AMIODARONE

Posology Adults:

It is particularly important that the minimum effective dose be used. In all cases the patient’s management must be judged on the individual response and well being. The following dosage regimen is generally effective.

Initial stabilisation:

Treatment should be started with 200mg, three times a day and may be continued for 1 week. The dosage should then be reduced to 200mg, twice daily for a further week.

Maintenance:

After the initial period the dosage should be reduced to 200mg daily, or less if appropriate. Rarely, the patient may require a higher maintenance dose. The maintenance dose should be regularly reviewed, especially where this exceeds 200mg daily.

General Considerations:

Initial dosing: A high dose is needed in order to achieve adequate tissue levels rapidly.

Maintenance:

Too high a dose during maintenance therapy can cause side effects which are believed to be related to high tissue levels of amiodarone and its metabolites. Amiodarone is strongly protein bound and has an average plasma half life of 50 days (reported range 20-100 days).

It follows that sufficient time must be allowed for a new distribution equilibrium to be achieved between adjustments of dosage. It is particularly important that the minimum effective dosage is used and the patient is monitored regularly to detect the clinical features of excess amiodarone dosage.

Therapy may then be adjusted accordingly.

Dosage reduction/withdrawal:

Side effects slowly disappear as tissue levels fall. Following drug withdrawal, residual tissue bound amiodarone may protect the patient for up to a month. However, the likelihood of recurrence of arrhythmia during this period should be considered.

In patients with potentially lethal arrythmias the long half life is a valuable safeguard as omission of occasional doses does not significantly influence the overall therapeutic effect.

Children:

The safety and efficacy of amiodarone in children has not been established. 2.

Elderly:

As with all patients it is important that the minimum effective dose is used. Whilst there is no evidence that dosage requirements are different for this group of patients they may be more susceptible to bradycardia and conduction defects if too high a dose is employed.

Particular attention should be paid to monitoring thyroid function. 8). Method of Administration For oral administration.

Amiodarone can cause serious adverse reactions affecting the lung, liver, thyroid gland, skin and peripheral nervous system (see below). Because these reactions can be delayed, patients on long term treatment should be carefully supervised.

01%), unknown (frequency cannot be estimated from the available data). • Blood and lymphatic system disorders Very rare: Haemolytic anaemia, aplastic anaemia, thrombocytopenia. In patients taking amiodarone there have been incidental findings of bone marrow granulomas.

The clinical significance of this is unknown.

Unknown:

Neutropenia, agranulocytosis. • Immune system disorders Very rare: Hypersensitivity reaction involving vasculitis, renal involvement with moderate elevation of creatinine levels or thrombocytopenia.

Unknown:

Anaphylactic reaction, anaphylactic shock. 4).

Rarely:

Refractory thyrotoxicosis (usually sudden, severe and short lived).

Very Rare:

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) • Nervous system disorders Common: Extrapyramidal tremor (regression usually occurs after reduction of dose or withdrawal), nightmares, sleep disorders. 4).

Very rare:

Cerebellar ataxia (regression usually occurs after reduction of dose or withdrawal), benign intracranial hypertension, headache, vertigo.

Unknown:

Parkinsonism, parosmia • Eye disorders Very common: Corneal microdeposits, usually limited to the area under the pupil, which are usually only discernible by slit lamp examination. They may be associated with coloured halos in dazzling light or blurred vision.

Corneal microdeposits are lipid complexes and are reversible following discontinuation of treatment. The deposits are considered essentially benign and do not require discontinuation of amiodarone. 4). • Cardiac disorders Common: Bradycardia, generally moderate and dose related.

5).

Very rare:

Marked bradycardia or sinus arrest in patients with sinus node dysfunction and/or in elderly patients. 4).

Very rare:

Bronchospasm in patients with severe respiratory failure and especially in asthmatic patients, adult respiratory distress syndrome following surgery (possible interaction with a high oxygen concentration). 5). • Gastrointestinal disorders Very common: Benign gastrointestinal disorders (nausea, vomiting, dysgeusia, metallic taste), usually occurring with loading dosage and resolving with dose reduction.

5 to 3 times normal range) and occurs at the beginning of therapy. 4). 4). 4). 4).

Common:

Slate grey or bluish pigmentation of light exposed skin, particularly the face, in patients undergoing prolonged treatment at high daily dosages; such pigmentation slowly disappears following treatment discontinuation, eczema.

Very rare:

Erythema during the course of radiotherapy, skin rashes (usually non- specific), exfoliative dermatitis, alopecia. Unknown: severe skin reactions as toxic epidermal necrolysis (TEN), Stevens- Johnson syndrome (SJS), bullous dermatitis, Drug reaction with eosinophilia and systematic symptoms (DRESS).

