CORDARONE Sanofi-Aventis

Transcription

1 CORDARONE Sanofi-Aventis Composition Amiodarone 200 mg; tablets. Also AMPOULES 150 mg/3 ml. Indications Tablets Prevention of recurrence of the following: life-threatening ventricular tachycardias in which cases treatment should be established in hospital under monitoring; reflex ventricular tachycardias; atrioventricular tachycardias not responsive to other antiarrhythmic agents; auricular fibrillation. Treatment of atrioventricular tachycardias: slow down or reduction of auricular fibrillation or flutter. Amiodarone could be used even with underlying congestive heart failure or coronary disease. Injectable Treatment of severe rhythm disorders when oral route is not suitable, namely: Atrial arrhythmias associated with a rapid ventricular rhythm disorders; tachycardias due to Wolff- Parkinson-White syndrome; ventricular rhythm disorders. Contraindications Sinus bradycardia and sinoatrial heart block in the absence of pacemaker. Sick sinus syndrome in the absence of pacemaker (risk of sinus arrest). High degree conduction disorders in the absence of pacemaker. Circulatory collapse, severe systemic hypotension. Hyperthyroidism, due to potential worsening effect of amiodarone. Known hypersensitivity to iodine or to amiodarone. Combined therapy with drugs which may induce torsades de pointes (see Drug Interactions). Pregnancy, unless exceptional circumstance. Lactation. Side Effects Side effects observed with amiodarone are often related to too high a dosage. They may be prevented or reduced to a minimum by determining the lowest effective dosage. Ophthalmological Corneal microdeposits, which appear in the majority of patients. Formed of complex lipid deposits, they are always reversible upon termination of treatment. A few cases of optic neuritis with blurred vision and impaired visual acuity have been reported. The causal relationship with amiodarone has not currently been established. Dermatological Photosensitivity. Patients should avoid sun exposure (and as a rule UV rays exposure). Skin rashes, usually of specificity, including exceptional cases of exfoliative dermatitis have been reported with no clearlyestablished causal relationship to amiodarone. Slategrey or bluish pigmentations of the skin may occur in case of prolonged treatments with high daily doses. Such pigmentations slowly disappear following treatment discontinuation (10 to 24 months later). Thyroid Gland Apart from any clinical evidence of thyroid dysfunction, dissociated thyroid hormone levels are usual (increased levels of T4, normal or slightly decreased T3): they should not lead to discontinuation of treatment. Hypothyroidism: clinical signs (usually slight): weight gain, apathy, drowsiness; a clear increase in serum ultrasensitivity TSH (TSHu) confirms the diagnosis. Cessation of treatment restores normal thyroid function within 1 to 3 months. In lifethreatening situations, amiodarone may be continued in combination with thyroid replacement therapy by L-thyroxine. TSHu levels provide a guide to L-thyroxine dosage. Hyperthyroidism: giving rise to few symptoms (unexplained light weight loss, decreased effectiveness

2 in angina and/or arrythmia); psychiatric aspect in elderly patients; sharply reduced TSHu confirms the diagnosis. Amiodarone should be withdrawn. Clinical recovery usually occurs within 3 to 4 weeks. In severe cases, the inconstant efficacy of synthetic antithyroid drugs may require the concomitant administration of corticosteroids (1 mg/kg) for a sufficient course (3 months). In patients with increased risk of thyroid dysfunction (family history of thyroid disease, doubtful personal history) regular assessment of thyroid function tests is recommended. Pulmonary Cases of diffuse interstitial pulmonary fibrosis have been reported. Onset of exertional dyspnea, whether alone or in combination with deterioration of general health (fatigue, weight loss, fever) requires that a chest x-ray be performed. Early withdrawal of amiodarone, with or without concomitant corticosteroid therapy, leads to regression of disturbances. Clinical symptoms usually disappear within 3 to 4 weeks, but functional and radiological improvement occurs slowly (several months). Neurological Sensitive motor peripheral neuropathy and/or myopathy, usually reversible on treatment discontinuation. Other disturbances reported: extrapyramidal tremor, cerebellar ataxia, exceptional benign intracranial hypertension, and nightmares. Hepatic Regular monitoring of liver function tests (transaminases) is recommended during the course of therapy. The following adverse reactions have been reported: At the Beginning of Treatment: Elevation of serum transaminases, isolated and usually moderate (1.5 to 3 times normal values) returning to normal with dose reduction, or even spontaneously. Acute liver disorders exceptionally (a few isolated cases) with elevated serum transaminases and/ or jaundice. Regression of such conditions always occurs when treatment is withdrawn. During Lengthy Treatments: A few rare cases of chronic liver disease have been reported. Histological findings reveal lesions resembling pseudo-alcoholic hepatitis. The subtle clinical signs and biological changes (possible hepatomegaly, elevated transaminases 1.5 to 5 times normal) justify regular monitoring of liver function tests. Elevated serum transaminases, even moderate, developing after treatment for longer than 6 months should suggest this diagnosis. Clinical and biological abnormalities usually regress upon cessation of treatment. A few cases of irreversible progression have been reported. Cardiac Bradycardia, which generally is moderate and dose-related. In some cases (sinus node dysfunction, elderly subjects) marked bradycardia or more exceptionally sinus arrest have been reported. There have been rare instances of conduction disturbances (sinoatrial block, AV block of various degrees). Amiodarone has a weak arrhythmia-inducing potential, less than that observed with most of the other anti-arrhythmic drugs, and it occurs generally in case of certain drug associations (see Drug Interactions) or electrolytic disorders. Others Benign digestive disorders (nausea, vomiting, dysgeusia) which usually occur with loading dosage and disappear with dose reduction. A few isolated cases, of various clinical features, have been observed in a context suggesting a hypersensitivity reaction: vasculitis, renal involvement with moderate elevation of creatinine levels, and thrombopenia. A few cases of epididymitis have been reported. The relationship with amiodarone has not been established. Particular to I.V. administration: Hot flushes, sweating, nausea (intravenous injection). Decrease in blood pressure, usually moderate and transient. Cases of severe hypotension or collapse have been reported following overdosage or a too rapid injection. Moderate bradycardia. In some cases, and especially in elderly patients, marked bradycardia, or more exceptionally sinus arrest, requires the discontinuation of therapy. Occurrence of arrhythmia, or aggra-

3 vation 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 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 electrolytic disorders (see Drug Interactions). Isolated elevation of serum transaminases, which are usually moderate (1.5 to 3 times normal) have been reported at the beginning of therapy; they may regress with dose reduction or even spontaneously. A few cases of acute liver disorders with elevated serum transaminases and/or jaundice, which included some fatalities have also been reported; treatment should be discontinued, and monitoring of liver function test is therefore recommended. Other and apparently exceptional effects (a few isolated cases) have been reported following I.V. injection: anaphylactic shock, benign intracranial hypertension (pseudotumor cerebri), bronchospasm and/ or apnea in case of severe respiratory failure, and especially in asthmatic patients. Warnings Specific to the Injectable Route Cordarone I.V. should never be used through a peripheral venous route. It should be exclusively infused by a central catheter. As injection, even when it is very slow, may worsen an hypertension, a cardiac failure, or a severe respiratory failure. In the elderly, heart rate may be more markedly decreased. Cordarone induces ECG Changes: QT prolongation (in relation with prolonged repolarization) with the possible development of U-waves; these changes are evidence of itspharmacological action and do not reflect toxicity. Amiodarone contains iodine; as a consequence, results of some thyroid function tests may be altered (radioiodine uptake). Precautions Electrolytic disturbances, especially hypokalemia; these disturbances could enhance proarrhythmic effects and have to be rebalanced before using Cordarone. Undesirable effects (see Side Effects) are related in most cases with drug overloading; therefore careful attention should be paid in determining the minimum effective maintenance dosage in order to avoid or minimize undesirable effects. Patients should be instructed to avoid sun exposure or to use protective measures during therapy. In patients with personal or family history of thyroid disorders, caution should be exercised when administering Cordarone if it is necessary; the minimum effective dosage should be used and careful clinical and biological monitoring should be undertaken. Amiodarone intravenous should only be used in a special care unit under continuous monitoring (ECG, blood pressure). Caution should be exercised in case of hypotension, severe respiratory failure, decompensated myocardiopathy or severe heart failure. Pregnancy and Lactation Pregnancy: In view of its effects on the fetal thyroid gland, amiodarone is contraindicated during pregnancy, except in exceptional cases. Lactation: Amiodarone is excreted in breast milk in significant quantities; therefore amiodarone is contraindicated in nursing mothers. Overdosage Little information is available regarding acute overdosage with amiodarone. Sinus bradycardia or spontaneously resolving attacks of ventricular tachycardia may occur. Most often the patient does not demonstrate clinical signs. Nevertheless, due to the pharmacokinetics of amiodarone, the patient should be monitored long enough, particularly with regard to cardiac status. Neither amiodarone or its metabolites can be dialysed. Drug Interactions Contraindicated Non antiarrhythmic agents causing torsades de

4 pointes (such as astemizole, bepridil, I.V. erythromycin, halofantrine, pentamidine, sparfloxacine, sultopride, terfenadine, vincamine): increased risk of potentially lethal torsades de pointes. Not Recommended Antiarrhythmic agents Class Ia (quinidine type agents, disopyramide), sotalol: increased risk of potentially lethal torsades de pointes. Injectable diltiazem: risk of bradycardia and AV block. Clinical and ECG monitoring is necessary. Stimulative laxative agents as their use may cause hypokalemia and therefore increase the risk of torsades de pointes; another type of laxative agents should be used. To be Used with Caution Beta-blockers and certain calcium channel inhibitors (verapamil, diltiazem). Agents which may induce hypokalemia: Diuretics inducing hypokalemia, either alone or combined. Systemic corticosteroids (glyco-, mineralo-), tetracosactide. Amphotericin B (I.V.) It is necessary to prevent the occurrence of hypokalemia (and to correct hypokalemia when required); QT interval should be monitored and, in case of torsades de pointes, antiarrhythmic agents should not be given (electrosystolic pacing should be instituted; I.V. magnesium may be used). Oral Anticoagulant Agents: Due to the potentiation of oral anticoagulant therapy and the increased risk of bleeding, more frequent monitoring of prothrombin level is necessary. Digitalis: Disturbances of automaticity (excessive bradycardia) and atrioventricular conduction (synergistic action) may occur; in addition, with digoxin, there is a possible increase in the plasma digoxin concentration (due to the decrease of digoxin clearance). Clinical, ECG, and biological monitoring (including digoxin plasma levels if relevant) should be undertaken; dosage adjustment of digitalis treatment may be necessary. Phenytoin: Possible increase of plasma phenytoin levels with signs of over-dosage (particularly neurological signs); clinical monitoring should be undertaken and phenytoin dosage should be reduced as soon as overdosage signs appear; phenytoin plasma levels may be determined. General anesthesia, oxygen therapy: Potentially severe complications have been reported in patients undergoing general anesthesia: bradycardia unresponsive to atropine, hypotension, disturbances of conduction, decreased cardiac output. A few cases of severe respiratory complications, resulting sometimes in fatalities, have been observed most often in the period immediately after surgery (acute adult respiratory distress syndrome); a possible interaction with a high oxygen concentration may be implicated. Before surgery, the anesthesiologist should be informed that the patient is taking amiodarone. Dosage and Administration Cordarone should only be given under close medical supervision. The dosage and mode of administration in each particular case, depends on the desired therapeutic effects, the patient s individual response and the possible Side effects. Tablets Loading dose: Average dosage: 200 mg (1 tablet) three times a day for 8-10 days. Dosage and Administration may be increased to 4 or even 5 tablets daily for short periods and under ECG monitoring. Maintenance dose: mg (½ - 2 tablets) daily. The treatment should be given once or twice daily, with or just after meals. The minimum effective maintenance dosage should be used. Ampoules Injectable route should only be used where cardiac monitoring and defibrillation facilities are available. Cordarone I.V. must be diluted in 5% dextrose only. Intravenous Infusion Due to galenic reasons, concentration less than 2 vials in 500 ml should not be used. Isotonic dextrose infusion should be used exclusively. Do not mix with other preparations in infusion solution. Loading dose: 5 mg/kg diluted in 250 ml 5% dex-

5 trose given over 20 minutes to 2 hours and renewed 2 to 3 times per 24 hours. Therapeutic effect appears within the first minutes and then it is progressively decreasing. Therefore, an infusion should be set up to take over. Maintenance dose: Usual dosage is mg/kg/24 hours ( mg/24 hours) in 250 ml 5% dextrose over few days. It is recommended that Cordarone be infused by a central venous catheter. Take over with oral administration from the first day of infusion. Packaging a: 150 mg/3 ml x 6 t: 200 mg x 30.