Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion

1 ml Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion contains 50 mg amiodarone hydrochloride equivalent to 46.9 mg amiodarone.

Each ampoule with 3 ml of Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion contains 150 mg amiodarone hydrochloride.

One ampoule of Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion diluted as recommended in 250 ml of 5 % w/v Glucose Intravenous Infusion results in a concentration of 0.6 mg/ml of amiodarone hydrochloride.

Excipients:

1 ml Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion contains 22.2 mg of benzyl alcohol.

Each ampoule with 3 ml contains 66.6 mg of benzyl alcohol.

For a full list of excipients, see section 6.1.

Concentrate for Solution for Injection and Infusion.

Clear pale yellow sterile solution practically free from particles, in a clear and colourless glass ampoule.

pH: 3.5-4.5

Amiodarone hydrochloride is indicated for the treatment of serious cardiac arrhythmias, in cases where other therapies are not effective or contraindicated:

- atrial arrhythmias, including atrial fibrillation or flutter;

- AV nodal arrhythmias and AV reentrant tachycardia, e.g. as a manifestation of Wolff-Parkinson-White syndrome;

- life-threatening ventricular arrhythmias, including persistent or non-persistent ventricular tachycardia or episodes of ventricular fibrillation.

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

Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion can be used where a rapid response is required or where oral administration is not possible.

Route of administration: intravenous use.

Amiodarone hydrochloride should only be used when facilities exist for cardiac monitoring, defibrillation and cardiac pacing.

Via infusion:

For dilution with glucose 5% also see section 6.6.

Loading dose:

Administer 5 mg per kg body weight in 250 ml 5% glucose solution over 20 minutes to 2 hours and repeat 2 - 3 times every 24 hours up to 1200 mg (approximately 15 mg/kg body weight) in up to 500 ml 5% glucose per 24 hours, the rate of infusion being adjusted on the basis of clinical response (see section 4.4).

The effect occurs within a few minutes and decreases gradually therefore it must be followed by a maintenance dose.

Maintenance dose:

10 - 20 mg per kg body weight in 5% glucose solution every 24 hours (on average 600 to 800 mg/ 24 hours up to a maximum of 1200 mg/ 24 hours corresponding to 4-5 ampoules, maximum 8 ampoules) for a few days. On account of the stability of the solution, do not use concentrations below 300 mg per 500 ml and do not add other medicinal products to the infusion fluid.

To prevent local reactions (phlebitis), do not use concentrations exceeding 3 mg/ml.

It is advisable to start with an oral maintenance dose on the first day of the infusion. Repeated or continuous infusions via peripheral veins may lead to local reactions (inflammation). Whenever repeated or continuous infusions are intended, administration via a central line is recommended.

Caution: When given by infusion amiodarone may reduce drop size. If appropriate, adjustments should be made to the rate of infusion.

Direct intravenous injection ("bolus"):

In extreme clinical emergency amiodarone hydrochloride may, at the discretion of the doctor, be given as a slow injection. Administer 5 mg per kg body weight over at least 3 minutes. The duration of injection should always be no less than 3 minutes except in cases of cardiopulmonary resuscitation of shock-resistant ventricular fibrillation. A second bolus injection must not be administered within 15 minutes of the first, even if the initial injection consisted of only one ampoule (risk of irreversible shock).

Patients treated in this way must be carefully monitored, e.g. in an intensive care unit. Administer bolus injections only in an emergency and do not use any other medicinal products in the same syringe.

The indicated dose of 5 mg per kg, given as a direct injection, must not be exceeded.

Cardiopulmonary resuscitation of shock-resistant ventricular fibrillation/pulseless ventricular tachycardia:

The starting dose is 300 mg (or 5 mg/kg body weight) diluted in 20 ml 5% glucose which should be given by rapid injection. An additional dose of 150 mg (or 2.5 mg/kg body weight) i.v. may be considered if ventricular fibrillation persists.

See section 6.2 for information on incompatibilities.

Paediatric population:

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

Currently available data are described in sections 5.1 and 5.2.

Due to the presence of benzyl alcohol, amiodarone intravenous administration is contraindicated in neonates, infants and children up to 3 years old.

