SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Tambocor^ta XL 200mg capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains flecainide acetate 200mg For excipients see 6.1

3    PHARMACEUTICAL FORM

Prolonged release capsule hard.

Size 1 hard gelatin capsule with light grey cap and opaque pink body with 3M 200 printed in black ink.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Tambocor is a potent sodium channel blocking agent for the treatment of the conditions listed below:

The effect on the JT interval is insignificant at therapeutic levels.

Tambocor XL capsules are indicated for:

a)    AV nodal reciprocating tachycardia, arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways.

b)    Paroxysmal atrial fibrillation in patients with disabling symptoms when treatment need has been established and in the absence of left ventricular dysfunction (see 4.4, Special warnings and precautions for use).

Arrhythmias of recent onset will respond more readily. Tambocor XL capsules can be used for the maintenance of normal rhythm following conversion by other means.

Tambocor XL capsules are for oral administration.

4.2 Posology and method of administration

The controlled-release form of flecainide acetate is administered as a once-daily dose. Tambocor XL should not be used for control of arrhythmias in acute situations. Treatment should be initiated with either Intravenous or oral Tambocor IR formulations then switched to Tambocor XL.

Adults: Supraventricular arrhythmias: The recommended starting dosage is 50mg twice daily (IR formulation) and most patients will be controlled at this dose. If required the dose may be increased to a maximum of 300mg (IR formulation) daily.

Those patients controlled on 200mg (IR) daily may be switched to one 200mg XL capsule once daily. After 3-5 days it is recommended that the dosage be progressively adjusted to the lowest level which maintains control of the arrhythmia. It may be possible to reduce dosage during long-term treatment.

Children: Tambocor is not recommended in children under 12, as there is insufficient evidence of its use in this age group.

Elderly Patients: The rate of flecainide elimination from plasma may be reduced in elderly people. This should be taken into consideration when making dose adjustments.

Plasma levels: Based on PVC suppression, it appears that plasma levels of 200 -1000ng/ml may be needed to obtain the maximum therapeutic effect. Plasma levels above 700 - 1000ng/ml are associated with increased likelihood of adverse experiences.

Renal impairement: In patients with significant renal impairment (creatinine clearance of 35ml/min/1.73 sq.m. or less) the maximum initial dosage should be 100mg IR daily. When used in such patients, frequent plasma level monitoring is strongly recommended.

It is recommended that intravenous treatment with Tambocor should be administered in hospital.

Treatment with Tambocor XL should be under direct hospital or specialist supervision for patients with:

a)    AV nodal reciprocating tachycardia; arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways.

b)    Paroxysmal atrial fibrillation in patients with disabling symptoms.

Treatment for patients with other indications should continue to be initiated in hospital.

4.3 Contraindications

Hypersensitivity to flecainide or to any of the excipients.

Tambocor is contra-indicated in cardiac failure and in patients with a history of myocardial infarction who have either asymptomatic ventricular ectopics or asymptomatic non-sustained ventricular tachycardia.

Flecainide is contra-indicated in the presence of cardiogenic shock.

It is also contra-indicated in patients with long standing atrial fibrillation in whom there has been no attempt to convert to sinus rhythm, and in patients with haemodynamically significant valvular heart disease.

Known Brugada syndrome.

Unless pacing rescue is available, Tambocor should not be given to patients with sinus node dysfunction, atrial conduction defects, second degree or greater atrioventricular block, bundle branch block or distal block.

4.4 Special warnings and precautions for use

Electrolyte disturbances (e.g. hypo- and hyperkalaemia) should be corrected before using Tambocor (see section 4.5 for some drugs causing electrolyte disturbances). .

Since flecainide elimination from the plasma can be markedly slower in patients with significant hepatic impairment, flecainide should not be used in such patients unless the potential benefits clearly outweigh the risks. Plasma level monitoring is strongly recommended in these circumstances.

Tambocor is known to increase endocardial pacing thresholds - i.e. to decrease endocardial pacing sensitivity. This effect is reversible and is more marked on the acute pacing threshold than on the chronic. Tambocor should thus be used with caution in all patients with permanent pacemakers or temporary pacing electrodes, and should not be administered to patients with existing poor thresholds or nonprogrammable pacemakers unless suitable pacing rescue is available.

