Tetrabenazine Prescribing Information
Tetrabenazine tablet is contraindicated in patients:
• Who are actively suicidal, or in patients with untreated or inadequately treated depression[see Warnings and Precautions (5.1)].• With hepatic impairment[see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].• Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine tablet should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI[see Drug Interactions (7.3)].• Taking reserpine. At least 20 days should elapse after stopping reserpine before starting Tetrabenazine tablet[see Drug Interactions (7.2)].• Taking deutetrabenazine or valbenazine [seeDrug Interactions (7.7)].
• Actively suicidal, or who have depression which is untreated or undertreated (4, 5.1 )• Hepatic impairment (4, 8.6, 12.3)• Taking MAOIs or reserpine (4, 7.2, 7.3)
Patients with Huntington's disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Tetrabenazine tablet increases the risk for suicidality in patients with HD. All patients treated with Tetrabenazine tablet should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with Tetrabenazine tablet.
In a 12-week, double-blind placebo-controlled study in patients with chorea associated with Huntington's disease, 10 of 54 patients (19%) treated with Tetrabenazine tablet were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients. In two open-label studies (in one study, 29 patients received Tetrabenazine tablet for up to 48 weeks; in the second study, 75 patients received Tetrabenazine tablet for up to 80 weeks), the rate of depression/worsening depression was 35%.
In all of the HD chorea studies of Tetrabenazine tablet (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation.
When considering the use of Tetrabenazine tablet, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with Tetrabenazine tablet should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with Tetrabenazine tablet.
Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with Tetrabenazine tablet and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately.
Contraindications (4) 01/2018
Warnings and Precautions, Tardive Dyskinesia (5.12-removal) 01/2018
Tetrabenazine tablet is indicated for the treatment of chorea associated with Huntington's disease.
Following treatment interruption of greater than five (5) days, Tetrabenazine tablet 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.
Tetrabenazine tablet are available in the following strengths and packages:
The 12.5 mg Tetrabenazine tablets are white cylindrical biplanar tablets with beveled edges, debossed '707' on one side and plain on the other side.
The 25 mg Tetrabenazine tablets are yellowish-buff, cylindrical biplanar tablets with beveled edges, debossed '708' on one side and scored on the other side.
Patients who require doses of Tetrabenazine tablet greater than 50 mg per day, should be first tested and genotyped to determine if they are poor (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of Tetrabenazine tablet should then be individualized accordingly to their status as either poor (PMs) or extensive metabolizers (EMs)
The dose of Tetrabenazine tablet should be individualized.
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 tablet 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 tablet treatment or initiating other specific treatment (e.g: antidepressants)
Patients who require doses of Tetrabenazine tablet 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 tablet should then be individualized accordingly to their status as PMs or EMs
Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of Tetrabenazine tablet 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 tablet treatment or initiating other specific treatment (e.g, antidepressants)
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
Before prescribing a daily dose of Tetrabenazine tablet that is greater than 50 mg per day, patients should be genotyped to determine if they express the drug metabolizing enzyme, CYP2D6. CYP2D6 testing is necessary to determine whether patients are poor metabolizers (PMs), extensive (EMs) or intermediate metabolizers (IMs) of Tetrabenazine tablet.
Patients who are PMs of Tetrabenazine tablet will have substantially higher levels of the primary drug metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than patients who are EMs. The dosage should be adjusted according to a patient's CYP2D6 metabolizer status. In patients who are identified as CYP2D6 PMs, the maximum recommended total daily dose is 50 mg and the maximum recommended single dose is 25 mg
Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-α-DHTBZ. β-HTBZ is subsequently, metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
The effects of food on the bioavailability of Tetrabenazine tablet were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax, or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ
Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of11C-labeled tetrabenazine or α-HTBZ, with the highest binding in the striatum and lowest binding in the cortex.
The
After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are the major circulating metabolites, and they are, subsequently, metabolized to sulfate or glucuronide conjugates. α-HTBZ and β-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP4 50 enzymes, principally CYP2D6 , with some contribution of CYP1A2 to form 9-desmethyl-α-DHT BZ, a minor metabolite. β-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-β-DHTBZ.
The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, or β-HTBZ or 9-desmethyl-β-DHTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its α- or β-HTBZ or 9-desmethyl-α-DHTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
Neither tetrabenazine nor its α- or β-HTBZ or 9-desmethyl-β-DHTBZ is likely to be a substrates or inhibitors of P-glycoprotein at clinically relevant concentrations
No
After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ have half-lives of 7 hours, 5 hours and 12 hours respectively. In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β- HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.
There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.
The disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received a single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ. The mean tetrabenazine Cmaxin subjects with hepatic impairment was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (tmax) of α-HTBZ and β-HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half-lives of the α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours, respectively. The exposure to α-HTBZ and β-HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, Tetrabenazine tablet is contraindicated in patients with hepatic impairment
Although the pharmacokinetics of TETRABENAZINE and its metabolites in patients who do not express the drug metabolizing enzyme, CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively)
Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure to TETRABENAZINE and its metabolites has not been evaluated
Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that Tetrabenazine tablet (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, TETRABENAZINE does not affect P-glycoprotein in the intestinal tract.
Poor CYP2D6 metabolizers (PMs) will have substantially higher levels of exposure to the primary metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) compared to EMs. The dosage should, therefore, be adjusted according to a patient's CYP2D6 metabolizer status by limiting a single dose to a maximum of 25 mg and the recommended daily dose to not exceed a maximum of 50 mg/day in patients who are CYP2D6 PMs
The dose of Tetrabenazine tablet should be individualized.
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 tablet 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 tablet treatment or initiating other specific treatment (e.g: antidepressants)
Patients who require doses of Tetrabenazine tablet 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 tablet should then be individualized accordingly to their status as PMs or EMs
Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of Tetrabenazine tablet 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 tablet treatment or initiating other specific treatment (e.g, antidepressants)
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
Before prescribing a daily dose of Tetrabenazine tablet that is greater than 50 mg per day, patients should be genotyped to determine if they express the drug metabolizing enzyme, CYP2D6. CYP2D6 testing is necessary to determine whether patients are poor metabolizers (PMs), extensive (EMs) or intermediate metabolizers (IMs) of Tetrabenazine tablet.
Patients who are PMs of Tetrabenazine tablet will have substantially higher levels of the primary drug metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than patients who are EMs. The dosage should be adjusted according to a patient's CYP2D6 metabolizer status. In patients who are identified as CYP2D6 PMs, the maximum recommended total daily dose is 50 mg and the maximum recommended single dose is 25 mg
Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-α-DHTBZ. β-HTBZ is subsequently, metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
The effects of food on the bioavailability of Tetrabenazine tablet were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax, or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ
Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of11C-labeled tetrabenazine or α-HTBZ, with the highest binding in the striatum and lowest binding in the cortex.
The
After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are the major circulating metabolites, and they are, subsequently, metabolized to sulfate or glucuronide conjugates. α-HTBZ and β-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP4 50 enzymes, principally CYP2D6 , with some contribution of CYP1A2 to form 9-desmethyl-α-DHT BZ, a minor metabolite. β-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-β-DHTBZ.
The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, or β-HTBZ or 9-desmethyl-β-DHTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its α- or β-HTBZ or 9-desmethyl-α-DHTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
Neither tetrabenazine nor its α- or β-HTBZ or 9-desmethyl-β-DHTBZ is likely to be a substrates or inhibitors of P-glycoprotein at clinically relevant concentrations
No
After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ have half-lives of 7 hours, 5 hours and 12 hours respectively. In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β- HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.
There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.
The disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received a single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ. The mean tetrabenazine Cmaxin subjects with hepatic impairment was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (tmax) of α-HTBZ and β-HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half-lives of the α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours, respectively. The exposure to α-HTBZ and β-HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, Tetrabenazine tablet is contraindicated in patients with hepatic impairment
Although the pharmacokinetics of TETRABENAZINE and its metabolites in patients who do not express the drug metabolizing enzyme, CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively)
Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure to TETRABENAZINE and its metabolites has not been evaluated
Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that Tetrabenazine tablet (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, TETRABENAZINE does not affect P-glycoprotein in the intestinal tract.
In extensive (EMs) or intermediate metabolizers (IMs), the dosage of Tetrabenazine tablet can be titrated to a maximum single dose of 37.5 mg and a recommended maximum daily dose of 100 mg
The dose of Tetrabenazine tablet should be individualized.
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 tablet 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 tablet treatment or initiating other specific treatment (e.g: antidepressants)
Patients who require doses of Tetrabenazine tablet 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 tablet should then be individualized accordingly to their status as PMs or EMs
Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of Tetrabenazine tablet 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 tablet treatment or initiating other specific treatment (e.g, antidepressants)
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
Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-α-DHTBZ. β-HTBZ is subsequently, metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
The effects of food on the bioavailability of Tetrabenazine tablet were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax, or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ
Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of11C-labeled tetrabenazine or α-HTBZ, with the highest binding in the striatum and lowest binding in the cortex.
The
After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are the major circulating metabolites, and they are, subsequently, metabolized to sulfate or glucuronide conjugates. α-HTBZ and β-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP4 50 enzymes, principally CYP2D6 , with some contribution of CYP1A2 to form 9-desmethyl-α-DHT BZ, a minor metabolite. β-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-β-DHTBZ.
The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, or β-HTBZ or 9-desmethyl-β-DHTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its α- or β-HTBZ or 9-desmethyl-α-DHTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
Neither tetrabenazine nor its α- or β-HTBZ or 9-desmethyl-β-DHTBZ is likely to be a substrates or inhibitors of P-glycoprotein at clinically relevant concentrations
No
After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ have half-lives of 7 hours, 5 hours and 12 hours respectively. In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β- HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.
There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.
The disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received a single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ. The mean tetrabenazine Cmaxin subjects with hepatic impairment was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (tmax) of α-HTBZ and β-HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half-lives of the α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours, respectively. The exposure to α-HTBZ and β-HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, Tetrabenazine tablet is contraindicated in patients with hepatic impairment
Although the pharmacokinetics of TETRABENAZINE and its metabolites in patients who do not express the drug metabolizing enzyme, CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively)
Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure to TETRABENAZINE and its metabolites has not been evaluated
Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that Tetrabenazine tablet (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, TETRABENAZINE does not affect P-glycoprotein in the intestinal tract.