^ ^ ^ ^ I ^ ^ ^ ^ II ^ II ^ ^ ^ ^ ^ II ^ ^ ^ ^ ^ ^ ^ ^ ^ I ^ � European Patent Office Office europeen des brevets EP 0 965 341 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) |nt C|.6: A61 K 31/44 22.12.1999 Bulletin 1999/51 // (A61 K3i/44> 3-| ;-|8) (21) Application number: 99303489.1 (22) Date of filing: 04.05.1999 (84) Designated Contracting States: (72) Inventors: AT BE CH CY DE DK ES Fl FR GB GR IE IT LI LU • Friedrich, Tilman MC NL PT SE Groton Long Point 06340, Connecticut (US) Designated Extension States: • Billing, Clare B., Jr. AL LT LV MK RO SI Mystic 06355, Connecticut (US) • Falk, Rodney H. (30) Priority: 14.05.1998 US 85496 P Newton 02159, Massachusetts (US) (71) Applicants: (74) Representative: Baillie, lain Cameron • Pfizer Products Inc. Ladas & Parry, Groton, Connecticut 06340 (US) Dachauerstrasse 37 • BOSTON UNIVERSITY 80335 Miinchen (DE) Boston, MA 02215 (US) (54) Combination of dofetilide and a calcium channel blocker (57) Pharmaceutical compositions and methods compositions and methods are useful for the treatment comprising dofetilide and calcium channel blockers. The of arrhythmias. CM < CO lO CO O) o a. LU Printed by Jouve, 75001 PARIS (FR) EP 0 965 341 A2 Description BACKGROUND OF INVENTION 5 [0001] This invention relates to pharmaceutical combination of dofetilide and a calcium channel blocker, kits con- taining such combinations and the use of such combinations to treat atrial fibrillation in mammals. [0002] Dofetilide is a selective inhibitor of the rapid component of the delayed rectifier potassium current which pro- longs the action potential duration and the effective refractory period in a concentration dependent manner. Clinical studies have demonstrated that dofetilide is effective in treating patients with atrial as well as ventricular arrhythmias. 10 Specifically, for example, dofetilide has been studied in patients with severe left ventricular dysfunction (William M. Bailey et al., Electrophysiologic and Hemodynamic Effects of Dofetilide in Patients with Severe Left Ventricular Dys- function, Circulation, 1 992, Vol. 86, Part 4, Supplement 1 , page 1 265) in which it was found that, unlike class I agents, dofetilide is safe in patients with congestive heart failure. [0003] Studies have shown that episodes of atrial fibrillation result in acute shortening of the atrial refractory period. is This is known as "electrical remodeling" of the atrium and is reversible after conversion to sinus rhythm. Prior to com- plete reversal of the decreased refractory period, the atrium has increased vulnerability for relapse to atrial fibrillation. However, Tieleman et al., in A Clinical Illustration of Reduction of Electrical Remodeling by the use of Intracellular Calcium Lowering Drugs During AF, NASPE Abstract, Pace, Vol. 20, page 1142, No. 368, April 1997 concluded "[p] atients using intracellular calcium lowering drugs during AF seem to experience a lower incidence of relapse of AF 20 after cardioversion. This could be explained by a reduction of electrical remodeling of the atria by prevention of intra- cellular calcium overload during AF." In addition, Daoud et al., in Circulation, vol. 96, No. 5, Sept. 1997 "Effect of Ver- apamil and Procainamide on Atrial Fibrillation-Induced Electrical Remodeling in Humans" concluded "pretreatment with the calcium channel antagonist verapamil, but not the sodium channel antagonist procainamide, markedly atten- uates acute, AF-induced changes in atrial electrophysiological properties. These data suggest that calcium loading 25 during AF may be at least partially responsible for AF-induced electrical remodeling." [0004] Amlodipine is a calcium channel blocker that has seen widespread acceptance. It is approved for the treatment of hypertension. Further, U.S. Pat. No. 5,155,120 discloses its use for the treatment of congestive heart failure. [0005] Although there are some therapies for the treatment of atrial fibrillation there is a continuing search in this field of art for new therapies. 30 SUMMARY OF THE INVENTION [0006] This invention is directed to pharmaceutical compositions comprising dofetilide or a pharmaceutical^ accept- able salt thereof and a calcium channel blocker and for the use of such compositions for the treatment of arrhythmia, 35 including atrial fibrillation, in mammals (e.g., humans either male or female). [0007] The combinations comprise therapeutically effective amounts of dofetilide and a calcium channel blocker. [0008] Another aspect of this invention is a method for treating arrhythmias in a mammal comprising administering to a mammal in need of treatment thereof therapeutically effective amounts of 40 a. dofetilide; and b. a calcium channel blocker. [0009] A preferred method is wherein atrial fibrillation is