Consumer medicine information

Cordarone X

Amiodarone hydrochloride

BRAND INFORMATION

Brand name

Cordarone X

Active ingredient

Amiodarone hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cordarone X.

What is in this leaflet

This leaflet answers some common questions about Cordarone X tablets and injection.

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. In deciding to give you Cordarone X, your doctor has weighed the risks of you taking Cordarone X against the benefits it will have for you.

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

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

What Cordarone X is used for

Cordarone X is used to control a fast or irregular heart beat.

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

Cordarone X is not recommended for use in children.

Your doctor may have prescribed this medicine for another reason.

Ask your doctor or pharmacist if you have any questions about why this medicine has been prescribed for you.

Before you take it

When you must not use Cordarone X

  1. Do not use Cordarone X if you are allergic to amiodarone or iodine or any of the ingredients listed at the end of this leaflet.
The symptoms of an allergic reaction may include a rash, itching, swelling, coughing, an asthma attack or hay fever.
  1. Do not use Cordarone X if you are pregnant or intending to get pregnant.
Cordarone X is best avoided in the 3 months before getting pregnant and during pregnancy. This is because it can stay in the body for several months even after you stop taking it.
  1. Do not breastfeed if you are using Cordarone X as it can be found in breast milk.
    If you are breastfeeding, alternative feeding arrangements such as bottle feeding should be made for your baby.
    Talk to your doctor about the risks and benefits of taking Cordarone X during pregnancy and breastfeeding.
  2. Do not use Cordarone X if you have or have had any thyroid problems.
  3. Do not use Cordarone X if you have heart problems that may cause you to faint.
If you have a pacemaker, your doctor may allow the use of it.
  1. Do not use Cordarone X injection if you have any of the following:
  • Low blood pressure
  • Severe problems in breathing
  • Heart disease or failure
  • Shock
  1. Do not use Cordarone X injection in neonates (children less than one month of age) or premature neonates.

Talk to your doctor if you are unsure whether you have any of the conditions listed above.

Make sure your doctor is aware of all medications you are taking as some medications may affect how Cordarone X works.

Do not use Cordarone X after the expiry (EXP) printed on the pack. It you use the medicine after the expiry date has passed, it may not work as well.

Do not use Cordarone X if the packaging is torn or shows signs of tampering.

Do not use it to treat any other complaint unless your doctor says it is safe. Do not give this medicine to anyone else.

Before you start to use Cordarone X

Tell your doctor if you are pregnant or intend to become pregnant.

Tell your doctor if you are breastfeeding or planning to breastfeed.

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

  • Other heart conditions
  • Blood pressure problems
  • Liver problems
  • Thyroid problems

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

Taking other medicines

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

Some medicines may be affected by Cordarone X, or may affect how well Cordarone X works.

You need to tell your doctor if you are using any other medicines, including:

  • any medicines for your heart
  • any medicines for your blood pressure
  • medicines which reduce the activity of your immune system, such as ciclosporin, cortisone or tacrolimus
  • diuretics (water tablets)
  • antibiotics, including intravenous erythromycin and pentamidine
  • stimulant laxatives e.g. Bisacodyl, castor oil, senna
  • MAO inhibitors (a type of medicine used to treat depression)
  • antipsychotics (medicines used to treat certain mental and emotional conditions)
  • phenytoin (a medicine used to treat epilepsy)
  • warfarin and other medicines which thin the blood
  • simvastatin and other statins (medicines used to lower cholesterol)
  • colchicine (a medicine used to treat gout)
  • digoxin (a medicine used to treat heart conditions)
  • medicines to treat a fast or irregular heart beat such as flecainide and sotalol
  • fentanyl (a medicine used to treat pain)
  • sildenafil (Viagra)
  • triazolam (a medicine used to treat insomnia)
  • ergotamine (a medicine used to treat migraine)
  • general anaesthesia
  • lidocaine (lignocaine) (a topical anaesthetic)
  • amphotericin B (amphotericin) (a medicine used to treat fungal infections)
  • antiviral medication eg sofosbuvir, daclatasvir, simeprevir, ledipasvir

If you are unsure whether you are taking one of the above drugs, ask your doctor or pharmacist. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

If you have not told your doctor about any of these things, tell them before you take Cordarone X.

