Amiodarone Hydrochloride 100mg Tablets

Each tablet contains 100mg Amiodarone Hydrochloride.

For a full list of excipients, see section 6.1.

Tablets

Flat white tablets,marked ''MIL 100'',with breakline.

Atrial flutter and fibrillation when other drugs cannot be used.

All types of tachyarrhythmias of paroxysmal nature including supraventricular, nodal and ventricular tachycardias and ventricular fibrillation when other drugs cannot be used.

Tachyarrhythmias associated with Wolff-Parkinson-White Syndrome.

Tablets are used for stabilisation and long-term treatment.

Paediatric population

Amiodarone hydrochloride is not currently indicated in children.

Route of administration: Oral.

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's response and well-being.

Initial Stabilisation

Treatment should be started with 200mg, 3 times a day and may be continued for 1 week. The dosage should then be reduced to 200mg, twice daily, for a further week. The high initial dose is needed in order to rapidly achieve adequate tissue levels.

Maintenance

After the initial period the dosage should be reduced to 200mg daily, or less if appropriate. The scored 100mg tablet should be used to titrate the minimum dose required to maintain control of the arrhythmia. The Maintenance dosage should be regularly reviewed, especially in rare cases where the patient may require a higher maintenance dose and where this exceeds 200mg daily.

It is particularly important that the minimum effective dosage is used and the patient is monitored regularly to detect clinical signs of excess amiodarone dosage. Therapy may then be adjusted accordingly. Side effects can result from too high a dose during maintenance therapy.

Sufficient time must be allowed for a new distribution equilibrium to be achieved between dosage adjustments (amiodarone is strongly protein-bound and has an average plasma half-life of 50 days).

Changeover from Intravenous to Oral Therapy

If patients are being switched from intravenous Amiodarone therapy, oral administration should be initiated concomitantly at the usual loading dose (200mg, 3 times a day) and then intravenous therapy gradually phased out.

Dosage reduction /withdrawal

Side effects slowly disappear as tissue levels fall. Following drug withdrawal, residual tissue-bound amiodarone may protect a patient for up to 1 month. However, the likelihood of the occurrence of arrhythmia during this period should be considered. In patients with potentially lethal arrhythmias, the long half-life is an invaluable safeguard as omission of occasional doses is not significant regarding the overall therapeutic effect.

Paediatric population

Amiodarone is not currently indicated in children and no clinical studies in paediatric populations have been undertaken. Use in this patient population is contra-indicated (see Section 4.3, 'Contra-indications').

In published uncontrolled studies, the effective doses for children were determined as:

• Loading dose: 10 to 20mg/kg/day for 7 to 10 days (or 500mg/m²/day if expressed per square metre)

• Maintenance dose: the minimum effective dosage should be used; according to individual response, it may range between 5 to 10 mg/kg/day (or 250mg/m²/day if expressed per square metre).

Elderly

It is important that the minimum effective dosage is used. Whilst there is no evidence that dosage requirements are different for the elderly, they may be more susceptible to bradycardia and conduction defects if too high a dose is employed. Particular attention should be paid it to monitoring thyroid function. (See Sections 4.3, 4.4 and 4.8, 'Contra-indications', 'Special Warnings and Precautions for Use' and 'Undesirable Effects').

Sinus bradycardia and sino-atrial 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.

Where there is evidence or history of thyroid dysfunction. A thyroid function test should be performed prior to therapy in all patients.

Known hypersensitivity to iodine or to amiodarone (one 100mg tablet contains approximately 37.5mg of iodine,) or to any of the excipients (see Section 6.1, 'List of Excipients').

The combination of amiodarone with drugs which may prolong the QT interval and thereby induce Torsades de Pointes ventricular tachycardia is contra-indicated (see Section 4.5, 'Interaction with other medicinal products').

Amiodarone is contra-indicated in pregnancy (except in exceptional circumstances) or in nursing mothers (see Section 4.6, 'Pregnancy and Lactation').

