1. Name Of The Medicinal Product
Rythmodan Injection.
2. Qualitative And Quantitative Composition
Each glass ampoule contains 12.88mg disopyramide phosphate (equivalent to 10mg of disopyramide) per 1ml of solution.
For excipients, see section 6.1.
3. Pharmaceutical Form
Intravenous.
4. Clinical Particulars
4.1 Therapeutic Indications
Conversion of ventricular and supraventricular arrhythmias after myocardial infarction, including patients not responding to lignocaine or other intravenous treatment.
Control of ventricular and atrial extrasystoles, supraventricular tachycardia, and Wolff–Parkinson–White syndrome.
Control of arrhythmias following digitalis or similar glycosides when Rythmodan cannot be given orally.
4.2 Posology And Method Of Administration
Route of Administration: Rythmodan Injection is intended for intravenous use only.
Adults
The recommended dosage can be given by two different regimes:
1. An initial direct intravenous injection of 2mg/kg (but not exceeding 150mg (15ml) irrespective of body weight) should be given slowly over not less than five minutes, ie, the rate of injection must not exceed 30mg (3ml) per minute in order to reduce or avoid unwanted haemodynamic effects. If conversion occurs during this time the injection should be stopped. If the arrhythmia is to respond to Rythmodan it will usually do so within 10–15 minutes after completion of the injection.
If conversion is achieved by intravenous Rythmodan but the arrhythmia subsequently recurs, a further slow direct intravenous injection over not less than five minutes may be administered cautiously and preferably under ECG control. The total administration by the intravenous route should not exceed 4mg/kg (maximum 300mg) in the first hour, nor should the combined administration by the intravenous and oral routes exceed 800mg in 24 hours.
2. An initial direct intravenous injection as above, ie over not less than five minutes, maintained by intravenous infusion by drip of 20–30mg/hour (or 0.4mg/kg/hour) up to a maximum of 800mg daily. This regime should be employed if the patient is unable to take oral medication or in particularly serious arrhythmias being treated in coronary care units.
Children
Not applicable.
Rythmodan Injection is not intended for use in children.
Elderly
A dose reduction due to reduced renal and hepatic function in the elderly (especially elderly non-smokers) should be considered (see section 4.4).
4.3 Contraindications
Disopyramide is contra–indicated in un–paced second or third degree atrioventricular block; bundle–branch block associated with first degree atrioventricular block; un-paced bifascicular block; pre-existing long QT syndromes; severe sinus node dysfunction; severe heart failure, unless secondary to cardiac arrhythmia; and hypersensitivity to disopyramide. It is also contra–indicated in concomitant administration with other anti–arrhythmics or other drugs liable to provoke ventricular arrhythmias, especially Torsade de Pointes (see section 4.5). The sustained release formulation is contra–indicated in patients with renal or hepatic impairment.
4.4 Special Warnings And Precautions For Use
In view of the serious nature of many of the conditions being treated it is suggested that Rythmodan Injection should only be used when facilities exist for cardiac monitoring or defibrillation, should the need arise.
Antiarrhythmic drugs belonging to the class 1c (Vaughan Williams Classification) were included in the Cardiac Arrhythmia Suppression Trial (CAST), a long term multicentre randomised, double blind study in patients with asymptomatic non life–threatening ventricular arrhythmia who had a myocardial infarction more than six days but less than two years previously. A significant increase in mortality and non–fatal cardiac arrest rate was seen in patients treated with class 1c antiarrhythmic drugs when compared with a matched placebo group. The applicability of the CAST results to other antiarrhythmics and other populations (eg. those without recent infarction) is uncertain. At present, it is best to assume that the risk extends to other antiarrhythmic agents for patients with structural heart disease.
There is no evidence that prolonged suppression of ventricular premature contractions with antiarrhythmic drugs prevents sudden death. For this reason, antiarrhythmic drugs should not be prescribed for the treatment of patients with asymptomatic ventricular premature contractions.
All antiarrhythmic drugs can produce unwanted effects when they are used to treat symptomatic but not life threatening arrhythmia; the expected benefits should be balanced against their risks.
In patients with structural heart disease, proarrhythmia and cardiac decompensation are special risks associated with antiarrhythmic drugs. Special caution should be exercised when prescribing in this taken context.
Disopyramide should not be used in patients with uncompensated congestive heart failure, unless this heart failure is secondary to cardiac arrhythmia. If disopyramide is to be given under these circumstances, special care and monitoring are essential.
Life-threatening and haemodynamically significant arrhythmias are difficult to treat and affected patients have a high mortality risk. Treatment of these arrhythmias, by whatever modality, must be initiated in hospital.
Owing to its negative inotropic effect, disopyramide should be used with caution in patients suffering from significant cardiac failure. This group may be specially sensitive to the negative inotropic properties of disopyramide. Such patients should be fully digitalised or controlled with other therapy before treatment with disopyramide is commenced.
Aggravation of existing arrhythmia, or emergence of a new type of arrhythmia, demands urgent review of disopyramide treatment.
Similarly, if an atrioventricular block or a bifascicular block occurs during treatment, the use of disopyramide should be reviewed.
There have been reports of ventricular tachycardia, ventricular fibrillation and Torsade de Pointes in patients receiving disopyramide. These have usually, but not always, been associated with significant widening of the QRS complex or prolonged QT interval. The QT interval and QRS duration must be monitored and disopyramide should be stopped if these are increased by more than 25%. If these changes or arrhythmias develop the drug should be discontinued. Disopyramide should be used with caution in patients with atrial flutter or atrial tachycardia with block as conversion of a partial AV block to a 1:1 response may occur, leading to a potentially more serious tachyarrhythmia.
The occurrence of hypotension following disopyramide administration, requires prompt discontinuation of the drug. This has been observed especially in patients with cardiomyopathy or uncompensated congestive heart failure. Any resumption of therapy should be at a lower dose with close patient monitoring. Disopyramide should be used with caution in the treatment of digitalis intoxication.
Potassium imbalance: Antiarrhythmic drugs may be hazardous in patients with potassium imbalance, as potassium abnormalities can induce arrhythmias.
During treatment with disopyramide, potassium levels should be checked regularly. Patients treated with diuretics or stimulant laxatives are at particular risk of hypokalaemia.
Renal insufficiency: In renal insufficiency, the dosage of disopyramide should be reduced by adjusting the interval between administrations.
Hepatic insufficiency: Hepatic impairment causes an increase in the plasma half–life of Rythmodan and a reduced dosage may be required.
Hypoglycaemia: Hypoglycaemia has been reported in association with disopyramide administration. The risk of hypoglycaemia, sometimes severe, occurs particularly in elderly or malnourished subjects, treated diabetics and patients with renal insufficiency or cardiac failure. Blood sugar levels should be monitored in all patients. Strict adherence to the dosing recommendations is advised. If hypoglycaemia occurs then treatment with disopyramide should be stopped.
Hypoglycaemia may be associated with interactions with drugs metabolised by hepatic CYP3A (see Section 4.5 Interactions with other medicinal products and other forms of interaction).
Atropine–like effect: There is a risk of:
- ocular hypertension in patients with narrow–angle glaucoma,
- acute urinary retention in patients with prostatic enlargement,
- aggravation of myasthenia gravis
- cognitive disorders, especially in elderly patients (see also section 4.8).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Combination with other antiarrhythmic drugs: Combinations of antiarrhythmic drugs are not well researched and their effect may be unpredictable. Thus, antiarrhythmic combination should be avoided except under certain circumstances, eg. beta–blockers for angina pectoris; digoxin with beta–blocker and/or verapamil for the control of atrial fibrillation, when defined as effective for an individual.
Interaction with drugs associated with risk of Torsade de Pointes, such as:
– tricyclic and tetracyclic antidepressants
– All macrolide antibiotics (e.g. erythromycin, clarithromycin, azithromycin etc)
– astemizole; cisapride; pentamidine; pimozide; sparfloxacin; terfenadine and thioridazone.
Phosphodiesterase Type 5 Inhibitors:
There is evidence that phosphodiesterase Type 5 inhibitors may be potentially associated with a risk of QT prolongation. Concomitant administration of disopyramide with such drugs may potentially enhance this QT prolongation effect and is not recommended.
The concomitant use of these medications whilst undergoing treatment with disopyramide increases the chance of cardiac arrhythmia.
There is some evidence that disopyramide is metabolised by hepatic CYP3A. Concomitant administration of significant inhibitors of this isozyme (e.g. certain macrolide or azole antifungal antibiotics) may therefore increase the serum levels of disopyramide. On the other hand, inducers of CYP3A (e.g. rifampicin and certain anticonvulsants such as phenytoin, primidone and phenobarbital) may reduce disopyramide and increase MN–disopyramide serum levels. Since the magnitude of such potential effects is not foreseeable, such drug combinations are not recommended.
When prescribing a drug metabolised by CYP3A [such as theophylline, HIV protease inhibitors (e.g. ritonavir, indinavir, saquinavir), ciclosporin A, warfarin] it should be kept in mind that disopyramide is probably also a substrate of this isozyme and thus competitive inhibition of metabolism might occur, possibly increasing serum levels of these drugs.
Interactions with hypokalaemia inducing drugs: Concomitant use with drugs that can induce hypokalaemia such as: diuretics, amphotericin B, tetracosactide (corticotropin analogue), gluco and mineralo–corticoids may reduce the action of the drug, or potentiate proarrhythmic effects. Stimulant laxatives are not recommended to be given concomitantly, due to their potassium lowering potential.
Other drug interactions:
Atropine and other anticholinergic drugs, including phenothiazines, may potentiate the atropine–like effects of disopyramide.
4.6 Pregnancy And Lactation
Pregnancy: Although Rythmodan has undergone animal tests for teratogenicity without evidence of any effect on the developing foetus, its safety in human pregnancy has not been established. Rythmodan has been reported to stimulate contractions of the pregnant uterus. The drug should only be used during pregnancy if benefits clearly outweigh the possible risks to the mother and foetus.
Lactation: No data for Rythmodan Injection, but studies have shown that oral disopyramide is secreted in breast milk, although no adverse effects to the infant have been noted. However, clinical experience is limited and disopyramide should only be used in lactation if, in the clinician's judgement, it is essential for the welfare of the patient. The infant should be closely supervised, particularly for anticholinergic effects and drug levels determined if necessary. Ideally, if the drug is considered essential, an alternative method of feeding should be used.
4.7 Effects On Ability To Drive And Use Machines
Some adverse reactions may impair the patients' ability to concentrate and react, and hence the ability to drive or operate machinery. (See section 4.8).
4.8 Undesirable Effects
Cardiac: It is accepted that the arrhythmogenic potential of disopyramide is weak. However, as with all antiarrhythmic drugs, disopyramide may worsen or provoke arrhythmias. This proarrhythmic effect is more likely to occur in the presence of hypokalemia with the associated use of antiarrhythmic drugs, in patients with severe structural heart disease with prolongation of the QT interval.
Intra–cardiac conduction abnormalities may occur: QT interval prolongation, widening of the QRS complex, atrioventricular block and bundle–branch block.
Other types of arrhythmia have been reported: Bradycardia, sinus block, ventricular fibrillation, ventricular tachycardia and torsades de pointes.
Episodes of severe heart failure or even cardiogenic shock have also been described particularly in patients with severe structural heart disease. The resulting low cardiac output can cause hypotension, renal insufficiency and/or acute hepatic ischemia.
Other adverse reactions include:
Atropine-like effects (see also section 4.4):
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Psychiatric disorders.
Skin reactions: very rarely, rashes; isolated reports of anaphylactic–type reactions possibly culminating in shock (only reported in association with the injectable formulation).
Rarely: Hypoglycaemia, sometimes severe (see Section 4.4 Special warnings and precautions for use). In some cases, severe hypoglycaemia resulted in coma.
Very rarely: cholestatic jaundice, headache, dizzy sensation, neutropenia.
Rapid infusion may cause profuse sweating.
4.9 Overdose
There is no specific antidote for disopyramide. Prostigmine derivatives can be used to treat anticholinergic effects. Symptomatic supportive measures may include: early gastric lavage; administration of a cathartic followed by activated charcoal by mouth or stomach tube; IV administration of isoprenaline, other vasopressors and/or positive inotropic agents; if needed - infusion of lactate and/or magnesium, electro–systolic assistance, cardioversion, insertion of an intra–aortic balloon for counterpulsion and mechanically assisted ventilation. Haemodialysis, haemofiltration or haemoperfusion with activated charcoal has been employed to lower the serum concentration of the drug.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Class 1 antiarrhythmic agent.
5.2 Pharmacokinetic Properties
Following intravenous administration, disopyramide is rapidly distributed. Doses of 1.5–2mg/kg produce plasma levels of about 10microg/ml, declining rapidly to 3.8–4.2microg/ml at 5 minutes and to less than 3microg/ml at 15 minutes.
In multidose studies, direct slow intravenous injection of 2mg/kg followed by an infusion of 20mg/hr, maintained plasma levels of disopyramide between 2.5 and 2.8microg/ml from the first hour onwards.
Distribution T1/2: 2–4 minutes in healthy volunteers. Longer (15 minutes) in patients with acute myocardial infarct.
Elimination Phase Of Plasma T1/2: 5–8 hours. Increased in renal impairment, cardiac and hepatic disease.
Protein Binding: 50–60%. Saturable and concentration dependent.
Volume Of Distribution: Variable according to method of determination
Metabolism: Approximately 25% of a dose metabolised to a mono–n–dealkylated derivative. Additional 10% as other metabolites.
Excretion: 75% unchanged drug via urine, remainder in faeces. Mono–n–dealkylated metabolite 25% in urine, 64% via faeces.
5.3 Preclinical Safety Data
Not applicable.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Benzyl Alcohol
Sorbitol
Water for Injection.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
60 months.
6.4 Special Precautions For Storage
Store below 25°C
6.5 Nature And Contents Of Container
Colourless neutral glass ampoules are available as 5ml.
6.6 Special Precautions For Disposal And Other Handling
Not Applicable.
7. Marketing Authorisation Holder
Sanofi-aventis
One Onslow Street
Guildford
Surrey GU1 4YS
UK
8. Marketing Authorisation Number(S)
PL 04425/0660
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 10 March 2010
10. Date Of Revision Of The Text
10 March 2010
Legal Status
POM
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