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Amiodarone hydrochloride is a Class III antiarrhythmic agent. The active ingredient of Amiodarone Hydrochloride Injection Concentrate is amiodarone hydrochloride (2-n-butyl-3(4-(2-diethylaminoethoxy)-3,5-diiodobenzoyl) benzofuran hydrochloride).
Amiodarone hydrochloride is a fine white crystalline powder. It is slightly soluble in water and is soluble in alcohol and chloroform. It is an amphiphilic compound and contains iodine in its formulation.
Amiodarone Hydrochloride Injection Concentrate is a clear, slightly yellow sterile solution of amiodarone hydrochloride, polysorbate 80 and benzyl alcohol in water for injections. The pH of the solution is approximately 3.5. Amiodarone Hydrochloride Injection Concentrate is available in 150 mg/3 mL and 300 mg/6 mL presentations.
Amiodarone is a Class III antiarrhythmic agent prolonging the action potential duration and hence refractory period of atrial, nodal and ventricular tissues, thereby giving a very broad spectrum of activity. An increase in the refractory period of the atrial cells is a major contributing action to the control of atrial tachyarrhythmias.
A reduction in the permeability of the A-V node, both anterograde and retrograde, explains the efficacy of the drug in nodal tachycardias caused by re-entry through the A-V node.
Its action on ventricular arrhythmias is explained by a number of mechanisms. The effect on the atrium and A-V node results in a reduction in the frequency of stimuli reaching the ventricle thus giving the ventricular cell mass time to repolarise in cases where there has been desynchronisation of the refractory periods. Furthermore, a lengthening of the refractory period of the His-Purkinje system and ventricular contractile fibres reduces or prevents micro re-entry. Amiodarone increases coronary blood flow, decreases cardiac oxygen requirements without producing negative inotropic effects and also suppresses ectopic pacemakers, and this is particularly valuable in arrhythmias associated with ischaemic damage or angina pectoris.
The site and mode of action of amiodarone can be summarised in terms of its effect on myocardial electrophysiology.
Sinus Node: It decreases sinus automaticity by reducing the slow diastolic depolarisation gradient in the nodal cell. This is a direct effect and is not mediated through the sympathetic or parasympathetic system.
Atrio-Ventricular (A-V) Node: It reduces the speed of conduction and increases the refractory period of the A-V node.
His-Purkinje System: It increases the refractory period but does not modify the speed of conduction of the His-Purkinje system.
Contractile Fibres: It increases the action potential but does not alter the rate of depolarisation of the atrial or ventricular myocardial cells; an effect that is more marked in the atria than the ventricles.
Amiodarone exhibited peak drug concentrations from 5 - 41 micrograms/mL in a study of healthy individuals receiving a single intravenous dose of 5 mg/kg of amiodarone hydrochloride over 15 minutes. Peak drug concentrations of 7 - 26 micrograms/mL followed a 10 minute intravenous infusion of 150 mg amiodarone hydrochloride in patients with ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT). Amiodarone has a rapid distribution phase, which results in a 10% decline in peak values within 30 - 45 minutes of the completion of infusion. In clinical trials after 48 hours of continuous intravenous infusions (125, 500, or 1000 mg daily) plus supplemental infusions (150 mg) as required for recurrent arrythmias, mean serum concentrations of amiodarone ranged from 0.7 - 1.4 micrograms/mL. There is no established relationship between drug concentration and therapeutic response for short term intravenous use.
Distribution of amiodarone into human body tissues has not been fully characterised. Following intravenous administration in rats, amiodarone is distributed extensively into many tissues, including adipose tissue, liver, kidneys, heart, and to a lesser extent, the CNS. Following chronic oral administration in humans, amiodarone and N-desethylamiodarone are distributed extensively into many body tissues and fluids including adipose tissue, liver, lung, spleen, skeletal muscle, bone marrow, adrenal galnds, kidneys, pancreas, testes, semen, saliva, lymph nodes, myocardium, thyroid gland, skin and brain, as well as bile. The apparent volume of distribution of the drug or its major metabolite, desethylamiodarone, in healthy adults reportedly averages 65.8 L/kg (range: 18.3 - 147.7 L/kg) or ranges from 68 -168 L/kg, respectively, in healthy adults following a single intravenous dose. Amiodarone is highly protein bound (>96%). Amiodarone and desethylsmiodarone are reported to cross the placenta and appear in breast milk.
