Amiodaron HCl Apotex

Treatment should be initiated and normally monitored only under hospital or specialist supervision. Oral Amiodaron HCl Apotexe is indicated only for the treatment of severe rhythm disorders not responding to other therapies or when other treatment 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.

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.

Tachyarrhythmia 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.

Treatment should be initiated and normally monitored only under hospital or specialist supervision. Oral Amiodaron HCl Apotex X 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.

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 regiment is generally effective:

Initial stabilisation:

Treatment should be started with 200mg, three times a day and may be continued for 1 week.

The dosage should then be reduced to 200mg twice daily for a further week.

Maintenance:

After the initial period the dosage should be reduced to 200mg daily, or less if appropriate.

Rarely, the patient may require a higher maintenance dose. The 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 200mg daily.

General considerations

Initial dosing:

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

Maintenance:

Too high a dose during maintenance therapy can cause side effects which are believed to be related to high tissue levels of Amiodaron HCl Apotexe and its metabolites.

Amiodaron HCl Apotexe is strongly protein bound and has an average plasma half-life of 50 days (reported range 20 to 100days). 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 Amiodaron HCl Apotexe dosage. Therapy may then be adjusted accordingly.

Dosage reduction/withdrawal

Side effects slowly disappear as tissue levels fall. Following drug withdrawal, residual tissue bound Amiodaron HCl Apotexe 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 Amiodaron HCl Apotexe in children has not been established.

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..

Amiodaron HCl Apotexe is 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 200mg, three times a day and may be continued for 1 week. The dosage should then be reduced to 200mg, twice daily for a further week.

Maintenance

After the initial period the dosage should be reduced to 200mg daily, or less if appropriate. Rarely, the patient may require a higher maintenance dose. The 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 200mg 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 (200mg 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 to 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.

Paediatric population

Elderly

As with all patients it is important that the minimum effective dose is used.4 Special warnings and special precautions for use.

Amiodarone is 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 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 200 mg daily, or less if appropriate. Rarely, the patient may require a higher maintenance dose. The scored 100 mg 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.

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.

Amiodaron HCl Apotex X 100 is for oral administration.

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, Amiodaron HCl Apotexe should be used only in conjunction with a pacemaker.

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

The combination of Amiodaron HCl Apotexe with drugs which may induce Torsades de Pointes is contra- indicated.

Pregnancy - except in exceptional circumstances

Lactation .

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 100mg tablet contains approximately 37.5mg iodine), or to any of the excipients.

The combination of amiodarone with drugs which may induce Torsades de Pointes is contra-indicated (see 4.5 Interaction with other medicinal products and other forms of interaction).

Pregnancy - except in exceptional circumstances

Lactation .

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, Amiodaron HCl Apotex X should be used only in conjunction with a pacemaker.

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

Known hypersensitivity to iodine or to amiodarone, or to any of the excipients. (One 100 mg tablet contains approximately 37.5 mg iodine).

Pregnancy - except in exceptional circumstances .

Lactation .

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

Amiodaron HCl Apotexe can cause serious adverse reactions affecting the eyes, heart, lung, liver, thyroid gland, skin and peripheral nervous system. 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.

Before surgery, the anaesthetist should be informed that the patient is taking Amiodaron HCl Apotexe .

Cardiac disorders :

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, Amiodaron HCl Apotexe treatment should be withdrawn. If necessary, beta-adrenostimulants or glucagon may be given. Because of the long half-life of Amiodaron HCl Apotexe, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered.

Oral Amiodaron HCl Apotexe is not contraindicated in patients with latent or manifest heart failure but caution should be exercised as, occasionally, existing heart failure may be worsened. In such cases, Amiodaron HCl Apotexe may be used with other appropriate therapies.

The pharmacological action of Amiodaron HCl Apotexe 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.

Amiodaron HCl Apotexe 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 drug interactions and/or electrolytic disorders. Despite QT interval prolongation, Amiodaron HCl Apotexe exhibits a low torsadogenic activity.

Before starting Amiodaron HCl Apotexe, it is recommended to perform an ECG and serum potassium measurement. Monitoring of ECG is recommended during treatment.

Amiodaron HCl Apotexe 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.

