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Microsoft word - amiodacore spc version 11.1 declared 10.10.doc
2010 טסוגואב רשואו קדבנ ונכותו תואירבה דרשמ "
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 3ml ampoule contains 150mg amiodarone hydrochloride.
3. PHARMACEUTICAL FORM
Solution for injection.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment should be initiated and normally monitored only under hospital or specialist supervision. Amiodacore Injection is indicated for Coronary insufficiency, arrhytmias resistant to other treatments, Wolff Parkinson
Amiodacore Intravenous can be used where a rapid response is required or where oral administration is not possible.
4.2 Posology and method of administration
Amiodacore Injection should only be used when facilities exist for cardiac
monitoring, defibrillation, and cardiac pacing.
Amiodacore Injection 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% dextrose. This may be
followed by repeat infusion up to 1200mg (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. (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%
dextrose over a minimum of 3 minutes. This should not be repeated for at
least 15 minutes. Patients treated in this way with Amiodacore Injection
must be closely monitored, e.g. in an intensive care unit.(see section 4.4).
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). Amiodacore Injection should then be phased out gradually.
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.
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
See section 6.2 for information on incompatibilities
• 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, Amiodacore should be used only in
• 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 Amiodacore Injection as a bolus injection.
• Known hypersensitivity to iodine or to amiodarone, or to any of the
excipients. (One ampoule contains approximately 56mg iodine).
• The combination of Amiodacore with drugs which may induce torsades de pointes is contra-indicated (see section 4.5
•Amiodacore Injection ampoules contain 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. Amiodacore Injection should not be given to neonates or premature babies unless the rhythm disturbance is life
threatening and either resistant to other medication or alternative therapy
• Pregnancy - except in exceptional circumstances (see section 4.6)
4.4 Special warnings and precautions for use
Benzyl alcohol may cause toxic reactions and allergic reactions in infants
Amiodacore 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
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 Amiodacore may reduce drop size and, if
appropriate, adjustments should be made to the rate of infusion.
Anaesthesia (see section 4.5)
: Before surgery, the anaesthetist should be informed that the patient is taking amiodarone.
Caution should be exercised in patients with hypotension and
decompensated cardiomyopathy and severe heart failure (also see section
Amiodarone has a low pro-arrhythmic effect. Onsets of new arrhythmias or
worsening of treated arrhythmias, sometimes fatal, have been reported. It
is important, but difficult to differentiate a lack of efficacy of the drug from a proarrhythmic effect, whether or not this is associated with a worsening of the cardiac condition. Proarrhythmic effects generally occur in the
context of drug interactions and/or electrolytic disorders (see sections 4.5
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,
Amiodacore 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.
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.
Respiratory, thoracic and mediastinal disorders (see section 4.8)
Very rare cases of interstitial pneumonitis have been reported with
intravenous amiodarone. When the diagnosis is suspected, a chest X-ray
should be performed. Amiodarone therapy should be re-evaluated since
interstitial pneumonitis is generally reversible following early withdrawal of amiodarone, and corticosteroid therapy should be considered (see section
. Clinical symptoms often resolve within a few weeks followed by slower radiological and lung function improvement. Some patients can deteriorate
despite discontinuing Amiodacore . Fatal cases of pulmonary toxicity have been reported.
Very rare cases of severe respiratory complications, sometimes fatal, have been observed usually in the period immediately following surgery (adult
acute respiratory distress syndrome); a possible interaction with a high
oxygen concentration may be implicated (see sections 4.5 and 4.8)
Hepato-biliary disorders (see section 4.8)
Severe hepatocellular insufficiency may occur within the first 24 hours of IV
amiodarone, and may sometimes be fatal. Close monitoring of transaminases is therefore recommended as soon as amiodarone is started.
Drug interactions (see section 4.5)
Concomitant use of amiodarone with the following drugs is not recommended; beta-blockers, heart rate lowering calcium channel inhibitors (verapamil, diltiazem), stimulant laxative agents which may cause
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.
4.5 Interaction with other medicinal products and other forms of
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 oral anticoagulants (warfarin) and phenytoin by inhibition of CYP 2C9. 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 Amiodacore 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. Clinical, ECG and biological monitoring is recommended and digoxin dosage should
be halved. 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
• 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.