The principal metabolite of amiodarone, which has been detected in the plasma and other tissues, is N-desethylamiodarone. The enzymes responsible for the formation of this metabolite are believed to be the cytochrome P450 3A (CYP 3A) subfamily - principally CYP 3A4, which occurs in both the liver and intestines. The activity of N-desethylamiodarone in humans is not known, but in animals it is reported to possess antiarrhythmic activity.
Following a single intravenous dose in healthy adults, the half life of the drug in the terminal elimination phase has been reported to average 25 days (range 9-47 days). The elimination half life of N-desethylamiodarone is equal to or longer than that of the parent compound. Total plasma clearance of amiodarone averages about 1.9 mL/minute per kg (range: 1.4 -2.5 mL/minute per kg) following intravenous administration in healthy individuals. Amiodarone and N-desethylamiodarone, are excreted almost completely in faeces, presumably via biliary elimination. Renal excretion of amiodarone and desethylamiodarone appears to be negligible. Limited data suggests that amiodarone may undergo enterohepatic circulation.
Treatment should be initiated only under hospital or specialist supervision.
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 agents cannot be used. The injection is to be used when a rapid response is required.
Amiodarone Hydrochloride Injection Concentrate should only be used when facilities exist for cardiac monitoring and defibrillation, should the need arise. Intravenous injection is generally not advised because of hemodynamic risks (severe hypotension, circulatory collapse). Intravenous infusion should be preferred whenever it is possible.
The standard recommended dose is 5 mg/kg body weight given by intravenous infusion over a period of 20 minutes to 2 hours. This should be administered as a dilute solution in 250 mL 5% glucose.
Amiodarone Hydrochloride Injection Concentrate is incompatible with saline and should be administered solely in 5% glucose solution.
This may be followed by repeat infusions up to 1200 mg (approximately 15 mg/kg body weight) in up to 500 mL 5% glucose per 24 hours, the rate of infusion being adjusted on the basis of clinical response.
In extreme clinical emergency Amiodarone Hydrochloride Injection Concentrate may, at the discretion of the clinician, be given as a slow injection of 150-300 mg in 10-20 mL 5% glucose over a minimum of 3 minutes. This should not be repeated for at least 15 minutes. Patients treated in this way must be closely monitored, eg in an intensive care unit.
Do not mix amiodarone with other preparations in the same syringe or infusion solution.
Solutions containing less than 2 ampoules Amiodarone Hydrochloride Injection Concentrate in 500 mL 5% glucose are unstable and should not be used.
When given by infusion Amiodarone Hydrochloride Injection Concentrate may reduce drop size and, if appropriate, adjustments should be made to the rate of infusion.
Repeated or continuous infusion via the peripheral veins may lead to local discomfort and inflammation. When repeated or continuous infusion is anticipated, administration by a central venous catheter is recommended.
Experience has shown that amiodarone can be absorbed into PVC infusion bags and administration sets possibly because of the presence of plasticisers in PVC plastic. It is important to prepare the infusion solution immediately prior to use in either glass or rigid PVC bottles containing no plasticisers.
As with all patients it is important 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 used. Particular attention should be paid to monitoring of thyroid function.
Known hypersensitivity to iodine or amiodarone.
Pregnancy and Lactation (See under Pregnancy and Lactation).
In patients in whom bradycardia or AV block is sufficient to cause syncope, patients with sick sinus syndrome (risk of sinus arrest) or with severe conduction disorders, Amiodarone Hydrochloride Injection Concentrate should only be used in conjunction with a pacemaker.
Sinus bradycardia and sino-atrial heart block.
Amiodarone Hydrochloride Injection Concentrate is contraindicated in patients with evidence, or a history of thyroid dysfunction.
Combined therapy with drugs which may induce Torsades de Pointes (See under Drug Interactions).
Amiodarone Hydrochloride Injection Concentrate is contraindicated in the case of hypotension, severe respiratory failure, myocardiopathy, heart failure, circulatory collapse and severe arterial hypotension.
It is recommended to perform an ECG and serum potassium measurement before treatment initiation.
As amiodarone may induce thyroid disorders (see Adverse Reactions), particularly in patients with personal or family history of thyroid disorders, clinical and biological monitoring is recommended before starting treatment, ultrasensitive TSH (usTSH) assay, during treatment and for several months following treatment discontinuation. Serum usTSH levels should be measured when thyroid dysfunction is suspected.
Regular monitoring of liver function tests (transaminases) is recommended during treatment.
Amiodarone Hydrochloride Injection Concentrate is not contraindicated in patients with latent or manifest heart failure but caution should be exercised as existing heart failure may occasionally be worsened. In such cases amiodarone should be associated with the usual cardiotonic and diuretic treatment.
Excessive doses may lead to atropine resistant bradycardia and to conduction disturbances, particularly in elderly patients or during digitalis therapy. Amiodarone, like quinidine and disopyramide, has caused atypical ventricular tachycardia (see Adverse Reactions - Cardiovascular). In patients with previous history of the above condition, amiodarone should be avoided. Use of higher doses of amiodarone is not advisable in persons with a history of atypical ventricular tachycardia previously induced by another antiarrhythmic agent.
Treatment should be discontinued in case of onset of 2nd or 3rd degree A-V block, sinoatrial block or bifascicular block.
Regular ECG monitoring is recommended in patients on long term therapy with amiodarone. U waves, deformed T waves and QT prolongation may occur in the ECG because of the fixing of amiodarone in the myocardial tissues and is not an indication for withdrawing amiodarone.
The prolongation of QT interval occurs in almost all patients as this is related to the electrophysiological and antiarrhythmic properties of the drug. Prolongation of the actual QT above 0.60 seconds rather than QTC or QRS widening, may be an important warning sign that requires modification of therapy. Too high a dosage may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm (atypical ventricular tachycardia; Torsade de Pointes) particularly in elderly patients or during digitalis or other antiarrhythmic therapy. In such circumstances amiodarone should be temporarily withdrawn.
Corneal deposits develop in almost all patients (see Adverse Reactions - Ocular) and regular ophthalmological monitoring (e.g. slit lamp biomicroscopy, visual acuity, ophthalmoscopy, etc) is recommended.
Clinical and radiological evidence of pulmonary fibrosis and/or pneumonitis has been reported sometimes presenting as unexplained or disproportionate dyspnoea (see Adverse Reactions - Respiratory). Regular chest X-ray should be performed routinely in patients undergoing long term therapy. The effect has usually been reversible with corticosteroid therapy and/or reduction or withdrawal of amiodarone therapy.
Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity (see Adverse Reactions).
Elevation of liver enzyme (e.g. serum aspartate aminotransferase, serum alanine aminotransferase, glutamyl transpeptidase) levels occurs quite commonly in patients undergoing treatment with amiodarone and in some cases are asymptomatic. The changes appear to be dose dependent rather than an idiosyncratic type. Hepatotoxicity has occasionally been reported (see Adverse Reactions - Hepatic) and regular monitoring of hepatic function with liver function tests is recommended during treatment. If patients present with abnormal liver function tests dosage reduction should be considered. If liver function tests continue to rise despite reduction in dosage or in situations where dosage reduction is not feasible, discontinuation of the drug should be considered.
Because of the potential risk of hepatotoxicity and/or accumulation, amiodarone should be used with extreme caution in patients with hepatic disease.
Photosensitivity is quite common (see Adverse Effects - Dermatological) and there is a wide spectrum of skin reactions, ranging from an increased propensity to suntan during the summer months to intense burning and erythema and swelling of the exposed area. The intensity of these reactions could be alleviated by a reduction in dosage or by application of a protective sunscreen. Patients should be instructed to avoid exposure to the sun or use protective measures during therapy.
Some patients have developed skin pigmentation (slate grey/purple colour) of the exposed areas. This pigmentation can be avoided if doses are kept as low as possible. If the pigmentation is cosmetically unsightly, amiodarone should be discontinued if alternative therapy is possible.
Peripheral neuropathy could occur in patients on long term high dosage (generally over 400 mg/day) regime (see Adverse Effects - Nervous system).
Intracellular inclusion bodies, similar to those seen in skin have been demonstrated in peripheral nerve fibres. Sensorimotor neuropathy, with a glove and stocking distribution have been reported in patients. Histologically, segmental demyelination of the nerve fibres has also been demonstrated. After discontinuation of the drug, the neurological complication is slowly and incompletely resolved.
Renal excretion of the drug is minimal. This suggests that modification of the dose of amiodarone in patients with renal failure is unnecessary.
In a carcinogenicity study in rats, amiodarone caused a dose related increase in thyroid follicular tumours (adenomas and/or carcinomas) in both sexes. Although mutagenicity findings were negative, an epigenic rather than genotoxic mechanism is proposed for this type of tumour induction. In the mouse, carcinomas were not observed but dose dependent thyroid follicular hyperplasia was seen. The relevance of these findings to man is unknown. Clinical experience has indicated that amiodarone can effect thyroid function.
Because of the long half-life of amiodarone and its major metabolite, and the potential to cause abnormal thyroid function and bradycardia in the foetus, its use is probably best avoided in the three months before and throughout the duration of pregnancy. Where exposure of the foetus is unavoidable, thyroid function (including TSH) should be assessed promptly in the newborn infant.
No teratogenic effects have been observed in animals. The drug does cross the placenta. In one study a 35 year old woman administered amiodarone in the last weeks of pregnancy, transplacental passage of amiodarone and desethylamiodarone was found to be 10% and 25% respectively. Changes in maternal thyroid function were similar to those seen in other patients receiving amiodarone therapy (see Adverse Reactions - Endocrine) but there was no evidence of clinical hyperthyroidism. The baby's TSH level on day 4 was normal and it had no goitre and was clinically euthyroid. However the authors caution the use of amiodarone in pregnancy or in those likely to conceive whilst on amiodarone therapy. The long half-life of the drug requires that the drug be stopped several months before conception. The possible adverse effects of amiodarone on the foetal thyroid are of concern since administration of iodine (of which there are 75mg in a 200mg dose of amiodarone) during pregnancy may cause foetal goitre, hypothyroidism and mental retardation.
Another patient received 800mg amiodarone for 1 week (maintenance dose thereafter was 400mg daily) in her 34th week of pregnancy. Neonatal levels of amiodarone were 25% of the maternal level. Although the infants liver and thyroid function tests were normal it was bradycardic during labour and for the first 48 hours after birth. Amiodarone is contraindicated in pregnancy.
As amiodarone and its desethyl metabolite are secreted in breast milk and its safety in the new-born has not been established, it should not be given to nursing mothers. If a situation demands that amiodarone be given to a nursing mother, alternative infant feeding should be instituted.
Amiodarone Hydrochloride Injection Concentrate may cause moderate and transient reduction in blood pressure, and circulatory collapse may be precipitated by too rapid administration or overdosage. Atropine has been successfully used in such patients presenting with bradycardia. Temporary hot flushes, sweating, nausea have also been reported with Amiodarone Hydrochloride Injection Concentrate.
Amiodarone has been reported to cause frequent and potentially serious toxicity. The incidence, variety and severity of the effects varies from study to study. Most of the adverse effects are also related to dosage and duration of amiodarone, concurrent use of other antiarrhythmic agents, severity of underlying disease state, and individual variation in pharmacokinetic profile of the drug.
Possible inflammation of veins following intravenous infusion that may be avoided by the use of a central venous catheter.
Hot flushes and sweating.
Decrease in blood pressure, usually moderate and transient. Cases of severe hypotension or collapse have been reported following overdosage or a too rapid injection.
Moderate bradycardia. In some cases, and especially in elderly patients, marked bradycardia, or more exceptionally sinus arrest, requires the discontinuation of therapy.
Occurrence of arrhythmia, or aggravation of the pre-existing trouble, followed in some cases by cardiac arrest have been reported. In view of current knowledge, it is not possible to differentiate what may be due to the drug, from what may be related to the underlying cardiac condition, or what may be the result of a lack of efficacy of therapy. These effects are more rarely reported than with most of the other anti-arrhythmic agents and they occur in general in case of certain drug interactions or electrolyte disorders.
Isolated elevation of serum transaminases, which are usually moderate (1.5 to 3 times normal) have been reported at the beginning of therapy. They may regress with dose reduction or even spontaneously.
A few cases of acute liver disorders with elevated serum transaminases and/or jaundice, which included some fatalities have also been reported. Treatment should be discontinued and monitoring of liver function tests is therefore recommended.
A few isolated cases of anaphylactic shock and benign intra-cranial hypertension (pseudotumor cerebri) have been reported.
Bronchospasm and/or apnoea in the case of pre-existing severe respiratory failure and in asthmatic patients have also been reported.
