Consumer medicine information

APO-Amiodarone tablets

Amiodarone hydrochloride

BRAND INFORMATION

Brand name

APO-Amiodarone

Active ingredient

Amiodarone hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Amiodarone tablets.

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

The name of your medicine is APO- Amiodarone tablets. It contains the active ingredient amiodarone hydrochloride.

It is used to treat tachyarrhythmia (an excessively fast heart rate with an irregular rhythm).

Amiodarone belongs to a group of medicines called antiarrhythmics.

It works by lengthening the time between one heartbeat and the next, helping to bring the heart rate to a slower pace and more regular rhythm.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed amiodarone for another reason.

This medicine is available only with a doctor's prescription.

There is no evidence that this medicine is addictive.

Use in children

Amiodarone should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • any medicine containing amiodarone or iodine
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you have any of the following medical conditions:

  • thyroid problems
  • certain heart problems that may cause you to faint (check with your doctor), unless your doctor advises you can use amiodarone in combination with a pacemaker.

Do not take this medicine if you are pregnant. Amiodarone may affect your developing baby if you take it during pregnancy. Amiodarone should be avoided in the 3 months before becoming pregnant and during pregnancy.

Do not breastfeed if you are taking this medicine. Amiodarone passes into human breast milk. Do not take amiodarone if you are breastfeeding.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • other heart conditions
  • blood pressure problems
  • liver problems
  • breathing or lung (respiratory) problems
  • family history of thyroid disorders.

Tell your doctor if you have or have a pacemaker or implantable defibrillator.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and amiodarone may interfere with each other. These include:

  • beta-blocking agents or calcium antagonists used for the heart and blood pressure
  • digoxin, used to treat heart conditions
  • stimulant laxatives used to treat constipation
  • diuretics (also known as fluid or water tablets)
  • fluoroquinolones, erythromycin and intravenous pentamidine, antibiotics used to treat infections
  • medicines which reduce the activity of your immune system, such as cyclosporin, cortisone, tetracosactide or tacrolimus
  • intravenous amphotericin B, used for fungus infections
  • MAO inhibitors, used to treat depression
  • warfarin and other medicines which thin the blood
  • flecainide or sotalol, used to treat abnormal heart rhythms
  • phenytoin, used to treat epilepsy
  • certain types of statins such as simvastatin, atorvastatin or lovastatin, used to lower cholesterol
  • fentanyl, a painkiller
  • sildenafil, used for erectile dysfunction and hypertension
  • triazolam, used to treat insomnia
  • dihydroergotamine or ergotamine, used to treat migraine
  • anaesthesia and oxygen used during surgery
  • midazolam, used for pain relief and in anaesthetics
  • lignocaine, a topical anaesthetic
  • colchicine, used for gout
  • antiviral medicines such as sofosbuvir, daclatasvir, simeprevir, ledipasvir.

These medicines may be affected by amiodarone or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

The following medicines may cause torsades de pointes (a rare type of excessively fast heart rate). Do not take these medicines at the same time as amiodarone:

  • digoxin
  • disopyramide
  • procainamide
  • quinidine
  • mexiletine
  • sotalol
  • bepridil
  • vincamine
  • cisapride
  • certain antipsychotics (medicines used to treat certain mental and emotional conditions)
  • clarithromycin, erythromycin, azithromycin and intravenous pentamidine.

Other medicines not listed above may also interact with amiodarone.

How to take this medicine

Follow all directions from your doctor carefully. They may be different from the information in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

The usual dose is outlined below:

Initial Dose
200 mg three times a day for one week. The dose is then reduced to 200 mg twice a day for a further week.

Maintenance Dose
The dose may then be reduced to 200 mg once a day (or less if your doctor says so).

How to take it

Swallow the tablets with a glass of water.

When to take it

Take it at about the same time each day. Taking your medicine at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it for

Continue taking your medicine for as long as your doctor tells you. Amiodarone helps to control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time to take your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you experiencing side effects.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant or start breastfeeding while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure amiodarone is working and to prevent unwanted side effects. These include:

  • ECG
  • eye tests
  • chest X-rays
  • liver function tests
  • thyroid tests.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

Amiodarone may cause drowsiness, dizziness or blurred vision in some people, especially after the first dose.