Severe Bradycardia :

Cases of severe, potentially life-threatening bradycardia and heart block have been observed when Amiodaron HCl Apotexe is used in combination with sofosbuvir in combination with another hepatitis C virus (HCV) direct acting antiviral (DAA), such as daclatasvir, simeprevir, or ledipasvir. Therefore, coadministration of these agents with Amiodaron HCl Apotexe is not recommended.

If concomitant use with Amiodaron HCl Apotexe cannot be avoided, it is recommended that patients are closely monitored when initiating sofosbuvir in combination with other DAAs. Patients who are identified as being at high risk of bradyarrhythmia should be continuously monitored for at least 48 hours in an appropriate clinical setting after initiation of the concomitant treatment with sofosbuvir.

Patients receiving these hepatitis C medicines with Amiodaron HCl Apotexe, with or without other medicines that lower heart rate, should be warned of the symptoms of bradycardia and heart block and should be advised to seek urgent medical advice if they experience them.

Endocrine disorders

Amiodaron HCl Apotexe may induce hypothyroidism or hyperthyroidism, particularly in patients with a personal history of thyroid disorders. Clinical and biological [including ultrasensitive TSH (usTSH)] monitoring should be performed prior to therapy in all patients. Monitoring should be carried out during treatment, at six-monthly intervals, and for several months following its discontinuation. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular assessment is recommended. Serum usTSH level should be measured when thyroid dysfunction is suspected.

Amiodaron HCl Apotexe contains iodine and thus may interfere with radio-iodine uptake. However, thyroid function tests (free-T3, free-T4, usTSH) remain interpretable. Amiodaron HCl Apotexe 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 Amiodaron HCl Apotexe treatment if there is no clinical or further biological (usTSH) evidence of thyroid disease.

Hypothyroidism

Hypothyroidism should be suspected if the following clinical signs occur: weight gain, cold intolerance, reduced activity, excessive bradycardia. The diagnosis is supported by an increase in serum usTSH and an exaggerated TSH response to TRH. T₃ and T₄ levels may be low. Euthyroidism is usually obtained within 3 months following the discontinuation of treatment. In life-threatening situations, Amiodaron HCl Apotexe therapy can be continued, in combination with levothyroxine. The dose of levothyroxine is adjusted according to TSH levels.

Hyperthyroidism

Hyperthyroidism may occur during Amiodaron HCl Apotexe treatment, or, up to several months after discontinuation. Clinical features, such as weight loss, asthenia, restlessness, increase in heart rate, onset of arrhythmia, angina, 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

If blurred or decreased vision occurs, complete ophthalmologic examination including fundoscopy should be promptly performed. Appearance of optic neuropathy and/or optic neuritis requires Amiodaron HCl Apotexe withdrawal due to the potential progression to blindness. Unless blurred or decreased vision occurs, opthamological examination is recommended annually.

Hepato-biliary disorders :

Amiodaron HCl Apotexe 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 Amiodaron HCl Apotexe intravenous. It is advisable to monitor liver function particularly transaminases before treatment and six monthly thereafter. Amiodaron HCl Apotexe dose should be reduced or the treatment discontinued if the transaminases increase exceeds three times the normal range.

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 Amiodaron HCl Apotexe tablets.

Nervous system disorders :

Amiodaron HCl Apotexe may induce peripheral sensorimotor neuropathy and/or myopathy. Both these conditions may be severe, although recovery usually occurs within several months after Amiodaron HCl Apotexe withdrawal, but may sometimes be incomplete.

Respiratory, thoracic and mediastinal disorders :

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 Amiodaron HCl Apotexe 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 Amiodaron HCl Apotexe tablets.

Skin and subcutaneous tissue disorders

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

Severe bullous reactions:

Life-threatening or even fatal cutaneous reactions Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN). If symptoms or signs of SJS, TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present Amiodaron HCl Apotexe treatment should be discontinued immediately.

Drug interactions

Concomitant use of Amiodaron HCl Apotexe 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 co-administration of Amiodaron HCl Apotexe. The flecainide dose should be reduced accordingly and the patient closely monitored.

.

Excipient warnings

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

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 gland, skin and peripheral nervous system. 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.

