Drugs 15: 198-217 (1978)e ADIS Press 1978

Loxapine: A Review of its PharmacologicalProperties and Therapeutic Efficacy as anAntipsychotic Agent

R.C.Heel, R.N. Brogden, T.M.SpeightandG.s.Avery

Australasian Drug Information Services, Auckland

Various sect ions of the manuscript reviewed by: G. Bianchi, Consultant in PsychologicalMedicine, Surfers Paradise, Australia; K.D. Charalampous, Baylor College of Medicine, TexasMedical Center, Houston, Texas, USA; M.L. Clark, University of Oklahoma Health SciencesCenter, Oklahoma City, Oklahoma, USA; L. Hollister. Veterans Administrat ion Hospital, PaloAlto, Califomia, USA; L.G. Kiloh. University of New South Wales, Prince of Wales Hospital,Randwick, Australia; WR . McLeod, Psychiatric Hospital, Royal Park, Austra lia; NP.V. Nair,Douglas Hospital Centre, Montreal, Quebec, 'Canada; D. Pool, Tulane University School ofMedicine, New Or1eans, USA; B. Sbopsin, New York University Medical Center, New York, USA;RM. Ste inbook, School of Medicine, University of Miami, Miami, Florida, USA.

Table ofContents

Sum mary 199I. Pharmacodynamic Studies 200

1. 1 Effect on Dopamine Receptors ,....................... ........ 20 I1.2 Central Nervous System Effects 20 I

1.2.1 Animal Experiments 20 I1.2.2 EEG Effects in Patients with Schizophrenia 2021.2.3 Effect on Sleep Pattems 202

1.3 Antianxiety Activity 2021.4 Toxicology and Dysmorph ology Studies 202

2. Pharmacokinetic Studies 2022.1 Absorption 2022.2 Distribution 2032.3 Elimination 203

2.3.1 Melaboiism 2032.3.2 Excretion 203

3. Therapeutic Tr ials 2033.1. Open Trials 204

3.1.1 Treatment of Schizophrenia 2043.1.2 Treatme nt of Undifferentiated Psychoses 2093.1.3 Control of Destructive Behaviour 209

Loxapine: A Review 199

3.1.4 Parenteral Use in Psychoti c Episodes . 209

3.2 Comparative Trial s in Schizophrenia 209

3.2.1 Comparisons with Placebo 210

3.2.2 Comparisons with Chlorpromazine 210

3.2.3 Comparisons with Haloperidol <.......... 2113.2.4 Comparisons with Trifluoperazine 212

3.2.5 Comparisons with Thiothixene 2123.3 Onset of Effect 212

3.4 What Patients Show the BestResponse ? 2134. Side-Effects '... ............. 213

4.1 Common Side-Effects 213

4.2 Less Common Side-Effects 214

5. Overdosage . 215

6. Dosage 2157. Drug Interactions ., , '" 215References 215

Summary Synopsis: Loxapine' is a dibenzoxazepine, tricyclic compound recommended for the treat­ment of acute and chronic schizophrenia. /n its therapeutic effectiveness and profile and inci­dence ofside-effects, loxapine closely resembles the traditional antipsychotic agents. Althoughloxapine has tended to be less effective than SO/lIe standard antipsychotic drugs in a few short­term (J to 4 weeks) studies , it has been superior to a placebo and about as effective aschlorpromazine, haloperidol. trifluoperazine or thiothixene when evaluated after 4 to /2 weeks.

Like the phenothiazine (e.g, chlorpromazine) and butyrophenone (e.g. haloperidol) anti­psychotic agents, loxapine causes a high incidence of extrapyramidal reactions. Sedationoccurs frequently . especially dur ing early stages of treatment . Other, less common side-effectssuch as anticholinergic effects (dry mouth. blurred vision, etc.), hypotension. tachycardia andprecipitation of epileptic seizures , which occur with the older antipsychotic drugs , have alsobeen reported with loxapine.

Pharmacodynam ic studies : In animal studies. loxapine causes dopamine receptor blockadeand behavioural changes similar to those seen with other antipsychotic agents. such aschlorpromazine and haloperidol. In studies in man. low doses did not produce changes inEEG sleep patterns or in sleep time in healthy subjects but therapeutic doses (50 to 100mgdaily) increased total sleep time significantly when administered for I year to 4 patients withschizophrenia.

Pltarmacokinetic studies : There are no published studies on the pharmacokinetic proper­ties of loxapine. Unpublished data indicate that absorption in man is rapid after oral adminis­tration. peak levels of radioactivity occurring 2 hours after a radio labelled dose. In rats thediencephalic and mesencephalic areas of the brain. as well as the lungs. appear to be preferen­tial areas of distribution. In man metabolism is extensive and occurs rapidly. with only tracesof unmetabolised drug present in the plasma I hour after oral dosing . Metabolic pathways in­clude aromatic hydroxylation. oxidation. and desmethylation, and thus the major metabolitesare hydroxyloxapine, hydroxyloxapine-N-oxide. loxapine-N-oxide and hydroxydesmethylloxapine. Metabolites are partially conjugated to the glucuronide or sulphate forms before ex­cretion. and the urinary excretion products (56 to 70 % of administered radioactivity) consistmainly of the conjugated metabolites . while unconjugated metabolites are excreted primarilyin the faeces (15 to 22 % of administered radioactivity).

I 'Loxapac' : 'Loxitane' (Lederle) .

Loxapine: A Review 200

Therapeut ic trials: Most clinical studies of loxapine have been short-term, double-blindcomparative trials in patients with acute or chronic schizophrenia, using a traditional antip­sychotic agent as the comparison drug . The numbers of patients tested in such studies haveusually been relatively small, and may have been insufficient to detect minor differences, ifthey existed, between the study drugs . A few trials have used a placebo-control throughoutthe treatment period, but most have not. While in a few of the shorter-term (J to 4 weeks)studies loxapine has been less effective than the standard drugs used, and only slightly moreeffective than a placebo, in the majority of longer-term trials in acute and chronicschizophrenia it has been significantly superior to a placebo, and about equieffective withchlorpromazine, haloperidol , trifluoperazine , and thiothixene, after 4 to 12 weeks of treat­ment (see table 11). In the only longer-term controlled study to date, loxapine and haloperidolresulted in a similar improvement after administration to patients with acute schizophreniafor I year. In those patients who were diagnosed as having paranoid schizophrenia , loxapineappeared to be more effective; but further well-controlled, suitably designed studies in pa­tients with paranoid schizophrenia , using equipotent doses of loxapine and the comparisondrugs, are needed before such a specific effect for loxapine in this type of schizophrenia can beclaimed. A small number of acutely ill patients have been treated with intramuscular loxapinefor short periods of time (up to 200mg daily for 3 to 4 days), with most showing some im­provement.

Side-effects: The overall profile of side-effects which occur with loxapine is very similar tothat seen with other antipsychotic agents such as haloperidol and the phenothiazines. Ex­trapyramidial reactions, frequently requiring drug treatment, occur in about 40 % of patients.Sedation occurs often with initial doses, but tolerance to this effect develops in many patientsafter the first few days. Less common side-effects such as anticholinergic actions, hypoten­sion , and tachycardia, which occur with other antipsychotic drugs . have also occasionallybeen reported during loxapine administration. Precipitation of epileptic seizures and ocularchanges (corneal pigmentation, lens abnormalities) have been noted in a few patients, butwere not conclusively related to loxapine administration. Although tardive dyskinesia has notbeen reported in published studies, it .is reasonable to expect that this troublesome conditioncould occur with loxapine, in view of the incidence of other extrapyramidal effects and itspharmacological profile of activity.

Dosage: In the treatment of schizophrenia a low starting dose (about IOmg twice daily) isrecommended, but up to 50mg per day may be used in severely disturbed patients. Dosageshould then be fairly rapidly increased over 7 to 10 days according to individual requirementsand tolerance. The usual maintenance range is up to 100mg daily. but some patients may beadequately controlled on as little as 20mg daily. The lowest possible maintenance dose shouldbe used to minimise adverse reactions. Although doses in excess of 250mg daily are notrecommended by the manufacturer, up to 300mg per day has been used in a few clinicaltrials .

J. Pharmacodynamic Studies

Loxapine, 2~chloro-11 (4-methyl-l-piperazinyI)dibenz [b,n [1,4] oxazepine succinate, is a dibenzox­azepine derivative (fig. I) recommended for use as anantipsychotic agent in acute or chronic schizophrenia.

In animal experiments, loxapine possesseddopamine receptor blocking activity and produced

behavioural changes similar to those seen with tradi­tional antipsychotic agents such as chlorpromazine orhaloperidol.

Therapeutically equivalent doses of loxapine(IOOmg) and chlorpromazine (I ,OOOmg) producedqualitatively similar EEG changes in patients withschizophrenia, but changes were more pronouncedwith chlorpromazine . Loxapine increased total sleep

CH2CH2CHl.JlCH3)20::x)c

Loxapine : A Review

r>.N N-CH3

oeJOeo

Loxapine

Fig. 1. Chemical structure of Ioxapine and chlorpromazine.

time. but did not significantly alter the proportion ofREM sleep during longer-term (I year) administra­tion to a small number of patients withschizophrenia.

I. I Effect on Dopamine Receptors

The ability of all of the traditional antipsychoticagents to produce extrapyramidal effects in many pa­tients appears to be mediated through the samebiochemical mechanism (blocking of dopamine recep­tors) as their ability to lessen the symptoms ofschizophrenia. An antipsychotic agent which blockeddopamine receptors only in the mesolimbic systemshould be free of parkinson-like effects, whereasblockade in the corpus striatum and globus pallidus ofthe brain, as well as in the mesolimbic system. pro­duces extrapyramidal side-effects along with thedesired effects (Hollister, 1976).

Like chlorpromazine and haloperidol, loxapineblocked striatal dopamine receptors in isolated organanimal studies (Miller and Hiley, 1976; Coupet et al.,1976). and could thus be expected to produce ex­trapyramidal reactions in conjunction with its anti­psychotic activity. In intact animals, the developmentof apomorphine-induced stereotypy was blocked after

201

Chlorpromazine

single but not after repeated doses of loxapine. Thus,single oral doses of 2mg/kg prevented typicalapomorphine-induced behaviour in rats. but after2mg/kg daily for 7 days tolerance developed to thiseffect (Sayers et al., I975; Asper et al., 1973).

1.2 Central Nervous System Effects

1.2.1 Animal ExperimentsLoxapine produces sedation in most animal

species and causes motivational and emotionalbehavioural changes similar to those seen withchlorpromazine or haloperidol (Guerrero-Figueroa etal., 1968; Mulas et al., 1970). Loxapine was more po­tent than chlorpromazine or haloperidol (respectiveEDso,; 3.9, 12.7 and 16.9mg/kg) in potentiatingthiopentone narcosis in mice. When a high dose ofeach drug (25mg/kg) was administered, loxapinecaused the greatest hypothermic effect (5.15, 4.6 and4.3°C. respectively) [Kido et al., 1969]. Catalepsy inrats was produced at a lower oral dose with loxapine(0.5mg/kg) than with haloperidol (1.5mg/kg), andtolerance to this effect developed more rapidly withloxapine (Asper et al., 1973).

In cats with chemically-induced epileptic foci. in­traperitoneal or intravenous doses above 25mg/kg,

loxapine: A Review

and intracarotid doses above 2mg/kg, precipitatedepileptic convulsions (Guerrero-Figueroa et al.,1968). In dogs oral loxapine was more potent thanchlorpromazine or haloperidol in blockingapomorphine-induced vomiting (Kido et al., 1969).

1.2.2 EEG Eff ects in Patients with Schi zophreniaIn a double-blind study in 36 patients with chronic

schizophrenia, chlorpromazine (J ,000mg daily) pro­duced its typical EEG effects (more and slower alpharhythms and the emergence of slow rhythms) anddiffered significantly from a placebo on all test occa­sions. Loxapine (I OOmg daily) produced only a slightslowing of alpha rhythms and was significantlydifferent from placebo only in an increased number ofslow rhythms after 3 months of treatment(Serafetinides et al., 1971).

1.2.3 Effect on Sleep PatternsLow doses of loxapine (4 to 12mg daily), ad­

ministered to 3 normal subjects for 5 weeks, did notproduce consistent changes in EEG sleep patterns orin total sleep time, either during the period of drugadministration or in a 2-week 'washout' period afterdiscontinuing the drug. In 4 schizophrenic patientshowever, administration of therapeut ic doses (50 to100mg daily) for I year increased total sleep time(mean increase of I hour) and slightly increased thepercentage of REM sleep (4 % increase) [Brebbia etal., 1976].

1.3 Antianxiety Activity

In a short-term study in 15 volunteers with highanxiety scores, a low dose of loxapine (mean dose4mg per day) was not statistically different fromplacebo in relieving anxiety ater 5 days of treatment(Floyd and Gershon, 1971). All subjects had 2baseline evaluations I week apart, and then receiveddrug (10) or placebo (5) on a double-blind basis. Forthe first 2 days, all patients on loxapine and 2 onplacebo reported drowsiness; after 2 days drowsinessoccurred only in I placebo patient.

202

1.4 Toxicology and Oysmorphology Studies

The median lethal, single dose (LOl O) of loxapine is65mg/kg orally in mice and 40mg/kg in rats, whileoral doses of90mg/kg in dogs caused convulsionsand some deaths. In longer-term experiments , ratsreceived maintenance doses of 0.28 to11.60mg/kg/day for up to 19 months . Food andwater intake, body weight gain, and spontaneous ac­tivity decreased at all dose levels while irritability in­creased. No drug-related, microscopic postmortemfindings were reported. Similarly, other than centralnervous system depression, no drug-related effectsoccurred in dogs receiving up to 30mg/kg/day orallyin a 2-year toxicity study (unpublished data , LederleLaboratories).

Adm inistration of oral loxapine in doses up toIOmg/kg/day to pregnant rabbits, and 10 to15mg/kg/day to pregnant dogs, had nodysmorphogenic, embryotoxic or fetotoxic effects.Oral doses of 0.2 to 12mg/kg/day, administered torats from day I 6 of pregnancy until weaning, resultedin difficulty in parturition and increased neonatalmortality (unpublished data, Lederle Laboratories).

2. Pharmacokinetic Studies

There are no published studies on the phar­macokinetic properties of loxapine. Unpublished data(Lederle Laboratories) indicates that absorption israpid and nearly complete after oral administration toman . Loxapine is extensively metabolised througharomatic hydroxylation , demethylation and oxidationbefore being excreted as glucuronide or sulphate con­jugates in the urine, or as unconjugated metabolites inthe faeces.

2.1 Absorption

Peak serum levels of radioactivity, representing0.25 to 0.43/lg/ml (mean 0.35/lg/mI) of loxapineplus metabolites, occurred 2 hours after administra-

Loxapine : A Review

tion of an oral labelled dose, equivalent to 25mg ofloxapine base, to 6 healthy volunteers. Total urinaryand faecal recovery of radioactivity ranged from 71 to85 % of the administered dose.

When administered to 40 healthy subjects as acapsule or a liquid concentrate, loxapine (25mg) wasrapidly absorbed, peak serum levelsof unmetaboliseddrug occurring at 2 to 3 hours (9.83ng/mO and I to 2hours (I2.60ng/mO, respectively. The total areaunder the serum concentration-time curve was simi­lar for both formulations after 24 hours.

2. '2 Distribution

Following the administration of oral or in­travenous labelled doses in animals, radioactivity israpidly cleared from the plasma and redistributed tobody organs. 30 minutes after an intravenous dose of5mg/kg to rats. brain and lungs contained the highestconcentrations of radioactivity (equivalent to 25.2and 20.6pg/g of loxapine succinate). with lesseramounts in the spleen, pancreas, liver, kidneys andother body organs. The diencephalic and mesen­cephalic areas of the brain contained about twice theconcentration of the neocortex I hour after in­travenous dosing in rats (Latimer. 1969).

The extent of protein binding and the volume ofdistribution of loxapine or its metabolites have notbeen determined.

2.3 Elimination

2.3.1 MetabolismLoxapine is extensively and rapidly metabolised in

man. No unmetabolised drug was recovered in faecesor urine. and only traces were found in plasma, Ihour after administering 30mg of loxapine succinateto 3 healthy subjects. The major metabolite, account­ing for over 50 % of the excreted radioactivity, washydroxyloxapine which was conjugated to theglucuronide or sulphate forms before excretion. Othersignificant metabolites include hydroxyloxapine-N-

203

oxide. loxapine-N-oxide, and hydroxydesmethyllox­apine. The pharmacological activity of loxapinemetabolites has not been studied, but its rapidmetabolism suggests that I or more of themetabolites may represent the active form of the drugin man.

2.3.2 Excretion56 to 70 % of administered radioactivity was

recovered in the urine, and 15 to 22 % in the faeces.within 144 hours of administering a single 25mgdose of loxapine to 6 healthy volunteers. Urinary ex­cretion products are primarily the conjugatedmetabolites. while faecal excretion involves mainlyunconjugated metabolic products, The eliminationhalf-life of loxapine has not been determined.

3. Therapeutic Trials

As with all psychoactiveagents, trials to detect an­tipsychotic activity must be carefully designed tominimise bias and control variables which may in­fluence response rates. Well-controlled, double-blindstudies with large groups of patients are necessary todetect any small differences between test drugs whichcan be expected to have essentially similar effects.

Most controlled clinical trials of loxapine havemade reasonable attempts to avoid built-in bias byusing a double-blind format and by ensuring thattreatment groups were well matched for age, severityand duration of illness. marital and social status, diag­nosis. and sex distribution. which is an important fac­tor since alleviation of symptoms of schizophreniamay occur more readily in women than in men(Hollister. 1976). The majority of studies haveutilised either a pre-trial placebo or treatment-freeperiod ranging from a few days (probably inadequate)to 3 months. to allow the effect of previous anti­psychotic therapy to dissipate before establishing newbaseline evaluations. These positive factors however,are at least partially offset by the lack of a placebocontrol in most comparative studies, which thusfailed to demonstrate that the standard drug itself was

Loxapine: A Review

superior to a placebo under the trial conditions.Whena placebocontrol was used, loxapinewas superior to aplacebo during trials lasting longer than 4 weeks.Relatively small patient groups in most comparativestudies would not be expected to detect differences, ifthey existed, between the study drugs (Clark andDownie, 1966; Overall et al., 1962): Indeed, mostcomparisons have predictably not detected significantoverall differences in either effectiveness or incidenceof side-effects between loxapine and the traditionalantipsychotic agents.

All trials have used standard symptom and globalrating scales to assess results, such as the Brief Psy­chiatric Rating Scale (BPRS), the Clinical Global Im­pressions Scale (CGO and the Nurses' ObservationScale for Inpatient Evaluation (NOSIE). Unfor­tunately, discrepancies often occurred between resultsusing different methods of evaluation in the sametrial (e.g, Shopsin et al., 1972; Clark et al., 1975) andeven between results obtained using the same evalua­tion method, in the same patients, but performed by 2independent investigators (Wolpert et al., 1970), thusdemonstrating some of the difficulties in assessing ac­tivity of antipsychotic agents.

3.1 Open Trials

In a limited number of short-term open trials, oralloxapine appeared to be moderately effective in acuteand chronic schizophrenia, and intramuscular lox­apine was considered effective in some patients withacute schizophrenia or other acute psychoses. Mostpatients with undifferentiated psychoses, or retardedpatients with uncontrolled self-destructive behaviour,were not significantly improved during repeated lox­apine administration.

3././ Treatment ofSchizophreniaA 30 % spontaneous remission rate can be ex­

pected in patients with acute schizophrenia (Gershonet al., 1970). In short-term studies with small num­bers of acute schizophrenic patients, about two-thirdswere improved during loxapine administration . In

204

chronic schizophrenia, about a quarter of the patientsshowed marked or moderate improvement and an ad­ditional two-thirds were slightly improved. Ex­trapyramidal effects occurred frequently, and in Istudy were more severe and occurred at lower doses

- in men than in women (seesection 4). Sedation occur­red in most patients, particularly during the initialtreatment stages, but some studies reported thedevelopment of tolerance to this effect during con­tinued administration.

Acute Schizophrenia: In a 3-week trial in 20newly-admitted schizophrenic patients, up to 225mgof loxapine daily appeared to produce significant im­provement in a few BPRS items and factors, but theBPRS total score was not significantly changed(Chouinard et al. , 1977). In 2 other short-term, opentrials in a small number of patients (I 7 in total) withacute schizophrenia, a mean maximal daily dose of 56or 150mg of loxapineorally for 2 to 4 weeks caused amoderate to excellent improvement in global psy­chiatric rating scores in 5 of 10 and 7 of 7 patientsrespectively (Gershon et al., 1970; O'Connell et aI.,1977). Only 3 of 10 hospitalised patients were con­sidered sufficiently improved for discharge after 3 to4 weeks of treatment. Extrapyramidal symptoms oc­curred in all of 10 patients in I study (Gershon et al.,1970) and were more pronounced, and occurred atlower doses, in men than in women (quantitative datanot given). When 10 patients with acute paranoidschizophrenia were treated with 60 to 300mg of lox­apine daily for a longer period (12 weeks), 6 wereconsidered very much or much improved at the endof the treatment period (Nair et al., 1977). Six pa­tients required drug treatment for extrapyramidalreactions and loxapine had to be discontinued in I pa­tient due to uncontrollable, severe tremor.

In a 3-day study using intramuscular loxapine, 24female patients with acute schizophrenia receivedfrom 75 to 200mg daily in 2 to 4 divided doses(Paprocki, 1976). About 50% of patients showed ap­preciableclinicalglobal improvement at the end of thestudy period. All patients reported some side-effectsduring the study, the highest incidence (6.8 reportedside-effects per patient) occurring with the highest

Table I. Summary of open studies of loxapine in patients with chronic schizophrenia,....

Author No. Duration Treatment-free period Daily Results1 (% of patients) Side-effects0)(..

of of treat- (weeks) dose (%)2 '2 .::J

pts ment (mg) +++ + + + ± !I!

(months) seda-}>

pre- post- extra- :%!

treat - treat - pyra- tion ~

ment ment midal~.

Arik (1974) 36 11-36 3 4' 10-90 8 33 42 17 - 14...GaUant et al. (1973) 40 6 3 100-250 32 55 8 48 1005

Nair et al. (1976) 10 3 5 1 90-300 10 10 60 20 80 50. . .

Simpson et al. (1976) 31 12 4 40-250 7 81 25· . .20 24 4 4 40-250

Squit ino et al. (1977) 29 1 c 120 7 35· .Wolpert et al. (1970)8 6 3 4 50-100 83 17 83

13 2 4 < 200 69 31

10 2 3 < 200 7 90· .12 3 4 < 200 91 9

1 Overall clinical evaluation; + + + = marked improvement; + + = moderate improvement; + = mid improvement; ± = no change or worse.2 A dash indicates the side-effect occurred but the incidence was not given.3 All patients had previously received Ioxapine for 3 months in a controlled trial.4 In 17 patients only.5 All patients reported drows iness for the f irst few days of treatment .6 Until SPASscore of 30 reached.7 Results not expressed as percentage; improvement occurred in most patients and was maintained for the duration of the study.

8 Mult i-investigator study. ""s

Comparisons with trifluoperazine (T)6"Arik (1974) 50 - 20-100mg 10-5Omg No 4w 12 L >T L =T )(

Yes < 120mg < 60mg No 4w 8 L=T L=T IIIBishop and 24 1:lS'

Gallant (1970) !I!Moyano (1975) 49 Yes 20-80mg 20-40mg No 4w 12 L >T L > T (withdrawa l, L =T l>

::0haBucinations, CI)

thinking disorders, ~'BPAS total score)

Kiloh et al. 19 - 56mg9 31mg9 No 2w 12 L >T L > T (hostility, L >T(1976) tension, suspicion,

thoughts)

27 - 37mg 24mg 2w 12 L=T L > T (hostility)

Clark et al. 37 Yes < l00mg < 50mg Yes 4 L <T, L > P (only in L = T(1975) L=P guilt feelings item)

Simpson and 43 No (Ll 20-80mg 20-5Omg No 3d 4 L=T L =T

Cuculic (1976)

Comparisons with thioridazine (Th)Rainaut (1975) 36 - 10 10 No 12 L=Th, , , , . .

Comparisons with thiothixene (TtlCharalampous 17 43 Yes < 150mg <6Omg Yes lw 4 L <Tt, L<Ttet al. (1974) L =P

Rlho et al. 16 34 - 10-120mg 3-36mg No 2w 12 L >Ttll L=Tt(1975) L < Tt 12

Van Der Weide 76 <300mg < 60mg Yes 2w 6 L >Tt, L > T (withdrawal, L =Tt

and Kiltie (1975) L >P depression,hallucinations,thought content,blunted effect,thinking disorder)

Includes chronic patients with acute exacerbations. 6 Inpatient mult idimensional psychiatric scale.2 Population distribution favoured the drug indicated in parentheses, in 7 Crossover study.

each case because of sex distribution. 8 Drugs given intramuscularly for 4 days and then orally.3 Based on the overall results of the BPAS evaluation and/or other evalua- 9 Mean daily dose.

tion scales used. See also text. 10 Daily dose not stated; loxapine to th ioridazine dose ratio was 1:5.4 Summarises significant differences not obvious from the overall results. 11 In patients with a duration of illness of 10 years or less.

See also text . 12 In patients wi th a duration of illness of more than 10 years.5 Includes 1 patient with agitated depression and 6 patients with 'hypo-

I~mania'. ....

Table 1/1. Percentage of patients showing indicated response to Ioxapine and a compar ison drug in controlled studies in schizophrenia (includes only those studieswh ich reported the response rate in the indicated manner) II:)

)(II>

Author No. of patients Groups Daily Daily Placebo Pre- Duration Response rate (%)2 '2.~

well dose dose control treat- • of ~

acute 1 chronic matched Ioxapine other during tr ial loxapine other drugl>

ment :lJ

drug trial drug- (weeks) CDs,free

CD++ + ± + + + ± s

period

Comparisons with chlorpromazineMoore (1975) 58 Yes 20-12Omg l oo- 1200mg No 2w 6 76 24 48 51Schiele (1975) 50 Yes (; 150mg (; 1500mg No l w 12 35 62 42 58

Comparisons with trifluoperazineBishop and Gallant 24 Yes (; 12Omg (; 6Omg No 4w 8 9 75 16 75 25(1975)

Kiloh et al. 27 - 56mg3 31mg3 No 2w 12 88 12 100(1976) 19 - 37mg3 24mg3 No 2w 12 50 38 12 27 64 9Moyano (1975) 49 Yes 20-80mg 20-40mg No 4w 12 56 44 39 61

1 Includes chronic patients w ith acute exacerbations.2 + + = excellent or good improvement; + = moderate or slight improvement; ±3 Mean daily dose.

no change or worse.

~<Xl

Loxapine : A Review

dose. Sedation occurred in all patients on all doses,while severe extrapyramidal effects requiring drugtreatment occurred in 3 patients, and less severe ex­trapyramidal actions in most patients (number notgiven).

Chronic Schizophrenia: In a number of longer­term open trials (up to 3 years) in patients withchronic schizophrenia, loxapine appeared to producemild or moderate improvement in the majority(78 %) of patients treated (table O. The overall inci­dence of occurrence of extrapyramidal effects washigh (48 to 81 %) and more than 50 % of patients re­quired drug treatment with an antiparkinson agent.Drowsiness occurred frequently, particularly duringthe initial stages of therapy, but in I study (Gallant etal., I973) the development of tolerance to this side­effect was reported after a few days.

3.1.2 TreatmentofUndifferentiated Psychoses14 patients with acute (9) or chronic (5) un­

differentiated psychoses were treated with 75 toIOOmg of loxapine daily for up to 6 weeks (Garcia etal., 1970). A transient improvement occurred in allpatients, but 'only 5 continued to show improvementduring extended treatment (I to 4 months). Drowsi­ness leading to sleep was noted in all patients with in­itial doses of the drug, but subsequent doses causedless sedation.

3.1.3 ControlofDestructive BehaviourLoxapine only slightly improved severe destruc­

tive and self-destructive behaviour in 16 male patientswith chronic schizophrenia (8) or mental retardation(8). A 2-week treatment-free period was followed byloxapine in increasing dosage (from 35 to about100mg daily) for 12 weeks, and then by a I-weekplacebo period. 6 patients were dropped from the trialdue to seizures (2 epileptic patients), severe drowsi­ness (I), a dystonic reaction (I) , refusal to takemedication ( I) and unexplained rectal bleeding( I). Ofthe remaining 10 patients, 7 showed minimal im­provement in psychiatric evaluation after the activetreatment phase, while 3 were unchanged. Un­controllable self-destructive behaviour in retarded pa-

209

tients was not significantly improved, although .theoverall management of all patients was judged to 00slightly easier during loxapine administration .Drowsiness occurred more frequently, and at lowerdoses, in mentally retarded patients than in those withschizophrenia (Varga and Simpson, 1971).

3.1.4 Parenteral Usein Acute Psychotic EpisodesIntramuscular loxapine in a dosage of 75 to

100mg daily (in 2 or 3 doses per day) for 3 days, ap­peared to produce good or excellent improvement inclinicalglobal impression (CGOscores in 10 of 12 pa­tients diagnosed as having acute psychogenic psy­chosis. Extrapyramidal effects occurred in 5 patientsand included 3 episodes of acute dystonia. Drowsi­ness was reported in 4 of 6 patients who received50mg twice daily, but not in patients receiving 25mg3 times daily (Fruensgaard and Jensen, 1976).

3.2 Comparative Trials in Schizophrenia

Most controlled studies of loxapine to date havebeen short-term (J to 12 weeks) and have often in­volved small numbers of patients. Only a few haveused a placebo control throughout the trial, but inthose which did loxapine was usually statisticallysuperior to a placebo. Overall evaluation of results in­dicates that loxapine is about as effectiveas the stan­dard agents chlorpromazine, haloperidol,trifluoperazine, or thiothixene in patients withschizophrenia (table ID. There were only a few studieswhich classified results according to excellent, moder­ate,or no overall improvement, but in those whichdid loxapine was similar to chlorpromazine andtrifluoperazine (table IIO. The number of studies re­porting results in this way was too small to prove ordisprove a trend for superiority for any of the com­pared drugs. In placebo comparisons, 'lower' doses ofloxapine (up to 150mg daily) were equal to or onlyslightly superior to a placebo after 4 weeks of treat­ment, while 'higher' doses (up to 300mg daily) weresignificantly superior to placebo after 4 to 12 weeks.In I study in acute schizophrenia, the onset of max-

Loxapine: A Review

imum effect of loxapine was slower (greater than 4weeks) than that of trifluoperazine (about 2 weeks),but in chronic schizophrenia loxapine andchlorpromazine had a similar rate of onset of im­provement. Some authors (e.g. Clark et al., 1975;Charalampous et al., 1974; Shopsin et al., 1972) havesuggested that loxapine may be less effective inacutely ill, newly-diagnosed schizophrenic patientsthan the traditional antipsychotic drugs, but in alllonger-term (more than 4 weeks) comparative studieswith chlorpromazine, haloperidol, 'trifluoperazine orthiothixene, loxapine was as effective as the com­parison drug in acute schizophrenia.

As occurs with other antipsychotic agents, lox­apine causes a high incidence of extrapyramidaleffects. In controlled studies, the rate of occurrencewas usually similar to that with the comparison drug,although in 3 of 6 trials with chlorpromazine, lox­apine caused more extrapyramidal reactions than thestandard agent (see section 4).

3.2.1 Comparisons with PlaceboA single study has been published to date compar­

ing only loxapine and a placebo in patients withschizophrenia. Loxapine resulted in a dose-related im­provement which was superior to that with placebo.Other comparative trials with standard antipsychoticagents have occasionally incorporated a placebo com­parison into the study design (see sections 4.2.2 to4.2.6; table 11), and in these studies loxapine wasusually superior to a placebo, especially when resultswere evaluated after 4 weeks or longer.

Clark et al. (I 977) treated 36 patients with chronicschizophrenia (requiring institutionalisation for atleast 2 years without a significant remission) withloxapine 50mg daily (I I), loxapine 100mg daily (I 2)or placebo (I3). Patients were assigned to treatmentgroups at random by sex, and the groups were wellmatched with respect to onset and duration of illness.Following a 12-week period without treatment withpsychoactive agents, the assigned therapy was ad­ministered for an additional 12 weeks on a double­blind basis. After 8 and I2 weeks of treatment, BPRStotal score and global impressions of improvement

210

were significantly better (p <0.05) in patients receiv­ing loxapine than in those receiving placebo. TheIOOmg dose resulted in .greater improvement than50mg per day. 5 patients on each dose of loxapineex­perienced extrapyramidal symptoms and 6 patients (2on 50mg daily, 4 on IOOmg) required treatment withbenztropine, an antiparkinson agent. Drowsiness oc­curred in IS of 25 patients with loxapine and in Iwith placebo.

In other comparative studies in acute and chronicschizophrenia which used a placebo controlthroughout the trial, loxapine in daily doses of up to100 to 150mg daily was rated equal to or onlyslightly better than a placebo in 2 short-term (4 week)studies (Charalampous et al., 1974; Clark et al. ,1975), and significantly superior to a placebo in 4other studies, most of which used higher doses forlonger periods of time (up to 100 to 300mg daily for4 to 12 weeks) [Clark et al., 1972; Pool et al., 1976;Selman et al., 1976; Van Der Veldeand Kiltie, 1975].

3.2.2 Comparisons withChlorpromazineAll comparative studies with chlorpromazine have

used IOOmg dosage units of chlorpromazine andIOmg units of loxapine, and the same (I 0 to I)

chlorpromazine to loxapine maximum daily doseratio. In most comparisons in patients with acute orchronic schizophrenia, loxapine (20 to 150mg daily)had a similar overall efficiency to chlorpromazine(100 to I,500mg daily)[table 11]. The incidenceof ex­trapyramidal side-effects has usually been similar,although in some studies loxapine caused more ofthese reactions (see section 4). Drowsiness hasgenerally been more severe with chlorpromazine thanwith loxapine (e.g, Moore, 1975; Steinbook et al.,1973). In addition to extrapyramidal reactions andsedation, Clark et al, (I972) found ocular pigmentdeposits in I patient on each drug tested Ooxapine andchlorpromazine).

. In a study in patients with chronic schizophreniain which a placebowas administered to I group of pa­tients throughout the trial, both chlorpromazine andloxapine were significantly superior to placebo whenevaluated by clinical global impression (CGO or the

Loxapine: A Review

NOSIE scale, but all 3 treatments were equivalentwhen rated by BPRS scores (Clark et al., (972). Lox­apine-treated patients tended to show moderate im­provement (as opposed to slight improvement or nochange) more frequently than those receivingchlorpromazine .

In a shorter-term (3 weeks) study in 30 patientswith acute schizophrenia, loxapine (up to 120mgdaily) was judged less effective than chlorpromazine(up to 1,200mg daily) in overall efficacy (Shopsin etal., 1972). Some discrepancy was found in resultsachieved with different methods of assessment. Whilethe clinical global impression (CGI) and the patientdischarge rate (8 of 15 on chlorpromazine versus 2 of15 on loxapine, after 3 weeks) clearly favouredchlorpromazine, the In-Patient MultidimensionalPsychiatric Scale (IMPS) showed the 2 treatments tobe equal. In the Structured Clinical Interview (SCI)evaluation, behavioural status was normalised withloxapine but conceptual disorganisation and in­congruous ideation scores were only slightly im­proved, while chlorpromazine-treated patientsshowed considerable improvement in all areas of psy­chopathology measured by this technique.

Motor retardation scores after treatment were im­proved more with chlorpromazine when relativelylower doses were used (200 to 800mgchlorpromazine, 20 to 80mg loxapine), but loxapinewas superior in this item when higher doses were ad­ministered (up to 150 and 1,500mg of loxapine andchlorpromazine, respectively).

3.2.3 Comparisons with HaloperidolAll comparative trials with haloperidol have been

conducted in patients with acute schizophrenia, orwith acute exacerbations of chronic schizophrenia. Ina loxapine to haloperidol maximum daily dose ratiowhich varied from 8: I to 25:I, the 2 drugs had equaloverall efficacy in the majority of studies (table 11),

and both were superior to a placebo in those trialswhich utilised a placebo control throughout the studyperiod (Selman et al., 1976; Pool etal. , (976). In Icross-over study however, 50 % of 19'patients whohad improved on loxapine (60 to IOOmg per day for 4

211

weeks) relapsed after I week of treatment withhaloperidol at an unstated dose (Brunetti et al., I976).

In the longest comparative trial to date, loxapine(40 to 80mg daily) and haloperidol (4 to 6mg daily)were equally effectivewhen given to 50 patients withacute schizophrenia for I yeadPaprocki et al., (975).When patients were divided into paranoid and non­paranoid groups prior to data analysis, a number ofitems and factors significantly favoured loxapine inthe paranoid groups, including the BPRS items oftension, motor retardation, blunted affect and totalscore, the BPRS factors of depression and anergia,and the clinical global impression of severity of illness(see section 3.5).

Paprocki et al, (I977) treated 35 patients withschizophrenia, all of whom were female and severelyill, with intramuscular doses of loxapine (up to150mg daily) and haloperidol (up to 15mg daily) forthe first 4 days, and then switched to similar oraldoses providing some improvement had occurredduring parenteral treatment. I I of I7 loxapine pa­tients and 14 of 18 haloperidol patients were judgedsufficiently improved to receive oral therapy. As inthe overall results (table 11), there were few significantdifferences in rating scale scores between the paren­teral forms of the drugs. The degree of sedationfollowing intramuscular doses was similar with bothagents, but the peak sedative effect after the first doseoccurred slightly sooner with loxapine (6 hours) thanwith haloperidol (8 hours). Agitation and excitementwere reduced more by loxapine than by haloperidol,particularly at 4 and 6 hours after intramuscular ad­ministration . Similarly, in a double-blind study in I2agitated patients with acute schizophrenia (and I8 pa­tients diagnosed as having acute psychogenic psy­chosis) 25 to 50mg ofloxapine intramuscularly every6 to I2 hours for 3 days produced a more rapid andmore pronounced sedative effect than 2.5 to 5mg ofhaloperidol (Fruensgaard et al., (977).

Although the relative effect of loxapine andhaloperidol on motor retardation was variable, in ·1study both drugs caused a significant worsening inthis score, loxapine to a lesser extent than haloperidol(Paprocki et al., 1977). Similarly, the retardation fac-

Loxapine: A Review

tor of the NOSIE scale, in which all patients wereasymptomatic at the baseline evaluation, was wor­sened throughout the study by both agents.

The incidence of extrapyramidal effects was. highand very similar (60 to 70 % of patients) with bothdrugs when given orally (loxapine40 to 300mg daily;haloperidol 4 to 25mg daily). During an intramuscu­lar administration phase however, 6 of 18haloperidol-treated patients (up to 15mg daily) neededantiparkinson medication compared with 2 of 17 pa­tients receiving loxapine (up to 150mg daily)[Paprocki et al., 1977].

3.2.4 Comparisons with TrifluoperazineThe initial loxapine to trifluoperazine dosage ratio

used in all comparative studies was 2 to I, but themaintenance dosage ratio involved a slightly higherdose of trifluoperazine in 2 studies (Kilohet al., I976;Simpson and Cuculic, 1976).

In patients with chronic schizophrenia, loxapinewas at least as effective as trifluoperazine. In acuteschizophrenia both drugs were usually equally effec­tive (table II), although Clark et al. (J 975) foundtrifluoperazine to be slightly superior in a short-term(4 week) study. The loxapine group response was stillincreasing at the end of the fourth week, while thetrifluoperazine response reached a peak during thesecond week (see section 3.4).

The incidence of extrapyramidal effects was simi­lar in both groups of patients in all studies. A slightlyhigher incidence of anticholinergic effects (nasal con"gestion, dry mouth, blurred vision, constipation) oc­curred in I study with loxapine (57 % of patients)than with trifluoperazine (44 %) [Kiloh et al., 1976].

3.2.5 Comparisons with ThiothixeneComparative trials with thiothixene have pro­

duced varying results depending on the length of drugadministration, the duration of illness, and the dosageratio used (see table II).

In a 4-week placebo-controlled trial with thiothix­ene, in both acute and chronic schizophrenic patients,up to 150mg of loxapine daily was only slightly moreeffective than placebo, and was less effective than up

212

to 60mg daily of thiothixene (Charalampous et al.,1974). In studies of longer duration and usingrelatively larger doses of loxapine as compared tothiothixene (up to a 5-fold dosage ratio), both drugswere about equieffectiveoverall, with loxapine show­ing some tendency to be superior for certainsymptoms (table II) .

When I investigator evaluated results of treatmentaccording to the length of illness, loxapine wassuperior to thiothixene in patients with a shorterduration of illness (less than 10 years), but wasslightly less effective in patients with a duration of ill­ness greater than 10 years (Filho et al., I975)[see sec­tion 3.5].

The overall incidence of extrapyramidal effectswas similar for both agents (about 50 %). When'lower' doses of the drugs were used (J 0 to 120mgloxapine, 3 to 36mg thiothixene) anticholinergiceffects and sedation occurred more frequently withthiothixene than with loxapine (Filho et al., 1975),but with 'higher' doses (up to 300mg loxapine, 60mgthiothixene) the incidence of these side-effects wassimilar .

3.3 Onset of Effect

There have been few reports regarding the onset ofimprovement in schizophrenic patients with loxapinetreatment, as compared with other antipsychoticdrugs. There is some evidence to suggest however,that loxapine may possibly have a slower onset of ac­tion in patients with acute schizophrenia than some ofthe phenothiazine drugs. In chronic schizophrenia,loxapine and chlorpromazine cause a similar rate ofimprovement, some significant differences fromplacebo being evident by 4 weeks.

In a study in 37 newly-admitted patients withacute exacerbations of chronic schizophrenia, equipo­tent doses of loxapine (up to 100mg daily) andtrifluoperazine (up to 50mg daily)resulted in differentrates of improvement. While the response totrifluoperazine had reached a peak by the secondweek, the loxapine response was still increasing at the

loxapine: A Review

termination of the trial (4 weeks) [Clark et al., 1975].The only other comparative study in which loxapinewas less effective than a phenothiazine drug(chlorpromazine; Shopsin et al., 1972; table II) wasalso in patients with acute schizophrenia , and was ofeven shorter duration (3 weeks).

In a longer-term (12 weeks) study in which all pa­tients were long-term institutionalised chronicschizophrenics, equipotent doses of loxapine (up to100mg daily) and chlorpromazine (up to 1,000mgdaily) produced a similar rate of appearance of signifi­cant improvements (Clark et al., 1972). After 4weeks of treatment, both drugs had improved thesocial competence factor and total score of the NOSIEmore than placebo. and by 8 weeks the social interest ,irr itability, and manifest psychosis factors were alsosignificantly more improved with active drug treat­ment.

3.4 What Patients Show the Best Response?

Although it has not been firmly established thatsome types of schizophrenic patients respond better toloxapine therapy than others, a few authors have re­ported such findings.

When Filho et al. (1975) divided their patients into3 groups (Jess than 2 years, 2 to 10 years and over 10years duration of illness) before data analysis. lox­apine was superior to thiothixene after 12 weeks oftreatment in patients with a history of illness of under10 years (60 % of the patients in this group hadparanoid schizophrenia), but was slightly less effec­tive than thiothixene in patients with a longer dura­tion of illness (I I % of this group had paranoidschizophren ia)[see table II] . Other authors (seesection3.2) have reported a relatively poor response duringthe first few weeks of treatment of acutely-ill, newly­diagnosed schizophrenic patients , but when given formore than 4 weeks loxapine was as effective as otherantipsychotic drugs in acute schizophrenia .

In a long-term study (I year) which used arelatively 'higher' dose of loxapine, compared withhaloperidol, patients with paranoid schizophrenia (9

213

on each drug) showed greater improvement on lox­apine than on haloperidol (Paprocki et al., 1975; seesection 3.2.3). When Bishop et al. (I 977) reanalysedthe results from I 1 double-blind studies (about 400patients) dividing patients according to a diagnosis ofparanoid (about 140 patients) or non-paranoidschizophrenia , loxapine was superior tochlorpromazine or trifluoperazine in a number ofevaluation measures in the paranoid group of pa­tients.

4. Side-Effects

The overall side-effect profile of loxapine is similarto that of other antipsychotic agents such ashaloperidol and the phenothiazines. Extrapyramidalreactions (40 % of patients) and sedation (about 25 %of patients) are the most common adverse reactions.Other less common but expected side-effects of anti­psychotic agents have also occurred with loxapine: forexample anticholinergic effects, hypotension, andtachycardia . Precipitation of epileptic seizures duringtreatment with usual therapeutic doses, and ocularchanges have been reported in a few patients receivingloxapine.

4.1 Common Side-Effects

As with the traditional antipsychotic agents , ex­trapyramidal reactions are the most common side­effect seen during loxapine administration. They oc-

. cur frequently, and although loxapine caused moreextrapyramidal reactions than chlorpromazine in 3 of6 comparative studies with that drug (table 10, theoverall incidence with oral loxapine calculated for thisreview (39 % ; table IV) is identical to that reported inearlier studies with various phenothiazines (38.9 %;Blacow, 1972). During short-term intramuscular ad­ministration to a small number of patients, loxapinecaused fewer severe extrapyramidal effects thanhaloperidol (see section 3.2.3). Only I study has re­ported a sex difference in the incidence of ex-

Loxapine: A Review 214

Table IV. Incidence of the most common side-effectsfrom those studies analysed for this review which provided ap­propriate quantitative data

Side-effect Acute Chronic Overallschizo- schizo- incid-phrenia phrenia ence'N = 247 N = 290 N = 579

Extrapyramidal reactions 35% 40% 39%Rigidity 35% 24% 34%Tremor 11% 19% 16%Akathisia 12% 12% 15%Dystonia 9% 9% 14%Hypersalivation < 1% 5% 6%

Sedation 17% 27% 28%Anticholinergic effects 3% 3% 8%Cardiovascular' < 1% 6% 5%

1 Includes some studies in which side-effects were notdivided into acute and chronic patients.

2 Hypotension or tachycardia.

been reported in 3 patients. Although publishedstudies to date have not reported the occurrence ofpersistent tardive dyskinesia, in light of the inci­dence of other extrapyramidal effects, and con­sidering the drug's pharmacological profile of ac­tivity, it is reasonable to expect that this troublesomereaction may occur with loxapine. There is no estab­lished effective treatment for tardive dyskinesia.

Loxapine, as with other antipsychotic agents, ap­pears to lower the seizure threshold, and precipitationof epileptic seizures has occurred with the use ofmoderate therapeutic doses (see section 3.1.3).

Ocular changes (corneal pigmentation, lens abnor­malities), as have occurred during long-term use ofother antipsychotic agents, have occasionally been re­ported in loxapine-treated patients (Clark et al., 1972;Moyano, 1975). Although the relationship to lox-

anon Extrapyramidaleffects

-r-

.--

r-- r--

r- -

Ul

E.s10c-

oE.,e~ 50

100 Sed '

Fig. 2. Relationship of the occurrence of sedation and ex­trapyramidal effects to the maximum daily dose of Ioxapine(mean occurrence rate of all studies which provided appropri­ate quantitative data).

0;;; 100 > 100,> 150 0;;; 100 > 100, > 1500;;; 150 0;;; 150

Maximum daily dose (mg)

4.2 Less Common Side-Effects

Anticholinergic effects (e.g. dry mouth, blurred vi­sion, etc.) and cardiovascular effects (hypotension ortachycardia) have occurred in 8 % and 5 % of patientstreated, respectively. In addition to the extrapyrami­dal reactions listed in table IV, oculogyric crisis has

trapyramidal reactions (see section 3.1.1). Sexdifferences in the incidence of such effects are alsoseen with chlorpromazine, akathisia occurring moreoften in men than in women while the opposite ratiois seen with dyskinesia (Blacow, 1972).

Sedation occurs frequently with initial doses, butmany patients develop tolerance to this effect duringcontinued administration.

The occurrence of side-effects, particularly themost common ones (i.e. extrapyramidal reactions andsedation), appeared to be dose-related with a higherincidence in those studies using a maximum dailydose greater than 150mg than in studies using alower maximum dose (fig. 2).

Loxapine : A Review

apine administration was not unequivocally estab­lished in these occurrences, until further long-termstudies are available it must be assumed that loxapineis capable of producing such changes.

Transient haematological abnormalities (Nair etal., 1976) and abnormalities in liver function testvalues (Clark et al., 1972) have been observed in afew patients, but did not appear to be clinically sig­nificant.

5. Overdosage

There are no published reports of experience withloxapine overdosage in man. Based on animal studies.and side-effectswhich have occurred with therapeuticdoses. signs of overdosage could include convulsiveseizures, extrapyramidal symptoms, CNS depression.cardiovascular changes, respiratory depression andcoma. Treatment would essentially be supportive andsymptomatic (Lederle Laboratories Product Informa­tion. 1975). Early gastric lavage may be helpful butshould not be done during convulsion. Convulsionsmay be controlled with diazepam or short-acting bar­biturates , and extrapyramidal symptoms with anti­parkinson drugs or diphenhydramine. Intravenousfluids will adequately counter mild hypotension.while severe hypotension should respond tolevonoradrenaline or phenylephrine; adrenaline mayhave a paradoxical effect, lowering blood pressurefurther , and should not be used.

6. Dosage

Initial oral dosage of 10mg twice daily is recom­mended for the treatment of schizophrenia, but up to50mg daily may be used in severely disturbed pa­tients. Dosage should then be increased fairly rapidlyover the first 7 to 10 days according to individual re­quirements, and stabilised at the lowest possible level.The usual maintenance range is 60 to 100mg dailybut some patients may be satisfactorily maintained ata dosage level as low as 20mg per day. Doses in ex-

215

cess of 250mg daily are not recommended by themanufacturer, but doses of up to 300mg have beenused in a few clinical trials.

7. DrugInteractions

There is little information available on drug in­teractions with loxapine. Although it has been con­comitantly administered with a wide variety of otherdrugs. in view of its central nervous system effects itis reasonable to expect that it would potentiate thedepressant action of other central nervous systemdepressants such as barbiturates, narcotic analgesics.antihistamines. alcohol and other antipsychoticdrugs.

In the only reported drug interaction. loxapine (20to 40mg daily) appeared to stimulate phenytoinmetabolism in a single retarded patient, resulting insub-therapeutic phenytoin serum levels when bothdrugs were given concurrently over about a 3-monthperiod (Ryan and Matthews, I 977). The same dose ofphenytoin (460mg daily) administered for 10 daysafter discontinuing loxapine resulted in about a100% increase in phenytoin serum levelson the 10thday as compared with phenytoin levelsduring admin­istration of both drugs.

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Authors' address: R.C. Heel. R.N. Brogden. T.M. Speight andG.S. Avery. Australasian Drug Information Services . P.O. Box34-030. Birkenhead, Auckland 10 (New Zealand) .