This information is intended for use by health professionals

1. Name of the medicinal product

Amiodarone 30mg/ml Injection

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:

- 20mg/ml of benzyl alcohol

- 112mg of iodine

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.

- Tachyarrhythmias associated with 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.

4.2 Posology and method of administration

Route of administration: intravenous use.

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

Amiodarone may be used prior to DC cardioversion.

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) diluted in 20ml 5% w/v dextrose and rapidly injected. An additional 150 mg (or 2.5 mg/kg body-weight) IV dose may be considered if ventricular fibrillation persists.

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 and premature babies (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).

See section 6.2 for information on incompatibilities.

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 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. 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 induce torsades de pointes is contra-indicated (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 - except in exceptional circumstances (see section 4.6)

• Lactation (see section 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).

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.

Caution should be exercised in patients with hypotension and decompensated cardiomyopathy.

Amiodarone induces ECG changes: QT interval lengthening corresponding to prolonged repolarisation with the possible development of U and deformed T-waves; these changes are evidence of its pharmacological action and do not reflect toxicity.

Although there have been literature reports on the potentiation of hepatic adverse effects of alcohol, patients should be advised to moderate their alcohol intake while being treated with amiodarone.

Anaesthesia:

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

Amiodarone injection contains benzyl alcohol (20 mg/ml). Benzyl alcohol may cause toxic reactions and allergic reactions in infants and children up to 3 years old.

4.5 Interaction with other medicinal products and other forms of interaction

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

Amiodarone raises the plasma concentrations of highly protein bound drugs, for example oral anticoagulants and phenytoin.

The dose of warfarin should be reduced accordingly. More frequent monitoring of prothrombin time both during and after amiodarone treatment is recommended. Phenytoin dosage should be reduced if signs of overdosage appear and plasma levels may be measured.

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. Monitoring is recommended and digoxin dosage usually has to be reduced. A synergistic effect on heart rate and atrioventricular conduction is also possible.

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

• Anti-psychotics e.g. chlorpromazine, thioridazine, pimozide, haloperidol

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

• Certain antihistamines e.g. terfenadine, astemizole

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

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.

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.

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.

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. Reported examples of this interaction include immunosuppresives (ciclosporin, tacrolimus) and HMG-CoA Reductase Inhibitors / statins (simvastatin, atorvastatin). An increased risk of myopathy / rhabdomyolysis has been reported when amiodarone is taken with statins (particularly with simvastatin at doses exceeding 20 mg daily). Examples of other drugs known to be metabolized by CYP3A4 are: Fentanyl, lidocaine, macrolide antibiotics (clarithromycin), midazolam, sildenafil, ergotamine.

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. When changing from intravenous amiodarone to oral amiodarone the consumption of grapefruit juice should be avoided since it can increase the 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.

Amiodarone may supress other CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolised by those CYP450 enzymes like flecainide, dextromethorphan, metoprolol.

4.6 Fertility, pregnancy and lactation

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

Breast-feeding: Amiodarone is excreted into the breast milk in significant quantities and breast-feeding is contra-indicated.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

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, sweating and nausea. A moderate and transient reduction in blood pressure may occur. Circulatory collapse may be precipitated by too rapid administration or overdosage (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 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.

Ophthalmological: Patients on continuous therapy almost always develop microdeposits in the cornea. The deposits are usually only discernable by slit- lamp examinations and may rarely cause subjective symptoms such as visual haloes and blurring of vision. The deposits are considered essentially benign, do not require discontinuation of amiodarone and regress following termination of treatment. Rare cases of impaired visual 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: Bradycardia, which is generally moderate and dose dependent, has been reported. In some cases (sinus node disease, elderly patients) marked bradycardia or more exceptionally sinus arrest has occurred. There have been 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.

Pulmonary: Amiodarone can cause pulmonary toxicity (hypersensitivity pneumonitis, alveolar/interstitial pneumonia 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.

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.

Hepatic: 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.

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 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 chirrosis.

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: 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. 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: 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: Peripheral neuropathy can be caused by amiodarone. Myopathy has occasionally been reported. Both these conditions may be severe although they are usually reversible on drug withdrawal. An increased risk of myopathy and also rhabdomyolysis has been reported when amiodarone is taken with statins (see section 4.5). Nightmares, vertigo, headaches, sleeplessness and paraesthesia may also occur. Tremor and ataxia have also infrequently been reported usually with complete regression after reduction of dose or withdrawal of the drug. Benign intracranial hypertension (pseudo-tumour cerebri) has been reported.

Other: Other unwanted effects occasionally reported include nausea, vomiting, metallic taste (which usually occur with loading dosage which regress on dose reduction), fatigue, impotence, epididymo-orchitis, and alopecia. Isolated cases suggesting a hypersensitivity reaction involving vasculitis, renal involvement with moderate elevation of creatinine levels or thrombocytopenia have been observed. Haemolytic or aplastic anaemia have rarely been reported. Isolated cases of anapylatic shock have been reported. Rare events of bone marrow granulomas have been cited. Identified cases of pancreatitis and SIADH have been observed.

Endocrine disorders:

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

Gastrointestinal disorders:

Unknown: Pancreatitis (acute)

Psychiatric disorders:

Unknown: Delirium (including confusion)

Skin and subcutaneous tissue disorders:

Common: eczema

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Little information is available regarding acute overdosage with amiodarone. Few cases of sinus bradycardia, heart block, attacks of ventricular tachycardia, torsades de pointes, circulatory failure and hepatic injury have been reported.

In the event of overdose, treatment should be symptomatic, 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 their cardiac status, is recommended. Neither amiodarone nor its metabolites are dialysable.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiarrhythmic

ATC Code: CO1B DO1

Amiodarone is a product for the treatment of tachyarrhythmias and has complex pharmacological actions. Its effects are anti-adrenergic (partial α- and β-blockers). It has haemodynamic effects (increased blood flow and systemic/coronary vasodilation). The drug reduces myocardial oxygen consumption and has been shown to have a sparing effect of rat myocardial ATP utilisation, with decreased oxidative processes. Amiodarone inhibits the metabolic and biochemical effects of catecholamines on the heart and inhibits Na+ and K+ activated ATP-ase.

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. Absorption following oral administration is variable and may be prolonged, with enterohepatic cycling. The major metabolite is desethylamiodarone. Amiodarone is highly protein bound (> 95%).

Renal excretion is minimal and faecal excretion is the major route. 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.

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

5.3 Preclinical safety data

There are no pre-clinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

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.

6.3 Shelf life

2 years.

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

Refer to 4.2 above

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

06/09/2016