IPCS INCHEM Home
    MONOGRAPH FOR UKPID




    HALOPERIDOL




    HY Allen
    ZM Everitt
    AT Judd

    National Poisons Information Service (Leeds Centre)
    Leeds Poisons Information Centre
    Leeds General Infirmary
    Leeds
    LS1 3EX
    UK


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    MONOGRAPH FOR UKPID

    Drug name

    Haloperidol

    Chemical group

    Butyrophenone

    Origin

    Synthetic

    Name

    Brand name(s)

    Dozic(R), Haldol(R), Serenace(R)

    Synonyms

    Common names

    Product licence number

    Haldol(R) 5 mg                               0242/0031R
    Haldol(R) 10mg                               0242/0039R
    Haldol(R) 5mg/ml injectable solution         0242/0036R
    Haldol(R) 10mg/2ml injectable solution       0242/0036R
    Haldol(R) 2mg/ml oral liquid                 0242/0035R

    Serenace(R) 5mg ampoules                     0530/0368
    Serenace(R) 20 mg ampoules                   0530/0369
    Serenace(R) 1.5mg tablets                    0530/0370
    Serenace(R) 5 mg tablets                     0530/0371
    Serenace(R) 10 mg tablets                    0530/0372
    Serenace(R) 20 mg tablets                    0530/0373
    Serenace(R) 2mg/ml liquid                    0530/0374
    Serenace(R) 500 microgram capsules           0530/0375

    CAS number

    Haloperidol:   52-86-8

    Manufacturer

    of Dozic(R):
         Rosemont Pharmaceuticals Limited, Rosemont House, Yorkdale
         Industrial Park, Braithwaite Street, Leeds LS11 9XE
         Tel no. 0113244 1999

    of Haldol(R):
         Janssen-Cilag Limited, PO Box 79, Saunderton, High Wycombe, Bucks
         HP14 4HJ
         Tel no. 01494 567567

    of Serenace(R):
         Baker Norton, H. N.Norton & Co Limited, Gemini House, Flex
         Meadow, Harlow, Essex CM19 5TJ
         Tel no. 01279 426666

    Form

    Oral tablets
    Oral capsules
    Oral liquid
    Injection for intramuscular or intravenous use
    NOTE: a separate entry exists for depot injections - see under
    'Haloperidol Decanoate'.

    Formulation details

    Tablets of 1.5mg, 5mg, 10mg, 20mg
    Capsules of 500 micrograms
    Oral liquid of 1mg/ml, 2mg/ml
    Injection of 5mg/ml, 10mg/2ml, 20mg/2ml

    Pack size

    Dozic(R) oral liquid 1mg/ml and 2mg/ml: 100ml pack
    Haldol(R) tablets 5mg, 10mg: pack of 100
    Haldol(R) oral liquid 2mg/ml: 100ml pack
    Haldol(R) injection 5 mg/ml: 5x1ml ampoules
    Haldol(R) injection 10mg/2ml: 5x2ml ampoules

    Serenace(R) capsules 500 micrograms: various pack sizes, in bottles
    starting at 7 to 250 capsules and blister packs in sizes from 7 to 120
    capsules, also dispensing packs of 1,000 and 5,000 capsules.
    Serenace(R) tablets 1.5mg, 5mg, 10mg, 20mg: various pack sizes, in
    bottles starting at 7 to 250 tablets and blister packs in sizes from 7
    to 120 tablets, also dispensing packs of 1,000 and 5,000 capsules.
    Serenace(R) oral liquid 2mg/ml: 100ml and 500ml
    Serenace(R) 5mg ampoules: 6x1ml and 10x1ml
    Serenace(R) 20mg ampoules: 10x2ml

    Packaging

    Haldol(R) 5mg : blue cross-scored tablets and marked JANSSEN
    Haldol(R) 10 mg: yellow scored tablets marked JANSSEN and H/10

    Serenace(R) 1.5mg: white tablets marked NORTON 1.5 and SERENACE
    Serenace(R) 5 mg: bright pink tablets marked NORTON 5 and SERENACE
    Serenace(R) 10mg: pale pink tablets marked NORTON 10 and SERENACE
    Serenace(R) 20 mg: dark pink tablets marked NORTON 20 and SERENACE

