Chemical formula: C₂₅H₂₉I₂NO₃ Molecular mass: 645.312 g/mol PubChem compound: 2157
Amiodarone interacts in the following cases:
Co-administration of amiodarone with drugs known to prolong the QT interval (such as clarithromycin) must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase and patients should be monitored for QT prolongation.
CYP2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure.
Amiodarone raises the plasma concentrations of oral anticoagulants (warfarin) and phenytoin by inhibition of CYP2C9.
Given that CYP 2D6 substrates are mainly metabolised by CYP 2D6, by inhibiting this isoenzyme, amiodarone may increase CYP 2D6 substrates plasma levels; it is advised to reduce the CYP 2D6 substrates dose by 50% and to monitor the patient closely for adverse effects. Monitoring of CYP 2D6 substrates plasma levels is strongly recommended in such circumstances.
CYP3A4 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure. It is recommended to avoid CYP3A4 inhibitors during treatment with amiodarone.
When CYP P450 3A4 substrates 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.
Grapefruit juice inhibits cytochrome P450 3A4 and may increase the plasma concentration of amiodarone. Grapefruit juice should be avoided during treatment with oral amiodarone.
Amiodarone is a P-gp inhibitor. Co administration with P-gp substrates is expected to result in an increase of their exposure.
Combined therapy of amiodarone with agents which may induce hypokalaemia, such stimulant laxatives, which may cause hypokalaemia thus increasing the risk of torsades de pointes) is not recommended.
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.
Combined therapy with Class Ia anti-arrhythmic drugs e.g. quinidine, procainamide, disopyramide prolongs the QT interval is contra-indicated due to the increased risk of torsades de pointes.
Caution should be exercised over combined therapy of amiodarone 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.
Concomitant use of amiodarone with fluoroquinolones should be avoided (concomitant use with moxifloxacin is contraindicated). There have been rare reports of QTc interval prolongation, with or without torsades de pointes, in patients taking amiodrone with fluoroquinolones.
Combined therapy of amiodarone with drugs lowering heart rate or causing automaticity or conduction disorders, such beta blockers and heart rate lowering calcium channel inhibitors (diltiazem, verapamil) is not recommended. Potentiation of negative chronotropic properties and conduction slowing effects may occur.
Plasma levels of ciclosporin may increase as much as 2-fold when used in combination with amiodarone. A reduction in the dose of ciclosporin may be necessary to maintain the plasma concentration within the therapeutic range.
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.
Administration of amiodarone 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.
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.
Amiodarone raises the plasma concentrations of phenytoin by inhibition of CYP2C9. Phenytoin dosage should be reduced if signs of overdosage appear (resulting in neurological signs), and plasma levels may be measured.
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.
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.
Amiodarone raises the plasma concentrations of warfarin by inhibition of CYP2C9. The dose of warfarin should be reduced accordingly. More frequent monitoring of prothrombin time both during and after amiodarone treatment is recommended.
Amiodarone may induce hypothyroidism or hyperthyroidism, particularly in patients with a personal history of thyroid disorders. Clinical and biological [including ultrasensitive TSH (usTSH)] monitoring should be performed prior to therapy in all patients. Monitoring should be carried out during treatment, at six-monthly intervals, and for several months following its discontinuation. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular assessment is recommended. 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.
Hypothyroidism should be suspected if the following clinical signs occur: weight gain, cold intolerance, reduced activity, excessive bradycardia. The diagnosis is supported by an increase in serum usTSH and an exaggerated TSH response to TRH. T3 and T4 levels may be low. Euthyroidism is usually obtained within 3 months following the discontinuation of treatment. In life-threatening situations, amiodarone therapy can be continued, in combination with levothyroxine. The dose of levothyroxine is adjusted according to TSH levels.
Hyperthyroidism may occur during amiodarone treatment, or, up to several months after discontinuation. Clinical features, such as weight loss, asthenia, restlessness, increase in heart rate, onset of arrhythmia, angina, congestive heart failure should alert the physician. The diagnosis is supported by a decrease in serum usTSH level, an elevated T3 and a reduced TSH response to thyrotropin releasing hormone. Elevation of reverse T3 (rT3) may also be found.
In the case of hyperthyroidism, therapy should be withdrawn. Clinical recovery usually occurs within a few months, although severe cases, sometimes resulting in fatalities, have been reported. Clinical recovery precedes the normalisation of thyroid function tests.
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 (e.g. 1 mg/kg prednisolone) may be required for several weeks.
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.
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, sometimes fatal, most often in the period immediately after surgery have been observed. A possible interaction with a high oxygen concentration may be implicated.
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.
If, because of the long half-life of amiodarone, discontinuation of the drug is considered prior to planned conception, the real risk of reoccurrence of life threatening arrhythmias should be weighed against the possible hazard for the foetus.
Amiodarone is excreted into the breast milk in significant quantities and breast-feeding is contra-indicated.
The ability to drive or to operate machinery may be impaired in patients with clinical symptoms of amiodarone-induced eye disorders.
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).
*Oral administration:
Very rare: haemolytic anaemia, aplastic anaemia, thrombocytopenia
In patients taking amiodarone there have been incidental findings of bone marrow granulomas. The clinical significance of this is unknown.
Common: bradycardia, generally moderate and dose-related
Uncommon: onset or worsening of arrhythmia, sometimes followed by cardiac arrest, conduction disturbances (sinoatrial block, AV block of various degrees)
Very rare: marked bradycardia or sinus arrest in patients with sinus node dysfunction and/or in elderly patients
Not known: Torsade de pointes
Common: hypothyroidism, hyperthyroidism, sometimes fatal
Very rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Very common: corneal microdeposits usually limited to the area under the pupil, which are usually only discernable by slit-lamp examinations. They may be associated with colored halos in dazzling light or blurred vision. Corneal micro-deposits consist of complex lipid deposits and are reversible following discontinuation of treatment. The deposits are considered essentially benign and do not require discontinuation of amiodarone.
Very rare: optic neuropathy/neuritis that may progress to blindness
Very common: benign gastrointestinal disorders (nausea, vomiting, dysgeusia) usually occurring with loading dosage and resolving with dose reduction
Common: constipation
Uncommon: dry mouth
Not known: pancreatitis/acute pancreatitis
Not known: Granuloma, including bone marrow granuloma
Very common: isolated increase in serum transaminases, which is usually moderate (1.5 to 3 times normal range), occurring at the beginning of therapy. It may return to normal with dose reduction or even spontaneously.
Common: acute liver disorders with high serum transaminases and/or jaundice, including hepatic failure, which are sometimes fatal
Very rare: chronic liver disease (pseudo alcoholic hepatitis, cirrhosis), sometimes fatal.
Not known: Angioneurotic oedema (Quincke’s Oedema), Anaphylactic shock/anaphylactoid reaction including shock
Very rare: increase in blood creatinine
Not known: decreased appetite
Not known: lupus like syndrome
Common: extrapyramidal tremor, for which regression usually occurs after reduction of dose or withdrawal, nightmares, sleep disorders
Uncommon: peripheral sensorimotor neuropathy and/or myopathy, usually reversible on withdrawal of the drug
Very rare: cerebellar ataxia, for which regression usually occurs after reduction of dose or withdrawal, benign intracranial hypertension (pseudo- tumor cerebri), headache, vertigo
Not known: parkinsonism, parosmia
Not known: confusional state/delirium
Very rare: epididymo-orchitis, impotence
Common:__ pulmonary toxicity [hypersensitivity pneumonitis, alveolar/interstitial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans organising pneumonia (BOOP)], sometimes fatal
Very rare:__ bronchospasm in patients with severe respiratory failure and especially in asthmatic patients, surgery (possible interaction with a high oxygen concentration)
Pulmonary haemorrhage (there have been some reports of pulmonary haemorrhage, although exact frequencies are not known)
Very common: photosensitivity
Common: slate grey or bluish pigmentations of light-exposed skin, particularly the face, in case of prolonged treatment with high daily dosages; such pigmentations slowly disappear following treatment discontinuation, eczema
Very rare: erythema during the course of radiotherapy, skin rashes, usually non-specific, exfoliative dermatitis, alopecia
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
Very rare: vasculitis
IV administration:
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
Frequency not known: Torsade de pointes
Frequency not known: Optic neuropathy/neuritis that may progress to blindness
Frequency not known: Hyperthyroidism
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
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, severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal, 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
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