Generally a doubling of either pulse width or voltage is sufficient to regain capture, but it may be difficult to obtain ventricular thresholds less than 1 Volt at initial implantation in the presence of Tambocor.

The minor negative inotropic effect of flecainide may assume importance in patients predisposed to cardiac failure. Difficulty has been experienced in defibrillating some patients. Most of the cases reported had pre-existing heart disease with cardiac enlargement, a history of myocardial infarction, arterio-sclerotic heart disease and cardiac failure.

Tambocor has been shown to increase mortality risk of post-myocardial infarction patients with asymptomatic ventricular arrhythmia.

Tambocor, like other antiarrhythmics, may cause proarrhythmic effects, i.e. it may cause the appearance of a more severe type of arrhythmia, increase the frequency of an existing arrhythmia or the severity of the symptoms (see 4.8).

Tambocor should be used with caution in patients with impaired renal function (creatinine clearance < 35 ml/min/1.73 m2) and therapeutic drug monitoring is recommended.

The rate of flecainide elimination from plasma may be reduced in the elderly. This should be taken into consideration when making dose adjustments.

Tambocor is not recommended in children under 12 years of age, as there is insufficient evidence of its use in this age group. Severe bradycardia or pronounced hypotension should be corrected before using flecainide.

Tambocor should be avoided in patients structural organic heart disease or abnormal left ventricular function.

Tambocor should be used with caution in patients with acute onset of atrial fibrillation following cardiac surgery.

Tambocor prolongs the QT interval and widens the QRS complex by 12-20 %. The effect on the JT interval is insignificant.

A Brugada syndrome may be unmasked due to flecainide therapy. In the case of development of ECG changes during treatment with flecainide that may indicate Brugada syndrome, consideration to discontinue the treatment should be made.

In a large scale, placebo-controlled clinical trial in post-myocardial infarction patients with asymptomatic ventricular arrhythmia, oral flecainide was associated with a 2.2 fold higher incidence of mortality or non-fatal cardiac arrest as compared with its matching placebo. In that same study, an even higher incidence of mortality was observed in flecainide-treated patients with more than one myocardial infarction. Comparable placebo-controlled clinical trials have not been done to determine if flecainide is associated with higher risk of mortality in other patient groups.

Dairy products (milk, infant formula and possibly yoghurt) may reduce the absorption of flecainide in children and infants. Flecainide is not approved for use in children below the age of 12 years, however flecainide toxicity has been reported during treatment with flecainide in children who reduced their intake of milk, and in infants who were switched from milk formula to dextrose feedings.

Flecainide as a narrow therapeutic index drug requires caution and close monitoring when switching a patient to a different formulation.

For further warnings and precautions please refer to section 4.5 (Interaction).

4.5 Interaction with other medicinal products and other forms of interaction

Flecainide is a class I anti-arrhythmic and interactions are possible with other antiarrhythmic drugs where additive effects may occur or where drugs interfere with the metabolism of flecainide. Flecainide should not be administered concomitantly with other class I antiarrythmics. The following known categories of drugs may interact with flecainide:

Cardiac glycosides: Flecainide can cause the plasma digoxin level to rise by about 15%, which is unlikely to be of clinical significance for patients with plasma levels in the therapeutic range. It is recommended that the digoxin plasma level in digitalised patients should be measured not less than six hours after any digoxin dose, before or after administration of flecainide.

Class II anti-arrhythmics: the possibility of additive negative inotropic effects of beta-blockers and other cardiac depressants with flecainide should be recognised.

Class III anti-arrhythmics: when flecainide is given in the presence of amiodarone, the usual flecainide dosage should be reduced by 50% and the patient monitored closely for adverse effects. Plasma level monitoring is strongly recommended in these circumstances.

Class IV anti-arrhythmics: use of flecainide with other sodium channel blockers is not recommended.

Anti-depressants: fluoxetine, paroxetine increases plasma flecainide concentration, increased risk of arrhythmias with tricyclics, manufacturer of reboxetine advises caution.

Life-threatening or even lethal adverse events due to interactions causing increased plasma concentrations may occur (see 4.9). Flecainide is metabolised by CYP2D6 to a large extent, and concurrent use of drugs inhibiting (e.g. antidepressants, neuroleptics, propranolol, ritonavir, some antihistamines) or inducing (e.g. phenytoin, phenobarbital, carbamazepine) this iso-enzyme can increase or decrease plasma concentrations of flecainide, respectively (see below).