Anaesthesia: caution is advised in patients undergoing general anaesthesia, also in patients receiving high-dose oxygen therapy. Before surgery, the anaesthetist should be informed that the patient is taking amiodarone (see Sections 4.5 and 4.8, 'Interactions with other medicinal products and other forms of Interaction' and 'Undesirable Effects')

High dosage: too high a dose 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. If necessary, beta-adrenostimulants or glucagon may be given. If bradycardia is severe and symptomatic, the insertion of a pacemaker should be considered due to the long half-life of amiodarone.

Heart failure: amiodarone 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, amiodarone may be used with other appropriate therapies.

ECG changes: in patients taking amiodarone, QT interval lengthening has been seen, corresponding to prolonged repolarisation with the possible development of U and deformed T waves. These changes are evidence of its pharmacological action and do not reflect toxicity. Treatment should be discontinued in the case of onset of second or third-degree AV block, sino-atrial block, or bifascicular block. Before starting amiodarone, it is recommended that an ECG be performed and serum potassium levels be assessed. Monitoring of ECG is recommended throughout treatment.

Arrhythmias: the onset of new arrhythmias or worsening of pre-existing arrhythmias has been observed with sometimes a fatal outcome. It is difficult, to determine if this effect is due to a lack of efficacy or worsening of the pre-existing cardiac condition. Pro-arrhythmic effects generally occur in the context of drug interactions and/or electrolytic disorders (see Sections 4.5 and 4.8, 'Interactions with other medicinal products and other forms of interaction' and 'Undesirable Effects').

Hepatic effects: amiodarone may be associated with a variety of hepatic effects. In some cases, particularly following long-term therapy, the outcome of these effects has been fatal. It is advisable to monitor liver function particularly transaminases before treatment and 6-monthly thereafter.

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 no literature reports on the potentiation of hepatic adverse effects of alcohol; however, patients should be advised to moderate their alcohol intake while taking amiodarone.

Eye disorders: ophthalmological examination is recommended annually, unless blurred or decreased vision occurs in which case a complete ophthalmologic examination should be performed promptly.

Respiratory, thoracic and mediastinal disorders: patients should be carefully evaluated clinically and consideration given to chest X-rays before starting therapy. Of particular concern with patients taking amiodarone is pulmonary toxicity, the symptoms of which include dyspnoea, non-productive cough, and deterioration of general health. Pulmonary toxicity may also present as pulmonary fibrosis, pleuritis or pneumonitis, including hypersensitivity, alveolar, interstitial, or bronchiolitis obliterans organising pneumonitis. During treatment, if pulmonary toxicity is suspected, chest X-rays should be repeated and associated with lung function testing including, where possible, measurement of transfer factor. Initial radiological changes may be difficult to distinguish from pulmonary venous congestion. Pulmonary toxicity has usually been reversible following early withdrawal of amiodarone therapy, with or without corticosteroid therapy. However, some patients can deteriorate despite discontinuing amiodarone.

Endocrine disorders: amiodarone may induce hypothyroidism or hyperthyroidism, particularly in patients with a personal history of thyroid disorders. Simple monitoring of the usual biochemical tests is confusing because some tests such as free T4 and free T3 may be altered when the patient is euthyroid. Clinical and biological monitoring (including ultrasensitive TSH [usTSH]) should be performed prior to therapy in all patients and repeated at 6-monthly intervals and for several months following its discontinuation.

Amiodarone contains iodine and thus may interfere with radio-iodine uptake. There is no reason in such cases to discontinue amiodarone treatment if there is no clinical or further biological (usTSH) evidence of thyroid disease.

In life-threatening situations where clinical evidence of thyroid disorders exist, amiodarone therapy can be continued in combination with levothyroxine. The dose of levothyroxine is adjusted according to TSH levels. In the case of hyperthyroidism, therapy should be withdrawn.

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; such recoveries may sometimes, however, be incomplete.

Skin and subcutaneous tissue disorders: hypersensitivity to sunlight may occur and patients taking amiodarone should be instructed to avoid exposure to sun or if unavoidable to use adequate protection.

Drug interactions (see Section 4.5, 'Interactions with other medicinal products and other forms of Interaction')

Patients with galactose intolerance

Patients with the rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Elderly

In the elderly, heart rate may decrease markedly.

In patients with auto-immune thyroid disease, the risks of thyroid dysfunction during amiodarone therapy are greater and the elderly are at particular risk; in these groups monitoring is recommended before the start of treatment, then 6-monthly and should be continued for some months after discontinuation of treatment.

Pregnancy and lactation (see Section 4.6, 'Pregnancy and Lactation').

Some of the more important drugs that interact with amiodarone include warfarin, digoxin, phenytoin, fluoroquinolones and any drugs which prolong the QT interval.

Amiodarone raises the plasma concentrations of oral anticoagulants and phenytoin, and any other highly protein-bound drugs, through inhibition of CYP 2C9. The dose of warfarin should be reduced accordingly. More frequent monitoring of prothrombin time both during and after amiodarone treatment is recommended. Phenytoin dosage should be reduced if signs of overdosage appear, and plasma levels may be measured.

In patients already receiving digoxin, the subsequent administration of amiodarone will increase their plasma digoxin concentration levels, resulting in signs and symptoms associated with high levels of digoxin. Clinical, ECG and biological monitoring and a reduction of digoxin dosage by half are recommended. A synergistic effect on heart rate and atrioventricular conduction is also possible.

Combined therapy with any drug known to prolong the QT interval is contra-indicated (see Section 4.3, 'Contra-indications') due to the increased risk of Torsades de Pointes. They include the following:

• Class Ia anti-arrhythmic drugs e.g. quinidine, procainamide, disopyramide

• Class III anti-arrhythmic drugs e.g. sotalol, bretylium

• Intravenous erythromycin, co-trimoxazole or pentamidine injection

• Some anti-psychotics e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, amisulpride and sertindole

• Lithium and tricyclic anti-depressants e.g. doxepin, maprotiline, amitriptyline

• Certain antihistamines e.g. terfenadine, astemizole, mizolastine

• Anti-malarials e.g. quinine, mefloquine, chloroquine, halofantrine.

• Moxifloxacin

Combined therapy with the following drugs is not recommended:

• Beta blockers and certain calcium channel inhibitors (diltiazem, verapamil): potentiation of negative chronotropic properties and conduction showing effects may occur.

• Stimulant laxatives which may cause hypokalaemia, thus increasing the risk of Torsades de Pointes; other types of laxatives should be used.

Caution should be exercised over combined therapy with the following drugs which may cause hypokalaemia and/or hypomagnesaemia: diuretics, systemic corticosteriods, tetracosactide, intravenous amphotericin.

In the case of hypokalemia, corrective action should be taken and QT interval monitored.

In the case of Torsades de Points, anti-arrhythmic agents should not be given; pacing may be instituted and IV magnesium may be used.

General anaesthesia: caution is advised, also in patients receiving high dose oxygen therapy. The anaesthetist should be informed that the patient is taking Amiodarone.

Potentially severe complications have been reported in patients taking Amiodarone undergoing general anaesthesia, such as bradycardia unresponsive to atropine, hypotension, disturbances of conduction, decreased cardiac output.

A few cases of adult respiratory distress syndrome, most often in the period immediately after surgery, have been observed. A possible interaction with the high oxygen concentration may be implicated.

Fluoroquinolones

There have been rare reports of QTc interval prolongation, with or without Torsades de Pointes, in patients taking amiodarone with fluoroquinolones and as such, concomitant use of amiodarone should be avoided (concomitant use with moxifloxacin is contra-indicated).

Flecainide

Amiodarone may increase flecainide plasma levels by inhibiting CYP 2D6. It is advised to reduce the flecainide dose by 50% and to monitor the patient closely for adverse effects. Monitoring of flecainide plasma levels is strongly recommended in such circumstances.

Drugs metabolised by cytochrome P450 3A4

Amiodarone is an inhibitor of CYP 3A4 and such drugs metabolised by CYP 3A4 may obtain higher levels of plasma concentrations if co-administered with amiodarone, which may lead to possible toxicity. These include:

• Ciclosporin: plasma levels of ciclosporin may increase as much as 2-fold when used in combination. A reduction in the dose of ciclosporin may be necessary to maintain the plasma concentration within the therapeutic range.

• Other drugs metabolised by cytochrome P450 3A4: examples of such drugs are the statins, lidocaine, tacrolimus, sildenafil, fentanyl, midazolam and ergotamine.

• Simvastatin in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis and it is for this reason that if a statin is required, pravastatin should be preferred over simvastatin).

Interaction with substrates of other CYP 450 isoenzymes

In vitro studies show that amiodarone also has the potential to inhibit CYP 1A2, CYP 2C19 and CYP 2D6 through its main metabolite. When co-administered, amiodarone would be expected to increase the plasma concentration of drugs whose metabolism is dependent on these isoenzymes.

Grapefruit juice inhibits cytochrome P450 3A4 and may increase the plasma concentration of amiodarone. Grapefruit juice should be avoided during treatment with oral amiodarone.

Pregnancy

There are insufficient data on the use of amiodarone during pregnancy in humans to judge any possible toxicity. However, in view of the pharmacological properties of the drug on the foetus and its effects on the foetal thyroid gland, its administration in pregnancy should be avoided except in exceptional circumstances where the risk of risk of re-occurrence of life-threatening arrhythmias should be weighed against the possible hazard for the foetus.

Lactation

Amiodarone is excreted into the breast milk in significant quantities and breast-feeding is contra-indicated.

The ability to drive or to operate machinery may be impaired in patients with clinical symptoms of amiodarone-induced eye disorders.

No clinical trials using amiodarone have been conducted by Aurobindo..

The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention: very common ( 10%), common ( 1% and < 10%); uncommon ( 0.1% and < 1%); rare ( 0.01% and < 0.1%) and very rare (< 0.01%).

Due to possible serious adverse reactions affecting the lung, liver, thyroid gland, skin and peripheral nervous system, patients on long-term amiodarone treatment should be carefully supervised. These reactions can also be delayed.

Blood and lymphatic system disorders:

• Very rare:

- haemolytic anemia

- aplastic anaemia

- thrombocytopenia.

In patients taking amiodarone there have been incidental findings of bone marrow granulomas. The clinical significance of this is unknown.

Cardiac disorders:

• Common: bradycardia, generally moderate and dose-related.

• Uncommon:

- onset or worsening of arrhythmia, sometimes followed by cardiac arrest (see sections 4.4 and 4.5.)

- conduction disturbances (sinoatrial block, AV block of various degrees) (see section 4.4)

• Very rare: marked bradycardia or sinus arrest in patients with sinus node dysfunction and/or in elderly patients.

Endocrine disorders (see section 4.4):

• Common:

- hypothyroidism

- hyperthyroidism, sometimes fatal

• Very rare

- syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Eye disorders:

• Very common: corneal microdeposits usually limited to the 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 micro-deposits consist of complex lipid deposits and are reversible following discontinuation of treatment. The deposits are considered essentially benign and do not require discontinuation of amiodarone.

• Very rare: optic neuropathy/neuritis that may progress to blindness (see section 4.4).

Gastrointestinal disorders:

• Very common: benign gastrointestinal disorders (nausea, vomiting, dysgeusia) usually occurring with loading dosage and resolving with dose reduction.

Hepato-biliary disorders: (see section 4.4).

• Very common: isolated increase in serum transaminases, which is usually moderate (1.5 to 3 times normal range), occurring at the beginning of therapy. It may return to normal with dose reduction or even spontaneously.

• Common: acute liver disorders with high serum transaminases and/or jaundice, including hepatic failure, which are sometimes fatal

• Very rare: chronic liver disease (pseudo alcoholic hepatitis, cirrhosis), sometimes fatal.

Immune system disorders:

Angioedema (there have been some reports of angioedema, although exact frequencies are not known)

Investigations:

• Very rare: increase in blood creatinine.

Nervous system disorders:

• Common:

- extrapyramidal tremor, for which regression usually occurs after reduction of dose or withdrawal

- nightmares

- sleep disorders.

• Uncommon: peripheral sensorimotor neuropathy and/or myopathy, usually reversible on withdrawal of the drug (see section 4.4).

• Very rare:

- cerebellar ataxia, for which regression usually occurs after reduction of dose or withdrawal

- benign intracranial hypertension (pseudo- tumor cerebri)

- headache

- vertigo.

Reproductive system and breast disorders:

• Very rare:

- epididymo-orchitis

- impotence.

Respiratory, thoracic and mediastinal disorders:

• Common: pulmonary toxicity [hypersensitivity pneumonitis, alveolar/interstitial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans organising pneumonia (BOOP)], sometimes fatal (see section 4.4).

• Very rare:

- bronchospasm in patients with severe respiratory failure and especially in asthmatic patients

- surgery (possible interaction with a high oxygen concentration) (see sections 4.4 and 4.5).

Pulmonary haemorrhage (there have been some reports of pulmonary haemorrhage, although exact frequencies are not known)

Skin and subcutaneous tissue disorders:

• Very common: photosensitivity (see section 4.4).

• 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, usually non- specific

- exfoliative dermatitis

- alopecia.

Vascular disorders:

• Very rare: vasculitis

Amiodarone has been shown in animal studies to have a high LD50, hence it is unlikely that a patient will ingest an acute toxic dose. Few cases of sinus bradycardia, heart block, attacks of ventricular tachycardia, Torsades de Pointes, circulatory failure and hepatic injury have been reported. In the event of an overdose, treatment should be symptomatic; gastric lavage may be employed to reduce absorption in addition to general supportive measures. Neither amiodarone nor its metabolites are dialysable. The patient should be monitored and if bradycardia occurs, beta-adrenostimulants or glucagon may be given. Spontaneously resolving attacks of ventricular tachycardia may also occur. Due to the pharmacokinetics of amiodarone (long half-life), adequate and prolonged surveillance of the patient, particularly cardiac status, is recommended.

Pharmacotherapeutic Group:Antiarrhythmics- ATC code -C01BD01.

Amiodarone hydrochloride is an antiarrhythmic

Amiodarone is strongly protein-bound and has an average plasma half-life of 50 days. There may be considered inter-patient variation, with half-life values ranging from less than 20 days to more than 100 days having been reported. High initial doses of amiodarone, for example 600mg/day, should be given to achieve effective tissue levels as rapidly as possible. Owing to the long half-life of the drug, a maintenance dose of only 200mg/day or less is usually necessary. Sufficient time must be allowed for new distribution equilibrium to be achieved between dose adjustments.

The long half-life is a valuable safeguard for patients with potentially lethal arrhythmias as omission of occasional doses does not significantly influence the protection afforded by amiodarone.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

Lactose Monohydrate,

Pregelatinised Starch,

Povidone,

Colloidal Anhydrous Silica,

Maize Starch,

Magnesium Stearate.

Not applicable.

3 years.

Do not store above 25°C. Store in the original package.

Lithographed carton boxes containing PVC/Al blister strips of tablets. Each box contains a patient information leaflet.

Pack Size: 28 tablets.

Not applicable.

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

PL 16363/0078

9 August 2001

09/03/2012