Abnormal liver function tests (increased AST, ALT and alkaline phosphatase) have been reported.
Abnormal thyroid function tests (see Interference with Clinical, Laboratory, and Other Tests).
Atypical Ventricular Tachycardia (Torsade de Pointes): Amiodarone-induced atypical ventricular tachycardia has been described. Earlier reports describe combination therapy in which other drugs, or clinical situations, could have been implicated. However, in 2 patients given disopyramide and amiodarone, on withdrawal of the amiodarone, the disopyramide did not induce atypical ventricular tachycardia.
Bradycardia: significant sinus bradycardia has occasionally been reported.
Cardiac Failure: exacerbation of cardiac failure has been reported rarely.
Other: sinus arrest and intrahisian block have been reported.
Photosensitivity commonly occurs in patients on amiodarone therapy. This can usually be alleviated by the use of topical sunscreen and other protective measures. Less frequently bluish skin discolouration and slate grey facial pigmentation have been reported. These adverse effects are partially dependent on dose and duration of treatment. Erythema, facial flushing and hair loss have been reported.
Skin rashes, usually non-specific, including exceptional cases of exfoliative dermatitis have been reported; the relationship with the drug has not been formally established.
Nausea and more rarely vomiting, anorexia, constipation and salty or metallic taste in mouth have been reported.
Effects on the Thyroid: Both hyper- and hypothyroidism have occurred during or soon after treatment with amiodarone. Simple monitoring of the usual biochemical tests is confusing because some (PBI and 131I uptake) are invalidated and others (T4, T3 and FTI) may be altered where the patient is clearly euthyroid. Clinical monitoring is therefore recommended before starting treatment, during treatment and should be continued for some months after discontinuation of amiodarone treatment. Serum usTSH level should be measured when thyroid dysfunction is suspected.
The signs of thyroid hyperactivity to be sought are weight loss, asthenia, restlessness, recurrence of cardiac dysrhythmia, onset of angina or congestive heart failure. The diagnosis may be confirmed by the finding of an elevated serum triiodothyronine (T3), a low level of thyroid stimulating hormone (TSH) and a reduced TSH response to thyrotropin releasing hormone (TRH). (Elevation of reverse tri iodothyronine (rT3) may also be found). Hyperthyroidism occurring during amiodarone therapy could be serious due to coexistence of ischaemic heart disease and/or life threatening arrhythmias in most of the patients. The risk of developing hyperthyroidism persists for at least 3 months after discontinuation of treatment.
Patients who receive amiodarone should be instructed to consult their physician in the event of exacerbation of angina or recurrence of tachycardia after successful therapeutic response, even when such untoward episodes occur up to 6 months after the drug is discontinued.
The clinical features of hypothyroidism such as weight gain, reduced activity and/or, excessive bradycardia with regard to the expected effect of amiodarone, should alert the clinician. The onset may be abrupt. The diagnosis may be supported by the presence of an elevated serum TSH level and an exaggerated TSH response to TRH. The thyroxine (T4), T3 and free thyroxine index (FTI) may be low.
Courses of anti-thyroid drugs have been used for the treatment of thyroid hyperactivity; large doses may be required initially.
Thyroid hypofunction may be treated cautiously with L-thyroxine.
Other: Weight gain has occasionally been reported.
Elevations of liver enzymes may occur from time to time during therapy and are usually transient or respond to a reduction in dosage.
A few cases of acute liver disorders with high serum transaminases and/or jaundice have also been reported; in such cases treatment should be discontinued, which results in most cases in normalisation of liver function tests. However, some cases of death related to acute liver disorders have infrequently been reported.
There have also been reports of chronic liver disease (pseudo alcoholic hepatitis, cirrhosis). Clinical signs and biological changes may be minimal (possible hepatomegaly, transaminases elevated 1.5 to 5 times normal). Regular monitoring of liver function is therefore recommended during therapy. Clinical and biological abnormalities usually regress when treatment is stopped but fatal cases have been reported.
CNS effects include tremor, insomnia, headaches, dizziness, vertigo, fatigue, vivid dreams, paraesthesia, gait abnormalities, and abnormal nerve conduction. Extrapyramidal symptoms appeared in 2 of 51 (4%) patients taking 800 mg/day of amiodarone for 4 to 18 months and in one patient given 100 mg/day for 5 to 6 days respectively.
Several cases of neuropathy indicating amiodarone-induced neurolipidosis have been reported. In two studies electron microscope findings are detailed. Neuromyopathy has been reported in one patient given alternating doses of 200 to 400 mg/day and peripheral neuropathy in 5 patients taking between 600 and 800 mg/day for periods ranging 4 to 18 months. Proximal muscle weakness has been described in 4 to 6 % of patients, with thigh muscle being involved in patients taking high doses (800 mg/day or more).
Exceptional benign intracranial hypertension (pseudotumor cerebri).
Corneal microdeposits occur in over 90% of patients. In one study microdeposits were present in 30% at 5 to 8 weeks, in 55% at 3 months and in 95% at 9 months. In another study corneal deposits took 8 weeks to develop but were evident in all patients. Amiodarone keratopathy is related to dosage and duration of treatment. Patients on low doses (100 to 200mg/day) retain clear corneas or show stage 1 changes (characterised by the coalescence of fine punctate, greyish golden brown opacities into a horizontal linear pattern in the inferior cornea). Those on high doses (400 to 1400mg/day) develop stage 2 (characterised by additional arborizing and horizontal lines) and stage 3 (characterised by a verticillate, whorl like pattern) changes which are dependent on duration of treatment. The keratopathy progresses, even with reduced dosage, however, complete regression occurs when the drug is withdrawn. Complete clearing is reported to occur from between 3 and 7 months after withdrawal of the drug.
Corneal microdeposits are essentially benign in nature causing no visual disturbances and have only rarely given rise to symptoms such as visual haloes.
A few cases of neuropathy/optic neuritis have been reported. At present, the relationship to amiodarone has not been formally established. If blurred or decreased vision occurs, ophthalmological examination including fundoscopy is recommended. Appearance of optic neuropathy and/or optic neuritis calls for re-evaluation of amiodarone therapy.
Chronic anxiety has been reported.
Cases of pulmonary toxicity (alveolar/interstital pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans organizing pneumonia/Boop), sometimes resulting in fatalities have been reported.
Chest X-ray should be performed in patients developing dyspnoea (at effort), or any new respiratory symptom, while taking amiodarone, whether in isolation or associated with deterioration of general health status (fatigue, weight loss, fever).
Pulmonary disorders are generally reversible following early withdrawal of amiodarone therapy. Corticosteroid therapy may also be considered. Clinical signs usually resolve within 3 to 4 weeks, followed by slower radiological and lung function improvement (several months).
A few cases of bronchospasm have been reported in patients with severe respiratory failure and especially in asthmatic patients.
A few cases of adult acute respiratory distress syndrome, sometimes resulting in death, have been observed, usually immediately after surgery (a possible interaction with high oxygen concentration may be implicated).
Enhanced pustular psoriasis has been observed.
Worsening of chronic renal failure and one case of symptomatic hypercalcaemia have been reported.
There has been a single case of bone marrow depression but cause and effect was not established.
There have been rare cases of various clinical features which may suggest a hypersensitivity reaction: vasculitis, renal involvement with elevation of creatinine levels, thrombocytopenia.
A few exceptional cases of haemolytic anaemia or aplastic anaemia have also been reported.
Positive antinuclear antibodies and elevated immunoglobulin level were noted in one patient with amiodarone induced pulmonary fibrosis.
Delay in nerve conduction.
Interference with visual acuity has been rarely observed in association with corneal microdeposits; gritty eyes; blurred vision; itching or burning.
There have been reports of epididymo-orchitis as well as some cases of impotence.
Alopecia.
Bradycardia, conduction disturbances; atypical ventricular tachycardia.
Pulmonary fibrosis and/or alveolitis.
Combined therapy with drugs that may induce 'Torsade de Pointes' is contraindicated (see Contraindications ):
Class IA antiarrhythmic agents, including:
Mexiletine: Coadministration with amiodarone increases QT interval.
Sotalol
Erythromycin IV: As there is an increased risk of potentially lethal 'Torsades de Pointes.'
Pentamidine IV: As there is an increased risk of potentially lethal 'Torsades de Pointes.'
Beta adrenergic blocking drugs: Amiodarone itself exhibits noncompetitive alpha and beta adrenergic inhibition. It should be used with caution in patients on beta blockers as it may potentiate bradycardia.
Calcium Antagonists: Coadministration of amiodarone with drugs of the calcium antagonist type may lead to undue bradycardia.
MAO Inhibitors: Coadministration with monoamine oxidase inhibitors is contraindicated on theoretical grounds.
Stimulant laxative agents: Their use may cause hypokalaemia and therefore increase the risk of 'Torsades de Pointes'; other types of laxative agents should be used.
Agents which may induce hypokalaemia: For example: diuretics inducing hypokalaemia, either alone or combined; systemic corticosteroids (gluco-, mineralo-); tetracosactide; amphotericin B (IV).
Ciclosporin: Because of the possible increase of ciclosporin plasma levels related to a decrease of the clearance of this drug, dosages should be adjusted.
Digoxin: Coadministration of amiodarone to patients already receiving digitalis increases plasma digoxin concentrations by about 70% and therefore precipitates toxicity and could lead to severe bradycardia and conduction disturbances with the appearance of idioventricular rhythm. The mechanism of action is unknown but amiodarone may displace tissue glycoside or interfere with digoxin excretion.
General anaesthesia, oxygen therapy: Potentially severe complications have been reported in patients undergoing general anaesthesia, such as bradycardia unresponsive to atropine, hypotension, disturbances of conduction, decreased cardiac output.
A few cases of severe respiratory complications, such as adult acute respiratory distress syndrome, resulting sometimes in fatalities, have been observed most often in the period immediately after surgery. A possible interaction with a high oxygen concentration may be implicated.
Before surgery the anaesthetist should be informed that the patient is taking amiodarone.
Phenytoin: Possible increase in plasma phenytoin levels with signs of overdosage (particularly neurological signs); clinical monitoring should be undertaken and phenytoin dosage should be reduced as soon as overdosage signs appear; phenytoin plasma levels should be determined.
Warfarin and other anticoagulant agents: Amiodarone potentiates anticoagulant therapy and increases the risk of bleeding. More frequent monitoring of prothrombin level and dosage adjustment of oral anticoagulant during treatment with and after discontinuation of amiodarone therapy is necessary.
Other: Consideration should be given to the possibility that Amiodarone Hydrochloride Injection Concentrate may alter the plasma concentration of other drugs particularly those which are highly protein bound.
Amiodarone contains 2 atoms of iodine and bears a structural resemblance to the molecule of thyroxine. A 300 mg maintenance dose of amiodarone has been reported to yield 9 mg/day of iodine at steady state, well in excess of the highest normal dietary intake.
As a consequence of taking the drug and in the absence of any clinical thyroid dysfunction, changes in tests of thyroid function may occur, variable in number and degree. Typically, the PBI, iodine uptake, serum thyroxine (T4), reverse triiodothyronine (rT3) and free thyroxine index (FTI) rise and serum triiodothyronine (T3) falls.
Abnormalities, either multiple or single, may occur in approximately 12% of patients. In particular a low T3 syndrome has been described, as with other drugs such as dexamethasone.
It has been shown that there is a physical incompatibility of heparin and aminophylline with amiodarone when mixed in an infusion administration set. It is recommended that amiodarone for infusion not be mixed with other drugs.
The most likely effects of an inadvertent overdose of intravenous amiodarone are hypotension, cardiogenic shock, bradycardia, AV block and hepatotoxicity.
Management of amiodarone overdosage generally involves symptomatic and supportive care, with ECG and blood pressure monitoring. Hypotension and cardiogenic shock should be treated by slowing the infusion rate or with standard therapy (vasopressor drugs, positive inotropic agents and volume expansion). Bradycardia and AV block may require temporary pacing. Hepatic enzymes should be monitored closely.
There is no specific antidote for amiodarone intoxication. Amiodarone is not dialysable.
Shelf life of Amiodarone Hydrochloride Injection Concentrate is 36 months when stored at 25°C and protected from light.
Prescription Medicine.
Amiodarone Hydrochloride Injection Concentrate is available in glass ampoules in the following presentations.
| Product | Strength | Pack Size |
|---|---|---|
| 150 mg amiodarone hydrochloride/3 mL | 50 mg/mL | 10 ampoules |
| 300 mg amiodarone hydrochloride/6 mL | 50 mg/mL | 10 ampoules |
None.
Hospira NZ Limited
23 Haining Street
Te Aro
Wellington
New Zealand
1 October 2007