An increase of plasma levels may also result from renal impairment due to a reduced clearance of flecainide

Hypokalaemia but also hyperkalaemia or other electrolyte disturbances should be corrected before administration of flecainide. Hypokalaemia may result from the concomitant use of diuretics, corticosteroids or laxatives.

Anti-epileptics: limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination.

Anti-psychotics: clozapine - increased risk of arrhythmias.

Anti-histamines: increased risk of ventricular arrhythmias with mizolastine and terfenadine (avoid concomitant use).

Anti-malarials: quinine increases plasma concentration of flecainide.

Antivirals: plasma concentration increased by ritonavir, lopinavir and indinavir (increased risk of ventricular arrhythmias, avoid concomitant use).

Diuretics: Class effect due to hypokalaemia giving rise to cardiac toxicity.

H2 antihistamines (for the treatment of gastric ulcers): cimetidine inhibits metabolism of flecainide. In healthy subjects receiving cimetidine (1g daily) for one week, plasma flecainide levels increased by about 30% and the half-life increased by about 10%.

Anti-smoking aids: Co-administration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including flecainide, should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving flecainide, the need to decrease the dose of the original medication should be considered.

Anticoagulants:Treatment with Tambocor is compatible with use of oral anticoagulants.

4.6 Fertility, pregnancy and lactation

Pregnancy:

There is no evidence as to drug safety in human pregnancy. In New Zealand White rabbits, high doses of flecainide caused some foetal abnormalities, but these effects were not seen in Dutch Belted rabbits or rats (see 5.3). The relevance of these findings to humans has not been established. Data have shown that flecainide crosses the placenta to the foetus in patients taking flecainide during pregnancy. Flecainide should only be used in pregnancy if the benefit outweighs the risks.

Breast-feeding:

Flecainide is excreted in human milk. Plasma concentrations obtained in a nursing infant are 5-10 times lower than therapeutic drug concentrations (see 5.2). Although the risk of adverse effects to the nursing infant is very small, flecainide should only be used during lactation if the benefit outweighs the risks.

4.7 Effects on ability to drive and use machines

Tambocor XL 200mg capsules has no or negligible influence on the ability to drive and use machines. However, driving ability, operation of machinery and work without a secure fit may be affected by adverse reactions such as dizziness and visual disturbances (if present)

4.8 Undesirable effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/l0), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (> 1/10,000 and <1/1000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Uncommon: red blood cell count decreased, white blood cell count decreased and platelet count decreased

Immune system disorders:

Very rare: antinuclear antibody increased with and without systemic inflammation Psychiatric disorders:

Rare: hallucination, depression, confusional state, anxiety, amnesia, insomnia Nervous system disorders:

Very common: dizziness, which is usually transient

Rare: paraesthesia, ataxia, hypoaesthesia, hyperhidrosis, syncope, tremor, flushing, somnolence, headache, neuropathy peripheral, convulsion, dyskinesia

Eye disorders:

Very common: visual impairment, such as diplopia and vision blurred Very rare: corneal deposits

Ear and labyrinth disorders:

Rare: tinnitus, vertigo

Cardiac disorders:

Common: Proarrhythmia (most likely in patients with structural heart disease and/or significant left ventricular impairment).

Frequency not known (cannot be estimated from the available data). Dose-related increases in PR and QRS intervals may occur (see 4.4). Altered pacing threshold (see 4.4).

Uncommon: Patients with atrial flutter can develop a 1:1 AV conduction with increased heart rate.

Frequency not known (cannot be estimated from the available data): atrioventricular block-second-degree and atrioventricular block third degree, cardiac arrest, bradycardia, cardiac failure/ cardiac failure congestive, chest pain, hypotension, myocardial infarction, palpitations, sinus pause or arrest, and tachycardia (AT or VT) or ventricular fibrillation. Demasking of a pre-existing Brugada syndrome.