treated. [0010] It is especially preferred that maintenance of normal sinus rhythm is improved. A particularly preferred method 45 is the inhibition of electrical remodeling of the atrium prior to conversion to sinus rhythm. [0011] A particularly preferred mammal is a female or male human. [0012] It is particularly preferred that the human patient has sustained atrial fibrillation. [0013] Another preferred aspect of this method is wherein the calcium channel blocker is administered prior to ad- ministering dofetilide. so [0014] In another aspect of this method the above sequential administration is followed by substantially simultaneous administration of the calcium channel blocker and dofetilide. [0015] Another aspect of this invention is a kit comprising: a. a therapeutically effective amount of dofetilide and a pharmaceutical^ acceptable carrier in a first unit dosage 55 form; b. a therapeutically effective amount of a calcium channel blocker and a pharmaceutical^ acceptable carrier in a second unit dosage form; and c. means for containing said first and second dosage forms. 2 EP 0 965 341 A2 [0016] Another aspect of this invention is a synergistic pharmaceutical composition for improving the maintenance of normal sinus rhythm in a mammal comprising a. dofetilide; and 5 b. a calcium channel blocker, wherein the amount of dofetilide alone and the amount of the calcium channel blocker alone is insufficient to achieve the improved maintenance of normal sinus rhythm if administered alone and wherein the combined effect of the amount of dofetilide and the calcium channel blocker is greater than the sum of the sinus rhythm maintenance 10 effects achievable with individual amounts of the dofetilide and calcium channel blocker; and c. a pharmaceutical^ acceptable diluent or carrier. [0017] Yet another aspect of this invention is a synergistic method for improving the maintenance of normal sinus is rhythm in a mammal comprising administering to such a mammal a. an amount dofetilide; and b. an amount of a calcium channel blocker 20 wherein the amount of dofetilide alone and the amount of the calcium channel blocker alone is insufficient to achieve the improved maintenance of normal sinus rhythm if administered alone and wherein the combined effect of the amount of dofetilide and the calcium channel blocker is greater than the sum of the sinus rhythm maintenance effects achievable with individual amounts of the dofetilide and calcium channel blocker. [0018] In each of the above compositions, methods and kits, a preferred amount of dofetilide is about 0.1 mcg/kg/ 25 day to about 30 mcg/kg/day and an especially preferred amount of dofetilide is about 1 mcg/kg/day to about 15 meg/ kg/day. [0019] In each of the above compositions, methods and kits, a preferred amount of calcium channel blocker is about 0.001 mg/kg/day to about 10 mg/kg/day and an especially preferred amount of calcium channel blocker is about 0.01 mg/kg/day to about 5 mg/kg/day. 30 [0020] In each of the above compositions, methods and kits, especially preferred calcium channel blockers are am- lodipine, nifedipine, isradipine, diltiazem or verapamil or a pharmaceutical^ acceptable salt thereof. [0021] In each of the above compositions, methods and kits, especially preferred calcium channel blockers are am- lodipine, nifedipine or isradipine or a pharmaceutical^ acceptable salt thereof. [0022] In each of the above compositions, methods and kits, an especially preferred calcium channel blocker is 35 amlodipine or a pharmaceutical^ acceptable salt thereof, particularly the besylate salt thereof. [0023] Another aspect of this invention is a method for treating arrhythmias in a mammal comprising administering to a mammal in need of treatment thereof a therapeutically effective amount of amlodipine or a pharmaceutical^ ac- ceptable salt thereof, particularly the besylate salt thereof. [0024] A preferred method is wherein atrial fibrillation is treated. 40 [0025] It is especially preferred that maintenance of normal sinus rhythm is improved. [0026] A particularly preferred method is the inhibition of electrical remodeling of the atrium prior to conversion to sinus rhythm. [0027] A particularly preferred mammal is a female or male human. [0028] A preferred amount of amlodipine is about 0.001 mg/kg/day to about 1 0 mg/kg/day and an especially preferred 45 amount of calcium channel blocker is about 0.01 mg/kg/day to about 5 mg/kg/day. [0029] This invention makes a significant contribution to the field of anti-arrhythmic agents by a new treatment reg- imen: pretreatment of atrial fibrillation patients with an appropriate calcium channel blocker prior to cardioversion (phar- macological or electrical) improves maintenance of sinus rhythm in conjunction with administration