: C01BD01.
Antiarrhythmic properties:
• Lengthening of phase 3 of the cardiac action potential mainly due to a decrease in potassium channels (Vaughan Williams class III);
• Bradycardia-inducing effect by reducing sinus automaticity. This effect is not antagonized by atropine;
• Non-competitive alpha and beta-adrenergic antagonism;
• Slowing of sinoatrial, atrial and nodal conduction, which is more pronounced as heart rhythm becomes more rapid;
• No changes in intraventricular conduction;
• Prolongation of refractoriness and decreased myocardial excitability in the atria, nodal tissues and ventricles;
• Slowing of conduction and prolongation of refractoriness in the accessory atrioventricular pathways.
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.
Pediatric 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:
• 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).
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.
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.
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.
Lactose, maize starch, povidone, colloidal silica (anhydrous), magnesium stearate.
Not applicable.
Do not store above 30°C.
30 tablets in (PVC/aluminum) blisters. 50 tablets in (PVC/aluminum) blisters.
100 tablets in (PVC/aluminum) blisters.
No special requirements.
