SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Amiodarone Hydrochloride 200mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 200mg of amiodarone hydrochloride.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Tablet.

White, flat tablets, marked with ‘200’ on one side and a break line on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment should be initiated and normally monitored only under hospital or specialist supervision. Oral Amiodarone Hydrochloride 200mg Tablets are 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

Oral administration.

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.

Adults

It is important that the minimum effective dose be used. In each case the patient's management must be judged on the individual response and well being. The following dosage regimen is generally recommended.

Initial Stabilisation

A high dose is initially required in order to achieve adequate tissue levels rapidly. Treatment should be started with one 200mg tablet three times a day for up to a week and then reduced to one 200mg tablet twice daily for a further week.

Maintenance

After the initial period the dosage should be reduced to one 200mg tablet a day, or less if appropriate. The dosage should be titrated to the minimum required to maintain control of the arrhythmia. 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). Therefore sufficient time should be allowed for a new distribution equilibrium to be achieved between dosage adjustments. Rarely, the patient may require a higher maintenance dose. The maintenance dose should be regularly reviewed, particularly where this exceeds 200mg daily. It is especially 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

As tissue levels fall, side effects slowly disappear. 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 omission of occasional doses does not have a significant influence on the overall therapeutic effect because of the long half-life.

Elderly

Although there is no evidence that dosage requirements for this patient group are different, they may be more likely to experience bradycardia and conduction defects if too high a dose is employed.

Thyroid function should be carefully monitored especially in elderly patients. See Contra-indications, Warnings etc..

4.3 Contraindications

Known hypersensitivity to iodine, amiodarone or any of the excipients, (One 200mg tablet contains approximately 75mg iodine).

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 Hydrochloride 200mg Tablets should be used with a pacemaker.

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

Treatment with Amiodarone Hydrochloride 200mg Tablets in combination with drugs which may induce Torsades de Pointes is contra-indicated (see Drug Interactions section).

Lactation.

Pregnancy - except in exceptional circumstances (see section 4.6)

4.4 Special warnings and precautions for use

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

Amiodarone can cause serious adverse reactions affecting the eyes, heart, lung, liver, thyroid, skin and peripheral nervous system (see section 4.8). Because these reactions may be delayed, patients on long-term treatment should be carefully supervised.

Undesirable effects (see 4.8 Undesirable Effects) are usually dose related; therefore careful attention should be paid to determine the minimum effective maintenance dose in order to avoid or minimise undesirable effects.

Before surgery, the anaesthetist should be informed that the patient is taking amiodarone (see sections 4.5 and 4.8).

Cardiac disorders (see section 4.8)

Too high a dose may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm particularly in the treatment of the elderly or during digitalis therapy. Under these circumstances, treatment with Amiodarone Hydrochloride 200mg Tablets should be withdrawn. Beta-adrenostimulants or glucagon may be given if necessary. Because of the long half-life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered.

Amiodarone Hydrochloride 200mg Tablets should be used with caution in patients with latent or manifest heart failure as occasionally existing heart failure may be worsened. In such cases, Amiodarone Hydrochloride 200mg Tablets may be used with other appropriate therapies.

Heart rate may decrease markedly in the elderly.

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 Hydrochloride 200mg Tablets.

Treatment should be discontinued in case of onset of 2^nd or 3^rd 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 pro-arrhythmic effect, whether or not this is associated with a worsening of the cardiac condition. Pro-arrhythmic effects generally occur in the context of drug interactions and / or electrolytic disorders (see sections 4.5. and 4.8). Despite QT interval prolongation, amiodarone exhibits a low torsadogenic activity.

Before treatment initiation, it is recommended to perform an ECG, usTSH

assay and serum potassium measurement.

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.

Endocrine disorders (see section 4.8)

Amiodarone may induce thyroid disorders (see Undesirable Effects), particularly in patients with personal or family history of thyroid disorders. One 200 mg tablet contains approximately 75 mg of iodine. Therefore clinical and biological monitoring is recommended before starting treatment, during treatment and for several months following cessation of treatment. Serum usTSH levels should be measured when thyroid dysfunction is suspected.

Amiodarone contains iodine and may interfere with radio-iodine uptake. However, thyroid function tests (T3, T4 ultrasensitive TSH (usTSH) remains interpretable).

Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity (see Undesirable Effects).

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.

Hypothyroidis

m

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.

Hyperthyroidis

m

Hyperthyroidism may occur during amiodarone treatment, or, up to several months after discontinuation. Clinical features, such as weight loss, asthenia, restlessness, and 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 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.

1mg/kg prednisolone) may be required for several weeks.

Eye disorders (see section

4.8)

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, ophthalmological examination is recommended annually.

Hepato-biliary disorders (see section

4.8) :

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 intravenous formulations. 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 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 while taking amiodarone.

Nervous system disorders (see section

4.8) :

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 (see section

4.8) :

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. 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.

Skin and subcutaneous tissue disorders (see section

4.8)

Patients should be instructed to avoid exposure to sun and to use protective measures during therapy as patients taking amiodarone can become unduly sensitive to sunlight, which may persist after several months of discontinuation of amiodarone. In most cases symptoms are limited to tingling, burning and erythema of sun-exposed skin but severe phototoxic reactions with blistering may be seen.

Drug interactions (see section 45)

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 coadministration of amiodarone. The flecainide dose should be reduced and the patient closely monitored.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Concomitant treatment with the following drugs which prolong the QT interval is contra-indicated (see Contra-Indications section) 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

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

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

•    Certain antihistamines e.g terfenadine, astemizole, mizolastine

•    Anti-malaria’s e.g quinine, mefloquine, chloroquine, halofantrine.

