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FLECAINIDE ACETATE 100MG TABLETS

Active substance(s): FLECAINIDE ACETATE / FLECAINIDE ACETATE / FLECAINIDE ACETATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Flecainide Acetate 100 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains flecainide acetate 100 mg
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet
White to off-white, round [diameter 8.5 mm], biconvex, scored tablets
debossed with ‘1’ and ‘2’ separated by deep score line on one side and ‘CC’
on the other side. The tablet can be divided into equal halves.

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 acetate therapy and dose changes should be made under
medical supervision and monitoring of ECG and plasma level. Hospitalization could
be necessary during such procedures for certain patients, especially for patients with
life threatening ventricular arrhythmias.These decisions should be made under
supervision of 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 IC (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.
Elderly patients:

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. The dose for elderly patients should not exceed 300
mg per day (or 150 mg twice daily).
Children:

flecainide acetate is not recommended for use in children younger than 12
years, due to a lack of data on safety and efficacy.
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.
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).
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. 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 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.

-

Patients with long standing atrial fibrillation in whom there has been no attempt
to convert to sinus rhythm

-

Patients with reduced or impaired ventricular function, cardiogenic shock, severe
bradycardia (less than 50 bpm), severe hypotension

-

Use in combination with Class I antiarrhythmic drugs. (Sodium channel blockers)

-

In patients with haemo dynamically significant valvular heart disease.

4.4

-

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

-

Patients with asymptomatic or mildly symptomatic ventricular arrhythmias must
not be given flecainide.

-

Known Brugada syndrome.

Special warnings and precautions for use
Treatment with oral flecainide should be under direct hospital or specialist
supervision for patients with:


AV nodal reciprocating tachycardia; arrhythmias associated with WolffParkinson-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.
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 4.8).
Flecainide should be avoided in patients with structural heart disease or abnormal left
ventricular function (see 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.
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.
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.
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.

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

Flecainide is not recommended in children under 12 years of age, as there is
insufficient evidence of its use in this age group.
Electrolyte disturbances (e.g. hypo- and hyperkalaemia) should be corrected
before using flecainide (see 4.5 for some drugs causing electrolyte
disturbances).
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 nonprogrammable pacemakers unless suitable pacing rescue is available.
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.

For further warnings and precautions please refer to 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.

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 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 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: 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.
Lactation
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
Flecainide acetate has moderate influence on the ability to drive and use
machines. Driving ability and operation of machinery 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

Psychatric 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).
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 arrest, and tachycardia (AT or VT).
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, insterstitial 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

4.9

Overdose
Overdose 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
Pharmacotherapeutic group: Antiarrhythmics, class IC, Flecainide
ATC code: C01 BC 04
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.
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 fastchannel fibres for depolarisation but with a modest increase in the effective refractory
period when tested in isolated cardiac tissues. These electrophysiological properties
of flecainide acetate 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. Given intravenously the mean time to achieve peak serum concentration was
0.67 hours and the mean bioavailability was 98%, compared with 1 hour and 78% for
an oral solution and 4 hours and 81% for a tablet.

Distribution
Flecainide 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 m-O-dealkylated flecainide and m-O-dealkylated lactam of
flecainide, both of which may have some activity. Its metabolism appears to involve
the cytochrome P450 isoenzyme CYP2D6, which shows genetic polymorphism.

Excretion
Flecainide 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
Cellulose, Microcrystalline (E460)
Croscarmellose Sodium
Starch, Pregelatinized
Hydrogenated Vegetable Oil
Magnesium Stearate (E572)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicnal product does not require any special storage conditions.

6.5

Nature and contents of container
Flecainide acetate tablets are available in Clear PVC/PVdC - Aluminium foil
blister pack and HDPE bottle pack with polypropylene closure.
Blister: 20, 28, 30, 40, 50, 56, 60, 84, 90 and 100 tablets
HDPE: 20, 1000 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Not applicable

7

MARKETING AUTHORISATION HOLDER
Milpharm Limited
AresBlock
Odyssey Business Park
West End Road
Ruislip HA4 6QD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 16363/0326

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
31/05/2016

10

DATE OF REVISION OF THE TEXT
01/08/2015

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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