    Serenace(R) 500 micrograms: two-tone green capsules marked NORTON 500
    and SERENACE

    Chemical structure

    Haloperidol: C21H23ClFNO2 Molecular weight = 375.9

    Chemical name

    4-[4-(4-Chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone

    Indication

    Schizophrenia and other psychoses, especially paranoid, mania,
    short-term adjunctive management of psychomotor agitation, excitement,
    violent or dangerously impulsive behaviour, mental or behavioural
    disorders especially when associated with hyperactivity and
    aggression, short-term adjunctive management of severe anxiety,
    restlessness and agitation in the elderly, intractable hiccup, nausea
    and vomiting, Gilles de la Tourette syndrome and severe tics.

    Therapeutic dosage - adults

    By mouth:
         1-15mg daily in divided doses (up to 100mg in resistant
         schizophrenia)
         Reduced doses in elderly.

    By IM (or IV) injection:
         2-10 mg repeated (as frequently as every 30-60 minutes if
         required) to a maximum of 60mg.

    Therapeutic dosage - children

    By mouth:
         25-50 micrograms/kg daily in two divided doses to a maximum of
         10mg, or 30 mg in adolescents (exceptionally 60mg).
    By injection:
         Not recommended.

    Contra-indications

    Comatose states, CNS depression, Parkinson's disease, known
    hypersensitivity to haloperidol, lesions of the basal ganglia, and
    during lactation.

    Abuses

    Abuse of haloperidol has been reported.
    Doses between 10 mg and 60 mg taken by a number of young people
    resulted in a variety of extrapyramidal symptoms, cold sweats, and
    insomnia. The extrapyramidal effects included opisthotonus, protruding

    tongue, torticollis, and dystonia of the jaw, neck and mouth. The
    adverse effects were generally noticed within a few hours, although
    one patient reported a delay of 48 hours before first noticing any ill
    effect (Doenecke & Heuermann 1980, Kenyon-David 1981).

    Epidemiology

    Although widely used as an antipsychotic, acute poisoning with
    haloperidol is rare.

    Adverse effects

    Extrapyramidal effects such as acute dystonia, Parkinsonian rigidity,
    tremor, and akathisia. Also sedation, agitation, drowsiness, insomnia,
    headache, nausea, blurring of vision, urinary retention, hypotension,
    depression, confusional states, impairment of sexual function, skin
    reactions, epileptic fits, hyperprolactinaemia, ventricular
    arrhythmias, and abnormalities of liver function tests.
    Tardive dyskinesia, and neuroleptic malignant syndrome have both been
    associated with haloperidol therapy.

    Interactions

    PHARMACODYNAMIC

    1.   Enhancement of central nervous system depression produced by
         other CNS DEPRESSANT drugs.

    2.   Combination with other antidopaminergic agents, such as
         METOCLOPRAMIDE or PROCHLORPERAZINE increases the risk of
         extrapyramidal effects (Dollery 1991).

    PHARMACOKINETIC

    1.   The metabolism of TRICYCLIC ANTIDEPRESSANTS is impaired by
         haloperidol resulting in higher serum tricyclic levels (Stockley
         1996).

    OTHER

    1.   There is limited evidence to suggest that profound drowsiness and
         confusion may be associated with combined use of haloperidol and
         INDOMETHACIN (Stockley 1996).

    2.   Combination with high doses of LITHIUM have produced
         encephalopathic syndromes and severe extrapyramidal
         reactions(Cohen & Cohen 1974, Stockley 1996).

    ETHANOL

         Possible enhancement of central nervous system depression, and
    precipitation of extrapyramidal side effects by ALCOHOL (Stockley
    1996).

    Mechanism of action

    The precise mechanism of antipsychotic action is unclear, but is
    considered to be associated with the potent dopamine D2 receptor
    blocking activity of haloperidol and the resulting adaptive changes in
    the brain.
    It is also a potent antagonist of opiate receptors, and has weak
    antagonist activity at muscarinic, histamine H1, alpha-adrenergic, and
    serotonin receptors (Dollery 1991).

