Cordarone

Package leaflet: Information for the patient

Cordarone
50 mg/ml, solution for injection
Amiodaroni hydrochloridum
{logo sanofi}
Please read the following information carefully before using the medicine, as it contains
important information for the patient.

• Keep this leaflet for future reference.
• If you have any questions, please consult your doctor or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. The medicine may harm other people, even if their symptoms are the same.
• If you experience any adverse reactions, including those not listed in this leaflet, inform your doctor or nurse. See section 4.

Table of contents

1. What Cordarone is and what it is used for
2. Important information before using Cordarone
3. How to use Cordarone
4. Possible side effects
5. How to store Cordarone
6. Contents of the pack and other information

1. What Cordarone is and what it is used for

Cordarone is available as a solution for injection and contains the active substance
amiodarone hydrochloride. Amiodarone is a potent antiarrhythmic agent used in the treatment of irregular heartbeats.
Amiodarone is administered intravenously when rapid onset of action is required or when oral administration is not feasible.
It is used in the treatment of life-threatening cardiac arrhythmias:

• Arrhythmias associated with Wolff-Parkinson-White syndrome
• Atrial fibrillation and flutter, paroxysmal supraventricular tachycardias: supraventricular and nodal tachycardias, when other drugs cannot be used
• Ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation), when other antiarrhythmic drugs are ineffective.

2. Important information before using Cordarone

When not to use Cordarone:

• if the patient is allergic to iodine, amiodarone, or any of the other ingredients of this medicine (listed in section 6); if symptoms of allergy occur, such as itchy rash, difficulty swallowing or breathing, or swelling of the lips, face, throat, or tongue, contact a doctor immediately;
• in patients with heart diseases: sinus bradycardia, sinoatrial block, or sick sinus syndrome, except in patients with an implanted pacemaker (risk of sinus node inhibition);
• in patients with second- or third-degree atrioventricular block, except in patients with an implanted pacemaker;
• in patients with bifascicular or trifascicular block, except in patients with an implanted cardiac pacemaker or temporary pacing system;
• concomitantly with medicines that may cause life-threatening arrhythmias – torsade de pointes (see: Cordarone with other medicines);
• if the patient has thyroid disease;
• if the patient is pregnant or breastfeeding;
• in circulatory collapse or severe hypotension;
• in severe respiratory insufficiency;
• in patients with congestive cardiomyopathy or heart failure.

The above contraindications do not apply if amiodarone is administered in an intensive care unit during cardiopulmonary resuscitation for sudden cardiac arrest due to ventricular fibrillation when defibrillation is ineffective.

Warnings and precautions

Cordarone must be administered intravenously exclusively in an intensive care unit, where the patient's clinical condition is continuously monitored (ECG recording, blood pressure values).

