CNS Drugs 2011; 25 (12): 1073-1085

ADIS DRUG PROFILE 1172-7047/11/0012-1073/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

Tetrabenazine
For Chorea Associated with Huntington’s Disease
Lesley J. Scott
Adis, a Wolters Kluwer Business, Auckland, New Zealand

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073
1. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075
2. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078
4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081
5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
6. Tetrabenazine: Current Status For Chorea Associated with Huntington’s Disease . . . . . . . . . . . . . . . 1083

Abstract Features and properties of tetrabenazine (TBZ;

Xenazine®)
Oral tetrabenazine is currently the only drug
approved by the US FDA for the treatment of Indication
chorea associated with Huntington’s disease (HD). For the treatment of chorea associated with Huntington’s
disease
Although the precise antichorea mechanism of ac-
Mechanism of action
tion is unknown, it most likely involves reversible
Most likely involves reversible depletion of monoamines,
depletion of monoamines, particularly dopamine, especially dopamine, from presynaptic nerve terminals via
from presynaptic terminals via inhibition of human inhibition of human vesicular monoamine transporter type 2
vesicular monoamine transporter type 2. Pharmacokinetic profile (values are for the active
In a 12-week, double-blind, placebo-controlled metabolite α-dihydrotetrabenazine [DHTBZ])
trial conducted in the US in patients with HD, oral Time to attain maximum 1–1.5 h
tetrabenazine (£100 mg/day; n = 54) was significantly plasma concentration
(p = 0.0001) more efficacious than placebo (n = 30) at Metabolism TBZ is generally undetectable
in plasma, as it undergoes
improving adjusted mean Unified HD Rating Scale rapid and extensive first-pass
(UHDRS) total maximum chorea scores (reduced metabolism by carbonyl
from baseline by 5 vs 1.5) [primary endpoint]. reductase to α-DHTBZ (active)
and β-DHTBZ (inactive)
After 12 weeks, improvements in UHDRS total α-DHTBZ and β-DHTBZ are
maximum chorea scores of >3 were achieved by primarily metabolized by
significantly (p < 0.0001) more patients in the tetra- cytochrome P450 2D6
benazine group than in the placebo group. Elimination Primarily via renal route
The antichorea efficacy of tetrabenazine was main- Elimination half-life 7 h [α-DHTBZ]; 5 h [β-DHTBZ]
tained in an 80-week extension study (n = 75), with the Dosage and administration (individualized to optimal
adjusted mean UHDRS total maximum chorea score dosage; titrated to a tolerated dosage that reduces chorea)
significantly (p < 0.001) reduced from baseline (score Initial dosage 12.5 mg taken once daily in the
morning
of 14.9) by 4.6 points (primary outcome).
In the 12-week trial and 80-week extension study, Titration dosage 25 mg/day as two divided
doses, then 37.5–50 mg/day as
treatment-emergent adverse events in the tetra- three divided doses if required
benazine group mainly occurred during the dosage- Maximum dosage 100 mg/day as three divided
titration phase, a period during which the dosage doses
was individually optimized. Most of these events Route of administration Oral
were mild to moderate and were manageable with Most common treatment-emergent adverse events
dosage adjustments or discontinuation of study drug. (incidence ≥15% and greater than in placebo group)
Drowsiness/somnolence, insomnia, fatigue, fall, depression,
agitation, anxiety
1074
O consequence of neuronal degeneration and atro-
H3CO
N marked striatal and cortical atrophy are already
H3CO
Chemical structure of tetrabenazine
Huntington’s disease (HD) is an autosomal
dominant neurodegenerative disorder, with an esti-
mated prevalence in the Western world of 4–10
per 100 000 individuals.[1-3] In the US, an esti-
mated 25 000–30 000 individuals have HD, and
an estimated 150 000–250 000 individuals are at
risk for the disease.[4] HD occurs in all races and
ethnicities,[1] and men and women are affected
equally.[4] The typical age of onset of clinical symp-
toms is the third or fourth decade of life, although
onset may occur at any time from infancy to the
ninth decade of life.[1,2,4-6] Death usually occurs
within 10–20 years of disease onset.[1,2,4-6]
HD is caused by amplification of the CAG
(glutamine) trinucleotide in the huntingtin gene,
resulting in an abnormally long polyglutamate
repeat in the huntingtin protein.[1-3,5] The number
of repeats in the CAG expansion is inversely cor-
related with the age at clinical onset of the dis-
ease, with more repeats associated with earlier
onset of HD (‡50 repeats is associated with ju-
venile onset).[1,2,6] Environmental influences and
modifying genes are also likely to be involved in
determining the age of onset.[2] The number of
CAG repeats is also indicative of the likelihood of
developing HD: <36 repeats is considered normal
(typical range is 17–20), 36–39 repeats is con-
sidered abnormal and individuals may or may
not develop HD, and individuals with ‡40 repeats
will always develop the disease.[1,2,6]
The characteristic triad of clinical features of
HD are progressive motor dysfunction (such as
chorea, dystonia, bradykinesia), neuropsychiatric
manifestations (such as depression, obsessive-
compulsive disorders, anxiety) and cognitive
impairment (for example, disorganization as a
result of difficulties with planning, initiating and
organizing thoughts).[1,2,4-6] These features are a
ª 2011 Adis Data Information BV. All rights reserved.
Scott
CH3
phy, particularly in the striatum and cortex, that
results from the presence of an abnormal hun-
CH3 tingtin protein.[1,2,4-6] At the time of diagnosis,
likely to be present, with brain abnormalities
occurring years before the clinical symptoms
manifest.[1]
As with many chronic terminal illnesses, HD is
associated with an increased risk of depression/
depressed mood.[7-9] However, depression often
occurs several years before HD manifests, sug-
gesting that it may be an integral component of
HD.[7-9] As reviewed by van Duijn et al.,[9] the
prevalence of depressed mood is relatively high
in patients with HD (ranging from 33% to 69%).
For example, in a recent large cross-sectional
study in patients with HD (n = 2835), approximately
40% of patients had symptoms of depression
and more than half had sought treatment for
depression.[7]
Suicidal ideation and suicide are also common
features associated with HD, with reported sui-
cide rates that are 5–10 times greater than those
reported in the general population.[7,10] Of inter-
est, in patients with HD, suicidality may be asso-
ciated with impulsiveness, obsessive-compulsive
behaviours and/or a variety of socioeconomic
factors rather than correlating with the severity of
depression.[4] Studies show that suicide attempts
are not uncommon (occurring in up to 25%
of patients) in patients with HD.[7,10] Suicidal
ideation is generally greatest around the time of
diagnosis of manifest HD and again when
patients start to lose their functional abilities and
independence.[11]
There are currently no established disease-
modifying therapies that prevent or delay the pro-
gression of HD, with current treatment strategies
targeting the relief of symptoms, including the
classic choreic movements, to reduce the signif-
icant impact that HD has on the patient’s daily
living activities.[4-6] The dance-like movements,
known as chorea, are the most characteristic ini-
tial physical manifestation of HD and occur in
approximately 90% of patients.[8,10,12,13] Chorea
involves irregular, abrupt, uncontrolled move-
ments of the face, extremities and body that may
CNS Drugs 2011; 25 (12)
Tetrabenazine: Adis Drug Profile
appear dance-like because of the jerky, twisting
motions. Although initially chorea may be quite
mild, consisting of general restlessness or clum-
siness, as the disease progresses these movements
often make it very difficult to perform tasks of
daily living such as getting dressed. Ultimately,
chorea may interfere with voluntary movements
and thereby impact on activities like walking,
talking, eating and bladder control. However,
there is a poor correlation between the extent of
chorea and disease severity.[8,10,12,13]
Current pharmacotherapies used in the treat-
ment of chorea associated with HD include neu-
roleptic agents (atypical neuroleptic agents such
as olanzapine, aripiprazole and risperidone or
older neuroleptics such as haloperidol) and the
vesicular monoamine transporter (VMAT) type 2
(VMAT2) inhibitor tetrabenazine (Xenazine),
with VMAT2 inhibition resulting in depletion of
monoamines, especially dopamine, in presynap-
tic vesicles.[4-6] In a recent Cochrane review of 22
trials evaluating various pharmacotherapies for
the management of chorea associated with HD,
including anti-dopaminergic agents, glutamate re-
ceptor antagonists and energy metabolites, tetra-
benazine treatment provided the best clinical
dence for efficacy in the control of chorea.[14] To
date, tetrabenazine is the only drug that is ap-
proved by the US FDA for the treatment of
chorea associated with HD. This review focuses
on the use of oral tetrabenazine at dosages re-
commended in the US for the treatment of chorea
associated with HD (see section 5);[15] discussion
of its use in patient populations with other forms
of dyskinesia and of studies in which dosages
greater than those recommended were used is be-
yond the scope of this review.
Medical literature (including published and
unpublished data) on the use of tetrabenazine in
Huntington’s disease was identified by searching
databases since 1996 (including MEDLINE, EM-
BASE), bibliographies from published literature,
clinical trial registries/databases and web sites (in-
cluding those of regional regulatory agencies and the
manufacturer). Additional information (including
contributory unpublished data) was also requested
from the drug company. Searches were last updated
15 November 2011.
ª 2011 Adis Data Information BV. All rights reserved.
1075
1. Pharmacodynamic Properties
 Although the precise mechanism of action
involved in the antichorea effects of tetrabena-
zine is unknown, these effects are thought to
be mediated via reversible depletion of mono-
amines from presynaptic vesicles, especially do-
pamine. Tetrabenazine is a selective, reversible, high
affinity (inhibitory constant [Ki] »100 nmol/L[15])
inhibitor of VMAT2 (the neuronal isoform of
VMAT).[16-27] Inhibition of VMAT2 by tetra-
benazine reduces the uptake of monoamines into
presynaptic vesicles and thereby depletes concen-
trations of monoamines, particularly dopamine,
as observed in preclinical[16-25] and human post-
mortem[26,27] studies.
 The major active circulating metabolite of tetra-
benazine, a-dihydrotetrabenazine (see section 2),
also inhibited VMAT2 and reduced monoamine
uptake into presynaptic vesicles in in vitro[20] and
animal studies.[18,19] In rats, a-dihydrotetrabenazine
was as effective or more effective than tetrabenazine
in terms of its effects on monoamine depletion.[18]
Of the monoamines, dopamine concentrations de-
creased the most and serotonin concentrations de-
creased the least, with monoamine concentrations in
the brain returning to control concentrations within
12 hours. Serum and brain concentrations of tetra-
benazine and a-dihydrotetrabenazine peaked at
30 minutes post-dose, which correlated with the
time to peak depletion of monoamines.[18]
 In vitro studies indicated that tetrabenazine
only inhibited monoamine transport by neuronal
VMAT2, whereas reserpine inhibited both neu-
ronal VMAT2 and peripheral, endocrine-specific
VMAT type 1 (VMAT1) resulting in both central
and peripheral depletion of monoamines.[16,19,21,28]
This lack of inhibition of VMAT1 by tetrabena-
zine may, at least in part, explain its lower pro-
pensity than reserpine to cause hypotension and
gastrointestinal adverse effects such as epigastric
pain and diarrhoea.[4,29]
 Tetrabenazine also differs from reserpine in
chemical structure (tetrabenazine lacks the indole
ring of reserpine), reversible rather than irrevers-
ible inhibition of VMAT2, binding at intravesicular
sites rather than cytoplasmic sites and its shorter
duration of action (hours vs days).[16,18,26,29]
CNS Drugs 2011; 25 (12)
1076
 In in vitro studies, tetrabenazine exhibited a
low affinity for dopamine D2 receptors (Ki = 2100
nmol/L).[30,31] Since the affinity of tetrabenazine
at D2 receptors is approximately 1000-fold lower
than that for VMAT2, it appears unlikely that the
clinical antichorea effects of tetrabenazine are
mediated via this mechanism.[29]
 In postmortem brain tissue from patients with
HD, tetrabenazine-treated patients (n = 11) had
significantly lower concentrations of dopamine
in the caudate (1113 vs 3281 ng/g tissue [reduced
by 67%]; p < 0.01) and in the hippocampus (9.61
vs 22.2 ng/g tissue [reduced by 57%]; p < 0.05)
than patients who had not received tetrabenazine
(n = 7).[27] There were no significant between-
group differences in dopamine concentrations in
the amygdala or temporal cortex. The significant
reduction of dopamine concentrations in the
caudate probably explains the amelioration of
chorea observed with tetrabenazine treatment, as
chorea is thought to be related to hyperdopami-
nergic activity. Dopamine concentrations in post-
mortem brain tissue of tetrabenazine-treated
patients reflected those observed in a matched
control group.[27]
 In this study,[27] there were also significantly
(p < 0.05) lower concentrations of norepinephrine
(noradrenaline) in the amygdala (47.1 vs 105 ng/g
tissue in untreated patients [reduced by 55%]) and
hippocampus (14.1 vs 47.4 ng/g tissue [reduced by
70%]) in tetrabenazine-treated patients, but no
significant between-group differences in norepi-
nephrine concentrations in the temporal cortex.
There were no between-group differences in terms
of serotonin concentrations in any of these re-
gions of the CNS.
 In an observational study in ten patients with
HD, a single dose of tetrabenazine improved
chorea for a mean of 5.4 hours (minimum of
3.2 hours and maximum of 8.1 hours), as assessed
using the Unified HD Rating Scale (UHDRS)
total chorea score.[32] See section 3 for discussion
of the antichorea effects of tetrabenazine treat-
ment in patients with HD participating in short-
and long-term clinical studies.
 In a transgenic mouse model of HD (YAC128
mice), tetrabenazine treatment alleviated the motor
deficits and reduced striatal neuronal cell loss,
ª 2011 Adis Data Information BV. All rights reserved.
Scott
irrespective of whether tetrabenazine treatment
was initiated in younger (2 months of age) or
older mice (6 months of age).[33,34]
 Single doses of tetrabenazine 25 and 50 mg
increased the maximum time-matched placebo-
adjusted change from baseline in corrected QT
(QTc) interval by 3.6 and 7.7 msec in healthy adult
volunteers in a double-blind, Thorough QTc study,
as reported in the US FDA briefing document.[35]
To date, studies evaluating the effects of greater
doses of tetrabenazine or its metabolites on the
QTc interval have not been conducted.[15,35] Since
tetrabenazine treatment causes small increases in
the QTc interval, the use of tetrabenazine in com-
bination with drugs that are known to prolong
the QTc interval and in patients with congenital
long QT syndrome or with a history of cardiac
arrhythmias should be avoided because of poten-
tial adverse events, such as torsade de pointes-
type ventricular arrhythmias.[15]
 Since tetrabenazine or its metabolites bind to
melanin-containing tissues (assessed in animal
studies), they may accumulate in these tissues over
time and potentially be associated with toxicity
in these tissues (reported in the US manufacturer’s
prescribing information).[15] The clinical rele-
vance of the binding of tetrabenazine to melanin-
containing tissues is unknown. Ophthalmological
monitoring in humans was inadequate to exclude
the possibility of injury occurring after long-term
exposure to tetrabenazine.[15]
2. Pharmacokinetic Properties
There is a relative paucity of published data
relating to the pharmacokinetics of oral tetra-
benazine in humans,[36-38] with most data derived
from the US manufacturer’s prescribing informa-
tion[15] and the FDA briefing document for tetra-
benazine.[35]
 After oral administration, tetrabenazine is
rapidly absorbed in the gastrointestinal tract, with
the extent of absorption being at least 75% of the
administered dosage.[15]
 After single tetrabenazine doses of 12.5–50 mg,
plasma concentrations of tetrabenazine are gener-
ally below the limit of detection because of rapid
and extensive first-pass metabolism by carbonyl
CNS Drugs 2011; 25 (12)
Tetrabenazine: Adis Drug Profile
reductase to the major circulating metabolites,
a-dihydrotetrabenazine (biologically active) and
b-dihydrotetrabenazine (inactive).[15,36,37] Peak
plasma concentrations (Cmax) of a-dihydrotetra-
benazine and b-dihydrotetrabenazine are attained
within 1–1.5 hours post-dose and that of their
major metabolite, O-dealkyated-dihydrotetra-
benazine, is attained approximately 2 hours post-
dose.
 Across a dosage range of 37.5–112.5 mg/day,
tetrabenazine and dihydrotetrabenazine displayed
linear pharmacokinetics in four patients with tar-
dive dyskinesia.[36] Patients exhibit a high degree
of interindividual variability in the distribution,
metabolism (conversion to dihydrotetrabenazine)
and clearance of tetrabenazine and dihydrotetra-
benazine,[37] with the manufacturer’s prescribing
information[15] indicating that the dosage should
be optimized on an individual basis (section 5).
 There were no clinically relevant effects of
food on the bioavailability of tetrabenazine;[15,37]
thus, the drug may be taken without regard to
food.[15]
 Positron emission tomography scan studies in
humans showed that radioactivity is rapidly dis-
tributed into brain tissue following an intrave-
nous injection of radiolabelled tetrabenazine, with
the greatest binding occurring in the striatum
and the least binding in the cortex.[15] At human
plasma concentrations of 50–200 ng/mL, in vitro
protein binding of tetrabenazine, a-dihydrotetra-
benazine and b-dihydrotetrabenazine ranged
from 82% to 85%, 60% to 68% and 59% to 63%,
respectively.[15,37]
 After oral administration, tetrabenazine is
rapidly and extensively metabolized to at least
19 metabolites, including initial metabolism by
carbonyl reductase (mainly localized in the liver)
to a-dihydrotetrabenazine and b-dihydrotetrabe-
nazine.[15,36,37] These major metabolites are then
converted to O-deaklyated-dihydrotetrabenazine,
principally by cytochrome P450 (CYP) 2D6, with
some contribution from CYP1A2 in the case of
a-dihydrotetrabenazine. Subsequently, the major
metabolites are converted to sulfate and glu-
curonide conjugates.[15] In vitro studies indicate
that CYP1A2, CYP2A6, CYP2C9, CYP2C19
and CYP2E1 do not play a major role in the
ª 2011 Adis Data Information BV. All rights reserved.
1077
metabolism of a-dihydrotetrabenazine and b-
dihydrotetrabenazine.[15]
 In healthy volunteers, metabolites of tetrabe-
nazine were primarily eliminated via the renal
route, with approximately 75% of the dosage ex-
creted in the urine and 7–16% of in the faeces.[15]
Unchanged tetrabenazine has not been found in
human urine; a-dihydrotetrabenazine and b-dihy-
drotetrabenazine detected in the urine accounted
for less than 10% of the administered dose. The
majority of metabolites in the urine consisted of
sulfate and glucuronide conjugates of dihydrote-
trabenazine or products of oxidative metabolism.[15]
 The respective elimination half-lives (t½) of
a-dihydrotetrabenazine and b-dihydrotetrabena-
zine are 7 and 5 hours.[15]
In Special Patient Populations
 There is no apparent effect of the sex of an
individual on the pharmacokinetics of a-dihy-
drotetrabenazine and b-dihydrotetrabenazine.[15]
The pharmacokinetics of tetrabenazine and its pri-
mary metabolites have not been studied in paedi-
atric patients or in patients with renal impairment,
nor have they been formally studied in geriatric pa-
tients or in patients of different races.[15]
 Since tetrabenazine is extensively metabolized
in the liver, exposure to the drug is increased in
patients with hepatic impairment.[15] There was a
marked decrease in the metabolism of tetrabena-
zine in patients with mild to moderate hepatic
impairment (Child-Pugh scores 5–9; n = 12) com-
pared with sex-matched volunteers with normal
hepatic function, with plasma concentrations of
tetrabenazine being similar to those of a-dihy-
drotetrabenazine in patients with hepatic impair-
ment. Mean Cmax values for tetrabenazine were
approximately 7- to 190-fold greater in patients
with hepatic impairment than those in healthy
volunteers, with t½ values increased to approxi-
mately 17.5 hours in patients with hepatic impair-
ment. Hence, tetrabenazine is contraindicated in
patients with hepatic impairment.[15]
 Since a-dihydrotetrabenazine and b-dihydro-
tetrabenazine are principally metabolized by the
genetically polymorphic CYP2D6 pathway, it is
likely that exposure to these major metabolites of
CNS Drugs 2011; 25 (12)
1078
tetrabenazine will be increased in individuals who
are classified as poor metabolizers (PM) com-
pared with those classified as extensive meta-
bolizers (EM).[15] The increase in exposure to
a-dihydrotetrabenazine and b-dihydrotetrabenazine
would be expected to be similar to that observed
in patients receiving tetrabenazine concomitantly
with a strong CYP2D6 inhibitor such as parox-
etine (also see discussion below on potential drug
interactions), although the clinical relevance of
this remains to be fully elucidated.[15,35]
Potential For Drug Interactions
 Coadministration of tetrabenazine with a
strong CYP2D6 inhibitor (such as paroxetine,
fluoxetine, quinidine) may increase exposure to
a-dihydrotetrabenazine and b-dihydrotetrabena-
zine; caution is advised when coadministering these
agents and the dosage of tetrabenazine should be
halved.[15] Concomitant administration of a single
dose of tetrabenazine 50 mg following 10 days
of paroxetine 20 mg/day resulted in an increase
in Cmax and area under the plasma concentration-
time curve values for a-dihydrotetrabenazine of ap-
proximately 30% and 3-fold, with respective values
for b-dihydrotetrabenazine increasing 2.4- and 9-fold.
The effects of moderate or weak CYP2D6 inhib-
itors (such as duloxetine, amiodarone, terbinafine,
sertraline) have not been evaluated.[15]
 Based on in vitro studies, a clinically relevant
interaction between tetrabenazine and other CYP
inhibitors (except those inhibiting CYP2D6)
appears unlikely.[15] In these studies, tetrabena-
zine, a-dihydrotetrabenazine and b-dihydrotetra-
benazine resulted in no clinically significant inhib-
ition of CYP2D6, CYP1A2, CYP2C8, CYP2C9,
CYP2C19, CYP2E1 or CYP3A isoenzymes; their
effect on the CYP2B6 isoenzyme has not been
evaluated.[15] Similarly, it appears unlikely that they
result in any clinically significant induction of
CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9
or CYP2C19 isoenzymes.[15]
 Tetrabenazine, a-dihydrotetrabenazine and
b-dihydrotetrabenazine are also unlikely to be a
substrate for or inhibitor of P-glycoprotein, based
on in vitro studies.[15] In healthy volunteers, tetra-
benazine 25 mg twice daily for 3 days had no
ª 2011 Adis Data Information BV. All rights reserved.
Scott
affect on the bioavailability of digoxin (a sub-
strate for P-glycoprotein).[15]
3. Therapeutic Efficacy
The efficacy of oral tetrabenazine has been
evaluated in adult patients with HD in short-term
(<12 months’ duration)[39-44] and long-term (‡12
months’ duration)[45-48] studies. Discussion focuses
on the pivotal, 12-week, randomized, double-blind,
placebo-controlled, multicentre trial[39] conducted
in the US and an open-label extension phase[45] of
this study, both of which are fully published.
Short-Term Studies
Key trial design and study details, including the
dosage regimen and efficacy outcome measures,
for the 12-week, double-blind study are sum-
marized in table I.[39] There were generally no
significant between-group differences in baseline
demographics and HD history (including age,
HD duration, CAG repeat number and history of
depression [table I]), with the exception of base-
line scores for UHDRS symbol digit (18.1 in the
tetrabenazine group vs 24.4 in the placebo group;
p = 0.018) and Functional Impact Scale (1.3 vs 0.4;
p = 0.035) which favoured the placebo group. Pre-
dictably, the number of CAG repeats was inversely
correlated (p < 0.0001) with the age at disease onset.
 After 12 weeks’ treatment, tetrabenazine (£100
mg/day) was significantly more efficacious than
placebo at improving chorea, as measured by ad-
justed mean UHDRS total maximum chorea scores
(primary outcome) [figure 1].[39] The adjusted treat-
ment effect size for improvement in chorea severity
was -3.5 (95% CI -5.2, -1.9), with an average 23.5%
reduction from baseline in chorea severity. Improve-
ments in chorea with tetrabenazine treatment
occurred irrespective of age, sex of the patient,
CAG repeat number, sex of affected parent, baseline
Clinical Global Impression (CGI) severity score or
baseline UHDRS total maximum chorea score.
 More than two-thirds (69%) of patients receiv-
ing tetrabenazine had an improvement in UHDRS
total maximum chorea score of >3 compared with
20% of patients in the placebo group (odds ratio
9.9; 95% CI 3.2, 29.9; p < 0.0001).[39]
CNS Drugs 2011; 25 (12)
Tetrabenazine: Adis Drug Profile 1079

Table I. Key patient characteristics and trial design details for the double-blind, placebo (PL)-controlled, multicenter trial in patients (pts) with
Huntington’s disease (HD)[39]
Inclusion criteria HD as confirmed by presence of chorea, a family history and an expanded CAG repeat (n ‡ 37);
independently ambulatory; TFC score at screening of >5; TMC scorea of ‡10; pts who had
previously received DOP D2 receptor blockers were enrolled if they had discontinued this
treatment ‡4 wk before enrolment; pts continued existing antidepressant or benzodiazepine
drugs provided they had been taking a stable dosage for ‡8 wk prior to enrolment
Exclusion criteria Presence of disabling depression, dysphagia or dysarthria; prior treatment with TBZ or current
treatment with DOP-depleting drugs, DOP D2 receptor blockers, selective and nonselective
MAOIs, levodopa, DOP agonists, amantadine or memantine
Patient characteristics at baseline (TBZ Age 49.4 y,b 48.8b y [25–77 y]; CAG repeats 44.9,b 44.3b [39–54 repeats]; disease duration
group, PL group) [range] 8.7 y,b 7.5b y [1.6–25.6 y]; history of depression 63%, 47% of pts; female 61%, 63% of pts
Treatment regimen Pts were randomized to TBZ (n = 54) or PL (n = 30). During wk 0–7 (titration phase), the dosage
was titrated to up to a maximum of 8 tablets/day (TBZ 12.5 mg/tablet or PL tablet identical in
appearance) taken as 3 divided doses, with the dosage individualized to the optimum dosage
based on efficacy and tolerabilityc; during wk 7–12 (maintenance phase), the dosage remained
constant unless reduced because of intolerable adverse effects. After wk 12, there was a 1 wk
wash-out period
Optimized dosage range At wk 12, 27 of 49 pts (55%) in the TBZ group and 4 of 29 pts (14%) in the PL group were taking
less than the maximum dosage
Primary efficacy outcome The difference between the baseline TMC score and the average of the wk 9 and 12 scores,
with analyses conducted in the intention-to-treatd population; if either wk 9 or 12 data were
missing, the one available score was imputed for missing data; if neither wk 9 nor wk 12 data
were available, the last observation carried forward method was used to impute missing data
Secondary efficacy outcomes The study prespecified four secondary endpointse (mean change from baseline in CGI-GI,
UHDRS total motor score, UHDRS functional checklist and UHDRS gait score) to be analysed
in a hierarchical manner until there was no statistical between-group difference (p ‡ 0.05).
Thereafter, endpoints were considered to be exploratory endpoints
a Sum of maximum chorea score for facial, buccal-oral-lingual, trunk and each extremity from the motor subscale of the UHDRS. Chorea is
graded for each of these seven body regions on a scale of 0 (no chorea) to 4, giving a total score of 0–28.[49]
b Mean value.
c To reduce intolerable adverse effects, the dosage was reduced to the pt’s previously well tolerated level or lower if necessary.
d All randomized pts.
e Analysed using wk 9 and 12 data, as per the primary outcome measure, except CGI-GI data which only utilized wk 12 scores.
CAG = trinucleotide encoding glutamine; CGI-GI = Clinical Global Impression-Global Improvement; DOP = dopamine; MAOIs = monoamine
oxidase inhibitors; TBZ = tetrabenazine; TFC = total functional capacity; TMC = total maximum chorea; UHDRS = Unified HD Rating Scale.

 Tetrabenazine treatment was also more
efficacious than placebo in terms of improve-
ments in the adjusted mean CGI-Global Improve-
ment (GI) scores (figure 1), which was the first
outcome in the prespecified hierarchical plan of
analyses for secondary outcomes (see table I for
further details).[39] The adjusted mean treatment
effect size for the CGI-GI score at 12 weeks was -0.7
(95% CI -1.3, -0.2), representing an improvement in
favour of tetrabenazine treatment. These improve-
ments in CGI-GI scores significantly (p £ 0.0001)
correlated with improvements in UHDRS total
maximum chorea and total motor scores.
 Significantly more tetrabenazine recipients
than placebo recipients showed at least a mini-
mum global improvement (defined as a CGI-GI
score of £3) at 12 weeks (69% vs 24%; p = 0.0001),
with 45% and 7% of patients showing a greater
than minimum improvement (p < 0.001).[39]
 As per the hierarchical plan for analyses of
secondary outcomes, since the adjusted mean
changes from baseline in UHDRS total motor
scores failed to reach statistical significance
(mean treatment effect size -3.3; 95% CI -7.0,
0.3) [figure 1], all other efficacy endpoints were
considered exploratory.[39]
 For exploratory endpoints, significant between-
group differences in favour of placebo treatment
were observed for adjusted mean changes in
UHDRS functional checklist scores (-0.8 in the

ª 2011 Adis Data Information BV. All rights reserved. CNS Drugs 2011; 25 (12)
1080
Primary Secondary
Adjusted mean score/change from baseline
6 outcome outcomes
4
*
2
0 tional[46] and retrospective[44,48] studies.
−2
−4
−6 **
−8
UHDRS TMC CGI-GI
Fig. 1. Comparative efficacy of oral tetrabenazine (TBZ) in adult
patients (pts) with Huntington’s disease. Results from a 12-week,
randomized, double-blind, multicenter trial in which pts received TBZ
(n = 54; maximum dosage £100 mg/day) or placebo (PL; n = 30) for
12 weeks (see table I for dosage and design details).[39] Adjusted (for
site and baseline scores) mean changes from baseline in UHDRS
TMC and total motor scores (a decrease in score indicates an im-
provement) to study end, and the mean CGI-GI score (a score of
<4 = an improvement, 4 = no change and >4 = worsening) at study
end, as analysed in the intention-to-treat population. All scores were
rated by the investigator. Baseline scores in the TBZ and PL groups
were: UHDRS TMC 14.7 and 15.2; UHDRS total motor 47.0 and
44.8. CGI-GI = Clinical Global Impression-Global Improvement;
TMC = total maximum chorea; UHDRS = Unified Huntington’s Dis-
ease Rating Scale; * p = 0.007, ** p = 0.0001 vs PL.
tetrabenazine group vs 0.4 in the placebo group;
p = 0.02; lower scores represent a worsening), Ep-
worth sleepiness scores (1.5 vs -0.3; p = 0.02; greater
scores represent more sleepiness) and Stroop test
word reading scores (-4.8 vs 1.8; p = 0.01; lower
scores mean a deterioration).[39] There were no
significant between-group differences in Stroop
test colour naming or interference scores and
no clinically relevant changes in UHDRS gait
scores.
 At the end of the 1-week wash-out period
(weeks 12–13 of the study), there was no occur-
rence of rebound chorea, with no statistically
significant differences between the tetrabenazine
and placebo groups for changes in motor, cog-
nitive, behavioural or global measures of illness
severity during this period.[39] As might be pre-
dicted, compared with placebo recipients, tetra-
benazine-treated patients showed a significant
worsening of chorea severity during the wash-out
phase (adjusted treatment effect size of 4.4
UHDRS; 95% CI 2.8, 6.0; p < 0.0001).
ª 2011 Adis Data Information BV. All rights reserved.
Scott
TBZ Long-Term Studies
PL
The long-term efficacy of tetrabenazine has
been evaluated in the extension phase[45] of the
12-week, double-blind trial,[39] and in observa-
Of the 84 participants in the 12-week, double-
blind study,[39] 75 met the criteria for enrolment
in the 80-week, open-label extension phase.[45]
The criteria for inclusion in the extension study
were that patients had completed the initial
12-week study and had not had a severe adverse
UHDRS total motor
event during this 12-week period. The extension
study consisted of a 24-week phase (a 12-week
dose-titration phase followed by a 12-week main-
tenance phase; n = 75 enrolled patients), a 24-week
extension phase (total of 48 weeks of treatment;
n = 58) and a final extension through to week 80
(n = 46), with a 1-week wash-out between each of
these three phases. During the extension study,
the dosage of tetrabenazine was individually op-
timized over a 12-week period, with the dosage
adjusted every 3–7 days up to a maximum of
200 mg/day.[45]
 Of note, more than half of the patients
remained on the same tetrabenazine dosage from
24 weeks onwards (70% of patients between weeks
24 and 48, and 59% between weeks 48 and 80).[45]
Of the 44 patients with complete tetrabenazine
dosage data at 80 weeks, including three patients
receiving no study drug, 55% were receiving a
dosage of 37.5 or 50 mg/day. Moreover, the dos-
age of tetrabenazine remained relatively constant
following the dosage-titration phase; at week 24,
the mean tetrabenazine dosage in patients who
remained on study drug was 74.2 mg/day (n = 66),
at 48 weeks it was 71.5 mg/day (n = 54) and at
80 weeks it was 63.4 mg/day (n = 41).
 The efficacy of tetrabenazine during long-term
treatment was maintained during the 80-week
extension study.[45] There was a significant
(p < 0.0001) reduction from baseline (that is, the
start of the extension study; score 14.9) in
adjusted mean UHDRS total maximum chorea
score with tetrabenazine treatment (reduced by
4.6 units; primary outcome). Respective reduc-
tions from baseline in this score at weeks 24 and
48 were 5.8 and 5.6 (both p < 0.05).
CNS Drugs 2011; 25 (12)
Tetrabenazine: Adis Drug Profile
 At week 81, after discontinuation of the study
drug for 1 week, no rebound chorea was observed.[45]
The adjusted mean UHDRS total maximum cho-
rea score increased by 5.3 from the 80-week score
(p < 0.001), with no significant difference between
this score at week 81 and that at baseline.[45]
 Of the 45 patients who completed 80 weeks of
treatment, approximately one-third (36%) expe-
rienced an improvement in adjusted mean CGI
scores from baseline, 9% of patients experienced
a worsening and 55% showed no change in their
score (secondary outcome).[45] At week 80 there
was no significant change from baseline in UHDRS
total motor scores.
 Secondary efficacy outcomes assessing cogni-
tive and functional abilities generally showed a
deterioration during the 80-week study.[45] Thus,
there was a significant (p < 0.05) deterioration from
baseline in scores for the following cognitive
measures: verbal fluency (17.2 at baseline vs 13.6
at 80 weeks), symbol digit (19.3 vs 14.5), Stroop
colour naming (42.6 vs 31.6), Stroop words (49.8
vs 40.8) and Stroop interference (23.2 vs 18.2).
Similarly, for functional measures, there was a
significant (p < 0.05) worsening of scores from
baseline for UHDRS functional checklist (18.1 vs
15.5), UHDRS independence (75.7 vs 68.7) and
total functional capacity (7.6 vs 5.6).
 Results from this extension study are supported
by observational[46] (n = 29 with HD; average treat-
ment duration »29 months) and retrospective
studies (n = 24[48] and 68;[44] treatment duration
»1–53 months[48] and a median of 34 months[44]).
4. Tolerability
This section focuses on tolerability data from
the 12-week placebo-controlled trial[39] and its
extension study (see section 3 for dosage and de-
sign details). Adverse events were coded using
WHO preferred terms. Supplemental data are
derived from the US manufacturer’s prescribing
information[15] and FDA briefing document[35]
for tetrabenazine.
 In the 12-week, placebo-controlled study, one
death (a suicide) occurred in the tetrabenazine
group.[39] At the visit 2 weeks prior to the suicide,
neither the investigator nor the patient’s care-
ª 2011 Adis Data Information BV. All rights reserved.
1081
giver detected any signs of depression and no
abnormalities were detected on the patient’s
Hamilton Depression Scale (HAM-D) score at
that point in time.
 During this study, five patients discontinued
tetrabenazine treatment; four because of serious
adverse events and one because of akathisia.[39]
Serious adverse events included an intracerebral
haemorrhage following a fall, hospitalization for
restlessness that resolved within 48 hours of dos-
age reduction (2 weeks later the patient developed
depressive symptoms, irritability and suicidal
ideation) and breast cancer (the patient had
a breast lump prior to screening). There were no
occurrences of serious adverse events in the
placebo group.[39]
 Dosage titration of tetrabenazine was discontin-
ued or the dosage reduced in 52% of patients
because of the occurrence of one or more adverse
events.[15] Dosage-limiting events included sedation
(13 patients), akathisia (4), parkinsonism (2), depres-
sion as description of mood (3) and others (3).[39]
 Treatment-emergent adverse events in the
tetrabenazine group mainly occurred during
the dosage-titration phase, a period during which
the dosage was optimized based, for the most
part, on tolerability.[39] By the end of the main-
tenance phase, when presumably patients were
on an optimal individualized dosage, there were
no significant differences between the tetrabena-
zine and placebo groups in relation to the
frequency of specific adverse events that had not
been reported at baseline.[39]
 In the 12-week double-blind trial, 91% of
patients in the tetrabenazine group experienced
at least one adverse event versus 70% in the
placebo group (p = 0.01), most of which were mild
to moderate and manageable with dosage adjust-
ments or discontinuation of study drug.[39] The
most common (incidence ‡15% and greater in
the tetrabenazine group than in the placebo group)
treatment-emergent adverse events occurring during
the 12-week trial were drowsiness/somnolence,
insomnia, fatigue, fall, depression, agitation and
anxiety (figure 2).[39] Drowsiness/somnolence and
insomnia occurred with a significantly greater
incidence in the tetrabenazine group than in the
placebo group (figure 2). Of note, depression
CNS Drugs 2011; 25 (12)
1082
refers to a description of mood rather than a for-
mal diagnosis.
 The FDA briefing document for tetrabena-
zine[35] indicated that not all adverse events may
have been captured during the 12-week double-
blind study.[39] In the tetrabenazine group, the
FDA analysis identified an additional three cases
of parkinsonism, two cases of akathisia, three
cases of restlessness that could have been cases of
akathisia, two cases of depression and one case of
dysphagia.[35] No additional adverse events were
identified in the placebo arm. The incidences of
the most common adverse events, as reported in the
briefing document,[35] were sedation (32% in tetra-
benazine group vs 3% in placebo group), fatigue
(22% vs 13%), insomnia (22% vs 0%), akathisia/
restlessness (19% vs 0%), depression (19% vs 0%),
falls/traumatic injury (19% vs 13%), anxiety (15%
vs 3%) and parkinsonism (15% vs 0%).
 No clinically significant changes in laboratory
parameters were reported in patients receiving
tetrabenazine in clinical trials.[15] In controlled
clinical trials, there were small increases in mean
TBZ
URTI
PL
Purpura
Nausea
Anxiety
Agitation
θ presentation).[50] Depressed mood was defined as
Depression
θ
Fall
Fatigue
Insomnia
θ
* patients).
Drowsiness/ *
somnolence
0 5 10 15 20 25 30
Percentage of patients
Fig. 2. Tolerability profile of oral tetrabenazine (TBZ) in adult
patients with Huntington’s disease. Treatment-emergent adverse
events occurring in ‡10% of patients receiving TBZ (n = 54; max-
imum dosage £100 mg/day) and with a greater frequency in the TBZ
group than in the placebo (PL; n = 30) group in a 12-week, random-
ized, double-blind, multicentre trial discussed in section 3 (see table I
for dosage and design details).[39] Coding was based on the adverse
event log using WHO preferred terms. Depression applied to a de-
scription of mood, rather than a formal diagnosis. URTI = upper res-
piratory tract infection; y indicates a frequency of 0%; * p = 0.006
vs PL.
ª 2011 Adis Data Information BV. All rights reserved.
Scott
AST and ALT concentrations in patients receiv-
ing tetrabenazine compared with those receiving
placebo.[15] In the extension study (£80 weeks’
treatment), although three patients (4%) expe-
rienced an isolated increase in AST concentration
of ‡3 times the upper limit of normal, no patients
experienced clinical liver dysfunction.[45]
 Tetrabenazine treatment had no clinically
relevant effects on blood pressure, pulse and body-
weight in controlled clinical trials.[15]
 As discussed earlier, HD is associated with an
increased risk of depression and suicidal ideation
or behaviour. Tetrabenazine may potentially
increase these risks,[15] because along with deple-
tion of dopamine it also causes depletion of sero-
tonin and norepinephrine (section 1).
 In the 12-week double-blind study, 15% of pa-
tients receiving tetrabenazine had an adverse event
of depression (figure 2).[39] During this study, both
tetrabenazine-treated patients and placebo recip-
ients experienced an improvement in HAM-D
scores, with these improvements from baseline
being more marked in the placebo group than in
the tetrabenazine group (-2.4 vs -0.7; p = 0.003).
 The use of antidepressants by patients at base-
line (56% of patients) or a history of depression
(67%) were not associated with the development
of depressed mood during tetrabenazine treat-
ment, based on a post hoc analysis of data from
48 participants in the 12-week study (abstract
the incident development of the adverse event of
depressed mood (occurred in 10% of patients)
or at least a 2-point worsening on the depressed
mood item of the UHDRS (occurred in 8% of
 In a retrospective analysis of 518 patients with
various dyskinesias, including chorea (31% of
35 patients), 78 patients (15%) treated with tetrabe-
nazine developed depression for the first time or
had an exacerbation of their pre-existing depres-
sion.[51] In this study, of the 246 patients without
a history of depression prior to tetrabenazine treat-
ment, 11.4% were newly diagnosed with depression
during tetrabenazine treatment. Over the entire
cohort, the mean duration of tetrabenazine treat-
ment was 29.7 months and the mean daily dosage
was 53.0 mg/day.[51]
CNS Drugs 2011; 25 (12)
Tetrabenazine: Adis Drug Profile
 In studies evaluating the use of tetrabenazine
for the treatment of chorea associated with HD
(n = 187), one patient committed suicide, one at-
tempted suicide and six reported suicidal ideations.[15]
Long-Term Treatment
 In the long-term extension study (up to 80
weeks’ treatment) of the 12-week trial (n = 75
participants), the most commonly reported treat-
ment-related adverse events (excluding those of mild
severity) in the 44 patients who completed
the 80-week study were sedation/somnolence
(18 patients), depressed mood (17), anxiety (13),
insomnia (10) and akathisia (9).[45] Three patients
withdrew from the study because of adverse events,
including vocal tics, depression and delusions,
that were attributed to the study drug by inves-
tigators. One patient died of breast cancer during
the study.
 As was the case during the initial 12-week
study, the frequency of treatment-emergent ad-
verse events was greater during the dosage-
titration phase than during the maintenance
phase, with 39 patients experiencing at least
one adverse event during the dosage-titration
phase versus 20 patients during the maintenance
phase (p < 0.001).[45] Somnolence (occurred in
36 patients during the titration phase vs 11
patients during the maintenance phase; p < 0.0001),
insomnia (14 vs 2; p < 0.003) and diarrhoea (5 vs 1;
p < 0.05) generally resolved during the maintenance
phase.[45]
 From baseline to week 80, there were signif-
icant (p £ 0.002) increases in the mean UHDRS
parkinsonism score (by 2.1) and mean UHDRS
dysphagia scores (by 0.4), although there was no
significant change from baseline in the Unified
Parkinson’s Disease Rating Scale dysarthria score.[45]
There were no changes form baseline to week 80 in
HAM-D or Barnes Akathisia Rating Scale (BARS)
scores.
 During the extension study, ten patients (13.3%)
developed mild or moderate akathisia and a
further three (4%) patients had mild or moderate
akathisia at baseline.[45] One patient experienced
marked or severe akathisia (defined as a BARS
score of 4 or 5).
ª 2011 Adis Data Information BV. All rights reserved.
1083
5. Dosage and Administration
Oral tetrabenazine is approved in the US[15] for
the treatment of chorea associated with HD and is
approved in several other countries (including the
UK, Canada, France, Germany) for the treatment
of various movement disorders, including HD.[4]
Careful individualization of the dosage of tetra-
benazine is required.[15] The starting dosage
should be 12.5 mg per day given once in the
morning. After 1 week, the dosage should be in-
creased 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 dosage that reduces
chorea. Dosages of 37.5–50 mg/day should be
given as three divided doses, with the maximum
recommended single dose being 25 mg. Patients
requiring dosages above 50 mg/day should be
CYP2D6 genotyped to determine whether they
are PM or EM (see section 2). The maximum
dosage for PM is 50 mg/day, with a maximum
single dose of 25 mg. For EM and intermediate
metabolizers, the maximum dosage is 100 mg/day,
with a maximum single dose of 37.5 mg.[15]
Tetrabenazine is contraindicated for patients
who are actively suicidal or who have depression
that is untreated or undertreated.[15] It is also con-
traindicated for patients with hepatic impairment
and in those taking monoamine oxidase inhibitors
(MAOIs) or reserpine (see section 2). Tetrabena-
zine should also not be taken within 14 days of
discontinuing MAOIs or within 20 days of dis-
continuing reserpine (since reserpine binds irrevers-
ibly to VMAT2 and thus has a prolonged effect on
monoamine concentrations; see section 1).[15]
Local prescribing information should be
consulted for comprehensive prescribing details,
including precautions, special warnings, contra-
indications and use in special patient populations.
6. Tetrabenazine: Current Status For
Chorea Associated with Huntington’s
Disease
Oral tetrabenazine is the only drug approved
by the FDA for the treatment of chorea in
patients with HD. In a 12-week, double-blind
CNS Drugs 2011; 25 (12)
1084
trial in 84 patients with HD, oral tetrabenazine
(£100 mg/day) significantly improved chorea se-
verity compared with placebo, as assessed by the
adjusted mean change from baseline in UHDRS
total maximum chorea score. The beneficial ef-
fects of tetrabenazine treatment on chorea sever-
ity were sustained in an 80-week extension study.
The most common treatment-emergent adverse
events that occurred in the tetrabenazine groups
in these studies were drowsiness/somnolence, in-
somnia, fatigue, fall, depression, agitation and
anxiety. Most of these events were mild to mod-
erate, manageable with dosage adjustments or dis-
continuation of study drug, and mainly occurred
during the dosage-titration phase, a period during
which the dosage was individually optimized.
Acknowledgments and Disclosures
The manuscript was reviewed by: A. Antonini, Parkinson
Institute and Neuroradiology, Istituti Clinici di Perfeziona-
mento, Milan, Italy; J.J. Chen, Loma Linda University,
Movement Disorders Center, Schools of Medicine and Phar-
macy, Loma Linda, CA, USA; S. Mehta, Medical College of
Georgia, Department of Neurology, Augusta, GA, USA.
The preparation of this review was not supported by any
external funding. During the peer review process, the manu-
facturer of the agent under review was also offered an op-
portunity to comment on this article. Changes resulting from
comments received were made by the author on the basis of
scientific and editorial merit.
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