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea Rare: pneumonitis

Frequency not known (cannot be estimated from the available data): pulmonary fibrosis, interstitial lung disease

Gastrointestinal disorders:

Uncommon: nausea, vomiting, constipation, abdominal pain, decreased appetite, diarrhoea, dyspepsia, flatulence

Hepatobiliary disorders:

Rare: hepatic enzymes increased with and without jaundice

Frequency not known (cannot be estimated from the available data): hepatic

dysfunction

Skin and subcutaneous tissue disorders:

Uncommon: dermatitis allergic, including rash, alopecia

Rare: serious urticaria

Very rare: photosensitivity reaction

General disorders and administration site conditions:

Common: asthenia, fatigue, pyrexia, oedema

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Overdose

Overdosage with flecainide is a potentially life-threatening medical emergency. Increased drug susceptibility and plasma levels exceeding therapeutic levels may also result from drug interaction (see 4.5). No specific antidote is known. There is no known way to rapidly remove flecainide from the system. Neither dialysis nor haemoperfusion is effective.

Treatment should be supportive and may include removal of unabsorbed drug from the GI tract. Further measures may include inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol as well as mechanical ventilation and circulatory assistance (e.g. ballon pumping). Temporarily inserting a transvenous pacemaker in the event of conduction block should be considered. Assuming a plasma half-life of approximately 20 h, these supportive treatments may need to be continued for an extended period of time. Forced diuresis with acidification of the urine theoretically promotes drug excretion.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Tambocor is a Class 1 anti-arrhythmic (local anaesthetic) agent. ATC code: C01BC04.

Tambocor slows conduction through the heart, having its greatest effect on His Bundle conduction. It also acts selectively to increase anterograde and particularly retrograde accessory pathway refractoriness. Its actions may be reflected in the ECG by prolongation of the PR interval and widening of the QRS complex. The effect on the JT interval is insignificant.

5.2 Pharmacokinetic properties

Tambocor XL capsules contain polymer-coated microgranules, allowing controlled release of the active substance. Each microgranule constitutes a controlled release form of flecainide acetate, allowing prolongation of the absorption time without modifying the elimination parameters.

Absorption of flecainide acetate via the oral route is greater than 80% of the dose administered.

After administration of one XL capsule, plasma flecainide concentrations gradually increase after a lag time of 2 to 3 hours to reach a peak between the 21^st and 25^th hour and remain at plateau levels until after the 30^th hour.

Absorption of flecainide acetate from capsules is not modified by food.

Steady-state is reached after five days of treatment with minimal fluctuations, and 50% flattening of plasma concentration peaks compared to the tablet form.

Flecainide acetate is widely and rapidly distributed in the tissues. The mean volume of distribution is 8.31 l/kg. Protein binding is low (about 40%).

Flecainide acetate is essentially eliminated in the urine: 25% of the dose is eliminated after 24 hours in the unchanged form. Haemodialysis does not appear to be an effective way to eliminate flecainide acetate. Flecainide acetate is also eliminated by metabolism, especially via the cytochrome 2D6 pathway. The apparent plasma elimination half-life is about 12 to 27 hours, it is not modified with the XL capsule form.

No enzyme induction or inhibition phenomena have been observed after prolonged dosing.

5.3 Preclinical safety data

One rabbit tribe showed teratogenicity and embryotoxicity under flecainide. This effect was neither present in other rabbit tribes nor in rats or mice. Prolongation of gestation was seen in rats under a dose of 50 mg/kg. No effects on fertility were observed. No human data concerning pregnancy and lactation are available.

6.1 List of excipients

Excipients:

Microcrystalline Cellulose

Methacrylic acid-methyl methacrylate (1:2) copolymer

Macrogol 400

Talc

Capsule shell:

Gelatin

Titanium Dioxide (E171)

Iron Oxide Black (E172)

Erythrosine (E127)

Printing ink contains:

Shellac Glaze Esterified) In Ethanol Iron Oxide Black (E172) N-Butyl Alcohol Purified Water Propylene Glycol Dehydrated Ethanol Isopropyl Alcohol Ammonium Hydroxide 28%.

Or

Shellac

Dehydrated Alcohol Isopropyl Alcohol Butyl Alcohol Propylene Glycol Strong Ammonia Solution Black Iron Oxide (E172) Potassium Hydroxide Purified Water

6.2    Incompatibilities

None known

6.3    Shelf life

2 years

6.4    Special precautions for storage

Do not store above 25°C. Store in original package.

Nature and contents of container

UPVC/PVDC/Aluminium blister packs containing 15, 30 or 60 capsules.