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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Amiodarone 200mg Tablets BP

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Amiodarone hydrochloride 200mg For excipients, see 6.1

3 PHARMACEUTICAL FORM

Tablet

White, round tablets with a breakline on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment should be initiated and normally monitored only under hospital or specialist supervision. Oral amiodarone 200mg is indicated only for the treatment of severe rhythm disorders not responding to other therapies or when other treatments cannot be used.

Tachyarrhythmias associated with Wolff-Parkinson-White Syndrome.

Atrial flutter and fibrillation when other drugs cannot be used.

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

Tablets are used for stabilisation and long term treatment.

4.2 Posology and method of administration

Amiodarone Tablets BP 200mg are for oral administration.

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

Maintenance: After the initial period the dosage should be reduced to 200 mg 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 200 mg daily.

Changeover from intravenous to oral therapy: As soon as an adequate response has been obtained, oral therapy should be initiated concomitantly at the usual loading dose (200 mg three times a day). Intravenous amiodarone should then be phased out gradually.

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 arrhythmias the long half life is a valuable safeguard as omission of occasional doses does not significantly influence the overall therapeutic effect.

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. See Contraindications and Warnings.

Paediatric population

The safety and efficacy of amiodarone in children has not been established. Currently available data are described in sections 5.1 and 5.2.

4.3 Contraindications

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.

Evidence or history of thyroid dysfunction. Thyroid function tests should be performed prior to therapy in all patients.

Known hypersensitivity to iodine or to amiodarone. (One 200 mg tablet contains approximately 75 mg iodine.)

The combination of amiodarone with drugs which may induce Torsades de Pointes is contra-indicated (see Interactions section).

4.4 Special warnings and precautions for use

Too high a dosage may lead to severe bradycardia and to conduction disturbances with the appearances 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.

Oral 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.

Amiodarone induces ECG changes: QT interval lengthening 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. 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 while taking amiodarone.

4.5 Interaction with other medicinal products and other forms of interaction

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

Amiodarone raises the plasma concentrations of highly protein bound drugs, for example oral anticoagulants and phenytoin. 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.

Administration of amiodarone to a patient already receiving digoxin will bring an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with high digoxin levels. Monitoring is recommended and digoxin dosage usually has to be reduced. A synergistic effect on heart rate and atrioventricular conduction is also possible.

Combined therapy with the following drugs which prolong the QT interval is contraindicated due to the increased risk of Torsades de Pointes; for example:

—    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

—    Anti-psychotics e.g. chlorpromazine, thioridazine, pimozide, haloperidol

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

—    Certain antihistamines e.g. terfenadine, astemizole

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

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 slowing effects may occur.

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

In cases of hypokalaemia, corrective action should be taken and QT interval monitored. In case of Torsades de Pointes antiarrhythmic agents should not be given; pacing may be instituted and IV magnesium may be used.

Caution is advised in patients undergoing general anaesthesia, or receiving high dose oxygen therapy.

Potentially severe complications have been reported in patients taking amiodarone undergoing general anaesthesia: 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 a high oxygen concentration may be implicated. The anaesthetist should be informed that the patient is taking amiodarone.

Amiodarone may increase the plasma levels of cyclosporin when used in combination, due to a decrease in the clearance of this drug.

4.6 Fertility, pregnancy and lactation

Pregnancy

Although no teratogenic effects have been observed in animals, 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 effect on the foetal thyroid gland, its administration in pregnancy should be avoided.

Lactation

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

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

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

Pulmonary

Amiodarone can cause pulmonary toxicity (hypersensitivity pneumonitis, alveolar/interstitial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans and organising pneumonia). Sometimes this toxicity can be fatal.

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-ray 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. 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. Clinical symptoms often resolve within a few weeks followed by slower radiological and lung function improvement. Some patients can deteriorate despite discontinuing amiodarone. A few cases of adult respiratory distress syndrome, most often in the period after surgery, have been observed, resulting sometimes in fatalities (see Interactions).

Cardiac

Bradycardia which is generally moderate and dose dependent has been reported. In some cases (sinus node disease, elderly patients) marked bradycardia or, more exceptionally, sinus arrest has occurred. There have been rare instances of conduction disturbances (sino-atrial block, various degrees of AV block). Because of the long half life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered. Amiodarone has a low proarrhythmic effect. However arrhythmia (new occurrence or aggravation), followed in some cases by cardiac arrest has been reported; with current knowledge, it is not possible to differentiate a drug effect from the underlying cardiac condition or lack of therapeutic efficacy. This has usually occurred in combination with other precipitating factors particularly other antiarrhythmic agents, hypokalaemia and digoxin.

Hepatic

Amiodarone may be associated with a variety of hepatic effects, including cirrhosis, hepatitis and jaundice. Some fatalities have been reported, mainly following longterm therapy, although rarely they have occurred soon after starting treatment, particularly after intravenous amiodarone. It is advisable to monitor liver function particularly transaminases before treatment and six 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 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 six 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. Histological findings may resemble pseudo-alcoholic hepatitis, but they can be variable and include cirrhosis.

Thyroid

Both hyper and hypothyroidism have occurred during, or soon after, amiodarone treatment. Simple monitoring of the usual biochemical tests is confusing because some tests such as free T₄ and free T₃ may be altered where the patient is euthyroid. Clinical monitoring is therefore recommended before start of treatment, then six monthly and should be continued for some months after discontinuation of treatment. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular assessment is recommended.

Hyperthyroidism

Clinical features such as weight loss, asthenia, restlessness, increase in heart rate, recurrence of the cardiac dysrhythmia, angina or congestive heart failure, should alert the clinician. The diagnosis may be supported by an elevated serum tri-iodothyronine (T₃), a low level of thyroid stimulating hormone (TSH) as measured by high sensitivity methods, and a reduced TSH response to thyrotrophin releasing hormone (TRH). 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 weeks, although severe cases, sometimes resulting in fatalities, have been reported.

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.

Hypothyroidism

Clinical features such as weight gain, reduced activity or excessive bradycardia should suggest the diagnosis. This may be supported by an elevated serum TSH level and an exaggerated TSH response to TRH. T₄ and T₃ levels may be low. Thyroid hypofunction usually resolves within three months of cessation of therapy; it may be treated cautiously with L-thyroxine. Concomitant use of amiodarone should be continued only in life threatening situations, when TSH levels may provide a guide to L-thyroxine dosage.

Ophthalmological

Patients on continuous therapy almost always develop microdeposits in the cornea. The deposits are usually only discernible by slit-lamp examinations and may rarely cause subjective symptoms such as visual haloes and blurring of vision. The deposits are considered essentially benign, do not require discontinuation of amiodarone and regress following termination of treatment. Rare cases of impaired visual acuity due to optic neuritis have been reported, although at present, the relationship with amiodarone has not been established. Unless blurred or decreased vision occurs, ophthalmological examination is recommended annually.

Dermatological

Patients taking amiodarone can become unduly sensitive to sunlight and should be warned of this possibility. In most cases, symptoms are limited to tingling, burning and erythema of sun exposed skin but severe phototoxic reactions with blistering may be seen. Photosensitivity may persist for several months after discontinuation of amiodarone. Photosensitivity can be minimised by limiting exposure to UV light, wearing suitable protective hats and clothing and by using a broad spectrum sun screening preparation. Rarely, a slate grey or bluish discoloration of light exposed skin, particularly on the face, may occur. Resolution of this pigmentation may be very slow once the drug is discontinued. Other types of skin rashes including isolated cases of exfoliative dermatitis have also been reported. Cases of erythema have been reported during radiotherapy.

Peripheral neuropathy can be caused by amiodarone. Myopathy has occasionally been reported. Both these conditions may be severe although they are usually reversible on drug withdrawal. Nightmares, vertigo, headaches, sleeplessness and paraesthesia may also occur. Tremor and ataxia have also infrequently been reported usually with complete regression after reduction of dose or withdrawal of the drug. Benign intracranial hypertension (pseudotumour cerebri) has been reported.

Other

Other unwanted effects occasionally reported include nausea, vomiting, metallic taste (which usually occur with loading dosage and which regress on dose reduction), fatigue, impotence, epididymo-orchitis and alopecia. Isolated cases suggesting a hypersensitivity reaction involving vasculitis, renal involvement with moderate elevation of creatinine levels or thrombocytopenia have been observed. Haemolytic or aplastic anaemia have rarely been reported.

4.9 Overdose

Animal studies indicate that amiodarone has a high LD₅₀, hence it is most unlikely that a patient will ingest an acute toxic dose. In such an event gastric lavage may be employed to reduce absorption in addition to general supportive measures. The patient should be monitored; 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, adequate and prolonged surveillance of the patient, particularly cardiac status, is recommended. Neither amiodarone nor its metabolites are dialysable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Amiodarone hydrochloride is an antiarrhythmic.

No controlled paediatric studies have been undertaken.

In published studies the safety of amiodarone was evaluated in 1118 paediatric patients with various arrhythmias. The following doses were used in paediatric clinical trials.

Oral

-    Loading dose: 10 to 20 mg/kg/day for 7 to 10 days (or 500 mg/m /day if expressed per square meter)

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

Intravenous

-    Loading dose: 5 mg/kg body weight over 20 minutes to 2 hours,

-    Maintenance dose: 10 to 15 mg/kg/day from few hours to several days If needed oral therapy may be initiated concomitantly at the usual loading dose.

5.2 Pharmacokinetic properties

Amiodarone is strongly protein bound and the plasma half life is usually of the order of 50 days. However there may be considerable inter-patient variation; in individual patients a half life of less than 20 days and a half life of more than 100 days has been reported. High doses of amiodarone, for example 600 mg/day, should be given initially to achieve effective tissue levels as rapidly as possible. Owing to the long half life of the drug, a maintenance dose of only 200 mg/day, or less is usually necessary. Sufficient time must be allowed for a new distribution equilibrium to be achieved between adjustments of dose.

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.

No controlled paediatric studies have been undertaken. In the limited published data available in paediatric patients, there were no differences noted compared to adults.

5.3 Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate

Maize starch

Microcrystalline cellulose Magnesium stearate

6.2    Incompatibilities

Not applicable

6.3    Shelf life

Four years

6.4    Special precautions for storage

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

6.5    Nature and contents of container

Blister consisting of hard tempered aluminium foil (20 micron) and PVC film (250 micron) containing 28 and 30 tablets in cartons.

6.6    Special precautions for disposal

Not applicable