Elderly:

As with all patients it is important that the minimum effective dose is used. Whilst there is no evidence that dosage requirements are different for this group of patients they may be more susceptible to bradycardia and conduction defects if too high a dose is employed. Particular attention should be paid to monitoring thyroid function (see sections 4.3, 4.4 and 4.8).

Hepatic and renal impairment:

Although no dosage adjustment for patients with renal or hepatic abnormalities has been defined during chronic treatment with oral amiodarone, close clinical monitoring is prudent for elderly patients e.g. in an intensive care unit.

Change over from intravenous to oral therapy:

Start with an oral maintenance dose for amiodarone hydrochloride as soon as an adequate response has been obtained. Amiodarone hydrochloride I.V. should then be phased out gradually. In patients taking amiodarone concomitantly with simvastatin, the dose of simvastatin should not exceed 20 mg/day.

- Hypersensitivity to amiodarone, iodine or to any of the excipients. (One ampoule contains approximately 56 mg iodine.)

- Due to the presence of benzyl alcohol, intravenous amiodarone is contraindicated in neonates, infants and children up to 3 years old.

- Severe respiratory failure, circulatory collapse, or severe arterial hypotension; hypotension, heart failure and cardiomyopathy are also contra-indications when using Amiodarone Hydrochloride 50 mg/ml as a bolus injection.

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

- Sinus bradycardia, sino-atrial heart block and sick sinus syndrome in patients without a pacemaker. In patients with severe conduction disturbances (high grade AV block, bifascicular or trifascicular block) or sinus node disease, amiodarone should be used only in specialized units in conjunction with a pacemaker.

- Concomitant use of medicinal products which prolong the QT interval (see section 4.5).

- Pregnancy and lactation. The use is allowed only in special life-threatening circumstances as specified in sections 4.1, 4.4 and 4.6.

The above contraindications do not apply to the use of amiodarone hydrochloride for cardiopulmonary resuscitation of shock-resistant ventricular fibrillation.

Amiodarone must only be prescribed by competent specialists. Using amiodarone requires careful and regular monitoring of liver function tests, thyroid function, an ECG and a radiological examination of the thorax.

Administration of direct I.V. injections (bolus injections) is discouraged due to the risk of haemodynamic effects, such as serious hypotension and cardiovascular collapse. Such injections should only be used in an emergency - within a coronary intensive care unit and under ECG monitoring - when therapeutic alternatives have failed.

Repeated or continuous infusion via peripheral veins may lead to injection site reactions (see section 4.8). When repeated or continuous infusion is anticipated, administration by a central venous catheter is recommended.

Anaesthesia (see section 4.5): Before surgery, the anaesthetist should be informed that the patient is taking amiodarone.

Amiodarone hydrochloride should only be used with constant monitoring of ECG and arterial blood pressure.

Amiodarone hydrochloride should be used with extreme caution - with haemodynamic monitoring - in patients with severe pulmonary impairment, arterial hypotension or stable congestive heart failure. Such patients must not be given a bolus injection (risk of exacerbation).

The indicated dose of 5 mg per kg, given as a direct injection, must not be exceeded.

If the effect of this product is too strong (e.g. severe bradycardia), appropriate measures must be taken, i.e. use of a pacemaker or beta stimulation.

Use of amiodarone hydrochloride is not a contraindication for subsequent application of external defibrillation.

Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion contains benzyl alcohol (22.2 mg/ml).

Benzyl alcohol may cause toxic reactions and allergic reactions in infants and children up to 3 years old.

Adverse effects are mostly the result of excessive dosage. It is therefore advisable to use the lowest possible dosage, in order to minimise the extent and severity of adverse effects.

Cardiac disorders

Amiodarone hydrochloride can cause the development of new cardiac arrhythmias or exacerbate existing ones (proarrhythmic effect), sometimes with fatal sequelae. However, in comparison with some other antiarrhythmic agents, the incidence of this effect seems to be less frequent. Caution should be exercised, especially in patients with heart failure or first degree AV block. Furthermore, Torsades de Pointes has been described, a polymorphic ventricular tachycardia associated with QT prolongation. This arrhythmia occurs particularly in patients with a severely prolonged QT interval and/or in combination with medicinal products that cause hypokalaemia, certain antiarrhythmic agents and certain other agents that affect repolarisation (see also section 4.5).

