Tetrabenazine, a monoamine-depleting drug used in the treatment of hyperkinetic movement disorders

D.R.P. Guay

The American Journal of Geriatric Pharmacotherapy

Tetrabenazine, A Monoamine-Depleting Drug Used in the Treatment of Hyperkinetic Movement Disorders David R.P. Guay, PharmD Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, and Division of Geriatrics, HealthPartners Inc., Minneapolis, Minnesota

ABSTRACT Background: Few drugs are available for the management of hyperkinetic movement disorders such as the dystonias, choreas, dyskinesias, and tics. Those that are available (primarily neuroleptics) are associated with a wide range of potentially serious adverse effects, including induction of tardive movement disorders. Tetrabenazine (TBZ) is a monoamine-depleting agent initially studied in the 1950s and currently approved by the US Food and Drug Administration for the treatment of chorea in Huntington’s disease. Objective: This article reviews the chemistry, pharmacology, pharmacokinetics, therapeutic use, tolerability, druginteraction potential, and dosing and administration of TBZ. Methods: MEDLINE was searched (1950–February 2010) for English-language articles investigating any aspect of TBZ. Search terms included tetrabenazine, Ro 1-9569, Nitoman, benzoquinolizines, s and reserpine. The reference lists of the identified articles were searched for other pertinent publications, particularly those that were not indexed in the 1950s and 1960s. Results: In the search for a chemical compound that was simpler than reserpine while preserving reserpine-like psychotropic activity, TBZ was identified in the 1950s as one member of a large group of benzoquinolizine derivatives. TBZ acts by depletion of the monoamines serotonin, norepinephrine, and dopamine in the central nervous system (CNS). It does this by reversibly inhibiting vesicle monoamine transporter type 2 and thus preventing monoamine uptake into presynaptic neurons. Clinical studies suggest that TBZ may have therapeutic applications in a wide range of hyperkinetic movement disorders. TBZ has been associated with numerous adverse effects, some of them serious and potentially fatal; these include parkinsonism, other extrapyramidal symptoms (particularly akathisia), depression and suicidality, neuroleptic malignant syndrome, and sedation. TBZ is subject to important drug–drug interactions with inhibitors and inducers of cytochrome P450 (CYP) 2D6, reserpine, and lithium. It is one of very few drugs whose dosing is based, in part, on the results of genotyping (in its case, genotyping for CYP2D6 metabolizer status). Conclusions: TBZ is a complicated drug in terms of its mechanism of action and its activities against the 3 major monoamines in the CNS, making it difficult to predict its efficacy and tolerability in patients with hyperkinetic movement disorders. It is associated with numerous adverse effects and several important drug–drug interactions. Much work remains to be done to determine the therapeutic potential of TBZ in the treatment of hyperkinetic movement disorders. (Am J Geriatr Pharmacother. 2010;8:331–373) © 2010 Excerpta Medica Inc. Key words: tetrabenazine, norepinephrine, dopamine, serotonin, movement disorders, tardive disorders, benzoquinolizine derivatives. Accepted for publication July 1, 2010. Published online August 30, 2010. ª

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331

The American Journal of Geriatric Pharmacotherapy

D.R.P. Guay

INTRODUCTION Tetrabenazine (TBZ; Ro 1-9569) was first synthesized in 1956 and was approved for the treatment of neuroses and psychoses/schizophrenia in Finland, the Netherlands, Switzerland, and the United Kingdom in 1958.1,2 It was withdrawn from the market in 1966 due to its failure as a potent neuroleptic. However, from ~1971 onward, TBZ was in widespread unapproved use for the treatment of involuntary movement disorders.1 It was not approved by the US Food and Drug Administration (FDA) until May 2008,1 and its current FDA approval is limited to the treatment of chorea in Huntington’s disease.3 This paper reviews the chemistry, pharmacology, pharmacokinetics, therapeutic use, tolerability, druginteraction potential, and dosing and administration of TBZ.

METHODS MEDLINE was searched (1950–February 2010) for English-language articles investigating any aspect of TBZ. Search terms included tetrabenazine, Ro 1-9569, Nitoman, benzoquinolizines, s and reserpine. The reference lists of identified articles were searched for other pertinent publications, particularly those that were not indexed in the 1950s and 1960s.

CHEMISTRY TBZ was initially identified as one member of a large group of 1,2,3,4,6,7-hexa-hydro-11bH-benzo[a]quinolizine derivatives that were synthesized in the search for a simpler chemical compound than reserpine that retained reserpine-like activity.2,4 These agents had ≥2 asymmetric centers, thus introducing the complexities of stereochemistry.4 The ketones, of which TBZ is an example, proved to be the most interesting of these compounds, and a variety of synthetic processes for TBZ were described between 1953 and 1961.4 The chemical structure of TBZ is shown in Figure 1. Its chemical name is ciss rac-1,3,4,6,7,11b-hexahydro9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] quinolizin-2-one.3 Its molecular weight is 317.43, its acid dissociation constant is 6.51, and its empiric formula is C19H27NO3.

MECHANISM OF ACTION TBZ works as a reversible inhibitor of vesicle monoamine transporter type 2 (VMAT-2), inhibiting the uptake of monoamines (serotonin, norepinephrine, and particularly dopamine) into the granular vesicles of presynaptic neurons.1 All monoamines are probably accumu-

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lated within these vesicles by an identical mechanism, indicating the low specificity of the transporter.5 In fact, this transporter can, with similar efficiency, translocate dopamine, norepinephrine, epinephrine, serotonin, tyramine, histamine, and some nonphysiologic compounds.5 Catecholamine translocation is a form of secondary transport, being coupled to and driven by a transmembrane proton electrochemical gradient generated by inwardly directed proton pump adenosine triphosphatase acting on cytosolic adenosine triphosphate. In granules, the gradient drives uptake by activating the monoamine transporter, which is sensitive to both transmucosal pH and electrochemical gradients. The transporter catalyzes an electrodissipative catecholamine/antiport and, hence, forms a monoamine gradient.5 VMAT proteins should not be confused with plasma membrane monoamine transporters, which constitute a second monoamine uptake system present on monoaminergic cells, particularly neurons. Three classes of agents can block vesicular monoamine uptake: proton pump inhibitors, proton ionophores, and specific inhibitors of monoamine transport. TBZ (and reserpine) fall within the latter category. These agents work without altering the transmembrane pH and potential gradients of the vesicular membranes.5 Although reserpine and TBZ work by similar mechanisms, they can be readily distinguished from a mechanistic perspective.4,6 Reserpine is an irreversible inhibitor of VMAT-2, whereas TBZ is a reversible inhibitor. TBZ is 10- to 20-fold less potent than reserpine. Reserpine depletes monoamine stores to a greater extent than does TBZ (eg, reserpine depletes serotonin and norepinephrine stores to 10% of baseline, whereas TBZ depletes serotonin stores to 30%–50% of baseline and norepinephrine stores to 15%–25% of baseline). The time to peak effect is shorter and recovery of monoamine stores is faster with TBZ (16–24 hours) compared with reserpine (days–weeks).

CH3O N CH3O

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Figure 1. Chemical structure of tetrabenazine.

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D.R.P. Guay

PHARMACOLOGY Relatively few data are available regarding the pharmacology of TBZ in humans. Human synaptic vesicular monoamine transporter (SVMT) mRNA has been found in human brainstem (for 3.0 kilobase [kb] human SVMT) and hypothalamus (for 4.8 kb human SVMT), but it has not been found in high concentrations in human frontal cortex, parietal cortex, temporal cortex, occipital cortex, cingulate cortex, caudate, globus pallidum, thalamus, amygdala, cerebellum, or hippocampus.7 Significant human SVMT expression has also been found in human nigra compacta neurons.7 For example, high rates of specific (3H) binding of 15 nM dihydrotetrabenazine have been reported as follows in human brain: striatum caudate (766 fmoL/mg protein), striatum accumbens (751 fmoL/mg protein), striatum putamen (742 fmoL/mg protein), substantia nigra compacta (465 fmoL/mg protein), hypothalamus (245 fmoL/ mg protein), substantia nigra reticulata (141 fmoL/mg protein), external pallidum (128 fmoL/mg protein), and internal pallidum (115 fmoL/mg protein).5 All other areas exhibited <100 fmoL/mg protein-specific binding. Dihydrotetrabenazine binding to human caudate P1 and P3 membranes can be described by respective dissociation constant values of 4.12 and 4.86 nM and Bmax (total number of bound receptors) values of 482 and 356 fmoL/mg protein.7 Human SVMT exhibits nanomolar affinities for TBZ (inhibitory rate constant [K Ki] = 2.34 nM) and reserpine (K Ki = 73 nM).7 On the other hand, affinities are on the micromolar level for haloperidol (1.86 μM), serotonin (3.4 μM), mazindol (23 μM), nomifensin (416 μM), and D-amphetamine (381 μM). Affinities are on the millimolar level for dopamine, epinephrine, norepinephrine, and histamine. A controlled trial comparing TBZ, thiopropazate, and placebo in patients with Huntington’s chorea also measured cerebrospinal fluid (CSF) concentrations of monoamine metabolites.8 Administration of placebo was associated with CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) that did not differ significantly from values in controls with no cerebral disease. Similar findings were noted in thiopropazate recipients. TBZ had no significant effect on CSF 5-HIAA concentrations, but was associated with a significant increase in mean CSF HVA concentrations (from 34.0 to 54.5 ng/mL; P < 0.001). There was no clear correlation between CSF metabolite concentrations and clinical response, suggesting that monitoring of CSF metabolite concentrations has no value in predicting the response to therapy.

The American Journal of Geriatric Pharmacotherapy

Postmortem brain tissue from patients with Huntington’s chorea who had and had not received TBZ therapy (11 and 7 patients, respectively) was analyzed for levels of dopamine, norepinephrine, serotonin, and their metabolites.9 In tissue from those who had received TBZ therapy, monoamine concentrations were reduced in all parts of the brain studied, although the reductions were significant only for dopamine in the caudate (P P < 0.01), norepinephrine in the amygdala (P P < 0.05), and norepinephrine and dopamine in the hippocampus (both, P < 0.05). Concentrations of HVA and serotonin were not significantly reduced, despite absolute serotonin reductions of 16% to 35%. Concentrations of 5-HIAA were not significantly different from baseline. The dopamine effect in the caudate supports evaluation of TBZ in the treatment of chorea, and the norepinephrine/serotonin effects in the limbic system suggest an explanation for the emergence of depression as a frequent adverse effect. The electroencephalographic (EEG) effects of TBZ during chronic therapy were quantitated in a human pharmacology study.4 EEG changes after chronic dosing included a slowing of spontaneous activity and an increase in amplitude. In patients with posttraumatic cerebral injury, TBZ was found to counteract the depressed alpha rhythm. In another EEG study, longterm administration of TBZ at oral doses of 250 to 375 mg/d (ie, much higher than would be contemplated in clinical use at present) led to a slowing of alpha rhythm, an increase in subalpha and theta activity, a reduction in fast beta frequency, and increased voltage, beginning within a few days after initiation of TBZ and peaking during the first week.2 These effects were interpreted as a manifestation of reduced central nervous system activity and vigilance. Changes in EEG parameters were varied, but patients with depression usually exhibited increased alpha activity, while those with schizophrenia had diffuse or localized slow activity of variable duration. In another EEG study, 40 patients received a single 100-mg intramuscular injection of TBZ.2 Changes in EEG parameters occurred in 29 patients (73%). These changes varied widely, depending on previous EEG patterns. EEG abnormalities were exacerbated in most patients with epilepsy.

PHARMACOKINETICS The pharmacokinetics of TBZ have not been well studied in humans. This is in part because of the regulatory environment of the late 1950s when TBZ was first being investigated for human use and because of the diff ficulty of quantitating the drug and its active α- and

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D.R.P. Guay

β-dihydro metabolites in human body fluid compartments at that time. In a Phase I mass-balance trial, 2 healthy volunteers received tritium-labeled TBZ 90 mg injected via intravenous bolus.4,10 The serum concentration–time profiles were consistent with a 2-compartment kinetic model; however, neither compartmental nor noncompartmental analyses were carried out. Radioactivity fell to minimum levels within 10 hours after administration. By day 3, no activity was detectable. Total radioactivity excretion was 40% in urine and 2.5% in feces by 24 hours after administration. After 48 hours, 54% of total radioactivity had been excreted. Of interest, no radioactivity was found in the CSF. As part of a pilot study of TBZ as a tracer compound for use in diagnostic medicine, the intracerebral pharmacokinetics of 11C-TBZ were evaluated by positron emission tomography in 2 healthy volunteers.11 Injection of 11C-TBZ (27.5 and 27.6 mCi) as an intravenous bolus was followed by 60 minutes of imaging (30-second to 10-minute frames). Brain uptake was rapid and substantial, similar to the uptake of 11C-flumazenil and 11C-tropanylbenzylate, ligands known to readily cross the blood–brain barrier. Egress from the brain was also rapid. The intracerebral concentration–time curves were of similar shape in the striatum, thalamus, cerebellum, and frontal cortex. No detailed pharmacokinetic analyses were performed in this study. The prehepatic systemic availability of TBZ is at least 75%.3 Administration with a high-fat/high-calorie breakfast did not affect the systemic bioavailability of TBZ, which was quantitated based on the Cmax and AUC for the α- and β-dihydrotetrabenazine metabolites.3 Quantitation of the metabolites rather than the parent compound was performed because serum concentrations of the parent compound were usually below the lower limit of detection of the assay in both single- and multipledose studies.12 After oral dosing, the serum Cmax of dihydrotetrabenazine (metabolites I and II) and desmethyldihydrotetrabenazine (metabolites VII and VIII) occurred at means of 1 to 1.5 and 2 hours, respectively.3 The principal circulating moieties in serum are the α- and β-dihydrotetrabenazine and α- and β-Odesmethyldihydrotetrabenazine metabolites (along with their glucuronide and sulfate conjugates).3 The pharmacokinetic parameters of the α- and d β-dihydrotetrabenazine metabolites exhibit stereoselectivity.12 In general, systemic exposure to the α metabolite exceeds exposure to the β metabolite.3 For example, the mean Cmax of the α metabolite has been reported to be 1.5- to 2-fold greater than that of the β metabolite,

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whereas the corresponding increases were 1.3-fold and 1.3- to 1.4-fold for mean AUC and t1/2. However, there is substantial interpatient variability in all parameters, and the ratio of the α metabolite to the β metabolite can range from 5:1 to 8:1 in individual patients. Over a concentration range of 50 to 200 ng/mL, plasma protein binding of TBZ, α-dihydrotetrabenazine, and β-dihydrotetrabenazine ranged from 82% to 88%, 60% to 68%, and 59% to 63%, respectively.3 The steady-state pharmacokinetics of TBZ were evaluated in 4 patients receiving TBZ 12.5 to 37.5 mg TID for the treatment of tardive dyskinesia.13 The mean (SD) ratio of systemic exposure (ie, AUC) to the dihydro metabolite (sum of the α and β moieties) relative to systemic exposure to the parent compound was 148 (49) (range, 83–199). The apparent oral clearance of TBZ ranged from 252 to 1090 mL/min/kg. Plasma concentrations of the parent compound and the pooled α- and β-dihydro metabolites ranged from 0.24 to 6.22 ng/mL and 15.9 to 801 ng/mL, respectively. At concentrations of 10 and 25 ng/mL, the mean ratios of TBZ blood:plasma concentrations were 1.13 (0.11) and 1.19 (0.04), respectively. No parent compound was found in the urine of any patient. The bioavailability of TBZ in the systemic circulation was small and erratic (mean, 6.0% [2.6%]; range, 2%–8%). Pharmacokinetic studies of single intravenous and oral doses of TBZ were conducted in 7 patients with Huntington’s disease or tardive dyskinesia (Table I).14 The mean (SD) prehepatic systemic availability of TBZ was 81% (30%). However, due to extensive first-pass hepatic metabolism, the mean absolute oral bioavailability of the parent compound was only 4.9% (3.2%). The extent of metabolite accumulation (R Rm) was large (R Rm = 3.30 [2.76] after intravenous dosing, 35.0 [35.0] after oral dosing). There was great interindividual variation in almost all parameters for both the parent compound and the pooled α and β metabolites. The results of this study suggest that for therapeutic purposes, the dihydro metabolite may be preferable to TBZ due to its lesser extent of first-pass hepatic metabolism and plasma protein binding and its longer t1/2. After administration of TBZ 2 mg/kg SC followed by quantitative urine collection, 9 metabolites were found in urine (5 nonconjugated and 4 conjugated).15 Later studies found at least 19 metabolites.3 The major steps in TBZ metabolism are keto reduction at the C2 position, oxidation (to a hydroxyl group) at the 2′ position on the isobutyl side chain, and selective ether cleavage at the C9 position, followed by conjugation of the phenolics to glucuronic acid.15 The products of

D.R.P. Guay

The American Journal of Geriatric Pharmacotherapy

Table I. Pharmacokinetics of tetrabenazine (TBZ) and its dihydro metabolite (DHM; sum of the B and C moieties) after single intravenous doses of 10 mg administered over 1.5 to 3 minutes and single oral doses of 25 to 75 mg in 7 patients with Huntington’s disease or tardive dyskinesia.14 Values are mean (SD). %).

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keto reduction are α- and β-dihydrotetrabenazine; β-dihydrotetrabenazine and (–) α-dihydrotetrabenazine are pharmacologically inactive, whereas (+) α-dihydrotetrabenazine is an active metabolite.16 The primary entities in urine are the glucuronide conjugates. The α- and β-dihydrometabolites constitute <10% of a dose. The parent compound is not excreted in urine. Mass-balance studies in healthy volunteers found that 75% of a dose was eliminated in the urine and 7% to 16% in the feces.3 Figure 2 illustrates the proposed schema of TBZ metabolism. When metabolites I, II, and V were tested for pharmacologic activity (potentiation of ethanol narcosis), all were found to be less active than the parent compound.15 Keto reduction and O-dealkylation are mediated principally by the cytochrome P450 (CYP) 2D6 isozyme; O-dealkylation of α-dihydrotetrabenazine also involves CYP1A2.3 The t1/2 of α- and β-dihydrotetrabenazine ranges from 4 to 8 and 2 to 4 hours, respectively.3 Although the pharmacokinetics of TBZ and its metabolites have not been systematically evaluated in sub-

jects who do not express CYP2D6 (ie, poor metabolizers), it is likely that such subjects would have increased serum concentrations of α- and β-dihydrotetrabenazine, similar to concentrations in subjects coingesting a strong CYP2D6 inhibitor (eg, paroxetine).3 Thus, the prescribing information for TBZ recommends that CYP2D6 metabolizer status be determined before use of TBZ doses >50 mg/d, and those found to be poor metabolizers should not receive TBZ doses >50 mg/d.3 However, the test for CYP2D6 metabolizer status is available at few US laboratories, and the likelihood of adherence to this recommendation is low.

Special Populations There have been no formal studies of the pharmacokinetics of TBZ in pediatric or geriatric populations, specific racial/ethnic groups, or patients with renal impairment.3 In terms of gender effects, the mean Tmax of α- and β-dihydrotetrabenazine has been reported to be similar in men and women.12 However, the mean Cmax of the β metabolite was 1.25- to 1.3-fold greater

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The American Journal of Geriatric Pharmacotherapy

D.R.P. Guay

CYP2D6

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Glucuronidation/ sulfation

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Glucuronidation/ sulfation

Figure 2. Major metabolic pathways of tetrabenazine. CYP = cytochrome P450.

in women than in men, whereas the mean Cmax of the α metabolite did not differ between women and men. The mean AUC of the β metabolite was 1.5- to 2-fold greater in women than in men, whereas the mean AUC of the α metabolite did not differ between women and men. The mean t1/2 of the β metabolite was slightly longer in women (4–6 hours) compared with men (3–4.7 hours), whereas the mean t1/2 of the α metabolite did not differ between women and men. The clinical relevance of these gender differences in the pharmacokinetics of TBZ is not known. The pharmacokinetics of TBZ and its dihydro metabolites were compared in 12 subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment and 12 age-matched healthy control subjects.3 All received TBZ as a single 25-mg dose. In the patients with hepatic disease, serum concentrations of TBZ were greater than or equal to those of α-dihydrotetrabenazine. In the group with hepatic impairment, the Cmax was 7- to 190-fold higher than detectable serum concentrations in the control group. The mean t1/2 of TBZ was increased to ~17.5 hours (usual value, 6.5 hours). Exposure to α- and βdihydrotetrabenazine was increased by 30% to 39% compared with exposure in control subjects. The mean Tmax of the dihydrotetrabenazine metabolites was

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slightly increased in the group with hepatic impairment compared with control subjects (1.75 and 1.0 hour, respectively). The mean t1/2 of both dihydrotetrabenazine metabolites was increased compared with that in control subjects (α metabolite: 10 vs 4–8 hours, β metabolite: 8 vs 2–4 hours).

Drug–Drug Interactions In vitro studies found that TBZ and its dihydro metabolites did not significantly inhibit CYP2D6, 1A2, 2C8, 2C9, 2C19, 2E1, or 3A.3 In addition, they did not significantly induce CYP1A2, 3A4, 2B6, 2C8, 2C9, or 2C19. Neither TBZ nor its dihydro metabolites appear likely to be substrates for or inhibitors of P-glycoprotein at clinically relevant concentrations in vivo. The interaction between a single dose of TBZ 50 mg and multiple-dose paroxetine 20 mg/d was evaluated in 25 healthy volunteers.3 Pretreatment with paroxetine (a strong inhibitor of CYP2D6) was associated with mean 30% and 3-fold increases in the αdihydrotetrabenazine Cmax and AUC, respectively, and mean 2.4- and 9-fold increases in β-dihydrotetrabenazine Cmax and AUC. The t1/2 of both dihydrotetrabenazine moieties was increased to ~14 hours (usual values for the α- and β-moieties, 4–8 and 2–4 hours, respectively).

D.R.P. Guay

Because reserpine and TBZ have similar pharmacologic properties, reserpine should not be used as an antihypertensive when TBZ is to be used.3 The pharmacologic properties of neuroleptics (traditional or atypical) and metoclopramide also are similar to those of TBZ; concurrent use with TBZ is likely to exaggerate sedative, parkinsonian, and extrapyramidal adverse effects, as well as to increase the risk of neuroleptic malignant syndrome. Concurrent use of TBZ with monoamine oxidase inhibitors should be avoided. Based on observations from rat and mouse studies suggesting that lithium may inhibit the biochemical and behavioral effects of TBZ,17,18 caution is warranted when considering combined use of these agents.

THERAPEUTIC USE TBZ was initially investigated as a potentially more eff ficacious, better tolerated treatment for schizophrenia than reserpine in >20 open-label and comparative trials,2,19 and it was subsequently approved for this indication. Its popularity waned fairly quickly for reasons that are unclear, although its neuroleptic potency was moderate, at best. TBZ is currently approved for use in the treatment of a wide range of hyperkinetic movement disorders, varying from country to country. In the United States, it is approved only for the treatment of chorea associated with Huntington’s disease, as only efficacy data for this indication were submitted in the New Drug Application for TBZ. However, TBZ is used off label for many other muscle disorders.

Case Studies and Series The identified case studies and series included 51 patients, 60% of them female (based on data for 50 patients), with an overall mean age of 56.9 years (range, 10–92 years) (based on data for 43 patients).20–49 Of these 51 patients, 8 had hemiballismus with/without hemichorea, 26 had tardive disorders, and 17 had miscellaneous disorders. The mean ages of these groups were 61.7 years (range, 18–92 years) (based on data available for 7 patients), 58.2 years (range, 21–77 years) (based on data for 24 patients), and 51.6 years (range, 10–81 years) (based on data for 12 patients), respectively. The corresponding proportions of women were 86% (based on data for 7 patients), 62%, and 47%. A total of 18 adverse events (AEs) were reported: 3 cases of bradycardia; 2 cases each of rigidity, drowsiness, and restlessness; and 1 case each of depression, cognitive impairment, hypomimia, parkinsonism, rash, myalgias, tremor, insomnia, and gait disturbance.

The American Journal of Geriatric Pharmacotherapy

Retrospective Trials The retrospective trials of the efficacy and tolerability of TBZ identified by the literature search are summarized in Table II.50–59 Of the 1142 patients included in the retrospective trials, 806 (71%) had complete cessation of clinical signs and symptoms, an excellent response, very good improvement, or marked improvement (terms differed by study); 55 (5%) had mild improvement or a slight response; and 281 (25%) had a doubtful response, no response, worsening, or no improvement. The clinical response to TBZ appeared to vary by disorder. At least moderate clinical improvement or response occurred in 100% of patients with chorea (n = 103), tics (n = 75), Tourette’s syndrome (n = 27), myoclonus (n = 23), facial dyskinesia/dystonia (n = 7), and non– drug-related buccolingualmasticatory syndrome (n = 5); 99% of patients with dystonia (n = 163); 95% of patients with tardive disorder (n = 311); 80% of patients with hemiballismus (n = 5); 69% of patients with Huntington’s chorea (n = 85); 26% of patients with Meige’s syndrome (n = 31); and 0% of patients with parkinsonian tremor (n = 6) or intention tremor (n = 4). A total of 502 AEs occurred in the retrospective trials. The most frequently occurring AEs were drowsiness/ fatigue (30%), parkinsonism (27%), depression (14%), insomnia (9%), akathisia (8%), nervousness/anxiety (8%), and nausea/vomiting (4%). All other AEs occurred at a frequency of ≤3%.

Open-Label Trials A total of 881 patients participated in the open-label trials of TBZ monotherapy (16 trials) and combination therapy (9 trials) (Table III).60–84 Because it is difficult to draw conclusions regarding the efficacy of TBZ from the trials of combination therapy, which varied widely in design and quality, the 9 trials of combination therapy (represented by 10 publications) are not discussed here. Summary data from the 16 trials of TBZ monotherapy (represented by 15 publications) follow. A total of 628 patients participated in the open-label trials of TBZ monotherapy (range per trial, 5–217), representing a wide variety of hyperkinetic movement disorders. These included chorea in Huntington’s disease (n = 217), tardive dyskinesia (n = 188), Tourette’s syndrome (n = 26), generalized dystonias (n = 19), cranial dystonias (n = 57), tardive dystonia (n = 15), facial dystonias (n = 25), hemidystonia (n = 3), spontaneous oral dyskinesias (n = 6), olivocerebellar atrophy (n = 2), dystonia musculorum deformans (n = 6), spasmodic torticollis (n = 6), choreoathetosis (n = 2), Lesch-

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Table II. Efficacy and tolerability data from retrospective trials of tetrabenazine (TBZ) in patients with hyperkinetic movement disorders.

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay

)$
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Table II (continued).

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D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

339

340

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The American Journal of Geriatric Pharmacotherapy D.R.P. Guay

3FWJFX
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Table II (continued). 5PMFSBCJMJUZ
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D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

341

342

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Table II (continued).

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The American Journal of Geriatric Pharmacotherapy D.R.P. Guay


1BUJFOUT

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Table II (continued).

D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

343

344

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NZPDMPOVT
JO 
FBDI
UPMFSBODF
EFWFMPQFE
JO

PG
UIF


XJUI
JNQSPWFNFOU 
FBDI
XJUI
QFSJOBUBM
IZQPYJB XJUI
BUIFUPTJT
EZTUPOJB
NVTDVMPSVN
EFGPSNBOT
BOE
TQBTNPEJD
UPSUJDPMMJT

%SPXTJOFTT
SFQPSUFE
JO
iB
GFXw
QBUJFOUT
QBSLJOTPOJTN
EFWFMPQFE
CVU
TZNQUPNT
SFNJUUFE
XJUI
EPTF
SFEVDUJPO

5PMFSBCJMJUZ
0VUDPNFT

Table III. Efficacy and tolerability data from open-label trials of tetrabenazine (TBZ) in patients with hyperkinetic movement disorders.

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay

.D-FMMBO

4XBTI61 FU
BM
DPOU

CO

"VUIPST

Table III (continued).

5#;

NH
5*%
Y

E UJUSBUFE
PWFS

E

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NH
5*%
Y

E
UJUSBUFE
PWFS

E


1BUJFOUT
SFDFJWFE
5#;
GJSTU BOE

SFDFJWFE
BNBOUBEJOF
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3FHJNFO


1BUJFOUT

JNQSPWFE
XJUI
5#;
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BMNPTU
DPNQMFUF
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PG
BCOPSNBM
NPWFNFOUT
JO 
 


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OP
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BNBOUBEJOF IBE
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1BUJFOUT

PG
UIFN

1BUJFOUT
DPOUJOVFE 5#;

NH
#*%
JOJUJBMMZ
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NPWFNFOUT NPWFNFOUT
JO





XJUI
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lEPQB
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PG
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JEJPQBUIJD
QBSLJOTPOJTN
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GPS
ȑ
XL
o XJUI
JODSFBTFE
GVODUJPO
JO
 


OP
DIBOHF
JO




XJUI
DIPSFB
EVF
UP

NHE
NFBO

NHE 
JOUSBDSBOJBM
UVCFSDVMPNB EVSBUJPO
PG
UIFSBQZ
JO
UIPTF
7BSJPVT
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XJUI
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DIPSFB USFBUFE
GPS
ȑ
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o
NP
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PS
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XJUI
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JO FTTFOUJBM
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PG
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PG
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QBUJFOUT
XJUI
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XJUI
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IBE
OP
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BOE

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1BUJFOUT
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HC

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EVF
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"&T
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FBDI


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BHJUBUJPO
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FBDI 
PWFSBMM
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PG
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BOE
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CZ
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BOE



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BOE



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OP
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5#;
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QBUJFOUT
FBDI
OP
"&T
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XJUI
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5PMFSBCJMJUZ
0VUDPNFT

D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

345

346

,B[BNBUTVSJ
FU
BM &WBMVBUPS
CMJOEFE

"VUIPST

Table III (continued).


1BUJFOUT
XJUI
5%

1PQVMBUJPO 5#;

NHE
Y

E
JODSFBTFE UP

NHE
Y

E
BOE
UIFO
UP

NHE
Y

E
POMZ
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NHE
IBE
JODSFBTF
UP 
NHE

5#;
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XBT
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CZ
XL
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3FHJNFO "GUFS

XL
PG
5#;
UIFSBQZ

QBUJFOUT

IBE
UPUBM
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PG
EZTLJOFUJD
NPWFNFOUT


IBE
B o
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IBE
B
o
EFDSFBTF


IBE
B
o
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BOE


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B
o
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PS
XPSTFOJOH
P


WT
GJSTU
QMBDFCP QFSJPE 
BGUFS

XL
PG
5#;
UIFSBQZ
DPSSFTQPOEJOH
WBMVFT
XFSF
















BOE


P


WT
GJSTU
QMBDFCP
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BGUFS 
XL
PG
5#;
UIFSBQZ DPSSFTQPOEJOH
WBMVFT
XFSF 















BOE



QBUJFOUT
XFSF SFDFJWJOH

NHE
P


WT
GJSTU
QMBDFCP
QFSJPE 
JOUFOTJUZ
PG
NPWFNFOUT
BMTP
EFDSFBTFE
JO
NPTU
QBUJFOUT
CZ

XL
BGUFS 5#;
EJTDPOUJOVBUJPO
EZTLJOFUJD NPWFNFOUT
IBE
BMNPTU
SFUVSOFE
UP
CBTFMJOF
MFWFMT
OP
DIBOHFT
JO
QBUJFOU
CFIBWJPST EVSJOH
TUVEZ

&GGJDBDZ
0VUDPNFT

DPOUJOVFE


%JTDPOUJOVBUJPOT
BMM
EVSJOH XFFLT



PG
5#;
QFSJPE



EVF
UP
EJTDIBSHF

EVF
UP
B QTZDIPUJD
FYBDFSCBUJPO
BOE 
EVF
UP
"&T
"&
MFBEJOH
UP
EJTDPOUJOVBUJPO
XBT
TFWFSF
NBMBJTF
O

 
OP
PUIFS iTJHOJGJDBOUw
"&T
SFQPSUFE

5PMFSBCJMJUZ
0VUDPNFT

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay

1BLLFOCFSH
BOE
'PH

"VUIPST

Table III (continued).


1BUJFOUT
XJUI
PSBM
EZTLJOFTJBT BOE

XJUI
IZQFSLJOFTJBT
PG
FYUSFNJUJFT

1PQVMBUJPO

&GGJDBDZ
0VUDPNFT

5PMFSBCJMJUZ
0VUDPNFT

DPOUJOVFE

5#;
o
NHE
NFBO "&T
JODMVEFE
QBSLJOTPOJTN
BOE 5#;
NPOPUIFSBQZ 
NHE
XJUIXJUIPVU
i*NNFEJBUF
SFTQPOTFw
XBT TJBMPSSIFB

FBDI

QJNP[JEF
o
NHE
NFBO
UPUBM
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PG

NHE
DPNCJOBUJPO EZTLJOFTJBT
JO


HFOFSBMMZ
VTFE
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XIFO

PS
BOE
PCWJPVT
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JO CPUI
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BGUFS

NP
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PG
5#;
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UPUBM NPOPUIFSBQZ

NP
SBOHF EJTBQQFBSBODF
PG
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o
NP 
NFBO
EVSBUJPO
PG
JO




DPOUJOVFE DPNCJOBUJPO
UIFSBQZ

NP
PCWJPVT
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JO

SBOHF
o
NP




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JO




OP
DIBOHF
GSPN
CBTFMJOF
JO




BOE
EBUB
OPU
BWBJMBCMF
JO



$PNCJOBUJPO
UIFSBQZ i*NNFEJBUF
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XBT UPUBM
EJTBQQFBSBODF
JO
 
BOE
OP
DIBOHF
JO
  
BGUFS

NP
DPOUJOVFE UPUBM
EJTBQQFBSBODF
JO
 


PCWJPVT
SFEVDUJPO JO




SFEVDUJPO EPVCUGVM
JO




OP
DIBOHF
GSPN
CBTFMJOF
JO
 


BOE
EBUB
OPU
BWBJMBCMF
JO

 
CPUI
JOTUBODFT PG
OP
DIBOHF
JOWPMWFE
UIF
QBUJFOU
XJUI
IZQFSLJOFTJBT
PG
FYUSFNJUJFT

3FHJNFO

D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

347

348


1BUJFOUT
XJUI
5PVSFUUFT TZOESPNF


1BUJFOUT
XJUI
)$

.D"SUIVS
FU
BM66 CO

1PQVMBUJPO

4XFFU
FU
BM CO

"VUIPST

Table III (continued).

8L
o
5#;

NHE
JOJUJBMMZ JODSFBTFE
CZ

NHE
RE
UP
NBYJNVN
PG

NHE
QJNP[JEF

NHE
JOJUJBMMZ
JODSFBTFE
CZ

NHE
RE
UP
NBYJNVN
PG

NHE 8L
o
OP
5#;
QJNP[JEF 
NHE

QMBDFCP 8L
o
OP
5#;
QJNP[JEF
EJTDPOUJOVFE
TFDPOE
QMBDFCP
HJWFO 8L
o
5#;

NHE
O


PS

NHE
O



QJNP[JEF

NHE
O


PS 
NHE
O



5#;
HJWFO
2*%
UP
Ȑ
NHE O



NBYJNVN
5#;
EPTF

NHE
JO

QBUJFOUT
BOE 
NHE
JO

QBUJFOUT EVSBUJPO
PG
5#;
UIFSBQZ
o
E
NFBO

E

".15
HJWFO
2*%
HSBEVBMMZ JODSFBTFE
UP
Ȑ
NHE O



NBYJNVN
".15
EPTF

NHE
JO

QBUJFOU

NHE
JO

BOE 
NHE
JO

EVSBUJPO
PG
".15
UIFSBQZ
o
E
NFBO

E

".15
QFSJPE
QSFDFEFE
5#; QFSJPE
JO
BMM
QBUJFOUT
XJUI QIBTFT
TFQBSBUFE
CZ
XBTIPVU
QFSJPE
PG
o
E

3FHJNFO

5PMFSBCJMJUZ
0VUDPNFT

"MM
QBUJFOUT
IBE
JOJUJBM
iSBQJE
BOE
DPOTJEFSBCMFw
SFEVDUJPO JO
OVNCFS
PG
BCOPSNBM NPWFNFOUT
BU
SFTU
XIJDI
XBT NBYJNBM
BU
XL
o
BOE UIFSFBGUFS
SFHSFTTFE
UPXBSE
CBTFMJOF
JOEJWJEVBM
QBUJFOUT
IBE
FBSMZ
TVQQSFTTJPO
UP
 
BOE

PG
DPOUSPM
SFHSFTTJOH
UP


BOE

PG
DPOUSPM
BU
XL

JF
PGG
5#;
GPS

XL
PGG
QJNP[JEF
GPS 
XL 
DPNCJOBUJPO
PG
5#;
QJNP[JEF
XBT
NPTU
CFOFGJDJBM BMUIPVHI
SFHSFTTJPO
CFHBO EVSJOH
UIFSBQZ
QJNP[JEF BMPOF
IBE
B
TNBMM
TVQQSFTTJWF
FGGFDU
JO


QBUJFOUT

DPOUJOVFE


1BUJFOU
IBE
BHHSFTTJPO
JO XL
o
XIJDI
SFRVJSFE
SFJOUSPEVDUJPO
PG
5#;
GPS

XL BOE
EFQSFTTJPO
JO
XL
o XIJDI
SFRVJSFE
IBMPQFSJEPM QBUJFOU
XBT
XJUIESBXO
JO
XL
 EVF
UP
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"&T
XJUI
5#;
JODMVEFE 5#;

QBUJFOUT

EFQSFTTJPO
JO

QBUJFOUT JNQSPWFE
iSFNBSLBCMZw
BOE TFEBUJPO
JO

BOE
BLJOFTJB


SFDFJWFE
OP SFTUMFTT
MFHT
MFUIBSHZ
PDVMPHZSJD CFOFGJU DSJTJT
BLBUIJTJB
BOE
SFTUMFTTOFTT
".15

QBUJFOUT

IBE
JO

FBDI
BMM
QBUJFOUT
IBE
ȑ
"& NBSLFE
JNQSPWFNFOU
"&T
MFBEJOH
UP
EJTDPOUJOVBUJPO 

SFDFJWFE
TPNF
PG
".15
JODMVEFE
BHJUBUJPO CFOFGJU


SFDFJWFE BOE
CSFBUIMFTTOFTT
PUIFS
"&T
OP
CFOFGJU
BOE


XJUI
".15
JODMVEFE XJUIESFX DSZTUBMMVSJB
BOE
BLJOFTJB
JO 
QBUJFOUT
FBDI
MFUIBSHZ
JO
 FOVSFTJT
BOE
BLBUIJTJB
JO 
FBDI
BOE
TJBMPSSIFB
JOTPNOJB
EZTVSJB
SFTUMFTT
MFHT PDVMPHZSJD
DSJTJT
BOE
EZTBSUISJB JO

FBDI

&GGJDBDZ
0VUDPNFT

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay


1BUJFOUT
XJUI
)$


1BUJFOUT

XJUI
)$

XJUI )$
XJUIPVU
QPTJUJWF
GBNJMZ
IJTUPSZ

XJUI
DIPSFPBUIFUPTJT

XJUI
TQBTNPEJD
UPSUJDPMMJT 
XJUI
EZTUPOJB
NVTDVMPSVN
EFGPSNBOT

XJUI PMJWPQPOUPDFSFCFMMBS
BUSPQIZ 
XJUI
TQBTNPEJD
DPOUSBDUJPO
PG
BCEPNJOBM
XBMM

5PHMJB
FU
BM68

1PQVMBUJPO

)VBOH
FU
BM

"VUIPST

Table III (continued).

5#;

NH
#*%
JOJUJBMMZ JODSFBTFE
CZ

NHE
BU
XFFLMZ JOUFSWBMT
NBYJNVN
EBJMZ
EPTF o
NH
NFBO
EBJMZ
EPTF 
NH 
EVSBUJPO
PG
UIFSBQZ 
XLo
NP
NFBO

NP

5#;

NHE
JOJUJBMMZ
JODSFBTFE
CZ

NHE
RoE
UP
NBYJNVN
PG

NHE
EPTF DPVME
CF
SFEVDFE
UP

NHE JO
UIF
DBTF
PG
"&T
NFBO NBYJNVN
EBJMZ
EPTF

NH
SBOHF
o
NHE

3FHJNFO

)$
$PNQMFUF
DFTTBUJPO
PG
BMM
BCOPSNBM
NPWFNFOUT
JO




NPEFSBUF
JNQSPWFNFOU
JO




OP
JNQSPWFNFOU
JO



)$
XJUIPVU
QPTJUJWF
GBNJMZ
IJTUPSZ
NPEFSBUF JNQSPWFNFOU
JO



BOE
OP
JNQSPWFNFOU
JO 


.JTDFMMBOFPVT
EJTPSEFST
OP JNQSPWFNFOU
JO




1BUJFOUT

JNQSPWFE
BOE


EJE
OPU 
QBUJFOUT

XIP
JNQSPWFE
XFSF
DPOTJEFSFE
UP
IBWF
NBSLFE
JNQSPWFNFOU FWFO
XIFO
UIFSF
XBT
JNQSPWFNFOU
JO
USVODBM
BOE
MJNC
DIPSFJGPSN
NPWFNFOUT TPNF
QBUJFOUT
IBE
MJUUMF
SFEVDUJPO
JO
MJOHVBM
EZTLJOFTJBT

&GGJDBDZ
0VUDPNFT

DPOUJOVFE


1BUJFOU
XJUIESFX
EVF
UP
"&T
BLBUIJTJB
BOE
JOTPNOJB 
"&T PDDVSSFE
JO

QBUJFOUT
ESPXTJOFTT JO

JOTPNOJB
BOE
BLBUIJTJB
JO

FBDI
TXFBUJOH
QBSFTUIFTJBT
PG
UPOHVF
BOE
USBOTJFOU
GFWFS
JO 
FBDI

%JTDPOUJOVBUJPOT
EVF
UP
"&T
JO

QBUJFOUT
ESPXTJOFTT
QPTUVSBM IZQPUFOTJPO
BOE
BUBYJB
JO

QPTUVSBM
IZQPUFOTJPO
BOE
CSPODIPQOFVNPOJB
JO
 
"&T JODMVEFE
EZTQIBHJB
BOE
QPTUVSBM IZQPUFOTJPO

DBTFT
FBDI

ESPXTJOFTT
BOE
EFQSFTTJPO

DBTFT
FBDI


BOE
EZTBSUISJB BLBUIJTJB
BUBYJB
BOE
CSPODIPQOFVNPOJB

DBTF
FBDI 
BGUFS
UIF
DFTTBUJPO
PG
DIPSFJGPSN
NPWFNFOUT
JO 
QBUJFOU
B
EZTUPOJD
QPTUVSF EFWFMPQFE
PO
XBMLJOH

5PMFSBCJMJUZ
0VUDPNFT

D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

349

350

-BOH
BOE
.BSTEFO

"VUIPST

Table III (continued).


5#;OBJWF
QBUJFOUT

XJUI
EZTUPOJBT
BOE

XJUI DIPSFB
<
XJUI
)$>

1PQVMBUJPO

&GGJDBDZ
0VUDPNFT

1IBTF

5#;
OBJWF 
5#;
1IBTF


QBUJFOUT

IBE 
NH
#*%
JODSFBTFE
CZ
NBSLFE
CFOFGJU


IBE

NHE
RE
UP
NBYJNVN NPEFSBUF
CFOFGJU



PG

NHE
Y

XL IBE
NJME
CFOFGJU



1IBTF

FYDMVEJOH
UIPTF
XIP IBE
MJUUMF
PS
OP
DIBOHF



XFSF
5#;
JOUPMFSBOU
CFDBNF
XPSTF
BOE



PS
EJTDPOUJOVFE
BGUFS
QIBTF
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VOBCMF
UP
UPMFSBUF 
"EEFE
".15 USFBUNFOU
JO
UIPTF
BCMF
UP

NHE
JODSFBTFE
CZ UPMFSBUF
5#;
NFBO
GJOBM

NHE
RXL
UP
NBYJNVN
EBJMZ
EPTFT
XFSF

NH PG

HE

NH
2*% 
SBOHF
o
NH
JO
UIPTF XJUI
EZTUPOJBT
BOE

NH EFQFOEJOH
PO
SFTQPOTF ".15
DPVME
CF
DIBOHFE
UP SBOHF
o
NH
JO
UIPTF 20%
TDIFEVMF
5#;
EPTF XJUI
DIPSFB
P 


DPVME
CF
SFEVDFE
PS
EPTFT
PG
1IBTF


BOE

QBUJFOUT XJUI
EZTUPOJBT
BOE
DIPSFB CPUI
ESVHT
DPVME
CF
BEKVTUFE 1IBTF

UIPTF
XJUI SFTQFDUJWFMZ
XFSF
UP
SFDFJWF JNQSPWFNFOU
JO
NPWFNFOUT ".15
XJUIXJUIPVU
5#; BOEPS
GVODUJPO
BOE
UPMFSBCMF CVU

QBUJFOUT

XFSF
"&T 
5#;
DPOUJOVFE
BU
TBNF VOBCMF
UP
UPMFSBUF
".15 EPTF
".15
BOE
QMBDFCP
Y
MPOH
FOPVHI
UP
CF
FWBMVBUFE

XL
FBDI
JO
%#
$0
GBTIJPO PG

QBUJFOUT
XJUI
EZTUPOJBT TFQBSBUFE
CZ
XL
XBTIPVU SFDFJWJOH
".15
XJUI QFSJPE XJUIPVU
5#;






3FHJNFO

DPOUJOVFE

ȑ
.PEFSBUFTFWFSF
"&
PDDVSSFE JO

PG
QBUJFOUT
USFBUFE
XJUI 5#;
BOE

PG
QBUJFOUT
USFBUFE XJUI
".15
XJUIXJUIPVU
5#; 
NPTU
DPNNPO
"&T
JO
UIPTF
XIP
SFDFJWFE
5#;
XFSF
ESPXTJOFTT BOE
BLBUIJTJB

FBDI


EFQSFTTJPO



BOE
IZQFSTBMJWBUJPO
  NPTU
DPNNPO
"&T
JO
UIPTF
XIP
SFDFJWFE
".15
XJUIXJUIPVU
5#;
XFSF
ESPXTJOFTT


BLBUIJTJB



IZQFSTBMJWBUJPO



BOE
EFQSFTTJPO
BOE
QBSLJOTPOJTN

FBDI

5PMFSBCJMJUZ
0VUDPNFT

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay

-BOH
BOE
.BSTEFO DPOU

"VUIPST

Table III (continued). 1PQVMBUJPO

3FHJNFO

FYIJCJUFE
B
NPEFTU
SFTQPOTF PO
NPWFNFOU
TDPSFT
DPNQBSFE
XJUI
1IBTF

 
FYIJCJUFE
MJUUMF
PS
OP
CFOFGJU
BOE


XPSTFOFE
PG

QBUJFOUT
XJUI DIPSFB
SFDFJWJOH
".15


FYIJCJUFE
NJME
CFOFGJU PO
NPWFNFOU
TDPSFT



FYIJCJUFE
NPEFSBUF
CFOFGJU BOE


FYIJCJUFE
MJUUMF
PS OP
CFOFGJU
JOUSPEVDUJPO
PG
".15
OFDFTTJUBUFE SFEVDUJPO
PG
5#;
EPTF
CZ
B NFBO
PG

BOE

NHE
JO
QBUJFOUT
XJUI
EZTUPOJBT
BOE
DIPSFB
SFTQFDUJWFMZ

1IBTF


1BUJFOUT
SFDFJWJOH ".15
BMPOF

SFDFJWJOH
".15

5#;
QMBDFCP TVCTUJUVUJPO
MFE
UP
OP EFUFSJPSBUJPO
JO
NPUPS
TZNQUPNT
JO

QBUJFOU
XJUI
EZTUPOJBT
TMJHIU
EFUFSJPSBUJPO
JO

QBUJFOU
XJUI
EZTUPOJBT
BOE TJHOJGJDBOU
EFUFSJPSBUJPO
JO 
QBUJFOUT


XJUI
EZTUPOJBT

XJUI
DIPSFB

&GGJDBDZ
0VUDPNFT

DPOUJOVFE

5PMFSBCJMJUZ
0VUDPNFT

D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

351

352

+BOLPWJD
FU
BM

"VUIPST

Table III (continued).


1BUJFOUT
XJUI
5PVSFUUFT
TZOESPNF

1PQVMBUJPO .FBO
5#;
EPTF

NHE
SBOHF
¦
NHE 
EVSBUJPO
PG
UIFSBQZ
o
NP
NFBO

NP

3FHJNFO 
1BUJFOUT

IBE
NBSLFE
BOE
MBTUJOH
JNQSPWFNFOU
JO UJDT
BOE
CFIBWJPSBM
EZTGVODUJPO 

IBE
POMZ
NJME
PS USBOTJFOU
JNQSPWFNFOU


IBE
OP
JNQSPWFNFOU
JO
UIF

QBUJFOUT
XIP
IBE
VOEFSHPOF
TMFFQ
TUVEJFT
CFGPSF
USFBUNFOU
BOE
BGUFS
o
NP
PO
B
TUBCMF
EPTF
PG
5#;
5#;
XBT
BTTPDJBUFE XJUI
B
SFEVDFE
OVNCFS
PG
UJDT
QFS
SFDPSEJOH
TFTTJPO
NFBO GSPN

UP
 P
Ȑ


FMJNJOBUJPO
PG
TUBHF
FWFOUT
P 



FMJNJOBUJPO
PG
TMFFQ
BQOFB
JO

QBUJFOUT



BOE
SFEVDUJPO
JO
UPUBM
TMFFQ
UJNF
P




XJUIPVU
B
TJHOJGJDBOU DIBOHF
JO
QSPQPSUJPO
PG
3&. TMFFQ

&GGJDBDZ
0VUDPNFT

DPOUJOVFE

%SPXTJOFTT
JO

QBUJFOUT OFSWPVTOFTT
BOE
EFQSFTTJPO
JO

FBDI
BOE
QBSLJOTPOJTN
BOE
PDVMPHZSJD
DSJTJT
JO

FBDI

5PMFSBCJMJUZ
0VUDPNFT

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay

'BIO

"VUIPST

Table III (continued).


1BUJFOUT
XJUI
USBEJUJPOBM
OFVSPMFQUJDoBTTPDJBUFE
5%

1PQVMBUJPO .BYJNVN
5#;
EPTF
o 
NHE
EVSBUJPO
PG
UIFSBQZ
ȑ
Z

3FHJNFO

5PMFSBCJMJUZ
0VUDPNFT

DPOUJOVFE


1BUJFOU
IBE
BMNPTU
DPNQMFUF
1BSLJOTPOJTN
JO

5#;
SFDJQJFOUT
TZNQUPN
SFMJFG
XJUI
5#; 

NPOPUIFSBQZ
NBYJNVN EPTF

NHE 

QBUJFOU
XIP IBE
EFWFMPQFE
"&T
EVSJOH
USFBUNFOU
XJUI
SFTFSQJOF
BOE TXJUDIFE
UP
5#;
NPOPUIFSBQZ IBE
NBSLFE
TZNQUPN
SFMJFG

QBUJFOU
XIP
IBE
B
SFUVSO
PG
TZNQUPNT
EVSJOH
UIFSBQZ
XJUI SFTFSQJOF

".15
BOE TXJUDIFE
UP
5#;
NPOPUIFSBQZ IBE
BMNPTU
DPNQMFUF
TZNQUPN
SFMJFG
NBYJNVN
EPTF 
NHE 
JO

QBUJFOUT
XIP
DPNNFODFE
USFBUNFOU
XJUI 5#;
BMPOF
NBYJNVN
EPTFT

BOE

NHE
CVU
SFRVJSFE
UIF
BEEJUJPO
PG
".15
 BOE

NHE


UIF
QBUJFOU XIP
TXJUDIFE
UP
DPNCJOBUJPO
UIFSBQZ
EVF
UP
UIF
NPEFTU FGGJDBDZ
PG
5#;
BMPOF
IBE BMNPTU
DPNQMFUF
TZNQUPN SFMJFG
BOE
UIF
QBUJFOU
XIP TXJUDIFE
UP
DPNCJOBUJPO UIFSBQZ
EVF
UP
OP
SFTQPOTF
UP 5#;
BMPOF
IBE
OP
SFTQPOTF
UP DPNCJOBUJPO
UIFSBQZ

&GGJDBDZ
0VUDPNFT

D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

353

354

.BSTEFO
FU
BM

"VUIPST

Table III (continued).


1BUJFOUT
XJUI
TFWFSF
BYJBM
UPSTJPO
EZTUPOJBT

1PQVMBUJPO *OJUJBM
5#;
EPTFT
o 
NHE
O


BOE
o 
NHE
O

 
JO
UIF 
QBUJFOUT
DPOUJOVJOH
5#; NFBO
EPTF
XBT

NHE 
XFSF
SFDFJWJOH
Ȑ
NHE


UBLFO
GPS
B
NFBO
PG

NP
SBOHF
o
NP

"EEFE
QJNP[JEF

NHE O




JODSFBTFE
CZ

NHE
RXL
VOUJM
DPOUSPM
PG
EZTUPOJBT
PS
PDDVSSFODF
PG
VOBDDFQUBCMF
QBSLJOTPOJTN NFBO
EPTF

NHE
SBOHF
o
NHE


UBLFO GPS
B
NFBO
PG

NP SBOHF
o
NP

"U
UIJT
QPJOU
BO BOUJDIPMJOFSHJD
XBT
BEEFE
UP
5#;
NPOPUIFSBQZ
O


PS
5#;

QJNP[JEF
UIFSBQZ
O

 
XJUI
VQXBSE UJUSBUJPO
VOUJM
DPOUSPM
PG
QBSLJOTPOJBO
"&T
JG
EZTUPOJBT
DPOUJOVFE
UP
CF VODPOUSPMMFE
QJNP[JEF
BOEPS
BOUJDIPMJOFSHJD
EPTFT
DPVME
CF
GVSUIFS
UJUSBUFE

3FHJNFO 0O
UIFJS
GJOBM
SFHJNFOT 
QBUJFOUT

IBE
ESBNBUJD JNQSPWFNFOU


IBE NBSLFE
JNQSPWFNFOU


IBE
NPEFSBUF
JNQSPWFNFOU


IBE TMJHIU
JNQSPWFNFOU
BOE
 
IBE
OP
JNQSPWFNFOU

&GGJDBDZ
0VUDPNFT

DPOUJOVFE

*OJUJBMMZ
IJHI
5#;
EPTFT
XFSF
BTTPDJBUFE
XJUI
VOBDDFQUBCMF QSFWBMFODF
PG
EFQSFTTJPO
EVF
UP
XIJDI

QBUJFOUT
EJTDPOUJOVFE 5#;
BOE

SFRVJSFE
EPTF
SFEVDUJPO
JO
UIF

QBUJFOUT
XIP
DPOUJOVFE
UIFSBQZ
MPOH
UFSN
"&T
JODMVEFE

QBUJFOUT

XJUI
FWJEFOU QBSLJOTPOJTN


XJUI BLBUIJTJB


XJUI
PUIFS BOUJDIPMJOFSHJD
"&T
BOE


XJUI
TPNF
ESPXTJOFTT
BMM
XFSF BCMF
UP
DPOUJOVF
USFBUNFOU EFTQJUF
"&T

5PMFSBCJMJUZ
0VUDPNFT

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay


1BUJFOUT
XJUI
TQPOUBOFPVT PSBM
EZTLJOFTJBT


1BUJFOUT
XJUI
USBEJUJPOBM OFVSPMFQUJDoBTTPDJBUFE
5%ZTU

,BOH
FU
BM 

1PQVMBUJPO

#BSUFMT
BOE
;FMMFS

"VUIPST

Table III (continued).

5#;
o
NHE
NFBO

NHE

.FBO
EBJMZ
5#;
EPTFT
XFSF 
NH
O





NH
O



BOE

NH
O

 
NFBO
4%
EVSBUJPO
PG
UIFSBQZ 

NP

3FHJNFO

0WFSBMM


5#;
SFDJQJFOUT
IBE
B
iGBWPSBCMFw
SFTQPOTF
JO
UIF

QBUJFOUT SFDFJWJOH
5#;
NPOPUIFSBQZ 

IBE
B
iGBWPSBCMFw SFTQPOTF
JO
UIF

QBUJFOUT
JO
XIPN
5#;
XBT
BEEFE
UP QSFWJPVTMZ
VOTVDDFTTGVM
UIFSBQZ 

IBE
B
iGBWPSBCMFw SFTQPOTF
JO
UIF

QBUJFOUT

XIP
SFDFJWFE
5#;
BOE
SFTFSQJOF
NPOPUIFSBQZ
BU EJGGFSFOU
UJNFT


JNQSPWFE
PO
CPUI
ESVHT
 
EJE
OPU
SFTQPOE
UP
FJUIFS 

JNQSPWFE
PO
5#;
CVU EJE
OPU
SFTQPOEIBE
TJHOJGJDBOU
"&T
XJUI
SFTFSQJOF BOE


JNQSPWFE
PO
SFTFSQJOF
CVU
EJE
OPU
SFTQPOE IBE
TJHOJGJDBOU
"&T
XJUI
5#;

%ZTLJOFTJBT
XFSF
iESBNBUJDBMMZw
JNQSPWFE
JO

QBUJFOUT

BOE


IBE
HPPE
UP TBUJTGBDUPSZ
JNQSPWFNFOU HPPE
DPSSFTQPOEFODF
CFUXFFO
JNQSPWFNFOUT
JO
WJEFPUBQF &.(
EBUB
BOE
DMJOJDBM
JNQSFTTJPO
EBUB

&GGJDBDZ
0VUDPNFT

DPOUJOVFE

"&T
JO

QBUJFOUT

XFSF
TFSJPVT
FOPVHI
UP
MJNJU
5#; EPTBHF
"&T
JODMVEFE
QBSLJOTPOJTN
BOE
EFQSFTTJPO

FWFOUT
FBDI


MFUIBSHZ



BOE IBMMVDJOBUJPOT
DPOGVTJPO
EJ[[JOFTT WPNJUJOH
VOJMBUFSBM
MFH
USFNPS 
FBDI 
JO
UIF

QBUJFOUT
XJUI
B IJTUPSZ
PG
EFQSFTTJPO
NBYJNVN 5#;
EPTF

NHE




IBE
SFMBQTFT
PG
EFQSFTTJPO
BU
5#;
EPTFT
PG


BOE

NHE 
QBUJFOU
EFWFMPQFE
BO
BDVUF
EZTUPOJD
SFBDUJPO

5JSFEOFTT
BOE
QPTUVSBM PSUIPTUBUJD
IZQPUFOTJPO O


BOE
NJME
SJHJEJUZ O


BQQFBSFE
FBSMZ
XJUI
POMZ
UJSFEOFTT
BOE
QPTUVSBM PSUIPTUBUJD
IZQPUFOTJPO EJTBQQFBSJOH
BGUFS
o
XL

5PMFSBCJMJUZ
0VUDPNFT

D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

355

356

+BOLPWJD
BOE
0SNBO

"VUIPST

Table III (continued).


1BUJFOUT

XJUI
5%

XJUI
)$

XJUI
5PVSFUUFT
TZOESPNF

XJUI
HFOFSBMJ[FE EZTUPOJBT

XJUI
DSBOJBM
EZTUPOJBT

XJUI
5%ZTU

XJUI
GPDBM
EZTUPOJBT

XJUI FTTFOUJBM
CMFQIBSPTQBTN

XJUI
IFNJEZTUPOJB


1PQVMBUJPO %BJMZ
5#;
EPTFT
BOE
EVSBUJPOT‰5%
o
NH NFBO

NH
GPS
o 
NP
NFBO

NP 
)$
o
NH
NFBO

NH

GPS
o
NP
NFBO

NP 
5PVSFUUFT
TZOESPNF
o 
NH
NFBO

NH
GPS o
NP
NFBO

NP  HFOFSBMJ[FE
EZTUPOJBT
o 
NH
NFBO

NH
GPS o
NP
NFBO

NP 
DSBOJBM
EZTUPOJBT
o
NH NFBO

NH
GPS
o 
NP
NFBO

NP  5%ZTU
o
NH
NFBO

NH
GPS
o
NP
NFBO

NP 
GPDBM
EZTUPOJBT
o
NH
NFBO 
NH
GPS
o
NP
NFBO

NP

3FHJNFO 0WFSBMM
QPQVMBUJPO

 BOE

IBE
NBSLFE
NPEFSBUF
BOE
NJME
JNQSPWFNFOU
SFTQFDUJWFMZ XIJMF

IBE
OP
DIBOHF BOE

XPSTFOFE 5%
$PSSFTQPOEJOH QSPQPSUJPOT
XJUI
NBSLFE NPEFSBUF
BOE
NJME
JNQSPWFNFOU
BOE
OP
JNQSPWFNFOUXPSTFOJOH XFSF



BOE
 )$

IBE
NPEFSBUF JNQSPWFNFOU
BOE

IBE NJME
JNQSPWFNFOU 5PVSFUUFT
TZOESPNF



BOE

IBE
NJME NPEFSBUF
BOE
NBSLFE JNQSPWFNFOU
BOE
OP
JNQSPWFNFOUXPSTFOJOH
SFTQFDUJWFMZ 0WFSBMM
EZTUPOJB
QPQVMBUJPO
DPSSFTQPOEJOH
QSPQPSUJPOT
XJUI
NBSLFE
NPEFSBUF
BOE
NJME
JNQSPWFNFOU
BOE
OP JNQSPWFNFOUXPSTFOJOH XFSF



BOE


&GGJDBDZ
0VUDPNFT

DPOUJOVFE

1BSLJOTPOJTN
JO

ESPXTJOFTT
PS
GBUJHVF
JO

EFQSFTTJPO
JO

OFSWPVTOFTT
PS
BOYJFUZ
JO 
JOTPNOJB
BOE
SFTUMFTTOFTT BLBUIJTJB
JO

FBDI
BOE
 PUIFS
"&T
JO
Ȑ
FBDI
NPTU
"&T XFSF
EPTF
SFMBUFE
BOE
JNQSPWFE
XJUI
EPTF
SFEVDUJPO
OP
BQQBSFOU EJGGFSFODFT
JO
UZQFTSBUFT
PG
"&T
JO
QBUJFOUT
XJUI
EJGGFSFOU
NPWFNFOU
EJTPSEFST

5PMFSBCJMJUZ
0VUDPNFT

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay

+BOLPWJD
FU
BM CO

"VUIPST

Table III (continued).


1BUJFOUT
XJUI
-FTDI/ZIBO
TZOESPNF

1PQVMBUJPO 4FRVFOUJBM
USFBUNFOU
XJUI 
ESVHT
5#;
GMVQIFOB[JOF DBSCJEPQBMFWPEPQB
BOE
CSPNPDSJQUJOF


XJUI
HSBEVBM EPTF
JODSFBTFT
UP
NBYJNVN SFTQPOTF
PS
JOUPMFSBCMF
"&T

3FHJNFO 4FMGNVUJMBUPSZ
PS BVUPBHHSFTTJWF
CFIBWJPST 
QBUJFOUT

IBE NPEFSBUF
JNQSPWFNFOU
JNQBJSNFOU
OPX
POMZ TMJHIUMZ
EJTBCMJOH
XJUI
5#;


IBE
OP
DIBOHF
BOE 

XPSTFOFE )ZQFSLJOFUJD
NPWFNFOU EJTPSEFST

QBUJFOUT

IBE
NPEFSBUF
JNQSPWFNFOU
JNQBJSNFOU
OPX
POMZ TMJHIUMZ
EJTBCMJOH
XJUI
5#;


IBE
TMJHIU
JNQSPWFNFOU
JNQBJSNFOU
EFGJOJUFMZ
JOUFSGFSJOH
XJUI GVODUJPOJOH


BOE



IBE
OP
DIBOHF

&GGJDBDZ
0VUDPNFT

DPOUJOVFE

)JHI
JODJEFODF
PG
"&T
TPNF
PG
UIFN
JOUPMFSBCMF

5PMFSBCJMJUZ
0VUDPNFT

D.R.P. Guay The American Journal of Geriatric Pharmacotherapy

357

358

4UBDZ
FU
BM

"VUIPST

Table III (continued).


1BUJFOUT
XJUI
5%

XJUI
TUFSFPUZQZ

XJUI EZTUPOJBT

XJUI
BLBUIJTJB 
XJUI
USFNPS

XJUI
DIPSFB 
XJUI
NZPDMPOVT

IBE
B
DPNCJOBUJPO
PG
EJTPSEFST 
IBE
EZTUPOJB
BMPOF

IBE
TUFSFPUZQZ
BMPOF

1PQVMBUJPO 5#;
EPTF
OPU
TQFDJGJFE
GPS NFBO
EVSBUJPO
PG

NP
JO
TUFSFPUZQZ
HSPVQ
BOE

NP JO
EZTUPOJB
HSPVQ

3FHJNFO .FBO
JNQSPWFNFOUT
PO
QPJOU
TDBMF
XJUI
B
TDPSF
PG

SFQSFTFOUJOH
NPEFSBUF JNQSPWFNFOU
JO
JOUFOTJUZ BNQMJUVEF
PG
BCOPSNBM NPWFNFOUT
BOE
NPEFSBUF
GVODUJPOBM
JNQSPWFNFOU ‰ 
JO
UIPTF
XJUI
TUFSFPUZQZ
BMPOFJO
DPNCJOBUJPO

JO
UIPTF
XJUI
EZTUPOJBT
JO DPNCJOBUJPO

JO
UIPTF
XJUI EZTUPOJBT
BMPOF
BOE

JO
UIPTF
XJUI
BLBUIJTJB
PWFSBMM NFBO
JNQSPWFNFOU

PUIFS PVUDPNF
EBUB
BWBJMBCMF
GPS
POMZ 
QBUJFOUT
XIP
SFDFJWFE
SFTFSQJOF
CFGPSF
5#;
BOE
DPNQMFUFE
UIF
5#;
USJBM
PG
XIPN


IBE
NBSLFE JNQSPWFNFOU
XJUI
5#;


IBE
NPEFSBUF
JNQSPWFNFOU
BOE




IBE
MJUUMF
PS
OP
SFTQPOTF

&GGJDBDZ
0VUDPNFT

DPOUJOVFE

"&T
PDDVSSFE
JO

PG
QBUJFOUT
JODMVEJOH
EPTFSFMBUFE QBSLJOTPOJTN
JO

EFQSFTTJPO
EZTQIBHJB
IBMMVDJOBUJPOT
BOE
ESPXTJOFTT
JO

FBDI
BMM
"&T SFTPMWFE
XJUI
5#;
EPTF
SFEVDUJPO PS
EJTDPOUJOVBUJPO

5PMFSBCJMJUZ
0VUDPNFT

The American Journal of Geriatric Pharmacotherapy D.R.P. Guay


1BUJFOUT
XJUI
5%
SFMBUFE UP
NFUPDMPQSBNJEF
JO
 BNPYBQJOF
JO

GJSTUHFOFSBUJPO OFVSPMFQUJDT
JO

BOE UIJFUIZMQFSB[JOF
JO



1BUJFOUT
XJUI
)$

0OEP
FU
BM80

1PQVMBUJPO

0OEP
FU
BM

"VUIPST

Table III (continued).

5#;

NH
#*%
JOJUJBMMZ
UJUSBUFE
JO
XFFLMZ
JODSFNFOUT UP
NBYJNVN
PG

NH
5*% GJOBM
NFBO
4%
5#;
EPTF 

NHE
SBOHF
o 
NHE 
NFBO
EVSBUJPO
 
NP
SBOHF
o
NP

5#;

NH
#*%
JOJUJBMMZ
UJUSBUFE
JO
XFFLMZ
JODSFNFOUT UP
NBYJNVN
PG

NH
5*% NFBO
4%
GJOBM
EPTF
 
NHE
NFBO
EVSBUJPO


XL

3FHJNFO


1BUJFOU
XBT
MPTU
UP
GPMMPXVQ
QBUJFOUT
TFMGBTTFTTNFOUT
JOEJDBUFE
NBSLFE
JNQSPWFNFOU JO




NPEFSBUF
JNQSPWFNFOU
JO




NJME
JNQSPWFNFOU
JO
 


BOE
OP
DIBOHF
JO

 
CMJOEFE
BTTFTTNFOU
PG
WJEFPUBQFT
JOEJDBUFE
UIBU


IBE
JNQSPWFE
XJUI
5#;


XFSF
CFUUFS
CFGPSF
5#;
BOE


XBT
VODIBOHFE
P

 
P NFBO
4%
"*.4
NPUPS
TDPSFT JNQSPWFE
GSPN


UP 

P

 
BMM
QBUJFOUT DPOUJOVFE
5#;
BGUFS
DPNQMFUJPO
PG
TUVEZ


.FBO
JNQSPWFNFOU
PO
"*.4
NPUPS
TVCTFU
TDPSFT GSPN
NFBO
<4%>
PG

<>
UP

<> P 
 

NFBO
JNQSPWFNFOU
PO
TVCKFDUJWF
TDPSFT
GSPN

<>
UP

<> P

 
QBUJFOUT
TFMGBTTFTTNFOUT
JOEJDBUFE
NBSLFE
JNQSPWFNFOU
JO




NPEFSBUF
JNQSPWFNFOU
JO 



BOE
NJME JNQSPWFNFOU
JO



&GGJDBDZ
0VUDPNFT

DPOUJOVFE

"&T
JODMVEFE
BLBUIJTJB

DBTFT
BOE
JOTPNOJB
DPOTUJQBUJPO
EFQSFTTJPO
ESPPMJOH
BOE
TVCKFDUJWF
XFBLOFTT

DBTF
FBDI 
OP
DPNQMBJOUT
PG
QBSLJOTPOJTN
BMM "&T
XFSF
NJME
JO
JOUFOTJUZ
FYDFQU 
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α-methyl-para-tyrosine; DB = double blind; REM = rapid eye movement; EMG = electromyelogram; TDyst = tardive dystonia; AIMS = Abnormal Involuntary Movement Scale; UHDRS = Unified Huntington’s Disease Rating Scale; ADHD = attentiondeficit/hyperactivity disorder; OCD = obsessive-compulsive disorder; CGIC = Clinical Global Impression of Change.

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The American Journal of Geriatric Pharmacotherapy D.R.P. Guay

D.R.P. Guay

Nyhan syndrome (n = 5), bilateral athetosis (n = 2), hemiballismus (n = 2), chorea due to cerebrovascular disease (n = 4), chorea due to postencephalitic parkinsonism (n = 2), chorea due to L-dopa treatment of Parkinson’s disease (n = 3), chorea due to tuberculoma (n = 1), posttraumatic chorea (n = 2), essential tremor (n = 3), hereditary ataxia (n = 2), perinatal hypoxia (n = 1), progressive athetoid dystonia (n = 1), hypoxic encephalopathy/athetosis (n = 1), and kernicterus/ athetosis (n = 1). Positive clinical responses were noted in 72 of 109 patients (66%) with Huntington’s chorea,61,62,67,68,73,80,84 77 of 88 patients (88%) with tardive dyskinesia,63,76,79 and 23 of 26 patients (88%) with Tourette’s syndrome.70,73 Rates of positive response in patients with spontaneous oral dyskinesias73 and Lesch-Nyhan syndrome77 were 100% (6 of 6 patients) and 80% (4 of 5 patients), respectively. In some cases, the numbers of patients with each disorder cited here differ from those in the previous paragraph due to the use of a nonclinical definition of positive response in several of the studies.78,81,83 When response data for the patients with Huntington’s disease are removed from the data sets from 3 of the studies,61,62,76 it is possible to calculate pooled response rates for less-common hyperkinetic disorders, such as other choreas, hemiballismus, and the dystonias. In these 3 modified data sets, rates of response to TBZ were 40% (6 of 15 patients),61 32% (6 of 19),62 and 24% (30 of 124).76 Across studies, the most frequently reported AEs were parkinsonism (22%), drowsiness (20%), depression (14%), confusion (13%), postural hypotension (12%), anxiety (10%), akathisia (9%), insomnia (8%), and dysphagia (8%). McArthur et al66 reported the development of tolerance with continuous TBZ exposure in 3 patients with Huntington’s chorea treated with the combination of TBZ and pimozide. In this trial, combination therapy initially was associated with a “rapid and considerable” reduction in the number of abnormal movements. The response was maximal at 3 to 4 weeks after the initiation of TBZ and regressed toward baseline over the subsequent 3 to 4 weeks. Fasano et al83 reported similar findings in a trial of TBZ monotherapy in 68 patients with Huntington’s chorea. A 13% reduction in efficacy, as measured using the Unified Huntington’s Disease Rating Scale (UHDRS) chorea subscale, occurred between follow-up visit 1 (at a mean [SD] of 10 [8] months after initiation of TBZ) and follow-up visit 2 (at 34 [25] months) (P < 0.01). This occurred despite a mean 63% dose increase between the 2 followup visits (from 35 [15] to 58 [15] mg/d; P < 0.01).

The American Journal of Geriatric Pharmacotherapy

Fasano et al83 also investigated possible predictors of TBZ-associated improvement in chorea. Drug dose, sex, age at the time of TBZ treatment, and treatment duration were not significantly associated with outcomes. However, older age at the onset of disease predicted better outcomes (rr = 0.33, 0.33, and 0.38 for the first and last evaluations and the maximal effect achieved, respectively; P < 0.01).

Controlled Trials There have been 10 controlled trials of TBZ,8,85–93 the majority of them conducted many years ago. The major outcome measures used in these trials included the UHDRS, the Unified Parkinson’s Disease Rating Scale (UPDRS), and the Clinical Global Impression (CGI) scale.

Crossover Trials In a randomized, double-blind, active- and placebocontrolled crossover trial, Godwin-Austen and Clark85 compared TBZ (initiated at 25 mg BID for 3 days, followed by 25 mg QID for 4 days), diazepam (initiated at 1 mg BID for 3 days, followed by 1 mg QID for 4 days), and placebo for 7 days in the treatment of phenothiazine-induced tardive dyskinesia in 6 elderly (age range, 60–85 years) women who were long-stay residents of a psychiatric hospital. There was no washout period between phases. Three assessors (2 of clinical symptoms, 1 of videotapes made on the last day of each phase) provided blinded input on patients’ responses. Details of the 4-point response scale were not provided, although lower scores indicated greater improvement. With TBZ, the 6 patients had score reductions of 1.5, 2, 4, 4, 4, and 6 points after 1 week; the mean point tally fell from 6.4 at baseline to 2.8 points (56%). With diazepam, the 6 patients had score reductions of 1, 1, 2, 2.5, 3, and 3.5 points after 1 week, and the mean point tally fell from 6.4 to 4.3 points (33%). After 1 week of placebo, 3 patients had score reductions of 0.5, 2, and 1.5 points; 2 had no change; and 1 had a 1-point increase. The mean point tally was reduced from 6.4 to 5.9 (8%). No statistical analysis was provided. AEs were poorly described and quantitated. The authors reported that “most” patients experienced drowsiness during the TBZ phase that was no greater than that during the diazepam phase. Gilligan et al86 conducted a randomized, placebocontrolled, double-blind crossover trial of TBZ 150 mg/d in patients with a variety of abnormal movement disorders. Eighteen of the 27 enrolled patients (67%) completed the trial (6 with Huntington’s chorea, 9 with athetosis, 1 with bilateral facial spasms, 1 with chorei-

363

The American Journal of Geriatric Pharmacotherapy

D.R.P. Guay

form movements of the right arm, and 1 with chorea due to cerebral atherosclerosis). The treatment phases were 4 weeks each, with no washout between phases. Three blinded evaluators watched videotapes made before the study and at the end of each phase, and were asked to provide an opinion about the phase in which patients received TBZ. If they perceived no pattern of change during the 2 study phases, they could state that they had no opinion. For the 18 patients who completed the study, the evaluators had an opinion in 14 cases and were correct for 11 (79%) of them; they had no opinion in 4 cases. Thus, clinical improvement due to TBZ was noted in 11 of 18 patients (61%); however, it was the impression of the blinded evaluators that the degree of improvement was moderate in 3 of these 11 patients (27%) and mild in 8 (73%). When asked about their preference for the study regimens, 3 patients preferred TBZ, 6 preferred placebo, and 9 had no preference. Patients’ spontaneously volunteered reasons for their preferences appeared to be concerned more with the absence of drowsiness than with any change in motor control. Drowsiness (17 events), hypersalivation (2), and agitation (2) were reported as AEs. Both instances of hypersalivation occurred during the TBZ phase, and both instances of agitation occurred during the placebo phase. Drowsiness was reported by 3 patients during both phases. The placebo phase occurred first in 2 of these patients, so the double-reporting of this AE cannot be ascribed to persistence from the TBZ phase into the placebo phase in the absence of a washout between phases. Eleven patients reported drowsiness during only one of the study phases; in 8 cases, this coincided with the TBZ phase. Clearly, drowsiness is a frequent and important AE. In the randomized, double-blind, 3-way crossover trial by McLellan et al,8 TBZ, the phenothiazine thiopropazate, and placebo were compared in 10 patients with chorea (9 due to Huntington’s disease, 1 due to cerebral palsy). TBZ was titrated upward from 50 to 200 mg/d in increments of 25 mg every 2 days; thiopropazate was titrated upward from 5 to 30 mg/d in increments of 5 mg every 2 days. The total duration of therapy was 6 weeks, with no washout between phases. TBZ therapy was associated with marked improvement (“virtually complete suppression of the chorea”) in 5 patients (50%), moderate improvement in 2 patients (20%), slight improvement in 1 patient (10%), and no improvement in 1 patient (10%). One patient developed severe parkinsonism at a TBZ dose of 25 mg/d and was withdrawn from the trial. Thiopropazate therapy was associated with considerable improvement in

364

1 patient (10%), slight improvement in 3 patients (30%), and no improvement in 6 patients (60%). Placebo was associated with slight improvement in 3 patients (30%), no improvement in 6 patients (60%), and worsening in 1 patient (10%). No statistical analysis was provided. Eight blinded physicians evaluated videotapes from each study phase to assign chorea scores. Mean (SEM) pretreatment, TBZ, thiopropazate, and placebo scores were 2.06 (0.10), 1.24 (0.06), 1.53 (0.12), and 1.72 (0.17), respectively (P P < 0.001, pretreatment vs TBZ; P < 0.01, pretreatment vs thiopropazate). Scores for TBZ and thiopropazate were not compared statistically. During the TBZ, thiopropazate, and placebo phases, there were a total of 18 AEs in 8 patients, 7 AEs in 6 patients, and 10 AEs in 4 patients, respectively. Manual dexterity was tested as a marker of improvement in choreiform movements. The mean times to completion of the dexterity test with each hand in normal control subjects and TBZ, thiopropazate, and placebo recipients were 47.0, 74.1, 81.7, and 82.6 seconds, respectively. The corresponding mean times to write a standard sentence with the dominant hand were 18.0, 41.2, 45.6, and 61.2 seconds (statistical analysis not provided). In a randomized, double-blind, crossover trial, Asher and Aminofff87 compared TBZ and placebo in 32 patients with a variety of abnormal movement disorders (9 with Huntington’s chorea, 12 with tardive dyskinesia, and 11 with segmental or generalized dystonias). TBZ was initiated at 25 mg BID, followed by upward titration in daily increments of 25 mg every 3 days until the maximal therapeutic response was attained, AEs limited further dose escalation, or the maximum allowable dose of 200 mg/d was reached. The duration of the study was 6 weeks, with no washout between phases. Among the 26 patients (81%) who completed the trial, 15 (58%) exhibited clinical improvement, 10 (38%) had no change from baseline, and 1 (4%) exhibited worsening. Overall, 68% of patients had at least moderate clinical improvement. Patients were not evaluated in the same manner during the placebo phase as during the TBZ phase; it appears that placebo was used solely to determine whether clinical improvement/worsening could be attributed to TBZ. Sixteen patients (62%) chose to continue TBZ after the end of the study—7 of 8 (88%) with Huntington’s chorea, 7 of 10 (70%) with tardive dyskinesia, and 2 of 8 (25%) with dystonia. Of the 7 early withdrawals from the study, 6 (86%) occurred during the TBZ phase. AEs were cited by patients in the context of study withdrawal in only 3 cases (43%). Drowsiness, hypersaliva-

D.R.P. Guay

tion, parkinsonism, and depression were noted in 30%, 12%, 9%, and 6% of patients, respectively. Twenty patients with a variety of abnormal movement disorders (6 with Meige’s syndrome, 4 with tardive dyskinesia, 3 with adult-onset dystonia, 2 with dystonic choreoathetosis, 4 with various rarer dystonias, and 1 with Huntington’s disease) participated in a randomized, double-blind, crossover trial by Jankovic.88,89 TBZ was initiated at 25 mg/d and was titrated upward in 25-mg/d increments to 200 mg/d, in the absence of intolerable AEs. Patients were hospitalized at the beginning of each phase (mean of 10 days in first phase and 7 days in second phase). The duration of the treatment phases was not fixed, but was reported to be ~6 weeks each (range, 1–7 weeks). The treatment response was measured using an unvalidated hyperkinesia rating scale, as well as being evaluated by blinded assessment of videotapes made while patients performed standard tests. Overall, there was a significant reduction in the number of abnormal movements during the TBZ phase compared with the placebo phase (P P < 0.005). The responses differed by disorder. All 4 patients with tardive dyskinesia improved during the TBZ phase. Among the 6 patients with Meige’s syndrome, 4 had what was described as “definite” improvement during TBZ therapy and 1 each had no change or worsened due to emergence of parkinsonism and study withdrawal. Among the 9 patients with dystonic disorders, all exhibited some degree of improvement, while the patient with Huntington’s disease was “markedly” improved. Overall, 13 of 19 patients (68%) had at least moderate improvement (defined as a reduction of ≥25% in number of abnormal movements) during TBZ therapy. AEs were reported in 13 of 19 patients (68%). There were a total of 32 AEs, the most frequent being drowsiness (5), hypersalivation (4), insomnia and tremor (3 each), and fatigue and parkinsonism (2 each). Brusa et al90 conducted a randomized, evaluatorblinded, placebo- and active-controlled crossover study comparing 6 months’ treatment with TBZ and the neuroleptic aripiprazole in patients with chorea associated with Huntington’s disease. Both drugs were slowly titrated to the maximum tolerated doses (mean [SD], 95.83 [33.20] and 10.76 [4.91] mg/d, respectively) and continued at those doses for the remainder of the 3-month treatment period. There was no washout phase between treatment periods. Both drugs were associated with significant reductions from baseline in the UHDRS chorea item score in the “off” condition (ie, after drug[s] for chorea were withheld for ≥3 weeks);

The American Journal of Geriatric Pharmacotherapy

from a baseline value of 10 (1.58), the chorea item score decreased to 4.6 (1.67) with TBZ and to 4.8 (1.30) with aripiprazole (both, P < 0.01). No significant drug effect was noted on scores on the UHDRS parkinsonism item or Mini–Mental State Examination score. However, TBZ therapy was associated with significant sedative effects, with scores on the Epworth Sleepiness Scale increasing from a baseline value of 8.8 (0.83) to 11.2 (1.30) (P < 0.01). Aripiprazole was not associated with a significant change from baseline in Epworth Sleepiness Scale score, and the score with aripiprazole (9.0 [1.00]) was significantly lower than that with TBZ (P < 0.01). TBZ was also associated with a significant increase from baseline in scores on the Hamilton Rating Scale for Depression (P < 0.01); the difference between aripiprazole and TBZ was statistically significant (P < 0.01).

Noncrossover Trials Kazamatsuri et al91 conducted a 19-week, randomized, evaluator-blinded, active-controlled trial of TBZ and haloperidol in 13 patients with the typical abnormal buccolingualmasticatory movements associated with neuroleptic-induced tardive dyskinesia. TBZ was initiated at 50 mg BID and increased to 100 mg BID at week 15; haloperidol was initiated at 4 mg BID and increased to 8 mg BID at week 15. Placebo was substituted for active treatment at week 19 (end of the study). In the 6 TBZ recipients, 2 patients had a complete cessation of abnormal movements at the end of week 2, and 4 had no response. The mean frequency of oral dyskinesias decreased from 25.7 per minute at baseline to 12.8 per minute at the end of week 2 and to 16.8 per minute at the end of week 6. The TBZ response was maintained at approximately the same level from the end of week 6 through the end of week 18. Withdrawal of TBZ led to a rapid reemergence of dyskinesias at baseline levels of severity in all patients. TBZ was described as having significantly reduced the frequency of dyskinesias over time relative to baseline (P < 0.05), although no specific data were reported. In the 7 haloperidol recipients, 5 patients exhibited a complete cessation of oral dyskinesias at the end of week 2, and 2 had a marked reduction in the frequency of dyskinesias. Dyskinesia frequency decreased from a mean of 34.9 per minute at baseline to a mean of 2.4 per minute at the end of week 2. At the end of week 4, 4 haloperidol recipients had a complete cessation of dyskinesias and 3 had a reemergence of dyskinesias to nearly baseline frequencies (mean dyskinesia frequency in all 7 haloperidol recipients was 18.0 per minute). At

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the end of week 8, 2 haloperidol recipients had complete cessation of dyskinesias and 5 had continued dyskinesias (P < 0.01 for the latter), albeit at a lower frequency than at baseline (mean dyskinesia frequency in all 7 haloperidol recipients was 24.1 per minute). At the end of week 17 (ie, 2 weeks after doubling the haloperidol dose), 3 haloperidol recipients had a considerable reduction in dyskinesias, 2 had no change, and 2 could not tolerate the dose escalation and had to be withdrawn from therapy; the mean dyskinesia frequency was 21.8 per minute, still significantly less frequent than at baseline (34.9 per minute) (P P < 0.01). At the end of week 19 (when placebo replaced active drug), oral dyskinesias rapidly reappeared at baseline levels of severity. Haloperidol was said to significantly reduce the frequency of dyskinesias over time relative to baseline (P < 0.05), although again, no specific data were reported. Neither drug had a noticeable effect on patients’ behaviors. Reversible extrapyramidal symptoms appeared to be negatively correlated with changes in the frequency of oral dyskinesias with haloperidol (r = 0.6292; P < 0.02). However, only 40% of the variance in the data could be explained by this relationship. The same correlation was not significant for TBZ (r = 0.4149). The authors reported a lack of “significant” AEs with TBZ, whereas 2 haloperidol recipients developed severe malaise after dose escalation to 16 mg/d, necessitating their withdrawal from the study. In a 12-week, randomized, double-blind trial, the Huntington Study Group compared TBZ (n = 50) and placebo (n = 34) in patients with Huntington’s chorea.92 TBZ was initiated at 12.5 mg on day 1, increased to 12.5 mg BID on days 2 through 7, and increased by 12.5 mg/d at weekly intervals to a maximum of 100 mg/d (given in 3 divided doses). TBZ was associated with significant reductions from baseline in mean total maximum UHDRS chorea scores compared with placebo (–5.0 vs –1.5, respectively; P < 0.001) and a significant improvement in absolute CGI scores (to 3.0 vs 3.7; P = 0.007). More than minimal clinical improvement in chorea scores occurred in 45.1% of TBZ recipients and 6.9% of placebo recipients (P P < 0.001). At least minimal clinical improvement occurred in 69% and 24% of the respective groups (P P < 0.001). There were no significant differences between groups in UHDRS motor scores, color-naming test scores, or interference test scores. Placebo was significantly better than TBZ in terms of scores on the following measures: UHDRS functional checklist (P P = 0.02), 17-item Hamilton Rating Scale for Depression (P P = 0.003), Epworth Sleepiness Scale (P P = 0.02), and Stroop word-reading test (P =

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0.01). Taken in order, these results suggest that TBZ may have clinically relevant negative effects on performance of activities of daily living, mood, wakefulness, and cognition, respectively. TBZ had no effect on scores on the following measures: UHDRS gait assessment, UHDRS parkinsonism assessment, Functional Impact Scale, UHDRS independence scale, Barnes Akathisia Scale, UHDRS behavioral assessment, and UPDRS swallowing/speech scores. When TBZ was discontinued, the resulting chorea scores were significantly worse compared with those of former placebo recipients (P P < 0.001), as were CGI scores (P = 0.01). CGI scores were at least minimally worse in 71% of TBZ recipients and 22% of placebo recipients (P P = 0.01). The proportions of patients experiencing at least one serious AE did not differ significantly between groups. However, the mean (SE) number of new AEs per patient was significantly higher in TBZ recipients compared with placebo recipients (all events: 3.8 [3.1] vs 1.5 [1.8], respectively [P P = 0.001]; excluding mild events: 1.9 [2.0] vs 0.6 [0.9] [P P = 0.001]). The proportion of patients with at least one new AE was significantly higher in TBZ recipients compared with placebo recipients (all events: 49/54 [91%] vs 21/30 [70%] [P P = 0.01]; excluding mild events: 37/54 [69%] vs 10/30 [33%] [P P = 0.002]). At week 12, more TBZ recipients required a dose reduction due to AEs compared with placebo recipients (24/54 [44%] vs 1/30 [3%]; P < 0.001). Dose-limiting AEs associated with TBZ included sedation (27%), akathisia (8%), and parkinsonism and depression (4% each). Frank et al93 conducted a randomized, double-blind trial of TBZ withdrawal (on day 1) (n = 12), partial withdrawal (on day 3) (n = 12), and no withdrawal (n = 6) in patients with Huntington’s chorea over an observation period of 5 days. Adjusted chorea scores (the primary outcome) increased by a mean of 5.3 units from day 1 to day 3 in the withdrawal group, compared with an increase of 3.0 units in the pooled partialwithdrawal and no-withdrawal groups (P P = NS). Similar results were noted when age (dichotomized at the median) was added to the statistical model. The treatment-by-age interaction was not statistically significant. Because of a significant difference in total motor scores at baseline across groups (P P = 0.006), chorea scores were adjusted post hoc for baseline motor scores; the results remained nonsignificant. Four patients continued use of a neuroleptic throughout the study (1 each taking haloperidol and fluphenazine for chorea, 1 taking fluphenazine for unknown reasons, 1 taking quetiapine for sleep). When data from these 4 patients were

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excluded, the results were again nonsignificant. Adjustment for benzodiazepine use also had no effect. Chorea scores on day 1 and day 5 were not subjected to statistical analysis. Post hoc analysis of linear trends was positive for reemerging chorea (P P = 0.049). No significant changes were seen in total functional capacity (the secondary outcome) or in the exploratory end points, which included the UHDRS total motor score, cognitive assessment, behavioral assessment, functional assessment, independence scale, and clinical summary scores; the UPDRS dysarthria score; individual UHDRS items (gait score, verbal fluency, symbol digit modalities test, Stroop word-reading test, and Stroop interference test); and the CGI. No recognizable withdrawal syndrome (other than reemergence of chorea) was noted.

TOLERABILITY During product development, TBZ was administered to 773 unique individuals.3 Dosing and exposure varied widely, from single- and multiple-dose clinical pharmacology studies in healthy volunteers (n = 259) to open-label (n = 529) and double-blind (n = 84) clinical studies in patients. The AEs from a pivotal randomized, placebo-controlled clinical trial in patients with Huntington’s disease have been summarized in the prescribing information (Table IV).3 TBZ dose escalation was stopped or the dose reduced due to one or more AEs in 28 of 54 patients (52%). These AEs included sedation (15 cases), akathisia (7), parkinsonism (4), depression (3), anxiety (2), and fatigue and diarrhea (1 each). (The number of cases exceeds the number of patients with AEs, as patients could have had more than one AE and be counted more than once.) The overall frequency of extrapyramidal symptoms was 33%, including 10 patients (19%) with akathisia (which included the preferred terms akathisia, hyperkinesias, s and restlessness) and 8 patients (15%) with extrapyramidal events (which included the preferred terms bradykinesia, parkinsonism, extrapyramidal disorder, and hypertonia). TBZ was approved by the FDA despite its association with several serious and potentially fatal AEs. The most problematic of these are depression and suicidality. The frequency of depression in various case series and clinical studies has varied, but rates ranging from 4% to 42% (mean, 20%) have been reported. Patients developing depression/suicidality should be evaluated immediately, and a reduction in the TBZ dose and/or initiation of antidepressant therapy should be given strong consideration. Caution is necessary in selecting an antidepressant, as some antidepressants are potent inhibitors of CYP2D6 (eg, paroxetine, fluoxetine). If an antidepres-

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Table IV. Treatment-emergent adverse events occurr ring in ≥4% of the tetrabenazine group and with a higher frequency than in the placebo group in a 12-week, double-blind, placebocontrolled trial in patients with Huntington’s disease.3 Values are number (%) of patients. #PEZ
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sant with strong CYP2D6-inhibitory activity is selected, the TBZ dose should be reduced by 50%. If depression/ suicidality does not resolve, consideration should be given to discontinuation of TBZ. Patients with a history of depression or other psychiatric disorder should be carefully monitored during TBZ therapy.

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Kenney et al94 conducted a retrospective review of the charts of 518 patients with hyperkinetic syndromes and a history of depression to examine whether TBZ treatment was associated with recurrent or worsening depression. The patients ranged in age from 3 to 87 years and had one or more hyperkinetic syndromes—chorea in 162, dyskinesias in 156, dystonias in 142, tics in 95, myoclonus in 19, and other disorders in 15. The mean (SD) daily dose of TBZ at the last visit was 61.6 (38.7) mg, and the maximum dose achieved in any patient was 300 mg. The most frequent AEs were somnolence (27.4%), depression (15.1%), parkinsonism (11.8%), and akathisia (8.9%). At baseline, 272 patients (52.5%) had a history of depression and 246 (47.5%) did not. Among those with no history of depression, 28 (11.4%) developed depression during the study; among those with a documented history of depression, 50 (18.4%) developed a clinically significant exacerbation of depression (P P = 0.03). Of interest, patients with a history of depression had greater improvement (lower ratings) in abnormal movements than did those without a history of depression (mean response ratings: 1.8 vs 2.1, respectively; P < 0.01). Sixteen patients (3.1%) discontinued TBZ due to depression, 7 (2.6%) of those with a history of depression and 9 (3.7%) of those without a history (P P = NS). These 2 groups did not differ in terms of the proportion experiencing one or more AEs leading to drug discontinuation. Based on the findings of this study, depression associated with TBZ therapy appears more likely to occur or worsen in individuals with a history of depression than in those without such history. As a result of the dopamine blockade induced by TBZ, parkinsonism is a common dose-related AE.95 TBZ-associated parkinsonism is characterized by the bradykinesia, hypertonia, and rigidity seen in the idiopathic form of the disease. The appearance of parkinsonian symptoms may necessitate reduction of the TBZ dose or, in some cases, drug discontinuation. Carbidopa/ levodopa therapy for parkinsonism may sometimes produce symptomatic benefit without causing a worsening of abnormal involuntary movements. Extrapyramidal symptoms such as akathisia are common dose-related AEs of TBZ therapy, again as a result of dopamine blockade. Restlessness and agitation may be indicators of imminent akathisia. Appearance of these symptoms frequently necessitates a reduction in the TBZ dose, and drug discontinuation may be necessary in a small number of cases. The constellation of AEs such as akathisia, parkinsonism, dysphagia, sedation, hypotension, and cognitive decline may also be a

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manifestation of the progression of Huntington’s disease, thereby creating diagnostic ambiguity.96 Neuroleptic malignant syndrome is a potentially fatal AE associated with drugs interfering with dopaminergic neurotransmission, including TBZ.97 This AE may recur when the patient is rechallenged with the drug. Despite the breadth of potentially serious and occasionally fatal AEs associated with TBZ, relatively few AE reports have appeared in the literature over the years. There are published reports of neuroleptic malignant syndrome/hyperthermia in 5 patients, parkinsonism in 4 patients, acute dystonias in 4 patients, catastrophic (florid psychiatric) reactions in 2 patients, and depression in 1 patient.95,98–107 A multicenter trial by Mikkelsen108 evaluated the long-term tolerability of TBZ in 124 patients with a variety of hyperkinetic syndromes (primarily Huntington’s disease, abnormal buccolingualmasticatory movements, and tardive dyskinesia). Of the original 124 patients, 18 were lost to follow-up, 5 died (unrelated to therapy), 3 were considered clinical failures, 5 discontinued due to AEs, and 2 were discontinued because long-term therapy was not considered appropriate. Thus, results were available for 93 patients, 12 of them TBZ naive and 81 who had been receiving TBZ for a median of 2.3 years (maximum, 15 years). The median age was 67.3 years in the 35 males and 59.0 years in the 58 females. The median daily dose of TBZ was 70 mg both before and after the study (range, 12.5–225 mg). Observations were available for ≥12 months in 82% of patients and for <6 months in 6%. Twenty-one percent of patients had complaints that may have represented AEs, most frequently fatigue. Five of 124 enrollees (4%) discontinued due to AEs (depression in 2 and fatigue, sweating, and malaise in 1 each). No clinically important laboratory abnormalities were noted.

DOSING AND ADMINISTRATION In the United States, TBZ is available only through prescribers and pharmacists who are specially qualified to prescribe and dispense it. This is a component of the Risk Evaluation and Mitigation System required by the FDA as a condition of TBZ’s approval. A year’s supply of TBZ 50 mg/d costs ~$40,000. The manufacturer has a financial assistance program to make TBZ affordable for eligible patients.1 TBZ is available in unscored 12.5-mg tablets and scored 25-mg tablets.3 The initial dosage is 12.5 mg once daily in the morning. After a week, the dosage is increased to 12.5 mg BID. The dosage can then be titrated slowly upward in weekly increments of 12.5 mg/d. Doses

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of 37.5 to 50 mg should be given 3 times daily. The maximum recommended single dose is 25 mg. If TBZ therapy is interrupted for >5 days, it should be retitrated, starting at 12.5 mg once daily in the morning. In the case of an interruption of <5 days, TBZ can be restarted at the previous dose without titration. Patients in whom a TBZ dose >50 mg/d is desired should first undergo genotyping for CYP2D6 metabolizer status, if the test is available.3 In CYP2D6 extensive and intermediate metabolizers requiring >50 mg/d, the dose should be titrated in weekly increments of 12.5 mg/d. All doses >50 mg/d should be given 3 times daily. The maximum recommended daily dose in these patients is 100 mg, and the maximum single dose is 37.5 mg. Dosing is similar in CYP2D6 poor metabolizers, except that the maximum recommended daily dose is 50 mg and the maximum single dose is 25 mg. The TBZ dose should be halved in patients who are about to initiate concurrent therapy with strong CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine).3 In patients taking strong CYP2D6 inhibitors who are about to begin concurrent TBZ therapy, the dosing recommendations for CYP2D6 poor metabolizers should be followed. The effects of moderate or weak CYP2D6 inhibitors on TBZ pharmacokinetics have not been studied. TBZ use should be avoided in patients with any degree of hepatic impairment.

FUTURE RESEARCH QUESTIONS Although TBZ is approved by the FDA for the treatment of chorea in Huntington’s disease, there have been no comparative studies with neuroleptics (particularly haloperidol), which have been the drugs of choice for this disorder. Neuroleptics and TBZ have similar AE profiles, although given the serious AEs (eg, depression/suicidality) uniquely associated with TBZ, some incremental efficacy relative to neuroleptics should be required to justify its risks and cost. Although a recent Cochrane review found that among the 3 medication classes examined (antidopaminergics [n = 5], glutamate antagonists [n = 5], and energy metabolites [n = 5]), only TBZ had clear efficacy in the treatment of chorea,109 practitioners continue to believe in the efficacy of neuroleptics for this disorder. In terms of other hyperkinetic movement disorders, TBZ has been recommended for the tardive stereotypy, tardive chorea, and tardive tremor components of tardive dyskinesia,110 although this recommendation was based on the limited evidence of efficacy from randomized controlled trials. Given the cost of the test and the shortage of clinical laboratories offering it, more research is

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needed into the risk of not following the recommendation that CYP2D6 genotyping be performed before use of a TBZ dose >50 mg/d. Furthermore, there are almost no published data on the efficacy and tolerability of TBZ use over a period of years. There is a need for investigation of the magnitude and clinical importance of TBZ-induced cognitive impairment and impairment in the performance of activities of daily living, concerns brought to light in the course of the FDA’s review of the New Drug Application for TBZ.12 In addition, pharmacokinetic and drug–drug interaction studies are necessary to refine dosing recommendations.

CONCLUSIONS Approved by the FDA for the chorea of Huntington’s disease, TBZ has also been investigated in a variety of hyperkinetic movement disorders. It is associated with numerous AEs and several important drug–drug interactions. Over time and with the conduct of additional research trials, its role in the therapeutic armamentarium will become better defined.

ACKNOWLEDGMENT The author has indicated that he has no conflicts of interest with regard to the content of this article.

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Address correspondence to: David R.P. Guay, PharmD, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 7-148 Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455. E-mail: [email protected]

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