Be careful when drinking alcohol while you are taking amiodarone. The combination may make you feel more sleepy, dizzy or light-headed and less alert than usual.

Always use a 30+ sunscreen and wear a hat when outdoors. Do not use a sunlamp. Taking amiodarone tablets may make your skin more sensitive to the sun. This can range from an increased tendency to tan to intense redness and swelling.

Avoid drinking large quantities of grapefruit juice as it may affect the absorption of amiodarone.

Side effects

Tell your doctor as soon as possible if you do not feel well while taking amiodarone or if you have any concerns.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Treatment with amiodarone may cause serious lung, liver and eye damage and may worsen heart problems.

Tell your doctor if you notice any of the following:

  • symptoms of an overactive thyroid including increase in appetite, weight loss, restlessness, heat intolerance, increased sweating, tremors, swelling of your neck (goitre) and a rapid heart rate
  • symptoms of an underactive thyroid including tiredness, lethargy, muscle weakness, cramps, feeling the cold, a slow heart rate, dry and flaky skin, hair loss, a deep and husky voice and weight gain
  • rash or hives
  • a feeling of "pins and needles" or numbness in the hands, legs or feet
  • muscle weakness, uncontrolled movements or poor coordination
  • small cloudy spots on the eyeball
  • increased skin sensitivity to sunlight - always wear sunscreen while taking amiodarone
  • grey or bluish skin discolourations on areas exposed to the sun
  • unusual taste sensation
  • tremor, insomnia or vivid dreams
  • constipation
  • loss of appetite
  • slow heartbeat.

Tell your doctor immediately if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • fever, a painful, red rash that spreads quickly, which may peel or blister around the eyes, nose, mouth and genitals (rare life- threatening skin reactions)
  • yellowing of the skin or eyes (called jaundice, a symptom of liver changes)
  • clumsiness and lack of coordination, affecting balance and manner of walking, limb or eye movements and/or speech
  • chest pain, cough or spitting up blood
  • nausea or vomiting, stomach pain, unusual tiredness or passing dark-coloured urine
  • changes to heartbeat such as pounding heart, very rapid or very slow heartbeat
  • fainting or feeling faint
  • blurring or deterioration of vision, sensitisation of eyes to light.
  • shortness of breath, wheezing or other difficulty in breathing
  • swelling of the face, lips, mouth, tongue or throat

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

Keep this medicine in its original packaging until it is time to take them. If you take the tablets out of their original packaging they may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C. Protect it from light.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a windowsill or in the car on hot days. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and- a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine, or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Amiodarone tablets looks like

200 mg tablets:
White, round tablets, biconvex, scored on one side.

They are available in blister packs of 30 tablets. AUST R 80768.

Ingredients

Each tablet contains 200 mg amiodarone hydrochloride as the active ingredient.

It also contains the following inactive ingredients:

  • maize starch
  • lactose
  • povidone
  • magnesium stearate
  • . colloidal anhydrous silica

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

This leaflet was last updated in: July 2019.

Published by MIMS September 2019

BRAND INFORMATION

Brand name

APO-Amiodarone

Active ingredient

Amiodarone hydrochloride

Schedule

S4

 

1 Name of Medicine

Amiodarone hydrochloride.

2 Qualitative and Quantitative Composition

Each tablet contains 200 mg amiodarone hydrochloride as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White, round tablets, biconvex with score on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Severe cases of tachyarrhythmias (e.g. Wolff-Parkinson-White syndrome; supraventricular, nodal and ventricular tachycardias; atrial flutter and fibrillation; ventricular fibrillation) not responding to other therapy. Treatment should be initiated in hospital. It is recommended that the patient should be regularly monitored for possible toxicity (e.g. thyroid function, chest X-ray, ophthalmological examination, hepatic function) during the entire course of therapy and for several months after discontinuation.

4.2 Dose and Method of Administration

APO-Amiodarone tablets are intended for oral administration.

Dosage.

Due to poor absorption and wide inter-patient variability of absorption, the initial loading and subsequent maintenance dosage schedules in clinical use of the drug have to be individually titrated. It is particularly important that the minimum effective dose be used. In all cases, the patient's management must be judged on the individual response and wellbeing.
The following dosage regimen is usually effective.

Adults.

Initial stabilisation.

Treatment should be started with 200 mg three times daily and may be continued for one week. The dosage should then be reduced to 200 mg twice daily for a further week.

Maintenance.

After the initial period the dosage should be reduced to 200 mg daily, or less if appropriate. Rarely, the patient may require a higher maintenance dose. A scored 100 mg amiodarone tablet (available in other brands) should be used to titrate the minimum dosage required to maintain control of the arrhythmia. The maintenance dose should be regularly reviewed, especially where this exceeds 200 mg daily.

General considerations.

The high initial dose is necessary because of the slow onset of action whilst the necessary tissue levels of amiodarone are achieved. However, excessive dosing during maintenance therapy can cause side effects, some of which are believed to be related to excessive tissue retention of amiodarone. Side effects slowly disappear as the tissue levels fall after the dosage is reduced or the drug withdrawn. If the drug is withdrawn, residual tissue bound amiodarone may persist for 3-12 months, but the likelihood of re-occurrence of cardiac arrhythmias during this period should be a consideration. The important factor is that the patient requires monitoring regularly to ensure that adverse effects are detected early and the dosage adjusted accordingly. It is particularly important that the minimum effective dose be used.

Use in the elderly.

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 used. Particular attention should be paid to monitoring of thyroid function.

4.3 Contraindications

Known hypersensitivity to amiodarone, iodine or to any of the excipients in the tablet.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in 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 atrioventricular conduction disorders, amiodarone should only be used in conjunction with a pacemaker.
Evidence or a history of thyroid dysfunction.
Combined therapy with drugs that may induce torsades de pointes (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Sinus bradycardia and sinoatrial heart block.

4.4 Special Warnings and Precautions for Use

It is recommended to perform an ECG and serum potassium measurement before treatment initiation.
Caution should be exercised in case of hypotension, severe respiratory failure, uncompensated or severe heart failure.

Thyroid hormone abnormalities.

As amiodarone may induce thyroid disorders (see Section 4.8 Adverse Effects (Undesirable Effects)), particularly in patients with personal or family history of thyroid disorders, clinical and biological monitoring [ultrasensitive TSH (usTSH) assay] is recommended before starting treatment, during treatment and for several months following treatment discontinuation. Serum usTSH levels should be measured when thyroid dysfunction is suspected. Severe cases, with clinical presentation of thyrotoxicosis, sometimes fatal, require emergency therapeutic management.
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 thyroxine (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.
Hypothyroidism should be suspected if the following clinical signs, usually slight, occur: weight gain, cold intolerance, reduced activity, excessive bradycardia. The diagnosis is supported by a clear increase in serum usTSH. Euthyroidism is usually obtained within 1-3 months following the discontinuation of treatment. In life-threatening situations, amiodarone therapy can be continued, in combination with L-thyroxine. The dose of L-thyroxine is adjusted according to TSH levels.

Hyperthyroidism.

Hyperthyroidism may occur during amiodarone treatment or up to several months after discontinuation. Clinical features, usually slight, such as weight loss, onset of arrhythmia, angina and congestive heart failure should alert the physician. The diagnosis is supported by a clear decrease in serum usTSH level, in which case amiodarone should be withdrawn. Recovery usually occurs within a few months following withdrawal of treatment; clinical recovery precedes the normalisation of thyroid function tests. Severe and sometimes fatal cases, with clinical presentation of thyrotoxicosis, require emergency therapeutical management. The treatment should be adjusted to each individual case: for example anti-thyroid drugs, corticosteroid therapy, beta-blockers.

Neuromuscular disorders.

Amiodarone may induce peripheral sensorimotor neuropathy and/or myopathy. Recovery usually occurs within several months after amiodarone withdrawal, but may sometimes be incomplete.

Pacemakers/implantable defibrillators.

In the context of chronic administration of antiarrhythmic drugs, cases of increase in ventricular defibrillation and/or pacing threshold of pacemakers or implantable cardioverter defibrillator devices have been reported, potentially affecting their efficacy. Therefore, a repeated verification of the functioning of such devices before and during amiodarone treatment is recommended.

Anaesthesia.

Before surgery the anaesthetist should be informed that the patient is taking amiodarone.

Cardiac disorders.

The pharmacological action of amiodarone induces ECG changes such as QT prolongation (related to prolonged repolarisation), with the possible development of U-waves.
Amiodarone 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 Section 4.8 Adverse Effects (Undesirable Effects), More common 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 AV block, sinoatrial block, bifascicular or trifascicular block.
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 are more rarely reported with amiodarone than with the other antiarrhythmic agents, and generally occur in the context of drug interactions and/or electrolytic disorders (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Cases of severe, potentially life-threatening bradycardia and heart block have been observed when amiodarone is used in combination with sofosbuvir alone or in combination with another hepatitis C virus (HCV) direct acting antiviral (DAA), such as daclatasvir, simeprevir or ledipasvir. Therefore, co-administration 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 alone or 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 (such as shortness of breath, light-headedness, palpitations and fainting) and should be advised to seek urgent medical advice if they experience them.

ECG monitoring.

Regular electrocardiographic (ECG) monitoring is recommended in patients on long-term therapy with amiodarone. U-waves, deformed T-waves and QT prolongation (related to prolonged repolarisation) 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; torsades de pointes), particularly in elderly patients or during digitalis or other antiarrhythmic therapy. In such circumstances amiodarone should be temporarily withdrawn.

Ocular changes.

Corneal deposits develop in almost all patients (see Section 4.8 Adverse Effects (Undesirable Effects), More common reactions, Ocular) and regular ophthalmological monitoring (e.g. slit lamp biomicroscopy, visual acuity, ophthalmoscopy, etc.) is recommended. If blurred or decreased vision occurs, complete ophthalmological 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.

Pulmonary disorders.

Clinical and radiological evidence of pulmonary fibrosis and/or pneumonitis has been reported sometimes presenting as unexplained or disproportionate dyspnoea (see Section 4.8 Adverse Effects (Undesirable Effects), More common reactions, Respiratory). Regular chest X-ray should be performed routinely in patients undergoing long-term therapy or when diagnosis is suspected. 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 Section 4.8 Adverse Effects (Undesirable Effects)), such as interstitial pneumonitis. Very rare cases of interstitial pneumonitis have been reported with intravenous amiodarone. A chest X-ray should be performed when the diagnosis is suspected, in patients developing effort dyspnoea whether isolated or associated with deterioration of general health status (fatigue, weight loss, fever). Amiodarone therapy should be re-evaluated since interstitial pneumonitis is generally reversible following early withdrawal of amiodarone (clinical signs usually resolving within 3-4 weeks, followed by slower radiological and lung pulmonary function improvement within several months) and corticosteroid therapy should be considered.
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.

Hepatic dysfunction.

Regular monitoring of liver function tests (transaminases) is recommended as soon as amiodarone is started and during treatment.
Elevation of hepatic enzyme levels (e.g. serum aspartate aminotransferase, serum alanine aminotransferase, glutamyl transpeptidase) 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 Section 4.8 Adverse Effects (Undesirable Effects), More common reactions, Hepatic) and close monitoring of hepatic function with liver function tests is recommended as soon as amiodarone is started and regularly during treatment.
Acute liver disorders (including severe hepatocellular insufficiency or hepatic failure, sometimes fatal) and chronic liver disorders may occur with oral and intravenous forms. Therefore, amiodarone dose should be reduced or the treatment discontinued if the transaminases increase exceeds three times the normal range. Clinical and biological signs of chronic liver disorders due to oral amiodarone may be minimal (hepatomegaly, transaminases increased up to five times the normal range) and reversible after treatment withdrawal, however fatal cases have been reported.

Use in hepatic impairment.

Because of the potential risk of hepatotoxicity and/or accumulation, amiodarone should be used with extreme caution in patients with hepatic disease.

Skin reaction.

Photosensitivity is quite common (see Section 4.8 Adverse Effects (Undesirable Effects), More common reactions, Dermatological) and there is a wide spectrum of skin reactions, ranging from an increased propensity to suntan 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.
If symptoms or signs of Stevens-Johnson syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) (e.g. progressive skin rash often with blisters or mucosal lesions) are present, amiodarone treatment should be discontinued immediately.

Neurological toxicity.

Peripheral neuropathy could occur in patients on long-term high dosage (generally over 400 mg/day) regime (see Section 4.8 Adverse Effects (Undesirable Effects), More common reactions, Central 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, and myopathy 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.

Use in renal impairment.

