Amiocard Tablets

/ CTS

Initial treatment: The usual dosage regimen is 3 tablets per day, for 8 to 10 days.
In some cases, the initial treatment has involved higher doses (4 to 5 tablets per day), always for short periods and under electrocardiographic monitoring.
Maintenance treatment: Seek the minimum effective dose, which varies depending on the patient, ranging from 1/2 tablet per day (1 tablet every 2 days) to 2 tablets every day.

Coronary insufficiency arrhythmias resistant to other treatments.

– Sinus bradycardia and sinoatrial heart block without pacemaker. – Sinus node disease (Sick sinus syndrome) without a pacemaker (risk of sinus arrest).
– Severe atrioventricular conduction disorders without a pacemaker.
– Thyroid dysfunction. Thyroid function tests should be performed in all patients prior to therapy.
– Known hypersensitivity to iodine, amiodarone or to one of the excipients.
– pregnancy, unless exceptional circumstance .
– Breast-feeding women.
– Combination with medicinal products liable to induce torsades de pointes.

Amiodarone can cause serious adverse reactions affecting the eyes, heart, lung, liver, thyroid gland, skin and peripheral nervous system. Because these reactions may be delayed, patients on long-term treatment should be carefully supervised and reviewed regularly. As undesirable effects are usually dose-related, the minimum effective maintenance dose should be given.
Before surgery, the anaesthetist should be informed that the patient is taking amiodarone.
Cardiac disorders:
Too high a dosage may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm, particularly in elderly patients or during digitalis therapy. In these circumstances, the treatment should be withdrawn. If necessary, beta- adrenostimulants or glucagon may be given. Because of the long half-life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered the drug is not contra-indicated in patients with latent or manifest heart failure but caution should be exercised as, occasionally, existing heart failure may be worsened. In such cases, it may be used with other appropriate therapies.
The pharmacological action of amiodarone induces ECG changes: QT prolongation (related to prolonged repolarisation) with the possible development of U-waves and deformed T- waves; these changes do not reflect toxicity.
In the elderly, heart rate may decrease markedly.
Treatment should be discontinued in case of onset of 2nd or 3rd degree A-V block, sino-atrial block, or bifascicular block.
Amiodarone has a low pro-arrhythmic effect. Onsets of new arrhythmias or worsening of treated arrhythmias, sometimes fatal, have been reported. It is important, but difficult, to
differentiate a lack of efficacy of the drug from a proarrhythmic effect, whether or not this is associated with a worsening of the cardiac condition. Proarrhythmic effects generally occur in the context of QT prolonging factors such as drug interactions and/or electrolytic disorders. Despite QT interval prolongation, amiodarone exhibits a low torsadogenic activity.
Before starting amiodarone, it is recommended to perform an ECG and serum potassium measurement. Monitoring of ECG is recommended during treatment.
Amiodarone may increase the defibrillation threshold and/or pacing threshold in patients with an implantable cardioverter defibrillator or a pacemaker, which may adversely affect the efficacy of the device. Regular tests are recommended to ensure the proper function of the device after initiation of treatment or change in posology.
Severe Bradycardia and heart block:
Life-threatening cases of bradycardia and heart block have been observed when sofosbuvir- containing regimens are used in combination with amiodarone.
Bradycardia has generally occurred within hours to days, but later cases have been mostly observed up to 2 weeks after initiating HCV treatment.
Amiodarone should only be used in patients on sofosbuvir- containing regimen when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated.
Should concomitant use of amiodarone be considered necessary, it is recommended that patients undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on sofosbuvir- containing regimen.
All patients receiving amiodarone in combination with sofosbuvir-containing regimen should be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.
Primary graft dysfunction (PGD) post cardiac transplant: In retrospective studies, amiodarone use in the transplant recipient prior to heart transplant has been associated with an increased risk of PGD. PGD is a life-threatening complication of heart transplantation that presents as left, right or biventricular dysfunction occurring within the first 24 hours of transplant surgery for which there is no identifiable secondary cause (see section 4.8). Severe PGD may be irreversible. For patients who are on the heart transplant waiting list, consideration should be given to use an alternative antiarrhythmic drug as early as possible before transplant.
Endocrine disorders:
Amiodarone may induce hypothyroidism or hyperthyroidism, particularly in patients with a personal history of thyroid disorders. Clinical and biological [including ultrasensitive TSH (usTSH)] monitoring should be performed prior to therapy in all patients. Monitoring should be carried out during treatment, at six-monthly intervals, and for several months following its discontinuation. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular assessment is recommended. Serum usTSH level should be measured when thyroid dysfunction is suspected.
