Drug Evaluation
`
`Drugs 33: 31-49 (1987)
`0012-6667/87/0001-0031/$09.50/0
`© ADIS Press Limited
`All rights reserved .
`
`Haloperidol Decanoate
`A Preliminary Review of Its Pharmacodynamic and
`Pharmacokinetic Properties and Therapeutic Use in Psychosis
`
`R. Beresford and A. Ward
`ADIS Drug Information Services, Auckland
`
`Various sections ofthe manuscript reviewed by: L.P. de C. Beehelli, Psychiatric Hospital
`of Ribeirao Preto, Ribeirao Preto, Brazil; G. GhouilUlrd, Clinical Psychopharmacology
`Unit, Royal Victoria Hospital, Montreal, Canada; L. Germain, Clinical Psychopharma(cid:173)
`cology Un it, Royal Victoria Hospital, Montreal, Canada; L.M. Gunne, Psychiatric Re(cid:173)
`search Centre, Ullerater Hospital, Uppsala, Sweden; LE. Hollister, Veterans Admin is(cid:173)
`tration Medical Center, Palo Alto, California, USA; W. Kissling, Psychiatrische Klinik
`und Poliklinik rechts der Isar der Technischen Universitat Munchen, Munchen, West
`Germany; M.H. Lader, Institute of Psychiatry , De Crespigny Park, London, England; G.
`Meeo, Dipartimento di Scienze Neurologiche Universita, Viale dell'Universita, Roma,
`Italy; T.R. Norman, Department of Psychiatry , Austin Hospital, Heidelberg, Victoria,
`Australia; W. Rapp, Department of Forensic Psychiatry, Umea, Sweden; R. Takahashi,
`Department of Neuropsychiatry, Tokyo Medical and Dental University, Tokyo , Japan;
`B. Wistedt, Department of Psychiatry, Karolinska Institutet, Danderyd, Hospital, Dan(cid:173)
`deryd , Sweden; H.A. Youssef, Department of Psychiatry , St Davnet's Hospital, Mon(cid:173)
`aghan, Eire.
`
`Summary
`I. Pharmacodynamic Studies
`1.1 Pharmacodynamic Properties of Haloperidol
`1.2 Pharmacodynamic Properties of Haloperidol Decanoate
`1.2.1 Central Effects
`1.2.2 Other Effects
`2. Pharmacokinetic Studies
`2.1 Pharmacokinetics of Haloperidol
`2.2 Pharmacokinetics of Haloperidol Decanoate
`2.2.1 Animal Studies
`2.2.2 Human Studies
`3. Therapeutic Trials
`3.1 Use of Haloperidol in Psychoses
`3.2 Use of Haloperidol Decanoate in Psychoses
`3.2.1 Open Studies
`3.2.2 Comparison with Placebo
`3.2.3 Comparison with Oral Haloperidol
`3.2.4 Comparison with Other Depot Antipsychotic Preparations
`3.3 Use of Haloperidol Decanoate in Gilles de la Tourette's Syndrome
`4. Side Effects
`4.1 Extrapyramidal Symptoms
`4.2 Other Clinical Side Effects
`4.3 Laboratory Effects
`
`32
`33
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`34
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`36
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`38
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`42
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`.45
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`46
`
`Contents
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0001
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`5. Dosage and Administration
`6. Place of Haloperidol Decanoate in Therapy
`
`Summary
`
`32
`
`46
`.47
`
`Synopsis
`
`Pharmacodynamic Studies
`
`Pharmacokinetic Studies
`
`Therapeutic Trials
`
`is a depot preparation of haloperidol, a commonly used bu-
`Haloperidol decanoate'
`tyrophenone derivative with antipsychotic activity. Haloperidol decanoate has no intrinsic
`activity: its pharmacodynamic actions are those ofhaloperidol- primarily that ofcentral
`antidopamine activity. The monthly administered depot formulation has several clinical
`and practical advantages over oral haloperidol: better compliance and more predictable
`absorption; more controlled plasma concentrations; fewer extrapyramidal side effects; less
`frequent reminders of condition; and reduced medical workload. In open and controlled
`studies, haloperidol decanoate has produced adequate maintenance or improvement ofthe
`condition ofpatients with psychoses (mainly schizophrenia) when an abrupt change from
`orally administered haloperidol or other antipsychotic drugs has been instituted. Limited
`comparative studies indicate that the depot and oral forms of haloperidol are equally ef
`fective, and that haloperidol decanoate is at least as effective as depot forms offluphen(cid:173)
`azine, pipothiazine, flupenthixol and perphenazine in controlling the symptoms of psy(cid:173)
`chosis. Extrapyramidal side effects and the need for concomitant anti-Parkinsonian drugs
`may be a problem, but may be less frequent than with oral haloperidol or other depot
`antipsychotics. Thus, haloperidol decanoate offers a useful alternative in the treatment of
`psychoses to orally administered haloperidol or to other depot antipsychotic drugs.
`
`Haloperidol decanoate is a depot form of haloperidol with no intrinsic activity. Its
`pharmacodynamic effects are those of haloperidol; it has a central antidopamine action,
`antagonising the effects of apomorphine and amphetamine and releasing prolactin. Dop(cid:173)
`amine turnover is also increased and dopamine metabolites accumulate. Glutamic acid
`decarboxylase activity in the substantia nigra is reduced (an event which may be asso(cid:173)
`ciated with the production of tardive dyskinesia). Like haloperidol, haloperidol decanoate
`has little effect on the cardiovascular system or on the motility of smooth muscle.
`
`Haloperidol decanoate is injected in a sesame oil vehicle into muscle. It is then hy-
`drolysed relatively slowly to haloperidol and decanoic acid. Peak plasma concentrations
`are not reached for 3 to 9 days and are proportional to the administered dose. Steady(cid:173)
`state plasma concentrations are reached within 2 to 3 months (compared with 7 days for
`the oral preparation). The pharmacokinetic disposition appears to be essentially the same
`as that of oral haloperidol, which is approximately 92%bound to plasma proteins, crosses
`the blood-brain barrier and passes into the milk of nursing mothers. Haloperidol is me(cid:173)
`tabolised mainly by oxidative dealkylation to inactive metabolites. The plasma elimin(cid:173)
`ation half-life of the depot preparation (about 3 weeks) is considerably longer than that
`of the oral form (about 24 hours).
`
`Haloperidol is a widely used antipsychotic drug in the treatment of psychotic disord-
`ers. Haloperidol decanoate is a depot formulation of haloperidol, usually administered
`monthly, which has recently been used in the treatment of psychoses (mainly schizo(cid:173)
`phrenia) in an attempt to minimise side effects and compliance problems while main(cid:173)
`taining clinical efficacy. Open and controlled studies have shown that haloperidol de(cid:173)
`canoate is more effective than placebo, and at least as effective as oral haloperidol and
`a number of other depot antipsychotic agents, including fluphenazine decanoate, pipoth-
`
`I
`
`'Haldol Decanoate' (Janssen; McNeill).
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0002
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`33
`
`iazinepalmitate,flupenthixol decanoateand perphenazine enanthate. Symptoms of schiz(cid:173)
`ophrenia, such as emotional withdrawal, conceptual disorganisation, depression, para(cid:173)
`noia, hallucinatory behaviour and catatonia, are well controlled and indeed may be
`improved in most patients even when previous medication, upon whichthey are usually
`stabilised, has been abruptly discontinued. Dose-ranging studies to determine the opti(cid:173)
`mum dose for clinicalefficacy and improved toleranceoriginally used a protocolof high
`initial doses (usually 20 times the previous daily oral haloperidol dose) which were re(cid:173)
`duced as necessary. Currently, initial doses are often lower (10 to 15 times the previous
`daily oral dose) and are increased if required.
`
`The major unwantedeffectof antipsychotic therapy, includinghaloperidol decanoate,
`is the production of extrapyramidal symptoms. The incidence and intensityof symptoms
`may be less with haloperidoldecanoate than other antipsychotic drugs, especially when
`the dose is not too high. The concomitant use of anti-Parkinsonian drugs also tends to
`be lesswith the depot preparation.Other side effects reportedwith haloperidol decanoate,
`apart from 2 cases of neuroleptic malignant syndrome, have been mild and short-lived.
`
`Haloperidol decanoate is usually given as a monthly intramuscular injection. Al-
`though earlier investigators gave an initial dose which was 20 times the daily oral halo(cid:173)
`peridol dose, more recent investigations have tended to give a lower initial dose, often
`between 10 and 15 times the daily oral haloperidol dose (i.e. about 50 to 100mg). This
`may be increasedduring subsequentinjectionsas required, and tends to maximiseanti(cid:173)
`psychotic effects and minimise extrapyramidal effects.
`
`Side Effects
`
`Dosage and Administration
`
`1. Pharmacodynamic Studies
`
`Haloperidol decanoate (fig. 1) is a depot anti(cid:173)
`psychotic agent, an ester of haloperidol and deca(cid:173)
`noic acid. After injection it is released gradually
`from muscle tissue and hydrolysed slowly into free
`haloperidol which then enters the systemic circu(cid:173)
`lation.
