2 DOSAGE AND ADMINISTRATION • Individualization of dose with careful weekly titration is required. The 1st week’s starting dose is 12.5 mg daily; 2nd week, 25 mg (12.5 mg twice daily); then slowly titrate at weekly intervals by 12.5 mg to a tolerated dose that reduces chorea. (2.1, 2.2) • Doses of 37.5 mg and up to 50 mg per day should be administered in three divided doses per day with a maximum recommended single dose not to exceed 25 mg. (2.2) • Patients requiring doses above 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is a poor metabolizer (PM) or an extensive metabolizer (EM ). (2.2, 5.3 ) • Maximum daily dose in PMs: 50 mg with a maximum single dose of 25 mg (2.2) • Maximum daily dose in EMs and intermediate metabolizers (IMs): 100 mg with a maximum single dose of 37.5 mg (2.2) • If serious adverse reactions occur, titration should be stopped and the dose should be reduced. If the adverse reaction(s) do not resolve, consider withdrawal of tetrabenazine. (2.2) 2.1 General Dosing Considerations The chronic daily dose of tetrabenazine used to treat chorea associated with Huntington’s disease (HD) is determined individually for each patient. When first prescribed, tetrabenazine therapy should be titrated slowly over several weeks to identify a dose of tetrabenazine that reduces chorea and is tolerated. Tetrabenazine can be administered without regard to food [see Clinical Pharmacology ( 12.3 )]. 2.2 Individualization of Dose The dose of tetrabenazine should be individualized. Dosing Recommendations Up to 50 mg per day The starting dose should be 12.5 mg per day given once in the morning. After one week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. Tetrabenazine should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. If a dose of 37.5 to 50 mg per day is needed, it should be given in a three times a day regimen. The maximum recommended single dose is 25 mg. If adverse reactions such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing tetrabenazine treatment or initiating other specific treatment (e.g., antidepressants) [see Adverse Reactions ( 6.1 )]. Dosing Recommendations Above 50 mg per day Patients who require doses of tetrabenazine greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of tetrabenazine should then be individualized accordingly to their status as PMs or EMs [see Warnings and Precautions ( 5.3) , Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3) ]. Extensive and Intermediate CYP2D6 Metabolizers Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of tetrabenazine above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. Doses above 50 mg per day should be given in a three times a day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing tetrabenazine treatment or initiating other specific treatment (e.g., antidepressants) [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. Poor CYP2D6 Metabolizers In PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. 2.3 Dosage Adjustment with CYP2D6 Inhibitors Strong CYP2D6 Inhibitors Medications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g., fluoxetine, paroxetine) significantly increase the exposure to α-HTBZ and β-HTBZ; therefore, the total dose of tetrabenazine should not exceed a maximum of 50 mg and the maximum single dose should not exceed 25 mg [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. . 2.4 Discontinuation of Treatment Treatment with tetrabenazine can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of tetrabenazine [see Drug Abuse and Dependence ( 9.2 )]. 2.5 Resumption of Treatment Following treatment interruption of greater than five (5) days, tetrabenazine therapy should be re-titrated when resumed. For short-term treatment interruption of less than five (5) days, treatment can be resumed at the previous maintenance dose without titration.