Active ingredients: Amiodarone (amiodarone hydrochloride)
CORDARONE 150 mg / 3 ml solution for injection for intravenous use
Cordarone package inserts are available for packs:- CORDARONE 150 mg / 3 ml solution for injection for intravenous use
- CORDARONE 200 mg tablets
Why is Cordarone used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antiarrhythmic, class III
THERAPEUTIC INDICATIONS
Intravenous cordarone should be used when a rapid response is required or when oral administration is not possible.
- Treatment and prevention of severe rhythm disturbances resistant to other specific therapies: supraventricular tachycardias (paroxysmal and non-paroxysmal), atrial extrasystoles, atrial flutter and fibrillation.
- Paroxysmal reciprocating supraventricular tachycardias as in the course of Wolff-Parkinson-White Syndrome. Ventricular extrasystoles and tachycardias.
Contraindications When Cordarone should not be used
- Sinus bradycardia, sinoatrial block and sinus disease without electro-stimulator (risk of sinus arrest).
- Conduction disturbances, without electro-stimulator (atrioventricular blocks, bi- or trifascicular blocks). In these cases, injectable amiodarone can be used in specialized units and by means of an electrosystolic stimulator.
- Cardiovascular collapse, severe arterial hypotension.
- Combination with drugs capable of causing "torsade de pointes" (see "Interactions").
- Dystyroidism in progress or resolved. In doubtful cases, perform a thyroid function test before treatment.
- Hypersensitivity to iodine or amiodarone or to any of the excipients.
- Pregnancy, except in exceptional cases, due to its effects on the thyroid gland of the fetus.
- Breastfeeding, as amiodarone is excreted in breast milk in significant quantities.
- Intravenous injection is contraindicated in cases of hypotension, severe respiratory failure, myocardiopathy or heart failure (risk of worsening).
- Given the presence of benzyl alcohol in the formulation, intravenous administration of amiodarone is contraindicated in newborns, infants and children up to 3 years of age.
Precautions for use What you need to know before taking Cordarone
Intravenous administration of amiodarone should only be performed in specialized hospital units and under continuous monitoring (ECG, blood pressure).
To avoid injection site reactions, amiodarone should be administered through a central venous line whenever possible (see "Undesirable Effects").
Amiodarone can frequently give rise to pulmonary toxicity: the utmost attention must be paid especially in patients suffering from cardiomyopathies and severe coronary heart diseases. In the event of symptoms such as productive cough, difficulty breathing, fever, weight loss, it is necessary for patients to contact to your doctor in order to carry out diagnostic investigations and take appropriate therapeutic measures. In some cases, pulmonary toxicity can manifest itself late, even after weeks of discontinuing therapy: especially those with suboptimal body functions who could eliminate the drug more slowly , should not underestimate the aforementioned symptoms.
Use caution in case of hypotension, severe respiratory failure, severe and uncompensated heart failure.
Pediatric patients: in these patients the safety and efficacy of amiodarone have not been demonstrated. Therefore the use of the drug is not recommended in pediatric patients.
CORDARONE injectable contains benzyl alcohol (see "Composition - Excipients") as a preservative and must not be used in infants. Cases of fatal gasping syndrome have been reported following intravenous administration of solutions containing this preservative in neonates (less than one month of age). Symptoms include abrupt onset of wheezing, hypotension, bradycardia, and cardiovascular collapse.
The medicine contains 60.6 mg of benzyl alcohol in each 3 ml ampoule. Benzyl alcohol can cause toxic and allergic reactions in infants and children up to 3 years of age.
Anesthesia. Prior to surgery, the anesthetist should be informed that the patient is being treated with amiodarone (see "Interactions").
Interactions Which drugs or foods can modify the effect of Cordarone
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Drugs that induce Torsade de Pointes or QT prolongation
Drugs that induce Torsade de Pointes
The association with drugs capable of giving "torsade de pointes" is contraindicated (see "Contraindications"):
- antiarrhythmics such as those of Class IA, sotalol, bepridil.
- non-anti-arrhythmic drugs such as vincamine, some neuroleptic drugs including sultopride, cisapride, erythromycin E.V., pentamidine (for parenteral administration) as there may be an increased risk of life-threatening "torsade de pointes".
QT Prolonging Drugs.
The concomitant administration of amiodarone with other medicinal products known to prolong the QT interval requires careful consideration of the potential risks and benefits for each patient as the risk of torsade de pointes may be increased and patients should be monitored for QT prolongation.
Fluoroquinolones should be avoided in patients on amiodarone therapy.
Drugs that reduce heart rate or cause automatism and / or conduction disturbances.
The association with these drugs is not recommended:
- Beta-blockers and calcium channel blockers that reduce heart rate (verapamil, diltiazem) due to the possibility of automatism (excessive bradycardia) and conduction disorders.
F.actors that can induce hypokalemia
The association with drugs that can induce hypokalaemia is not recommended:
- Stimulant laxatives: due to the appearance of a possible hypokalaemia, consequently increasing the risk of "torsade de pointes"; other types of laxatives must therefore be used.
Caution should be exercised when the following drugs are combined with Cordarone:
- diuretics capable of giving hypokalaemia, alone or in combination
- systemic glucocorticoids and mineralocorticoids, tetracosactide
- amphotericin B via the E.V. Hypokalaemia should be prevented (and corrected), QT interval monitored, and antiarrhythmics should not be administered in the event of "torsade de pointes" (ventricular pacing should be initiated; IV magnesium may be used).
General anesthesia (see "Precautions for use" and "Undesirable effects")
Potentially serious complications have been reported in patients undergoing general anesthesia: bradycardia (insensitive to atropine), hypotension, conduction disturbances, decreased cardiac output.
Very rare cases of severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal, have been observed, generally in the period immediately following surgery. This may be related to a possible interaction with a high concentration of oxygen.
Effect of Cordarone on other medicinal products
Amiodarone and / or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein and may increase exposure to their substrates.
Due to the long half-life of amiodarone, interactions can be observed for several months after stopping amiodarone.
- PgP substrates
Amiodarone is a P-glycoprotein (P-gp) inhibitor. Concomitant administration with P-gp substrates is expected to lead to an increase in their exposure.
Digital
Disturbances in automatism (excessive bradycardia) and in atrioventricular conduction (synergistic action) may occur; in addition, an increase in plasma digoxin concentrations due to a decrease in digoxin clearance is possible.
Electrocardiographic and plasma digoxin levels should therefore be monitored; and patients should be monitored for clinical signs of digitalis toxicity. Digitalis dosage may need to be adjusted.
Dabigatran
Caution should be exercised when administering amiodarone with dabigatran due to the risk of bleeding. The dosage of dabigatran may need to be adjusted according to the authorized product information.
- CYP2C9 substrates
Amiodarone increases the concentrations of CYP2C9 substrates such as warfarin or phenytoin by inhibition of cytochrome P450 2C9.
Warfarin
The combination of warfarin and amiodarone can potentiate the effect of the oral anticoagulant, thus increasing the risk of bleeding. It is necessary to monitor the prothrombin levels (INR) more regularly and adjust the dosage of anticoagulants both during treatment with amiodarone and after its interruption.
Phenytoin
The combination of phenytoin with amiodarone may lead to phenytoin overdose resulting in neurological symptoms. Clinical monitoring should be performed and the dosage of phenytoin should be reduced as soon as symptoms of overdose appear; plasma phenytoin levels should be determined.
- CYP 2D6 substrates
Flecainide
Amiodarone increases plasma concentrations of flecainide by inhibition of cytochrome CYP 2D6. Then the flecainide dosage should be adjusted.
- CYP P450 3A4 substrates
When these drugs are co-administered with amiodarone, an inhibitor of CYP 3A4, an increase in their plasma concentrations may occur which may lead to an increase in their toxicity.
Statins: The risk of muscle toxicity is increased by the concomitant administration of amiodarone with statins metabolised by CYP 3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended that a statin not metabolised by CYP 3A4 be used when co-administered with amiodarone.
Ciclosporin Combination with amiodarone may increase plasma levels of cyclosporine by decreasing clearance. Dosage should be adjusted.
Fentanyl: Combination with amiodarone may enhance the pharmacological effects of fentanyl and increase its risk of toxicity.
Other drugs metabolised by CYP 3A4: lidocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine, colchicine
Effect of other medicinal products on Cordarone Inhibitors of CYP 3A4 and CYP 2C8 have the potential to inhibit the metabolism of amiodarone and increase its exposure. It is recommended that CYP 3A4 inhibitors (eg grapefruit juice and some medicinal products) be avoided. during treatment with amiodarone.
Warnings It is important to know that:
For intravenous injection see also "Contraindications".
- Administration by intravenous injection is generally not recommended due to haemodynamic risks (severe hypotension, cardiovascular collapse); therefore, whenever possible, administration by venous infusion is preferable.
- Intravenous injection should be limited to urgent situations, and in cases where other alternative therapies have failed and should only be used in cardiological resuscitation units and under continuous monitoring (ECG, blood pressure).
- The dosage is about 5 mg / kg body weight in a time of not less than 3 minutes. The intravenous injection should not be repeated within 15 minutes following the first injection even if the last injection was only 1 ampoule (risk of irreversible collapse).
- Do not add any other products to the same syringe. Do not inject other products in the same line. If treatment is to be continued, intravenous infusion should be used (see "Dose, method and time of administration").
- The product is incompatible with aminophylline, heparin and sodium chloride solutions.
- The use of medical equipment and devices containing plasticisers such as DEHP (di-2-ethylphenylphthalate) may result in their release in the presence of amiodarone. To minimize patient exposure to DEHP, the final dilution of amiodarone for infusion should preferably be administered through media not containing DEHP.
- Periodic monitoring of lung function is recommended; in case of onset of non-productive cough, isolated dyspnoea or associated with a deterioration of the general state (fatigue, weight loss), fever, a pulmonary radiographic check is indicated and, if necessary, appropriate clinical and instrumental investigations. In case of pulmonary toxicity it is necessary to consider the need to reduce or suspend treatment with amiodarone, setting up a cortisone therapy. It should be borne in mind that the time to onset of pulmonary toxicity can be very variable (from a few days to months) and that in many cases a delay in diagnosis can lead to a fatal outcome.
Cardiac alterations
New onset or worsening of treated arrhythmias, sometimes fatal, have been reported. It is important, but difficult, to differentiate a loss of drug efficacy from a proarrhythmic effect, in any case this is associated with a worsening of the heart condition. Proarrhythmic effects are reported more rarely with amiodarone than with other antiarrhythmics and generally occur in the context of factors that prolong the QT interval such as interactions with other drugs and / or electrolyte disturbances (see Interactions and Undesirable Effects).
Liver disorders (see Undesirable Effects)
Close monitoring of liver function (transaminases) is recommended at the initiation of amiodarone therapy, and regularly during treatment. Acute liver disorders (including severe hepatocellular insufficiency or hepatic insufficiency, sometimes fatal) and chronic liver disorders may occur with oral and intravenous amiodarone and within the first 24 hours of IV administration. Therefore, the amiodarone dose should be reduced or treatment discontinued if the transaminase elevation is greater than 3 times the upper limit of normal.
The clinical and biological signs of chronic liver disorders due to oral amiodarone may be minimal (hepatomegaly, transaminase elevations up to 5 times the value corresponding to the upper limit of normal) and reversible upon discontinuation of treatment, however cases have been reported. with a fatal outcome.
In case of hepatomegaly or suspected cholestasis, the drug should be promptly discontinued and the patient undergo ultrasound control. For these reasons the drug cannot be used in patients with evident clinical and laboratory signs of active liver disease; in milder cases it can be used only when indispensable and must be suspended when there is a worsening of liver damage
Drug interactions (see Interactions)
The concomitant use of amiodarone with the following drugs is not recommended: beta blockers, calcium channel blockers that reduce heart rate (verapamil, diltiazem), stimulant laxatives that can cause hypokalaemia.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnant
Amiodarone is contraindicated except where the benefit outweighs the risk, due to its effects on the thyroid gland of the fetus.
Significant amounts of amiodarone are excreted in breast milk; natural breastfeeding is therefore contraindicated in patients treated with the drug.
Association with statins
It is recommended that a statin not metabolised by CYP 3A4 be used when co-administered with amiodarone (see Interactions).
Dosage and method of use How to use Cordarone: Dosage
In relation to the pharmaceutical characteristics, concentrations lower than 600 mg / l should not be used. Use only 5% isotonic dextrose solution (glucose). Do not add any other products to the infusion solution. Venous infusion:
- Loading dosage: the average dosage is 5 mg / kg exclusively in 250 ml of 5% dextrose solution (glucose), administered over a period of time between 20 minutes and 2 hours, this dose is repeatable from 2 to 3 times in 24 hours. The infusion rate must be adjusted to the clinical response. The therapeutic effect appears within the first few minutes and then progressively diminishes, so a subsequent infusion must be performed.
- Maintenance dosage: 10 to 20 mg / kg in 24 hours (generally 600-800 mg / 24 hours and up to 1200 mg / 24 hours) in 250 ml of 5% dextrose solution (glucose) for a few days. Switch to the oral route from the first day of infusion.
Intravenous injection
(see also "Special warnings")
The dosage is 5 mg / kg, the duration of the injection should be no less than 3 minutes. Do not add any other product to the syringe.
Concomitant therapy
For patients taking amiodarone concomitantly with statins, see Precautions for use and interactions.
Pediatric population
The safety and efficacy of amiodarone in children has not been established.
Given the presence of benzyl alcohol in the formulation, intravenous administration of amiodarone is contraindicated in newborns, infants and children up to 3 years of age.
Overdose What to do if you have taken too much Cordarone
There is no information available regarding cases of overdose with intravenous amiodarone.
Not much information is available regarding acute overdose with orally administered amiodarone. A few cases of sinus bradycardia, cardiac arrest, ventricular tachycardia, "torsade de pointes", circulatory failure and liver damage have been reported.
Treatment must be symptomatic. Neither amiodarone nor its metabolites are dialysable.
In case of accidental intake of an excessive dose of CORDARONE, notify your doctor immediately or go to the nearest hospital.
IF YOU HAVE ANY DOUBTS ABOUT USING CORDARONE, CONTACT YOUR DOCTOR OR PHARMACIST.
Side Effects What are the side effects of Cordarone
Like all medicines, CORDARONE can cause side effects, although not everybody gets them.
The following adverse reactions are classified by system organ class and frequency using the following convention: very common (≥ 10%), common (≥ 1% and <10%), uncommon (≥ 0.1% and <1%) , rare (≥ 0.01% and <0.1%), very rare (<0.01%), not known (cannot be estimated from the available data).
Cardiac pathologies
Common: generally moderate bradycardia
Very rare:
- marked bradycardia, sinus arrest requiring discontinuation of therapy, especially in patients with sinus node dysfunction and / or elderly patients
- onset or worsening of arrhythmia, sometimes followed by cardiac arrest (see Special Warnings and Interactions)
Frequency not known: Torsade de pointes (see "Interactions")
Endocrine pathologies
Frequency not known: Hyperthyroidism
Gastrointestinal disorders
Very rare: nausea
General disorders and administration site conditions
Common: Injection site reactions such as pain, erythema, edema, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes.
Disorders of the hepatobiliary system
Very rare:
- isolated increase in serum transaminases, usually moderate (1.5 to 3 times normal values) at the start of therapy. They may return to normal with dose reduction or even spontaneously
- acute liver disease with elevated serum transaminase levels and / or jaundice, including hepatic failure, sometimes fatal. In such cases, treatment should be discontinued and monitoring of liver function is therefore recommended (see Special warnings).
Disorders of the immune system
Very rare: anaphylactic shock
Frequency not known: angioneurotic edema (Quincke's edema)
Musculoskeletal and connective tissue disorders
Frequency not known: back pain.
Alterations of the nervous system
Very rare
- benign intracranial hypertension (pseudo-tumor cerebri)
- headache.
Respiratory, thoracic and mediastinal disorders
- Severe, sometimes fatal, pulmonary toxicity can occur, especially if not diagnosed promptly. This toxicity includes pulmonary alveolitis, pneumonia, asthma symptoms, lipoid pneumonia and pulmonary fibrosis. Pulmonary toxicity, cough and dyspnoea may be accompanied by radiographic and functional signs of interstitial pneumonia (altered alveolar-capillary diffusion); The emergence of these clinical signs requires the suspension of therapy and the administration of corticosteroid drugs. Such symptoms can also occur late after discontinuation of therapy: careful and prolonged monitoring of the patient is therefore required in order to identify possible alterations in pulmonary function.
Very rare
- interstitial pneumonia (see Precautions for use). Chest X-ray should be done when diagnosis is suspected. Amiodarone therapy should, however, be re-evaluated as interstitial pneumonia is generally reversible after early treatment discontinuation with amiodarone; a cortisone treatment should also be considered.
- severe, sometimes fatal, respiratory complications (adult acute respiratory distress syndrome) (see Interactions).
- bronchospasm and / or apnea in cases of severe respiratory insufficiency and especially in asthmatic patients.
Skin and subcutaneous tissue disorders
Very rare: sweating
Frequency not known: urticaria
Vascular pathologies
Common: decrease in blood pressure, usually moderate and transient. There have been reports of severe hypotension or collapse after overdose or too rapid injection
very rare: hot flashes.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Store at a temperature not exceeding 25 ° C.
Expiry: see the expiry date printed on the package. The expiry date indicated refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Keep this medicine out of the reach and sight of children.
COMPOSITION
One ampoule contains Active ingredient: amiodarone hydrochloride 150 mg Excipients: benzyl alcohol 60.6 mg, polysorbate 80, water for injections.
PHARMACEUTICAL FORM AND CONTENT
Solution for injection 5 and 6 ampoules of 150 mg / 3 ml
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CORDARONE 150 MG / 3 ML SOLUTION FOR INJECTION FOR INTRAVENOUS USE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains:
Active principle: amiodarone hydrochloride 150 mg
Excipients: benzyl alcohol
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection for intravenous use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Intravenous cordarone should be used when a rapid response is required or when oral administration is not possible.
Treatment and prevention of severe rhythm disturbances resistant to other specific therapies: supraventricular tachycardias (paroxysmal and non-paroxysmal), atrial extrasystoles, atrial flutter and fibrillation.
Paroxysmal reciprocating supraventricular tachycardias as in the course of Wolff-Parkinson-White Syndrome. Ventricular extrasystoles and tachycardias.
04.2 Posology and method of administration
See also section 6.6.
Venous infusion:
• Loading dosage: the average dosage is 5 mg / kg exclusively in 250 ml of 5% dextrose solution (glucose), administered over a period of time between 20 minutes and 2 hours, this dose is repeatable from 2 to 3 times in 24 hours. The infusion rate must be adjusted to the clinical response.
The therapeutic effect appears within the first few minutes and then progressively diminishes, so a subsequent infusion must be performed.
• Maintenance dosage: from 10 to 20 mg / kg in 24 hours (generally 600-800 mg / 24 hours and up to 1200 mg / 24 hours) in 250 ml of 5% dextrose solution (glucose) for a few days.
Switch to the oral route from the first day of infusion.
Intravenous injection
(see section 4.4).
The dosage is 5 mg / kg, the duration of the injection should be no less than 3 minutes. Do not add any other product to the syringe.
Pediatric population
The safety and efficacy of amiodarone in children has not been established.
Currently available data are described in sections 5.1 and 5.2.
Given the presence of benzyl alcohol in the formulation, intravenous administration of amiodarone is contraindicated in newborns, infants and children up to 3 years of age.
Concomitant therapy
For patients taking amiodarone concomitantly with HMG-CoA reductase inhibitors (statins), see sections 4.4 and 4.5.
04.3 Contraindications
• Sinus bradycardia, sinoatrial block and sinus disease without electro stimulator (risk of sinus arrest).
• Conduction disturbances, without electro-stimulator (atrio-ventricular blocks, bi- or trifascicular blocks). In these cases, injectable amiodarone can be used in specialized units and by means of an electrosystolic stimulator.
• Cardiovascular collapse, severe arterial hypotension.
• Combination with drugs capable of determining "torsade de pointes" (see section 4.5).
• Dystyroidism in progress or resolved. In doubtful cases, perform a thyroid function test before treatment.
• Hypersensitivity to iodine, or to amiodarone or to any of the excipients.
• Pregnancy, except in exceptional cases (see section 4.6).
• Breastfeeding (see section 4.6).
• Intravenous injection is contraindicated in case of hypotension, severe respiratory failure, myocardiopathy or heart failure (risk of worsening).
• Due to the presence of benzyl alcohol in the formulation, intravenous administration of amiodarone is contraindicated in newborns, infants and children up to 3 years of age.
04.4 Special warnings and appropriate precautions for use
Special warnings
For intravenous injection see also section 4.3.
• Administration by intravenous injection is generally not recommended due to haemodynamic risks (severe hypotension, cardiovascular collapse); therefore, whenever possible, administration by venous infusion is preferable.
• Intravenous injection should be limited to urgent situations, in cases where other alternative therapies have failed and should only be used in cardiological resuscitation units and under continuous monitoring (ECG, blood pressure).
• The dosage is about 5 mg / kg body weight; amiodarone must be injected in no less than 3 minutes. The intravenous injection should not be repeated within 15 minutes following the first injection even if the last injection was only 1 ampoule (risk of irreversible collapse).
• Do not add any other products to the same syringe. Do not inject other products in the same line. If treatment is to be continued, venous infusion should be used (see section 4.2).
Cardiac alterations
New onset or worsening of treated arrhythmias, sometimes fatal, have been reported. It is important, but difficult, to differentiate a loss of drug efficacy from a proarrhythmic effect, in any case this is associated with a worsening of the heart condition. Proarrhythmic effects are reported more rarely with amiodarone than with other antiarrhythmics and generally occur in the context of factors that prolong the QT interval such as interactions with other drugs and / or electrolyte disturbances (see sections 4.5 and 4.8).
Hepatic disorders (see section 4.8)
Close monitoring of liver function (transaminases) is recommended at the initiation of amiodarone therapy, and regularly during treatment. Acute liver disorders (including severe hepatocellular insufficiency or hepatic insufficiency, sometimes fatal) and chronic liver disorders may occur with oral and intravenous amiodarone and within the first 24 hours of IV administration.
Therefore, the amiodarone dose should be reduced or treatment discontinued if the transaminase elevation is greater than 3 times the upper limit of normal.
The clinical and biological signs of chronic liver disorders due to oral amiodarone may be minimal (hepatomegaly, transaminase elevations up to 5 times the value corresponding to the upper limit of normal) and reversible upon discontinuation of treatment, however cases have been reported. with a fatal outcome.
In case of hepatomegaly or suspected cholestasis, the drug should be promptly discontinued and the patient undergo ultrasound control.
For these reasons the drug cannot be used in patients with evident clinical and laboratory signs of active liver disease; in milder cases it can be used only when indispensable and must be suspended when there is a worsening of liver damage.
Drug interactions (see section 4.5)
The concomitant use of amiodarone with the following drugs is not recommended: beta blockers, calcium channel blockers that reduce heart rate (verapamil, diltiazem), stimulant laxatives that can cause hypokalaemia.
Precautions for use
Intravenous administration of amiodarone should only be performed in specialized hospital units and under continuous monitoring (ECG, blood pressure).
To avoid injection site reactions, amiodarone should be administered through a central venous line whenever possible (see section 4.8).
Use caution in case of hypotension, severe respiratory failure, severe and uncompensated heart failure.
Pediatric patients : in these patients the safety and efficacy of amiodarone have not been demonstrated. Therefore, the use of the drug is not recommended in pediatric patients.
CORDARONE injectable vials contain benzyl alcohol (see section 6.1) as a preservative and should not be used in neonates. Cases of fatal gasping syndrome have been reported following intravenous administration of solutions containing this preservative in neonates (less than one month of age). Symptoms include abrupt onset of wheezing, hypotension, bradycardia, and cardiovascular collapse.
The medicine contains 60.6 mg of benzyl alcohol in each 3 ml ampoule.
Benzyl alcohol can cause toxic and anaphylactic reactions in infants and children up to 3 years of age.
Anesthesia. Prior to surgery, the anesthetist should be informed that the patient is being treated with amiodarone (see section 4.5).
Association with statins.
It is recommended that a statin not metabolised by CYP 3A4 be used when co-administered with amiodarone (see section 4.5).
Pulmonary toxicity
Pulmonary toxicity related to the intake of amiodarone is a frequent and serious adverse reaction that can occur in up to 10% of patients and that can be fatal in about 8% of affected patients, mainly due to a lack of diagnosis. The time of onset of the reaction during therapy varies from a few days to a few months or years of intake; in some cases the onset may also occur after a certain period of time from the suspension of treatment.
However, the risk of toxicity does not make the risk / benefit ratio of amiodarone unfavorable, which maintains its usefulness. However, the utmost attention must be paid to immediately identify the first signs of pulmonary toxicity, especially in patients suffering from cardiomyopathy and severe coronary heart disease. in which such identification can be more problematic.
The risk of amiodarone pulmonary toxicity increases with doses above 400 mg / day, but can also occur at low doses taken for less than 2 years.
Pulmonary toxicity is manifested by pulmonary alveolitis, pneumonia, interstitial pneumonia, pulmonary fibrosis, bronchial asthma. Patients who develop pulmonary toxicity often present with non-specific symptoms, such as non-productive cough, dyspnoea, fever, and weight loss.
All these symptoms can be masked by the pathology for which amiodarone is indicated, and can be considerably serious in patients over 70 years of age, who usually have reduced functional capacity or pre-existing cardiac diseases. -respiratory. Early diagnosis by means of pulmonary radiographic control and possibly the necessary clinical and instrumental investigations, is of crucial importance as pulmonary toxicity is highly reversible, especially in the forms of obliterating bronchiolitis and pneumonia.
Pulmonary symptoms and objectivity must therefore be checked periodically, and therapy must be suspended in the event of suspected pulmonary toxicity, taking into account cortisone therapy: symptoms usually regress within 2-4 weeks of discontinuing amiodarone. In some cases, pulmonary toxicity can manifest itself late, even weeks after the suspension of therapy: subjects with suboptimal organic functions, who could eliminate the drug more slowly, must therefore be carefully monitored.
04.5 Interactions with other medicinal products and other forms of interaction
• Drugs that induce Torsade de Pointes or QT prolongation
- Drugs that induce Torsade de Pointes
The combination with drugs capable of causing "torsade de pointes" is contraindicated (see section 4.3):
• antiarrhythmics such as those of Class IA, sotalol, bepridil.
• non-anti-arrhythmic drugs such as vincamine, some neuroleptic drugs including sultopride, cisapride, erythromycin E.V., pentamidine (for parenteral administration) as there may be an increased risk of life-threatening "torsade de pointes".
• QT-prolonging drugs.
The concomitant administration of amiodarone with other medicinal products known to prolong the QT interval requires careful consideration of the potential risks and benefits for each patient as the risk of torsade de pointes may be increased and patients should be monitored for QT prolongation.
Fluoroquinolones should be avoided in patients on amiodarone therapy.
• Drugs that reduce heart rate or cause automatism and / or conduction disturbances.
The association with these drugs is not recommended:
• beta-blockers and calcium channel blockers which reduce heart rate (verapamil, diltiazem) due to the possibility of automatism (excessive bradycardia) and conduction disorders.
• Factors that can induce hypokalaemia
The association with drugs that can induce hypotassemia is not recommended:
• stimulating laxatives: due to the appearance of a possible hypokalaemia, consequently increasing the risk of "torsade de pointes"; other types of laxatives must therefore be used.
Caution should be exercised when the following drugs are combined with Cordarone:
• diuretics capable of causing hypokalaemia, alone or in combination
• systemic glucocorticoids and mineralocorticoids, tetracosactide
• amphotericin B via the E.V.
Hypokalaemia should be prevented (and corrected): QT interval should be monitored and antiarrhythmics should not be administered in the case of "torsade de pointes" (ventricular pacing should be initiated; magnesium IV can be used).
• General anesthesia (see sections 4.4 and 4.8)
Potentially serious complications have been reported in patients undergoing general anesthesia: bradycardia (insensitive to atropine), hypotension, conduction disturbances, decreased cardiac output.
Very rare cases of severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal, have been observed, generally in the period immediately following surgery. This may be related to a possible interaction with a high concentration of oxygen.
Effect of Cordarone on other medicinal products
Amiodarone and / or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein and may increase exposure to their substrates.
Due to the long half-life of amiodarone, interactions can be observed for several months after stopping amiodarone.
• PgP substrates
Amiodarone is a P-glycoprotein (P-gp) inhibitor. Concomitant administration with P-gp substrates is expected to lead to an increase in their exposure.
• Digital
Disturbances in automatism (excessive bradycardia) and in atrioventricular conduction (synergistic action) may occur; in addition, an increase in plasma digoxin concentrations due to a decrease in digoxin clearance is possible.
Electrocardiographic and plasma digoxin levels should therefore be monitored; and patients should be monitored for clinical signs of digitalis toxicity. Digitalis dosage may need to be adjusted.
• Dabigatran
Caution should be exercised when administering amiodarone with dabigatran due to the risk of bleeding. The dosage of dabigatran may need to be adjusted according to the authorized product information.
• CYP2C9 substrates
Amiodarone increases the concentrations of CYP2C9 substrates such as warfarin or phenytoin by inhibition of cytochrome P450 2C9.
- Warfarin
The combination of warfarin and amiodarone may potentiate the effect of the oral anticoagulant, thus increasing the risk of bleeding. Prothrombin levels (INR) should be monitored more regularly and the dosage of anticoagulants adjusted both during treatment with amiodarone than after its interruption.
• Phenytoin
The combination of phenytoin with amiodarone may lead to phenytoin overdose resulting in neurological symptoms. Clinical monitoring should be performed and the dosage of phenytoin should be reduced as soon as symptoms of overdose appear; plasma phenytoin levels should be determined.
• CYP2D6 substrates
• Flecainide
Amiodarone increases plasma concentrations of flecainide by inhibition of cytochrome CYP 2D6. Then the flecainide dosage should be adjusted.
• CYP P450 3A4 substrates:
When these drugs are co-administered with amiodarone, an inhibitor of CYP 3A4, an increase in their plasma concentrations may occur which may lead to an increase in their toxicity.
• Statins: The risk of muscle toxicity is increased by the concomitant administration of amiodarone with statins metabolised by CYP 3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended that a statin not metabolised by CYP 3A4 be used when co-administered with amiodarone.
• Cyclosporine: The combination with amiodarone may increase the plasma levels of cyclosporine by reducing the clearance. The dosage should be adjusted.
• Fentanyl: The combination with amiodarone may enhance the pharmacological effects of fentanyl and increase its risk of toxicity.
• Other drugs metabolised by CYP 3A4: lidocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine, colchicine.
Effect of other medicinal products on Cordarone
CYP3A4 and CYP2C8 inhibitors have the potential to inhibit the metabolism of amiodarone and increase its exposure.
It is recommended to avoid CYP3A4 inhibitors (e.g. grapefruit juice and some medicines) during treatment with amiodarone.
04.6 Pregnancy and lactation
Pregnancy
Amiodarone is contraindicated in pregnancy, unless the benefit outweighs the risk, due to its effects on the fetal thyroid.
Feeding time
Amiodarone is contraindicated in nursing mothers as it is excreted in breast milk in significant quantities.
04.7 Effects on ability to drive and use machines
Not relevant.
04.8 Undesirable effects
The following adverse reactions are classified by system organ class and frequency using the following convention: very common (≥ 10%), common (≥ 1% and
Cardiac pathologies
• Common:
generally moderate bradycardia.
• Very rare:
• marked bradycardia, sinus arrest requiring discontinuation of therapy, especially in patients with sinus node dysfunction and / or elderly patients.
• onset or worsening of arrhythmia, sometimes followed by cardiac arrest (see sections 4.4 "Special Warnings" and 4.5).
• Frequency not known:
Torsade de pointes (see section 4.5)
Endocrine pathologies
Frequency not known: Hyperthyroidism
Gastrointestinal disorders
• Very rare: nausea
General disorders and administration site conditions
• Common: Injection site reactions such as pain, erythema, edema, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes.
Hepatobiliary disorders
Very rare:
• isolated increase in serum transaminases, usually moderate (1.5 to 3 times normal values) at the start of therapy. They may return to normal with dose reduction or even spontaneously.
• acute liver disease with elevated serum transaminase levels and / or jaundice, including hepatic failure, sometimes fatal. In such cases, treatment should be stopped and monitoring of liver function is therefore recommended (see section 4.4 "Special Warnings").
Disorders of the immune system
Very rare: anaphylactic shock
Frequency not known: angioneurotic edema (Quincke's edema)
Musculoskeletal and connective tissue disorders
Frequency not known: back pain.
Nervous system disorders
Very rare:
• benign intracranial hypertension (pseudo-tumor cerebri)
• headache.
Respiratory, thoracic and mediastinal disorders
• Severe pulmonary toxicity, sometimes fatal, may occur in about 10% of patients, especially if not diagnosed promptly. This toxicity includes pulmonary alveolitis, pneumonia, asthma symptoms, lipoid pneumonia and pulmonary fibrosis. Pulmonary toxicity, cough and dyspnoea may be accompanied by radiographic and functional signs of interstitial pneumonia (altered alveolar-capillary diffusion); The emergence of these clinical signs requires the suspension of therapy and the administration of corticosteroid drugs. Such symptoms can also occur late after discontinuation of therapy: careful and prolonged monitoring of the patient is therefore required in order to identify possible alterations in pulmonary function.
Very rare
• interstitial pneumonia (see section 4.4 "precautions for use"). Chest X-ray should be done when diagnosis is suspected. Amiodarone therapy should, however, be re-evaluated as interstitial pneumonia is generally reversible after early discontinuation of amiodarone treatment; cortisone treatment should also be considered.
• severe, sometimes fatal, respiratory complications (adult acute respiratory distress syndrome) (see section 4.5).
• bronchospasm and / or apnea in cases of severe respiratory failure and especially in asthmatic patients.
Skin and subcutaneous tissue disorders
• Very rare: sweating
• Frequency not known: hives
Vascular pathologies
• Common
• decrease in blood pressure, usually moderate and transient. There have been reports of severe hypotension or collapse after overdose or too rapid injection
• very rare: hot flashes.
04.9 Overdose
There is no information available regarding cases of overdose with intravenous amiodarone.
Not much information is available regarding acute overdose with orally administered amiodarone. A few cases of sinus bradycardia, cardiac arrest, ventricular tachycardia, "torsade de pointes", circulatory failure and liver damage have been reported.
Treatment must be symptomatic. Neither amiodarone nor its metabolites are dialyzable.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cardiovascular system, antiarrhythmics, class III; ATC code: C01BD01
Anti-arrhythmic properties :
• Phase 3 elongation of the action potential of the cardiac fiber mainly due to a decrease in potassium current (Class III according to the classification of Vaughan Williams); this elongation is not correlated with heart rate.
• Reduced sinus automaticity, leading to bradycardia, insensitive to the administration of atropine.
• Non-competitive alpha- and beta-adrenergic inhibition.
• Slowing in sinoatrial, atrial and nodal conduction, which is more pronounced when heart rate is high.
• No changes in intraventricular conduction.
• At the atrial, nodal and ventricular levels: increase in the refractory period and decrease in excitability of the myocardium.
• Slowing of conduction and prolongation of refractory periods in accessory atrioventricular tracts.
Anti-ischemic properties :
• Moderate drop in peripheral resistance and decrease in heart rate resulting in reduced oxygen requirements.
• Non-competitive antagonism for alpha- and beta-adrenergic receptors.
• Increased coronary output due to a direct effect on the smooth muscle of the myocardial arteries.
• Maintenance of cardiac output due to decreased aortic pressure and peripheral resistance.
Other :
• Reduced cardiac contractility especially after intravenous injection.
Pediatric population
No controlled pediatric studies have been performed.
In published studies, the safety of amiodarone was evaluated in 1118 pediatric patients with various arrhythmias. The following dosages were used in pediatric clinical studies.
Intravenous route
• loading dose: 5 mg / kg body weight administered over a period of time between 20 minutes and 2 hours - maintenance dose: 10 to 15 mg / kg / day from a few hours to several days
If necessary, oral therapy can be started concurrently at the usual loading dose.
05.2 Pharmacokinetic properties
After administration by injection, the blood concentration of amiodarone decreases
rapidly since amiodarone is deposited in the tissues; the maximum efficacy is obtained after 15 minutes from the injection and is exhausted in the following 4 hours. In the case of a single administration, the drug is progressively eliminated; it accumulates in the tissues in the case of repeated injections or if therapy is continued orally.
Amiodarone is mainly metabolised by CYP3A4 and also by CYP2C8.
Amiodarone and its metabolite, desethylamiodarone, have the potential to inhibit CYP1A1, CYP1A2, CYP2C19, CYP2D6, CYP3A4 in vitro. Amiodarone and desethylamiodarone are also potentially able to inhibit some transporters such as P-gp. In vivo data describe the interactions of amiodarone with CYP3A4, CYP2C9, CYP2D6 and P-gp substrates.
No controlled pediatric studies have been performed. In the limited published data available in pediatric patients, no differences were found compared to adults.
05.3 Preclinical safety data
Acute toxicity: LD50 in rat 170 mg / kg E.V.,> 3000 mg / kg os, in mice 450 mg / kg i.p.,> 3000 mg / kg os, in beagle dog 85-150 mg / kg E.V.
Chronic toxicity: no mortality, weight loss or change in biological parameters were detected at oral doses up to 37.5 mg / kg / day (4 weeks) and 16 mg / kg / day (52 weeks) in rats and up to to 12.5 mg / kg / day in dogs.
Teratogenesis: investigations carried out in rats (100 mg / kg / day) and rabbits (75 mg / kg / day) did not reveal any signs of fetal toxicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
benzyl alcohol, polysorbate 80, water for injections (q.s. to 3 ml).
06.2 Incompatibility
Incompatible with aminophylline, heparin and sodium chloride solutions.
The use of medical equipment and devices containing plasticisers such as DEHP (di-2-ethylhexyl phthalate) may result in their release in the presence of amiodarone. To minimize patient exposure to DEHP, the final dilution of amiodarone for infusion should preferably be administered through media not containing DEHP.
See also section 6.6.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Store at a temperature not exceeding 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Cardboard box containing 5 and 6 ampoules.
06.6 Instructions for use and handling
In relation to the pharmaceutical characteristics, concentrations lower than 600 mg / l should not be used. Use only 5% isotonic dextrose solution (glucose). Do not add any other products to the infusion solution.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi-Aventis S.p.A. - Viale L. Bodio, 37 / B - 20158 Milan
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 025035027 CORDARONE 150 mg / 3 ml solution for injection for intravenous use - 5 ampoules
A.I.C. n. 025035039 CORDARONE 150 mg / 3 ml solution for injection for intravenous use - 6 ampoules
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal: 01.06.2010
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of June 2013