In the ECG T wave changes and possible U wave occurrence result from a prolongation of the repolarisation phase by amiodarone. As with some other antiarrhythmic agents, this phenomenon can lead to atypical ventricular tachycardias ("Torsades de Pointes") in exceptional cases.

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 (see sections 4.5 and 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. Because of the long half-life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered.

Pulmonary disorders

Cases of pulmonary toxicity (interstitial pneumonitis), sometimes with fatal sequelae, have been reported during use of intravenous amiodarone. A chest X-ray and pulmonary function testing should be performed at the onset of dyspnoea (on exertion), independent of whether or not the dyspnoea is accompanied by any changes in the patient's general condition (tiredness, weight loss, fever).

Undesirable pulmonary effects are generally reversible and resolve rapidly upon discontinuation of treatment. Corticosteroid treatment can possibly be considered. In most cases, clinical symptoms resolve within 3 to 4 weeks, followed by a less rapid normalisation of radiological and lung function tests (up to a few months).

Very rare cases of severe respiratory complications, sometimes fatal, have been observed usually in the period immediately following surgery (adult acute respiratory distress syndrome); a possible interaction with a high oxygen concentration may be implicated (see sections 4.5 and 4.8).

Hepatic disorders

Severe liver failure can occur within the first 24 hours after administration of I.V. amiodarone, sometimes with fatal sequelae. Therefore, close monitoring of transaminases is recommended from the outset of treatment.

Drug interactions (see section 4.5)

Use of amiodarone hydrochloride in combination with the following medicinal products is not recommended: beta-blockers, heart rate lowering calcium channel blockers (verapamil, diltiazem), stimulant laxatives capable of causing hypokalaemia, fluoroquinolones and HIV-protease inhibitors.

In patients receiving amiodarone concomitantly with simvastatin, the dose of simvastatin should not exceed 20 mg/day (see section 4.5).

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.

After cessation of therapy a therapeutic concentration of amiodarone may remain in the blood serum for some weeks in case of a repeated intravenous administration because of the long half-life of amiodarone. After further reduction of the amiodarone level, arrhythmias can recur. Patients must be monitored regularly after stopping treatment.

Pregnancy and lactation

Amiodarone hydrochloride must not be used during pregnancy or lactation unless clearly necessary. Amiodarone hydrochloride should only be used in pregnant women at life-threatening and pregnancy-threatening arrhythmias. The neonate should be monitored closely for thyroid dysfunction (see section 4.6).

In view of the long and variable half-life of amiodarone (approximately 50 days), potential for drug interactions exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone.

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

Warfarin

Amiodarone increases warfarin concentrations by inhibiting cytochrome P450 enzyme 2C9. Amiodarone may therefore potentiate the effect of coumarin derivatives, resulting in an increased risk of bleeding. Thus, in patients receiving anticoagulation therapy, the prothrombin time must be frequently monitored and the anticoagulant dose adjusted, both during and after treatment with amiodarone.

Phenytoin

Amiodarone increases phenytoin plasma levels by inhibiting cytochrome P450 enzyme 2C9. During concomitant use of amiodarone and phenytoin, it is possible that phenytoin plasma levels may increase (onset of neurological abnormalities) and monitoring is required. If symptoms of phenytoin overdosage are observed, the phenytoin dose must be reduced. Phenytoin plasma levels should be measured.

Digitalis

Disturbances in cardiac automatism (severe bradycardia) and atrioventricular conduction (synergistic effect) can occur.

Serum digoxin levels may be increased as a result of reduced digoxin clearance. Digoxin plasma levels and ECG must be monitored and patients be monitored for clinical signs of digitalis intoxication. A reduction of the digoxin dose may be required.

Concomitant use of medicinal products that prolong the QT interval, thereby increasing the risk of potentially fatal Torsades de Pointes, is contraindicated (see section 4.3); for example:

- Class Ia antiarrhythmic drugs e.g. quinidine, procainamide and disopyramide.

- Class III anti-arrhythmic drugs e.g. sotalol and bretylium.

- Intravenous erythromycin, co-trimoxazole or pentamidine injection.

- Lithium and tricyclic antidepressants e.g. doxepin, maprotiline, amitriptyline.

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

- Some antihistamines e.g. terfenadine, astemizole and mizolastine.

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

- Moxifloxacin.

- Other medicinal products such as vincamine and cisapride.

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 amidarone with fluoroquinolones should be avoided (concomitant use with moxifloxacin is contraindicated, see above).

Concomitant use of the following medicinal products is not recommended:

- Beta-blockers and certain calcium channel inhibitors (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction slowing effects may occur.

- Stimulant laxatives, which may cause hypokalaemia, thereby increasing the risk of Torsades de Pointes; a different type of laxative should be used.

- HIV protease inhibitors: Amiodarone is metabolised by cytochrome P450 isoenzymes CYP3A4 and CYP2C8 and interactions can occur with inhibitors of these enzymes, especially inhibitors of CYP3A4 such as HIV protease inhibitors. The combination may lead to inhibition of amiodarone's metabolism, resulting in increased amiodarone concentrations and increased risk of serious adverse events (such as arrhythmias). The combination should be avoided. If the combination is necessary, the patient should be closely monitored.

Caution should be exercised during concomitant use of the following medicinal products:

• Other medicinal products that may cause hypokalaemia, such as

- diuretics, alone or concomitantly.

- systemic glucocorticoids and mineralocorticoids, tetracosactide.

- amphotericin B (I.V.).

Hypokalaemia must be avoided and corrected where necessary. The QT interval should be monitored. In cases of Torsades de Pointes, antiarrhythmic agents must not be given (ventricular pacing may be instituted, I.V. magnesium may be administered).

• Patients undergoing general anaesthesia, or receiving high dose oxygen therapy

- In patients receiving amiodarone and having undergone general anaesthesia, the following complications (among others) have been described: bradycardia (refractory to atropine), hypotension, conduction disturbances and reduced cardiac output.

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

In surgical interventions, it is important to inform the anaesthetist that the patient is receiving 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.

Medicinal products metabolised by cytochrome P450 enzyme 3A4

Amiodarone is a cytochrome P450 enzyme 3A4 inhibitor. If medicinal products - whose metabolism is dependent on this enzyme system - are concomitantly administered with amiodarone, increased plasma concentrations of these products may result in increasing their potential toxicity:

- Ciclosporin: Concomitant administration of ciclosporin and amiodarone is associated with the risk of elevated ciclosporin plasma levels. The ciclosporin dose should be adjusted, if required.

- Fentanyl: Amiodarone can potentiate the effect of fentanyl, thereby increasing the risk of 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. In patients receiving amiodarone concomitantly with simvastatin, the dose of simvastatin should not exceed 20 mg/day.

- Other medicinal products metabolised by cytochrome P450 enzyme 3A4 include: tacrolimus, lidocaine, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine.

Flecainide

Amiodarone increases the plasma level of Flecainide via cytochrome P450 enzyme 2D6 inhibition. The flecainide dose should be adjusted, if required.

Interactions with substrates of other CYP450 isoenzymes

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

Pregnancy

Data on a limited number of exposed pregnancies are available. Amiodarone and N-desmethylamiodarone cross the placental barrier and achieve 10-25% of the maternal plasma concentrations in the infant. Most frequent complications include impaired growth, preterm birth and impaired function of the thyroid gland in newborn babies. Hypothyroidism, bradycardia and prolonged QT intervals were observed in approximately 10 % of the newborn babies. In isolated cases an increased thyroid gland or cardiac murmurs were found. The malformation rate does not appear to be increased. However, the possibility of cardiac defects should be kept in mind. Therefore, amiodarone must not be used during pregnancy unless clearly necessary and the real risk of reoccurrence of life threatening arrhythmias should be weighed against the possible hazard for the foetus. Given the long half-life of amiodarone, women of child-bearing age would need to plan for a pregnancy starting at least half a year after finishing therapy, in order to avoid exposure of the embryo/foetus during early pregnancy.

Lactation

The passage into mother's milk is proven for the active ingredient and for the active metabolite. If therapy is required during the lactation period, or if amiodarone was taken during pregnancy, breast-feeding should be stopped.

Fertility

Elevated serum levels of LH and FSH were found in male patients after long-term treatment indicating testicular dysfunctions.

Amiodarone hydrochloride may affect the ability to drive or use machines.

The most common adverse drug effects reported with intravenous amiodarone hydrochloride are infusion phlebitis, bradycardia, and hypotension.

Frequency of the adverse reaction listed below is defined according to 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)

Immune system disorders

Very rare

- Anaphylactic shock.

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

Nervous system disorders

Very rare

- Benign intracranial hypertension (pseudo-tumour cerebri).

- Headache.

Cardiac disorders

Common

- Dose-dependent bradycardia.

Very rare

- Severe bradycardia (in cases of sinus node dysfunction and in the elderly) or (more rarely) sinus arrest: this may necessitate discontinuation of the treatment.

- Occurrence of new - and exacerbation of existing - arrhythmias, including atypical ventricular tachycardias (Torsades de Pointes) (see also sections 4.4 and section 4.5).

- Conduction disturbances (sinoatrial block, AV block).

Vascular disorders

Common

- Hypotension and increased heart rate immediately following injection. These are generally moderate and transient in nature. Cases of severe hypotension or shock have been reported following overdose or too rapid administration (bolus injection).

Very rare

- Hot Flushes.

Respiratory, thoracic and mediastinal disorders

Very rare

- Interstitial pneumonitis (see section 4.4).

- Acute ARDS (adult respiratory distress syndrome), sometimes with fatal sequelae.

- Bronchospasm in patients with serious respiratory problems, especially patients with asthma.

Gastrointestinal disorders

Very rare

- Nausea.

Hepatobiliary disorders

Very rare

- A mild to moderate increase in transaminase levels (1.5 to 3 times above normal) at the start of treatment, which is often transient in nature and resolves spontaneously upon lowering the dose.

- Acute liver function disorders, with increased serum transaminase and/or jaundice, including hepatic failure, sometimes with fatal sequelae (see section 4.4).

Skin and subcutaneous tissue disorders

Very rare

- Sweating.

Not known

- Urticaria.

Blood and lymphatic system disorders

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

General disorders and administration site conditions

Common

- At the site of injection or infusion: pain, erythema, oedema, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes.

Rare

- The excipient benzyl alcohol may cause hypersensitivity reactions.

A few rare cases with various clinical symptoms, indicative of hypersensitivity reactions, have been reported: vasculitis, reduced renal function with a rise in creatinine levels, thrombocytopenia, anaphylaxis.

There is no information regarding overdosage with intravenous amiodarone.

In cases of acute overdose or too rapid intravenous administration, the following can be observed: nausea, vomiting, constipation, sweating, bradycardia and prolonged QT interval. Following substantial overdose, onset of hypotension, heart block and Torsades de Pointes should also be expected. In exceptional cases, hyperthyroidism may occur.

Following substantial overdose, prolonged ECG monitoring must be performed. Intensive care unit admission should be considered. Hypotension can be treated with infusion fluids or vasopressors. The use of alpha- or beta adrenergic agents or temporary pacing may be indicated. Class Ia and III antiarrhythmic agents should be avoided, as they are associated with QT interval prolongation and induction of Torsades de Pointes. Further treatment should be supportive and symptomatic.

Amiodarone and its metabolites cannot be dialysed.

Due to the pharmacokinetics of amiodarone, adequate and prolonged surveillance of the patient, particularly cardiac status, is recommended.