There have been rare reports of QTc interval prolongation, with or without torsades 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).
Combined therapy with the following drugs is not recommended:
• Beta blockers and certain calcium channel inhibitors (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction
• Stimulant laxatives, which 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, e.g.
diuretics, systemic corticosteroids, tetracosactide, 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
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
a high oxygen concentration may be implicated.
Grapefruit juice inhibits cytochrome P450 3A4 and may increase the plasma
concentration of amiodarone. Grapefruit juice should be avoided during
Drugs metabolised by cytochrome P450 3A4
When drugs are co-administered with amiodarone, an inhibitor of CYP 3A4,
this may result in a higher level of their plasma concentrations, which may
lead to a possible increase in their toxicity:
• 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
• Statins: the risk of muscular toxicity is increased by concomitant
administration of amiodarone with statins metabolised by CYP 3A4 such as
simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolised by CYP 3A4 when given with amiodarone.
• Other drugs metabolised by cytochrome P450 3A4: examples of such drugs are lidocaine, tacrolimus, sildenafil, fentanyl, midazolam, triazolam,
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
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.
4.6 Pregnancy and lactation
There are 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,
Amiodarone is excreted into the breast milk in significant quantities and
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention: very
common (> = 10%), common (> = 1% and < 10%); uncommon (> =
0.1% and < 1%); rare (> = 0.01% and < 0.1%), very rare (< 0.01%), not known (cannot be estimated from the available data).
• In patients taking amiodarone there have been incidental findings of bone
marrow granulomas. The clinical significance of this is unknown
• Common: bradycardia, generally moderate.
- marked bradycardia, sinus arrest requiring discontinuation of amiodarone,
especially in patients with sinus node dysfunction and/or in elderly patients
- onset of worsening of arrythmia, sometimes followed by cardiac arrest
General disorders and administration site conditions:
• Common: injection site reactions such as pain, erythema, oedema,
necrosis, extravasation, infiltration, inflammation, induration,
thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes.
- isolated increase in serum transaminases, which is usually moderate (1.5
to 3 times normal range) at the beginning of therapy. They may return to
normal with dose reduction or even spontaneously.
- acute liver disorders with high serum transaminases and/or jaundice,
including hepatic failure, sometimes fatal (see section 4.4)
Angioedema (there have been some reports of angioedema, although exact
• Very rare: benign intra-cranial hypertension (pseudo tumor cerebri), headache.
Respiratory, thoracic and mediastinal disorders:
- interstitial pneumonitis (see section 4.4)
- severe respiratory complications (adult acute respiratory distress
syndrome), sometimes fatal (see sections 4.4 and 4.5)
- bronchospasm and/or apnoea in case of severe respiratory failure, and
• Common: decrease in blood pressure, usually moderate and transient.
Cases of hypotension or collapse have been reported following overdosage
There is no information regarding overdosage with intravenous amiodarone.
Little information is available regarding acute overdosage with oral amiodarone. Few cases of sinus bradycardia, heart block, attacks of ventricular tachycardia, torsades de pointes, circulatory failure and hepatic
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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Amiodacore is a product for the treatment of tachyarrhythmias and has complex pharmacological actions. Its effects are anti-adrenergic (partial alpha and beta blocker). 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.
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.
5.3 Preclinical safety data
There are no pre-clinical 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
Benzyl alcohol, Polysorbate 80 and Water for Injections.
Amiodacore Injection is incompatible with saline and should be
administered solely in 5% dextrose solution. Amiodacore Injection, diluted
with 5% dextrose solution to a concentration of less than 0.6mg/ml, is unstable. Solutions containing less than 2 ampoules Amiodacore Injection 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-ethylhexylphthalate) 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
6.4 Special precautions for storage
Do not store above 25oC. Store in the original container.
6.5 Nature and contents of container
Each carton contains 5 or 6 glass ampoules.
6.6 Special precautions for disposal and other handling
Refer to 4.2 above.
7. MARKETING AUTHORISATION HOLDER
: Sanofi Aventis, France
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