Amiodarone Injection Minijet 30mg/ml. Solution for injection.

Amiodarone Hydrochloride 30mg/ml

(Each 10ml vial contains 300mg)

For excipients, see section 6.1.

Solution for injection.

Treatment should be initiated and normally monitored only under hospital or specialist supervision. Amiodarone injection 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. The injection is to be used where a rapid response is required.

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

In children, amiodarone injection normally should be given under the supervision of a paediatric cardiologist.

IV infusion is preferred to bolus due to the haemodynamic effects sometimes associated with rapid injection.

Amiodarone injection may be used prior to DC conversion.

Repeated or continuous infusion via peripheral veins may lead to local discomfort and inflammation. When repeated or continuous infusion is anticipated, administration by a central venous catheter is recommended.

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% dextrose. This may be followed by repeat infusion up to 1,200mg (approximately 15mg/kg bodyweight) in up to 500ml 5% dextrose per 24 hours, the rate of infusion being adjusted on the basis of clinical response.

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% dextrose over a minimum of 3 minutes. This should not be repeated for at least 15 minutes.

Patients treated with amiodarone injection must be continuously monitored e.g. in an intensive care unit.

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

Changeover from intravenous to oral therapy: as soon as an adequate response has been obtained, oral therapy should be initiated concomitantly at the usual loading dose (200mg three times a day). Amiodarone injection should then be phased out gradually.

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 effects if too high a dose is employed. Particular attentions should be paid to monitoring thyroid function. See Contraindications, Section 4.3 and Precautions, Section 4.4.

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 injection should only be used in conjunction with a pacemaker.

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

Severe respiratory failure, cardiovascular collapse, or severe arterial hypotension; congestive heart failure and cardiomyopathy are also contraindications when using amiodarone injection as a bolus injection.

Known hypersensitivity to iodine or to amiodarone (one ampoule contains approximately 112mg iodine).

The combination of amiodarone injection with drugs which may induce torsades de pointes is contraindicated (see Interactions, Section 4.5).

Lactation (see section 4.6 Lactation)

Amiodarone Injection Minijet contains benzyl alcohol. There have been reports of fatal “gasping syndrome” in neonates (hypotension, bradycardia and cardiovascular collapse) following the administration of intravenous solution containing this preservative. Amiodarone Injection Minijet is therefore contraindicated in infants or young children up to 3 years old.

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

Too high a dose 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 no 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 Interactions with other Medicinal Products and other Forms of Interaction).

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 Interactions 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 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 contraindicated (see Contraindications, 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 cause hypokalaemia and/or hypomagnesaemia: diuretics, systemic corticosteroids, tetracosactrin, intravenous amphotericin.

In case 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 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 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 (CYP3A4). 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 (simvastatin, atorvastatin). 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 metabolized by those CYP450 enzymes like for example flecainide, dextromethorphan, metoprolol.

Pregnancy: Although no teratogenic effects have been observed in animals, there are insufficient data on the use of amiodarone during pregnancy in humans to judge any possible toxicity. However, in view of the pharmacological properties of the drug on the foetus and its effects on the foetal thyroid gland, amiodarone is contraindicated during pregnancy, except in exceptional circumstances.

Lactation: Amiodarone is excreted into the breast milk in significant quantities and breast-feeding is contraindicated.

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

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 Interactions, 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. 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.

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

Pharmacotherapeutic group: antiarrhythmic, Class III; ATC code: C01BD 01.

Amiodarone is a product for the treatment of tachyarrythmias and has complex pharmacological actions. Its effects are anti-adrenergic (partial alpha and beta blockers). It has haemodynamic effects (increased blood flow and systematic/coronary vasodilatation). 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 metallic and biochemical effects of catecholamines on the heart and inhibits Na+ and K+ activated ATP-ase.

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.

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

Benzyl alcohol

Polysorbate 80

Water for injections

Amiodarone Injection is incompatible with saline and when diluted should be administered solely in 5% dextrose solution. Solutions containing less than 300mg amiodarone hydrochloride 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.

36 months.

Do not store above 25°C. Keep vial in the outer carton.

The solution is contained in a type I glass vial with an elastomeric closure and a plastic vial cap.

An IMS Minijet^® injector is supplied in the carton.

The product is available as 10ml.

The container is specially designed for use with the IMS Minijet^® injector. The instructions for the use of the injector can be found on the side of the outer carton and are as follows;

• Remove the protective caps

• Carefully thread glass vial into injector 3 half turns or until the needle penetrates the stopper

• Remove the needle cap, point needle upwards and expel air.

All infusions longer than 2 hours should be made in glass containers.

International Medication Systems (UK) Ltd

208 Bath Road

Slough

Berkshire

SL1 3WE

UK

PL 03265/0076

28 January 2004

Approved: November 2007