PHARMACEUTICAL COMPOSITIONS
This invention relates to the use of low doses of (+)-α-dihydrotetrabenazine for the treatment of movement disorders, such as Tourette's syndrome.
1 . A method of treating a movement disorder in a subject in need thereof, which treatment comprises the steps of:
(a) administering to the subject an initial daily dosage of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof, wherein the initial daily dosage is an amount of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 5 mg of (+)-α-dihydrotetrabenazine free base;
(b) carrying out a clinical evaluation of the subject for efficacy and side effects arising from the treatment;
(c) where the clinical evaluation (b) has established that an increased daily dosage of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof is desirable, administering an increased daily dosage which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 5 mg of (+)-α-dihydrotetrabenazine free base; or, where the clinical evaluation has established that an increased daily dosage is not desirable, either maintaining the initial daily dosage, reducing the dosage, or discontinuing the treatment;
(d) where an increased daily dosage has been administered, carrying out a further clinical evaluation of the subject for efficacy and side effects arising from the treatment with the increased daily dosage;
(e) where the further clinical evaluation (d) has established that a further increased daily dosage of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof is desirable, administering a further increased daily dosage which is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 5 mg of (+)-α-dihydrotetrabenazine free base; or, where the clinical evaluation has established that a further increased daily dosage is not desirable, maintaining the immediately preceding daily dosage, reducing the immediately preceding dosage or discontinuing the treatment; and
(f) optionally repeating steps (d) and (e) as often as desired until an optimum daily dosage is reached.
2 . A method according to claim 1 wherein the initial daily dosage of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof, is an amount corresponding to from 0.5 mg to 3 mg of (+)-α-dihydrotetrabenazine free base.
3 . A method according to claim 2 wherein the initial daily dosage of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof, is an amount corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)-α-dihydrotetrabenazine free base.
4 . A method according to claim 1 wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 3 mg of (+)-α-dihydrotetrabenazine free base.
5 . A method according to claim 4 wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)-α-dihydrotetrabenazine free base.
6 . A method according to claim 1 wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to from 0.5 mg to 3 mg of (+)-α-dihydrotetrabenazine free base.
7 . A method according to claim 6 wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)-α-dihydrotetrabenazine free base.
8 . A method according to claim 1 wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof, which is an amount corresponding to no greater than 20 mg of (+)-α-dihydrotetrabenazine free base.
9 . A method according to claim 8 wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof, which is an amount corresponding to no greater than 10 mg of (+)-α-dihydrotetrabenazine free base.
10 . A method according to claim 1 wherein the treatment comprises determining an approximate weight of the subject and:
(i) when the subject has a weight of 30 kg to 50 kg, administering a maximum (e.g. optimized) daily amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 2 mg to 7.5 mg of (+)-α-dihydrotetrabenazine free base;
(ii) when the subject has a weight of 50 kg to 75 kg, administering a maximum (e.g. optimized) daily amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 5 mg to 10 mg of (+)-α-dihydrotetrabenazine free base;
(iii) when the subject has a weight of 75 kg to 95 kg, administering a maximum (e.g. optimized) daily amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 7.5 mg to 15 mg of (+)-α-dihydrotetrabenazine free base; or
(iv) when the subject has a weight of greater than 95 kg, administering a maximum (e.g. optimized) daily amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 15 mg to 20 mg of (+)-α-dihydrotetrabenazine free base the amount of (+)-α-dihydrotetrabenazine administered per day is from 15 mg to 20 mg.
11 . A method of treating a movement disorder in a subject in need thereof, which treatment comprises administering to the subject an effective amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof, wherein the said effective amount corresponds to an amount of (+)-α-dihydrotetrabenazine free base of from 0.05 mg/kg to 0.3 mg/kg per day.
12 . A method according to claim 1 wherein the daily dosage, daily amount or effective amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof administered to the subject is sufficient to cause a level of blocking of between 50% and 85% of VMAT2 proteins in the subject.
13 . A method according to claim 11 wherein the daily dosage, daily amount or effective amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof administered to the subject is sufficient to cause a level of blocking of between 50% and 85% of VMAT2 proteins in the subject.
14 . A method according to claim 1 wherein the movement disorder is selected from tardive dyskinesia, Tourette's syndrome and Huntington's disease.
15 . A method according to claim 14 wherein the movement disorder is Tourette's Syndrome.
16 . A method according to claim 14 wherein the movement disorder is Huntington's Disease.
17 . A method according to claim 1 wherein the (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof is administered to the subject once per day.
18 . A method according to claim 1 wherein the (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof is not administered in combination with a therapeutically effective amount of amantadine.
19 . A method according to claim 1 wherein the subject is a human subject from 5 years old to 16 years old, having a weight of 80 kg or less, for example a weight in the range from 17 kg to 70 kg.
20 . A unit dosage form comprising from 0.5 mg to 3 mg of (+)-α-dihydrotetrabenazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.