Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Aventis Pharma Limited, One Onslow Street, Guildford, Surrey, GU1 4YS, UK or trading as: Sanofi-aventis or Sanofi, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
All these above contra-indications do not apply to the use of amiodarone for cardiopulmonary resuscitation of shock resistant ventricular fibrillation.
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.
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.
Cordarone X Intravenous 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).
Do not mix other preparations in the same syringe. Do not inject other preparations in the same line. If Cordarone X should be continued, this should be via intravenous infusion (see section 4.2).
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 Cordarone X 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 4.3).
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.
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, Cordarone X 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.
Cases of severe, potentially life-threatening bradycardia and heart block have been observed when amiodarone is used in combination with sofosbuvir in combination with another hepatitis C virus (HCV) direct acting antiviral (DAA), such as daclatasvir, simeprevir, or ledipasvir. Therefore, coadministration of these agents with amiodarone is not recommended.
If concomitant use with amiodarone cannot be avoided, it is recommended that patients are closely monitored when initiating sofosbuvir in combination with other DAAs. Patients who are identified as being at high risk of bradyarrhythmia should be continuously monitored for at least 48 hours in an appropriate clinical setting after initiation of the concomitant treatment with sofosbuvir.
Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on sofosbuvir alone or in combination with other direct DAAs.
Patients receiving these hepatitis C medicines with amiodarone, with or without other medicines that lower heart rate, should be warned of the symptoms of bradycardia and heart block and should be advised to seek urgent medical advice if they experience them.
Amiodarone IV may induce hyperthyroidism, particularly in patients with a personal history of thyroid disorders or patients who are taking/have previously taken oral amiodarone. Serum usTSH level should be measured when thyroid dysfunction is suspected.
Amiodarone contains iodine and thus may interfere with radio-iodine uptake. However, thyroid function tests (free-T3, free-T4, usTSH) remain interpretable. Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, free-T3 being slightly decreased or even normal) in clinically euthyroid patients. There is no reason in such cases to discontinue amiodarone treatment if there is no clinical or further biological (usTSH) evidence of thyroid disease.
Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity such as interstitial pneumonitis. 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 4.8). Clinical symptoms often resolve within a few weeks followed by slower radiological and lung function improvement. Some patients can deteriorate despite discontinuing Cordarone X. 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).
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.
Life-threatening or even fatal cutaneous reactions Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) (see section Section 4.8). If symptoms or signs of SJS, TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present amiodarone treatment should be discontinued immediately.
If blurred or decreased vision occurs, complete ophthalmologic examination including fundoscopy should be promptly performed. Appearance of optic neuropathy and/or optic neuritis requires amiodarone withdrawal due to the potential progression to blindness.
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 hypokalaemia.
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.
Some of the more important drugs that interact with amiodarone include warfarin, digoxin, phenytoin and any drug which prolongs the QT interval.
Combined therapy with the following drugs which prolong the QT interval is contra-indicated (see section 4.3 Contraindications) due to the increased risk of torsade de pointes; for example:
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).
Combined therapy with the following drugs is not recommended:
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 B.
In cases of hypokalaemia, corrective action should be taken and QT interval monitored. In case of torsade 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.
Very rare cases of severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal, have been observed usually in the period immediately following surgery. A possible interaction with a high oxygen concentration may be implicated.
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.
Amiodarone is a P-gp inhibitor. Co administration with P-gp substrates is expected to result in an increase in their exposure.
Administration of Cordarone X 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), a synergistic effect on heart rate and atrioventricular conduction may occur. Clinical, ECG and biological monitoring is recommended to observe for signs of digitalis toxicity and digoxin dosage should be halved.
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.
Amiodarone raises the plasma concentrations of CYP 2C9 substrates such as oral anticoagulants (warfarin) and phenytoin by inhibition of the cytochrome P450 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.
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.
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:
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.
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.
Coadministration of amiodarone with sofosbuvir in combination with another HCV direct acting antiviral (such as daclatasvir, simeprevir, or ledipasvir) is not recommended as it may lead to serious symptomatic bradycardia. The mechanism for this bradycardia effect is unknown.
If coadministration cannot be avoided, cardiac monitoring is recommended (see section 4.4).
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, except in exceptional circumstances.
Amiodarone is excreted into the breast milk in significant quantities and breast-feeding is contra-indicated.
Not relevant.
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.
Frequency not known: Neutropenia, agranulocytosis
Common: bradycardia, generally moderate.
Very rare: marked bradycardia, sinus arrest requiring discontinuation of amiodarone, especially in patients with sinus node dysfunction and/or in elderly patients, onset of worsening of arrhythmia, sometimes followed by cardiac arrest (see sections 4.4 and 4.5)
Frequency not known: Torsade de pointes (see 4.4 and 5.1)
Frequency not known: Optic neuropathy/neuritis that may progress to blindness (see section 4.4)
Frequency not known: Hyperthyroidism (see section 4.4)
Very rare: Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Very rare: nausea
__Pancreatitis/acute pancreatitis
Common: injection site reactions such as pain, erythema, oedema, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes
Very rare: 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)
Very rare: anaphylactic shock
Frequency not known: Angioneurotic oedema (Quincke’s Oedema)
Frequency not known: Back pain
Very rare: benign intra-cranial hypertension (pseudo tumor cerebri), headache
Very rare: interstitial pneumonitis or fibrosis, sometimes fatal (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 especially in asthmatic patients.
Frequency not known: Confusional state/delirium
Frequency not known: Libido decreased
Common: Eczema
Very rare: sweating
Frequency not known: Urticaria, severe skin reactions sometimes fatal including toxic epidermal necrolysis/Stevens-Johnson syndrome, Bullous dermatitis and Drug reaction with eosinophilia and systematic symptoms.
Common: decrease in blood pressure, usually moderate and transient. Cases of hypotension or collapse have been reported following overdosage or a too rapid injection
Very rare: hot flushes
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Cordarone X Intravenous is incompatible with saline and should be administered solely in 5% dextrose solution. Cordarone X Intravenous, diluted with 5% dextrose solution to a concentration of less than 0.6mg/ml, is unstable. Solutions containing less than 2 ampoules Cordarone X Intravenous 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.
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