Before surgery, the anaesthetist should be informed that the patient is taking amiodarone .

Cardiac disorders :

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. Because of the long half-life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered.

Amiodarone Tablets may markedly reduce the heart rate of elderly patients.

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.

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 proarrhythmic effect, whether or not this is associated with a worsening of the cardiac condition. Proarrhythmic effects generally occur in the context of drug interactions and / or electrolytic disorders.

Before starting amiodarone, it is recommended to perform an ECG and serum potassium measurement. Monitoring of ECG is recommended during treatment.

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

Amiodarone may induce hypothyroidism or hyperthyroidism, particularly in patients with a personal history of thyroid disorders. Clinical and biological [including ultrasensitive TSH (usTSH)] monitoring should be performed prior to therapy in all patients. Monitoring should be carried out during treatment, at six-monthly intervals, and for several months following its discontinuation. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular assessment is recommended. Serum usTSH level should be measured when thyroid dysfunction is suspected.

Amiodarone contains iodine and thus may interfere with radio-iodine uptake. However, thyroid function tests (free-T₃, free-T₄, usTSH) remain interpretable. Amiodarone inhibits peripheral conversion of levothyroxine (T₄) to triiodothyronine (T₃) and may cause isolated biochemical changes (increase in 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.

Hypothyroidism

Hypothyroidism should be suspected if the following clinical signs occur: weight gain, cold intolerance, reduced activity, excessive bradycardia. The diagnosis is supported by an increase in serum usTSH and an exaggerated TSH response to TRH. T₃ and T₄ levels may be low. Euthyroidism is usually obtained within 3 months following the discontinuation of treatment. In life-threatening situations, amiodarone therapy can be continued, in combination with levothyroxine. The dose of levothyroxine is adjusted according to TSH levels.

Hyperthyroidism

Hyperthyroidism may occur during amiodarone treatment, or, up to several months after discontinuation. Clinical features, such as weight loss, asthenia, restlessness, increase in heart rate, onset of arrhythmia, angina, 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

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.

Hepato-biliary disorders :

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 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 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 :

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 :

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

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

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 co-administration of amiodarone. The flecainide dose should be reduced accordingly and the patient closely monitored.

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 gland, skin and peripheral nervous system. 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.

Before surgery, the anaesthetist should be informed that the patient is taking amiodarone .

Cardiac disorders :

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, Amiodaron HCl Apotex X treatment should be withdrawn. If necessary beta-adrenostimulants or glucagon may be given. Because of the long half-life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered.

Oral Amiodaron HCl Apotex X 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, Amiodaron HCl Apotex X 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.

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. Despite QT interval prolongation, amiodarone exhibits a low torsadogenic activity.

Before starting amiodarone, it is recommended to perform an ECG and serum potassium measurement. Monitoring of ECG is recommended during treatment.

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.

Severe Bradycardia :

Cases of severe, potentially life-threatening bradycardia and heart block have been observed when amiodarone is used in combination with sofosbuvir in combination with another hepatitis C virus (HCV) direct acting antiviral (DAA), such as daclatasvir, simeprevir, or ledipasvir. Therefore, coadministration of these agents with amiodarone is not recommended.

If concomitant use with amiodarone cannot be avoided, it is recommended that patients are closely monitored when initiating sofosbuvir in combination with other DAAs. Patients who are identified as being at high risk of bradyarrhythmia should be continuously monitored for at least 48 hours in an appropriate clinical setting after initiation of the concomitant treatment with sofosbuvir.

Patients receiving these hepatitis C medicines with amiodarone, with or without other medicines that lower heart rate, should be warned of the symptoms of bradycardia and heart block and should be advised to seek urgent medical advice if they experience them.

Endocrine disorders :

Amiodarone may induce hypothyroidism or hyperthyroidism, particularly in patients with a personal history of thyroid disorders. Clinical and biological [including ultrasensitive TSH (usTSH)] monitoring should be performed prior to therapy in all patients. Monitoring should be carried out during treatment, at six-monthly intervals, and for several months following its discontinuation. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular assessment is recommended. Serum usTSH level should be measured when thyroid dysfunction is suspected.

