| Active Ingredient | DEUTETRABENAZINE |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AUSTEDO | 208082 | TEVA PHARMS USA INC | TABLET;ORAL | 6MG, 9MG, 12MG | TBD | April 3, 2017 | Apr 3, 2022 | Apr 3, 2024 | 1 New molecular entity (NME) | STANDARD | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one |
| CAS No | 1392826-25-3 |
| Molecular Formula | C19H21D6NO3 |
| Molecular Weight | 323.46 |
| Appearance | A white to slightly yellow crystalline powder |
| Solubility | It is sparingly soluble in water and soluble in ethanol. |
| Water Solubility | - |
| Polymorphism | Deutetrabenazine is a racemic mixture. |
| pKa (Strongest Acidic) | 6.31 |
| pKa (Strongest Basic) | - |
| Log P | 3.23 (Predicted) |
| Identification | - |
| Degradation | - |
| Hygroscopic | - |
| Photostability study | - |
| Melting Point | - |
| BCS Class | - |
| Manufacture of API | - |
| Parameters | Details |
|---|---|
| Indications and Usage | AUSTEDO™ is indicated for the treatment of chorea associated with Huntington’s disease. |
| Dosage and Administration |
The dose of AUSTEDO is determined individually for each patient based on reduction of chorea and tolerability.When first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor), the recommended starting dose of AUSTEDO is 6 mg administered orally once daily. The dose of AUSTEDO may be increased at weekly intervals in increments of 6 mg per day to a maximum recommended daily dosage of 48 mg. Administer total daily dosages of 12 mg or above in two divided doses. Administer AUSTEDO with food. Swallow AUSTEDO whole. Do not chew, crush, or break tablets. Refer FDA label for more information. |
| Mechanism of action | The precise mechanism by which AUSTEDO (deutetrabenazine) exerts its anti-chorea effects is unknown but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. The major circulating metabolites (α-dihydrotetrabenazine [HTBZ] and β-HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. |
| Absorption |
After oral dosing up to 25 mg, plasma concentrations of deutetrabenazine are generally below the limit of detection because of the extensive hepatic metabolism of deutetrabenazine to the active deuterated dihydro metabolites (HTBZ), α-HTBZ and β-HTBZ. Linear dose dependence of Cmax and AUC was observed for the active metabolites following single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). Following oral administration of deutetrabenazine, the extent of absorption is at least 80%. Plasma concentrations of deutetrabenazine are generally below the limit of detection after oral dosing. Peak plasma concentrations (Cmax) of deuterated α-HTBZ and β-HTBZ are reached within 3 to 4 hours after dosing. |
| Food Effect | The effects of food on the bioavailability of AUSTEDO were studied in subjects administered a single dose with and without food. Food had no effect on the area under the plasma concentration-time curve (AUC) of α-HTBZ or β-HTBZ, although Cmax was increased by approximately 50% in the presence of food. |
| Distribution |
The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of AUSTEDO are approximately 500 L and 730 L, respectively. Results of PET-scan studies in humans show that following intravenous injection of 11C-labeled tetrabenazine or α-HTBZ, radioactivity is rapidly distributed to the brain, with the highest binding in the striatum and lowest binding in the cortex. The in vitro protein binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%. |
| Metabolism |
AUSTEDO is primarily renally eliminated in the form of metabolites. The half-life of total (α+β)-HTBZ from deutetrabenazine is approximately 9 to 10 hours. The median clearance values (CL/F) of the α-HTBZ, and the β-HTBZ metabolites of AUSTEDO are approximately 47 L/hour and 70 L/hour, respectively, in the Huntington’s disease patient population. In vitro experiments in human liver microsomes demonstrate that deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase, to its major active metabolites, α-HTBZ and β-HTBZ, which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites. |
| Elimination | In a mass balance study in 6 healthy subjects, 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary excretion of the α-HTBZ and β-HTBZ metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. |
| Peak plasma time (Tmax) | 3 to 4 hours |
| Half life | 9 to 10 hours |
| Bioavailability | - |
| Age, gender | There is no apparent effect of gender on the pharmacokinetics of α-HTBZ and β-HTBZ of deutetrabenazine. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| Not Available | ||||
| Parameters | Details | |||
|---|---|---|---|---|
| Strength | 6MG | 9MG | 12MG | |
| Excipients used | ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake, FD&C red #40 lake |
ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake. |
ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake, FD&C yellow #6 lake |
|
| Composition of coating material | - | |||
| Composition of caspule shell | - | |||
| Pharmaceutical Development | - | |||
| Manufacture of the product | - | |||
| Tablet / Capsule Image | ||||
| Appearance | round, purple-coated tablets, with “SD” over “6” printed in black ink on one side. | round, blue-coated tablets, with “SD” over “9” printed in black ink on one side. | round, beige-coated tablets, with “SD” over “12” printed in black ink on one side. | |
| Imprint code / Engraving / Debossment | “SD” over “6” printed in black ink on one side. | “SD” over “9” printed in black ink on one side. | “SD” over “12” printed in black ink on one side. | |
| Score | no score | no score | no score | |
| Color | Purrple | Blue | Beige | |
| Shape | Round | Round | Round | |
| Dimension | 10 mm | 10 mm | 10 mm | |
| Mfg by | - | |||
| Mfg for | - | |||
| Marketed by | - | |||
| Distributed by | Teva Pharmaceuticals | |||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N208082 | 1 | 8524733 | March 27, 2031 | DS | DP | - | - | Download |
| N208082 | 1 | 9233959 | September 18, 2033 | - | DP | - | - | Download |
| N208082 | 1 | 9296739 | September 18, 2033 | - | DP | - | - | Download |
| N208082 | 1 | 9550780 | September 18, 2033 | DS | DP | U-1846 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) over a disk (62 mm with 16 mesh) | 75 | pH 3.0 Acid Phthalate Buffer | 500 | 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours | November 2, 2017 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | |
| European Public Assessment Report |
| - |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