`
`1.1 Pharmacodynamic Properties of
`Haloperidol
`
`Haloperidol is a butyrophenone derivative with
`a therapeutic effect (like that of other antipsychotic
`agents) thought to be the result of its central an(cid:173)
`tidopamine activity. It antagonises the effects of
`apomorphine (a direct dopamine agonist) and am(cid:173)
`phetamine (an indirect dopamine antagonist), its
`activity being similar to that of trifluoperazine and
`fluphenazine, slightly greater than chlorpromazine
`and much greater than that of thioridazine. The
`turnover rates of striatal dopamine and its metab(cid:173)
`olites, particularly homovanillic acid, are increased
`and the concentration of dopamine reduced by
`
`haloperidol at doses ranging between 3 and 15mg.
`However tolerance to this effect of haloperidol de(cid:173)
`velops after 7 days. Receptor binding studies show
`that haloperidol is equivalent to fluphenazine and
`about twice as active as chlorpromazine as an in(cid:173)
`hibitor of dopamine binding to central dopamine
`receptors (pakes 1982a).
`Animal studies have shown that haloperidol has
`low antiadrenergic activity and thus has little tend(cid:173)
`ency to produce orthostatic hypotension and/or
`tachycardia. It also has low anticholinergic activ(cid:173)
`ity, and is less sedative than many other antipsy(cid:173)
`chotic agents. However haloperidol does produce
`motivational, emotional and behavioural changes,
`although it is less likely than chlorpromazine, for
`example, to produce ptosis or catalepsy in rats or
`to potentiate thiopentone narcosis. Studies carried
`out in humans have shown that haloperidol alters
`patterns of sleep by increasing stages 1 and 2 and
`reducing stages 3 and 4 without affecting REM
`sleep. In addition, in computerised EEG studies, it
`reduces the energy level of the EEG in schizo(cid:173)
`phrenia patients but increases it in healthy subjects
`(Pakes I982a).
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0003
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`34
`
`°II
`F If_ ~ C-CH2-CH2-CH2-N~ - ,--
`
`O-C-(CH2)a-CH3
`
`0 0
`Haloperidol decanoate Q1rtvorolvsis
`
`CI
`
`°
`FO~-CH2-CH2-CH2-N~
`
`OH
`
`Q
`
`CI
`
`Haloperidol
`
`+
`
`0,\
`C-(CH2)a-CH3
`
`/
`HO
`
`Decanoic acid
`
`Fig. 1. Structural formula of haloperidol decanoate and its hydrolysis into haloperidol and decanoic acid.
`
`Haloperidol can produce any of the 5 different
`types of extrapyramidal syndrome: Parkinsonism,
`akathisia, acute dystonic reactions, tardive dyskin(cid:173)
`esia and (rarely) perioral tremor. These side effects
`are dose-related and common, but variable. How(cid:173)
`ever, the drug has very little tendency to produce
`jaundice (Baldessarini 1980).
`
`1.2 Pharmacodynamic Properties of
`Haloperidol Decanoate
`
`1.2.1 Central Effects
`Since haloperidol decanoate is a depot prepar(cid:173)
`ation of a long-established drug, it was used clinic(cid:173)
`ally (and found to be valuable) before many animal
`studies had been carried out to validate its use as
`a haloperidol prodrug. However, subsequent stud(cid:173)
`ies have been undertaken to elucidate the phar(cid:173)
`macological activity of the drug.
`the adminis(cid:173)
`Niemegeers (1981) reported that
`tration of haloperidol decanoate produced plasma
`concentrations of haloperidol which paralleled the
`antagonism to apomorphine-induced emesis in
`dogs. Oka and colleagues (1985) found that halo(cid:173)
`peridol decanoate had no intrinsic activity in a
`
`model of antipsychotic-like behaviour in rats and
`mice, and had only 2.5% of the activity of halo(cid:173)
`peridol in in vitro dopamine receptor binding. In(cid:173)
`tracerebroventricular injections of haloperidol and
`haloperidol decanoate resulted in an increased ac(cid:173)
`cumulation of the dopamine metabolites homo(cid:173)
`vanillic acid and 3,4-dihydroxyphenylacetic acid
`after haloperidol but little change after haloperidol
`decanoate. After a single injection of haloperidol
`decanoate, the concentration ofhaloperidol in dop(cid:173)
`amine-rich areas of the brain (frontal cortex, limbic
`forebrain, striatum) peaked at day 2, remained high
`for 7 days and then fell slowly.
`Oka et al. (1985) found that the time courses of
`the behavioural and biochemical events following
`intramuscular haloperidol decanoate injection in
`rodents were variable. Haloperidol decanoate re(cid:173)
`duced the conditioned avoidance rate for a long
`period. The effect peaked 24 hours after injection,
`remained high for up to 9 days and then declined
`slowly, returning to its predrug level by the twenty(cid:173)
`eighth day. Similarly, the concentrations of homo(cid:173)
`vanillic acid and 3,4-dihydroxyphenylacetic acid in
`the frontal cortex peaked after 8 hours and re(cid:173)
`mained significantly higher than normal 21 days
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0004
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`35
`
`after injection. The prolactin-releasing and the an(cid:173)
`tiapomorphine activity of haloperidol decanoate did
`not last as long. Both effects peaked within 24 hours
`but returned to pretreatment levels within 7 days.
`Accumulation of dopamine metabolites in the
`striatum peaked 8 hours after injection of halo(cid:173)
`peridol decanoate, but returned to normal within
`21 days. The differential accumulation of dopa(cid:173)
`mine metabolites might help explain why haloper(cid:173)
`idol decanoate has a long-lasting antipsychotic
`clinical effect but a less prolonged extrapyramidal
`effect since it is widely accepted that extrapyram(cid:173)
`idal side effects are due to dopamine receptor
`blockade in the nigrostriatal dopamine system (Oka
`et al. 1985). However, this is disputed by Molloy
`and Waddington (1985) and O'Boyle and Wad(cid:173)
`dington (1985) whose experiments in rats indicate
`that something other
`than dopamine receptor
`blockade may be involved in such reactions. Oro(cid:173)
`facial dyskinesias could be produced in rats by both
`fluphenazine decanoate and haloperidol decanoate
`(Molloy & Waddington 1985). Despite the similar
`behavioural effects produced by the 2 drugs, halo(cid:173)
`peridol decanoate increased striatal dopamine re(cid:173)
`ceptor density whereas fluphenazine decanoate did
`not. In older rats there was less increase in dopa(cid:173)
`mine receptor density and a lessening of the effect
`of haloperidol decanoate (O'Boyle & Waddington
`1985).
`There may be a connection between one partic(cid:173)
`ular form of extrapyramidal activity, namely tar(cid:173)
`dive dyskinesia, and the GABA-ergic neuron sys(cid:173)
`tem. Haloperidol decanoate
`can
`produce
`a
`corresponding disorder in rats. Vacuous mouth
`movements persisted during an 8 month study pe(cid:173)
`riod and reappeared on challenge with a single dose
`of haloperidol. This effect was associated with a
`reduction in glutamic acid decarboxylase activity
`in the substantia nigra (Gunne & Growdon 1982;
`Gunne & Haggstrom 1983; Gunne et al. 1982,
`1984).
`Computerised pharmacodynamic studies of the
`EEG in man have shown that haloperidol deca(cid:173)
`noate 75 to 300 mg/month increased the theta
`spectrum power of psychotic patients during the
`first week after injection, the increase being cor-
`
`related with clinical improvement (De Buck et al.
`1981). Haloperidol decanoate 50 to 180 mg/month
`also increased serum prolactin concentration in
`some geriatric patients during a 6-month study
`(Viukari et al. 1982).
`
`1.2.2 Other Effects
`Other pharmacodynamic actions of haloperidol
`decanoate are similar to those of haloperidol itself.
`Doses of 25 mg/kg had little effect on locomotor
`activity in mice whereas very high doses (200 mg/
`kg) produced catalepsy and piloerection. Doses of
`50 to 200 rug/kg did not affect the haemodynamic
`responses or electrocardiograph of rats, cats or dogs.
`Neither did it affect the in vitro motility of guinea(cid:173)
`pig ileum or motility of the uterus of non-pregnant
`rats (Matsuno et al. 1985).
`Like haloperidol, haloperidol decanoate re(cid:173)
`duced intestinal transport, increased gastric empty(cid:173)
`ing and reduced acid output in rats. It also in(cid:173)
`creased the urine volume in saline-loaded rats
`without affecting sodium/potassium excretion. It
`did not affect the response to acetylcholine or sero(cid:173)
`tonin and had a weaker (32%) antihistamine effect
`than did haloperidol (Matsuno et al. 1985).
`
`2. Pharmacokinetic Studies
`2.1 Pharmacokinetics of Haloperidol
`
`The pharmacokinetics of haloperidol have been
`reviewed by Pakes (1982b). Haloperidol
`is ab(cid:173)
`sorbed rapidly after oral administration but the ex(cid:173)
`tent of absorption is very variable. When it was
`given as a solution, bioavailability ranged from 38
`to 86% (Bianchetti et al. 1980); given as tablets, it
`ranged from 44 to 74% (Forsman & Ohman 1976).
`Two plasma concentration peaks were observed
`after oral administration, the first occurring within
`3 to 6 hours and the second (probably the result
`of enterohepatic cycling) at 12 to 20 hours (Fors(cid:173)
`man & Ohman 1976). Multiple dose studies have
`shown that steady-state is achieved in about 7 days
`(Bianchetti et al. 1980), the steady-state serum con(cid:173)
`centration increasing linearly with increasing dose
`(Forsman & Ohman 1976).
`Haloperidol is distributed rapidly to extravas(cid:173)
`cular tissues such as the liver (where its concen-
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0005
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`36
`
`tration is 1000 times that of serum). It crosses the
`blood-brain barrier and its concentration in the
`cerebrospinal fluid is about 10 times that of free
`haloperidol concentrations in serum (Forsman &
`Ohman I977a, 1979). It also passes into the milk
`of nursing mothers, milk concentrations being
`about 54 to 69%of plasma concentrations (Stewart
`is
`et al. 1980; Whalley et al. 1981). Haloperidol
`approximately 92% bound to plasma proteins
`(Forsman & Ohman 1977a) and has an apparent
`volume of distribution of 1000 to 1489L (Forsman
`& Ohman 1976).
`Haloperidol is metabolised mainly by oxidative
`dealkylation to 2 hydrophilic metabolites which
`may then be conjugated with glycine (Forsman et
`al. 1977). When given for a long period (up to 3
`years), haloperidol did not induce its own metab(cid:173)
`olism. However, its metabolism could be also in(cid:173)
`duced by other drugs used at the same time, es(cid:173)
`pecially by barbiturates and phenytoin (Forsman
`& Ohman I977b).
`Haloperidol and its metabolites are eliminated
`in urine (about 33%) and faeces (about 21%) [Illett
`et al. 1978].Its elimination half-lifeappears to vary
`with the route of administration, being about 24
`hours following intravenous administration and 19
`hours following oral administration (Forsman &
`Ohman 1977b).
`The relationship between the serum concentra(cid:173)
`tion of haloperidol and its clinical effects is unclear
`since there is considerable interindividual vari(cid:173)
`ation. Different studies have reported widely dif(cid:173)
`ferent 'effective' serum concentrations, ranging from
`3 to 10 jLg/L (Forsman & Ohman 1977b) to 8 to
`18 jLg/L (Magliozzi et al. 1981).The optimum dose
`of haloperidol given to any individual patient must
`thus be tailored carefully to that individual (pakes
`I982b).
`
`2.2 Pharmacokinetics of Haloperidol
`Decanoate
`
`Once haloperidol decanoate has been released
`from its intramuscular depot site, it is hydrolysed
`into haloperidol and decanoic acid. Thereafter, the
`
`the
`pharmacokinetics of haloperidol decanoate,
`prodrug, are similar to those of haloperidol, the ac(cid:173)
`tive drug.
`
`2.2.1 Animal Studies
`Haloperidol decanoate is an ester which is
`formed from a tertiary alcohol. The steric hind(cid:173)
`rance which this confers upon the molecule may
`be partly responsible for the stability of the ester
`bond and, therefore, for its slower hydrolysis and
`longer duration of action than many other depot
`antipsychotics (Heykants & Gelders 1984; Janssen
`1985). The relatively slow release of haloperidol
`from its oily intramuscular depot may be due to
`several factors: absorption of some of the vehicle
`(sesame oil) into the blood stream; some macro(cid:173)
`phage absorption; and some absorption into the
`lymphatic system (Heykants & Gelders 1984). The
`concentration of haloperidol decanoate is greater
`in (dog) lymph than in plasma during the first 2
`days after injection.
`Studies carried out in dogs (Heykants & Nei(cid:173)
`megeers 1979)and rats (Matsunaga et al. 1986)have
`shown that haloperidol could be detected in the
`bloodstream 1 hour after an intramuscular injec(cid:173)
`tion of 0.5 mg/kg and 50 mg/kg haloperidol de(cid:173)
`canoate, respectively. However, peak plasma con(cid:173)
`centrations were not obtained until some 3 to 9
`days after injection in dogs (Heykants & Nieme(cid:173)
`geers 1979). Thereafter, plasma concentrations
`decreased monophasically (for low doses) or bi(cid:173)
`phasically for high doses (up to 8 rug/kg). Radiol(cid:173)
`abelled haloperidol could still be detected in the
`plasma for 4 weeks after a single injection of 2 mg/
`kg (Lucchetti 1981) and for up to 3 months after
`an injection of 8 mg/kg (Janssen 1985). The plasma
`concentrations of haloperidol obtained after single
`and repeated doses of haloperidol decanoate were
`proportional to the dose of the depot preparation
`administered in dogs. Steady-state concentrations
`were reached within 3 months with 1 and 4 mg/
`kg doses and within 4 to 6 months with 16 mg/kg
`doses (Heykants & Gelders 1984; Janssen 1985).
`After intravenous administration of haloperidol
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0006
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`37
`
`decanoate 50 mg/kg in rats, about 95% of the dose
`was excreted within 10 days, and the elimination
`half-life was 1 to 5 days. After intramuscular
`administration of 5 and 50 mg/kg doses, about 90%
`was excreted after 42 days with half-lives of 16.4
`and 1l.2 days, respectively. The major metabolite
`was p-fluorophenylaceturic acid, with no un(cid:173)
`changed drug detected in the excreta. Less than 2%
`of the dose was excreted in the bile (Matsunaga et
`al. 1986).
`
`2.2.2 Human Studies
`The pharmacokinetics of haloperidol decanoate
`have been extensively studied in psychotic (mainly
`schizophrenic) patients (table I).
`Patients have generally been switched abruptly
`from their previous antipsychotic medication, most
`being given a monthly dose of haloperidol deca(cid:173)
`noate which corresponded to 20 times their pre(cid:173)
`vious daily oral haloperidol or haloperidol equiv(cid:173)
`alent dose (Suy et al. 1982). Forsman and Ohman
`(1977b) calculated that the mean bioavailability of
`oral haloperidol was 60 to 70%. A monthly injec(cid:173)
`tion 20 times the daily oral dose would thus pro(cid:173)
`vide the patient with approximately the same
`amount of haloperidol. In one study, however, a
`loading dose equivalent to 40 times the haloperidol
`dose was given (De Cuyper et al. 1986). In another
`study in geriatric psychotic patients a monthly dose
`of haloperidol decanoate 20 times the oral dose was
`given for the first 2 months and a lower dose, 15
`times the oral haloperidol dose, was given for a
`further 3 months (Viukari et al. 1982).
`An increased concentration of plasma haloper(cid:173)
`idol is observed during the first few days after the
`initial
`intramuscular injection of the decanoate
`preparation (De Buck et al. 1981; Deberdt et al.
`1980; Nayak et al. 1985; Viukari et al. 1982) al(cid:173)
`though this increase is relatively small and does
`not
`indicate 'dose-dumping'. Plasma concentra(cid:173)
`tions then decrease slowly, the elimination half-life
`of haloperidol being about 3 weeks (Reyntjens et
`al. 1982). During the fourth week after the initial
`injection the plasma concentration of haloperidol
`is generally equivalent to that found during treat-
`
`ment with oral haloperidol (De Buck et al. 1981;
`Viukari et al. 1982).
`Plasma concentrations rise after the second in(cid:173)
`jection and reach steady-state during the second to
`third month in most studies (table I). When a load(cid:173)
`ing dose 40 times the daily haloperidol dose was
`given, steady-state was achieved within the first few
`days of administration (De Cuyper et al. 1986).
`Steady-state plasma concentrations were usually
`equivalent to those obtained after long term oral
`haloperidol
`treatment, and were strongly corre(cid:173)
`lated with the injected dose of haloperidol deca(cid:173)
`noate (fig. 2). However, steady-state concentrations
`were significantly higher after haloperidol deca(cid:173)
`noate (I5 to 20 times the oral dose) than those ob(cid:173)
`tained during long term oral dosing with haloper(cid:173)
`idol during the second and third months of a study
`in geriatric psychotic patients (Viukari et al. 1982).
`In general, low doses (20 to 100mg) of the deca(cid:173)
`noate gave a steady-state haloperidol concentration
`of 3 ~g/L. Medium doses (10I to 200mg) produced
`a concentration of 5 ~gjL and a high dose (201 to
`300mg) produced a steady-state concentration of
`10 ~g/L (Reyntjens et al. 1982). No accumulation
`of haloperidol has occurred in studies over periods
`of 3 months (Mortensen 1982), I year (Deberdt et
`al. 1980) or 2 years (Reyntjens et al. 1982), even
`in those patients given repeated high doses of halo(cid:173)
`peridol decanoate (Deberdt et al. 1980). Steady-state
`concentrations lower than those obtained with oral
`haloperidol have been noted in some patients, but
`these results have yet to be fully reported (Nayak
`et al. 1985).
`
`3. Therapeutic Trials
`
`At least 10 depot antipsychotics have been syn(cid:173)
`thesised and are used therapeutically (pakes 1982c).
`Several advantages to patients and medical staff
`result from the use of such preparations. The con(cid:173)
`trolled release of their active medication provides
`steady and reliable blood concentrations for long
`periods. Interindividual differences in oral absorp(cid:173)
`tion are thus avoided as are other problems asso(cid:173)
`ciated with non-compliance although some patients
`dislike injections and local irritation at site of
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0007
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`38
`
`antipsychotic drugs (Pakes 1982c). In a review of
`96 open studies, orally administered haloperidol
`was found to produce significant improvement in
`40 to 70% of patients (over 5300) with chronic
`schizophrenia, the most effective dose range being
`8 to 32 mg/day. Symptoms responding well to
`haloperidol treatment included overactivity, agi(cid:173)
`tation, mania, withdrawal and paranoid ideation.
`Retardation, depression and apathy responded less
`well (Crane 1967).
`Extrapyramidal reactions tend to occur fairly
`frequently with haloperidol (Ban & Lehman 1967),
`especiallywith oral doses greater than 30mg (Simp(cid:173)
`son et al. 1967).
`
`/ . -/;----..
`
`> 200mg
`
`10
`
`::J
`"0;5
`
`3
`2
`1
`Time (days)
`
`4
`
`5
`
`/
`
`/
`
`12
`
`~oc8'
`
`"E
`III'"C.
`"CD
`~ 1
`
`c'
`
`Fig. 2. Haloperidol plasma concentrations in chronic schizo(cid:173)
`phrenic patients during 2 years' treatment with haloperidol de(cid:173)
`canoate at 3 different dose levels (after Reyntjens et al. 1982).
`
`3.2 Use of Haloperidol Decanoate in
`Psychoses
`
`administration may occur. The overall amount of
`drug used is often lower than that incurred by daily
`ingestion of the oral compound, and although
`plasma and brain haloperidol concentrations are
`similar after daily oral and monthly intramuscular
`administration, the incidence and severity of ad(cid:173)
`verse effects appears to be reduced. Depot prep(cid:173)
`arations can have non-clinical benefits also; the in(cid:173)
`frequency of their use means that patients are not
`constantly reminded of their sickness and medical
`staff have their workload reduced (Janssen 1985;
`Pakes 1982c).
`
`3.1 Use of Haloperidol in Psychoses
`
`Like all antipsychotic agents, haloperidol is not
`specific for any single disease entity and has been
`used since the late 1950s to treat a variety of dis(cid:173)
`orders. These include schizophrenia, dementia and
`delirium,
`the manic phase of manic depression,
`childhood psychoses, Gilles de la Tourette's syn(cid:173)
`drome and Huntington's disease, another psy(cid:173)
`chotic condition characterised by abnormal muscle
`activity (Baldessarini 1980).
`It has most frequently been used in the man(cid:173)
`agement ofacute and chronic schizophrenia, where
`it is as effective or more effective than most other
`
`3.2.1 Open Studies
`Studies in small groups of psychotic patients in(cid:173)
`dicated that haloperidol decanoate was at least as
`effective as previous treatment with oral haloper(cid:173)
`idol or other antipsychotic medication in control(cid:173)
`ling symptoms of chronic schizophrenia (Bjomdal
`1982; Bucci & Marini 1985; Fensbo 1982; Fer(cid:173)
`nando et al. 1984; Kristjansen 1982; Lund 1982).
`A total of 116 patients were switched from their
`previous antipsychotic medication to haloperidol
`decanoate. The initial dose was usually 50 to 300mg
`(20 times their previous oral haloperidol dose), and
`subsequent injections weregiven every 3 or 4 weeks,
`the frequency and dose depending on the clinical
`response. The majority of patients improved in all
`studies. Bjomdal (1982), and Bucci and Marini
`(1985) reported significantimprovement (p < 0.05)
`in Brief Psychiatric Rating Scale symptoms (no(cid:173)
`tably depression, stupor and thought disorders). In
`37 (mainly schizophrenic) patients treated with
`haloperidol decanoate for 18 months, about 30%
`showed improvement from their previous state, al(cid:173)
`though the monthly dose (mean 200mg) appeared
`to be too high to tolerate for some patients, despite
`being limited to 20 times the previous oral halo(cid:173)
`peridol dose (Kristjansen 1982).
`Determining the optimal dose range, i.e. that
`which controls psychiatric symptoms without pro-
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0008
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`39
`
`Table I. Pharmacokinetic studies of haloperidol decanoate (HD) in psychotic patients
`
`References
`
`No. of
`patients
`
`Deberdt et al.
`(1980)
`
`De Buck et al.
`(1981)
`
`De Cuyper et al.
`(1986)
`
`Mortensen
`(1982)
`
`Nayak et at,
`(1985)
`
`Parent et al.
`(1981)
`
`38
`
`29
`
`21
`
`11
`
`22
`
`8
`
`Reyntjens et al.
`(1982)
`
`181
`
`Suyet al.
`(1982)
`
`Viukari et al.
`(1982)
`
`11
`
`11
`
`Comments
`
`Dose and
`frequency
`(oral
`haloperidol
`equivalent)
`
`Duration
`of study
`(months)
`
`Plasma
`haloperidol
`concentration
`("gIL)
`
`3 (20
`30-300mg
`every 4 weeks patients)
`(10-30 H)
`12 (18
`patients)
`
`0.8-3.2
`(month 1)
`2-8 (month 2)
`2-8 (month 3)
`
`Time to
`achieve
`steady-
`state
`(months)
`
`3
`
`10-30
`
`High initial plasma
`concentrations
`
`2-9 (100mg)
`4-7 (200mg)
`8-16 (400mg)
`
`20
`
`2-3
`
`No accumulation of
`haloperidol
`
`2
`
`4
`
`3
`
`5
`
`75-300mg
`every 3-4
`weeks
`(20 H)
`
`100-400mg
`(40 H)
`then 50-
`200mg at 4
`weeks
`(20 H)
`
`4 weeks
`(20 H)
`
`50-150mg
`then 75-
`500mg at 4
`weeks
`
`~ 30-> 240mg 6
`
`24
`
`20-100mg,
`101-200mg, or
`201-300mg at
`4 weeks
`(20 H)
`
`0.5-4.2
`(month 1)
`2.0-13.0
`(month 6)
`
`3,
`5,
`10
`
`Steady-state, peak,
`maximum and minimum
`plasma concentrations,
`HD < H
`
`Stable concentrations to 24
`months
`
`No change in steady-state
`after formulation change
`from 50 gIL to 100 gIL
`
`2-3
`
`3
`
`3
`
`(20 H)
`
`24
`
`3
`
`5
`
`3-4
`
`20-180mg
`(20 H) at 4
`weeks then
`15-135mg
`(15 H)
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2017 - 0009
`
`

`
`Haloperidol Decanoate: A Preliminary Review
`
`40
`
`Teble II. Summary of open trials of haloperidol decanoate (HD) psychotic patients previously controlled on oral haloperidol (H) or
`other antipsychotic medication
`
`Previous
`daily H
`(mg)
`
`7.5-22.5
`
`HD dose (mg).
`frequency
`
`Duration of
`trial
`(months)
`
`Overall BPRS
`or NOSIE
`score"
`
`Extrapyramidal effects
`
`150-600 every 4
`weeks
`
`5
`
`Mild. abated quickly with
`treatment
`
`References
`
`Patients
`
`Arap Mengech &
`Wazome (1984)
`
`De Cuyper et al.
`(1986)
`
`30
`
`21
`
`1.5-30 (12 pts) 100-400 then 50-200
`at 4 weeks and
`thereafter
`
`Deberdt et al. (1980)
`
`38
`
`0.5-30
`
`20-300 every 4 weeks
`
`3 (26
`patients) .
`12 (18
`patients)
`
`t (month 1&2)
`I (month 3&4)
`
`No change
`
`Ermentini et al. (1985) 120
`
`Not given
`
`50-300 every 3-4
`weeks
`
`10
`
`Slight
`
`Gelders et at. (1982)
`
`239
`
`2.5-15
`(119 patients)
`
`50-300 every 4 weeks 12
`
`I (Hypertonia. tremor )
`no change (hypokinesia.
`akathisla, dyskinesia)
`
`Meco et al. (1983)
`
`23
`
`2.5-12.5
`
`Miserda et at. (1982)
`
`16
`
`6-40
`
`50-250 (127 mean)
`then 71 (mean) every
`4 weeks
`
`3 (20
`patients)
`12 (6
`patients)
`
`120-300 (271 mean)
`down to 201 (mean)
`every 4 weeks
`
`6
`12 (9
`patients)
`
`St