This information is intended for use by health professionals

1. Name of the medicinal product

Amiodarone 30mg/ml Solution for injection/infusion in pre-filled syringe

2. Qualitative and quantitative composition

Each 10ml pre-filled syringe contains 300mg amiodarone hydrochloride equivalent to 30mg amiodarone hydrochloride per ml.

Excipients:

Each pre-filled syringe contains:

- 112mg of iodine

Excipients with known effect:

Benzyl alcohol: This medicinal product contains 200mg in each 10ml pre-filled syringe.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection/infusion

Amiodarone 30mg/ml Injection is a clear, slightly yellow solution, practically free from particulates.

4. Clinical particulars
4.1 Therapeutic indications

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

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

- All types of tachyarrhythmias including supraventricular, nodal and ventricular tachycardias; atrial flutter and fibrillation; ventricular fibrillation; when other drugs cannot be used.

Amiodarone can be used where a rapid response is required or where oral administration is not possible.

Amiodarone Hydrochloride 30mg/ml injection can be used where a rapid response is required or where oral administration is not possible.

4.2 Posology and method of administration

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

Amiodarone may be used prior to DC cardioversion.

Posology

The standard recommended dose is 5mg/kg bodyweight given by intravenous infusion over a period of 20 minutes to 2 hours. This should be administered as a dilute solution in 250ml 5% w/v dextrose. This may be followed by repeat infusion up to 1200mg (approximately 15mg/kg bodyweight) in up to 500ml 5% w/v dextrose per 24 hours; the rate of infusion being adjusted on the basis of clinical response (see section 4.4).

In extreme clinical emergency, the drug may, at the discretion of the clinician, be given as a slow injection of 150-300mg in 10-20ml 5%w/v dextrose over a minimum of 3 minutes. This should not be repeated for at least 15 minutes. Patients treated in this way with Amiodarone must be closely monitored, e.g. in an intensive care unit (see section 4.4).

Cardiopulmonary resuscitation:

The recommended dose for ventricular fibrillations/pulseless ventricular tachycardia resistant to defibrillation is 300 mg (or 5 mg/kg body-weight) as a rapid injection. An additional 150 mg (or 2.5 mg/kg body-weight) IV dose may be considered if ventricular fibrillation persists.

See section 6.2 for information on incompatibilities

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 (i.e. 200mg three times a day). Amiodarone injection should then be phased out gradually.

Paediatric population:

Due to the presence of benzyl alcohol, intravenous amiodarone is usually contraindicated in neonates, infants and children up to 3 years old. (see section 4.3).

No controlled paediatric studies have been undertaken. In published uncontrolled studies, effective doses for children were (see section 4.4):

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

• Maintenance dose: 10 to 15mg/kg/day from a few hours to several days. If needed, oral therapy may be initiated concomitantly

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.

Method of administration

For intravenous injection or infusion

4.3 Contraindications

• Hypersensitivity to the active substance, iodine or to any of the excipients listed in section 6.1 (one pre-filled syringe contains approximately 112mg iodine).

• Sinus bradycardia and sino-atrial heart block. 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. Patients with Brugada syndrome.

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

• Severe respiratory failure, circulatory collapse, or severe arterial hypotension; hypotension, heart failure and cardiomyopathy are also contra-indications when using Amiodarone as a bolus injection

• The combination of Amiodarone with drugs which may prolong the QT interval (see section 4.5)

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

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

All these above contra-indications do not apply to the use of amiodarone for cardiopulmonary resuscitation of shock resistant ventricular fibrillation.

4.4 Special warnings and precautions for use

Amiodarone Injection should only be used in a special care unit under continuous monitoring (ECG and blood pressure).

IV infusion is preferred to bolus due to the haemodynamic effects sometimes associated with rapid injection (see section 4.8). Circulatory collapse may be precipitated by too rapid administration or overdosage (atropine has been used successfully in such patients presenting with bradycardia). 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.

When given by infusion amiodarone hydrochloride may reduce drop size and, if appropriate, adjustments should be made to the rate of infusion.

Anaesthesia:

Before surgery, the anaesthetist should be informed that the patient is being treated with amiodarone (see section 4.5).

Cardiac disorders:

Caution should be exercised in patients with hypotension and decompensated cardiomyopathy and severe heart failure (see section 4.3).

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 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 prolongation factors such as drug interactions and/or electrolytic disorders (see sections 4.5 and 4.8). Despite QT interval prolongation, amiodarone exhibits a low torsadogenic activity.

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.

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.

This medicine contains 200mg of benzyl alcohol in each 10ml syringe Benzyl alcohol may cause allergic reactions.

The administration of medications containing benzyl alcohol to newborns or premature neonates has been associated with a fatal “Gasping Syndrome” (symptoms include a striking onset of gasping syndrome, hypotension, bradycardia and cardio-vascular collapse). As benzyl alcohol may cross the placenta, solution for injection should be used with caution in pregnancy.

In those with liver disease or kidney disease or those who are pregnant or breast-feeding, large amounts of benzyl alcohol can accumulate resulting in metabolic acidosis.

4.5 Interaction with other medicinal products and other forms of interaction

Drugs inducing “Torsade de Pointes” or prolonging the QT interval

Combined therapy with the following drugs which prolong the QT interval is contra- indicated (see section 4.3) due to the increased risk of torsades de pointes; for example:

• Class Ia anti-arrhythmic drugs e.g. quinidine, procainamide, disopyramide

• Class III anti-arrhythmic drugs e.g. sotalol, bretylium

• Intravenous erythromycin, co-trimoxazole or pentamidine injection

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

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

• Certain antihistamines e.g. terfenadine, astemizole, mizolastine

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

• Moxifloxacin

Fluoroquinolones

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

Drugs lowering heart rate, causing automaticity or conduction disorders

Combined therapy with the following drugs is not recommended; beta blockers and certain calcium channel blockers (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction slowing effects may occur.

Stimulant laxatives may cause hypokalaemia thus increasing the risk of torsades de pointes; other types of laxatives should be used.

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

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

General anaesthesia

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

Potentially severe complications have been reported in patients taking amiodarone while undergoing general anaesthesia: bradycardia unresponsive to atropine, hypotension, disturbances of conduction, decreased cardiac output.

A few cases of adult respiratory distress syndrome, most often in the period immediately after surgery, have been observed. A possible interaction with a high oxygen concentration may be implicated. The anaesthetist should be informed that the patient is taking amiodarone.

Effect of amiodarone hydrochloride on other medicinal products

Amiodarone and/or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein and may increase exposure of their substrates. Due to the long half-life of amiodarone, interactions may be observed for several months after discontinuation of amiodarone.

Pgp Substrates

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

Digoxin

Administration of amiodarone injection to a patient already receiving digoxin will bring about an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with high digoxin levels; disturbances in automaticity (excessive bradycardia) and conduction may occur. Clinical ECG and biological monitoring is recommended to observe sign of digitalis toxicity and digoxin dosage should be halved. A synergistic effect on heart rate and atrioventricular conduction is also possible.

Dabigatran

Caution should be exercised when amiodarone is co administered with dabigatran due to the risk of bleeding. It may be necessary to adjust the dosage of dabigatran as per its label.

CYP2C9 substrates

Amiodarone raises the plasma concentrations of CYP 2C9 substrates such as oral anticoagulants (warfarin) and phenytoin by inhibition of the cytochrome P450 2C9.

Warfarin

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

Phenytoin

Phenytoin dosage should be reduced if signs of overdosage appear and plasma levels may be measured.

CYP2D6 substrates

Flecainide

Given that flecainide is mainly metabolised by CYP 2D6, by inhibiting this isoenzyme, amiodarone may increase flecainide plasma levels; it is advised to reduce the flecainide dose by 50% and to monitor the patient closely for adverse effects. Monitoring of flecainide plasma levels is strongly recommended in such circumstances.

CYP P450 3A4 substrates

Amiodarone is an inhibitor of the hepatic microsomal cytochrome 3A4 isoenzyme (CYP 3A4). This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by CYP3A4 enzymes:

• Ciclosporin: plasma levels of ciclosporin may increase as much as 2-fold when used in combination. A reduction in the dose of ciclosporin may be necessary to maintain the plasma concentration within the therapeutic range.

• Statins: the risk of muscular toxicity (myopathy/rhabdomyolysis) is increased by concomitant administration of amiodarone with statins metabolised by CYP 3A4 such as simvastatin (particularly with simvastatin at doses exceeding 20 mg daily as there is an increased risk of myopathy/rhabdomyolysis), atorvastatin and lovastatin. It is recommended to use a statin not metabolised by CYP 3A4 when given with amiodarone.

• Other drugs metabolised by cytochrome P450 3A4: examples of such drugs are lidocaine, tacrolimus, sildenafil, fentanyl, midazolam, triazolam, macrolide antibiotics (clarithromycin), dihydroergotamine, ergotamine and colchine.

Since amiodarone is a substrate for CYP3A4, drugs or substances that inhibit these isoenzymes may decrease the metabolism and increase the serum concentration of amiodarone.

Known inhibitors of CYP3A4 like protease inhibitors (indinavir), histamine H2 antagonists (cimetidine), macrolide antibiotics (clarithromycin), azol antifungals (ketoconazole, itraconazole) can increase plasma levels of amiodarone.

Drugs and substances that stimulate the synthesis of CYP3A4 (enzyme inducers) may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include antibiotics (rifampicin). The use of St. John's Wort (Hypericum perforatum) in patients receiving amiodarone could result in reduced amiodarone levels.

, Interaction with substrates of other CYP 450 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.

Effect of other products on amiodarone hydrochloride

CYP3A4 inhibitors and CYP2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure. It is recommended to avoid CYP 3A4 inhibitors (e.g. grapefruit juice and certain medicinal products) during treatment with amiodarone. Grapefruit juice inhibits cytochrome P450 3A4 and may increase the plasma concentration of amiodarone. Grapefruit juice should be avoided during treatment with oral amiodarone.

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

Amiodarone is contraindicated during pregnancy, except in exceptional circumstances (see section 4.3).

Breast-feeding

Amiodarone and its active metabolite are excreted into the breast milk in significant quantities. Breast-feeding is contra-indicated during amiodarone treatment. 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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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)

Following intravenous infusion, inflammation of veins is possible. This may be avoided by the use of a central venous catheter.

Rapid administration of amiodarone injection has been associated with hot flushes (very rare), sweating and nausea. A moderate and transient reduction in blood pressure and increased heart rate (common), following injection may occur. Cases of severe hypotension or shock have been reported following overdose or too rapid administration (bolus injection). Atropine has been used successfully in such patients presenting with bradycardia. In case of respiratory failure, notably in asthmatics, bronchospasm and/or apnoea may also occur. Isolated cases of anaphylactic shock and angioedema have been reported.

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

Eye disorders: Patients on continuous therapy almost always develop microdeposits at the anterior surface of the cornea, usually limited to the area below the pupil (very common)'. The deposits are usually only discernable by slit- lamp examinations and may rarely cause subjective symptoms such as colored halos in dazzling light and blurring of vision. The deposits are considered essentially benign, do not require discontinuation of amiodarone and regress 6-12 months following termination of treatment. Rare cases of impaired visual acuity due to optic neuritis have been reported, although at present, the relationship with amiodarone has not been established. Unless blurred or decreased vision occurs, opthalmological examination is recommended annually.

Cardiac disorders: Bradycardia, which is generally moderate and dose dependent, has been commonly reported. In very rare cases (sinus node disease, elderly patients) marked bradycardia or more exceptionally sinus arrest has occurred. This may necessitate discontinuation of the treatment. There have been very rare instances of conduction disturbances (sino-atrial block, various degrees of AV-block). Because of the long half-life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered. Amiodarone has a low proarrhythmic effect. However, arrhythmia (new occurrence or aggravation) followed in some cases by cardiac arrest has been reported; with current knowledge it is not possible to differentiate a drug effect from the underlying cardiac condition or lack of therapeutic efficacy. This has usually occurred in combination with other precipitating factors particularly other antiarrhythmic agents, hypokalaemia and digoxin. Occurrence of new- and exacerbation of existing- arrhythmias, including atypical ventricular tachycardias (Torsades de Pointes) sometimes followed by cardiac arrest have been very rarely reported (see also section 4.4 and section 4.5).

Respiratory, thoracic and mediastinal disorders :

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

Presenting features can include dyspnoea (which may be severe and unexplained by the current cardiac status), non-productive cough and deterioration in general health (fatigue, weight loss and fever). The onset is usually slow but may be rapidly progressive. Whilst the majority of cases have been reported with long-term therapy, a few have occurred soon after starting treatment. Very rarely, acute ARDS (adult respiratory distress syndrome, sometimes with fatal sequelae can occur as well as bronchospasm/and or apnoea in patients with serious respiratory problems, especially patients with asthma.

Patients should be carefully evaluated clinically, and consideration given to chest X- ray before starting therapy. During treatment, if pulmonary toxicity is suspected, this should be repeated and associated with lung function testing including where possible measurement of transfer factor. Initial radiological changes may be difficult to distinguish from pulmonary venous congestion. Pulmonary toxicity has usually been reversible following early withdrawal of amiodarone therapy, with or without corticosteroid therapy. Clinical symptoms often resolve within a few weeks followed by slower radiological and lung function improvement. Some patients can deteriorate despite discontinuing amiodarone. A few cases of adult respiratory distress syndrome, most often in the period after surgery, have been observed, resulting sometimes in fatalities (see section 4.5).

A few cases of bronchospasm have been reported in patients with severe respiratory failure and especially in asthmatic patients.

Hepatobiliary disorders: Amiodarone may be associated with a variety of hepatic effects, including cirrhosis, hepatitis and jaundice. Some fatalities have been reported, mainly following long-term therapy, although rarely they have occurred soon after starting treatment. It is advisable to monitor hepatic functions particularly transaminases before treatment and six monthly thereafter.

Very rarely, at the beginning of therapy, elevation of serum transaminases which can be in isolation (1.5 to 3 times normal) may occur. This is often transient in nature and resolves spontaneously with dose reduction.

Very rarely, acute liver function disorders, with increased serum transaminase and/or jaundice, including hepatic failure, sometimes with fatal sequelae may occur (see section 4.4) 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. Histological findings may resemble pseudo-alcoholic hepatitis, but they can be variable and include cirrhosis.

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

Hyperthyroidism (Not known): Clinical features such as weight loss, asthenia, restlessness, increase in heart rate, recurrence of the cardiac dysrhythmia, angina, or congestive heart failure, should alert the clinician. The diagnosis may be supported by an elevated serum T3, a low level of thyroid stimulating hormone (TSH) as measured by high sensitivity methods and a reduced TSH response to TRH. Elevation of reverse T3 (r T3) may also be found. In the case of hyperthyroidism, therapy should be withdrawn (see section 4.4). Clinical recovery usually occurs within a few weeks, although severe cases, sometimes resulting in fatalities, have been reported.

Courses of anti-thyroid drugs have been used for the treatment of severe thyroid hyperactivity; large doses may be required initially. These may not always be effective and concomitant high dose corticosteroid therapy (eg 1mg/kg prednisolone) may be required for several weeks.

Hypothyroidism (Not known): Clinical features such as weight gain, reduced activity or excessive bradycardia should suggest the diagnosis. This may be supported by an elevated serum TSH level and an exaggerated TSH response to TRH. T4 and T3 levels may be low. Thyroid hypofunction usually resolves within 3 months of cessation of therapy; it may be treated cautiously with L-thyroxine. Concomitant use of amiodarone should be continued only in life threatening situations, when TSH levels may provide a guide to L-thyroxin dosage.

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

Neurological: Nightmares, vertigo, and sleeplessness may also occur. Ataxia have also infrequently been reported usually with complete regression after reduction of dose or withdrawal of the drug.

Other: Other unwanted effects occasionally reported include vomiting, metallic taste (which usually occur with loading dosage which regress on dose reduction), fatigue, impotence, epididymo-orchitis, and alopecia. A few rare cases with various clinical symptoms, indicative of hypersensitivity reactions, have been reported: vasculitis, reduced renal function with moderate elevation of creatinine levels or thrombocytopenia have been observed. Haemolytic or aplastic anaemia have rarely been reported. Very rare cases of anapylatic shock and angiodema have been reported.

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.

Endocrine disorders:

Very rare: Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Gastrointestinal disorders:

Very rare: Nausea

Unknown: Pancreatitis (acute)

Psychiatric disorders:

Unknown: Delirium (including confusion)

Nervous system disorders:

Common: Extrapyramidal tremor

Uncommon: Peripheral sensorimotor neuropathy and/or myopathy, usually reversible on withdrawal of the drug.

Very rare: Benign intracranial hypertension (pseudo-tumour cerebri); headache

Skin and subcutaneous tissue disorders: Common: eczema

Very rare: Sweating

Unknown: Urticaria, severe skin reaction as toxic epidermal necrolysis (TEN)/Stevens- Johnson syndrome (SJS), bullous dermatitis and Drug reaction with eosinophilia and systematic symptoms (DRESS).

Musculoskeletal and Connective Tissue Disorders

Not known: Back pain

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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.

Few cases of sinus bradycardia, heart block, attacks of ventricular tachycardia, torsades de pointes, circulatory failure and hepatic injury have been reported.

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. 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 their cardiac status, is recommended. Neither amiodarone nor its metabolites are dialysable.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cardiac therapy, antiarrhythmics, class III

ATC Code: CO1BDO1

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.

5.2 Pharmacokinetic properties

Pharmacokinetics of amiodarone are unusual and complex and have not been completely elucidated.

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 is highly protein bound (> 95%).

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 renally.

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.

A study in both healthy volunteers and patients after intravenous administration of amiodarone reported that the calculated volumes of distribution and total blood clearance using a two-compartment open model were similar for both groups. Elimination of amiodarone after intravenous injection appeared to be biexponential with a distribution phase lasting about 4 hours. The very high volume of distribution combined with a relatively low apparent volume for the central compartment suggests extensive tissue distribution. A bolus IV injection of 400mg gave a terminal T½ of approximately 11 hours.

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.

5.3 Preclinical safety data

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 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.

6. Pharmaceutical particulars
6.1 List of excipients

Polysorbate 80

Benzyl alcohol

Water for Injections

6.2 Incompatibilities

Amiodarone is incompatible with saline and should be administered solely in a 5% w/v dextrose solution.

Amiodarone, diluted with 5% dextrose solution to a concentration of less than 0.6mg/ml, is unstable. Solutions containing less than 1 pre-filled syringe of Amiodarone in 500ml dextrose 5% are unstable and should not be used.

The use of administration equipment or devices containing plasticizers such as DEHP (di-2-ethylhexyphthalate) in the presence of amiodarone may result in leaching out of DEHP. In order to minimise patient exposure to DEHP, the final amiodarone dilution for infusion should preferably be administered through non DEHP-containing sets such as polyolefin (PE, PP) or glass sets. No other agents may be added to amiodarone infusions.

6.3 Shelf life

2 years.

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.

6.4 Special precautions for storage

Do not store above 25°C. Store the syringe in the outer carton until needed.

6.5 Nature and contents of container

10ml type 1 glass pre-filled syringe with rubber stopper and rubber tip cap.

6.6 Special precautions for disposal and other handling

Amiodarone 30mg/ml Injection 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 or slightly yellow and the container is undamaged and intact.

Prior to administration by intravenous infusion this product should be diluted according to directions with the recommended infusion fluid (see section 6.2).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Aurum Pharmaceuticals Ltd

T/A Martindale Pharma

Bampton Road

Harold Hill

Romford

Essex RM3 8UG

United Kingdom

8. Marketing authorisation number(s)

PL 12064/0047

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 23 November 2000

10. Date of revision of the text

01/11/2019