Absorption, Distribution and Excretion
Following oral administration, bubenazine is absorbed at least 75%. After a single oral dose of 12.5 to 50 mg, plasma concentrations are typically below the limit of detection due to rapid and extensive metabolism in the liver. Food does not affect the absorption of bubenazine. In patients with HD or tardive dyskinesia, the Cmax of oral bubenazine is 4.8 ng/mL; the Tmax is 69 minutes. After oral administration, bubenazine is extensively metabolized in the liver, and its metabolites are primarily excreted by the kidneys (75%). Bubenazine is also cleared in feces (7% to 16%). Unmetabolized bubenazine is not found in human urine. The urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) is less than 10% of the administered dose. In patients with Huntington's disease or tardive dyskinesia, the steady-state plasma concentration after intravenous injection is 385 L. Bubenazine is rapidly distributed to the brain after intravenous injection. The striatum has the highest binding rate, while the cortex has the lowest. In patients with Huntington's disease or tardive dyskinesia, the venous blood flow velocity is 1.67 L/min. The oral absorption rate of deuterated butylbenazine is 80%. Because deuterated butylbenazine is extensively metabolized to its major active metabolite after administration, a linear dose-dependent peak plasma concentration (Cmax) and AUC of the metabolite are observed after single or multiple doses (6 mg to 24 mg, and twice daily 7.5 mg to 22.5 mg). Peak plasma concentrations (Cmax) of deuterated α-HTBZ and β-HTBZ are reached within 3–4 hours after administration. Food can increase the Cmax of α-HTBZ or β-HTBZ by approximately 50%, but is unlikely to affect AUC. Deuterated butylbenazine is primarily excreted in the urine as a metabolite. In healthy subjects, approximately 75% to 86% of the dose of deuterated butylbenazine is excreted in the urine, with a fecal recovery rate of 8% to 11%. Sulfate and glucuronide conjugates of α-HTBZ and β-HTBZ, as well as oxidative metabolites, are the main components of urinary metabolites. The proportion of α-HTBZ and β-HTBZ metabolites in urine is less than 10% of the administered dose. The median volume of distribution (Vc/F) of the α-HTBZ and β-HTBZ metabolites of deuterated butylbenazine is approximately 500 L and 730 L, respectively. Human PET scans of butylbenazine show rapid distribution to the brain, with the highest binding rate in the striatum and the lowest in the cortex. A similar distribution pattern is expected for deuterated butylbenazine. In patients with Huntington's disease, the median clearance (CL/F) of the deuterated buphenazine metabolites α-HTBZ and β-HTBZ was approximately 47 L/h and 70 L/h, respectively. The in vitro protein binding of buphenazine, α-dihydrobuphenazine (a-HTBZ), and β-dihydrobuphenazine (b-HTBZ) was assessed in human plasma at concentrations ranging from 50 to 200 ng/mL. The binding rates of tetraphenylazine were between 82% and 85%, α-dihydrotetraphenylazine (α-HTBZ) between 60% and 68%, and β-dihydrotetraphenylazine (β-HTBZ) between 59% and 63%.
Human PET scans showed that after intravenous injection of (11)C-labeled tetraphenylazine or α-dihydrotetraphenylazine (α-HTBZ), the radioactive material rapidly distributed to the brain, with the highest binding rate in the striatum and the lowest in the cortex.
Tetraphenylazine or its metabolites can bind to melanin-containing tissues (e.g., eyes, skin, hair) in colored rats. Following a single oral dose of radiolabeled buphenazine, radioactivity was still detectable in the eyes and hair 21 days later.
In a mass balance study of six healthy volunteers, approximately 75% of the dose was excreted in the urine, with fecal recovery ranging from approximately 7% to 16%. Unmetabolized buphenazine was not found in human urine.
The absorption rate of buphenazine after oral administration is at least 75%. Following a single oral dose of 12.5 to 50 mg, plasma concentrations of buphenazine are typically below the limit of detection because it is rapidly and extensively metabolized in the liver by carbonyl reductase to the active metabolites α-dihydrobuphenazine (a-HTBZ) and β-dihydrobuphenazine (b-HTBZ). a-HTBZ and b-HTBZ are primarily metabolized by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1.5 hours after administration. Subsequently, α-HTBZ is metabolized to a minor metabolite, 9-demethyl-α-DHTBZ. β-HTBZ is then metabolized to another major circulating metabolite, 9-demethyl-β-DHTBZ, with its peak plasma concentration (Cmax) reached approximately 2 hours after administration.
Human PET scan studies indicate that after intravenous injection of 11C-labeled butylbenazine or α-dihydrobutylbenazine, the radioactive material rapidly distributes to the brain, with the highest binding rate in the striatum and the lowest in the cortex.
Oral administration of deuterated butylbenazine results in an absorption rate of at least 80%.
In a mass balance study of six healthy subjects, 75% to 86% of the deuterated butylbenazine dose was excreted in the urine, with fecal recovery accounting for 8% to 11% of the total dose. The urinary excretion of the deuterated butylbenazine metabolites α-dihydrobutylbenazine and β-dihydrobutylbenazine is less than 10% of the administered dose. The sulfate and glucuronide conjugates of the deuterated butylbenazine metabolites α-dihydrobutylbenazine and β-dihydrobutylbenazine, as well as oxidative metabolites, constitute the major portion of the metabolites in the urine.
Osterdol is primarily excreted via the kidneys as metabolites.