• Cordarone causes changes in the ECG trace – however, this does not indicate drug intoxication.
• Cordarone may cause cardiac arrhythmias or worsen existing arrhythmias, particularly due to interactions with certain drugs (see: Cordarone with other medicines and section 4) and/or in the presence of electrolyte disturbances (decreased blood potassium and/or magnesium levels). Hypokalemia (low potassium levels in the body) must be avoided, and potassium deficiency should be corrected.
• Concomitant use of Cordarone with the following medicines is not recommended: beta-blockers, calcium channel blockers that reduce heart function (verapamil, diltiazem), and laxatives that may cause hypokalemia (see Cordarone with other medicines).
• Before starting Cordarone, discuss with your doctor or pharmacist if the patient is currently taking a medicine containing sofosbuvir, used in the treatment of hepatitis C virus infection, as this may cause life-threatening bradycardia. The doctor may consider alternative treatment options. If treatment with both amiodarone and sofosbuvir is necessary, additional cardiac monitoring may be required.
• Contact your doctor immediately if the patient is taking a medicine containing sofosbuvir for hepatitis C and during treatment experiences:
  • slow or irregular heartbeat or arrhythmias,
  • shortness of breath or worsening of existing dyspnea,
  • chest pain,
  • dizziness,
  • palpitations,
  • near-fainting or fainting.
• Cordarone may cause interstitial lung disease. It presents with dyspnea and dry cough. If interstitial lung disease is suspected, the doctor should perform a chest X-ray and consider discontinuing Cordarone therapy, as interstitial lung disease usually resolves if treatment is promptly stopped. The doctor may also consider corticosteroid treatment.
• Very rarely, severe respiratory complications, sometimes fatal, have been observed, usually in the immediate postoperative period (see Cordarone with other medicines and section 4).
• The anesthesiologist must be informed before surgery that the patient has been administered Cordarone.
• During use of Cordarone and within 24 hours after administration, acute or chronic liver function disturbances may occur, sometimes leading to death. Therefore, the doctor will regularly order liver function tests (measurement of serum aminotransferase activity) from the beginning of treatment. If liver function disturbances occur, the doctor may consider reducing the dose or discontinuing treatment.
• Cordarone treatment must be immediately discontinued if severe skin reactions occur during therapy (e.g. progressive rash with blisters or mucosal lesions, fever, joint pain, severe rapidly progressing illness with large subepidermal blisters, extensive skin erosions, shedding of large epidermal sheets, and fever – see also section 4). These symptoms may be life-threatening.
• If blurred vision or visual deterioration occurs, a complete ophthalmological examination, including fundoscopy, should be performed immediately. If optic nerve damage and/or inflammation is detected, Cordarone must be discontinued due to the risk of vision loss.
• To avoid local adverse effects at the injection site, Cordarone should be administered via a central venous access.
• If the patient is on a heart transplant waiting list, the treating physician may change the treatment regimen prior to transplantation. This is because amiodarone use before heart transplantation increases the risk of a life-threatening complication (primary graft dysfunction), in which the transplanted heart fails to function properly within the first 24 hours after surgery.

Cordarone with other medicines

Inform your doctor about all medicines currently taken, recently taken, or planned for use.

Cordarone must not be used concomitantly with medicines that may cause life-threatening cardiac arrhythmias (type torsade de pointes). These include:

• antiarrhythmic drugs (for irregular heartbeat): quinidine, disopyramide, procainamide, sotalol, bretylium, bepridil,
• intravenous erythromycin (antibiotic), cotrimoxazole (antibacterial), or the antiprotozoal agent pentamidine,
• antipsychotics such as: chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, amisulpride, sertindole,
• certain drugs used for other psychiatric disorders: lithium preparations and tricyclic antidepressants, e.g. doxepin, amitriptyline,
• certain antihistamines used for allergies: terfenadine, astemizole, mizolastine,
• antimalarial drugs: quinine, chloroquine, mefloquine, halofantrine,
• vincamine – used to treat cerebral circulation disorders, dizziness, tinnitus, memory and learning difficulties, especially in the elderly,
• neuroleptics,
• cisapride – used to treat delayed gastric emptying.

Concomitant use of Cordarone is not recommended with:

• fluoroquinolone antibiotics: ciprofloxacin, ofloxacin, levofloxacin,
• beta-blockers used in heart diseases, e.g. propranolol,
• calcium channel blockers that slow heart rate, used in angina (heart disease) or hypertension (high blood pressure): verapamil, diltiazem,
• antiviral drugs used in hepatitis C treatment, e.g. sofosbuvir, daklatasvir, symeprevir, or ledipasvir, due to the risk of bradycardia,
• certain laxatives (used for constipation) causing low blood potassium: bisacodyl, senna,
• cholesterol-lowering drugs – statins, e.g. simvastatin, atorvastatin, lovastatin.