    Mechanism of toxicity

    Toxicity is due to an extension of the pharmacological actions. The
    various receptor antagonist actions of haloperidol result in
    extrapyramidal reactions, a reduction in seizure threshold,
    hypothermia, orthostatic hypotension, QT prolongation on the ECG,
    sedation, and antimuscarinic effects.

    Pharmacokinetics

    ABSORPTION

    Following oral administration peak plasma concentrations usually occur
    within 3-6 hours (Kunka & Perel 1989). Oral bioavailability is about
    65% after first-pass metabolism (Holley et al. 1983).
    Following intramuscular administration peak plasma haloperidol
    concentrations occur within 15-60 minutes, and the systemic
    bioavailability is approximately 75% (Adam & Fernandez 1987, Javaid
    1994).

    DISTRIBUTION

    Haloperidol is about 92% bound to plasma proteins (Forsman & Ohman
    1977b). It is widely distributed in the body, with an apparent volume
    of distribution of about 18 L/kg (Holley et al. 1983).

    METABOLISM

    The pharmacokinetic profile of haloperidol varies widely between
    individuals, largely resulting from metabolic differences.
    It is metabolised in the liver via three major pathways. Oxidative
    dealkylation forms inactive metabolites, reduction produces the active
    metabolite reduced haloperidol, and conjugation of both haloperidol
    and reduced haloperidol forms inactive metabolites (Forsman et al.
    1977, Forsman & Larsson 1978). Reduced haloperidol is much less active
    than haloperidol, but the conversion is reversible and re-oxidation to
    haloperidol occurs (Chakraborty et al. 1989, Cheng & Jusko 1993).
    The cytochrome P452D6 has been shown to be involved in the oxidative
    metabolic pathway (Llerena et al 1992).

    ELIMINATION

    Haloperidol is excreted slowly in the urine and faeces. About 30% of a
    dose is excreted in urine and about 20% of a dose in faeces via
    biliary elimination (Beresford & Ward 1987). Only 1% of a dose is
    excreted as unchanged drug in the urine (Forsman et al. 1977). It
    takes 28 days to fully eliminate a single oral dose (Dollery 1991).
    There is evidence of enterohepatic recycling (Chakraborty et al.
    1989).

    Half-life - substance

    About 20 hours but widely variable (range 10-36 hours)
    (Forsman & Ohman 1976, Holley et al 1983).

    Half-life - metabolites

    NA

    Special populations

    ELDERLY

    Haloperidol plasma concentrations in the elderly tend to be higher
    than in younger patients on equivalent doses but the difference is not
    significant (Forsman & Ohman 1977a).

    RENAL IMPAIRMENT

    It is not anticipated that renal impairment would alter the
    pharmacokinetic profile of haloperidol.

    HEPATIC IMPAIRMENT

    The clearance of haloperidol may be reduced in severe liver
    impairment.

    GENDER

    Gender has been found not to influence haloperidol plasma
    concentrations (Forsman & Ohman 1977a).

    BREAST MILK

    Haloperidol is excreted into breast milk.
    In one patient, levels of haloperidol in the breast milk were 0.005
    mg/L following an average dose of 30mg daily. Using these data and
    assuming a milk intake of 1.5L daily, an infant could receive up to
    0.0075 mg haloperidol daily, or 0.02% of the maternal dose (Stewart et
    al. 1980).
    In a second patient receiving 10 mg haloperidol daily, milk levels up
    to 0.0235 mg/L were measured. The milk to plasma ratio for haloperidol
    in this patient was 0.6 (Whalley et al. 1981).

    Toxicokinetics

    Absorption

    Distribution

    Metabolism

    Elimination

    Half-life - substance

    Half-life - metabolites

    Special populations

    CHILDREN: elimination half-lives between 9 and 39 hours (average 19
    hours) have been reported following accidental ingestions in children
    (Yoshida et al. 1993).

    Breast milk

    Summary

    TYPE OF PRODUCT

    Antipsychotic

    INGREDIENTS

    Capsules of 500 micrograms
    Tablets of 1.5 mg, 5 mg, 10 mg, and 20 mg
    Oral liquid of 1 mg/ml, 2 mg/ml, 10mg/ml
    Ampoules of 5 mg/ml, 10 mg/2ml, and 20 mg/2ml for IM or IV use.
    NOTE: a separate entry exists for depot injections - see under
    'Haloperidol Decanoate'.

