Use of [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate in combination therapy

1. A method for treating a patient who is suffering from epilepsy with co-administering a therapeutically effective amount of (i) [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate (cenobamate) or a pharmaceutically acceptable salt thereof and (ii) one or two antiepileptic drugs, said method comprising:

modifying the therapeutically effective amount of the antiepileptic drug to adjust AUC of the antiepileptic drug obtained after the co-administration having at least 5% difference to the level of AUC obtained after the administration of antiepileptic drug to the patient without cenobamate or a pharmaceutically acceptable salt thereof,

wherein the therapeutically effective amount of cenobamate or a pharmaceutically acceptable salt thereof is from about 100 mg/day to about 400 mg/day, and

wherein the antiepileptic drug is selected from the group consisting of phenobarbital and phenytoin.

2. The method according to claim 1 , wherein the therapeutically effective amount of cenobamate is achieved by the following titration method:

(1) administering cenobamate to the patient about 12.5 mg once daily for about two weeks;

(2) then administering cenobamate to the patient about 25 mg once daily for two weeks;

(3) then administering cenobamate to the patient about 50 mg once daily for about two weeks; and

(4) then increasing the dose in about bi-weekly increments by no more than about 50 mg once daily to a therapeutically effective amount.

3. The method according to claim 1 , wherein the therapeutically effective amount of cenobamate is achieved by the following titration method:

(1) administering cenobamate to the patient about 50 mg once daily for about two weeks; and

(2) then increasing the dose in about bi-weekly increments by about 50 mg once daily to about 200 mg/day once daily,

wherein cenobamate is administered for about 6 weeks and the therapeutically effective amount of cenobamate is about 200 mg/day.

4. The method according to claim 1 , wherein the therapeutically effective amount of cenobamate is achieved by the following titration method:

(1) administering cenobamate to the patient about 50 mg once daily which is increased with 50 mg once daily per week to about 100 mg/day;

(2) optionally increasing the dose in about weekly increments by about 50 mg once daily per week to about 200 mg/day; and

(3) optionally increasing the dose in about weekly increments by about 100 mg/day per week to about 400 mg/day,

wherein cenobamate is administered for about 2 weeks, 4 weeks, or 6 weeks depending on therapeutically effective amount of cenobamate which is required and the therapeutically effective amount of cenobamate is about 100 mg/day, about 200 mg/day or about 400 mg/day.

5. The method according to claim 1 , wherein the antiepileptic drug is phenobarbital.

6. The method according to claim 5 , wherein the therapeutically effective amount of phenobarbital is decreased by about 20% to about 50% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy.

7. The method according to claim 6 , wherein the therapeutically effective amount of phenobarbital is decreased by about 25% to about 45% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy.

8. The method according to claim 5 , wherein the therapeutically effective amount of phenobarbital is decreased to adjust about 20% to about 50% increase in AUC of phenobarbital obtained after the co-administration to the level of AUC obtained after the administration of phenobarbital to the patient without cenobamate.

9. The method according to claim 8 , wherein the therapeutically effective amount of phenobarbital is decreased to adjust about 25% to about 45% increase in AUC of phenobarbital obtained after the co-administration to the level of AUC obtained after the administration of phenobarbital to the patient without cenobamate.

10. The method according to claim 1 , wherein the antiepileptic drug is phenytoin.

11. The method according to claim 10 , wherein the therapeutically effective amount of phenytoin is decreased by about 7% to about 55% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy.

12. The method according to claim 11 , wherein the therapeutically effective amount of phenytoin is decreased by about 10% to about 40% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy.

13. The method according to claim 10 , wherein the therapeutically effective amount of phenytoin is decreased to adjust about 10% to about 100% increase in AUC of phenytoin obtained after the co-administration to the level of AUC obtained after the administration of phenytoin to the patient without cenobamate.

14. The method according to claim 13 , wherein the therapeutically effective amount of phenytoin is decreased to adjust about 10% to about 60% increase in AUC of phenytoin obtained after the co-administration to the level of AUC obtained after the administration of phenytoin to the patient without cenobamate.