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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Amiodarone Hydrochloride 100 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 mg amiodarone hydrochloride Excipient with known effect: Each tablet contains 48 mg of lactose For the full list of excipients: see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

White, round, biconvex tablet of diameter 8.0-8.2mm and height of 3.2-3.5mm with one-sided score notch

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses

4.1 Therapeutic indications

Treatment should be initiated and normally monitored only under hospital or specialist supervision. Oral amiodarone 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.

4.2 Posology and method of administration

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 200 mg, three times a day and may be continued for 1 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 200mg daily, or less if appropriate. Rarely, the patient may require a higher maintenance dose. The scored 100mg tablet should be used to titrate the minimum dosage required to maintain control of the arrhythmia. The maintenance dose should be regularly reviewed, especially where this exceeds 200 mg 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. 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.

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.

Paediatric population:The safety and efficacy of amiodarone in children has not been established.

Currently available data are described in section 5.1 and 5.2 but no recommendation on posology can be made.

Older people: 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 sections 4.3, 4.4 and 4.8.)

Method of administration:

Amiodarone 100mg is for oral administration.

4.3 Contraindications

Hypersensitivity to iodine or amiodarone or to any of the excipients listed in section 6.1. (One 100 mg tablet contains approximately 37.5 mg 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 should be used only in conjunction with a pacemaker.

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

Pregnancy - except in exceptional circumstances (see section 4.6) Breastfeeding (See section 4.6)

The combination of Amiodarone Tablets with drugs which may induce Torsades de Pointes is contra-indicated (see section 4.5 ).

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 because it contains lactose.

Amiodarone can cause serious adverse reactions affecting the eyes, heart, lung, liver, thyroid gland, skin and peripheral nervous system (see section 4.8.). Because these reactions may be delayed, patients on long-term treatment should be carefully supervised. As undesirable effects are usually dose-related, the minimum effective maintenance dose should be given.

Cardiac disorders (see section 4.8):

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, 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.

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 2^nd or 3^rd degree A-V block, sino-atrial block or bifascicular 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 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 (see sections 4.5. and 4.8). Despite QT interval prolongation, amiodarone exhibits a low torsadogenic activity.

Amiodarone induces ECG changes and it is recommended that an ECG and serum potassium measurement be performed before treatment initiation and during treatment: 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.

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.

Respiratory, thoracic and mediastinal disorders (see section 4.8):

Amiodarone can cause pulmonary toxicity (hypersensitivity pneumonitis, alveolar/interstitial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans 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.

Onset of dysponea or non- productive cough may be related to pulmonary toxicity (see 4.8 Undesirable Effects).

Hepatic (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 administration of 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 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 pseudoalcoholic 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 tablets.

Regular monitoring of liver function tests (transaminases) is recommended during treatment.

Dermatological (see section 4.8): Patients taking amiodarone can become unduly sensitive to sunlight which may persist after several months of discontinuation of amiodarone 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. Patients should be instructed to avoid exposure to sun or to use protective measures during therapy.

Thyroid (see section 4.8): Amiodarone may induce hypothyroidism or hyperthyroidism (see 4.8 Undesirable Effects) particularly in patients with personal or family history of thyroid disorders.

Therefore clinical and biological [including ultrasensitive TSH (usTSH)] monitoring is recommended before starting the treatment, during treatment at six-monthly intervals, and for several months following treatment discontinuation. Serum usTSH (ultrasensitive TSH) level should be measured when thyroid dysfunction is suspected.

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. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular assessment is recommended.

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.

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

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, recurrence of the cardiac dysrhythmia, onset of arrhythmia, angina or congestive heart failure, should alert the clinician. The diagnosis may be supported by elevated serum triiodothyronine (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 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.

Hypothyroidism: Clinical features such as weight gain, cold intolerance, reduced activity or excessive bradycardia should suggest the diagnosis. This may be supported by an elevated serum us TSH level and an exaggerated TSH response to TRH. T₄ and T₃ levels may be low.

Thyroid hypofunction (Euthyroidism) usually obtained within 3 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.

Before treatment initiation, it is recommended to perform an ECG, usTSH assay and serum potassium measurement.

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.

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, opthamological examination is recommended annually

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

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.

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 4.5)

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 accordingly and the patient closely monitored (see section 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction).

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 by 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 (resulting in neurological signs), and plasma levels may be measured.

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 usually has to be reduced/halved. A synergistic effect on heart rate and atrioventricular conduction, is also possible.

Phamacodynamic interactions

Drugs inducing Torsade de Pointes or prolonging QT Drugs inducing Torsade de Pointes

Combined therapy with the following drugs which prolong the QT interval is contra-indicated (see section 4.3) 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, 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 - 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). There have been rare reports of QTc interval prolongation, with or without torsades de pointes, in patients taking amiodrone with fluoroquinolones (see section 4.3).

Drugs lowering heart rate or causing automaticity or conduction disorders

Fluoroquinolones

There have been rare reports of QTc interval prolongation, with or without torsades de pointes, in patients taking amiodarone with fluoroquinolones. Concomitant use of amiodarone with fluoroquinolones should be avoided (concomitant use with moxifloxacin is contra-indicated, see above

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:.

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    hypocalcaemia, hypokalaemia and/or

hypomagnesaemia: diuretics,    systemic corticosteroids, tetracosactrin,

intravenous amphotericin.

In cases of hypocalcaemia/ 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, sometimes fatal most often in the period immediately after surgery, have been observed. A possible interaction with a high oxygen concentration may be implicated.

Interaction with substrates of other CYP 450 isoenzymes In vitro studies show that amiodarone and/or its metabolite, desethylamiodarone also has the potential to inhibit CYP1A1, CYP3A4, CYP 1A2, CYP 2C19 CYP 2D6 and P- Glycoprotein and may increase exposure of their substrates through its main metabolite. When co-administered, amiodarone would be expected to increase the plasma concentration of drugs whose metabolism is dependent upon CYP 1A2,CYP 2C19 and CYP 2D6.

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.

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.

Drugs metabolised by cytochrome P450 3A4

When 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:

•    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.

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.

Drugs metabolised by CYP 2D6 substrates

Flecainide

Probable increase in flecainide plasma levels (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 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:

There are insufficient data in the use of amiodarone during pregnancy in humans to judge any possible toxicity. However, in view of its effect on the foetal thyroid gland, amiodarone is contraindicated during pregnancy except in exceptional circumstances.

If, because of the long half life of amiodarone, discontinuation of the drug is considered prior to planned conception, the real risk of recurrent of life threatening arrhythmias should be weighed against the possible hazard for the foetus.

Breast-feeding

Amiodarone is excreted into the breast milk in significant quantities and 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

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.

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).

\ Frequency Orgak System\	Very common	Common	Uncommon	Very rare	Not known
Cardiac disorders		Bradycardia which is generally moderate and dose dependent has been reported.	There have been 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. (see section 4.4) Amiodarone has a low proarrhythmic effect. However arrhythmia (new occurrence or aggravation), followed	In some cases (sinus node disease, elderly patients) marked bradycardia or more exceptionally sinus arrest has occurred.	Torsade de pointes

			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 conditions or lack of therapeutic efficacy. This has usually occurred in combination with other precipitating factors particularly other antiarrhythmic agents, hypokalaemia and digoxin. (see sections 4.4 and 4.5.)
Nervous system disorders		Nightmares, sleeplessness/ sleep disorders. Extrapyramidal tremors have also infrequently been reported usually with complete regression after reduction of dose or withdrawal of the drug.	Peripheral sensorimotor 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.	- cerebellar ataxia, for which regression usually occurs after reduction of dose or withdrawal -Benign intracranial hypertension (pseudotumour cerebri) has been reported. -vertigo, -headaches,	paraesthesi a may also occur.
Gastrointesti nal disorders	benign gastrointestinal disorders include nausea, vomiting, metallic taste, dysgeusia (which usually occur with loading dosage and which regress on dose reduction)
General disorders and administratio n site conditions					Fatigue
Blood and lymphatic system disorders:				haemolytic anemia, aplastic anaemia, thrombocytope nia.	In patients taking amiodarone there have been incidental findings of

					bone marrow granulomas . The clinical significanc e of this is unknown.
Skin and subcutaneous tissue disorders	Photosensitivity (see section 4.4) 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.	A slate grey or bluish pigmentations/ discoloration of light exposed skin, particularly on the face, may occur. in case of prolonged treatment with high daily Dosages Resolution of the 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, skin rashes, usually nonspecific, alopecia,	urticaria
Eye disorders	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 colored/ visual haloes in dazzling light 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			Optic neuropathy/ne uritis that may progress to blindness

	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, ophthalmologica l examination is recommended annually.
Respiratory, thoracic and mediastinal disorders:		Pulmonary toxicity [hypersensitivity pneumonitis, alveolar/interstit ial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans organising pneumonia (BOOP)], sometimes fatal (see section 4.4).		-A few cases of bronchospasm have been reported in patients with severe respiratory failure and especially in asthmatic patients. -A few cases of adult respiratory distress syndrome, most often in the period after surgery, (possible interaction with a high oxygen concentration) have been observed, resulting sometimes in fatalities (see 4.5 Interactions). Pulmonary haemorrhage (there have been some reports of pulmonary haemorrhage, although exact frequencies are

				not known)
Hepato biliary disorders:	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.	acute liver disorders with high serum transaminases and/or jaundice, including hepatic failure, which are sometimes fatal		chronic liver disease (pseudo alcoholic hepatitis, cirrhosis), sometimes fatal.
Endocrine disorders		hypothyroidism hyperthyroidism , sometimes fatal		syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Immune system disorders:					Angioedem a (there have been some reports of angioedem a, although exact frequencies are not known)
Investigations				increase in blood creatinine.
Vascular disorders				Isolated cases suggesting a hypersensitivit y reaction involving vasculitis

Reproductive System & Breast Disorders

impotence, epididymoorch itis

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

Little information is available regarding acute overdosage with amiodarone. 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 overdose treatment should be symptomatic, gastric lavage may be employed to reduce absorption in addition to general supportive measures. The patient should be monitored and if bradycardia occurs beta-adrenostimulatnts or glucagons may be given. 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 ATC Code C01B D01

In myocardium, amiodarone inhibits the potassium efflux during the stage III of the action potential. Thus, it selectively prolongs the duration of repolarisation and the refactory period of the action potential leading depression of ectopies and re-entry mechanisms without impairment of the contractile force of the myocardium.

The prolongation of the slow diastolic depolarisation of the pacemaker potential leads to the depression in autoimmunity in the pacemaker tissue and, consequently, to a decrease in the heart rate.

Amiodarone also exhibits a dose- dependent non-competitive alpha and beta-adrenoreceptor antagonism which is haemodynamically expressed by a dilatatory effect on coronary and other vessels and an improvement in the oxygen balance.

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/m²/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/m2/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 a 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

In a 2-year carcinogenicity study in rats, amiodarone caused an increase in thyroid follicular tumours (adenomas and/or carcinomas) in both sexes at clinical relevant exposures. Since mutagenicity findings were negative, an epigenic rather than genotoxic mechanism is proposed for this type of tumour induction. In the mouse, carcinomas were not observed, but a dose-dependent thyroid follicular hyperplasia was seen. These effects on the thyroid in rats and mice are most likely due to effects of amiodarone on the synthesis and/or

release of thyroid gland hormones. The relevance of these findings to man is low

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Maize starch Polyvidone

Colloidal silicon dioxide Magnesium stearate

6.2 Incompatibilities

None

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Do not store above 30^oC.

Keep blisters in the outer carton.

6.5    Nature and contents of container

The tablets are packed in polypropylene /aluminium blisters and inserted into a carton. Pack sizes: 28 or 30 tablets.

Not all packs sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.