• Reproductive system and breast disorders Very rare: Epididymo-orchitis, impotence. • Metabolic and nutrition disorders Unknown: Decreased appetite • Psychiatric disorders: Common: Libido decreased Unknown: Delirium (including confusion), hallucination.

4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Amiodarone can cause serious adverse reactions affecting the eyes, heart, lung, liver, thyroid gland, skin and peripheral nervous system. Patients on long term treatment should be carefully supervised because these reactions may be delayed.

The minimum effective maintenance dose should be given because undesirable effects are usually dose related. The anaesthetist should be informed that the patient is taking amiodarone before surgery. 8). • Blood disorders Amiodarone should not be used in patients with porphyria.

It should be prescribed only when the benefit outweighs the risk and in such cases treatment should be discussed with an expert centre. • Endocrine disorders Amiodarone may induce hypothyroidism or hyperthyroidism, particularly in patients with a personal history of thyroid disorders.

Clinical and biological monitoring, including ultrasensitive TSH (usTSH) should be performed prior to therapy in all patients. Monitoring should be carried out before treatment is started and at 6 monthly intervals during treatment.

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 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 thyrotrophin releasing hormone (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 and 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 TSH. Elevation of reverse T3 (rT3) may also be found. Therapy should be withdrawn in patients who develop hyperthyroidism. Clinical recovery usually occurs within a few months but severe cases, sometimes resulting in fatalities, have been reported.

Clinical recovery precedes the normalisation of thyroid function tests. Anti-thyroid drugs have been used for the treatment of severe thyroid hyperactivity. Large doses may be required initially. g. 8). • Nervous system disorders Amiodarone may induce peripheral sensorimotor neuropathy and/or myopathy.

Both these conditions may be severe. 8). • Eye disorders If blurred or decreased vision occurs, complete ophthalmological 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.

8). • Cardiac disorders Excessive dosage of amiodarone 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, amiodarone treatment should be withdrawn.

Inotropic sympathomimetics or glucagon may be given if necessary. The insertion of a pacemaker should be considered if bradycardia is severe and symptomatic because of the long half life of amiodarone. Oral amiodarone is not contraindicated in patients with latent or manifest heart failure but caution should be exercised as, occasionally, existing heart failure may be worsened.

Amiodarone may be used with other appropriate therapies in such patients. The pharmacological action of amiodarone induces QT prolongation (related to prolonged repolarisation) with the possible development of U waves and deformed T waves.

These ECG changes do not reflect toxicity. The heart rate may decrease markedly in elderly patients. Treatment should be discontinued in case of onset of second or third degree AV block, sinoatrial block or bifascicular block. Amiodarone has a weak proarrhythmic effect.

Onsets of new arrhythmias or worsening of treated arrhythmias, sometimes fatal, have been reported. It is important, but difficult, to differentiate a lack of efficacy of the drug from a proarrhythmic effect, whether or not this is associated with a worsening of the cardiac condition.

Proarrhythmic effects generally occur in the context of drug interactions and/or electrolytic disorders. An ECG should be performed and serum potassium should be measured before starting treatment with amiodarone. 8). Primary Graft Dysfunction post cardiac transplant In retrospective studies, amiodarone use in the transplant recipient prior to heart transplant has been associated with an increased risk of […]

• Known hypersensitivity to the active ingredient or any of the excipients. The amiodarone molecule contains iodine so hypersensitivity reactions to iodine are possible (one 200mg tablets contains approximately 75mg of iodine). 5) due to the increased risk of Torsades de Pointes; for example: − antiarrhythmic drugs eg: quinidine, procainamide, disopyramide.

− beta-blockers eg: sotalol − antibacterial drugs eg: parentral erythromycin, moxifloxacin, co- trimoxazole or pentamidine injection − antipsychotics eg: amisulpride, sertindole, chlorpromazine, thioridazine, pimozide, haloperidol, fluphenazine − lithium and tricyclic antidepressants eg: doxepin, maprotiline, amitriptyline − antihistamines eg: terfenadine, mizolastine − antimalarials eg: artemether/lumefantrine, chloroquine, mefloquine and quinine Amiodarone should not be used in patients with the following conditions: • sinus bradycardia and sinoatrial heart block.

In patients with severe conduction disturbances (high grade AV block, bifascicular or trifascicular block) or sinus node disease, amiodarone should be used only in conjunction with a pacemaker • evidence or history of thyroid dysfunction.

6).