USE OF DRONEDARONE OR A PHARMACEUTICALLY ACCEPTABLE SALT
THEREOF, FOR THE PREPARATION OF A MEDICAMENT FOR
ADMINISTRATION SHORTLY AFTER AMIODARONE DISCONTINUATION
The present invention relates to the use of dronedarone or a pharmaceutically
acceptable salt thereof, for the preparation of a medicament for use in the
prevention or treatment of atrial fibrillation (usually abbreviated to AF) and/or
atrial Flutter (usually abbreviated to AFL) shortly after discontinuation of a
previous treatment with amiodarone.
Restoration and maintenance of sinus rhythm remain major therapeutic goals for
patients with atrial fibrillation.
Amiodarone is an especially potent atrial antifibrillatory agent, which is effective in
maintaining sinus rhythm in atrial fibrillation but it is also associated with
potentially serious toxic effects in some patients.
Dronedarone is a new antiarrhythmic agent on the market, pharmacologically
related to amiodarone but developed to reduce the risk of side effects. Indeed,
dronedarone is a benzofuran derivative with an electropharmacologic profile
closely resembling that of amiodarone but with structural differences intended to
eliminate the effects of amiodarone on thyroid and pulmonary functions. 2-n-Butyl-
3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulphonamidobenzofuran, or
dronedarone, and pharmaceutically acceptable salts thereof, in particular its
hydrochloride salts, are described in European Patent EP 0 471 609 B 1. The
elimination half-life of dronedarone is about 1 to 2 days.
Moreover, dronedarone is effective in maintaining sinus rhythm in patients
presenting atrial fibrillation or atrial flutter.
The use of drugs that are devoid of such effects but that retain the antiarrhythmic
potential of amiodarone are therapeutically sought.
Thus, Dronedarone, a new multichannel blocker for atrial fibrillation/flutter
(AF/AFL), may be indicated for patients on prior amiodarone.
However, physicians may hesitate to start other antiarrhythmic drugs after
amiodarone intake, given the following: that the elimination half-life of
amiodarone is long, between 28 to 180 days, in general between 30 to 55 days,
and that tissue accumulation can cause severe organ toxicity.
It is well known that the association of agents prolonging the QT-interval of the
electrocardiogram is contraindicated because of the increased risk of
lifethreatening ventricular arrhythmia such as torsades de pointes.
For this reason the package insert (US) of Multaq contraindicates the
concomitant use of dronedarone with other agents prolonging the QT-interval of
the electrocardiogram (so called Class III antiarrhythmics because they prolong
cardiac repolarization) : "Concomitant use of drugs or herbal products that prolong
the QT interval and might increase the risk of Torsade de Pointes, such as
phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide
antibiotics, and Class I and III antiarrhythmics Co-administration of drugs
prolonging the QT interval (such as certain phenothiazines, tricyclic
antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics)
is contraindicated because of the potential risk of Torsade de Pointes-type
ventricular tachycardia."
The same recommendations are found in the European SmPc of
Multaq : "Medicinal products inducing torsades de pointes such as
phenothiazines, cisapride, bepridil, tricyclic antidepressants, terfenadine and
certain oral macrolides, Class I and III antiarrhythmics Medicinal products
inducing torsades de pointes such as phenothiazines, cisapride, bepridil, tricyclic
antidepressants, certain oral macrolides, terfenadine and Class I and III
antiarrhythmics are contraindicated because of the potential risk of proarrhythmia
(see section 4.3)."
Amiodarone is a drug well known to prolong cardiac repolarization (Antiarrhythmic
with Class III properties).
According to current knowledge (US and EU package insert of dronedarone
summarized above) dronedarone must not be used concomitantly
with amiodarone (an agent with Class III properties).
Amiodarone is also known to have an extremely long half-life between 28 to 180
days, in general between 30 to 55 days because it accumulates in fatty tissue and
that tissue accumulation can cause severe organ toxicity.
It is usually considered that the pharmacodynamic effects of a drug persist for up
to 5 plasma half lives after their discontinuation.
This implies that the effects of amiodarone for example on cardiac repolarization
are expected to persist for several months after its discontinuation.
Based on these pharmacokinetic/pharmacodynamic concepts and on the
Multaq package insert recommendations it would be considered common practice
for one skilled in the art to discontinue amiodarone for several months prior to the
start of dronedarone therapy in order to reduce the risk of potentially
lifethreatening complications such as torsades de pointes.
So, it is of the utmost importance to find how to switch therapeutic treatment after
the use of amiodarone by a patient in order to use dronedarone without harmful
effects such torsades de pointes for said patient, given the long elimination halflife
of amiodarone and the risk of potential additive effects.
To solve this problem, the applicant has evaluated the effect of dronedarone start
after amiodarone discontinuation.
Now, the applicant surprisingly found a new and advantageous scheme of
administration where amiodarone is discontinuated and dronedarone is started
without observing a washout period for amiodarone of 5 plasma half-lives of
amiodarone.
The instant invention therefore relates to dronedarone or a pharmaceutically
acceptable salt thereof, can be used for the preparation of a medicament for use
in the prevention and/or treatment of patients with cardiovascular history, shortly
after the discontinuation of a previous treatment with amiodarone, i.e. without
observing a washout period for amiodarone of 5 plasma half-lives of
amiodarone.
The meaning of "shortly after the discontinuation of a previous treatment with
amiodarone" may be defined as a period lower than five elimination half-lives of
amiodarone, for example one elimination half-life of amiodarone, and more
particularly four weeks, two weeks or 2 days after amiodarone discontinuation or
even 1 day after said discontinuation.
Said dronedarone or pharmaceutically acceptable salt thereof, can be taken by
these patients within a period lower than five elimination half-lives of amiodarone,
for example, within four weeks, two weeks or 2 days after amiodarone
discontinuation or even within 1 day after said discontinuation.
The patients concerned by the present invention have a cardiovascular history.
They may be affected, for example, by a Atrial Fibrillation such as a persistent
Atrial Fibrillation, a paroxysmal Atrial Fibrillation or a permanent Atrial Fibrillation
or by a Atrial Flutter.
According to one embodiment, patients are chosen from patients with a persistent
Atrial Fibrillation and in particular patients for whom cardioversion, anti-arrhythmic
treatment and anticoagulation treatment are indicated.
According to another embodiment, patients are chosen from patients with
paroxysmal or persistent atrial fibrillation.
According to the invention, patients may have received a previous treatment with
amiodarone for at least 28 days + or - 2 days or for at least 2 months or for at
least 6 months before said discontinuation.
According to one embodiment, this previous treatment with amiodarone may be
short. A short-term treatment / regimen may be defined as a treatment lower than
six months, for example may be for at least 28 days + or - 2 days or for at least 2
months before said discontinuation.
According to another embodiment, this previous treatment with amiodarone may
be long. A long-term treatment / regimen of amiodarone may be defined as a
treatment of at least 6 months before said discontinuation.
The American College of Cardiology, American Heart Association, and the
European Society of Cardiology recommend in their guidelines the following
classification system based on simplicity and clinical relevance:
> Patients with Paroxysmal Atrial Fibrillation means patients with
recurrent episodes that self-terminate in less than 7 days.
> Patients with persistent Atrial Fibrillation means patients with recurrent
episodes that last more than 7 days.
If a first detected episode self-terminates in less than 7 days and then another
episode begins later on, the case has moved into the category of paroxysmal AF.
Although patients in this category have episodes lasting up to 7 days, in most
cases of paroxysmal AF the episodes will self-terminate in less than 24 hours. If
instead the episode lasts for more than 7 days, it is unlikely to self-terminate and it
is called persistent AF. In this case, the episode may be terminated by
cardioversion.
> If cardioversion is unsuccessful or it is not attempted, and the episode is
ongoing for a long time (e.g. a year or more), the patient's AF is called permanent.
Among the patients having a cardiovascular history according to the invention, in
particular having a history of atrial fibrillation or atrial flutter, mention may also be
made of patients also exhibiting at least one additional risk factors, such as:
age equal to or above 70, or even above 75
hypertension,
diabetes,
prior cerebrovascular disease,
- left atrial diameter greater than or equal to 50 mm measured by
echocardiography,
left ventricular ejection fraction less than 40%, measured by twodimensional
echography.
Among the patients having a cardiovascular history according to the invention, in
particular having a history of atrial fibrillation or atrial flutter, mention may also be
made of patients also exhibiting additional risk factors, i.e. at least one
pathologies chosen from :
Structural heart disease,
- Lone Atrial Fibrillation,
Coronary heart disease, and
Dilated cardiomyopathy,
and/or at least one cardiac device chosen from:
Pacemaker, and
Valvular heart.
Among the patients having a cardiovascular history according to the invention, in
particular having a history of atrial fibrillation or atrial flutter, mention may also be
made of patients also taking in at least a baseline medication chosen from:
oral anticoagulant (usually abbreviated to OAC),
Beta blocking agents,
- Angiotensin I converting enzyme (usually abbreviated to ACE) or
Angiotensin I I receptor blocker (usually abbreviated to ARB),
Chronic antiplatelet therapy,
Diuretics,
Statins,
- Digitalis,
- Moderate inhibitors of CYP3A4,
Nonsteroidal anti-inflammatory drugs (usually abbreviated to NSAID) .
For their therapeutic use, dronedarone and pharmaceutically acceptable salts
thereof are generally introduced into pharmaceutical compositions.
These pharmaceutical compositions contain an effective dose of dronedarone or
of a pharmaceutically acceptable salt thereof, and also at least one
pharmaceutically acceptable excipient.
Said excipients are chosen according to the pharmaceutical form and the method
of administration desired, from the usual excipients which are known to those
skilled in the art.
In said pharmaceutical compositions for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or
rectal administration, dronedarone, or the salt thereof, can be administered in unit
administration form, as a mixture with conventional pharmaceutical excipients, to
animals and to humans in the cases mentioned above.
The suitable unit administration forms comprise forms for oral administration, such
as tablets, soft or hard gel capsules, powders, granules and oral solutions or
suspensions, sublingual, buccal, intratracheal, intraocular or intranasal
administration forms, forms for administration by inhalation, topical, transdermal,
subcutaneous, intramuscular or intravenous administration forms, rectal
administration forms, and implants. For topical application, dronedarone and
pharmaceutically acceptable salts thereof can be used in creams, gels, ointments
or lotions.
By way of example, a unit administration form of dronedarone or a
pharmaceutically acceptable salt thereof, in tablet form, may correspond to one of
the following compositions (Examples 1 - 4) according to the invention:
EXAMPLE 1
Ingredients mg
Dronedarone hydrochloride (corresponding to 400 mg of 426
base)
Methylhydroxypropylcellulose 2 1. 1
Lactose monohydrate 46.55
Maize starch 45.5
Polyvinylpyrrolidone 65
Poloxamer 407 40
Anhydrous colloidal silica 2.6
Magnesium stearate 3.25
650
EXAMPLE 2
Ingredients mg
Dronedarone hydrochloride (corresponding to 400 mg of 426
base)
Microcrystalline cellulose 65
Anhydrous colloidal silica 2.6
Anhydrous lactose 42.65
Polyvinylpyrrolidone 13
Poloxamer 407 40
Macrogol 6000 57.5
Magnesium stearate 3.25
650
EXAMPLE 3
Ingredients mg
Dronedarone hydrochloride (corresponding to 400 mg of 426
base)
Microcrystalline cellulose 26
Maize starch 45.5
Polyvinylpyrrolidone 65
Poloxamer 407 40
Anhydrous colloidal silica 3.25
Magnesium stearate 3.25
Lactose monohydrate 4 1.65
650
EXAMPLE 4
Ingredients mg
Dronedarone hydrochloride (corresponding to 400 mg of 213
base)
Microcrystalline cellulose 13
Maize starch 22.75
Polyvinylpyrrolidone 32.5
Poloxamer 407 20
Anhydrous colloidal silica 1.3
Magnesium stearate 1.625
Lactose monohydrate 20.825
650
The dose of dronedarone administered per day, orally, may reach 800 mg, taken
in one or more intakes. More specifically, the dose of dronedarone administered
may be taken with food. For example, the dose of dronedarone administered per
day, orally, may reach 800 mg, taken in two intakes with a meal.
The dose of dronedarone administered per day, orally may be taken at a rate of
twice a day (usually abbreviated BID) with a meal for example with the morning
and the evening meal. More specifically, the two intakes may comprise same
quantity of dronedarone.
Advantageously, the dose of dronedarone administered, orally, may reach 400 mg
BID, taken together with a meal, for example with the morning and the evening
meal.
There may be specific cases where higher or lower dosages are appropriate; such
dosages do not depart from the context of the invention. According to the usual
practice, the dosage appropriate for each patient is determined by the physician
according to the method of administration, the weight, the pathology, the body
surface, the cardiac output and the response of said patient.
According to another of its aspects, the present invention also relates to a method
for treating the pathologies indicated above, which comprises the administration,
to a patient, of an effective dose of dronedarone or a pharmaceutically acceptable
salt thereof.
Amiodarone treatment may be stopped directly or the administered dose of
amiodarone may decrease progressively before its discontinuation. More
particularly, this dose of amiodarone may decrease from a loading dose to a
maintenance dose for example from about 600 mg to about 200 mg per day,
orally, taken in one or more intakes.
According to one embodiment, the administered dose of amiodarone is 600 mg
daily for about 1 week, then 400 mg daily for about 1 week, and finally 200 mg
daily for about 2 weeks before discontinuation.
According to another embodiment, the administered dose of amiodarone is a
maintenance dose for example about 200 mg daily. This maintenance dose may
be administrated for a defined period before discontinuation for example at least
two months before discontinuation.
The objectives of the present study is to show the effects of dronedarone start on
patients having a cardiovascular history, indeed said patients being previously
treated with amiodarone and, in particular, the effects of treatment change after a
variable duration of wash-out between the two drugs periods.
Methods: In EURIDIS and ADONIS studies mentioned in the article of the New
England Journal of Medicine , 357, 10, September 6, 12007), 828 and 409
AF/AFL patients were randomized after conversion to SR to dronedarone (400 mg
BID) or placebo for 1 year.
During this study, a subgroup (average age: 63.5 years, 35.7% of women)
of 98 patients treated with dronedarone and 56 patients treated with the placebo
were switched from amiodarone to dronedarone or placebo within 48 hours.
Results: Dronedarone decreased AF/AFL recurrence compared to placebo
(HR=0.64 [95% CI 0.44-0.95], P=0.022) in this subgroup. Rates of adverse events
(abbreviated AEs), specifically bradyarrhythmia, in this subgroup were compared
to 334 patients treated with placebo and 680 patients treated with dronedarone
(average age: 62.8 years; 29.7% of women) with no previous amiodarone use and
a smaller group of 17 and 35 patients (average age: 65.5 years; 30.8% of women)
switched after 48 h of discontinuation. All the results are included in the table 1
below.
TABLE 1
Events A stopped A stopped more No amiodarone
within 2 days than 2 days treatment before
before before randomization
randomization randomization
Drug PI D PI D PI D
Tested population n=56 n=98 n=17 n=35 n= 334 n=680
Deaths (n) 1 1 1 2 2 5
Rate of Serious
adverse events (%) 14.3 15.3 11.8 17.1 16.2 13.7
Bradyarrhythmia(%) 0 1 0 0 0.9 1.3
Rate of Adverse
Events with 3.6 8.2 11.8 20.0 6.3 9.1
dronedarone
discontinuation (%)
0 3.1 0 0 0 0.7
Bradyarrhythmia(%)
PR-interval >or =
200 msec and
increase >or = 20 14.5 25.8 12.5 22.9 12.8 28.0
msec versus
baseline
QTc-Fridericia >or =
500 msec 3.6 7.9 6.7 14.3 0.3 4.4
In the table 1 above, "A" means Amiodarone, "D" means" dronedarone, "PI"
means Placebo, "n" is the number of patients tested with "PI" or "D".
There were slightly more bradyarrhythmic events leading to drug discontinuation
and numerically more QTc-prolongations in switch patients, as expected from the
pharmacodynamic profile of the drugs.
Rate of serious AEs was low and similar across groups with no episodes of
torsades de pointes.
Conclusions: This post hoc analysis of a small patient cohort switched rapidly
from A to D resulted in good tolerability.
Further to these results, another study has been initiated to evaluate the optimal
timing of dronedarone treatment start after conversion with loading dose of
amiodarone in patients with a cardiovascular history, in particular patients with
persistent atrial fibrillation requiring Atrial Fibrillation conversion.
For that, the study primary objectives are to evaluate the rate of AF recurrences
one month after randomization according to different timings of initiation of
dronedarone hydrochloride.
The study design concerns international, prospective, multicenter, open-label
study, randomized in 3 parallel groups according to dronedarone treatment
initiation patterns following a loading dose of amiodarone in patients with
persistent atrial fibrillation requiring AF conversion.
I. PATIENT SELECTION
1.1 . Main inclusion criteria of the patients at screening:
• Male or female,
• Patients with persistent AF for more than 48 hours (documented by an ECG
taken within the last 48 hours) for whom cardioversion, anti-arrhythmic
treatment and anticoagulation treatment are indicated,
• Naive of amiodarone treatment in the last three months prior to screening,
• QTcB < 500 ms on 12-lead ECG,
• Patient with at least one cardiovascular risk factor (i.e. age > 70, hypertension,
diabetes, prior cerebrovascular disease, left atrial diameter ³ 50 mm or left
ventricular ejection fraction [LVEF] < 40%).
1.2. Main inclusion criteria of the patients before randomization:
• Outpatients (only hospitalization of 48h for a planned cardio-version is
allowed),
· Patients in sinus rhythm,
• Patients under effective oral anticoagulation according to ACC/AHA/ESC 2006
guidelines,
• QTcB < 500 ms and PR < 280 ms on 12-lead ECG,
• Patients having received 28 days ± 2 days of amiodarone.
1.3. Main general exclusion criteria at screening (S) and randomization (R):
• Contraindication to oral anticoagulation (S),
• Any documented AF episode motivating inclusion in the study after an acute
condition known to cause AF (S),
· Permanent AF in which cardioversion has failed (S),
• Paroxysmal AF (S),
• Bradycardia < 50 bpm on the 12-lead ECG (S, R),
• Clinically overt congestive heart failure (S, R):
o with New York Heart Association (NYHA) classes III and IV heart
failure,
o or NYHA class I I with a recent decompensation requiring
hospitalization or referral to a specialized heart failure clinic,
o as well as any patients in unstable hemodynamic conditions,
• Previous treatment with class I or class III anti-arrhythmic drugs (including
sotalol) if taken less than one week before screening (S, R) ,
• Previous history of amiodarone intolerance or toxicity (S),
• Any contraindication as per dronedarone and amiodarone labelling (S, R),
• Wolff-Parkinson-White Syndrome (S),
• Previous ablation for atrial fibrillation or any planned ablation in the next 2
months (S).
1.4. Main exclusion criteria related to concomitant medications:
Patients in whom a contraindicated concomitant treatment is mandatory (refer to
protocol body for more details), said treatment including:
o use of potent cytochrome P450 (CYP3A4) inhibitors,
o concomitant use of drugs or herbal products that prolong the QT
interval and known to increase the risk of Torsades de Pointes,
o use of class I or III anti-arrhythmic drugs (including sotalol).
II. DURATION, SCHEDULE AND TREATMENT
II. 1. Duration of study participation:
Patients are screened for a maximum of 10 weeks and a minimum of 5 weeks
prior to randomization. After randomization, patients are treated with dronedarone
for 8, 6 or 4 weeks (according to the duration of the amiodarone discontinuation)
until the end of treatment (EOT)/end of study visit (EOS), visit occurring at Week 8
after randomization.
II.2. Assessment schedule:
Patients have regular visits (V) during:
PHASE I: Screening phase : maximum of 3 visits
• Screening (V1) (up to maximum of Week -10 (Day -70) if no previous
anticoagulation to minimum of Week -5 (Day -35) if patient already under
effective anticoagulation at screening),
• Initiation of amiodarone (V2) (Day -28 ± 2 days),
• Electrical cardioversion (V3) (allowed after 7 days of amiodarone
treatment and up to Day 1 included). This visit is optional and the electrical
cardioversion is only required if the patient is still in AF.
PHASE II: Randomization (V4) (Day 1, maximum of 10 weeks and minimum of 5
weeks after screening). After randomization, start of dronedarone in group A and
start of wash-out periods in groups B and C.
During the randomized phase, there is a maximum of 6 visits per arm after
randomization:
o V5: start of dronedarone
o V6: after 2 days of dronedarone
o V7: after 1 week of dronedarone
o V8: after 2 weeks of dronedarone
o V9: after 4 weeks of dronedarone
V10 = End of treatment visit/end of study visit: after 8, 6 or 4 weeks of
dronedarone according to the duration of amiodarone discontinuation.
PHASE III: Results
Primary Endpoint are assessed at 4 weeks after randomization.
11_3- Treatment:
Patients are randomized in three parallel groups in which the timing of initiation of
dronedarone after the loading regimen of amiodarone differs, namely:
> immediate start of dronedarone in the group A, and
> start after more than 2 days, (i.e. after a 2-week or 4-week wash-out) in
the groups B and C respectively.
Treatment is initiated using tablets containing either 400 mg of dronedarone or
tablets containing 200 mg of amiodarone.
The dose regimen is:
(i) for dronedarone: 400 mg BID, and
(ii) for amiodarone: 600 mg daily for 1 week, 400 mg daily for 1 week and
200 mg daily for 2 weeks.
Another study has been initiated to evaluate the optimal timing of dronedarone
treatment start after discontinuation of amiodarone in patients with a
cardiovascular history, in particular patients with paroxysmal or persistent atrial
fibrillation and wherein said patients have received at least 6 months of
amiodarone.
For that, the study primary objectives are to explore dronedarone and its active
metabolite PK profiles according to different timing of dronedarone initiation and
secondary objectives are to explore potential PK interaction between dronedarone
and amiodarone, to evaluate the rate of AF recurrence one month and two
months after randomization and to assess the safety of the change from
amiodarone to dronedarone and dronedarone safety.
The study design concerns international, prospective, multicenter, open-label study,
randomized in 3 parallel groups according to dronedarone treatment initiation patterns
following long-term regimen of amiodarone in patients with paroxysmal or persistent
atrial fibrillation.
I. PATIENT SELECTION
1.1 . Main inclusion criteria of the patients at screening:
• Male or female,
• Outpatients,
• Patients with paroxysmal or persistent AF having received at least 6 months of
amiodarone before screening with at least the last 2 months at a regimen of
200 mg/day prior screening,
• Requiring a change from amiodarone treatment whatever the reason, but
without major amiodarone-related toxicity (interstitial lung disease, thyroid or
hepatotoxicity).
· QTcB < 500 ms on 12-lead ECG,
• Patient with at least one cardiovascular risk factor (i.e. age > 70, hypertension,
diabetes, prior cerebrovascular disease, left atrial diameter ³ 50 mm or left
ventricular ejection fraction [LVEF] < 40%),
I.2. Main inclusion criteria of the patients before randomization:
• Outpatients (only hospitalization of 48h for a planned cardio-version will be
allowed)
• Patients in sinus rhythm before randomization,
• Patients under effective oral anticoagulation according to ACC/AHA/ESC 2006
guidelines,
• QTcB < 500 ms and PR < 280 ms on 12-lead ECG.
1.3. Main general exclusion criteria at screening (S) and randomization (R):
• Contraindication to oral anticoagulation,
• Any documented AF episode motivating inclusion in the study after an acute
condition known to cause AF,
• Permanent AF in which cardioversion has failed,
• Bradycardia < 50 bpm on the 12-lead ECG before randomization,
• Clinically overt congestive heart failure:
o with New York Heart Association (NYHA) classes III and IV heart
failure,
o or NYHA class I I with a recent decompensation requiring
hospitalization or referral to a specialized heart failure clinic,
o as well as any patients in unstable hemodynamic conditions
• Previous treatment with class I or class III anti-arrhythmic drugs (including
sotalol) if taken less than one week before,
• Previous history of amiodarone intolerance or toxicity,
• History of thyroid dysfunction,
• Any contraindication as per dronedarone labelling,
• Wolff-Parkinson-White Syndrome,
· Previous catheter ablation for atrial fibrillation,
• Catheter ablation scheduled in the next 10 weeks
• Patients previously treated with class I or class III anti-arrhythmic drugs other
than amiodarone if the anti-arrhythmic drug was taken less than one week
before the day of screening (If taken more than one week before screening,
the patient can be included).
1.4. Main exclusion criteria related to concomitant medications:
Patients in whom a contraindicated concomitant treatment is mandatory (refer to
protocol body for more details), said treatment including:
o use of potent cytochrome P450 (CYP3A4) inhibitors,
o concomitant use of drugs or herbal products that prolong the QT
interval and known to increase the risk of Torsades de Pointes,
o use of class I or III anti-arrhythmic drugs (including sotalol).
II. DURATION, SCHEDULE AND TREATMENT
II. 1. Duration of study participation:
Patients can be screened for a maximum of 10 days and a minimum of 3 days
prior to randomization. After randomization, patients will be treated with
dronedarone for 8, 6 or 4 weeks (according to the group) until the end of
treatment (EOT)/end of study visit (EOS) visit occurring at Week 8 after
randomization.
After the last dose of dronedarone, the investigator will be free to continue with
the treatment of his choice.
11.2. Assessment schedule:
Patients have regular visits (V) during:
PHASE I: Screening phase :
• Screening visit (V1): Day-10 to Day-3 before randomization. Patient will
remain on amiodarone at a regimen of 200mg/day until randomization.
• Electrical cardioversion (V2, allowed from screening to Day 1 included).
This visit is optional , and the electrical cardioversion is only required if the
patient is still in A F
PHASE II: Randomization (V3) (Day1 . After randomization, start of dronedarone
in group A and start of washout periods in groups B and C).
During the randomized phase, there is a maximum of 6 visits per arm after
randomization:
o V4: start of dronedarone
o V5: after 2 days of dronedarone
o V6: after 1 week of dronedarone
o V7: after 2 weeks of dronedarone
o V8: after 4 weeks of dronedarone
o V9 = End of treatment visit (EOT)/ end of study visit (EOS): after 8,
6 or 4 weeks of dronedarone according to treatment group
11-3 - Treatment:
Patients are randomized in three parallel groups in which the timing of initiation of
dronedarone after discontinuation of amiodarone treatment differs, namely:
> immediate start of dronedarone in the group A, and
> start after more than 2 days, (i.e. after a 2-week or 4-week wash-out) in
the groups B and C respectively.
Treatment is initiated using tablets containing either 400 mg of dronedarone or
tablets containing 200 mg of amiodarone.
The dose regimen is:
(iii) for dronedarone: 400 mg BID, and
(iv) for amiodarone: 200 mg daily.
CLAIMS
1. Use of dronedarone or a pharmaceutically acceptable salt thereof, for the
preparation of a medicament for use in the prevention and/or treatment of patients
with atrial fibrillation (AF) or atrial Flutter (AFL), shortly after discontinuation of a
previous treatment with amiodarone.
2. Use according to claim 1, for the preparation of a medicament for use in
the prevention and/or treatment of patients with atrial fibrillation (AF) and/or atrial
Flutter (AFL) within a period lower than five elimination half-lives of amiodarone
after said discontinuation.
3. Use according to anyone of the claims 1 or 2, for the preparation of a
medicament for use in the prevention and/or treatment of patients with atrial
fibrillation (AF) and/or atrial Flutter (AFL) shortly, within four weeks after said
discontinuation.
4. Use according to anyone of the claims 1 to 3, for the preparation of a
medicament for use in the prevention and/or treatment of patients with atrial
fibrillation (AF) and/or atrial Flutter (AFL) shortly, within two weeks after said
discontinuation.
5. Use according to anyone of the claims 1 to 4, for the preparation of a
medicament for use in the prevention and/or treatment of patients with atrial
fibrillation (AF) or atrial Flutter (AFL) within two days after said discontinuation.
6. Use according to anyone of the claims 1 to 5, for the preparation of a
medicament for use in the prevention and/or treatment of patients with atrial
fibrillation (AF) and/or atrial Flutter (AFL) within one day after said discontinuation.
7. Use according to anyone of the preceding claims, for the preparation of a
medicament for use in the prevention and/or treatment of patients with persistent
Atrial Fibrillation.
8. Use according to the preceding claim, characterized in that patients with a
persistent Atrial Fibrillation are chosen from patients for whom cardioversion, anti
arrhythmic treatment and anticoagulation treatment are indicated.
9. Use according to anyone of the claims 1 to 6, for the preparation of a
medicament for use in the prevention and/or treatment of patients with
paroxysmal Atrial Fibrillation.
10. Use according to anyone of the claims 1 to 6, for the preparation of a
medicament for use in the prevention and/or treatment of patients with permanent
Atrial Fibrillation .
11. Use according to anyone of the preceding claims, characterized in that
patients have received a previous treatment with amiodarone for at least 28 days
+ or - 2 days before said discontinuation .
12. Use according to anyone of the preceding claims, characterized in that
patients have received a previous treatment with amiodarone for at least 2 months
before said discontinuation .
13. Use according to anyone of the preceding claims, characterized in that
patients have received a previous treatment with amiodarone for at least 6 months
before said discontinuation .
14. Use according to anyone of the preceding claims, characterized in that the
dose of dronedarone administered orally, is 400 mg BID.
15. Use according to anyone of the preceding claims, characterized in that the
administered dose of amiodarone decreases progressively before its
discontinuation .
16. Use according to the preceding claim, characterized in that the administered
dose of amiodarone decreases from a loading dose to a maintenance dose.
17. Use according to anyone of the preceding claims 15 or 16, characterized in
that the dose of amiodarone administered is about 600 mg to about 200 mg per
day, orally, taken in one or more intakes.
18. Use according to anyone of the preceding claims, characterized in that the
dose of amiodarone administered is 200 mg daily for at least two months before
discontinuation.
19. Use according to anyone of the preceding claims, characterized in that
patients also exhibit at least one additional cardiovascular risk factor chosen from:
age equal to or above 70, or even above 75,
hypertension,
diabetes,
prior cerebrovascular disease,
left atrial diameter greater than or equal to 50 mm measured by
echocardiography, and
left ventricular ejection fraction less than 40%, measured by twodimensional
echography.
20. Use according to anyone of the preceding claims, characterized in that
patients also exhibit at least one pathologies chosen from :
Structural heart disease,
Lone Atrial Fibrillation,
Coronary heart disease, and
Dilated cardiomyopathy,
and/or at least one cardiac device chosen from:
Pacemaker, and
Valvular heart.
2 1. Use according to anyone of the preceding claims, characterized in that
patients also take in at least a baseline medication chosen from:
oral anticoagulant,
Beta blocking agents,
Angiotensin I converting enzyme or Angiotensin I I receptor blocker,
Chronic antiplatelet therapy,
- Diuretics,
Statins,
Digitalis,
- Moderate inhibitors of CYP3A4,
Nonsteroidal anti-inflammatory drugs.