Caution is required when using the following medicines concomitantly with Cordarone:

• diuretics, e.g. furosemide,
• anti-inflammatory drugs – systemic corticosteroids, e.g. hydrocortisone, prednisolone,
• tetracosactide – used in testing certain hormonal disorders,
• antifungal agent – intravenous amphotericin B,
• anesthetics used in general anesthesia or high oxygen concentrations administered during surgical procedures (see Warnings and precautions in section 2 and section 4). Before surgery, inform the anesthesiologist about Cordarone use,
• phenytoin – used to treat epileptic seizures: close monitoring is required, and phenytoin dose should be reduced immediately if signs of overdose occur; serum phenytoin levels should be measured,
• digitalis glycosides, e.g. digoxin – used in heart diseases: the doctor will order serum digoxin level tests and ECG monitoring, and may adjust the digoxin dose; the patient should be monitored for signs of digitalis toxicity,
• anticoagulants – warfarin, dabigatran: regular coagulation tests are necessary to adjust oral anticoagulant doses both during and after Cordarone treatment; dabigatran dose adjustment may be required,
• immunosuppressants to prevent transplant rejection – cyclosporine, tacrolimus, sirolimus,
• flecainide – used to treat arrhythmias: treatment must be closely monitored; the doctor will adjust the flecainide dose,
• fentanyl – a strong analgesic,
• lidocaine – an anesthetic agent,
• sildenafil – used to treat impotence,
• midazolam – used for anxiety and sedation before surgical procedures,
• triazolam – used for insomnia,
• dihydroergotamine and ergotamine – antimigraine drugs,
• colchicine – used to treat acute gout attacks.

Cordarone with food and drink

Grapefruit juice should be avoided during treatment with Cordarone.

Pregnancy, breastfeeding, and effects on fertility

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult a doctor before using this medicine.

Pregnancy

Due to Cordarone's effects on the fetal thyroid gland, the use of this medicine during pregnancy is contraindicated. Consult a doctor before use.

Breastfeeding

The use of Cordarone during breastfeeding is contraindicated. Consult a doctor before use.

Fertility

There is no data available on the effect of amiodarone on human fertility.

Driving and operating machinery

Based on safety data for amiodarone use, the medicine does not impair the ability to drive or operate machinery.

Cordarone contains benzyl alcohol

Cordarone contains 60 mg of benzyl alcohol per ampoule (equivalent to 20 mg/ml) as a preservative.

Benzyl alcohol may cause allergic reactions.

Administration of benzyl alcohol to neonates and small children carries a risk of severe adverse effects, including respiratory disorders (so-called "gasping syndrome").

This medicine must not be administered to neonates (up to 4 weeks of age) without medical advice.

This medicine must not be administered to small children (under 3 years of age) for longer than one week without medical advice.

Pregnant or breastfeeding women should consult a doctor or pharmacist before using this medicine, as high amounts of benzyl alcohol may accumulate in their bodies and cause adverse effects (so-called metabolic acidosis).

Patients with liver or kidney disease should consult a doctor or pharmacist before using this medicine, as high amounts of benzyl alcohol may accumulate in their bodies and cause adverse effects (so-called metabolic acidosis).

3. How to use Cordarone

The medicine is administered by a doctor or nurse according to the doctor's instructions. If in doubt, consult your doctor.
The medicine must be administered intravenously while continuously monitoring the patient's condition (ECG recording, arterial blood pressure measurements).
Cordarone must be diluted before administration to the patient.
The doctor selects the appropriate dose for each patient depending on body weight and medical condition.
The usual dosage is as follows:
Adults:
Intravenous infusion
Loading dose: 5 mg/kg body weight given in 250 ml of 5% glucose solution as an infusion lasting from 20 minutes to 2 hours. The infusion may be repeated 2 to 3 times daily. The infusion rate should be adjusted according to the therapeutic effect achieved.
Maintenance dose: 10–20 mg/kg body weight/day (usually 600 to 800 mg/24 hours up to a maximum of 1200 mg/24 hours) administered as an infusion in 250 ml of 5% glucose solution for several days.
As soon as the desired therapeutic effect is achieved, the doctor will recommend starting concomitant oral administration of amiodarone at the usual loading dose (3 x 200 mg per day). The intravenous dose should then be gradually reduced.
In emergency situations, 150–300 mg of amiodarone in 10–20 ml of 5% glucose solution should be administered as a slow intravenous injection lasting at least 3 minutes.
A subsequent injection may be repeated no sooner than after 15 minutes, even if in the first injection only the solution from one ampoule (150 mg) was administered. If further doses of amiodarone are required, they should be administered as intravenous infusion.
Cardiopulmonary resuscitation
In the exceptional case of cardiopulmonary resuscitation of a patient with defibrillation-resistant ventricular fibrillation, the first dose of 300 mg (or 5 mg/kg) of amiodarone should be administered as an intravenous injection after diluting the appropriate volume of Cordarone solution in 20 ml of 5% glucose solution. If ventricular fibrillation persists, an additional intravenous dose of amiodarone of 150 mg (or 2.5 mg/kg) may be considered.
Do not mix other medicines with Cordarone in the same syringe.
Do not inject other medicines through the same intravenous access.
If you feel that the effect of Cordarone is too strong or too weak, consult your doctor.
Use in elderly patients
There are no specific dosage data available for elderly patients.
Particular caution should be exercised when administering the medicine to elderly patients.
Use in children and adolescents
Caution should be exercised when administering intravenous medicines containing benzyl alcohol to children under 3 years of age (see also "Cordarone contains benzyl alcohol").
Administration of a higher than recommended dose of Cordarone
Since the medicine will be administered to the patient during hospitalization, it is unlikely that too low or too high a dose will be given. However, if the patient has any doubts, they should inform the doctor or nurse.
Missed administration of Cordarone
Cordarone is used in a hospital setting.
Discontinuation of Cordarone
If you have any further doubts regarding the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
You should stop using Cordarone and seek immediate medical advice if any of the following occur:
Frequency unknown (cannot be estimated from the available data):

• Quincke's edema – a severe allergic reaction causing swelling of the face, difficulty breathing and swallowing;
• Life-threatening skin reactions characterized by rash, blisters, skin peeling, and pain [toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), bullous dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS)];
• Irregular heartbeat, which may be a symptom of a life-threatening arrhythmia called torsade de pointes (see Warnings and precautions and Cordarone and other medicines in section 2);
• Blurred vision or worsening of vision; these may be symptoms of optic nerve damage, which may lead to loss of vision (see Warnings and precautions in section 2);
• Seeing, hearing or feeling things that are not there (hallucinations);
• Increased frequency of infections. This may be due to a reduced number of white blood cells (neutropenia);
• Significant reduction in white blood cells, increasing the likelihood of infections (agranulocytosis). Very rare (occurs in fewer than 1 in 10,000 patients):
• Anaphylactic shock (a clinical syndrome in which the body's autoregulatory mechanisms fail to maintain adequate blood flow to vital organs and tissues, caused by a rapidly progressing allergic reaction), presenting as confusion, weakness, fainting;
• Dizziness, fatigue, and shortness of breath; these may be symptoms of significant slowing of the heart rate, sinus node arrest, especially in patients with sinus node dysfunction and/or elderly patients, development of a new type of arrhythmia or worsening of existing arrhythmias, sometimes with cardiac arrest;
• Yellowing of the eyes and skin (jaundice), abdominal pain, loss of appetite, fatigue, fever, elevated liver aminotransferase activity in blood tests; these are symptoms of life-threatening acute liver dysfunction or liver failure;
• Breathlessness and dry cough; these may be symptoms of life-threatening interstitial lung disease or pulmonary fibrosis (see Warnings and precautions in section 2), or bronchospasm and/or respiratory arrest in cases of severe respiratory failure, especially in patients with bronchial asthma;
• Headache worsening in the morning or after exertion, nausea, seizures, fainting, visual disturbances or disorientation; these may be symptoms of brain dysfunction due to increased intracranial pressure (pseudotumor cerebri).

Other side effects of Cordarone may occur with the following frequencies:
Common (occurs in 1 to 10 out of 100 patients):

• Slowing of the heart rate, usually mild to moderate;
• Reactions at the site of administration such as: pain, redness, swelling, necrosis, phlebitis, infiltration, inflammation, sclerosis, thrombophlebitis, phlebitis, connective tissue inflammation, infection, skin discoloration;
• Low blood pressure, usually mild and transient, manifesting as dizziness, disorientation, and fainting. Cases of severe hypotension or circulatory collapse have been reported following overdose or too rapid administration of the drug;
• Itchy red rash (urticaria);
• Decreased sexual desire.

Very rare (occurs in fewer than 1 in 10,000 patients):

• Malaise, disorientation or weakness, nausea (feeling sick), loss of appetite, irritability. This may indicate a condition called "syndrome of inappropriate antidiuretic hormone secretion (SIADH)";
• Nausea;
• Increased aminotransferase activity detected in blood tests, usually moderately elevated (1.5 to 3 times above the upper limit of normal), occurring at the beginning of treatment. These abnormalities may return to normal values either after dose reduction or spontaneously;
• Headaches;
• Sweating;
• Sudden flushing of the face.

Frequency unknown (cannot be estimated from the available data):

• Back pain;
• Urticaria;
• Hyperthyroidism presenting as restlessness, weight loss, increased sweating;
• Acute pancreatitis or sudden onset of acute pancreatitis;
• Decreased libido;
• Delirium (including confusion), hallucinations;
• Life-threatening complication after heart transplantation (primary graft dysfunction), in which the transplanted heart fails to function properly (see Warnings and precautions in section 2).

Reporting of side effects
If any adverse effects occur, including any adverse effects not listed in this leaflet, please inform your doctor or nurse. Adverse effects can be reported directly to the Department of Monitoring of Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 4921301, fax: +48 22 4921309,
Website: https://smz.ezdrowie.gov.pl
Adverse effects can also be reported to the marketing authorization holder or its representative in Poland.
Reporting adverse effects helps provide more information on the safety of the medicine.

5. How to store Cordarone

Store the medicine at a temperature below 25°C.
Keep the medicine out of the sight and reach of children.
Do not use the medicine after the expiry date stated on the packaging after "EXP". The expiry date refers to the last day of the stated month.

6. Contents of the pack and other information

What Cordarone contains

• The active substance is amiodarone hydrochloride. Each ampoule contains 150 mg of amiodarone hydrochloride.
• The other ingredients are: benzyl alcohol, polysorbate 80, water for injections.

What Cordarone looks like and contents of the pack

The pack contains 6 ampoules of 3 ml each.

Marketing Authorisation Holder:
Sanofi Winthrop Industrie
82, Avenue Raspail
94250 Gentilly
France

Manufacturer:
Sanofi-Winthrop Industrie
1, rue de la Vierge
33440 Ambares
France
Delpharm Dijon
6 boulevard de l'Europe
21800 Quetigny
France
Sanofi S.r.l.
Via Valcanello, 4
03012 Anagni (FR)
Italy

For further information, please contact the local representative of the Marketing Authorisation Holder in Poland:
Sanofi Sp. z o.o.
ul. Marcina Kasprzaka 6
01-211 Warszawa
tel.: +48 22 280 00 00

Information intended exclusively for healthcare professionals:

For complete drug information, please refer to the Product Characteristics (SmPC).
Dosage and administration
Cordarone, injection solution, should be used only in intensive care units equipped with cardiac monitoring, defibrillation, and cardiac pacing capabilities. The medicinal product must be administered intravenously by infusion. For continuous or repeated infusions, amiodarone should be given via a central venous access to avoid adverse reactions at the injection site (see section 4.8).

Due to the risk of severe hypotension and circulatory collapse, intravenous amiodarone should be administered only in emergency situations when other drugs have proven ineffective, exclusively in an intensive care setting with continuous electrocardiographic monitoring. The recommended dose is approximately 5 mg/kg body weight. Except in cases of cardiopulmonary resuscitation for ventricular fibrillation when defibrillation is ineffective, the amiodarone injection should last at least 3 minutes.

The medicinal product Cordarone, injection solution, is incompatible with physiological sodium chloride solution and must be used exclusively with 5% glucose solution. An amiodarone solution with a concentration lower than 0.6 mg/mL (less than 300 mg [2 ampoules] in 500 mL of 5% glucose solution) is unstable and should not be used.

Intravenous infusion
Loading dose: typically 5 mg/kg body weight administered in 250 mL of 5% glucose solution over 20 minutes to 2 hours. This infusion may be repeated 2 to 3 times daily. The infusion rate should be adjusted according to the therapeutic response. The therapeutic effect appears within the first few minutes and then gradually diminishes; therefore, to prolong the effect, continued infusion administration is required.

Maintenance dose: 10–20 mg/kg body weight/day (usually 600 to 800 mg/24 hours, up to 1200 mg/24 hours) administered as an infusion in 250 mL of 5% glucose solution for several days. In all cases, the lowest effective dose should be used.

Transition from intravenous to oral administration: as soon as the desired therapeutic effect is achieved, oral amiodarone should be initiated concurrently at the standard loading dose (3 × 200 mg daily). The intravenous dose should then be gradually reduced.

Dosing in emergency situations: administer 150–300 mg amiodarone in 10–20 mL of 5% glucose solution as a slow intravenous injection lasting at least 3 minutes. A subsequent injection may be repeated no sooner than 15 minutes later, even if only one ampoule (150 mg) was used in the first injection, due to the risk of circulatory collapse. If further doses of amiodarone are required, they should be administered by intravenous infusion.

Cardiopulmonary resuscitation
In the specific case of cardiopulmonary resuscitation for defibrillation-resistant ventricular fibrillation, the first dose of 300 mg (or 5 mg/kg) of amiodarone should be administered as an intravenous bolus after diluting the appropriate volume of Cordarone solution in 20 mL of 5% glucose solution. If ventricular fibrillation persists, an additional intravenous dose of 150 mg (or 2.5 mg/kg) may be considered.

Do not mix other drugs with amiodarone in the same syringe.
Do not administer other drugs through the same venous access.

Use in elderly patients
There are no specific dosage data available for elderly patients. However, particular caution should be exercised in elderly patients due to the potential risk of severe bradycardia or conduction disturbances.

Children and adolescents
The safety and efficacy of amiodarone in children have not been established. Available data are described in sections 5.1 and 5.2 of the SmPC.

Due to the presence of benzyl alcohol, caution is required when administering amiodarone intravenously to neonates, infants, and children up to 3 years of age (see section 4.4).

How to open the ampoule:
Hold the ampoule so that the coloured dot faces the person opening it (Fig. 1). Place the top of the ampoule between the thumb and index finger (with the thumb on the coloured dot), then press the back of the ampoule (Figs. 2 and 3).

Pharmaceutical incompatibilities
The use of plastic medical devices containing DEHP (di-2-ethylhexyl phthalate) in the presence of intravenous amiodarone solution may lead to DEHP leaching. To minimize patient exposure to DEHP, it is recommended to perform final dilution before infusion and to use DEHP-free administration sets.

Cordarone medicinal product for intravenous use is also incompatible with physiological sodium chloride solution and must be used exclusively with 5% glucose solution. An amiodarone solution with a concentration lower than 0.6 mg/mL (less than 300 mg [2 ampoules] in 500 mL of 5% glucose solution) is unstable and should not be used.

Special warnings and precautions for use
Amiodarone may be administered intravenously only in an intensive care unit where the patient's clinical status is continuously monitored (ECG recording, blood pressure values). Whenever possible, intravenous amiodarone should be administered via a central venous access to avoid local adverse reactions (see section 4.8).

Close attention should be paid to any signs of hypotension, severe respiratory failure, or uncompensated or severe heart failure.

Detailed information on intravenous injections
Due to the risk of hemodynamic disturbances (severe hypotension, circulatory collapse), intravenous bolus injection is not recommended for routine use. Intravenous infusion is preferred whenever possible.

Amiodarone may be administered as an intravenous bolus injection only in emergency situations when other drugs are ineffective, exclusively in an intensive care unit with continuous patient monitoring (ECG recording, blood pressure values).

The dose is approximately 5 mg/kg body weight. Amiodarone should be administered as an intravenous injection lasting at least 3 minutes, except in cases of cardiopulmonary resuscitation for ventricular fibrillation when defibrillation is ineffective. A subsequent injection may be repeated no sooner than 15 minutes later, even if only one ampoule (150 mg) was used in the first injection, due to the risk of irreversible circulatory collapse.

If further doses of amiodarone are required, they should be administered by intravenous infusion. Do not mix other drugs with amiodarone in the same syringe. Do not administer other drugs through the same venous access.

Cardiac disorders (see section 4.8 of SmPC)
The pharmacological action of amiodarone causes ECG changes: QT interval prolongation (due to prolonged repolarization phase) with possible appearance of U waves. However, these changes do not indicate amiodarone toxicity.

Cases of new-onset arrhythmias or worsening of treated arrhythmias have been reported, sometimes leading to death. It is important, but difficult, to differentiate whether this is due to lack of drug efficacy, a proarrhythmic effect of the drug, or worsening of the underlying arrhythmia. Proarrhythmic effects with amiodarone are reported less frequently than with other antiarrhythmic drugs. The proarrhythmic effect of amiodarone may occur particularly as a result of interactions with QT-prolonging drugs and/or in the presence of electrolyte imbalances (see sections 4.5 and 4.8). Despite QT prolongation, amiodarone has low activity in inducing torsade de pointes arrhythmias.

Severe bradycardia and heart block
Life-threatening cases of bradycardia and heart block have been observed when amiodarone is used concomitantly with regimens containing sofosbuvir.

Bradycardia usually occurred within hours to days, but cases with longer onset times, typically up to 2 weeks after initiating HCV treatment, have also been reported.

Amiodarone should be administered to patients receiving a sofosbuvir-containing regimen only if alternative antiarrhythmic drugs are contraindicated or not tolerated.

If concomitant use of amiodarone is necessary, cardiac monitoring is recommended in a hospital setting for the first 48 hours after initiating concomitant therapy; thereafter, heart rate should be monitored in an outpatient setting or by the patient daily for at least the first 2 weeks of treatment.

Due to the long half-life of amiodarone, cardiac monitoring as described above should also be performed in patients who have discontinued amiodarone within the past several months and are about to start a sofosbuvir-containing regimen.

All patients receiving amiodarone in combination with a sofosbuvir-containing regimen should be informed of the risk of bradycardia and heart block symptoms and advised to seek immediate medical help if such symptoms occur.

Respiratory disorders (see section 4.8 SmPC)
Dyspnea and non-productive cough may be signs of pulmonary toxicity, such as interstitial pneumonitis. Very rare cases of interstitial pneumonitis have been reported after intravenous administration of amiodarone. If this diagnosis is suspected in a patient presenting with exertional dyspnea, either as the sole symptom or associated with deterioration in general condition (fatigue, weight loss, fever), a chest X-ray should be performed. In such cases, the continuation of amiodarone therapy should be re-evaluated, as interstitial pneumonitis is usually reversible upon early discontinuation of amiodarone (clinical symptoms typically resolve within 3 to 4 weeks, followed by gradual improvement in radiological and pulmonary function test results over several months). Consideration should also be given to initiating corticosteroid therapy.

A few very rare cases of severe respiratory complications, sometimes fatal, have been reported, usually occurring immediately after surgical procedures (adult respiratory distress syndrome). This may be related to interactions with high-concentration oxygen therapy (see sections 4.5 and 4.8).

Hepatic disorders (see section 4.8 SmPC)
Regular and close monitoring of liver function (measurement of aminotransferase activity) is recommended from the start of amiodarone therapy. The dosage of amiodarone should be reduced or treatment discontinued if aminotransferase activity increases to more than three times the upper limit of normal, which may indicate acute severe liver dysfunction (including severe hepatocellular failure or liver failure, sometimes fatal) or chronic liver disorders. These may occur during treatment with either the oral or intravenous formulation and within 24 hours after intravenous administration of amiodarone. Clinical and biological signs of chronic liver dysfunction may be mild (possible hepatomegaly, aminotransferase activity increased 1.5 to 5 times above the upper limit of normal). These abnormalities usually resolve after discontinuation of amiodarone. However, fatal cases have been reported.

Severe skin reactions
Amiodarone treatment must be discontinued immediately if skin reactions occur that may indicate Stevens-Johnson syndrome (SJS) (progressive rash with blisters or mucosal lesions, fever, and joint pain), toxic epidermal necrolysis (TEN) (a severe rapidly progressing disease characterized by rupturing large subepidermal blisters, extensive skin erosions, detachment of large epidermal sheets, and fever), bullous dermatitis, or drug reaction with eosinophilia and systemic symptoms (DRESS). These reactions may be life-threatening and even fatal.

Ocular disorders (see section 4.8)
In case of blurred vision or visual deterioration, a complete ophthalmological examination including fundoscopy should be performed immediately. Optic neuropathy and/or optic neuritis, if diagnosed, require discontinuation of amiodarone due to the risk of progression to vision loss.

Interactions with other medicinal products (see section 4.5 SmPC)
Concomitant use of amiodarone with the following drugs is not recommended: beta-blockers, calcium channel blockers with heart rate-slowing effects (verapamil, diltiazem), laxatives causing hypokalemia, antiviral drugs used in the treatment of hepatitis C virus (HCV), such as sofosbuvir, daklatasvir, simeprevir, or ledipasvir, due to the risk of severe bradycardia. Concomitant administration of amiodarone with regimens containing sofosbuvir may lead to serious symptomatic bradycardia. If concomitant use of amiodarone with sofosbuvir-containing regimens cannot be avoided, cardiac monitoring after administration is recommended (see section 4.4 SmPC).

Anaesthesia
The anaesthesiologist should be informed about the patient's amiodarone therapy prior to surgery.

Children and adolescents
The safety and efficacy of amiodarone in children have not been established. Available data are described in sections 5.1 and 5.2.

The Cordarone injection solution contains benzyl alcohol at a concentration of 20 mg/mL (see section 6.1). Benzyl alcohol may cause toxic and allergic reactions in neonates, infants, and children up to 3 years of age. Intravenous administration of solutions containing this preservative has been associated with the occurrence of a "gasping syndrome," which can be fatal in neonates (children under one month of age). Symptoms include sudden onset of "gasping syndrome," hypotension, bradycardia, and cardiovascular collapse.

Additional special warnings regarding long-term amiodarone use are available in the Product Characteristics of Cordarone tablets, 200 mg.

Overdose
There are no available data on overdose with intravenously administered amiodarone. Only limited reports exist on overdose with oral amiodarone.

Possible manifestations include sinus bradycardia, atrioventricular block, ventricular tachycardia, torsade de pointes arrhythmias, circulatory failure, hypotension, and liver damage.

Neither amiodarone nor its metabolites are removed by dialysis.
Overdose requires professional medical intervention; treatment is symptomatic.