How to use Cordarone X

How to take it (tablets)

Therapy will be started as soon as possible once your heart beat is controlled. An overlap of up to 2 days with the injection may occur.

Swallow Cordarone X tablets whole, with water or another liquid such as tea or milk.

How much to take (tablets)

The usual dose is outlined below:

  • 200 mg, three times a day for 1 week.
  • Therapy is then continued with 200 mg two times a day for a further week.
  • The dose may then be reduced to 200 mg once per day.

Your doctor or pharmacist will tell you how many Cordarone X tablets you should take.

The directions given to you by your doctor or pharmacist may be different from the information in this leaflet.

Talk to your doctor or pharmacist if you are unsure what dose to take.

Do not stop taking it unless your doctor tells you to, even if you feel better.

How to give it (injection)

The injectable dose will only be given in hospitals.

How much to give (injection)

The usual dose is:

  • 5 mg/kg given slowly over a period of 20 minutes to 2 hours.

Further doses may also be given based upon your response to the treatment. An overlap of up to 2 days with the tablets may occur.

If you forget to take it

If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the dose you missed, and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, or have trouble remembering when to take your medicine, ask your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26 or New Zealand 0800 POISON or 0800 764766), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Cordarone X. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using Cordarone X

Things you must do

Be sure to keep all of your doctor appointments so that your progress can be checked.

  • To help prevent unwanted side effects, your doctor may need to perform the following tests, depending on the length of treatment with Cordarone X:
  • ECG
  • Eye tests
  • Chest X-rays
  • Liver function tests
  • Thyroid tests

Take Cordarone X exactly as your doctor has prescribed.

Tell all the doctors, dentists and pharmacists who are treating you that you are using Cordarone X.

Tell your doctor if you become or intend to become pregnant while using Cordarone X.

Things you must not do

Do not suddenly stop taking Cordarone X without checking with your doctor.

Do not use Cordarone X to treat any other complaints unless your doctor says it is safe.

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

Things to be careful of

Always use a 30+ sunscreen and wear a hat and protective clothing when you are outdoors. Do not use a sunlamp. Using Cordarone X may make your skin more sensitive to the sun or sunlamps. This can range from an increased tendency to tan to intense redness and swelling of the skin.

If you are going to have surgery, tell the anaesthetist that you are using Cordarone X. This medicine may affect some of the medicines that may be needed, such as general anaesthetics.

Tell your doctor or medical professional that you are using Cordarone X before you are given any medical procedure or any new medicines.

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

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while using Cordarone X.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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 and they worry you:

  • symptoms of an overactive thyroid including increase in appetite, weight loss, restlessness, heat intolerance, increased sweating, tremors, swelling of your neck (goiter) 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
  • allergic condition which causes joint pain, skin rashes, fever and kidney problems
  • a feeling of "pins and needles" or numbness in the hands, legs or feet
  • muscle weakness, uncontrolled movements or poor coordination
  • small cloudy spots forming on the eyeball. These usually go away after you stop the drug and they rarely affect your sight
  • increased skin sensitivity to sunlight - always wear a sunscreen
  • bluish skin discolouration
  • rash or hives
  • pain or swelling at the site where you were injected
  • tremor, insomnia or other sleep disorders, vivid dreams or nightmares
  • metallic taste
  • constipation
  • loss of appetite
  • slow heart beat

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

  • yellowing of the skin or eyes (called jaundice, a symptom of liver changes)
  • shortness of breath, wheezing or other difficulty in breathing
  • swelling of the face, lips, mouth, tongue or throat
  • clumsiness and lack of coordination, affecting balance and manner of walking, limb or eye movements and/or speech
  • chest pain, cough or spitting up of blood
  • nausea or vomiting, stomach pain, yellow skin, unusual tiredness or passing dark-coloured urine
  • changes to heartbeat such as pounding heart, very rapid or very slow heartbeat
  • faintness or light headedness
  • blurring or deterioration of vision, sensitisation of eyes to light
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals

These may be serious side effects of Cordarone X. If any of the above symptoms occurs or you suspect any other drug reaction, please consult your doctor immediately.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Your doctor will monitor you very carefully for side effects. This will involve blood tests to check how well your liver and thyroid are functioning. It will also involve regular chest x-rays, ECGs and eye tests.

Your doctor will tell you how often you need to have these tests. This will depend on how long you are on Cordarone X for and what dose you are on.

After using Cordarone X

Storage

Tablets

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the box or blister pack they may not keep well.

Keep it in a cool, dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. 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.

Injection

If you need to store it before taking it to a hospital, make sure it is stored in a place where the temperature is between 8 and 25°C. Do not refrigerate.

Cordarone X injection should only be given to you in a hospital.

Disposal

If your doctor tells you to stop taking Cordarone X, or it has passed its expiry date, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Tablets

Cordarone X tablets are available in two different strengths:

  • 100mg tablets: white to off-white circular tablets, scored on one side with logo on reverse side marked with 100.
  • 200mg tablets: white to off-white circular tablets, scored on one side with logo on reverse side marked with 200.

Each box contains 30 tablets.

Injection

Cordarone X injection is a clear, pale yellow solution. The injection comes as a 3 mL ampoule.

Each box contains 6 ampoules.

Ingredients

Tablets

Active Ingredient:

  • 100mg tablets: each tablet contains amiodarone hydrochloride 100mg.
  • 200mg tablets: each tablet contains amiodarone hydrochloride 200mg.

Other Ingredients:

The tablets also contain lactose monohydrate, maize starch, povidone, anhydrous colloidal silica and magnesium stearate.

Injection

Active Ingredient:

Each 3mL ampoule contains amiodarone hydrochloride 150mg.

Other Ingredients:

The injection also contains benzyl alcohol, polysorbate 80 and water for injections.

Manufacturer

Cordarone X is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113

Cordarone X is supplied in New Zealand by:

sanofi-aventis new zealand limited
Level 8, 56 Cawley Street
Ellerslie
Auckland

This leaflet was prepared in April 2020

Australian Registration Number:

100 mg Tablets: AUST R 15359

200 mg Tablets: AUST R 15361

Injection: AUST R 15360

® Registered Trademark

cordarone-x-ccdsv20-cmiv14-28apr20

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Cordarone X

Active ingredient

Amiodarone hydrochloride

Schedule

S4

 

1 Name of Medicine

Amiodarone hydrochloride.

2 Qualitative and Quantitative Composition

The active ingredient of the Cordarone X range of products is amiodarone hydrochloride.

Tablets.

Each 200 mg tablet of amiodarone contains approximately 75 mg organic iodine and in the steady state, metabolism of 300 mg amiodarone yields 9 mg/day of iodine.

Injection.

Each ampoule contains 150 mg amiodarone hydrochloride in 3 mL.
For the full list of excipients, see Section 6.1 List of Excipients.
Excipient with known effect: Tablets contain Lactose monohydrate.

3 Pharmaceutical Form

Tablets.

Cordarone X 100.

White to off-white circular tablets, scored on one side with logo on reverse side. Approximately 8.7 mm in diameter, each containing 100 mg amiodarone hydrochloride.

Cordarone X 200.

White to off-white circular tablets, scored on one side with logo on reverse side. Approximately 10.5 mm in diameter, each containing 200 mg amiodarone hydrochloride.

Injection.

Cordarone X Intravenous is a clear, pale yellow solution for intravenous administration.

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, liver function etc.) during the entire course of therapy and for several months after discontinuation.
Cordarone X Intravenous may be used for treatment initiated in a hospital for severe cases of tachyarrhythmias (atrial, junctional and ventricular) not responding to other therapy and when a rapid response is required. Cordarone X Intravenous should only be used where facilities exist for cardiac monitoring and defibrillation should the need arise.

4.2 Dose and Method of Administration

Due to poor absorption and wide inter-patient variability of absorption, the initial loading and subsequent maintenance dosage schedules of the drug in clinical use has 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 well being. 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. The scored 100 mg tablet 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 to 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.