Amiodarone contains iodine and thus may interfere with radio-iodine uptake. However, thyroid function tests (free-T3, free-T4, usTSH) remain interpretable. Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, free-T3 being slightly decreased or even normal) in clinically euthyroid patients. There is no reason in such cases to discontinue amiodarone treatment if there is no clinical or further biological (usTSH) evidence of thyroid disease.
Hypothyroidism: Hypothyroidism should be suspected if the following clinical signs occur: weight gain, cold intolerance, reduced activity, excessive bradycardia. The diagnosis is supported by an increase in serum usTSH and an exaggerated TSH response to TRH. T3 and T4 levels may be low. Euthyroidism is usually obtained within 3 months following the discontinuation of treatment. In life-threatening situations, amiodarone therapy can be continued, in combination with levothyroxine. The dose of levothyroxine is adjusted according to TSH levels.
Hyperthyroidism: Hyperthyroidism may occur during amiodarone treatment, or, up to several months after discontinuation. Clinical features, such as weight loss, asthenia, restlessness, increase in heart rate, onset of arrhythmia, angina, congestive heart failure should alert the physician. The diagnosis is supported by a decrease in serum usTSH level, an elevated T3 and a reduced TSH response to thyrotropin releasing hormone. Elevation of reverse T3 (rT3) may also be found.
In the case of hyperthyroidism, therapy should be withdrawn. Clinical recovery usually occurs within a few months, although severe cases, sometimes resulting in fatalities, have been reported. Clinical recovery precedes the normalisation of thyroid function tests.
Courses of anti-thyroid drugs have been used for the treatment of severe thyroid hyperactivity; large doses may be required initially. These may not always be effective and concomitant high dose corticosteroid therapy (e.g. 1 mg/kg prednisolone) may be required for several weeks.
Eye disorders:
If blurred or decreased vision occurs, complete ophthalmologic examination including fundoscopy should be promptly performed. Appearance of optic neuropathy and/or optic neuritis requires amiodarone withdrawal due to the potential progression to blindness. Unless blurred or decreased vision occurs, opthamological examination is recommended annually.
Hepato-biliary disorders:
Amiodarone may be associated with a variety of hepatic effects, including cirrhosis, hepatitis, jaundice and hepatic failure. Some fatalities have been reported, mainly following long-term therapy, although rarely they have occurred soon after starting treatment particularly after amiodarone. It is advisable to monitor liver function particularly transaminases before treatment and six monthly thereafter. Amiodarone dose should be reduced or the treatment discontinued if the transaminases increase exceeds three times the normal range.
At the beginning of therapy, elevation of serum transaminases which can be in isolation (1.5 to 3 times normal) may occur. These may return to normal with dose reduction, or sometimes spontaneously.
Isolated cases of acute liver disorders with elevated serum transaminases and/or jaundice may occur; in such cases treatment should be discontinued.
There have been reports of chronic liver disease. Alteration of laboratory tests which may be minimal (transaminases elevated 1.5 to 5 times normal) or clinical signs (possible hepatomegaly) during treatment for longer than 6 months should suggest this diagnosis. Routine monitoring of liver function tests is therefore advised. Abnormal clinical and laboratory test results usually regress upon cessation of treatment, but fatal cases have been reported. Histological findings may resemble pseudo-alcoholic hepatitis, but they can be variable and include cirrhosis.
Although there have been no literature reports on the potentiation of hepatic adverse effects of alcohol, patients should be advised to moderate their alcohol intake.
Nervous system disorders:
Amiodarone may induce peripheral sensorimotor neuropathy and/or myopathy. Both these conditions may be severe, although recovery usually occurs within several months after amiodarone withdrawal, but may sometimes be incomplete.
Respiratory, thoracic and mediastinal disorders:
Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity (hypersensitivity pneumonitis, alveolar/interstitial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans organising pneumonitis. Presenting features can include dyspnoea (which may be severe and unexplained by the current cardiac status), non-productive cough and deterioration in general health (fatigue, weight loss and fever). The onset is usually slow but may be rapidly progressive. Whilst the majority of cases have been reported with long term therapy, a few have occurred soon after starting treatment.
Patients should be carefully evaluated clinically and consideration given to chest X-rays before starting therapy. During treatment, if pulmonary toxicity is suspected, this should be repeated and associated with lung function testing including, where possible, measurement of transfer factor. However, initial radiological changes may be difficult to distinguish from pulmonary venous congestion and high-definitions computerised tomography scans may therefore be more useful than chest x-rays in confirming a diagnosis. Pulmonary toxicity has usually been reversible following early withdrawal of amiodarone therapy, with or without corticosteroid therapy. Clinical symptoms often resolve within a few weeks followed by slower radiological and lung function improvement. Some patients can deteriorate despite discontinuing amiodarone.

Skin and subcutaneous tissue disorders:
Patients should be instructed to avoid exposure to sun and to use protective measures during therapy as patients can become unduly sensitive to sunlight, which may persist after several months of discontinuation. In most cases symptoms are limited to tingling, burning and erythema of sun-exposed skin but severe phototoxic reactions with blistering may be seen.
Severe bullous reactions:
Life-threatening or even fatal cutaneous reactions Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN). If symptoms or signs of SJS, TEN (e.g., progressive skin rash often with blisters or mucosal lesions) are present amiodarone treatment should be discontinued immediately.
Drug interactions:
Concomitant use of amiodarone is not recommended with the following drugs: beta- blockers, heart rate lowering calcium channel inhibitors (verapamil, diltiazem), stimulant laxative agents which may cause hypokalaemia.
Increased plasma levels of flecainide have been reported with co-administration of amiodarone. The flecainide dose should be reduced accordingly and the patient closely monitored.
Lactose
The drug contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ocular signs:
– Very common: Corneal microdeposits usually limited to then area under the pupil, which are usually only discernable by slit-lamp examinations. They may be associated with colored halos in dazzling light or blurred vision. Corneal microdeposits consist of complex lipid deposits and are reversible following discontinuation of treatment.
– Very rare: Optic neuropathy/neuritis that may progress to blindness
Cutaneous signs:
– Very common: photosensitivity.
– Common: Slate grey or bluish pigmentations of light-exposed skin, particularly the face in case of prolonged treatment with high daily dosages; such pigmentations slowly disappear following treatment discontinuation.
Very rare: – erythema during the course of radiotherapy,
– skin rashes, generally not very specific,
– exfoliative dermatitis,
– hair loss (alopecia).
Not known: Urticaria.
Thyroid signs:
Common: Hypothyroidism, Hyperthyroidism (sometimes fatal).
Very rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Pulmonary signs:
Common: Pulmonary toxicity (hypersensitivity pneumonitis , alveolar/interstitial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans organizing pneumonia/BOOP), sometimes fatal
Very rare: – Bronchospasm in patients with severe respiratory failure and especially, in asthmatic patients.
– Adult acute respiratory distress syndrome, sometimes fatal, sometimes immediately following surgery (a possible interaction with high doses of oxygen).
Not known: Pulmonary haemorrhage
Neurological signs:
Common: – extra-pyramidal Tremor,
– sleep disorders
– Nightmares,
Uncommon: Peripheral sensorimotor neuropathy and/or myopathy, usually reversible on withdrawal of the drug.
Very rare: – Cerebellar ataxia,
– Benign intracranial hypertension (pseudo-tumor cerebri),
– Headaches
– Vertigo
Hepatic signs:
– Very common: Generally moderate and isolated elevation in transaminases (1.5 to 3 times normal) occurring at the beginning of therapy. It may return to normal with dose reduction or even spontaneously.
– Common: Acute liver damage with elevated blood transaminases and/or jaundice, including hepatic failure, occasionally with a fatal outcome
– Very rare: chronic liver disease (pseudo alcoholic hepatitis, cirrhosis) (sometimes fetal)
Cardiac effects:
– Common: generally moderate, dose-dependent bradycardia.
– Uncommon: conduction disturbances (sino-atrial block, atrioventricular block of varying degrees). Onset or worsening of arrhythmia, sometimes followed by cardiac arrest.
– Very rare: marked bradycardia or sinus arrest in patients with sinus node dysfunction and/or in eldery patients.
Not known: Torsade de pointes
Gastrointestinal effects:
– Very common: benign gastrointestinal disturbances (nausea, vomiting, dysgeusia), usually occurring during initial treatment and disappearing when the dosage is reduced.
Effects on the reproductive system:
– Very rare: epididymitis, epididymo-orchitis, impotence
Vascular effects:
– Very rare: Vasculitis
Abnormal laboratory findings:
– Very rare: Increased serum creatinine
Effects on the blood and lymphatic system:
– Very rare: thrombocytopenia, haemolytic anemia, aplastic anaemia.
In patients taking amiodarone there have been incidental findings of bone marrow granulomas. The clinical significance of this is unknown.
Immune system disorder:
Not Known: Angioedema (there have been some reports of angioedema, although exact frequencies are not known)
General disorders:
Not Known: Granuloma, including bone marrow granuloma.

Combination with medicinal products liable to induce torsades de pointes:
– class Ia antiarrhythmics (e.g quinidine, hydroquinidine, disopyramide, bepridil)
– class III antiarrhythmics (e.g sotalol, dofetilide, ibutilide)
– Non-antiarrhythmic agents such as vincamine, some neuroleptic agents, cisapride
– Intravenous erythromycin, co-trimoxazole or pentamidine injection
– Some anti-psychotics (e.g Chlorpromazine, Thioridazine, Fluphenazine, Pimozide Haloperidol, Amisulpiride and Sertindole)
– Lithium and tricyclic anti-depressants (e.g Doxepin, Maprotiline and Amitriptyline)
– Certain antihistamines (e.g Terfenadine, Astemizole and Mizolastine)
– Anti-malarials (e.g Quinie, Mefloquine, Chloroquine and Halofantrine)
– Moxifloxacin
Drugs prolonging QT:
Co-administration of amiodarone with drugs known to prolong the QT interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase and patients should be monitored for QT prolongation.
Fluoroquinolones should be avoided in patients receiving amiodarone.
Drugs lowering heart rate or causing automaticity or conduction disorders:
Combined therapy with these drugs is not recommended.
Beta-blockers and heart rate lowering calcium channel inhibitors (Verapamil, diltiazem) as potentiation of negative chronotropic properties and conduction slowing effects may occur.
Agents which may induce hypokalaemia:
– Combined therapy with the following drugs is not recommended.
Stimulating laxative agents which may cause hypokalaemia thus increasing the risk of torsade de pointes; other types of laxatives should be used.
– Caution should be exercised when using the following drugs which may also cause hypokalaemia and/or hypomagnesaemia in combination with amiodarone:
Diuretics inducing hypokalaemia, either alone or combined
Systemic corticosteroids (gluco-, mineralo-), tetracosactide
Amphotericin B (IV)
It is necessary to prevent the onset of hypokalaemia (and to correct hypokalaemia); the QT interval should be monitored and, in case of torsade de pointes, anti-arrhythmic agents should not be given (ventricular pacing should be initiated; IV magnesium may be used).
General anaesthesia:
Caution is advised in patients undergoing general anaesthesia, or receiving high dose oxygen therapy.
Potentially severe complications have been reported in patients undergoing anaesthesia: bradycardia (unresponsive to atropine), hypotension, conduction disorders, decreased cardiac output.
Very rare cases of severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal, have been observed usually in the period immediately following surgery. A possible interaction with a high oxygen concentration may be implicated.
Effect of amiodarone on other medicinal products
Amiodarone and /or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein and may increase exposure of their substrates.
Due to the long half-life of amiodarone, interactions may be observed for several months after discontinuation of amiodarone.
PgP substrates: Amiodarone is a PgP inhibitors. Co administration with PgP substrates is expected to result in an increase of their exposure.
– Digitalis: Disturbances in automaticity (excessive bradycardia) and atrioventicular conduction (synergistic action) may occur; in addition, an increase in plasma digoxin concentrations is possible due to the decrease in digoxin clearance.
ECG, and digoxin plasma levels should be monitored, and patients should be observed for clinical signs of digitals toxicity. It may be necessary to adjust dosage of digitals treatment.
– Dabigatran: Caution should be exercised when amiodarone is co administered with dabigatran due to the risk of bleeding. It may be necessary to adjust the dosage of dabigatran as per its label.
CYP2C9 substrates: Amiodarone raises the concentrations of CYP2C9 substrates such as warfarin or phenytoin by inhibition of cytochromne P450 2C9.
– Warfarin: The combination of warfarin with amiodarone may exacerbate the effect of the oral anticoagulant thus increasing the risk of bleeding. It is necessary to monitor prothrombin (INR) levels more regulary and to adjust oral doses of anticoagulant agents both during treatment with amiodarone and after discontinuation of amiodarone treatment.
– Phynytoin: The combination of phynytoin with amiodarone may lead to phynytoin overdosage, resulting in neurological signs. Clinical monitoring should be undertaken and phynytoin dosage should be reduced as soon as overdosage signs appear; phynytoin plasma levels should be determined.
CYP2D6 substrates:
– Flecainide: Amiodarone raises plasma concentrations of flecainide by inhibition of cytochrome CYP2D6.
Therefore, flecainide dosage should be adjusted.
CYP P450 3A4 substrates: When such drugs are co-administered with amiodarone, an inhibitor of CYP 3A4, this may result in a higher level of their plasma concentrations, which may lead to a possible increase in their toxicity:
– Cyclosporin: its combination with amiodarone may increase cyclosporin plasma levels. Dosage should be adjusted.
– Fentanyl: its combination with amiodarone may enhance the pharmacologic effects of fentanyl and increase the risk of its toxicity.
– Statins: The risk of muscular toxicity is increased by concomitant administration of amiodarone with statins metabolized by CYP 3A 4 such as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolized by CYP 3A4 when given with amiodarone.
– Other drugs metabolized by CYP 3A4: lidocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine, colchicine.
Metadone: Increased risk of ventricular arrhythmias,,particularly torsades de pointes. ECG and clinical monitoring.
Orlistat: Risk of a reduction in plasma concentrations of amiodarone and of its active metabolism.
Clinical monitoring and, if necessary, ECG monitoring.
CYP3A4 inhibitors and CYP2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure.
It is recommended to avoid CYP 3A4 inhibitors (e.g. grapefruit juice and certain medicinal products) during treatment with amiodarone.
OTHER DRUG INTERACTIONS WITH AMIOCARD: Co-administration of amiodarone with sofosbuvir alone or in combination with another HCV direct acting antiviral (such as daclatasvir, simeprevir or ledipasvir) is not recommended as it may lead to serious symptomatic bradycardia.
If co-administration cannot be avoided, cardiac monitoring is recommended.

Pregnancy: In view of its effects on the fetal thyroid gland, amiodarone is contraindicated during pregnancy, except if the benefits outweigh the risks.
Lactation: Amiodarone is excreted in breast milk in significant quantities and is therefore contraindicated in breast-feeding mothers.

There is little documentation available on the acute administration of high doses of amiodarone. A few cases of sinus bradycardia, ventricular tachycardia, heart block, , torsades de pointes, circulatory failure and hepatic impairment have been reported.
Treatment must be symptomatic, gastric lavage may be employed to reduce absorption in addition to general supportive measures. Given the kinetic profile of the product, cardiac monitoring, in particular, over a sufficiently long period of time, is recommended. If bradycardia occurs beta-adrenostimulants or glucagon may be given. Spontaneously resolving attacks of ventricular tachycardia may also occur.
Amiodarone and its metabolites are not dialysable.