    SUMMARY OF TOXICITY

    Features of toxicity generally become evident within 2-12 hours of an
    ingestion, and may last for several days. Ingestions of up to 50 mg
    have resulted in rigidity, dystonic reactions, drowsiness, and tremor.
    Larger amounts have been associated with hypotension, prolongation of
    the QT interval, and the development of torsade de pointes.
    Antimuscarinic effects are rare.
    Children appear particularly susceptible to dystonic reactions and
    disturbances of temperature and blood pressure.

    FEATURES

    Acute dystonic reactions, drowsiness, hypotension or hypertension,
    cardiac arrhythmias, and hypothermia.

    SUMMARY OF MANAGEMENT: SUPPORTIVE

    1.   Maintain a clear airway and adequate ventilation if consciousness
         is impaired.

    2.   If within 1 hour of the ingestion and more than 30 mg has been
         ingested by an adult or more than 100 microgram/kg by a child,
         give oral activated charcoal.

    3.   Acute dystonic reactions can be managed with IV procyclidine or
         benztropine.

    4.   Check the cardiac rhythm and blood pressure.

    5.   Manage hypotension with IV fluids.

    6.   Cardiac overdrive pacing is the preferred management for torsade
         de pointes.

    7.   Other measures as indicated by the patients clinical condition.

    Features - acute

    Ingestion

    Acute dystonic reactions and other extrapyramidal signs (such as
    rigidity, and tremor), drowsiness, hypotension (or rarely
    hypertension), hypothermia, hypokalaemia, and cardiac arrhythmias
    particularly prolongation of the QT interval and torsade de pointes
    (Aunsholt 1989, Cummingham & Challapalli 1979, Henderson et al. 1991,
    Scialli & Thornton 1978, Sinaniotis et al. 1978, Yoshida et al. 1993,
    Zee-Cheng et al. 1985).

    Inhalation

    NA

    Dermal

    NA

    Ocular

    Other routes

    BY INJECTION: as for acute ingestion.

    Features - chronic

    Ingestion

    As for acute ingestion, but with the additional risks of the
    development of neuroleptic malignant syndrome (characterised by
    hyperthermia, muscle rigidity, autonomic instability, altered

    consciousness, and coma), and tardive dyskinesia (involuntary
    movements of the tongue, face, jaw, or mouth).

    Inhalation

    NA

    Dermal

    NA

    Ocular

    Other routes

    BY INJECTION: as for chronic ingestion.

    At risk groups

    ELDERLY

    Increased risk of toxic events.

    PREGNANCY

    The safety of haloperidol in human pregnancy has not been established.
    There are two reports of limb defects in infants after first trimester
    use of haloperidol given with other potentially teratogenic drugs
    (AHFS 1998, Briggs 1994, Kopelman et al. 1975). Other investigators
    have not found an association between haloperidol and birth defects.

    CHILDREN

    There appears to be a high incidence of dystonic reactions reported in
    children (Yoshida et al. 1993).

    ENZYME DEFICIENCIES

    The metabolism of haloperidol is subject to genetic polymorphism.
    Subjects deficient in the isoenzyme P4502D6 are poor metabolisers of
    haloperidol and will be at risk from high haloperidol plasma
    concentrations due to a reduced metabolic capacity (Llerena et al.
    1992). Approximately 7% of the caucasian population is deficient in
    this enzyme.

    ENZYME INDUCED

    Reduced risk of toxicity from haloperidol.
    Therapeutic administration with enzyme inducing drugs for a period of
    1-3 weeks results in lower haloperidol plasma concentrations (Forsman
    & Ohman 1977a, Jann et al. 1985).

    Occupations

    Others

    RENAL IMPAIRMENT: renal impairment is unlikely to increase the risk of
    toxicity.
    HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired
    metabolism.
    CARDIAC DISEASE: increased risk of cardiotoxicity due to underlying
    disease.
    EPILEPSY: increased risk of seizures due to lowered seizure threshold.

    Management

    Decontamination

    If within one hour of ingestion, and more than 30 mg has been taken by
    an adult or more than 100 microgram/kg by a child, oral activated
    charcoal should be given to reduce the absorption.

         ADULT DOSE; 50 g,
         CHILD DOSE; 1 g/kg.

    If the patient is drowsy this should be administered via a nasogastric
    tube, and if there is no gag reflex present, using a cuffed
    endotracheal tube to protect the airway.

    Supportive care

    MANAGEMENT OF THE SYMPTOMATIC PATIENT: SUPPORTIVE

    Clear and maintain the airway, and give cardiopulmonary resuscitation
    if necessary.
    Evaluate the patient's condition and provide support for vital
    functions.

    1. ACUTE DYSTONIC AND OTHER EXTRAPYRAMIDAL REACTIONS
    Severe dystonic reactions can be controlled within a few minutes by
    giving procyclidine or benztropine by the intravenous (or
    intramuscular) route. Subsequent oral doses may be required for 2-3
    days to prevent recurrence. Less severe extrapyramidal symptoms can be
    controlled by oral doses of procyclidine, benztropine, or other
    similar anticholinergic drug (Corre et al. 1984, Guy's, Lewisham & St.
    Thomas Paediatric Formulary 1997, BNF 1998).

    Procyclidine IV, IM:
         Adult dose:                   5-10 mg (use lower end of dose
                                       range in elderly),
         Child dose under 2 years:     500 micrograms-2 mg (unlicensed
                                       indication)
         Child dose 2-10 years:        2-5 mg (unlicensed indication).

    Procyclidine oral:
         Adult dose:                   2.5-10mg three times a day
         Child 7-14 years              1.25mg three times a day
                                       (unlicensed indication)
         Child over 14 years           2.5mg three times a day (unlicensed
                                       indication)

    Benztropine dose IV, IM, and oral:
         Adult dose:    1-2 mg (use lower end of dose range in elderly),
         Child dose:    20 micrograms/kg (unlicensed indication).

    2. HYPOTENSION
    Hypotension should be managed by the administration of intravenous
    fluids and by physical means. Where these measures fail, consideration
    may be given to the use of a direct acting sympathomimetic such as
    noradrenaline with appropriate haemodynamic monitoring (e.g. insertion
    of Swan-Ganz catheter).

         ADULT DOSE: IV infusion of noradrenaline acid tartrate 80
    micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) in
    dextrose 5% via a central venous catheter at an initial rate of 0.16
    to 0.33 ml/minute adjusted according to response (BNF 1998).
         CHILD DOSE (unlicensed indication): IV infusion of noradrenaline
    acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1
    microgram/kg/minute of noradrenaline base) in glucose 5% or
    glucose/saline via a central venous catheter (Guy's, Lewisham & St
    Thomas Paediatric Formulary 1997).

    NOTE: sympathomimetics with mixed alpha and beta adrenergic effects
    (e.g. adrenaline and dopamine) should not be used as hypotension may
    be exacerbated.

    3. CARDIAC ARRHYTHMIAS
    The ventricular arrhythmia, torsade de pointes, may prove difficult to
    manage. Treatment is aimed at shortening the QT interval by
    accelerating the heart rate. The preferred method is by CARDIAC
    OVERDRIVE PACING (Henderson et al. 1991).

    Alternatively isoprenaline may be used to increase the heart rate, but
    with caution, as the unopposed beta2-adrenergic agonist effects will
    exacerbate hypotension.
         ADULT DOSE: intravenous isoprenaline infused at a starting dose
    of 0.2 micrograms/minute and titrated to maintain a heart rate of 100
    beats per minute (Kemper et al. 1983).

    Intravenous magnesium sulphate has also been shown to be effective in
    the management of torsade de pointes (Tzivoni et al. 1988).

         ADULT DOSE; 8 mmol of magnesium sulphate (4 ml of 50% solution)
    by intravenous injection over 10-15 minutes, repeated once if
    necessary (BNF 1998). CHILD DOSE: clinical experience in children is
    lacking, but based on the above recommendations for management in 

    adults, doses of 0.08-0.2 mmol/kg (0.04-0.1 ml/kg of 50% solution) may
    be considered appropriate (based on Guy's, Lewisham & St Thomas
    Paediatric Formulary, 1997).

    4. TEMPERATURE DISTURBANCES
    Where the patient is hypothermic the body temperature should be
    allowed to recover naturally by wrapping the patient in blankets to
    conserve body heat.
    Conventional external cooling procedures should be used in patients
    who are hyperthermic.

    5. NEUROLEPTIC MALIGNANT SYNDROME
    The development of NMS with a high central temperature (over 39C) is
    best treated by paralysing and mechanically ventilating the patient.
    This usually controls the muscle spasm and allows the temperature to
    fall. If the body temperature is 40C or over, administer intravenous
    dantrolene.

         ADULT DOSE: dantrolene 1 mg/kg body weight by rapid IV injection
    repeated as required to a cumulative maximum of 10 mg/kg (BNF 1998).

    Monitoring

    Monitor the heart rate and rhythm, blood pressure, and body
    temperature. Correct any electrolyte abnormalities.

    OBSERVE for a minimum of 12 hours post-ingestion where:
         i)   more than 15 mg has been ingested by an adult (or more than
         the patients' normal therapeutic dose, if this is greater),
         ii)  more than 50 microgram/kg has been ingested by a child,
         iii) the patient is symptomatic.

    Antidotes

    There is no specific antidote.

    Elimination techniques

    Forced diuresis, peritoneal dialysis, haemodialysis, and charcoal
    haemoperfusion are ineffective (Dollery 1991).

    Investigations

    Management controversies

    Gastric lavage is not recommended as the procedure may be associated
    with significant morbidity, and there is no evidence that it is of any
    greater benefit than activated charcoal used alone.
    If the procedure is used (i.e. in cases where activated charcoal
    cannot be administered), a cuffed endotracheal tube should be used to
    protect the airway if the patient is drowsy, and activated charcoal
    left in the stomach following the lavage.

    Case data

    CASE REPORT 1 - Hypokalaemia and prolonged QT interval after 300 mg
    haloperidol in an adult.

    A 56 year old woman reportedly ingested 300 mg of haloperidol in a
    suicide attempt. Her plasma electrolytes had been assessed three weeks
    before the attempt when her serum potassium was 4.4 mmol/L. All other
    tests including her ECG were normal at this assessment. On admission
    she complained of dry mouth and blurred vision, was pale and drowsy,
    with a blood pressure of 120/60 mm Hg. An ECG revealed a sinus rhythm
    of 80 beats per minute with a prolonged QT interval of 0.6s (corrected
    QT of 0.71s). The corrected serum calcium was 2.47 mmol/L and the
    serum potassium was 2.7 mmol/L. The potassium depletion was corrected
    by intravenous infusion. The QT interval returned to normal after 12
    hours and at no time were ventricular arrhythmias observed. The
    patient was discharged 32 hours after admission (Aunsholt 1989).

    CASE REPORT 2 - Delayed hypertension following haloperidol ingestion
    in an infant.

    A 22-month-old presented with profound lethargy, urticaria, dystonia,
    rigidity, and fine tremor 26 hours after an accidental ingestion of 15
    or 20 mg haloperidol. Her blood pressure was 136/66 mm Hg rising to
    164/134 mm Hg over the next 10 hours. She was given IV hydralazine,
    and required antihypertensive therapy for five days. Subsequent
    recovery was complete with no other cause for the hypertension being
    found (Cummingham & Challapalli 1979).

    CASE REPORT 3 - Torsade de pointes after haloperidol and orphenadrine
    ingestion in an adult.

    A 48 year old woman was admitted to hospital shortly after ingesting
    up to 210mg haloperidol and 1400 mg orphenadrine. She was
    semi-conscious and pulseless. ECG monitoring revealed a broad complex
    polymorphous tachycardia. Once in sinus rhythm after resuscitative
    measures her blood pressure was 110/60 mg Hg. gastric lavage was
    performed followed by activated charcoal administration. A mild
    hypokalaemia was corrected. Further ECG monitoring revealed frequent
    multiform ventricular extrasystoles, with episodes of polymorphous
    ventricular tachycardia. An IV injection of 100 mg lignocaine followed
    by a lignocaine infusion did not prevent recurrent episodes of
    polymorphous ventricular tachycardia. A diagnosis of torsade de
    pointes was made, the lignocaine discontinued, and atrial overdrive
    pacing started at a rate of 85 per minute. The QT interval became
    normal 2 days after admission and the patient returned to sinus rhythm
    when atrial pacing was discontinued (Henderson et al. 1991).

