Austedo 12Mg Start Titr(Wk1-4) (deutetrabenazine)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent. The drug is a deuterium-substituted derivative of tetrabenazine.
Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent. The drug is a deuterium-substituted analog of tetrabenazine; deuterium, a nontoxic, naturally occurring isotope of hydrogen with a higher relative mass, forms a stronger bond with carbon molecules that hinders metabolism by cytochrome P-450 isoenzymes. Deuterium substitution results in deutetrabenazine active metabolites that have a longer elimination half-life, higher AUC, and lower peak plasma concentrations than those achieved with an equivalent dose of tetrabenazine.
Patients with Huntington's disease appear to exhibit oversensitivity to dopamine stimulation, resulting in choreic movements. Although the exact mechanism by which deutetrabenazine exerts its effects in the treatment of tardive dyskinesia and chorea in patients with Huntington's disease has not been fully elucidated, the drug, like tetrabenazine, selectively and reversibly inhibits VMAT2-mediated uptake of monoamine neurotransmitters (e.g., dopamine, norepinephrine, serotonin, histamine) into presynaptic vesicles in the CNS; monoamines not transported into synaptic vesicles are degraded by monoamine oxidase (MAO), resulting in depleted monoamine stores in nerve terminals. Like tetrabenazine, deutetrabenazine and its active metabolites preferentially affect dopaminergic neurotransmission in the CNS over adrenergic, serotonergic, and histaminergic neurotransmission at clinically relevant plasma concentrations.
Following oral administration, deutetrabenazine is rapidly and extensively metabolized, mainly by carbonyl reductase, to the active metabolites deuterated alpha-dihydrotetrabenazine (deuterated alpha-HTBZ) and deuterated beta-dihydrotetrabenazine (deuterated beta-HTBZ); plasma concentrations of the parent drug are generally undetectable. Peak plasma concentrations of deuterated alpha-HTBZ and deuterated beta-HTBZ occur within 3-4 hours following oral administration of the drug; sustained concentration plateaus for several hours are achieved with the extended-release formulation. Administration with food increases peak plasma concentrations of deuterated alpha-HTBZ and deuterated beta-HTBZ by approximately 50% with the immediate-release formulation, but has no effect on the AUC.
The drug distributes rapidly into the CNS, with highest and lowest concentrations occurring in the striatum and cortex, respectively. Deuterated alpha-HTBZ and deuterated beta-HTBZ are metabolized primarily by CYP2D6 with minor contributions by CYP isoenzymes 1A2 and 3A4/5 to form several minor metabolites. Approximately 75-86 and 8-11% of a deutetrabenazine dose is eliminated in urine and feces, respectively, with <10% eliminated as unchanged deuterated alpha-HTBZ and deuterated beta-HTBZ.
The half-life of deuterated alpha-HTBZ and deuterated beta-HTBZ combined is approximately 9-10 hours.
Deutetrabenazine is available as immediate- and extended-release formulations. The clinical studies detailed in this section were conducted with the immediate-release formulation. The efficacy of the extended-release formulation is based on a relative bioavailability study comparing extended-release tablets given once daily to immediate-release tablets twice daily.
Generic name: deutetrabenazine
Pronunciation: (DU-tet-ra-BEN-a-zeen)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Austedo 12Mg Start Titr(Wk1-4)
Indications
The following indications are listed for Austedo 12Mg Start Titr(Wk1-4):
- Chorea Associated With Huntington's Disease
- Tardive Dyskinesia
Dosing
Dosage of deutetrabenazine should be individualized based on efficacy (i.e., reduction of chorea or tardive dyskinesia) and tolerability.
Deutetrabenazine immediate-release tablets should be administered orally with food. Extended-release deutetrabenazine tablets are administered orally with or without food. Both immediate- and extended-release tablets should be swallowed whole and not chewed, crushed, or broken.
Total daily dosages of the immediate-release tablets less than 12 mg are administered once daily; total daily dosages of 12 mg or higher should be administered in 2 divided doses.
Store deutetrabenazine immediate- and extended-release tablets at 25degreesC; excursions permitted between 15-30degreesC. Protect from light and moisture.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Drug interaction studies evaluating the effect of deutetrabenazine or its active metabolites (deuterated alpha-dihydrotetrabenazine (deuterated alpha-HTBZ) and deuterated beta-dihydrotetrabenazine (deuterated beta-HTBZ)) on cytochrome P-450 (CYP) isoenzymes or P-glycoprotein (P-gp) have not been conducted to date. In vitro studies indicate that other metabolites of deutetrabenazine (M1 and M4) are not expected to cause clinically important drug interactions.
Tetrabenazine, a closely related VMAT2 inhibitor, and its active metabolites (alpha-HTBZ and beta-HTBZ) do not substantially inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, nor do they substantially induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro. Neither tetrabenazine nor its active metabolites are likely to be substrates or inhibitors of P-gp at clinically relevant concentrations.
Deutetrabenazine's active metabolites (deuterated alpha-HTBZ and deuterated beta-HTBZ) are substrates of CYP2D6.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Patients with Huntington's disease who are suicidal or have untreated or inadequately treated depression.
*Hepatic impairment.
*Concomitant therapy with reserpine. At least 20 days should elapse between discontinuance of reserpine and initiation of deutetrabenazine.
*Concomitant therapy with a monoamine oxidase (MAO) inhibitor. At least 14 days should elapse between discontinuance of an MAO inhibitor and initiation of deutetrabenazine.
*Concomitant therapy with tetrabenazine or valbenazine.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects occurring in patients with Huntington's disease with an incidence >8% and more than placebo include: somnolence, diarrhea, dry mouth, and fatigue.
Adverse effects occurring in patients with tardive dyskinesia with an incidence of 4% and more than placebo include: nasopharyngitis and insomnia.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
The manufacturer states that the safety and efficacy of deutetrabenazine in pediatric patients have not been established for the treatment of chorea associated with Huntington's disease or for the treatment of tardive dyskinesia.
Safety and efficacy of deutetrabenazine have not been established in pediatric patients for the treatment of Tourette syndrome+. Efficacy was not demonstrated in 2 randomized controlled trials in patients 6-16 years of age with Tourette syndrome+. One study evaluated fixed doses of deutetrabenazine over 8 weeks (NCT03571256); the other study evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943). The studies included 274 patients who received at least one dose of deutetrabenazine or placebo. The primary efficacy endpoint in both studies was the change from baseline to end-of-treatment on the Yale Global Tic Severity Scale Total Tic Score (TGTSS-TSS). Deutetrabenazine was not substantially different from placebo in reducing tics based on changes from baseline to week 8 on the YGTSS-TTS in either study. Adverse effects were mild to moderate and no new safety signals were identified.
The manufacturer states that there are no adequate data regarding the developmental risk associated with the use of deutetrabenazine in pregnant women. Reproduction studies revealed no clear adverse effect on embryofetal development when deutetrabenazine was administered orally during the period of organogenesis to rats at dosages up to 6 times the maximum recommended human dosage. However, when tetrabenazine (a closely related VMAT2 inhibitor) was administered to rats throughout pregnancy and lactation, increased stillbirths, reduced pup survival, and delayed pup maturation were observed.
It is not known whether deutetrabenazine or its metabolites are distributed into milk in humans. The effects of deutetrabenazine or its metabolites on breast-fed infants or on milk production also are unknown. The developmental and health benefits of breast-feeding to the infant should be considered along with the mother's clinical need for deutetrabenazine and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
The manufacturer states that dosage of deutetrabenazine should be selected with caution in geriatric patients, usually beginning with the lower end of the dosage range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy in such patients.
Clinical studies of deutetrabenazine did not include sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger adults. Other clinical experience with deutetrabenazine has not identified differences in responses between geriatric and younger adult patients.
Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer recommends that dosage selection of deutetrabenazine in geriatric patients should be cautious, usually beginning with the lower end of the dosage range.
ICD codes
No ICD codes are available for this drug.
Formulary status
Search health-plan coverage for this drug by ZIP code.
Choose the first character of a health plan name.
Last reviewed · Source: First Databank (FDB) drug data
On this page
Actions
Sign in to save favorites
Saving this drug requires a free Physicians Office Resource account.