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Metabolism/Metabolites
Butenarazine is metabolized in the liver. Hepatic carbonyl reductases are responsible for generating two major active metabolites: α-dihydrobutenarazine (α-HTBZ) and β-dihydrobutenarazine (β-HTBZ). α-HTBZ is further metabolized to 9-demethyl-α-DHTBZ, the major metabolite of CYP2D6, with CYP1A2 also involved. β-HTBZ is metabolized by CYP2D6 to another major circulating metabolite, 9-demethyl-β-DHTBZ. The time to peak concentration (Tmax) of this metabolite is 2 hours after butenarazine administration.
Deuterated butenarazine undergoes extensive hepatic biotransformation mediated by carbonyl reductases to form its major active metabolites, α-HTBZ and β-HTBZ. These metabolites may be further metabolized into several minor metabolites, with CYP2D6 playing a major role and CYP1A2 and CYP3A4/5 playing minor roles. In a mass balance study of six healthy volunteers, approximately 75% of the dose was excreted in the urine, with fecal recovery ranging from approximately 7% to 16%. No altered buphenazine was found in human urine. Less than 10% of the administered dose is excreted in urine as either α-dihydrobuphenazine (a-HTBZ) or β-dihydrobuphenazine (b-HTBZ). Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites and oxidative metabolites, constitute the majority of metabolites in urine. After oral administration, buphenazine is primarily metabolized in the liver, and its metabolites are primarily excreted by the kidneys. In vitro studies have shown that buphenazine, α-dihydrobuphenazine (a-HTBZ), β-dihydrobuphenazine (b-HTBZ), or 9-demethyl-β-dihydrobuphenazine are unlikely to cause clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies have also shown that buphenazine and its metabolites α- or β-buphenazine, or 9-demethyl-β-dihydrobuphenazine, are unlikely to cause clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. At least 19 buphenazine metabolites have been identified after oral administration in humans. α-Dihydrobutenazine (α-HTBZ), β-dihydrobutenazine (β-HTBZ), and 9-demethyl-β-dihydrobutenazine are the major circulating metabolites, subsequently metabolized to sulfate or glucuronide conjugates. α-HTBZ and β-HTBZ are primarily generated by carbonyl reductases in the liver. α-HTBZ undergoes O-dealkylation mainly by CYP450 enzymes (primarily CYP2D6, with minor involvement of CYP1A2) to produce the minor metabolite 9-demethyl-α-dihydrotetraphenylazine. β-HTBZ undergoes O-dealkylation mainly by CYP2D6 to produce 9-demethyl-β-dihydrotetraphenylazine. After oral administration, the absorption rate of tetraphenylazine is at least 75%. Following a single oral dose of 12.5 to 50 mg, plasma concentrations of tetraphenylazine are typically below the limit of detection because it is rapidly and extensively metabolized in the liver by carbonyl reductases to the active metabolites α-dihydrotetraphenylazine (α-HTBZ) and β-dihydrotetraphenylazine (β-HTBZ). α-HTBZ and β-HTBZ are primarily metabolized via CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1.5 hours after administration. α-HTBZ is subsequently metabolized to a minor metabolite, 9-demethyl-α-DHTBZ. β-HTBZ is then metabolized to another major circulating metabolite, 9-demethyl-β-DHTBZ, whose Cmax peaks approximately 2 hours after administration. In a mass balance study of six healthy subjects, 75% to 86% of the deuterated butylbenazine dose was excreted in the urine, with fecal recovery ranging from 8% to 11%. The urinary excretion of the deuterated butylbenazine metabolites α-dihydrobutylbenazine and β-dihydrobutylbenazine was less than 10% of the administered dose. The main components of the metabolites in the urine were sulfate and glucuronide conjugates of the α-dihydrobutylbenazine and β-dihydrobutylbenazine metabolites, as well as oxidative metabolites. In vitro human liver microsomal assays showed that deuterated butylbenazine undergoes extensive biotransformation primarily via carbonyl reductases to generate its main active metabolites α-dihydrobutylbenazine and β-dihydrobutylbenazine, which are then primarily metabolized by CYP2D6, with minor involvement by CYP1A2 and CYP3A4/5, generating several minor metabolites.

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Biological Half-Life
The elimination half-life of bubenazine varies among individuals. Following an intravenous bolus injection, the elimination half-life of bubenazine is 10 hours. The oral half-lives of its metabolites α-HTBZ, β-HTBZ, and 9-demethyl-β-DHTBZ are 7 hours, 5 hours, and 12 hours, respectively. Following a single oral dose of 25 mg bubenazine, the elimination half-life in subjects with impaired hepatic function is approximately 17.5 hours. The half-life of total (α+β)-HTBZ produced from the metabolism of deuterated bubenazine is approximately 9 to 10 hours. The half-lives of α-dihydrobubenazine (a-HTBZ), β-dihydrobubenazine (b-HTBZ), and 9-demethyl-β-dihydrobubenazine are 7 hours, 5 hours, and 12 hours, respectively. /Butenazine Metabolites/
The half-life of total (α+β)-dihydrobutenazine, which is metabolized from deuterated butenazine, is approximately 9 to 10 hours.

Toxicity Summary
Identification and Uses: Bubenazine is a solid. It is used as an adrenergic reuptake inhibitor to treat Huntington's disease-related chorea. Pharmacological studies have shown that bubenazine reversibly inhibits the activity of vesicular monoamine transporter 2, leading to central dopamine depletion. Human Studies: Adverse reactions are dose- and age-related, including depression, fatigue, Parkinson's syndrome, and somnolence. Neuroleptic malignancy (NMS), a potentially fatal syndrome, has been reported in patients taking bubenazine and other dopamine-reducing drugs. Three overdose events occurred in open-label trials supporting registration. Eight overdose cases have been reported in the literature. These patients received doses ranging from 100 mg to 1 g. Possible adverse reactions from overdose include acute dystonia, oculomotor crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, flushing, and tremor. Of the 187 patients treated with bubenazine, one case of suicide death, one case of attempted suicide, and six cases of suicidal ideation were reported. The major human metabolite, 9-demethyl-β-dihydrobubenazine, did not show chromosome breakage in vitro in human peripheral blood mononuclear cell chromosome aberration assays, regardless of metabolic activation. Animal studies: No tumor growth was observed in transgenic mice after oral administration of the major human metabolite 9-demethyl-β-dihydrobubenazine (20, 100, and 200 mg/kg/day) for 26 weeks. Oral administration of bubenazine (5, 15, or 30 mg/kg/day) to female rats before and during mating, and continuing until day 7 of gestation, resulted in estrous cycle disturbances at doses greater than 5 mg/kg/day. No effects were observed on mating and fertility indicators or sperm parameters (motility, count, density) when male rats were orally administered bubenazine (5, 15, or 30 mg/kg/day). However, because rats administered buphenazine do not produce 9-demethyl-β-dihydrobuphenazine (a major human metabolite), this study may not have adequately assessed the potential impairment of this drug on human fertility. During organogenesis, oral administration of 9-demethyl-β-dihydrobuphenazine (8, 15, and 40 mg/kg/day) to pregnant and lactating rats resulted in increased embryonic mortality at 15 and 40 mg/kg/day, decreased fetal weight at 40 mg/kg/day, and maternal toxicity at this dose. Daily oral administration of buphenazine (mg/kg) to pregnant rats from organogenesis into lactation resulted in prolonged gestation, stillbirth, and increased postnatal mortality (40 mg/kg/day); decreased pup weight (40 mg/kg/day); and impaired neurobehavioral (increased activity, learning and memory impairment) and reproductive (reduced litter size) outcomes (15 and 40 mg/kg/day). Maternal toxicity was observed in the highest dose group. In in vitro bacterial reverse mutation assays, bubenazine and its metabolites α-dihydrobubenazine (a-HTBZ), β-dihydrobubenazine (b-HTBZ), and 9-demethyl-β-dihydrobubenazine were all negative. Under metabolic activation conditions, bubenazine was fragment-inducing in in vitro Chinese hamster ovary cell chromosome aberration assays. α-HTBZ and, with or without metabolic activation, β-HTBZ were fragment-inducing in Chinese hamster lung cells in in vitro chromosome aberration assays. In vivo micronucleus assays were performed in male and female rats and male mice. Bubenazine was negative in male mice and rats, but produced an indeterminate response in female rats.
Identification and Uses: Deuterated bubenazine is used as an adrenergic uptake inhibitor. It is indicated for the treatment of Huntington's disease (HD)-related chorea and tardive dyskinesia in adults. Human Studies: Cases of overdose of bubenazine (a closely related vesicular monoamine transporter 2 (VMAT2) inhibitor) ranging from 100 mg to 1 g have been reported in the literature. Adverse reactions following overdose include: acute dystonia, oculomotor crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, skin flushing, and tremors. Indirect treatment comparisons indicate that deuterated bubenazine is better tolerated than bubenazine in the treatment of Huntington's disease. Deuterated bubenazine may increase the suicide risk in patients with Huntington's disease. Deuterated bubenazine should be avoided in patients with congenital long QT syndrome and those with a history of arrhythmias. With or without metabolic activation, deuterated bubenazine and its deuterated α-dihydrobubenazine and β-dihydrobubenazine metabolites were negative in in vitro chromosomal aberration assays on human peripheral blood lymphocytes. Animal studies: During organogenesis, oral administration of deuterated butylbenazine (5, 10, or 30 mg/kg/day) to pregnant rats had no significant effect on embryonic development. Oral administration of deuterated butylbenazine (at doses of 5, 10, or 30 mg/kg/day) to female rats for three consecutive months resulted in estrous cycle disturbances in all dose groups. Deuterated butylbenazine and its deuterated α-dihydrobutylbenazine and β-dihydrobutylbenazine metabolites were negative in in vitro bacterial reverse mutation assays (regardless of metabolic activation) and in in vivo micronucleus assays in mice.

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Hepatotoxicity
Butenazine was not associated with a higher rate of elevated serum enzymes than the placebo group, but information on liver function test results during treatment was limited, and the sponsor reported occasional asymptomatic ALT.
Increased incidence of cases may lead to discontinuation or dose adjustment. In pivotal premarket registration trials involving hundreds of patients, bubenazine did not cause jaundice or hepatitis. Since its market launch, there have been no published reports of clinically significant liver injury, jaundice, or hepatitis caused by bubenazine. Therefore, the incidence of clinically significant liver injury, jaundice, or hepatitis is unclear. Even if bubenazine-induced liver injury with jaundice occurs, it is extremely rare. Probability score: E (unlikely to be the cause of clinically significant liver injury). Protein binding rates: Bubenazine = 82-88%; α-HTBZ = 60-68%; β-HTBZ = 59-63%. In vitro, at doses ranging from 50 to 200 ng/mL, the protein binding rates of bubenazine are 82% to 85%, α-HTBZ is 60% to 68%, and β-HTBZ is 59%. Up to 63%. The protein binding patterns of deuterated bubenazine and its metabolites are expected to be similar.

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Interactions
This article describes a case of an 81-year-old Japanese woman with neuroleptic malignancy who developed an adverse reaction 36 days after starting combination therapy with sulpiride (75 mg/day) and bubenazine (12.5 mg/day) for Huntington's disease. Prior to combination therapy, the patient had received sulpiride or bubenazine alone without any adverse reactions. At the start of combination therapy, the patient also had advanced breast cancer. To our knowledge, there have been no previous reports of neuroleptic malignancy resulting from the combination therapy of bubenazine and sulpiride. Extra caution should be exercised when bubenazine is used in combination with other neuroleptics, especially in patients with deteriorating general condition. The efficacy of the dopaminergic stabilizer pridopidine in reducing voluntary and involuntary motor symptoms in Huntington's disease (HD) is currently under clinical evaluation. Bubenazine is currently the only approved drug for the treatment of chorea (…). This study aimed to investigate the pharmacological interaction between pridopidine and bubenazine (a drug used to treat involuntary motor symptoms of HD). Both compounds affect monoaminergic neurotransmission. The purpose of this study was to investigate the effects of these compounds on dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum of male Sprague-Dawley rats, as well as the expression levels of active regulatory cytoskeleton-related genes (Arc) in the striatum and frontal cortex, using drug interaction experiments and dose-response data. The classic dopamine D2 receptor antagonist haloperidol was also tested as a control. Bubenazine 0.64... After administration of buphenazine at 0.12 mg/kg and pridopidine at 32 mg/kg, monitoring for 1 hour showed that motor activity (measured by distance of movement) in the buphenazine group was reduced by 61% compared to the control group (p < 0.001). Pridopidine significantly alleviated this phenomenon (distance of movement reached 137% compared to the control group). Compared with buphenazine alone, the co-administration of haloperidol (0.12 mg/kg) and buphenazine significantly inhibited motor activity (p < 0.01, a 41% reduction compared to the buphenazine group). The co-administration of pridopidine (10.5 mg/kg or 32 mg/kg) and buphenazine significantly (p < 0.05) and in a dose-dependent manner antagonized the decrease in frontal cortex Arc levels induced by buphenazine (0.64 mg/kg) (Arc mRNA at 32 mg/kg). The levels reached 193% of the mean in the bubenazine group; however, no such antagonistic effect was observed with haloperidol. When used concomitantly with pridopidine, bubenazine retained its characteristic neurochemical effects, namely increasing striatal DOPAC levels and decreasing striatal dopamine levels. Pridopidine alleviated the behavioral inhibition induced by bubenazine in rats. This effect may be related to the changes in cortical activity induced by pridopidine and may support clinical evaluation of pridopidine/bubenazine combination therapy. Concomitant use of xenazine and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) may increase the risk of Parkinson's syndrome and neuroleptic malignant syndrome (NMS). Risks of akathisia. Potential drug interactions (depletion of serotonin and norepinephrine in the central nervous system). Concomitant use is prohibited. Clinicians should wait for the recurrence of chorea symptoms after discontinuing reserpine before initiating bubenazine treatment. At least 20 days should pass after discontinuing reserpine before initiating bubenazine treatment. For more interaction information, please visit the HSDB records page for complete data on bubenazine (12 items in total). Austedo is contraindicated in patients taking bubenazine or valbenazo. Austedo can be started the day after discontinuing bubenazine. Concomitant use of alcohol or other sedatives may have an additive effect, exacerbating sedation and drowsiness. Concomitant use of Austedo with dopamine antagonists or antipsychotics may increase the risk of Parkinson's syndrome, neuroleptic malignancy (NMS), and akathisia. Austedo is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). It should not be used in combination with MAOI, nor should it be used within 14 days after discontinuation of MAOI. For more information on interactions (complete data) of deuterated benzodiazepine (6 items in total), please visit the HSDB record page. Access the HSDB record page.

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Non-human toxicity values
Mice intravenous LD50: 150 mg/kg
Mice subcutaneous LD50: 400 mg/kg
Mice intraperitoneal LD50: 250 mg/kg
Mice oral LD50: 550 mg/kg

[1]. Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: implications for animal models of the motivational symptoms of depression. J Neurosci. 2013 Dec 4;33(49):19120-30.

[2]. The vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine induces tremulous jaw movements in rodents: implications for pharmacological models of parkinsonian tremor. Neuroscience. 2013 Oct 10;250:507-19.

[3]. Tetrabenazine, an amine-depleting drug, also blocks dopamine receptors in rat brain. J Pharmacol Exp Ther. 1983 Jun;225(3):515-21.

Therapeutic Uses

Adrenergic Reuptake Inhibitors
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Bubenazine is listed in the database.
Sinazine is indicated for the treatment of Huntington's disease-related chorea. /Included in US Product Labelling/
/Therapeutic Trial/ Since levodopa-induced dyskinesia peaks (LIDs) may partially reflect excessive dopamine release from synaptic vesicles, we investigated whether the vesicle-depleting agent bubenazine (TBZ) could reduce LIDs in 10 patients with advanced Parkinson's disease (PD) and dyskinesia. After baseline assessment, patients received slow titration of TBZ orally twice daily for six weeks (maximum daily dose 50 mg), followed by reassessment after a levodopa challenge test. The primary efficacy endpoint was change in the Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia score (items 32–34). TBZ was well tolerated. Significant therapeutic effects were observed on levodopa-induced dyskinesia (LIDs) (up to 45%, p<0.05). Two patients required increased doses of anti-Parkinson's disease medication due to slight deterioration in motor function, but this did not worsen LIDs at peak doses. Patients experienced significant improvements in quality of life. In this open-label preliminary study, oral TBZ improved both objective and subjective symptoms of LIDs. Larger-scale pharmacological studies are currently underway.
For more complete data on the therapeutic uses of bubenazine (one of eight), please visit the HSDB record page.
Adrenergic Reuptake Inhibitors
/Clinical Trials/ ClinicalTrials.gov is a registry and outcomes database that tracks human clinical studies funded by public and private sources worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to other relevant health websites, such as the NLM's MedlinePlus (for patient health information) and PubMed (for citations and abstracts of academic articles in the medical field). This database contains duttetrabenazine. Austedo is indicated for the treatment of Huntington's disease-related chorea. (Included in the US product label) Austedo is indicated for the treatment of tardive dyskinesia in adults. /Included in the US product label/ /Exploratory Treatment/ Duttetrabenazine is a vesicular monoamine transporter type 2 (VMAT2) inhibitor that depletes presynaptic dopamine and is used to treat hyperkinesis. This study aimed to explore the safety, tolerability, and preliminary efficacy of duttetrabenazine in adolescents with Tourette syndrome (TS) and moderate to severe tic disorders. In this open-label study of TS-related tic disorders in patients aged 12–18 years, the dose of duttetrabenazine was gradually increased to 36 mg/day over 6 weeks to adequately suppress tic symptoms without significant adverse events (AEs), followed by maintenance of the optimal dose for 2 weeks. An independent, blinded assessor used the Yale Global Tic Severity Scale (YGTSS), the primary endpoint of treatment efficacy, to assess the severity of Tourette syndrome. Secondary endpoints included the Clinical Overall Impression of Tourette Syndrome (TS-CGI) and the Overall Impression of Change in Tourette Syndrome (TS-PGIC). Twenty-three enrolled patients received deuterated benzonazine and underwent at least one post-baseline Yale Tourette Syndrome Severity Scale (YGTSS) assessment. The baseline mean (standard deviation) of the total tic severity (TTS) score on the YGTSS was 31.6 (7.9), which decreased by 11.6 (8.2) points at week 8, representing a 37.6% reduction in tic severity (p<0.0001). The TS-CGI score improved by 1.2 (0.81) points (p<0.0001), and the TS-PGIC results at week 8 showed that 76% of patients had a significant or highly significant improvement compared to baseline. The mean (standard deviation) daily dose of deuterated benzonazine at week 8 was 32.1 (6.6) mg (range 18–36 mg). One week after discontinuation of deuterated benzonazine, the TTS score increased by 5.6 (8.4) points, confirming the efficacy of the drug. No serious or severe adverse events were reported. The results of this 8-week open-label study demonstrate that deuterated benzonazine is safe and effective, and improves tic symptoms in adolescents with Tourette syndrome (TS) and severe tic disorders.

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Drug Warning
/Black Box Warning/ Warning: Depression and Suicidal Tendency. Deuterated benzonazine may increase the risk of depression and suicidal thoughts and behaviors (suicidal tendencies) in patients with Huntington's disease. Anyone considering the use of deuterated benzonazine must weigh the risks of depression and suicidal tendencies against the clinical need to control chorea. Patients should be closely monitored for the development or exacerbation of depression, suicidal tendencies, or abnormal behavioral changes during treatment. Patients, their caregivers, and families should be informed of the risks of depression and suicide, and should be instructed to promptly report any worrying behaviors to their attending physician. Extra caution should be exercised in patients with a history of depression, suicide attempts, or suicidal ideation, as these conditions are more frequent in patients with Huntington's disease. Xenazine hydrochloride is contraindicated in patients with suicidal tendencies and in patients with untreated or undertreated depression. Bubenazine should be used with caution in patients with a history of depression, suicide attempts, or suicidal ideation, as these patients may have a higher suicide risk. This medication should not be used in patients with suicidal tendencies and in patients with untreated or undertreated depression. Huntington's disease is a progressive disorder characterized by alterations in mood, cognition, chorea, rigidity, and functional abilities over time. In a 12-week controlled trial, Xenazine was also shown to cause slight deterioration in mood, cognition, rigidity, and functional abilities. It is unclear whether these effects persist, subside, or worsen with continued treatment. Before taking more than 50 mg of buphenazine daily, the manufacturer recommends that patients be tested to determine their cytochrome P-450 (CYP) isoenzyme 2D6 status (i.e., poor metabolizer, good metabolizer, or moderate metabolizer). When given a dose to a poor metabolizer, drug exposure will be significantly higher than when given a dose to a good metabolizer (approximately three times that of α-dihydrobuphenazine (α-HTBZ) and approximately nine times that of β-dihydrobuphenazine (β-HTBZ), both of which are active metabolites). The manufacturer recommends that for patients with poor CYP2D6 metabolism, the daily dose of buphenazine should be limited to 50 mg and a single dose to 25 mg or less. For more drug warnings (full version) (22 in total) for buphenazine, please visit the HSDB record page [insert link here]. /Warning Box/ Warning: Depression and suicidal tendencies in patients with Huntington's disease. Austerdo may increase the risk of depression and suicidal thoughts and behaviors (suicidal tendencies) in patients with Huntington's disease. Anyone considering the use of Austerdo must weigh the risks of depression and suicidal tendencies against the clinical need to treat chorea. Closely monitor patients for the onset or worsening of depression, suicidal tendencies, or abnormal behavioral changes. Patients, their caregivers, and families should be informed of the risks of depression and suicidal tendencies and instructed to promptly report any worrying behavior to their attending physician. Extra caution should be exercised in patients with a history of depression or previous suicide attempts or suicidal ideation, as these conditions are more common in patients with Huntington's disease. Austerdo is contraindicated in patients with suicidal tendencies and in patients with untreated or inadequately treated depression. Huntington's disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional abilities over time. Vesicular monoamine transporter 2 (VMAT2) inhibitors, including deuterated benzodiazepine, may cause deterioration in mood, cognition, rigidity, and functional abilities. Prescribing physicians should periodically reassess the necessity of deuterated benzodiazepine use in patients, evaluating its effects on chorea and potential adverse reactions, including sedation/sleepiness, depression and suicidal tendencies, Parkinson's syndrome, akathisia, agitation, and cognitive decline. Differentiating adverse reactions from the progression of underlying disease can be difficult; dose reduction or discontinuation may help clinicians differentiate between the two possibilities. In some patients, the underlying chorea itself may improve over time, reducing the need for deuterated benzodiazepine. Deuterated benzodiazepine may increase the risk of akathisia, agitation, and restlessness in patients with Huntington's disease and tardive dyskinesia. In a 12-week double-blind, placebo-controlled trial of patients with Huntington's disease, 4% of patients in the deuterated benzodiazepine treatment group reported akathisia, agitation, or restlessness, compared to 2% in the placebo group; in patients with tardive dyskinesia, these conditions occurred in 2% of patients in the deuterated benzodiazepine treatment group and 1% in the placebo group. Patients receiving deuterated benzodiazepine should be monitored for signs and symptoms of agitation and restlessness, as these may be precursors to akathisia. If a patient develops akathisia during deuterated benzodiazepine treatment, the dose of deuterated benzodiazepine should be reduced. Some patients may need to discontinue treatment. Some medications that reduce dopaminergic transmission have been reported to cause a potentially fatal symptom cluster, sometimes referred to as neuroleptic malignant syndrome (NMS). While NMS has not been observed in patients taking deuterated benzodiazepine, it has been observed in patients taking benzodiazepine (a closely related VMAT2 inhibitor). Clinicians should be alert to signs and symptoms associated with NMS. Clinical manifestations of NMS include high fever, muscle rigidity, altered mental status, and evidence of autonomic dysfunction (irregular pulse or blood pressure, tachycardia, excessive sweating, and arrhythmias). Other signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. Diagnosis of NMS can be complex; similar signs and symptoms may also occur with other serious medical conditions (e.g., pneumonia, systemic infection) and untreated or poorly treated extrapyramidal disorders. Other important considerations in differential diagnosis include central anticholinergic toxicity, heatstroke, drug fever, and primary central nervous system disorders. /Bubenazine/
For more complete data on deuterated bubenazine (14 in total), please visit the HSDB record page.

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Pharmacodynamics
QTc interval prolongation was observed at a 50 mg dose. In rats, the binding of deuterated butylbenazine or its metabolites to melanin-containing tissues, such as the eyes and skin, has been observed. Radioactivity was still detectable in the eyes and hair 21 days after a single oral dose of radiolabeled butylbenazine. Clinical trials have shown that deuterated butylbenazine effectively improves involuntary motor symptoms in patients with tardive dyskinesia by reducing the mean abnormal involuntary movement scale (AIMS) score. In a randomized, double-blind, placebo-controlled crossover study in healthy male and female subjects, a single dose of 24 mg deuterated butylbenazine resulted in a mean QTc interval prolongation of approximately 4.5 ms. The effects of higher doses of deuterated butylbenazine or its metabolites have not been evaluated. Studies have shown that deuterated butylbenazine and its metabolites can bind to melanin-containing tissues, including the eyes, skin, and hair of colored rats. Radioactivity was still detectable in the eyes and hair 35 days after a single oral dose of radiolabeled deuterated butylbenazine.

C19H27NO3

317.4226

317.199

718635-93-9

Tetrabenazine;58-46-8;(+)-Tetrabenazine;1026016-83-0;Tetrabenazine-d6;1392826-25-3

6018

Light yellow to yellow solid powder

3.176

0

4

4

23

425

0

MKJIEFSOBYUXJB-UHFFFAOYSA-N

InChI=1S/C19H27NO3/c1-12(2)7-14-11-20-6-5-13-8-18(22-3)19(23-4)9-15(13)16(20)10-17(14)21/h8-9,12,14,16H,5-7,10-11H2,1-4H3

9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~157.52 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (7.88 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)