Amiodarone
QUALITATIVE AND QUANTITATIVE COMPOSITION:
Each tablet content :
Amiodarone (NN) hydrochlorida ........................................ 200 mg
Excipient: include lactose
PHARMACEUTICAL FORM
Tablet of 200 mg Amiodarone
PHARMACOLOGICAL PROPERTIES
Anti arrhythmic properties:
- Reduced sinus automaticity leading to bradycardia unresponsive to atropine administration.
- Non competitive alpha and beta adrenergic inhibition.
- Slowing in sino-atrial, atrial and nodal conduction, which is increased in proportion to rhythm rapidity
- No change in intra ventricular conduction.
- Increased in refractory period and decrease of myocardial oxcitability at the atrial, nodal and ventricular levels.
- Slowing in conduction and prolongation of refractory periods. in accessory atrioventricular pathways.
Other properties:
- Moderate drop in peripheral resistance and decrease in heart rate leading to a reduction of oxygen intake.
- Increase of coronary output due to a direct effect on myocardial arteries smooth muscle.
- Maintenance of cardiac output due to a decrease in aortic pressure and peripheral resistance.
Others
- No significant negative inotropic effect.
PHARMACOKINETIC PROPERTIES
Amiodarone has a slow transit and a high affinity to tissues.
Oral bioavailability has varied between 30 and 80% along with individual patients (mean value around 50%). Following single administration, peak plasma concentrations are reached after 3 to 7 hours. Therapeutic effects are usually obtained after one week (from a few days to two weeks), according to the loading dose.
Amiodarone has a long half-life including considerable inter-patient variability (from 20 to 100 days). During the fir days of therapy, the drug accumulates in almost all tissues, especially the adipose tissue.
Elimination occurs after a few days and steady-state plasma concentration is reached between 1 to several months depending on each individual patient. Due to the above characteristics, loading doses should be used in order to rapidly obtain the impregnation of tissues that is necessary to have a therapeutic effect.
Iodine is partly removed from the molecule and is found in urine as Iodure; this corresponds to 6mg/24 hours when 200mg of amiodarone is given daily. The remaining part of the molecule, thus including most of iodine, is eliminated in the faces following hepatic excretion.
The negligible renal excretion allows the administration or usual doses in patients with renal failure.
Following treatment discontinuation, the elimination continues ever several months; the persistence or a residual effect over 10 days to one month should be taken into account.
CLINICAL PARTICULARS
Therapeutic Indications
Cordarone® is indicated only for the treatment of severe rhythm disorders, not responding to other therapy or when other treatment cannot be used:
- Atrial rhythm disorders (conversion of fibrillation or flutter, and maintenance of sinus rhythm following conversion).
- Modal rhythm disorders
- Ventricular rhythm disorders (life-threatening ventricular tachycardia solves, prevention of ventricular tachycardia attacks or ventricular fibrillation episodes.
- Rhythm disorders associated with Wolf-Parkinson-While syndrome.
DOSAGE AND ADMINISTRATION
Initial stabilization: usual dosage is 600mg daily and may be continued for 8 to 10 days.
Maintenance: The minimum effective dosage should be used; according to individual response, It may. range between 100mg daily to 400mg daily. Cordarone® may be given on alternate (200 mg may be given every other day where 100mg are recommended daily);
CONTRA INDICATlONS
This medicine is contraindicated in the following situations:
- Sinus bradycardia and sino-atrial block not corrected by a pacemaker;
- Sinus disease not corrected by a pacemaker (risk of sinus arrest) .
- High-degree conduction disorders not corrected by a pacemaker;
- Hyperthyroidism due to its possible exacerbation by amiodarone;
- Known hypersensitivity to iodine or amiodarone;
- The last 6 months of pregnancy;
- Breast-feeding
- Combination with medicines that can induce torsades de pointes:
- class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide, etc).
- class III antiarrhythmics (sotalol, dofetillide, ibutilide etc),
- sultopride,
- other medicines, such as bepridil, cisapride, diphemanil, erythromycin IV, mizolastine, sparfloxacin, etc. (cf. Interactions with other medicinal products and other forms of interaction).
- injectable diltiazem,
- halofantrine, pentamidine, moxifloxacine,
- certain neuroleptics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, amisulpride, tiapride primozide, haloperidol, droperidol),
- and with beta-blockers other than sotalol and esmolol (cf. Interactions with other medicinal products and other forms of interaction).
SPECIAL WARNING
Warnings
An ECG must be performed before starting treatment.
- Slowing of heart rate may be accentuated in elderly patients.
- The electrocardiogram is modified under amiodarone. This "cordaronic" modification consists of a prolongation in QT reflecting a repolarisation prolongation, possibly with the appearance of a U wave; this is a sign of therapeutic impregnation and not of toxicity.
- The onset of 2nd or 3rd-degree atrioventricular block, sino-atrial block or bifascicular block should lead to suspension of treatment. 1st-degree atrioventricular block should lead to increased monitoring.
- The presence of iodine in the medicinal product falsifies certain thyroid tests (binding of radioactive iodine, PBI); however, thyroid function assessment is still possible (T3, T4, TSHus).
- Combination (cf. Interactions ,with other medicinal products and other forms of interaction) with:
- beta-blockers other than sotalol (contraindicated combination) and esmolol (combination requiring precautions for use).
- Verapamil and diltiazem, should only be considered in the prevention of life-threatening ventricular arrhythmias.
The onset of dyspnoea or a dry cough, alone or associated with a deterioration in general condition, should suggest the possibility of pulmonary toxicity and requires X-ray (Cf. Undesirable effects).
PRECAUTION
Precautions for use
Electrolyte balance disturbance and, in particular, hypokalaemia: it is important to take into account situations that may be associated with hypokalaemia since the latter can promote. the onset of proarrhythmic effects.
Hypokalaemia should be corrected prior to administration of amiodarone.
The undesirable effects mentioned below are usually related to excessive drug levels; they can be avoided or their severity minimized by carefully seeking the minimum maintenance dosage.
Patients should be advised to avoid exposure to sun or to use sun protection during treatment.
Amiodarone can cause thyroid anomalies (d Undesirable effects).
Assay of TSH is recommended in all patients before treatment and then regularly throughout treatment - for example, every 6 months - and several months after its withdrawal.
TSH levels should be measured in the event of clinical suspicion of dysthyroidism (cf. Undesirable effects).
In children, the safety and efficacy of amiodarone have not been evaluated by controlled clinical trials.
Regular monitoring of liver function (transaminase levels) is useful to screen for liver damage caused by amiodarone (cf. Undesirable effects).
Anaesthesia
Before surgery, the anaesthetist must be informed that the patient is treated with amiodarone.
Chronic treatment with amiodarone may lead to exacerbation, in terms of undesirable effects, of the haemodynamic risks of general or local anaesthetics.
These concern, in particular, bradycardiac and hypotensive effects, reduced cardiac output and conduction disturbances.
In addition, a few cases of acute respiratory distress have been observed immediately after surgery in patients treated with amiodarone. Consequently, close monitoring is recommended during artificial ventilation of such patients (Cf. Undesirable effects).
DRUG INTERACTIONS
A number of antiarrhythmics drugs depress cardiac automatism, conduction and contractility.
The combination of antiarrhythmics from different classes can provide a beneficial therapeutic effect, but is usually VERY DELICATE, requiring close clinical and ECG monitoring. The combination of antiarrhythmics inducing torsades de pointes (such as amiodarone) is CONTRAINDICATED.
The combination of antiarrhythmics from the same class is NOT RECOMMENDED. apart from in exceptional cases, due to the increased risk of cardiac undesirable effects. Combination with medicines with negative inotropic, bradycardiac and/or atrioventricular conduction slowing drugs is DELICATE and requires close clinical and ECG monitoring.
Contraindicated combinations
| - | Medicinal products that can induce torsades de pointes: |
| - | Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide), |
| - | Class III antiarrhythmics (dofetilide, ibutilide, sotalol), |
| - | Other medicinal products, such as: bepridil, cisapride, diphemanil, erythromycin IV, mizolastine, vincamine IV, |
| - | Sultopride, Increased risk of ventricular arrhythmia and in particular, torsades de pointes. |
| + | Sparfloxacin, Risk of torsades de pointes due to a prolongation in QT interval (addition of electrophysiological effects). |
Inadvisable combinations
| + | Neuroleptics inducing torsade de pointes: Some phenothiazine neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamide neuroleptics (amisulpride, sulpiride, tiapride), butyrophenone neuroleptics (droperidol, haloperidol), other neuroleptics (pimozide). Increased risk of ventricular arrhythmia and, in particular, torsades de pointes. |
| + | Halofantrine, moxifloxacine, pentamidine Increased risk of ventricular arrhythmia and, in particular, torsades de pointes. If possible, suspend the non-antibiotic torsadogenic drug. If the combination cannot be avoided, prior control of QT and constant electrocardiographic monitoring. |
| + | Injectable diltiazem Risk of bradycardia and atrioventricular block. If this combination cannot be avoided, only administer under close clinical and constant electrocardiographic monitoring. |
| + | Beta-blockers (other than sotalol and esmolol) Contractility, automatism and conduction disturbances (suppression of compensatory sympathic mechanisms). |
Combinations requiring precautions for use
| + | Oral anticoagulants Increased anticoagulant effect and haemorrhagic risk. More frequent control of prothrombin rate and monitoring of INR. Adjustment of oral anticoagulant dosage during treatment with amiodarone and after its withdrawal. |
| + | Ciclosporin Increase in circulating levels of ciclosporin due to a reduction in its hepatic metabolism with a risk of nephrotoxic effects. Assay of blood ciclosporin concentrations, monitoring of kidney function and adjustment of dosage during combination with amiodarone and after its withdrawal. |
| + | Oral diltiazem Risk of bradycardia or atrioventricular block, particularly in the elderly. Clinical and electrocardiographic monitoring. |
| + | Digitalis drugs Depression of automatism (excessive bradycardia) and atrioventricular conduction disturbances. In the event of use of digoxin, Increased blood digoxin levels due to reduced digoxin clearance. Clinical and electrocardiographic monitoring and, if necessary monitoring of blood digoxin levels and adjustment of digoxin dosage. |
| + | Esmolol Contractility, automatism and conduction disturbances (suppression of compensatory sympathic mechanisms). Clinical and electrocardiographic monitoring. |
| + | Potassium-lowering drugs: potassium-lowering diuretics (alone or in combination), stimulant laxatives, glucocorticoids (systemic route), tetracosactide, amphotericin B (IV route). Increased risk of ventricular arrhythmia and, in particular, torsades de pointes (hypokalaemia is a predisposing factor). Clinical, laboratory and electrocardiographic monitoring. |
| + | Phenytoin Increase in plasma concentrations of phenytoin with signs of overdose and, in particular, neurological signs (reduced hepatic metabolism of phenytoin). Clinical monitoring, control of plasma concentrations of phenytoin and, if necessary, adjustment of the latter's dosage. |
| + | Bradycardiac drugs: bradycardiac calcium antagonists. (diltiazem, verapamil), beta-blockers (except sotalol), clonidine; guanfacine, digitalis drugs mefloquine; anticholinesterase drugs (donezepil, galantamine, rivastigmine, tacrine, ambemonium, pyridostigmine, neostigmine). Increased risk of ventricular arrhythmia and, in particular, torsades de pointes. Clinical and electrocardiographic monitoring. |
| + | Simvastatin Increased risk of undesirable effects (dose-dependent), such as rhabdomyolysis (reduced hepatic metabolism of the cholesterol-lowering drug). Do not exceed a dosage of 20 mg/d simvastatin. If the therapeutic goal is not achieved at this dosage, use another statin not concerned by this type of interaction. |
PREGNANCY AND LACTATIONS
Pregnancy
Animal studies have not revealed any teratogenic effect. In the absence of any teratogenic effect in animals no malformative effect is expected in humans.
In fact, to date, substances 'responsible for malformations in humans have been revealed to be teratogenic in animals in the course of properly conducted studies in both species.
Clinically, no sufficiently relevant data are currently available to be able to assess a potential malformative effect of amiodarone when It IS administered during the first three months of pregnancy.
Since the foetal thyroid begins to blind iodine from 14 weeks after the last menstrual period, no effects on the foetal thyroid are expected in the event of administration prior to this.
Iodine overload related to the use of this medicine after this time can lead to foetal hypothyroidism, which may be biological or even clinical (goitre).
Consequently, the use of this medicine is contraindicated after the first 3 months of pregnancy.
Lactation
Amiodarone and its metabolite, along with iodine, cross into breast milk at concentrations greater than those in maternal plasma. Due to the risk of hypothyroidism In the newborn infant, breast-feeding is contraindicated in the event of treatment with this medicine.
EFFECT ON ABILITY TO DRIVE AND USE MACHINES
Not relevant
UNDESIRABLE EFFECTS
Ocular signs
Corneal micro-deposits, which are almost constant In adults, usually remain localized to the area under the pupil and do not contraindicate continuation of treatment. In exceptional cases these may be accompanied by perception of colored halos in dazzling light or sensations of mistiness.
Composed of complex lipid deposits, corneal micro-deposits are always entirely reversible on discontinuation of treatment.
A few cases of optic neuropathy (optic neuritis) with blurred vision, reduced vision and papillary oedema at the fundus of the eye have been reported. The outcome may be a more or less severe reduction in visual acuity. The relationship with amiodarone does not appear to have been established at the current time. However in the event of any other obvious cause, it is recommended that treatment be suspended.
Cutaneous signs
Photosensitisation. Subjects are advised to avoid exposure to sun (and ultraviolet rays in general) during treatment.
Cases of erythema have also been reported during radiotherapy.
Cases of skin rashes - generally not very specific - and a few cases of exfoliative dermatitis have been reported, without the relationship with the medicine having been clearly established.
Exceptional cases of lilac or slate-grey colored pigmentation of the skin may occur at high daily dosages prescribed for a long period of time; after treatment withdrawal, this pigmentation is slow to disappear (10 to 24 months).
Thyroid signs
In the absence of any clinical signs of dysthyroidism, a "dissociated" thyroid hormone level (increase in T4, T3 normal or slightly reduced) does not warrant withdrawal of treatment.
Hypothyroidism has a classic form: weight gain, apathy, drowsiness and clear elevation in TSH signal its diagnosis. Withdrawal of the treatment leads to a gradual return to normal thyroid function within a period of 1 to 3 months; this withdrawal is not essential. If the indication so warrants, amiodarone may be continued, combining it with L-thyroxine-based substitutive opotherapy, with TSH levels acting as a guide for the dosage.
Hyperthyroidism is more misleading: with few symptoms (slight unexplained weight loss, reduction in anti-angina and/or antiarrhythmic efficacy); psychiatric forms in the elderly, or even thyrotoxicosis. A reduction in ultra-sensitive TSH levels confirms the diagnosis.
It is essential to suspend amiodarone: this is usually enough to trigger clinical recovery within a period of 3 to 4 weeks; Severe cases can lead to the patient's death making it necessary to urgently instigate appropriate treatment. If. the thyrotoxicosis is worrying, either in itself or due to its effects on the precarious myocardial balance, the inconstant efficacy of synthetic anti-thyroid drugs leads to straightforward corticosteroid therapy (1 mg/kg) being recommended, for a sufficiently long period of time (3 months).
Cases of hyperthyroidism have been reported as long as several months following discontinuation of amiodarone.
Pulmonary signs
Cases of diffuse interstitial or alveolar pneumopathy and bronchiolitis obliterans organizing pneumonia (BOOP) have been reported. The onset of effort dyspnoea either isolated or associated with a deterioration In general condition (fatigue, weight loss, febricula) - requires radiological control and, if necessary, suspension of treatment. These types of pneumopathy can actually develop into pulmonary fibrosis.
Early withdrawal of amiodarone-associated or not with corticosteroid therapy leads to a regression in the disturbances. Clinical signs usually disappear in 3 or 4 weeks. Radiological and function improvement is usually slower (several months).
A few cases of pleurisy, generally associated with interstitial pneumopathies, have been reported.
A few cases of bronchospasm have been reported, particularly in asthmatic patients.
A few cases of acute respiratory distress syndrome, sometimes fatal, have been observed, sometimes immediately following surgery (a possible interaction with high doses of oxygen has been suggested) (cf. Special warnings and special precautions for use).
Neurological effects
These are rare:
- The prolonged administration of amiodarone can cause sensory, motor or mixed peripheral neurophaties and myopathies. These may occur after Just a few months of treatment but sometimes after several years. They are generally reversible on treatment withdrawal. However, this recovery may be incomplete, very slow and occur only several months after treatment discontinuation.
- Other disturbances reported: tremor or other extra-pyramidal symptoms, cerebellar-type ataxia, exceptional benign intra-cranial hypertension, sleep disturbances including nightmares.
Hepatic signs
Cases of liver disease have been reported; these cases have been diagnosed by an elevation in serum transaminase levels. In fact, the following have been reported:
- Isolated and generally moderate (1.5 to 3 times normal values) elevation in transaminase levels, regressing following a reduction in the dosage or even spontaneously.
- Exceptionally (a few isolated cases), acute liver disease with hypertransaminasaemia and/or jaundice, sometimes fatal, requiring suspension of treatment.
- Rare cases of chronic liver disease during prolonged treatment. The histology is that of pseudo-alcoholic hepatitis. The discretion of the clinical and laboratory picture (inconstant hepatomegaly, hypertransaminasaernia between 1.5 and 5 times normal levels) warrants regular monitoring of liver function. Hypertransaminasaemia - even moderate-occurring after treatment for more than 6 months may suggest a diagnosis of chronic liver disease. The clinical and laboratory disturbances usually regress after treatment is withdrawn. A few cases of an irreversible outcome have been reported.
Cardiac effects
Generally moderate, dose-dependent bradycardia. In certain cases (sinus dysfunction, elderly patients), marked bradycardia and, more exceptionally, sinus arrest have been reported.
Rarely: conduction disturbances (sino-atrial block, atrioventricular block of varying degrees).
The arrythmogenic effect of amiodarone is weak, less than that of most antiarrhythmic drugs and generally occurs in some drug combinations (cf. Interaction with other medicinal products and other forms of interaction) or electrolyte balance disturbances.
Miscellaneous effects
- Benign gastrointestinal disturbances (nausea, vomiting, dysgeusia), usually occurring during initial treatment and disappearing when the dosage is reduced. A few cases of epididymitis have been reported. The relationship with the medicine does not appear to have been established. A few rare cases of alopecia have been observed.
- A few isolated cases, expressed in a variety of ways, have been observed in a context suggesting a hypersensitivity reaction: vascularitis, renal impairment with a moderate elevation in creatinine, thrombopaenia.
OVER DOSAGE
There is little documentation available on the acute administration of high doses of amiodarone. A few cases of sinus bradycardia, ventricular arrhythmia - in particular, torsades de pointes - and liver damage have been reported. Treatment should be symptomatic. Given the kinetics of the product, monitoring for a sufficiently long period of time - particularly cardiac monitoring - is recommended.
Amiodarone and its metabolites cannot be dialysed.
Do not use later than the date of expiry date
SPECIAL PRECAUTIONS FOR STORAGE
Store at temperature below 30°C.
Harus Dengan Resep dokter
Reg.No.DKI8977400410A1
Pack size: Box of 3 blisters of 10 tablets
SANOFI-AVENTIS FRANCE
1-13 boulevard Romain Rolland
75014 PARIS - FRANCE
Manufacture by :
Sanofi Winthrop Industrie
1, rue de la Vierge - Ambares et Lagrave
33565 Carbon Blanc Cedex - France
Imported By
PT. sanofi-aventis Indonesia
Jakarta - INDONESIA
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