Dosing regimen for sedation with CNS 7056 (Remimazolam)

1. A method of sedating a subject comprising administering to the subject an initial dose of the besylate salt of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]-propionic methyl ester (CNS 7056) of formula (I)

wherein the initial dose is a fixed dose of between about 2 mg and about 10 mg and is irrespective of the body weight of the subject, in combination with one or more doses of an opioid.

2. The method of claim 1 , wherein the initial fixed dose of the besylate salt of the compound of formula (I) is selected from the group consisting of between about 3 mg and about 10 mg; between about 3 mg and about 9 mg; and between about 5 mg and about 8 mg.

3. The method of claim 1 , further comprising administering to the subject one or more subsequent doses of the besylate salt of the compound of formula (I), wherein the one or more subsequence doses are fixed doses, are irrespective of body weight, and are selected from the group consisting of between about 1 mg and about 4 mg; between about 1.5 mg and about 3.5 mg; and between about 2 mg and about 3 mg.

4. The method of claim 3 , wherein the initial fixed dose and the one or more subsequent fixed doses of the besylate salt of the compound of formula (I) administered to the subject are selected from the group consisting of:

a) about 8 mg of an initial fixed dose and about 3 mg of a subsequent fixed dose,

b) about 7 mg of an initial fixed dose and about 2 mg of a subsequent fixed dose, and

c) about 5 mg of an initial fixed dose and about 3 mg of a subsequent fixed dose.

5. The method of claim 3 , wherein the one or more subsequent fixed doses of the besylate salt of the compound of formula (I) is administered to the subject not earlier than 2 minutes from the time the initial fixed dose is administered to the subject.

6. The method of claim 3 , wherein not more than six subsequent fixed doses of the besylate salt of the compound of formula (I) are administered to the subject.

7. The method of claim 1 , wherein the opioid is selected from the group consisting of morphine, codeine, thebain, papaverin, narcotine, heroin, hydromorphone, dihydrocodeine, thebacon, hydrocodone, oxymorphone, oxycodone, ketobemidone, pethidine, anileridine, piminodine, phenoperidine, furethidine, [alpha]-prodin, trimeperidine, meptazinol, profadol, methadone, dextromoramide, levomethadyl acetate, phenadoxone, dipipanone, themalon, dextropropoxyphene, N-methylmorphinan, levorphanol, dextrometorphane, butorphanol, pentazocine, phenazocine, ketocyclazocine, bremazocine, sufentanil, carfentanil, fentanyl, lofentanil, alfentanil, ohmefentanil, remifentanil, pitramide, benztriamide, diphenoxylate, loperamide, tramadol, tilidine, U-50488, 1-Benzyl-4-(4-bromo-phenyl)-4-dimethylaminocyclohexanol, alfentanil, buprenorphine, butorphanol, codeine, dextromoramide, dextropropoxyphene, dezocine, diamorphine, dihydrocodeine, diphenoxylate, ethylmorphine, etorphine, hydrocodone, hydromorphone, ketobemidone, levomethadone, levomethadyl-acetate, levorphanol, meptazinol, morphine, nalbuphine, nalorphine, oxycodone, oxymorphone, pentazocine, pethidine, piritramide, remifentanil, sufentanil, tilidine, tramadol, tapentadol, Met-enkephalin, Leu-enkephalin, nociceptin, [beta]-endorphin, endomorphin-1, endomorphin-2, metorphamid, dynorphin-A, dynorphin-B and [alpha]-neoendorphin, or a pharmaceutically acceptable salt thereof.

8. The method of claim 2 , wherein the opioid is fentanyl, or a pharmaceutically acceptable salt thereof.

9. The method of claim 7 , wherein the opioid is selected from the group consisting of fentanyl, alfentanil, carfentanil, lofentanil, remifentanil, sufentanil, thiofentanyl, α-methylthiofentanyl, α-methylacetylfentanyl, α-methylfentanyl, ohmefentanyl, β-hydroxy-fentanyl, parafluorfentanyl, and 3-methylfentanyl, or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the opioid is fentanyl or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein the one or more doses of fentanyl, or a pharmaceutically acceptable salt thereof, is administered to the subject at a fixed dose of between about 50 mcg and about 200 mcg.

12. The method of claim 10 , wherein the one or more doses of fentanyl, or a pharmaceutically acceptable salt thereof, is administered to the subject before the initial fixed dose of the besylate salt of the compound of formula (I) is administered to the subject.

13. The method of claim 12 , wherein the one or more doses of fentanyl, or a pharmaceutically acceptable salt thereof, is administered to the subject within at least 1 minute, 2 minutes, 5 minutes or 10 minutes prior to the administration of the initial fixed dose of the besylate salt of the compound of formula (I) to the subject.

14. The method of claim 11 , wherein a first dose of fentanyl, or a pharmaceutically acceptable salt thereof, is administered to the subject at a fixed dose of between about 50 mcg and about 200 mcg, and a second dose of fentanyl, or a pharmaceutically acceptable salt thereof, is administered to the subject at a fixed dose of between about 10 mcg and about 50 mcg.

15. The method of claim 14 , wherein the second dose of fentanyl, or a pharmaceutically acceptable salt thereof, is administered to the subject no earlier than 5 minutes after the time the first dose of fentanyl, or a pharmaceutically acceptable salt thereof, is administered to the subject.

16. The method of claim 15 , wherein the second dose of fentanyl, or a pharmaceutically acceptable salt thereof, administered to the subject does not exceed 200 mcg of fentanyl or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein sedation of the subject is for the purpose of preoperative sedation, amnestic use for perioperative events, or conscious sedation during diagnostic, operative or endoscopic procedures.

18. The method of claim 1 , wherein sedation of the subject is for the purpose of operative or endoscopic procedures.

19. The method of claim 1 , wherein a mild to deep sedation of the subject is produced.

20. The method of claim 1 , wherein the subject exhibits a sedation having a MOAA/S score selected from the group consisting of equal to or below 4; from 1 to 4; from 2 to 4; and from 3 to 4.

21. The method of claim 18 , wherein the operative or endoscopic procedures is endoscopy or colonoscopy.

22. The method of claim 1 , wherein the besylate salt of the compound of formula (I) is administered intravenously.

23. A method of sedating a subject comprising administering to the subject one or more doses of fentanyl, or a pharmaceutically acceptable salt thereof, in combination with an initial dose of the besylate salt of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]-propionic methyl ester (CNS 7056) of formula (I)

wherein:

a) a first dose of fentanyl, or pharmaceutically acceptable salt thereof, is administered to the subject at a dose of between about 50 mcg and about 200 mcg no earlier than 10 minutes before the initial dose of the besylate salt of the compound of formula (I); and

b) the initial dose of the besylate salt of the compound of formula (I) is administered to the subject at a fixed dose of between about 5 mg and 8 mg, and is irrespective of the body weight of the subject.

24. The method of claim 23 , wherein the initial fixed dose of the besylate salt of the compound of formula (I) is 5 mg.

25. The method of claim 23 , wherein the first dose of fentanyl, or pharmaceutically acceptable salt thereof, is administered to the subject within 5 minutes prior to administration of the initial fixed dose of the besylate salt of the compound of formula (I) to the subject.

26. The method of claim 23 , wherein a second dose of the fentanyl, or pharmaceutically acceptable salt thereof, is administered to the subject at a dose of between about 10 mcg and about 75 mcg no earlier than 5 minutes after the time the first dose of fentanyl, or pharmaceutically acceptable salt thereof, is administered to the subject.

27. The method of claim 23 , further comprising administering to the subject one or more subsequent fixed doses of the besylate salt of the compound of formula (I) at a dose of between about 2 mg and about 3 mg no earlier than 2 minutes from the time the initial dose or previous subsequent dose of the besylate salt of the compound of formula (I) is administered to the subject, and wherein the one or more subsequent doses are fixed doses and are irrespective of the body weight of the subject.

28. The method of claim 27 , wherein the initial dose and a subsequent dose of the besylate salt of the compound of formula (I) administered to the subject are selected from the group consisting of:

a. an initial fixed dose of about 8 mg and a subsequent fixed dose of about 3 mg;

b. an initial fixed dose of about 7 mg and a subsequent fixed dose of about 2 mg; and

c) an initial fixed dose of about 5 mg and a subsequent fixed dose of about 3 mg.

29. A method of sedating a subject comprising administering to the subject an initial dose and one to three subsequent doses of the besylate salt of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]-propionic methyl ester (CNS 7056) of formula (I)

in combination with one or more doses of fentanyl, or a pharmaceutically acceptable salt thereof, wherein:

a) a first dose of fentanyl, or pharmaceutically acceptable salt thereof, is administered intravenously to the subject at a dose of between about 75 mcg and about 150 mcg within about 5 minutes prior to administration of the initial dose of the besylate salt of the compound of formula (I);

b) the initial dose of the besylate salt of the compound of formula (I) is intravenously administered to the subject at a dose of about 5 mg; and

c) one to three subsequent fixed doses of the besylate salt of the compound of formula (I) are intravenously administered to the subject at a dose of between about 2 mg and 3 mg no earlier than 4 minutes from the time the initial dose or previous subsequent dose of the besylate salt of the compound of formula (I) is administered to the subject

wherein all doses of the besylate salt of the compound of formula (I) administered to the subject are fixed doses and are irrespective of the body weight of the subject.

30. The method of claim 29 , wherein the first dose of fentanyl is administered to the subject at a dose of about 100 mcg.

31. The method of claim 29 , wherein a second dose of the fentanyl, or pharmaceutically acceptable salt thereof, is administered to the subject at a dose of between about 10 mcg and about 75 mcg no earlier than 5 minutes after the time the first dose of fentanyl, or pharmaceutically acceptable salt thereof is administered to the subject.

32. The method of claim 31 , wherein the second dose of fentanyl, or pharmaceutically acceptable salt thereof, is administered at a dose of about 25 mcg.