Renal excretion of the drug is minimal. This suggests that modification of the dose of amiodarone in patients with renal failure is unnecessary.

Drug interactions.

Concomitant use of amiodarone is not recommended with the following drugs: beta-blockers, heart rate lowering calcium channel inhibitors (verapamil, diltiazem) or stimulating laxative agents which may cause hypokalaemia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

In the elderly, heart rate may decrease markedly.

Paediatric use.

The safety and efficacy of amiodarone in paediatric patients have not been established. Therefore its use in paediatric patients is not recommended.

Effects on laboratory tests.

Thyroid function tests.

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 protein-bound iodine (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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Drugs inducing torsades de pointes.

Combined therapy with drugs that may induce torsade de pointes is contraindicated (see Section 4.3 Contraindications).

Antiarrhythmic agents.

Such as: Class IA antiarrhythmic agents:
Disopyramide: Combined treatment of amiodarone and disopyramide causes an increase in the QT interval.
Procainamide: Serum levels of procainamide increase significantly with co-administration of amiodarone and secondary to this increase cardiac, gastrointestinal and neural toxicity may develop.
Quinidine: Atypical ventricular tachycardia with QT prolongation may develop after amiodarone is added to a stable quinidine regimen. This is thought to be due to either a change in the protein or receptor binding of quinidine. Serum levels of quinidine can increase significantly with concomitant amiodarone therapy. Careful monitoring of the electrocardiogram for QT interval prolongation and of serum levels of quinidine is indicated when amiodarone is added to quinidine treatment.
Mexiletine: Co-administration with amiodarone increases QT interval.
Sotalol.
Bepridil.

Non-antiarrhythmic agents.

Such as vincamine, some neuroleptic agents, cisapride, erythromycin, clarithromycin, azithromycin or pentamidine IV, as there is an increase in the risk of potentially lethal torsades de pointes.

Drugs prolonging QT.

Co-administration of amiodarone with drugs known to prolong the QT interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsades de pointes may increase (see Section 4.4 Special Warnings and Precautions for Use) and patients should be monitored for QT prolongation.
Fluoroquinolones should be avoided in patients receiving amiodarone.

Drugs lowering heart rate or causing automaticity or conduction disorders.

Combined therapy with the following drugs is not recommended:

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 and conduction disorders may occur.

Calcium antagonists.

Co-administration of amiodarone with drugs of the calcium antagonist type may lead to undue bradycardia and conduction disorders may occur.

Monoamine oxidase (MAO) inhibitors.

Co-administration with MAOIs is contraindicated on theoretical grounds.

Agents which may induce hypokalaemia.

Combined therapy with the following drugs is not recommended:

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.
Caution should be exercised when using the following drugs in combination with amiodarone:
Diuretics inducing hypokalaemia, either alone or combined.
Systemic corticosteroids (gluco-, mineralo-); tetracosactide.
Amphotericin B (IV).
It is necessary to prevent the onset of hypokalaemia (and to correct hypokalaemia); the QT interval should be monitored and, in case of torsades de pointes, antiarrhythmic agents should not be given (ventricular pacing should be initiated; IV magnesium may be used).

General anaesthesia.

(See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
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, sometimes fatal, have been observed most often in the period immediately after surgery. A possible interaction with a high oxygen concentration may be implicated.

Effect of amiodarone on other medicinal products.

Amiodarone and/or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein (P-gp) 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.

P-gp substrates.

Amiodarone is a P-gp inhibitor. Co administration with P-gp substrates is expected to result in an increase of their exposure.

Digitalis.

Digoxin co-administration of amiodarone to patients already receiving digitalis increases plasma digoxin concentrations by about 70% this is possibly due to the decrease in digoxin clearance and therefore precipitates toxicity and could lead to disturbances in automaticity (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. ECG and digoxin plasma levels should be monitored and patients should be observed for clinical signs of digoxin toxicity. It may be necessary to adjust dosage of digoxin treatment.

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 concentrations of CYP2C9 substrates such as warfarin or phenytoin by inhibition of the cytochrome P450 2C9.

Warfarin and other anticoagulant agents.

Amiodarone raises the concentration of warfarin. The combination of amiodarone potentiates the effect of the anticoagulant therapy and increases the risk of bleeding. More frequent monitoring of prothrombin (INR) level and dosage adjustment of oral anticoagulant during treatment with, and after discontinuation of, amiodarone therapy is necessary.

Phenytoin.

Amiodarone raises plasma concentrations of phenytoin. The combination of phenytoin and amiodarone may lead to an 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.

CYP2D6 substrates.

Flecainide.

Amiodarone increases the concentration of flecainide plasma levels through inhibition of the cytochrome CYP2D6. Dosage of flecainide should be adjusted.

CYP3A4 substrates.

When such drugs are co-administered with amiodarone, an inhibitor of CYP3A4, this may result in a higher level of their plasma concentrations, which may lead to a possible increase in their toxicity.

Cyclosporin.

Dosage should be adjusted because decreased clearance of this drug can possibly increase cyclosporin plasma levels.

Fentanyl.

Combination with amiodarone may enhance the pharmacological effects of fentanyl and increase the risk of its toxicity.

Statins metabolised by CYP3A4.

The risk of muscular toxicity is increased by concomitant administration of amiodarone with statins metabolised by CYP3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolised by CYP3A4 when given with amiodarone.

Other drugs metabolised by CYP3A4.

Lignocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine, colchicine.

Effect of other medicinal products on amiodarone.

CYP3A4 inhibitors and CYP2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure. It is recommended to avoid CYP3A4 inhibitors (e.g. grapefruit juice and certain medicinal products) during treatment with amiodarone.
Co-administration of amiodarone with sofosbuvir, alone or 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 co-administration cannot be avoided, cardiac monitoring is recommended (see Section 4.4 Special Warnings and Precautions for Use).
Consideration should be given to the possibility that amiodarone may alter the plasma concentration of other drugs, particularly those which are highly protein bound.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Because of the long half-life of amiodarone and its major metabolite, and the potential to cause abnormal thyroid function, effects on the foetal thyroid gland, and bradycardia in the foetus, its use is probably best avoided in the three months before and throughout the duration of pregnancy. Amiodarone is contraindicated in 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 where a 35 year-old woman was administered amiodarone in the last weeks of pregnancy, the 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 Section 4.8 Adverse Effects (Undesirable Effects), More common 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 is 75 mg in a 200 mg dose of amiodarone) during pregnancy may cause foetal goitre, hypothyroidism and mental retardation.
Another patient received 800 mg amiodarone for one week (maintenance dose thereafter was 400 mg daily) in her 34th week of pregnancy. Neonatal level of amiodarone was 25% of the maternal level. Although the infant's liver and thyroid function tests were normal, it was bradycardic during labour and for the first 48 hours after birth.
 As amiodarone and its desethyl metabolite are secreted in breast milk and its safety in the newborn infant has not been established, it should not be given to breastfeeding mothers. Amiodarone is contraindicated in breastfeeding mothers. If a situation demands that amiodarone be given to a breastfeeding mother, alternative infant feeding should be instituted.

4.7 Effects on Ability to Drive and Use Machines

According to the safety data for amiodarone, there is no evidence that amiodarone impairs the ability to drive a vehicle or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Amiodarone has been reported to cause frequent and potentially serious toxicity. The incidence, variety and severity of the effects varied 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 the underlying disease state, and individual variation in the pharmacokinetic profile of the drug.

More common reactions.

Biochemical abnormalities.

Abnormal liver function tests (increased AST, ALT and alkaline phosphatase) have been reported.
Abnormal thyroid function tests (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).

Cardiovascular.

Atypical ventricular tachycardia (torsades 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 two patients given disopyramide and amiodarone, on withdrawal of the amiodarone, the disopyramide did not induce atypical ventricular tachycardia.

Bradycardia.

Marked bradycardia or sinus arrest has occasionally been reported in patients with sinus node dysfunction or elderly patients. Reports of moderate and dose related bradycardia are common.

Cardiac failure.

Exacerbation of cardiac failure has been reported rarely.

Other.

Sinus arrest and intrahisian block have been reported.

Dermatological.

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, during the course of radiotherapy; 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.

Gastrointestinal.

Nausea, vomiting, anorexia, constipation and dysgeusia have been reported.

Endocrine.

Effects on the thyroid.

Both hyperthyroidism 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 triiodothyronine (rT3) may also be found.
Hyperthyroidism occurring during amiodarone therapy could be serious and sometimes fatal 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 six 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 physician. 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 FTI may be low.
Courses of antithyroid 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.

Hepatic.

Elevations of hepatic enzymes may occur from time to time during therapy and are usually transient or respond to a reduction in dosage. Isolated elevation of serum transaminases, which are usually moderate, 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 high serum transaminases and/or jaundice, including hepatic failure, 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 sometimes fatal chronic liver disease (pseudo alcoholic hepatitis, cirrhosis). Clinical signs and biological changes may be minimal (possible hepatomegaly, transaminases elevated 1.5-5x 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.

Central nervous system.

CNS effects include tremor, insomnia, headaches, dizziness, vertigo, fatigue, sleep disorders, vivid dreams, nightmares, paraesthesia, gait abnormalities and abnormal nerve conduction. Extrapyramidal symptoms appeared in 2 of 51 (4%) patients taking 800 mg/day amiodarone for 4-18 months and in one patient given 100 mg/day for 5-6 days, respectively.
Uncommon reports of peripheral sensorimotor neuropathy and/or myopathy, usually reversible on withdrawal of the drug, have been received. 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 from 4-18 months. Proximal muscle weakness has been described in 4-6% of patients, with thigh muscle being involved in patients taking high doses (800 mg/day or more).

Ocular.

Corneal microdeposits occur in over 90% of patients. In one study, microdeposits were present in 30% of patients at 5-8 weeks, in 55% at three months and in 95% at nine months. In another study corneal deposits took eight weeks to develop, but were evident in all patients.
Amiodarone keratopathy is related to dosage and duration of treatment. Patients on low doses (100-200 mg/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 (400-1400 mg/day) develop stage 2 (characterised by additional arborising 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 between 3-7 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 coloured haloes in dazzling light or blurred vision. Corneal microdeposits consist of complex lipid deposits and are reversible following discontinuation of treatment.
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 should be promptly performed. Appearance of optic neuropathy and/or optic neuritis requires amiodarone withdrawal due to the potential progression to blindness.

Psychiatric.

Chronic anxiety has been reported.

Respiratory.

Cases of pulmonary toxicity (alveolar/interstitial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans organising 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 3-4 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).

Less common reactions.

Cardiovascular.

Onset or worsening of arrhythmia, sometimes followed by cardiac arrest.
Conduction disturbances (sinoatrial block, AV block of various degrees).
Marked bradycardia or sinus arrest in patients with sinus node dysfunction and/or in elderly patients.
Cases of torsades de pointes have been reported.

Dermatological.

Enhanced pustular psoriasis has been observed.
Alopecia, urticaria and eczema have been reported.

Genitourinary.

Worsening of chronic renal failure and one case of symptomatic hypercalcaemia have been reported.

Haematological.

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.
These include vasculitis, renal involvement with elevation of creatinine levels, thrombocytopenia.
Very rarely, cases of haemolytic anaemia or aplastic anaemia have also been reported.
Neutropenia, agranulocytosis and granuloma, including bone marrow granuloma has been reported.

Immunological.

Positive antinuclear antibodies and elevated immunoglobulin levels were noted in one patient with amiodarone induced pulmonary fibrosis.

Musculoskeletal and connective tissue disorders.

Lupus-like syndrome has been reported.

Nervous system.

Delay in nerve conduction.
Parkinsonism and parosmia have also been reported.

Ocular.

Interference with visual acuity has been rarely observed in association with corneal microdeposits; gritty eyes; blurred vision; itching or burning.

Endocrine.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Gastrointestinal.

Pancreatitis/acute pancreatitis, dry mouth, constipation and decreased appetite have been reported.

Psychiatric disorders.

Confusional state/delirium and hallucination have very occasionally been reported.

Other.

There have been reports of epididymitis, epididymo-orchitis, impotence and decreased libido.
Isolated cases of angioneurotic oedema (Quincke's oedema) and pulmonary haemorrhage have been reported. Cerebellar ataxia, benign intracranial hypertension (pseudotumour cerebri) are very rarely reported.

Serious or life-threatening reactions.

Cardiovascular.

Bradycardia, conduction disturbances; atypical ventricular tachycardia.

Respiratory.

Pulmonary fibrosis and/or alveolitis.