Amiodarone contains iodine and thus may interfere with radio-iodine uptake. However, thyroid function tests (free-T₃, free-T₄, usTSH) remain interpretable. Amiodarone inhibits peripheral conversion of levothyroxine (T₄) to triiodothyronine (T₃) and may cause isolated biochemical changes (increase in 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.

Hypothyroidism:

Hypothyroidism should be suspected if the following clinical signs occur: weight gain, cold intolerance, reduced activity, excessive bradycardia. The diagnosis is supported by an increase in serum usTSH and an exaggerated TSH response to TRH. T₃ and T₄ levels may be low. Euthyroidism is usually obtained within 3 months following the discontinuation of treatment. In life-threatening situations, amiodarone therapy can be continued, in combination with levothyroxine. The dose of levothyroxine is adjusted according to TSH levels.

Hyperthyroidism:

Hyperthyroidism may occur during amiodarone treatment, or, up to several months after discontinuation. Clinical features, such as weight loss, asthenia, restlessness, increase in heart rate, onset of arrhythmia, angina, 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. 1 mg/kg prednisolone) may be required for several weeks.

Eye disorders :

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.

Hepato-biliary disorders :

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 Amiodaron HCl Apotex X intravenous. It is advisable to monitor liver function particularly transaminases before treatment and six monthly thereafter. Amiodarone dose should be reduced or the treatment discontinued if the transaminases increase exceeds three times the normal range.

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 Amiodaron HCl Apotex X.

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, but may sometimes be incomplete.

Respiratory, thoracic and mediastinal disorders :

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 Amiodaron HCl Apotex X.

Skin and subcutaneous tissue disorders :

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

Severe bullous reactions:

Life-threatening or even fatal cutaneous reactions Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN). If symptoms or signs of SJS, TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present amiodarone treatment should be discontinued immediately.

Drug interactions :

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 co-administration of amiodarone. The flecainide dose should be reduced accordingly and the patient closely monitored.

The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention: Very common (>1/10), Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very rare (<1/10,000), not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

- Very rare:

- haemolytic anemia

- aplastic anaemia

- thrombocytopenia.

In patients taking Amiodaron HCl Apotexe 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

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

- 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 :

- 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 Amiodaron HCl Apotexe.

- Very rare: optic neuropathy/neuritis that may progress to blindness.

Gastrointestinal disorders:

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

- Common: Constipation

- Uncommon: Dry mouth

- Unknown: pancreatitis/acute pancreatitis

General Disorders:

- Not known: Granuloma, including bone marrow granuloma

Hepato-biliary disorders:.

- 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:

Not known:

- Angioneurotic oedema (Quincke's Oedema)

- Anaphylactic shock/anaphylactoid reaction including shock

Investigations:

Very rare:

- increase in blood creatinine.

Metabolic and nutrition disorders

Not known:

- decreased appetite

Musculoskeletal and connective tissue disorders:

Not known:

- lupus like syndrome

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.

- Very rare:

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

- benign intracranial hypertension (pseudo- tumor cerebri)

- headache

- vertigo.

Not known:

- parkinsonism

- parosmia

Psychiatric disorders:

Not known:

- confusional state/delirium

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.

- Very rare:

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

- surgery (possible interaction with a high oxygen concentration).

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

Skin and subcutaneous tissue disorders:

- Very common: photosensitivity.

- Common:

- eczema,

- 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.

- Unknown/ Not known:

- urticarial,

- severe skin reactions sometimes fatal including toxic epidermal necrolysis (TEN)/ Stevens- Johnson syndrome (SJS),

-bullous dermatitis, Drug reaction with eosinophilia and systematic symptoms (DRESS).

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 Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard.

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%).

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

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

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

Endocrine disorders :

- 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.

Gastrointestinal disorders:

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

Hepato-biliary disorders:.

- 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.

- 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.

- Very rare:

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

- surgery (possible interaction with a high oxygen concentration).

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

Skin and subcutaneous tissue disorders:

- Very common: photosensitivity.

- 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.

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 anaemia

- 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

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

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 :

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.

Gastrointestinal disorders:

Very common:

- benign gastrointestinal disorders (nausea, vomiting, dysgeusia) usually occurring with loading dosage and resolving with dose reduction.

Common:

- constipation

Uncommon:

- dry mouth

Not known:

- pancreatitis/acute pancreatitis

General Disorders:

Not known:

- Granuloma, including bone marrow granuloma

Hepato-biliary disorders: :

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:

Not known:

- Angioneurotic oedema (Quincke's Oedema)

- Anaphylactic shock/anaphylactoid reaction including shock

Investigations:

Very rare:

- increase in blood creatinine.

Metabolism and nutrition disorders:

Not known:

- decreased appetite

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.

Very rare:

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

- benign intracranial hypertension (pseudo- tumor cerebri)

- headache

- vertigo.

Not known:

- parkinsonism

- parosmia

Psychiatric disorders:

Not known:

- confusional state/delirium

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.

Very rare:

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

- surgery (possible interaction with a high oxygen concentration).

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

Skin and subcutaneous tissue disorders:

Very common:

- photosensitivity.

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.

- eczema

Very rare:

- erythema during the course of radiotherapy

- skin rashes, usually non- specific

- exfoliative dermatitis

- alopecia

Not known:

- urticaria

- severe skin reactions sometimes fatal including toxic epidermal necrolysis/Stevens-Johnson syndrome

- bullous dermatitis and drug reaction with eosinophilia and systematic symptoms

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Little information is available regarding acute overdosage with Amiodaron HCl Apotexe. 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-adrenostimulants or glucagon may be given. Spontaneously resolving attacks of ventricular tachycardia may also occur. Due to the pharmacokinetics of Amiodaron HCl Apotexe, adequate and prolonged surveillance of the patient, particularly cardiac status, is recommended. Neither Amiodaron HCl Apotexe nor its metabolites are dialysable.

Little information is available regarding acute overdosage with oral 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-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.

Little information is available regarding acute overdosage with oral 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-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.

Pharmacotherapeutic group: Amiodaron HCl Apotexe hydrochloride is an antiarrhythmic.

ATC-Code: CO1B DOl

Paediatric population

No controlled paediatric studies have been undertaken.

In published studies the safety of Amiodaron HCl Apotexe 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.

Pharmacotherapeutic group: Amiodaron HCl Apotex is an antiarrhythmic.

ATC-Code: C01B D01

Paediatric population

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 few hours to several days

If needed oral therapy may be initiated concomitantly at the usual loading dose.

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/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.

Amiodaron HCl Apotexe 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 Amiodaron HCl Apotexe, 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 Amiodaron HCl Apotexe.

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

Amiodaron HCl Apotexe is metabolised mainly by CYP3A4, and also by CYP2C8. Amiodaron HCl Apotexe and its metabolite, desethylAmiodaron HCl Apotexe, exhibit a potential in vitro to inhibit CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, CYP2B6 and 2C8. Amiodaron HCl Apotexe and desethylAmiodaron HCl Apotexe have also a potential to inhibit some transporters such as Pgp and organic cation transporter (OCT2) (One study shows a 1.1% increase in concentration of creatine (a OCT 2 substrate). In vivo data describe Amiodaron HCl Apotexe interactions on CYP3A4, CYP2C9, CYP2D6 and Pgp substrates.

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 600mg/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 200mg/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.

Paediatric population

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

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 Amiodaron HCl Apotex X, 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 Amiodaron HCl Apotex X.

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

Amiodarone is metabolised mainly by CYP3A4, and also by CYP2C8. Amiodarone and its metabolite, desethylamiodarone, exhibit a potential in vitro to inhibit CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, CYP2B6 and 2C8. Amiodarone and desethylamiodarone have also a potential to inhibit some transporters such as P-gp and organic cation transporter (OCT2) (One study shows a 1.1% increase in concentration of creatine (a OCT 2 substrate). In vivo data describe amiodarone interactions on CYP3A4, CYP2C9, CYP2D6 and P-gp substrates.

In a 2-years carcinogenicity study in rats, Amiodaron HCl Apotexe 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 Amiodaron HCl Apotexe on the synthesis and/or release of thyroid gland hormones. The relevance of these findings to man is low.

In a 2-years 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.

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.

Not applicable

None stated

Not applicable.

No special requirements

Not applicable.

Not applicable