    Analysis

    Agent/toxin/metabolite

    The measurement of plasma haloperidol is of little benefit as no
    correlation has been established between plasma haloperidol
    concentration and therapeutic or toxic effect.

    Sample container

    NA

    Storage conditions

    NA

    Transport

    NA

    Interpretation of data

    It has been suggested that a plasma haloperidol concentration of
    0.005-0.012 mg/L may be associated with a clinical response, but this
    range should only be viewed as a rough guide (Van Putten et al. 1992).

    Conversion factors

    1 micromole/L = 0.376 mg/L
    1mg/L = 2.659 micromoles/L

    Others

    NA

    Toxicological data

    Carcinogenicity

    An increase in mammary neoplasms has been observed in rodents
    following long term administration of prolactin-stimulating
    antipsychotic agents. Although no association between human breast
    cancer and long term administration of these drugs has been shown,
    current evidence is too limited to be conclusive (AHFS 1998).

    Genotoxicity

    Mutagenicity

    Reprotoxicity

    Hyperprolactinaemia resulting from haloperidol therapy may lead to
    infertility in women and impotence in men.

    Teratogenicity

    Haloperidol has been shown to be teratogenic and fetotoxic in animals
    at dosages 2-20 times the usual maximum human dosage (AHFS 1998).
    In human pregnancy, haloperidol has not been associated with
    teratogenic effects when used alone, but there are two reports of limb
    defects following the first trimester administration of haloperidol
    with other drugs (Briggs 1994, Kopelman et al. 1975).

    Relevant animal data

    Relevant in vitro data


    Authors

    HY Allen
    ZM Everitt
    AT Judd

    National Poisons Information Service (Leeds Centre)
    Leeds Poisons Information Centre
    Leeds General Infirmary
    Leeds
    LS1 3EX
    UK

    This monograph was produced by the staff of the Leeds Centre of the
    National Poisons Information Service in the United Kingdom. The work
    was commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Prepared October 1996
    Updated May 1998

    References

    Adam S, Fernandez F.
    Intravenous use of haloperidol. Hosp Pharm 1987; 22: 306-307.

    AHFS.
    AHFS (American Hospital Formulary Service) Drug Information. Bethesda
    MD: American Society of Health-System Pharmacists Inc, 1998.

    Aunsholt NA.
    Prolonged Q-T interval and hypokalemia caused by haloperidol. Acta
    Psychiatr Scand 1989; 79: 411-412.

    Beresford R, Ward A.
    Haloperidol decanoate: a preliminary review of its pharmacodynamic and
    pharmacokinetic properties and therapeutic use in psychosis. Drugs
    1987; 33: 31-49.

    BNF.
    Joint Formulary Committee. British National Formulary, Number 35.
    London: British Medical Association & Royal Pharmaceutical Society of
    Great Britain, 1998.

    Briggs GG, Freeman RK, Yaffe SJ.
    Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams &
    Wilkins, 1994: 409/h-410/h.

    Chakraborty BS, Hubbard JW, Hawes EM, McKay G, Cooper JK, Gurnsey T,
    Korchinski ED, Midha KK.
    Interconversion between haloperidol and reduced haloperidol in healthy
    volunteers. Eur J Clin Pharmacol 1989; 37: 45-48.

    Cheng H, Jusko WJ.
    Pharmacokinetics of reversible metabolic systems. Biopharm Drug Dispos
    1993; 14: 721-766.

    Cohen WJ, Cohen NH.
    Lithium carbonate, haloperidol, and irreversible brain damage. J Am
    Med Assoc 1974; 230: 1283-1287.

    Corre KA, Niemann JT, Bessen HA.
    Extended therapy for acute dystonic reactions. Ann Emerg Med 1984; 13:
    194-197.

    Cummingham DG, Challapalli M.
    Hypertension in acute haloperidol poisoning. J Pediatr 1979; 95: 489-
    490.

    Doenecke AI, Heuermann RC.
    Treatment of haloperidol abuse with diphenhydramine. Am J Psychiatry
    1980; 137: 487-488.

    Dollery C (Ed).
    Therapeutic Drugs Volume 2. Edinburgh: Churchill Livingstone, 1991:H1-
    H4.

    Forsman A, Folsch G, Larsson M, Ohman R.
    On the metabolism of haloperidol in man. Curr Ther Res 1977; 21: 606-
    617.

    Forsman A , Larsson M.
    Metabolism of haloperidol. Curr Ther Res 1978; 24: 567-568.

    Forsman A, Ohman R.
    Applied pharmacokinetics of haloperidol in man. Curr Ther Res 1977a;
    21: 396-411.

    Forsman A, Ohman R.
    Studies on serum protein binding of haloperidol. Curr Ther Res 1977b;
    21: 245-255.

    Forsman A, Ohman R.
    Pharmacokinetic studies on haloperidol in man. Curr Ther Res 1976; 20:
    319-336.

    Guy's, Lewisham and St. Thomas' Paediatric Formulary.
    4th edition. London: Guy's and St. Thomas' Hospitals Trust, 1997.

    Henderson RA, Lane S, Henry JA.
    Life-threatening ventricular arrhythmia (Torsade de Pointes) after
    haloperidol overdose. Human Exper Toxicol 1991; 10: 59-62.

    Holley FO, Magliozzi JR, Stanski DR, Lombrozo L, Hollister LE.
    Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol
    Ther 1983; 33: 477-484.

    Jann MW, Ereshefsky L, Saklad SR, Seidel DR, Davis CM, Burch NR,
    Bowden CL.
    Effects of carbamazepine on plasma haloperidol levels. J Clin
    Psychopharmacol 1985; 5: 106-109.

    Javaid JI.
    Clinical Phamacokinetics of antipsychotics. J Clin Pharmacol 1994; 34:
    286-295.

    Kemper AJ , Dunlap R, Pietro DA.
    Thioridazine-induced torsade de pointes: successful therapy with
    isoproterenol. J Am Med Assoc 1983; 249: 2931-2934.

    Kenyon-David D.
    Haloperidol intoxication. NZ Med J 1981; 92: 165.

    Kopelman AE, McCullar FW, Heggeness L.
    Limb malformations following maternal use of haloperidol. J Am Med
    Assoc 1975; 231: 62-64.

    Kunka RL, Perel JM.
    Haloperidol pharmacokinetics in healthy volunteers. Curr Ther Res
    1989; 45: 1088-1096.

    Llerena A, Alm C, Dahl M-L, Ekqvist B, Bertilsson L.
    Haloperidol disposition is dependent on debrisoquine hydoxylation
    phenotype. Ther Drug Monit 1992; 14: 92-97.

    Scialli JVK, Thornton WE.
    Toxic reactions from a haloperidol overdose in two children: thermal
    and cardiac manifestations. J Am Med Assoc 1978; 239: 48-49.

    Sinaniotis CA, Spyrides P, Vlachos P, Papadatos C.
    Acute haloperidol poisoning in children. J Pediatr 1978; 93:
    1038-1039.

    Stewart RB, Karas B, Springer PK.
    Haloperidol excretion in human milk. Am J Psychiatry 1980; 137:
    849-850.

    Stockley IH. Drug Interactions. 4th ed. London: The Pharmaceutical
    Press, 1996

    Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, Stern
    S.
    Treatment of torsade de pointes with magnesium sulfate. Circulation
    1988; 77: 392-397.

    Van Putten T, Marder SR, Mintz J, Poland RE.
    Haloperidol plasma levels and clinical response: a therapeutic window
    relationship. Am J Psychiatry 1992; 149: 500-505.

    Whalley LJ, Blain PG, Prime JK.
    Haloperidol secreted in breast milk. Br Med J 1981; 282: 1746-1747.

    Yoshida I, Sakaguchi Y, Matsuishi T, Yano E, Yamashito Y, Hayata S,
    Hitoshi T,
    Yamashita F.
    Acute accidental overdosage of haloperidol in children. Acta Paediatr
    1993; 82 :877-880.

    Zee-Cheng C-S, Mueller CE, Seifert CF, Gibbs HR.
    Haloperidol and torsade de pointes. Ann Int Med 1985; 102: 418.