Immune system disorders.

Anaphylactic/anaphylactoid reaction including shock.

Dermatological.

Severe skin reactions, sometimes fatal, including toxic epidermal necrolysis/Stevens-Johnson syndrome, bullous dermatitis and drug reaction with eosinophilia and systemic symptoms.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

A case of attempted suicide with 2,600 mg amiodarone is reported in the literature. No clinical symptoms, changes in heart rate or blood pressure were reported. The ECG revealed considerable lengthening of the QT interval and T-wave inversion in the precordial leads with transient disappearance of R-wave in leads V1 to V4, simulating an anteroseptal infarction.
In another case of attempted suicide with 8 g amiodarone, the only symptom reported was profuse perspiration. No signs of cyanosis, dyspnoea or decreased sensitivity were found. No clinical side effects were documented over the monitored period of 3 months.
Overdosage 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, amiodarone should be temporarily withdrawn and if necessary, beta-adrenostimulants or glucagon given.

Treatment.

In the event of ingestion of a toxic dose, general supportive measures should be applied in the event of ingestion of a toxic dose.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Site and mode of action.

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 atrioventricular (AV) node, both anterograde and retrograde, explains the efficacy of the drug in nodal tachycardias caused by re-entry through the AV node.
Its action on ventricular arrhythmias is explained by a number of mechanisms. The effect on the atrium and AV 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.

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.

AV node.

It reduces the speed of conduction and increases the refractory period of the atrioventricular 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.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

In general, pharmacokinetic data relating to amiodarone are incomplete.

Absorption.

Amiodarone is incompletely and erratically absorbed following oral administration. Absolute bioavailability ranges from 22% to 86%, but there is extensive inter-subject variation.

Distribution.

An HPLC method is available for estimation of amiodarone plasma levels. However, the value of this is limited because the correlation of therapeutic effect and plasma level has not been established. Steady state plasma levels are generally around 1-2 microgram/mL, although inter-subject variations are common.
Considerably higher values have been reported, especially subsequent to large single doses. Peak plasma concentrations of 6.9 ± 4.2 microgram/mL have been recorded following a single dose of 1600 mg and 1.7 ± 0.3 microgram/mL after a single dose of 800 mg. Steady state levels of 1.57 ± 0.1 microgram/mL and 3.9 microgram/mL have been recorded after daily oral dosing in the range 800-1800 mg.
The half-life of amiodarone is long and with chronic oral dosing can be from 14 to 110 days, but is usually in the range 14-59 days. The principal metabolite of amiodarone, which has been detected in the plasma and other tissues, is desethylamiodarone. This metabolite is reported to have a longer half-life than amiodarone i.e. 10 hours after a single dose of amiodarone and 60-90 days after chronic dosing with amiodarone. The activity of this metabolite is not known.
Amiodarone is highly protein bound and is thought to bind strongly to protein at concentrations of 10 microgram/mL.
The apparent volume of distribution after oral (200-400 mg) amiodarone is 6.31 ± 4.93 L/kg. Amiodarone appears to accumulate in adipose tissue and in highly perfused organs (lung, bone marrow, adrenals, liver, pancreas, heart, spleen and kidney). The concentration of amiodarone in packed red blood cells is approximately 60% of that in plasma.

Metabolism.

First-pass metabolism in the gut wall and/or in the liver may be a factor in determining the availability of the drug.

Excretion.

It is believed that most of the drug is excreted via the liver and gastrointestinal tract by biliary excretion. There may be some hepatic recirculation.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

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 affect thyroid function.

6 Pharmaceutical Particulars

6.1 List of Excipients

Maize starch, lactose monohydrate, povidone, magnesium stearate, colloidal anhydrous silica.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Blister packs (PP/Al or PVC/PVDC/Al) of 30. AUST R 80768.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Amiodarone hydrochloride is a white, fine crystalline powder, very slightly soluble in water and soluble in alcohol and chloroform. It is an amphiphilic compound and contains iodine in its formulation.
Chemical Name: 2-butyl-3-benzofuranyl 4-(2-diethylaminoethoxy)-3, 5-di-iodophenyl ketone hydrochloride.
Molecular Formula: C25H29I2NO3.HCl.
Molecular Weight: 681.8.

Chemical structure.


CAS number.

19774-82-4.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes