CORDARONE X Solution for injection Ref.[6724] Active ingredients: Amiodarone

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

Contraindications

  • 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, Cordarone X should be used only in conjunction with a pacemaker.
  • 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 Cordarone X Intravenous 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 Cordarone X with drugs which may induce torsades de pointes is contra-indicated (see section 4.5).
  • Due to the content of benzyl alcohol, Cordarone X Intravenous is contraindicated in newborns or premature 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.

Special warnings and precautions for use

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.

Cardiac disorders

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.

Severe Bradycardia (see section 4.5)

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.

Endocrine disorders (see section 4.8)

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.

Respiratory, thoracic and mediastinal disorders (see section 4.8)

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).

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.

Severe bullous reactions

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.

Eye disorders (see section 4.8)

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.

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 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.

Interaction with other medicinal products and other forms of interaction

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

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:

  • 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, amisulpiride 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 inhibitors (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction slowing effects may occur.
  • Stimulant laxatives, which may cause hypokalaemia thus increasing the risk of torsade 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 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.

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 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.

Effect of Cordarone X 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 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.

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

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 range.
  • Statins: the risk of muscular toxicity (e.g. rhabdomyolysis) 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, dihydroergotamine and ergotamine and colchine.

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 Cordarone X

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.

Other drug interactions with amiodarone (see section 4.4)

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).

Pregnancy and lactation

Pregnancy

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.

Lactation

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

Effects on ability to drive and use machines

Not relevant.

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).

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.

Frequency not known: Neutropenia, agranulocytosis

Cardiac disorders

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)

Eye disorders

Frequency not known: Optic neuropathy/neuritis that may progress to blindness (see section 4.4)

Endocrine disorders

Frequency not known: Hyperthyroidism (see section 4.4)

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

Gastrointestinal disorders

Very rare: nausea

__Pancreatitis/acute pancreatitis

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

Hepato-biliary disorders

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)

Immune system disorders

Very rare: anaphylactic shock

Frequency not known: Angioneurotic oedema (Quincke’s Oedema)

Musculoskeletal and Connective Tissue Disorders

Frequency not known: Back pain

Nervous system disorders

Very rare: benign intra-cranial hypertension (pseudo tumor cerebri), headache

Respiratory, thoracic and mediastinal disorders

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.

Psychiatric disorders

Frequency not known: Confusional state/delirium

Reproductive system and breast disorders

Frequency not known: Libido decreased

Skin and subcutaneous tissue disorders

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.

Vascular disorders

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 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Incompatibilities

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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