Intravenous.

Cordarone X Intravenous injection 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. Cordarone X Intravenous injection is incompatible with saline and should be administered solely in 5% glucose solution.
When repeated or continuous infusion is anticipated, administration by a central venous catheter is recommended to avoid thrombophlebitis. Repeated or continuous infusion via the peripheral veins may lead to local discomfort and inflammation.
This may be followed by repeat infusions up to 1200 mg, i.e. 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 the drug may, at the discretion of the clinician, be given as a slow injection of 150-300 mg in 10-20 mL 5% glucose over 1-2 minutes (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients treated in this way must be closely monitored, e.g. in an intensive care unit.
Do not mix amiodarone with other preparations in the same syringe or infusion solution.
Oral therapy should be initiated as soon as possible after an adequate response is obtained and the intravenous therapy gradually phased out and an overlap of oral and intravenous medication of up to two days is recommended to prevent plasma levels falling and efficacy being lost.
Ampoules in which a precipitate or cloudiness have formed should be discarded. Cordarone X Intravenous does not contain any preservative and should be prepared immediately prior to use and used within 12 hours.
When given by infusion, Cordarone X Intravenous may reduce drop size; the alteration in drop size may be equipment dependent but a reduction in drop size to two-thirds has been reported. This problem may be overcome either by using a volumetric infusion pump or by adjusting the rate of infusion, however, the important criterion is clinical response and continuous monitoring of the patient's physiological parameters should be carried out during infusion.
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 and use within 12 hours.
The use of medical equipment or devices containing plasticiser such as DEHP (di-2-ethylhexyl phthalate) in the presence of amiodarone injection may result in leaching out of DEHP. In order to minimise patient exposure to DEHP, the final amiodarone dilution for infusion may preferably be administered through non-DEHP containing sets.

Use in the elderly.

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.

4.3 Contraindications

Known hypersensitivity to iodine or amiodarone or to any of the excipients.
Pregnancy and lactation (see Section 4.6 Fertility, 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 atrioventricular conduction disorders, amiodarone should only be used in conjunction with a pacemaker.
Sinus bradycardia and sino-atrial heart block.
Amiodarone is contraindicated in patients with evidence, or a history of thyroid dysfunction.
Combined therapy with drugs which may induce torsades de pointes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Cordarone X Intravenous injection is contraindicated in the case of hypotension, severe respiratory failure, cardiomyopathy, heart failure, circulatory collapse and severe arterial hypotension. It is also contraindicated in bi- or tri-fascicular conduction disorders, unless a permanent functioning pacemaker is fitted or unless the patient is in a special care unit and amiodarone is used under the cover of electrosystolic pacing. Due to the benzyl alcohol content, Cordarone X Intravenous injection is contraindicated in neonates (children less than one month of age) or premature neonates (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

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.
Intravenous injection is generally not advised because of haemodynamic risks (severe hypotension, circulatory collapse); intravenous infusion is preferable whenever possible. Intravenous injection is to be done only in emergency where alternative therapies have failed and only in an intensive care unit under continuous monitoring (ECG, blood pressure). Intravenous injection should not be repeated less than 15 minutes following the first injection even if the latter was only one ampoule (possible irreversible collapse). To avoid injection site reactions, amiodarone IV should, whenever possible, be administrated through a central venous line (see Section 4.2 Dose and Method of Administration). Do not mix other preparations in the same syringe. Do not inject other preparations in the same line. If amiodarone should be continued, this should be via intravenous infusion.

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 to 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 ultrasensitive TSH (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), 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, 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.

Primary graft dysfunction (PGD) post cardiac transplant.

In retrospective studies, amiodarone use in the transplant recipient prior to heart transplant has been associated with an increased risk of PGD.
For patients who are on the heart transplant waiting list, consideration should be given to the use of an alternative antiarrhythmic drug as early as possible before transplant.

ECG monitoring.

Regular 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), 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), 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 nonproductive 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 to 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 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 Section 4.8 Adverse Effects (Undesirable Effects), 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 and within the first 24 hours of IV amiodarone. 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 disease.

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), 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) regimen (see Section 4.8 Adverse Effects (Undesirable 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, 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.

Hypotension.

Hypotension may occur when amiodarone is given by the intravenous route. In some cases, hypotension may be refractory, resulting in fatal outcomes (see Section 4.8 Adverse Effects (Undesirable Effects), Cordarone X Intravenous).

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.
Cordarone X Intravenous injection contains benzyl alcohol (see Section 6.1 List of Excipients). There have been reports of fatal "gasping syndrome" in neonates (children less than one month of age) or premature neonates following the administration of intravenous solutions containing this preservative. Symptoms include a striking onset of gasping syndrome, hypotension, bradycardia, and cardiovascular collapse. Cordarone X Intravenous injection should not be given to neonates or premature neonates.

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 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 'torsades de pointes' is contraindicated (see Section 4.3 Contraindications).

Antiarrhythmic agents.

Class IA antiarrhythmic agents, including:
Disopyramide: combined treatment of amiodarone and disopyramide causes an increase in the QT interval.
Procainamide: serum level of procainamide increases significantly with coadministration 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: coadministration with amiodarone increases QT interval.
Sotalol.
Bepridil.

Non-antiarrhythmic agents.

Such as vincamine, some neuroleptic agents, cisapride, erythromycin IV or pentamidine IV, as there is an increased 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.

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

MAO inhibitors.

Coadministration with monoamine oxidase inhibitors 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 (tetracosactrin);
amphotericin B (amphotericin) (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 CYP 1A1, CYP 1A2, CYP 3A4, CYP 2C9, CYP 2D6 and P-glycoprotein and may increase exposure of their substrates.
Due to the long half life of amiodarone, interactions may be observed for several months after discontinuation of amiodarone.

P-gp substrates.

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

Digitalis.

Digoxin coadministration 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 coadministered with dabigatran due to the risk of bleeding. It may be necessary to adjust the dosage of dabigatran as per its label.

CYP 2C9 substrates.

Amiodarone raises the concentrations of CYP 2C9 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 warfarin with 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 increases 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.

CYP 2D6 substrates.

Flecainide.

Amiodarone increases the concentration of flecainide plasma levels through inhibition of the cytochrome CYP 2D6. The dosage of flecainide should be adjusted.

CYP 3A4 substrates.

When such drugs are coadministered with amiodarone, an inhibitor of CYP 3A4, this may result in a higher level of their plasma concentrations, which may lead to a possible increase in their toxicity.

Ciclosporin.

Because of the possible increase of ciclosporin plasma levels related to a decrease of the clearance of this drug, dosage should be adjusted.

Fentanyl.

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

Statins metabolised by CYP 3A4.

The risk of muscular toxicity is increased by concomitant administration of amiodarone with statins metabolised by CYP 3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolised by CYP 3A4 when given with amiodarone.

Other drugs metabolised by CYP 3A4.

Lidocaine (lignocaine), tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine, colchicine.

Effect of other medicinal products on amiodarone.

CYP 3A4 inhibitors and CYP 2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure.
It is recommended to avoid CYP 3A4 inhibitors (e.g. grapefruit juice and certain medicinal products) during treatment with amiodarone.
Coadministration 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 coadministration cannot be avoided, cardiac monitoring is recommended (see Section 4.4 Special Warnings and Precautions for Use).
Other 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, 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 Section 4.8 Adverse Effects (Undesirable Effects), 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 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 1 week (maintenance dose thereafter was 400 mg daily) in her 34th week of pregnancy. Neonatal levels of amiodarone were 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.
Cordarone X Intravenous injection contains benzyl alcohol (see Section 6.1 List of Excipients). The administration of medications containing benzyl alcohol to neonates or premature neonates has been associated with a fatal "gasping syndrome". As benzyl alcohol may cross the placenta, Cordarone X Intravenous injection should be used with caution 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. Amiodarone is contraindicated in breast-feeding mothers. If a situation demands that amiodarone be given to a nursing 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)

Cordarone X Intravenous 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 Cordarone X Intravenous.
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 underlying disease state, and individual variation in 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 2 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 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 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 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.

Hepatic.

Elevations of liver 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 chronic liver disease (pseudo alcoholic hepatitis, cirrhosis) sometimes fatal. 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.

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 of amiodarone for 4 to 18 months and in one patient given 100 mg/day for 5 to 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 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).

Ocular.

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 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 to 1400 mg/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 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 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).

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: 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 level 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.

Injury, poisoning and procedural complications.

Primary graft dysfunction post cardiac transplant.

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 systematic symptoms.

Adverse reactions - Cordarone X Intravenous.

Local.

Possible inflammation of veins following intravenous infusion may be avoided by the use of a central venous catheter. Common injection site reactions such as pain, erythema, urticaria, oedema, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes.

Systemic.

Hot flushes and sweating have been reported very rarely.
Common reports of decrease in blood pressure, usually moderate and transient, have been received. Cases of severe hypotension or collapse (sometimes fatal) have been reported following overdosage or a too rapid injection.
Cases of neutropenia and agranulocytosis have been reported.
Moderate bradycardia. In some cases, and especially in patients with sinus node dysfunction and/or 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.
Cases of torsade de pointes have been reported.
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.
Cases of hyperthyroidism and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported.
Very rare cases of acute liver disorders with elevated serum transaminases and/or jaundice, which included hepatic failure, sometimes fatal have also been reported. Treatment should be discontinued and monitoring of liver function tests is therefore recommended.
Optic neuropathy/neuritis progressing to blindness has been reported (see Section 4.4 Special Warnings and Precautions for Use, Ocular changes).
Cases of pancreatitis/acute pancreatitis have been reported.
Very rare cases of interstitial pneumonitis or fibrosis, sometimes fatal, have been reported with intravenous amiodarone.
Very rare cases of severe respiratory complications, sometimes resulting in death have been observed usually in the period immediately following surgery (acute adult respiratory distress syndrome), sometimes fatal: a possible interaction with high oxygen concentrations may be implicated. Bronchospasm and/or apnoea in the case of pre-existing severe respiratory failure and especially in asthmatic patients have also been reported.
Very rare cases of anaphylactic shock and benign intra-cranial hypertension (pseudotumour cerebri) have been reported.
Nausea and headache have been reported very rarely. Cases of confusional state, delirium, hallucinations and libido decrease have been reported. Isolated cases of angioneurotic oedema (Quincke's oedema) have been reported.
Cases of eczema, urticaria, severe skin reactions sometimes fatal, including toxic epidermal necrolysis/Stevens-Johnson syndrome, bullous dermatitis and drug reaction with eosinophilia and systemic symptoms have been reported.
Back pain.

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.

4.9 Overdose

A case of attempted suicide with 2600 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 antero-septal infarction.
In another case of attempted suicide with 8 g amiodarone, the only symptoms reported were 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. In the event of ingestion of a toxic dose, general supportive measures should be applied.
For information on the management of overdose, contact the Poison 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 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.

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.

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.

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

Metabolism.

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 to 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 to 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.

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.

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.

Carcinogenicity.

In a carcinogenicity study in rats, amiodarone caused a dose related increase in thyroid follicular tumours (adenomas and/or carcinomas) in both sexes.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients contained in each tablet are lactose monohydrate, maize starch, povidone, magnesium stearate, and colloidal anhydrous silica.
The excipients contained in the intravenous solution are polysorbate 80, benzyl alcohol, and water for injections.

6.2 Incompatibilities

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.

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

Tablet.

Store below 30°C. Protect from light.

Injection.

Store below 25°C. Do not refrigerate. Protect from light.

6.5 Nature and Contents of Container

The tablets are presented blister packed in strips of 10 tablets in packs containing 30 tablets.
The ampoules are packed in units of 6 or 10# on a tray contained in a cardboard carton.
# Not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

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.

Chemical structure.

(2-n-butyl-3(4-(2-diethylaminoethoxy)- 3,5-diiodobenzoyl) benzofuran hydrochloride).
Mol. Formula: C25H29NI2O3.HCl.
Mol. Wt.: 681.8.

CAS number.

1951-25-3.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes