Consumer medicine information

Rythmodan

Disopyramide

BRAND INFORMATION

Brand name

Rythmodan Capsules

Active ingredient

Disopyramide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rythmodan.

What is in this leaflet

This leaflet answers some common questions about Rythmodan. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you taking Rythmodan against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Rythmodan is used for

Rythmodan belongs to a group of medications called antiarrhythmics. This means it acts to correct irregular heartbeats to a normal rhythm and to slow an overactive heart. This allows the heart to work more efficiently.

Rythmodan is used to treat and prevent ventricular arrhythmias (irregular heartbeat).

Ask your doctor if you have any questions about why Rythmodan has been prescribed for you.

Your doctor may have prescribed Rythmodan for another reason. This medicine is available only with a doctor's prescription.

Before you take Rythmodan

When you must not take it

Do not take Rythmodan if you have an allergy to Rythmodan or any of the ingredients listed at the end of this leaflet.

Some symptoms of an allergic reaction may include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Do not give Rythmodan to a child or adolescent. Rythmodan is not recommended for use during pregnancy, unless you and your doctor or pharmacist have discussed the risks and benefits involved.

Do not take Rythmodan if you are taking other antiarrhythmics or other heart medications without first discussing with your doctor.

Do not take Rythmodan without first discussing all previous and preexisting heart problems with your doctor.

Do not take Rythmodan if you are breast-feeding or plan to breast-feed.

Rythmodan passes into breast milk and therefore there is a possibility that the breast-fed baby may be affected.

Rythmodan is not recommended for use in children.

Do not take Rythmodan after the expiry date (EXP) printed on the pack.

If you take this medicine after the expiry date has passed, it may not work as well.

Do not take Rythmodan if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.If you are not sure whether you should start taking Rythmodan, contact your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor or pharmacist if you are pregnant or intend to become pregnant.

Your doctor or pharmacist will discuss the possible risks and benefits of using Rythmodan during pregnancy.

Tell your doctor or pharmacist if you are breast-feeding or plan to breast-feed.

Rythmodan is not recommended while you are breast-feeding.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • Diabetes
  • Glaucoma or a family history of glaucoma
  • Chronic muscular weakness (Myasthenia Gravis)
  • Kidney problems
  • Liver problems
  • Heart problems including heart failure, heart attack, chest pain
  • Low blood pressure (dizziness or light-headedness)
  • Low or high potassium levels in your blood
  • Bowel problems
  • Difficult urination or
  • Enlarged prostate

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Rythmodan may interfere with each other. These include:

  • Other antiarrhythmics used to treat heart conditions such as beta-blockers, amiodarone and calcium channel blockers
  • Diuretics or antiangina medication
  • Medicines used to treat epilepsy or fits, especially phenytoin and phenobarbitone
  • Tricyclic and tetracyclic antidepressants
  • Antibacterials to treat infections such as rifampicin, erythromycin, roxithromycin and clarithromycin
  • Antifungals such as fluconazole, ketoconazole, itraconazole and amphotericin B
  • Antimicrobials to treat infections, such as pentamidine
  • Medications used to treat HIV
  • Antihistamines such as terfenadine and astemizole
  • Cisapride, a medicine used to treat stomach problems
  • Pimozide, a medicine used to treat certain mental illnesses
  • Laxatives for constipation
  • Medicines for erectile dysfunction such as Viagra or Levitra
  • Warfarin, a medicine used to prevent blood clots

These medicines may be affected by Rythmodan, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while taking Rythmodan.

How to take it

How much to take

The dose of Rythmodan may be different for each person. Your doctor will decide the right dose for you.

How to take it

Swallow Rythmodan whole with plenty of fluid.

The daily dose of Rythmodan is usually taken in three equally divided doses.

When to take it

Take Rythmodan at about the same time each day.

Taking your capsules at the same time each day will have the best effect. It will also help you
remember when to take your medicine.

It does not matter if you take Rythmodan before or after food.

This medicine works best when there is a constant amount in the blood. To help keep the amount constant it is best to take the doses at evenly spaced intervals day and night.

How long to take it

Rythmodan helps control your condition, but does not cure it. Therefore you must take Rythmodan every day. Continue taking the capsules for as long as your doctor or pharmacist tells you.

Do not stop taking your capsules because you are feeling better.

If you forget to take it

If it is almost time for your next dose (within 4 hours), skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not try to make up for a missed dose by taking more than one dose at a time.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 11 26 and in New Zealand telephone 0800 764766) or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much Rythmodan. Do this
even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much Rythmodan, you may feel cold and dizzy, light-headed, weak or you may faint. You may also experience palpitations (your heart may feel like it "skips a beat") and have difficulty breathing. You may notice your pulse is rapid and weak.

While you are taking it

Things you must do

Tell all the doctors, dentists, and pharmacists who are treating you that you are taking Rythmodan.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking Rythmodan.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking Rythmodan.

Rythmodan may cause hypoglycaemia (low blood sugar) in some people.

Patients with congestive heart disease or diabetes should be aware of the signs (see side effects) and if the signs appear eat or drink a food containing sugar and call your doctor.

Rythmodan may cause dryness of the mouth, nose and throat.

For temporary relief of mouth dryness melt bits of ice in your mouth. However, if dryness continues for more than 2 weeks, check with your medical doctor or dentist.

If you become pregnant while taking Rythmodan, tell your doctor or pharmacist.

Things you must not do

Do not give Rythmodan to anyone else, even if they have the same condition as you.

Do not take Rythmodan to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking Rythmodan, or lower the dosage, without checking with your doctor or pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Rythmodan affects you.

It may cause dizziness, light-headedness or fainting in some people. Make sure you know how you react to it before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive.

The effects of alcohol could be made worse while taking Rythmodan. It is not recommended that you drink alcohol while taking Rythmodan.

Alcohol may make the low blood sugar (hypoglycaemia) effect worse and/or increase the possibility of dizziness or fainting.

Side effects

All medicines have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor or pharmacist has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Rythmodan.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Dry mouth, eyes, nose or throat
  • Bloating or stomach pain
  • Blurred vision
  • Constipation or diarrhoea
  • Drowsiness
  • Frequent urge to urinate
  • Loss of appetite
  • Nausea and vomiting
  • Increased perspiration
  • Increased skin sensitivity to light

These are mild side effects of this medicine and usually short-lived.

Tell your doctor or pharmacist as soon as possible if you notice any of the following:

  • Difficult urination
  • Redness, itching, swelling, blistering, itchy or raised skin rash, and/or hives
  • Chest pains
  • Dizziness, light-headedness or fainting
  • Fast or irregular heartbeat
  • Muscle weakness
  • Shortness of breath
  • Swelling of feet or lower legs
  • Frequent infections such as sore throat or fever
  • Yellowing of the skin and/or eyes
  • Hypoglycaemia (low blood sugar). The signs and symptoms of hypoglycaemia are: chills, cold
    sweats, confusion, cool and pale skin, drowsiness, headache, fast heartbeat, excessive hunger, nausea, shakiness, unusual tiredness/weakness.

These may be serious side effects of Rythmodan. You may need urgent medical attention.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.

Other side effects not listed above may occur in some patients.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

After taking it

If you have any queries about any aspect of your medicine, or any questions regarding the information in this leaflet, discuss them with your doctor or pharmacist.

Storage

Keep your capsules in the pack until it is time to take them.

Keep your capsules in a cool dry place where the temperature stays below 30°C. Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in a car or on a windowsill.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking Rythmodan or the capsules have passed their expiry date, ask your pharmacist what to do with any that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Rythmodan 100mg capsules are green and beige, marked with RY on one part and RL on the other.

Rythmodan 150mg capsules# are white, marked with RY on one part and 150 on the other.

Rythmodan is available in blister packs of 100 capsules.

Ingredients

Rythmodan capsules contain either 100mg or 150mg of disopyramide, as the active ingredient. Each capsule also contains: magnesium stearate, maize starch, purified talc, gelatin, titanium dioxide. The 100mg capsules also contain yellow iron oxide and indigo carmine.

Rythmodan does not contain lactose, sucrose, gluten, tartrazine or azo-dyes.

Sponsor

Rythmodan is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park
NSW 2113
Australia

Rythmodan is supplied in New Zealand by:

sanofi-aventis new zealand limited
Level 8, 56 Cawley Street
Ellerslie, Auckland
New Zealand

Australian Registration Numbers:

100mg capsules: AUST R 13537

150mg capsules#: AUST R 13538

New Zealand Registration Numbers:

100mg capsules: TT50-2101

150mg capsules#: TT50-2101a

Date of preparation: August 2017

#Not marketed

rhythmodan-ccdsv6-cmiv6-aug17

BRAND INFORMATION

Brand name

Rythmodan Capsules

Active ingredient

Disopyramide

Schedule

S4

 

1 Name of Medicine

Disopyramide.

2 Qualitative and Quantitative Composition

Each Rythmodan 100 mg capsule contains 100 mg of disopyramide.
Each Rythmodan 150 mg# capsule contains 150 mg of disopyramide.
# Not marketed.

Excipients with known effect.

The gelatin capsule contains sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsule.

100 mg capsules.

Size no 2 two toned gel caps containing white powder. The cap is opaque green and the body opaque beige, printed with RY one part and RL on other in black.

150 mg capsules#.

Size no 2 hard gel cap containing white powder. The cap and body are opaque white, printed with RY on one part and 150 on the other in black.

4 Clinical Particulars

4.1 Therapeutic Indications

Rythmodan capsules are indicated for the management of documented ventricular arrhythmias, such as sustained ventricular tachycardia, which are judged to be life threatening. Because of its proarrhythmic potential, the use of disopyramide is not recommended for lesser arrhythmias.
Treatment of asymptomatic ventricular premature contractions should be avoided.
In patients with structural heart disease, proarrhythmia and cardiac decompensation are a special risk associated with antiarrhythmic medicines. Special caution should be exercised when prescribing disopyramide for these patients (see Section 4.4 Special Warnings and Precautions for Use).

4.2 Dose and Method of Administration

The daily dose of Rythmodan capsules must be administered as no less than 3 equal divided doses.

Adults with normal hepatic and renal function.

The recommended dosage in adults with normal hepatic and renal functions is 300 to 800 mg daily.
Treatment should be initiated at 400-600 mg per day. The effective maintenance dose is then reached by progressively reducing the starting dose by no more than 100 mg per day to reach a final maintenance dose of 300-400 mg per day.
When treating arrhythmia by electroconversion it is advisable to start Rythmodan one to two days prior to the applied electric shock. During this period sinus rhythm may be achieved.
Control of arrhythmia in some patients may be obtained within eight hours of oral administration.

Adults with renal impairment.

For patients with severe renal insufficiency (creatinine clearance < 40 mL/minute), the recommended dosage regimen is a 200 mg loading dose followed by a 100 mg maintenance dose given approximately every half-life (t½). ECG and plasma concentrations should be monitored.
Table 1 shows the relationship between creatinine clearance, half-life and the maintenance dosing interval:

Adults with hepatic impairment.

Dosage should be reduced by 25% in patients with hepatic impairment. The ECG and plasma concentrations should be monitored and used to adjust the regimen if necessary.

4.3 Contraindications

Cardiogenic shock.
Second or third degree atrio-ventricular block (if no pacemaker is present.
Bundle branch block associated with first degree atrio-ventricular block.
Double block (e.g. left posterior or anterior hemiblock and right bundle branch block).
Pre-existing long QT.
Severe sinus node dysfunction.
Cardiac insufficiency unless secondary to cardiac arrhythmia.
Concomitant use with other antiarrhythmics, or other medicines liable to provoke ventricular arrhythmias or torsades de pointes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Known hypersensitivity to disopyramide.

4.4 Special Warnings and Precautions for Use

Myocardial infarction.

Antiarrhythmic medicines belonging to class 1c were included in the Cardiac Arrhythmia Suppression Trial (CAST), a long-term multi-centred randomised double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously. An excess mortality or non-fatal cardiac arrest rate was seen in patients treated with antiarrhythmic medicines belonging to the class 1c, encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months.
While there are no comparable mortality trial data for other Class I antiarrhythmic agents post-myocardial infarction or in other clinical settings, meta-analyses of small scale clinical trials of these agents in similar populations suggest a trend towards increased mortality compared to placebo and no evidence of benefit.
All Class I antiarrhythmic agents share the capacity to produce slowing of conduction velocity which can promote tachycardias via re-entry mechanisms.
Therefore, the prophylactic use of Class I antiarrhythmic medicines following myocardial infarction is potentially hazardous. Indeed the use of these agents for other than life-threatening arrhythmias or severe symptoms due to arrhythmias is not recommended.
Antiarrhythmic drugs should not be prescribed for the treatment of patients with asymptomatic ventricular premature contractions, haemodynamically non-significant ventricular premature contractions.
In the event of aggravation of the pre-existing arrhythmia or emergence of a new type of arrhythmia, treatment with disopyramide should be reconsidered.

Heart failure/hypotension.

Disopyramide may cause or worsen congestive heart failure or produce severe hypotension as a consequence of its negative inotropic properties. Hypotension has been observed primarily in patients with structural heart disease or inadequately compensated congestive heart failure. Disopyramide should not be used in patients with uncompensated or marginally compensated congestive heart failure or hypotension unless the congestive heart failure or hypotension is secondary to cardiac arrhythmia. If hypotension occurs or congestive heart failure worsens, Rythmodan should be discontinued and, if necessary, restarted at a lower dosage only after adequate cardiac compensation has been established.

Structural heart disease.

Proarrhythmia and cardiac decompensation are a special risk associated with antiarrhythmic drugs. Special caution should be exercised. In patients with structural heart disease, the negative inotropic effects of disopyramide may be of concern; treatment should be given under strict supervision and cardiac function monitored. Rythmodan should not be administered to patients with structural heart disease and associated congestive heart failure unless the patient is adequately treated. Patients with myocarditis or other cardiomyopathy may develop significant hypotension in response to the usual dosage of disopyramide, probably due to cardiodepressant mechanisms. Therefore, a loading dose of disopyramide should not be given to such patients and initial dosage and subsequent dosage adjustments should be made under close supervision.

Anticholinergic activity.

Because of its anticholinergic properties, disopyramide should not be used in patients with urinary retention unless adequate overriding measures are taken; these consist of catheter drainage or operative relief.
Urinary retention may occur in patients of either sex as a consequence of disopyramide administration, but males with benign prostatic hypertrophy or prostatic adenoma are at particular risk.
Disopyramide should be not be used in patients with glaucoma.
In patients with a family history of glaucoma, intraocular pressure should be measured before initiating disopyramide therapy and controlled as necessary during treatment.
There is a risk of paralytic ileus occurring, especially in the elderly, and when disopyramide is taken with other anticholinergic medications or in situations where there is an increase in plasma levels of disopyramide, (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.9 Overdose).
Disopyramide should be used with special care in patients with myasthenia gravis since its anticholinergic properties could precipitate a myasthenic crisis in such patients.
There is a risk of cognitive disorders in elderly patients that require medical attention. For other atropine-like effects, see Section 4.8 Adverse Effects (Undesirable Effects).

Heart block.

If an atrio-ventricular block or a double block occurs, treatment should be discontinued.

QRS widening.

QRS complex duration should be monitored. If significant widening (greater than 20%) of the QRS complex occurs, the medicine should be discontinued.

QT prolongation.

QT interval should be monitored. Prolongation of the QT interval (corrected) and worsening of the arrhythmia may occur. Patients who have evidenced prolongation of the QT interval in response to quinidine may be at particular risk. If a QT prolongation of greater than 20% is observed, the medicine should be discontinued.

Hypoglycaemia.

Significant lowering of blood glucose values has been reported during disopyramide administration. The physician should be alert to this possibility, especially in aged or malnourished patients, diabetics, and patients with renal insufficiency. In these patients hypoglycaemia can be severe and as such blood glucose levels should be monitored.

Hypokalaemia.

Serum potassium must be monitored. Potassium abnormalities may induce arrhythmias. Antiarrhythmic medicines may be ineffective in patients with hypokalaemia. Undesirable cardiac effects of antiarrhythmics may be provoked by hyper- or hypo-kalaemia.
Before and during treatment with disopyramide, potassium imbalance should be looked for and corrected, particularly in case of treatment with potassium lowering diuretics or laxatives.

Use in hepatic impairment.

As hepatic impairment causes an increase in the plasma half-life of disopyramide, dosage should be reduced by 25% (see Section 4.2 Dose and Method of Administration). The electrocardiogram should be carefully monitored for signs of overdosage (see Section 4.9 Overdose).

Use in renal impairment.

As more than 50% of disopyramide is excreted in the urine unchanged, dosage should be reduced in patients with impaired renal function (see Section 4.2 Dose and Method of Administration). The electrocardiogram should be carefully monitored for prolongation of PR and QT intervals, evidence of QRS widening or other signs of overdosage (see Section 4.9 Overdose).

Use in the elderly.

See Section 4.4 Special Warnings and Precautions for Use, Anticholinergic activity.

Paediatric use.

Rythmodan is not approved for paediatric use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Combinations of antiarrhythmic medicines are not well researched and their effect may be unpredictable. Thus, antiarrhythmic combination should be avoided except under certain circumstances, e.g. beta-blockers for angina pectoris; digoxin with a beta-blocker and verapamil for the control of atrial fibrillation, when defined as effective for an individual by specialised procedure.

Contraindicated associations.

Disopyramide should not be co-administered with the following medicines.
Other antiarrhythmics (Vaughan Williams classification): class I (most medicines, including phenytoin); class II (beta-blocking medicines); class III (amiodarone, bretylium, sotalol, ibutilide); class IV (verapamil, diltiazem, lidoflazine, bepridil, prenylamine).
Medicines associated with the risk of torsades de pointes, such as: tricyclic or tetracyclic antidepressants; parenterally administered erythromycin; vincamine; sultopride.

Not recommended.

The co-administration of disopyramide with some other medicines associated with a potential for torsades de pointes is not recommended. Such medicines include: astemizole, cisapride, pentamidine, pimozide, sparfloxacin, terfenadine.

Phosphodiesterase type 5 inhibitors.

There is evidence that phosphodiesterase type 5 inhibitors may potentially lead to QT prolongation. Concomitant administration of phosphodiesterase 5 inhibitors with disopyramide may potentially enhance this QT prolongation effect and is not recommended.
There is some evidence that disopyramide is metabolised by hepatic CYP3A. Although human studies are not available, 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, certain anticonvulsants) may reduce disopyramide and increase MN-disopyramide serum levels. Since the magnitude of such potential effects is not forseeable, such medicine combinations are not recommended.
Stimulant laxatives are not recommended (see Section 4.4 Special Warnings and Precautions for Use, Hypokalaemia).

Precautions for use.

Care is advised when the following medicines are used concomitantly with disopyramide:
Hypokalaemia-inducing medicines (see Section 4.4 Special Warnings and Precautions for Use, Hypokalaemia) such as diuretics, amphotericin B (amphotericin), tetracosactide (tetracosactrin), gluco- and mineralo-corticoids.

To be considered.

Atropine and other anticholinergic medicines, including phenothiazines, may potentiate the atropine like effects of disopyramide (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
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.
Other interactions include the following:
Roxithromycin: an in vitro study has shown that roxithromycin can displace protein bound disopyramide; such an effect in vivo could result in increased serum levels of disopyramide.
If treatment with any of these medicines is necessary, cardiac function and therapeutic drug levels must be strictly monitored.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Animal studies have revealed only minimal evidence of impaired fertility.
(Category B2)
Animal studies have not demonstrated any teratogenic effect and a slightly lower weight in treated rats at the time of weaning. However, no controlled studies of disopyramide have been performed in pregnant women and experience with Rythmodan during pregnancy is limited. Disopyramide has been reported to stimulate contractions of the pregnant uterus and also passes into foetal circulation. Therefore, use of Rythmodan in women of childbearing potential requires that the benefits of therapy be weighed against its possible hazards to the mother and foetus.

Labour and delivery.

It is not known whether use of disopyramide during labour or delivery has immediate or delayed adverse effects on the foetus, whether it prolongs the duration of labour, or increases the possibility of forceps delivery or other obstetrical intervention.
Disopyramide passes into breast milk. If use of the medicine is deemed essential, an alternative method of infant feeding should be instituted.

4.7 Effects on Ability to Drive and Use Machines

Some adverse reactions may impair the patient's ability to concentrate and react, and hence the ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Disopyramide may worsen or provoke ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation and torsades de pointes). This pro-arrhythmic effect is more likely to occur in the presence of hypokalaemia and/or the associated use of other antiarrhythmic medicines and/or severe structural heart disease and/or prolongation of QT interval.
Hypotension, QT interval prolongation, widening QRS, atrioventricular block, bundle branch block, bradycardia, sinus block, nodal rhythm dissociation and cardiac arrest have been reported. An occasional paradoxical ventricular tachycardia, evolving sometimes to fibrillation, has been observed.
Episodes of severe cardiac failure, collapse or cardiogenic shock states have been observed, particularly in patients with severe structural heart disease. The resulting low cardiac output can cause hypotension, renal and/or acute hepatic insufficiency mimicking acute hepatocellular hepatitis.
The most common adverse effects which are dose dependent are associated with the anti-cholinergic properties of the medicine. These may be transitory, but may be persistent and can be severe. Urinary retention is the most serious anticholinergic effect.
The following adverse effects are reported in more than 10% of patients:

Anticholinergic.

Dry mouth, acute urinary retention, especially in prostatism and constipation.

Gastrointestinal.

Nausea, indigestion, vomiting, diarrhoea, flatulence, bad taste in the mouth, anorexia.
The following adverse effects are reported in 1 to 10% of patients:

Anticholinergic.

Blurred vision, dry eyes/nose/throat, urinary hesitation and frequency.

Cardiovascular.

Hypotension with or without CHF, increased CHF, cardiac conduction disturbances, proarrhythmic effects, oedema, dyspnoea, cyanosis, chest pain.

Dermatologic.

Skin reactions including pruritus, urticaria, morbilliform eruption, rash, photosensitisation.

General.

Dizziness, vertigo, drowsiness, profuse sweating.

Other.

Raised SGOT levels. Isolated reports of anaphylactic type reactions (e.g. urticaria, angioedema) possibly culminating in shock (reported in association with the I.V. injection).
The following adverse effects are reported in less than 1% of patients:
Dysuria, headache, feeling of warmth, pallor, peripheral paraesthesia, fatigue, malaise, insomnia, confusion, transitory psychosis, elevated BUN, elevated creatinine, decreased haemoglobin/haematocrit, hypoglycaemia which can be severe (see Section 4.4 Special Warnings and Precautions for Use), neutropenia, idiosyncratic reaction.
In a few instances, cholestatic jaundice has been reported. A definite causal relationship has not been established, however one case has been reported as probably related.
A high plasma concentration has been associated with impotence.
With intravenous administration, the occurrence of side effects, especially profuse sweating, was often associated with too rapid administration of the medicine.
Other adverse effects which have been reported include psychiatric disorders, cognitive disorders, agranulocytosis, ocular disturbances of accommodation and diplopia, and epigastralgia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Toxic plasma levels are reflected by ECG abnormalities such as (a) marked prolongation of QT interval premonitory of other arrhythmias, in particular torsades de pointes, which can result in repeated syncopes; (b) widening of the QRS complex; and (c) variable degrees of atrio-ventricular block.
The clinical signs of overdose may include paralytic ileus, bilateral mydriasis (suggestive); syncope, hypotension or shock; cardiac arrest due to intra-ventricular block or asystole; respiratory symptoms; and coma (with bilateral mydriasis) in cases of massive intoxication.

Treatment.

Except for neostigmine or physostigmine which may be used for treating anticholinergic effects, there is no specific antidote. Treatment of acute overdose should be carried out in an Intensive Care Unit under continuous cardiac monitoring.
Symptomatic therapeutic measures may include:
administration of a cathartic followed by activated charcoal by mouth or stomach tube;
IV administration of isoprenaline and/or other vasopressors and/or positive inotropic agents;
if needed, infusion of lactate and/or magnesium, electro-systolic assistance, electroconversion, insertion of an intra-aortic balloon for counterpulsation, and mechanically assisted ventilation;
haemodialysis, haemofiltration or haemoperfusion with activated charcoal.
Altering the urinary pH does not affect the plasma half-life or the amount of disopyramide excreted in the urine.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiarrhythmias, Class Ia, ATC code: C01BA03.

Mechanism of action.

It is a sodium channel blocker with membrane stabilising effect. It reduces automaticity in cardiac Purkinje fibres by depressing the slope of phase 4 diastolic depolarisation; slows conduction velocity in atria, AV node, Purkinje fibres and ventricular muscle by decreasing the rate of rise of phase 0 depolarisation in these fibres; prolongs action potential duration and refractory period in atria, Purkinje fibres and ventricular muscle; depresses excitability of both atrial and ventricular muscle by its direct effect on the myocardium.

Electrophysiology.

Disopyramide prolongs the effective refractory period of the atria and the ventricles. The effective refractory period of the atrioventricular node is either slightly shortened or unchanged. The relative refractory period of the His-Purkinje system is prolonged. Atrioventricular nodal conduction time is unchanged by disopyramide. Conduction through the His-Purkinje system is unchanged or slightly delayed.

Haemodynamics.

The haemodynamic effects vary according to the condition of the patient and the dose administered. The main changes induced by disopyramide are as follows: heart rate unchanged or slightly increased; cardiac output decreased by about 10%; peripheral resistance increased; slight, transient fall in blood pressure which is compensated for by increased peripheral resistance; left ventricular end diastolic pressure unchanged or increased; negative inotropic effect which can be marked in patients with depressed left ventricular function. Thus, disopyramide produces a slight and transient myocardial depressant effect on the heart. This is more pronounced after intravenous administration than after oral administration.

Anticholinergic activity.

Disopyramide possesses anticholinergic properties and has been shown to be up to 10% as potent as atropine in in vitro tests. The oral form has little or no effect on resting sinus rate. The anticholinergic side effects may affect the gastrointestinal and/or urogenital systems (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). These effects may be transitory or disappear upon reduction of dose.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

After administration disopyramide is rapidly and almost completely absorbed from the gut. In hospitalised patients, approximately one hour after a single oral dose of 100 mg disopyramide, a mean peak plasma concentration of 1 microgram/mL was reached. Plasma concentrations ranging from 2.3 to 3.4 microgram/mL have been predicted following an initial oral dose of 300 mg, a second dose of 100 or 200 mg at 6 hours and a maintenance dose of 100 mg every 6 hours. Predicted mean steady-state levels with an oral dose of 100 mg four times daily varied between 1.9 and 7.2 microgram/mL.

Distribution.

The half-life of distribution is 15 minutes and the volume of distribution is about 80 L. Disopyramide shows no selective accumulation in specific tissues and is distributed predominantly in the peripheral compartment of an open two compartment body model (9 L in the first and 80 L in the second in healthy subjects).

Metabolism.

Disopyramide is metabolised by N-dealkylation. Using radioactive material it was found that 82% of the drug in plasma was unchanged, 7% occurred as the mono-N-dealkylated metabolite and the remaining 11% was unidentified metabolites.
In one study, it was shown that disopyramide had no effect on liver microsomal enzymes.
During chronic administration, the mono-N-dealkylated metabolite reaches plasma concentrations about 30% of those of disopyramide.

Excretion.

50 to 70% of the drug is excreted unchanged and the remainder is metabolised. Approximately 80% is excreted in the urine. Biliary secretion accounts for up to 20% of the drug in man.
The mean half-life of elimination for the capsules is 4.5 to 8.2 hours in healthy volunteers. It is prolonged in patients with renal insufficiency (17 hours) and in patients with haemodynamically symptomatic arrhythmias (even with an intact renal function).
In one study, the apparent half-lives of the alpha and beta phases after intravenous administration were 2 minutes and 4.5 hours.

Protein binding.

Both disopyramide and its mono-N-dealkylated metabolite bind to plasma proteins, the extent of the binding being dependent on the plasma concentration. In the therapeutic range, protein binding is 30-40% to α1-acid glycoprotein. The presence of the metabolite reduces the binding of the parent drug while a high concentration of disopyramide decreases the binding of the metabolite.
Competitive binding studies with quinidine have demonstrated that these two drugs do not compete for the same binding sites on protein molecules. However in vitro studies have shown that disopyramide may displace lignocaine from plasma proteins resulting in an increase of unbound lignocaine by about 20%.

Correlation of plasma levels with therapeutic effect.

Total plasma concentrations of 2 to 4 microgram/mL of disopyramide are needed for efficacy. Effects correlate better with unbound concentrations than with total concentrations. There is significant interindividual variability in the relationship between total concentration and therapeutic effect.

Cardiac patients.

After the oral administration of 200 mg of disopyramide to 10 bed-ridden patients with borderline to moderate heart failure, the mean time to peak serum concentration (2.3 hours) and the mean peak serum concentration (4.8 microgram/mL) were higher than in healthy volunteers. After intravenous administration in these same patients, the mean elimination half-life was 9.7 hours (range in healthy volunteers: 4.4 to 7.8 hours). In a second study of the oral administration of disopyramide to 7 patients with heart disease, including left ventricular dysfunction, the mean plasma half-life was slightly prolonged to 7.8 hours.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Gelatin, magnesium stearate, maize starch, pregelatinised maize starch, purified talc and titanium dioxide. Rythmodan 100 mg capsules also contain iron oxide yellow and indigo carmine.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

100 mg capsules.

100 capsules per blister pack.

150 mg capsules#.

100 capsules per blister pack.
# Not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Disopyramide (base) is 4-di-isopropylamino-2-phenyl-2-(2-pyridyl) butyramide. Rythmodan is a racemic mixture of the d- and l-isomers of disopyramide.
Disopyramide base (MW = 339.5) is a stable white powder, which is insoluble in water but soluble in dilute acid and organic solvents.

Chemical structure.


Chemical Formula: C21H29N3O.

CAS number.

3737-09-5.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes