USE OF DRONEDARONE FOR THE PREPARATION OF A MEDICAMENT FOR USE IN THE PREVENTION OF CARDIOVASCULAR HOSPITALIZATION OR OF MORTALITY

• US 20100048694A1
• Filed: 04/16/2009
• Published: 02/25/2010
• Est. Priority Date: 04/17/2008
• Status: Active Grant

• Current Assignee: Sanofi
• Original Assignee: Sanofi-Aventis (Sanofi )
• Inventors: RADZIK, David, HAMDANI, Nacera, GAUDIN, Christophe, VAN EICKELS, Martin
• Granted Patent: US 8,410,167 B2
• Time in Patent Office: Days
• US Class Current: 514/469
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Methods of using dronedarone or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in the prevention of cardiovascular hospitalization or of mortality, articles of manufacture and packages related thereto.

Claims

1. A method of decreasing the risk of mortality, cardiac hospitalizations, or the combination thereof in a patient, said method comprising administering to said patient an effective amount of dronedarone or a pharmaceutically acceptable salt thereof, with food.

2. The method according to claim 1 wherein said patient has a history of or current atrial fibrillation or flutter.

4. The method according to claim 1, wherein said patient has a history of or a current, non permanent atrial fibrillation or atrial flutter.

6. The method according to claim 1, wherein said patient has a recent history of or a current paroxysmal or persistent atrial fibrillation or atrial flutter.

8. The method according to any one of claims 1, 2 and 3 wherein the administration of dronedarone or pharmaceutically acceptable salt thereof prevents cardiovascular hospitalizations.

9. The method according to claim 1 wherein the mortality is a cardiovascular mortality.

10. The method according to claim 1 wherein the mortality is a sudden death.

11. The method according to claim 1 wherein said patient has a permanent atrial fibrillation or atrial flutter.

13. The method according to claim 1, claim 2 or claim 3 wherein said patient has structural heart disease.

14. The method according to claim 1, claim 2 or claim 3 wherein said patient has congestive heart failure in a stable hemodynamic condition.

15. The method according to claim 14 wherein said congestive heart failure is defined as NYHA class III in a stable hemodynamic condition.

16. The method according to claim 14 wherein said congestive heart failure is defined by a reduced left ventricular ejection fraction below 0.35 in a stable hemodynamic condition.

19. The method according to any one of claims 1, 2, 3, 17 and 18 wherein said patient further receives a diuretic-based treatment.

20. The method according to claim 19 wherein said diuretic is a non-potassium-sparing diuretic.

21. The method according to claims 1, 2, 3, 17 or 18 wherein the patient also exhibits associated risk factors.

22. The method according to claims 1, 2, 3, 17 or 18 wherein the patient also exhibits at least one risk factor selected from the group consisting of:

age,

diabetes,

history of cerebral stroke or of systemic embolism,

left atrial diameter greater than or equal to 50 mm measured by echocardiography, and

left ventricular ejection fraction less than 40%, measured by two-dimensional echography.

23. The method according to claims 1, 2, 3, 17 or 18 wherein the patient also exhibits at least one risk factor selected from the group consisting of:

hypertension,

underlying structural heart disease,

tachycardia,

coronary disease,

non-rheumatic heart valve disease,

dilated cardiomyopathy of ischemic origin,

catheter ablation of atrial fibrillation or flutter,

supraventricular tachycardia other than atrial fibrillation or flutter,

history of valve surgery,

non-ischemic dilated cardiomyopathy,

hypertrophic cardiomyopathy,

rheumatic valve disease,

sustained ventricular tachycardia,

congenital cardiopathy,

catheter ablation for tachycardia other than for atrial fibrillation or flutter, and

ventricular fibrillation,

and/or at least one cardiac device chosen from;

a cardiac stimulator, and

an implantable defibrillator (“

ICD”

).

24. The method according to any one of claims 1, 2, 3, 17 and 18 wherein the dose of dronedarone administered per day, orally, is less than or equal 800 mg, measured in base form, and taken in one or more intakes.

3. A method of regulating the potassium level in the blood of a patient having a history of or current atrial fibrillation or atrial flutter, said method comprising administering to said patient dronedarone or a pharmaceutically acceptable salt thereof, with food.

5. The method according to claim 3, wherein said patient has a history of or a current, non permanent atrial fibrillation or atrial flutter.

7. The method according to claim 3, wherein said patient has a recent history of or a current paroxysmal or persistent atrial fibrillation or atrial flutter.

12. The method according to claim 3 wherein said patient has a permanent atrial fibrillation or atrial flutter.

17. A method of preventing the worsening or development of congestive heart failure in a patient with a history of or current atrial fibrillation or atrial flutter, said method comprising administrating to said patient a therapeutically effective amount of dronedarone or a pharmaceutically acceptable salt thereof.

18. A method of preventing coronary disease in a patient with a history of or current atrial fibrillation or atrial flutter, said method comprising administrating to said patient a therapeutically effective amount of dronedarone or a pharmaceutically acceptable salt thereof.

25. A method of treating a patient with a recent history of or current atrial fibrillation or flutter, said method comprising administrating to said patient a therapeutically effective amount of dronedarone, or a pharmaceutically acceptable salt thereof, wherein said patient does not have severe heart failure.

26. The method according to claim 25 wherein said severe heart disease is indicated by one or more selected from the group consisting of:

a) history of, or current symptoms of congestive heart failure at rest;

b) symptoms of heart failure with minimal exertion within the last month;

c) hospitalization for heart failure within the last month;

d) NYHA Class IV;

e) NYHA Class III within the last month;

f) recent decompensation as indicated by the need for hospitalization or intravenous therapy; and

g) recent decompensation requiring hospitalization or intravenous therapy for the treatment of heart failure.

27. A method of decreasing the risk of cardiovascular hospitalizations or mortality in a patient having a history of atrial fibrillation or atrial flutter, said method comprising administering dronedarone, or a pharmaceutically acceptable salt thereof, twice a day with a meal to a patient in need thereof, wherein said patient does not have severe heart failure.

28. A method of promoting the use of dronedarone or a pharmaceutically acceptable salt thereof, the method comprising the step of conveying to a recipient at least one message selected from the group consisting of:

a) a primary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was the time to first hospitalization for cardiovascular reasons or death from any cause;

b) a secondary endpoint of a study of dronedarone, or pharmaceutically acceptable salt thereof, was death from any cause;

c) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to death from any cause;

d) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to cardiovascular death;

e) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for cardiovascular reasons;

f) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for atrial fibrillation and other supraventricular rhythm disorders;

g) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for worsening heart failure;

h) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for myocardial infarction;

i) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for myocardial infarction;

j) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for transient ischemic event or cerebral stroke; and

k) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to sudden death.

30. The method according to claim 28 or 29, wherein the message is provided in a label or package insert.

29. A method of promoting the use of dronedarone or a pharmaceutically acceptable salt thereof, the method comprising the step of conveying to a recipient at least one message selected from the group consisting of:

a. dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by about 24 percent;

b. dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2 percent;

c. dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2 percent, driven by a reduction in cardiovascular hospitalization;

d. the total duration of hospitalization was lower with dronedarone when compared to placebo;

e. patients with NYHA Class III heart failure at baseline showed a reduction in cardiovascular hospitalization or death; and

f. the risk of hospitalization for heart failure was less in the dronedarone group, or a pharmaceutically acceptable salt thereof, when compared to the placebo group.

31. A method of providing dronedarone or a pharmaceutically acceptable salt thereof, wherein said dronedarone or pharmaceutically acceptable salt thereof is provided along with information indicating that dronedarone or pharmaceutically acceptable salt thereof is indicated in patients with a recent history of or current atrial fibrillation or flutter and without severe heart failure.

32. The method according to claim 31 wherein the information indicates that the atrial fibrillation or flutter is non-permanent.

33. The method according to claim 31 wherein the information indicates that the atrial fibrillation or flutter is associated with at least one risk factor.

34. The method according to any one of claims 31 to 33 wherein the information indicates that severe heart failure is indicated by one or more of the following:

a) a history of, or current symptoms of congestive heart failure;

b) symptoms of heart failure with minimal exertion within the last month;

c) hospitalization of the patient for heart failure within the last month;

d) hospitalization of the patient for NYHA Class IV heart failure;

e) hospitalization of the patient for NYHA Class III heart failure within the last month; and

f) hospitalization of the patient for heart failure with recent decompensation as indicated by the need for hospitalization or intravenous therapy.

35. The method according to claim 31 wherein the information comprises printed matter that advises that dronedarone or a pharmaceutically acceptable salt thereof is indicated in patients with either a recent history of or current atrial fibrillation or flutter with associated risk factors and without severe heart failure.

36. The method according to claim 35 wherein said printed matter is a label.

37. A method of promoting the use of dronedarone or a pharmaceutically acceptable salt thereof, the method comprising the step of conveying to a recipient at least one message selected from the group consisting of:

(a) dronedarone or a pharmaceutically acceptable salt thereof should be prescribed to a patient who has not been diagnosed with severe heart failure;

(b) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with a history of, or current symptoms of congestive heart failure;

(c) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure;

(d) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with symptoms of heart failure with minimal exertion within the last month;

(e) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients who were hospitalized for heart failure within the last month;

(f) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients who were hospitalized for NYHA Class IV heart failure;

(g) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients who were hospitalized for NYHA Class III heart failure within the last month;

(h) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients who were hospitalized for heart failure with recent decompensation as indicated by the need for hospitalization or intravenous therapy; and

(i) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients who were hospitalized for heart failure with recent decompensation requiring hospitalization or intravenous therapy for the treatment of heart failure.

38. An article of manufacture comprising

a) a packaging material;

b) dronedarone or a pharmaceutically acceptable salt thereof; and

c) a label or package insert contained within the packaging material indicating that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure.

39. The article according to claim 38 wherein the packaging material indicates that that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by one or more of the following:

a) a history of, or current symptoms of congestive heart failure;

b) symptoms of heart failure with minimal exertion within the last month;

c) hospitalization of the patient for heart failure within the last month;

d) hospitalization of the patient for NYHA Class IV heart failure;

e) hospitalization of the patient for NYHA Class III heart failure within the last month;

f) hospitalization of the patient for heart failure with recent decompensation as indicated by the need for hospitalization or intravenous therapy; and

g) hospitalization of the patient for heart failure with recent decompensation requiring hospitalization or intravenous therapy for the treatment of heart failure.

40. The article according to claim 38 wherein the packaging material indicates that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by hospitalization of the patient for NYHA Class IV heart failure.

41. The article according to claim 38 wherein the packaging material indicates that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by hospitalization of the patient for NYHA Class III heart failure within the last month.

42. A package comprising dronedarone or a pharmaceutically acceptable salt thereof and a label, said label comprising a printed statement which informs a prospective user that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure.

43. The package according to claim 42 wherein the printed statement informs a prospective user of one or more of the following:

a) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by a history of, or current symptoms of congestive heart failure;

b) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by symptoms of heart failure with minimal exertion within the last month;

c) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by hospitalization for heart failure within the last month;

d) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by NYHA Class IV;

e) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by NYHA Class III within the last month;

f) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by recent decompensation as indicated by the need for hospitalization or intravenous therapy; and

g) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients who were hospitalized for heart failure with recent decompensation requiring hospitalization or intravenous therapy for the treatment of heart failure.

44. A package comprising dronedarone or a pharmaceutically acceptable salt thereof and a label, said label comprising at least one message selected from the group consisting of:

a) a primary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was the time to first hospitalization for cardiovascular reasons or death from any cause;

b) a secondary endpoint of a study of dronedarone, or pharmaceutically acceptable salt thereof, was death from any cause;

c) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to death from any cause;

d) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to cardiovascular death;

e) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for cardiovascular reasons;

f) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for atrial fibrillation and other supraventricular rhythm disorders;

g) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for worsening heart failure;

h) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for myocardial infarction;

i) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for myocardial infarction;

j) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for transient ischemic event or cerebral stroke; and

k) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to sudden death.

45. A package comprising dronedarone or a pharmaceutically acceptable salt thereof and a label, said label comprising at least one message selected from the group consisting of:

a) dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by about 24 percent;

b) dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2 percent;

c) dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2 percent, driven by a reduction in cardiovascular hospitalization;

d) the total duration of hospitalization was lower with dronedarone when compared to placebo;

e) patients with NYHA Class III heart failure at baseline showed a reduction in cardiovascular hospitalization or death; and

f) the risk of hospitalization for heart failure was less in the dronedarone group, or a pharmaceutically acceptable salt thereof, when compared to the placebo group.

46. A method of transforming a patient with a recent history of or current atrial fibrillation or flutter by decreasing the patient'"'"'s risk of cardiovascular hospitalizations or mortality, comprising administrating to said patient a therapeutically effective amount of dronedarone, or a pharmaceutically acceptable salt thereof, wherein said patient does not have severe heart failure.