Pharmacotherapeutic group: Antiarrhythmics, class III

ATC code: C01B D01

Amiodarone is a di-iodinated benzofuran derivative and is classified as a class III antiarrhythmic agent owing to its ability to increase the cardiac action potential duration in both atrial and ventricular myocytes via block of cardiac K⁺ channels (mainly of the rapid component of the delayed rectifier K⁺ current, IKr). Thus, it prolongs the refractory period of the action potential leading to depression of ectopies and re-entry-arrhythmias and to prolongation of the QTc interval in the ECG. Furthermore, amiodarone also blocks cardiac Na⁺ currents (class I effect) and Ca²⁺ currents (class IV effect). The latter may lead to slowing of conduction through the sinoatrial and atrioventricular nodes.

During long-term administration, amiodarone also seems to inhibit the trafficking of ion channels from the endoplasmic reticulum to the plasma membrane in cardiac myocytes, and these effects may contribute to the cardiac electrophysiological actions of amiodarone under chronic administration.

Furthermore, amiodarone is a non-competitive antagonist at both ß- and α-adrenoceptors and, therefore, has haemodynamic effects: dilatation of coronary arteries and peripheral vasodilation leading to a reduction of systemic blood pressure. Negative inotropic, negative chronotropic and negative dromotropic effects seem to be induced by the ß-adrenergic antagonistic effects induced by Amiodarone.

Some effects of amiodarone are comparable with hypothyroidism, which might be due to inhibition of thyroid hormone synthesis. Amiodarone is a potent inhibitor of iodothyronine-5´-monodeiodinase activity (the main T4-T3 converting enzyme). In rats, increases in serum thyroid-stimulating hormone (TSH), thyroxine (T4) and reverse triiodothyronine (rT3) and decreases in serum triiodothyronine (T3) as a result of inhibition of deiodination of T4 to T3 have been observed. These antithyroid actions of amiodarone might contribute to its cardiac electrophysiological effects.

The main metabolite N-desethylamiodarone has effects on cardiac electrophysiology similar to those of the parent compound.

The safety and efficacy of amiodarone IV in patients with out-of-hospital cardiac arrest as a result of shock-resistant ventricular fibrillation have been evaluated in two double-blind studies: the ARREST study, which compared amiodarone with placebo, and the ALIVE study, which compared amiodarone with lidocaine. The primary endpoint of both studies was the number of patients who survived until hospital admission.

In the ARREST study, 504 patients – with out-of-hospital cardiac arrest as a result of ventricular fibrillation, or pulseless ventricular tachycardia refractory to 3 or more defibrillator shocks and epinephrine – were given either 300 mg amiodarone diluted in 20 ml 5% glucose as a rapid injection into a peripheral vein (246 patients) or placebo (258 patients). Of the 197 patients (39%) who survived the journey to hospital, amiodarone significantly increased the chances of resuscitation and hospital admission: 44% in the group receiving amiodarone versus 34% in the group treated with placebo (p = 0.03). After adjustment for other independent predictors, the adjusted ratio for survival to hospital admission was 1.6 (95% confidence interval, 1.1 to 2.4; p = 0.02) in the group receiving amiodarone, compared with the placebo group. Incidence of hypotension (59% versus 25%, p = 0.04) and bradycardia (41% versus 25%, p = 0.004) was more common in patients receiving amiodarone than in patients receiving placebo.

In the ALIVE study, 347 patients – with ventricular fibrillation refractory to 3 or more defibrillator shocks, epinephrine and another defibrillator shock, or with recurrent ventricular fibrillation after initial successful defibrillation – were given either amiodarone (5 mg/kg) or lidocaine (1.5 mg/kg). Amiodarone significantly increased the chances of resuscitation and hospital admission: 22.8% in the group receiving amiodarone (41 out of 180 patients) versus 12% in the group receiving lidocaine (20 out of 167 patients), p = 0.009. After adjustment for other factors affecting survival, the adjusted ratio for survival to hospital admission was 2.49 (95% confidence interval, 1.28 to 4.85; p = 0.007) in the group receiving amiodarone, compared with the group receiving lidocaine. The percentage of patients sustaining cardiac arrest after administration of the initial study medication, after defibrillation, was significantly higher in the group receiving lidocaine (28.9%) than in the group receiving amiodarone (18.4%), p = 0.04.

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 has a slow elimination rate and a marked affinity for tissue. Absorption of amiodarone hydrochloride from the gastrointestinal tract following oral administration is 50 %. After a single dose plasma levels will be reached in 3-7 hours. The accumulation of amiodarone in the myocardial tissue is required for its therapeutic efficacy. Depending on the saturation dosage the therapeutic effects can be expected between a few days and up to two weeks.

Intravenous administration

After injection the maximal effect is reached after 15 minutes. After this time there is distribution into the tissue and a fast decrease of the plasma level within 4 hours.

To achieve saturation of the tissue treatment needs to be continued intravenously or orally. During saturation amiodarone is accumulated particularly in the fat tissue and steady state is reached within a period of one to several months.

Because of these characteristics the recommended saturating dosage should be given in order to reach fast saturation of the tissue which is the prerequisite for therapeutic efficacy.

Amiodarone hydrochloride has a long half-life which varies interindividually between 20 and 100 days.

The main elimination route is via the liver and the bile. 10 % of the substance is eliminated renaly.

Due to the low renal elimination the usual dosage can be administered to patients with renal insufficiency.

After discontinuation amiodarone is excreted over several months.

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.

In chronic toxicity studies, amiodarone led to pulmonary damage (fibrosis, phospholipidosis; in hamsters, rats and dogs). Pulmonary toxicity appears to result from radical formation and perturbation of cellular energy production. In addition, amiodarone caused liver damage in rats.

Regarding the genotoxicity aspects the in vitro Ames test and in vivo mouse bone marrow micronucleus test have been conducted. Both studies yielded negative results.

In a carcinogenicity study in rats, amiodarone caused an increased incidence of follicular tumours of the thyroid gland (at doses from 5 mg/kg/day in males and 16 mg/kg/day in females), which seems to result from the effects of amiodarone on the synthesis and/or release of thyroid gland hormones. Hence no carcinogenic potential can be deduced from these investigations for the therapeutic administration of amiodarone in humans.

Polysorbate 80 (E433)

Benzyl alcohol

Water for injections

Amiodarone hydrochloride is incompatible with saline solution and may only be administered in a 5% w/v Glucose intravenous infusion.

In the presence of amiodarone the use of administration equipment containing softening agents such as DEHP (di-2-ethylhexyl phthalate) may cause DEHP to leach into the solution. In order to minimise patient exposure to DEHP, diluted amiodarone solutions for infusion should be administered through sets that do not contain DEHP, such as polyolefin (PE, PP) or glass sets. No other agents may be added to amiodarone infusions.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

2 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature.

From a microbiological point of view, the product should be used immediately.

For single use only. Any unused solution from opened ampoules should be discarded.

Do not store above 25°C. Do not refrigerate or freeze.

Keep the ampoules in the outer carton in order to protect from light.

For storage of the diluted medicinal product see section 6.3.

Each folding box contains 5 ml clear glass ampoules, type I, with 3 ml sterile concentrate.

Pack sizes:

5, 10 x 5 ml ampoules

Not all pack sizes may be marketed.

Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion is intended for single dose use only. Any unused solution should be discarded immediately after initial use.

Before use, the sterile concentrate should be visually inspected for clarity, particulate matter, discolouration and the integrity of the container. The solution should only be used if it is clear and the container is undamaged and intact.

Prior to administration by intravenous infusion, Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion should be diluted according to directions with the recommended infusion fluid, 5% w/v Glucose Intravenous Infusion. One ampoule of Amiodarone Hydrochloride 50 mg/ml Concentrate for Solution for Injection/Infusion diluted as recommended in 250 ml of 5 % w/v Glucose Intravenous Infusion results in a concentration of 0.6 mg/ml of amiodarone hydrochloride.

Administer 5 mg per kg body weight in 250 ml of 5 % glucose solution over 20 minutes to 2 hours.

On account of the stability of the solution, do not use concentrations below 300 mg per 500 ml and do not add other medicinal products to the infusion fluid (see section 4.2).

hameln pharma plus gmbh

Langes Feld 13

31789 Hameln

Germany

25215/ 0026

13/08/2010

11/2011