Flecainide Acetate Tablets 100mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Flecainide Acetate Tablets 100mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 100mg Flecainide Acetate For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet.
White, circular, biconvex, uncoated tablets one side embossed with a breakline and the identifying letters “C” above the line and “FJ” below, the reverse side embossed with a breakline.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic Indications
Treatment of AV nodal reciprocating tachycardia; arrhythmias associated with
Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways, when other treatment has been ineffective.
Treatment of severe symptomatic and life-threatening paroxysmal ventricular arrhythmia which has failed to respond to other forms of therapy or where other treatments have not been tolerated.
Treatment of paroxysmal atrial arrhythmias (atrial fibrillation, atrial flutter and atrial tachycardia) in patients with disabling symptoms after conversion provided that there is definite need for treatment on the basis of severity of clinical symptoms, when other treatment has been ineffective. Structural heart disease and/or impaired left ventricular function should be excluded because of the increased risk for pro-arrhythmic effects.
4.2 Posology and method of administration
Posology
Initiation of flecainide therapy and dose changes should be made in hospital under ECG and plasma level monitoring. The clinical decision to initiate flecainide treatment should be made in consultation with a specialist. In patients with an underlying organic cardiopathy and especially those with a history of myocardial infarction, flecainide treatment should only be started when other arrhythmic agents, other than class 1C (especially amiodarone), are ineffective or not tolerated and when non-pharmacological treatment (surgery, ablation, implanted defibrillator) is not indicated. Strict medical monitoring of ECG and plasma levels during treatment is required.
Adults and adolescents (13-17 years of age):
Supraventricular arrhythmias: The recommended starting dose is 50mg twice daily and most patients will be controlled at this dose. If required the dose may be increased to a maximum of 300mg daily.
Ventricular arrhythmias: The recommended starting dose is 100mg twice daily. The maximum daily dose is 400mg and this is normally reserved for patients of large build or where rapid control of the arrhythmia is required. 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.
Older people:
In elderly patients the maximum initial daily dosage should be 100mg daily (or 50mg twice daily) as the rate of flecainide elimination from plasma may be reduced in elderly people. This should be taken into consideration when making dose adjustments.
Paediatric population:
Not recommended for children under 12 years of age.
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.
Patients with impaired renal function:
In patients with significant renal impairment (creatinine clearance of 35ml/min/1.73sq.m.or less) the maximum initial dosage should be 100mg daily (or 50mg twice daily). When used in such patients, frequent plasma level monitoring is strongly recommended. Depending on the effect and tolerability the dose may then be cautiously increased. After 6-7 days the dose may be adjusted, depending on the effect and the tolerability. Some patients with severe renal failure can have a very slow clearance of flecainide and thus a prolonged half-life (60-70 hours).
Patients with impaired liver function:
In patients with impaired liver function, the patient should be closely monitored and the dose should not exceed 100mg daily (or 50mg twice daily).
Patients with a permanent pacemaker in situ should be treated with caution and the dose should not exceed 100mg twice daily.
In patients concurrently receiving cimetidine or amiodarone close monitoring is required. In some patients the dose may have to be reduced and should not exceed 100mg twice daily. Patients should be monitored during initial and maintenance therapy.
Plasma level monitoring and ECG control are recommended at regular intervals (ECG control once a month and long term ECG every 3 months) during therapy. During initiation therapy and when the dose is increased, an ECG should be performed every 2-4 days.
When flecainide is used in patients with dosage restrictions, frequent ECG control (additional to the regular flecainide plasma monitoring) should be made. Dose adjustment should be made at intervals of 6-8 days. In such patients an ECG should be performed in weeks 2 and 3 to control the individual dosage.
Method of Administration
For oral use. These tablets should be swallowed whole with water. In order to avoid the possibility of food affecting the absorption of the drug, flecainide should be taken on an empty stomach or one hour before food.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Flecainide is contraindicated in cardiac failure and in patients with a history of myocardial infarction who have either asymptomatic ventricular ectopics or asymptomatic non-sustained ventricular tachycardia.
• It is also contraindicated in patients with long standing atrial fibrillation in whom there has been no attempt to convert to sinus rhythm; in patients with reduced or impaired ventricular function, cardiogenic shock, severe bradycardia (less than 50 bpm), severe hypotension; use in combination with disopyramide, and in patients with haemodynamically significant valvular heart disease.
• Known Brugada syndrome.
• Unless pacing rescue is available, flecainide should not be given to patients with sinus node dysfunction, atrial condition defects, second degree or greater atrio-ventricular block, bundle branch block or distal block.
• Patients with asymptomatic or mildly symptomatic ventricular arrhythmias should not be given flecainide.
4.4 Special warnings and precautions for use
Cardiac
Initiation of flecainide therapy and dose changes should be made in hospital under ECG and plasma level monitoring.
Treatment with oral flecainide should be under direct hospital or specialist supervision for patients with:
• AV nodal reciprocating tachycardia; arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways.
• Paroxysmal atrial fibrillation in patients with disabling symptoms.
Flecainide has been shown to increase mortality risk of post-myocardial infarction patients with asymptomatic ventricular arrhythmia. An acceleration of the ventricular rate of atrial fibrillation in case of therapy failure has been reported.
Flecainide has a selective effect that increases the refractory period of the anterograde, and especially, the retrograde pathways.
Flecainide, 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 section 4.8).
Flecainide should be avoided in patients with structural heart disease or abnormal left ventricular function (see section 4.8).
Flecainide should be used with caution in patients with acute onset of atrial fibrillation following cardiac surgery.
Treatment for patients with other indications should continue to be initiated in hospital.
Flecainide prolongs the QT interval and widens the QRS complex by 12-20 %. The effect on the JT interval is insignificant. Nevertheless, there have been reports of prolongation of the JT interval of up to 4%. This action is less marked than that observed with the class 1a antiarrhythmic drugs however. Flecainide should be used with caution in patients with sick sinus syndrome.
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.
Severe bradycardia or pronounced hypotension should be corrected before using flecainide.
Flecainide 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. Flecainide 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 non-programmable 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 flecainide.
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.
Patients with hepatic impairment
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 outweigh the risks. Plasma level monitoring is recommended.
Patients with renal impairment
Flecainide 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.
Electrolyte disturbances (e.g. hypo- and hyperkalaemia) should be corrected before using flecainide (see section 4.5 for some drugs causing electrolyte disturbances). Hypokalaemia may occur in patients who use diuretics, corticosteroids or laxatives.
Older people
The rate of flecainide elimination from plasma may be reduced in the elderly. This should be taken into consideration when making dose adjustments.
Paediatric population
Flecainide is not recommended in children under 12 years of age, as there is insufficient evidence of its use in this age group.
For further warnings and precautions please refer to section 4.5.
4.5 Interaction with other medicinal products and other forms of interaction
Class I antiarrhythmics: Flecainide should not be administered concomitantly with other class I antiarrythmics.
Class II antiarrhythmics: The possibility of additive negative inotropic effects of Class II antiarrhythmics, i.e. beta-blockers, with flecainide should be recognised.
Class III antiarrhythmics: If 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 antiarrhythmics: The use of flecainide with calcium channel blockers, e.g. verapamil, should be considered with caution.
Life-threatening or even lethal adverse events due to interactions causing increased plasma concentrations may occur (see 4.9). Flecainide is metabolized by CYP2D6 to a large extent, and concurrent use of drugs inhibiting or inducing this iso-enzyme can increase or decrease plasma concentrations of flecainide, respectively. Drugs that induce Cytochrome P450 can reduce the plasma level of flecainide.
An increase of plasma levels may also result from renal impairment due to a reduced clearance of flecainide (see 4.4).
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.
Antihistamines: Increased risk of ventricular arrhythmias with mizolastine, astemizole and terfenadine (avoid concomitant use).
Antivirals: Plasma concentrations are increased by ritonavir, lopinavir and indinavir (increased risk of ventricular arrhythmias) (avoid concomitant use).
Antidepressants: Fluoxetine and other antidepressants increases plasma flecainide concentration; increased risk of arrhythmias with tricyclics.
Antiepileptics: Limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination.
Antipsychotics: Clozapine - increased risk of arrhythmias.
Antimalarials: Quinine and halofantrine increases plasma concentrations of flecainide.
Antifungals: Terbinafine may increase plasma concentrations of flecainide resulting from its inhibition of CYP2D6 activity.
Diuretics: Class effect due to hypokalaemia giving rise to cardiotoxicity.
H2 antihistamines (for the treatment of gastric ulcers): The H2 antagonist cimetidine inhibits metabolism of flecainide. In healthy subjects receiving cimetidine (1 g daily) for 1 week, the AUC of flecainide increased by about 30 % and the half-life increased by about 10 %.
Antismoking aids: Co-administration of bupropion (metabolised by CYP2D6) with 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.
Cardiac glycosides: Use of flecainide with other sodium channel blockers is not recommended. 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.
Anticoagulants: The treatment with flecainide is compatible with the 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
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
Very common: > 1/10 Common: >1/100, <1/10 Uncommon: >1/1,000, <1/100 Rare: >1/10,000, <1/1000 Very rare: <1/10,000
Not known: Cannot be estimated from the available data
• Blood and lymphatic system disorders:
Uncommon: reductions in red and white blood cells and platelets, these changes are usually mild.
• Immune system disorders:
Rare: cases of increases in anti-nuclear antibodies, with and without systemic inflammatory involvement.
• Psychiatric disorders:
Common: depression, anxiety, insomnia
Uncommon: hallucinations, confusion, amnesia,
Rare: nervousness.
• Nervous system disorders:
Very common: dizziness, and light headedness which are usually transient. Giddiness, headache.
Common: paraesthesia, ataxia, dyskinesia, hypaesthesia, hyperhidrosis, syncope, tremor, vertigo, flushing, somnolence, tinnitus, increased sweating.
Uncommon: peripheral neuropathy, convulsions
• Eye disorders:
Very common: visual disturbances, such as double vision and blurring of vision these are usually transient and disappear upon continuing or reducing the dosage.
Very rare: corneal deposits.
• Cardiac disorders:
Common: pro-arrhythmic effects are most likely in patients with structural heart disease and/or significant left ventricular impairment. These proarrhythmic effects include the increase of the frequency of premature ventricular contractions to more severe forms of ventricular tachycardia. Frequency not known (cannot be estimated from the available data): specific ECG changes (prolongation of PQ, QT, PR or QRS interval, increase in number or severity of arrhythmia), altered pacing threshold, incidences of bradycardia, sinus arrest or inducement or worsening of heart failure. In patients with atrial flutter the use of flecainide has been associated with 1:1 AV conduction following initial atrial slowing with resultant ventricular acceleration.
Frequency not known (cannot be estimated from the available data): AV block (II and III grades), bundle branch block or SA block, cardiac arrest, chest pain, hypotension, myocardial infarction, palpitations, sinus arrest, and tachycardia (AT or VT) has been reported. In these cases the therapy with flecainide should be discontinued. Demasking of a pre-existing Brugada syndrome.
• Respiratory, thoracic and mediastinal disorders:
Common: dyspnoea Uncommon: interstitial pneumonitis
Frequency not known (cannot be estimated from the available data): pulmonary fibrosis, interstitial lung disease
• Gastrointestinal disorders:
Common: nausea, vomiting, diarrhoea, constipation, abdominal pain Uncommon: dysgeusia, dry mouth, decreased appetite, dyspepsia, flatulence
• Hepatobiliary disorders:
Rare: elevated liver enzymes and jaundice.
Frequency noy known (cannot be estimated from the available data): hepatic dysfunction
• Skin and subcutaneous tissue disorders:
Uncommon: dermatitis allergic, including rash, alopesia Rare: serious urticaria
Not known: photosensitivity, flushing, allergic skin reactions
• Musculoskeletal and connective tissue disorders:
Very rare: arthralgia and myalgia
• Reproductive system and breast disorders:
Very rare: impotence.
• 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; website: www.mhra.gov.uk/yellowcard
4.9 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 if there are severe conduction disturbances or the patients left ventricular function is otherwise compromised. 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.
In one case report amiodarone was administered to a patient after a flecainide overdose for therapy resistant ventricular fibrillation. However, the efficacy and safety are not proven and amiodarone is not regarded as an antidote to the flecainide overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiarrhythmics, class 1c, Flecainide ATC code: CO1 BC 04
Mechanism of action
Flecainide acetate is a Class IC antiarrhythmic agent used for the treatment of severe symptomatic life-threatening ventricular arrhythmias and supraventricular arrhythmias.
Electrophysiologically, flecainide is a local anaesthetic-type (Class IC) of antiarrhythmic compound. It is an amide type of local anaesthetic, being structurally related to procainamide and encainide in so far as these agents are also benzamide derivatives.
Pharmacodynamics effects
The characterisation of flecainide as a Class IC compound is based on a triad of features: marked depression of the fast sodium channel in the heart; slow onset and offset kinetics of inhibition of the sodium channel (reflecting slow attachment to and dissociation from sodium channels); and the differential effect of the drug on the action potential duration in ventricular muscle versus Purkinje fibres, having no effect in the former and markedly shortening it in the latter. This composite of properties leads to a marked depression in conduction velocity in fibres dependant on the fast-channel fibres for depolarisation but with a modest increase in the effective refractory period when tested in isolated cardiac tissues. These electrophysiological properties of flecainide may lead to prolongation of the PR-interval and QRS duration on the ECG. At very high concentrations flecainide exerts a weak depressant effect on the slow channel in the myocardium. This is accompanied by a negative inotropic effect.
5.2 Pharmacokinetic properties
Absorption
Flecainide is almost completely absorbed after oral administration and does not undergo extensive first-pass metabolism. The bioavailability from flecainide acetate tablets has been reported to be about 90%.
The therapeutic plasma concentration range is generally accepted as 200 to 1000ng per ml.
Distribution
Flecanide is about 40% bound to plasma proteins. Flecainide passes the placenta and is excreted in breast milk.
Metabolism
Flecainide is extensively metabolised (subject to genetic polymorphism), the 2 major metabolites being w-O-dealkylated flecainide and w-O-dealkylated lactam of flecainide, both of which may have some activity.
Excretion
It is excreted mainly in the urine, approximately 30% as unchanged drug and the remainder as metabolites. About 5% is excreted in the faeces. Excretion of flecainide is decreased in renal failure, liver diseases, heart failure, and in alkaline urine. Haemodialysis removes only about 1% of unchanged flecainide.
The elimination half-life of flecainide is about 20 hours
5.3 Preclinical safety data
The only preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC are the following effects found on reproduction. In one breed of rabbits flecainide caused teratogenicity and embryotoxicity. There were insufficient data to establish a safety margin for this effect. However, these effects were not seen in another breed of rabbits, rats and mice.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Croscarmellose sodium, magnesium stearate, maize starch,
pregelatinised maize starch microcrystalline cellulose (E460).
6.2 Incompatibilities
Not applicable.
6.3 Shelf-life
3 years.
6.4
Special precautions for storage
Polypropylene and Polyethylene containers Do not store above 25°C.
Store in the original container.
Blister packs
Do not store above 25°C. Keep container in the outer carton.
6.5 Nature and contents of container
The blister packs are manufactured from 250pm white rigid PVC/PVDC coated with 60gm-2 PVDC and 20pm hard temper aluminium foil with 5-7g/m PVC/PVDC compatible heat seal lacquer. The polypropylene containers are manufactured from rigid injection moulded polypropylene with snap-on polyethylene lids. An alternative container is a container with a snap-on polyethylene lid.
Pack sizes:
Blister: 20s, 28s, 30s, 50s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s. Polypropylene container: 100s, 250s, 500s, 1000s.
Polyethylene container:100s.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis) Whiddon Valley BARNSTAPLE N Devon EX32 8NS
8 MARKETING AUTHORISATION NUMBER(S)
PL 00142/0431
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 03/08/2009
10
DATE OF REVISION OF THE TEXT
26/10/2015