•    Moxifloxacin

Drugs prolonging QT interval

Co-administration of amiodarone with drugs known to prolong the QT interval (such as clarithromycin) 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.

Concomitant use of amiodarone with fluoroquinolones should be avoided (concomitant use with moxifloxacin is contra-indicated, see above).

There have been rare reports of QTc interval prolongation, with or without torsades de pointes, in patients taking amiodarone with fluoroquinolones.

•    Drugs lowering heart rate or causing automaticity or conduction disorders Combined therapy with the following drugs is not recommended:

•    Beta blockers and heart rate lowering calcium channel inhibitors (diltiazem, verapamil); 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.

•    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 also cause hypokalaemia and/or hypomagnesaemia, e.g. diuretics, systemic corticosteroids, tetracosactide, 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.

Amiodarone raises the plasma concentrations of highly protein bound drugs, for example oral anti-coagulants and phenytoin. Therefore the dose of warfarin should be reduced accordingly. It is recommended that the prothrombin time, both during and after amiodarone treatment, should be monitored regularly. The dosage of phenytoin should be reduced if signs of overdosage appear, and plasma levels may be measured.

Administration of Amiodarone Hydrochloride 200mg Tablets to a patient already taking digoxin will result in an increased plasma digoxin concentration and thus precipitate signs and symptoms of high digoxin levels. The digoxin level usually has to be reduced and should be carefully monitored. A synergistic effect on heart rate and atrioventricular conduction is also possible.

•    General anaesthesia

Caution is advised in patients undergoing general anaesthesia, or receiving high dose oxygen therapy. In patients taking amiodarone undergoing general anaesthesia the following potentially severe complications have been reported, bradycardia unresponsive to atropine, hypotension, disturbances of conduction and decreased cardiac output. A few cases of adult respiratory distress syndrome, most often in the period immediately after surgery, have also been observed. A possible interaction with a high oxygen concentration may be implicated. The anaesthetist should be informed that the patient is taking Amiodarone Hydrochloride 200mg Tablets.

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 P-gp inhibitor. Co administration with P-gp substrates is expected to result in an increase of their exposure.

Digitalis

Administration of amiodarone to a patient already receiving digoxin will bring about an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with high digoxin levels. Clinical, ECG and biological monitoring is recommended and digoxin dosage should be halved.

A synergistic effect on heart rate and atrioventricular conduction is also possible.

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.

•    CYP 2C9 substrates

Amiodarone raises the plasma concentrations of oral anticoagulants (warfarin) and phenytoin by inhibition of CYP 2C9.

-    warfarin

The dose of warfarin should be reduced accordingly. More frequent monitoring of prothrombin time both during and after amiodarone treatment is recommended.

-    Phenytoin

Phenytoin dosage should be reduced if signs of overdosage appear (resulting in neurological signs), and plasma levels may be measured.

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:

•    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.

•    Statins: the risk of muscular toxicity is increased by concomitant administration of amiodarone with statins metabolised by CYP 3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolised by CYP 3A4 when given with amiodarone.

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

•    CYP 2D6 substrates Flecainide

Given that flecainide is mainly metabolised by CYP 2D6, by inhibiting this isoenzyme, amiodarone may increase flecainide plasma levels; 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.

Effect of other products on amiodarone

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 during treatment with amiodarone.

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

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 suggest any possible toxicity. In view of the pharmacological properties of the drug on the foetus and its effect on the foetal thyroid gland, administration of amiodarone should be avoided in pregnancy except in exceptional circumstances.

If discontinuation of Amiodarone is considered prior to conception because of the long half-life of the drug, the real risk of recurrence 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 therefore breast feeding is contra-indicated.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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%), very rare (< 0.01%), not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Very

rare:

- haemolytic anemia

- aplastic anaemia

thrombocytop enia

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.

Not known : Torsade de pointes

Endocrine disorders (see section 4.4):

Common: hypothyroidis

m

-    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 coloured 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 nonspecific

-    exfoliative dermatitis alopecia • Not known: urticaria

Vascular

disorders: • Very rare: vasculitis.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Animal studies indicate that amiodarone has a high LD₅₀, therefore it is very unlikely that a patient will ingest an acute toxic dose. In an overdose situation gastric lavage may be employed to reduce absorption in addition to general supportive measures; the patient should be carefully monitored. If bradycardia occurs beta-adrenostimulants or glucagon may be given. Spontaneously resolving attacks of ventricular tachycardia may also occur. The pharmacokinetics of amiodarone, requires that adequate and prolonged surveillance of the patient, particularly cardiac status, is employed. Neither amiodarone nor its metabolites are dialysable.

5.1 Pharmacodynamic properties

ATC Code: C01B D01

Amiodarone hydrochloride is an anti-arrhythmic.

No controlled paediatric studies have been undertaken.

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

Oral

2

-    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 250mg/m²/day if expressed per square meter

5.2 Pharmacokinetic properties

Amiodarone is strongly protein bound and the plasma half life is typically 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 Hydrochloride 200mg Tablets, for example 600mg/day, should be given initially to achieve effective tissue levels as rapidly as possible. Due 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 a new distribution equilibrium to be achieved between dosage adjustments.

In patients with potentially lethal arrhythmias the omission of occasional doses does not have a significant influence on the overall therapeutic effect because of the long half-life.

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 additional pre-clinical data of relevance to the prescriber, which is not already provided in other sections of the SPC.

6.1 List of excipients

Lactose monohydrate Maize starch Povidone (K90)

Silica, colloidal anhydrous Magnesium stearate Pregelatinised starch

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

Amiodarone Hydrochloride 200mg Tablets are supplied in PVC/aluminium blister strips of 28 or 30 tablets packed in an outer cardboard carton.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford