MONOGRAPH FOR UKPID
HALOPERIDOL DECANOATE
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 decanoate
Chemical group
Butyrophenone
Origin
Synthetic
Name
Brand name
Haldol(R) Decanoate
Synonyms
Common names
Product licence number
Haldol(R) Decanoate 50mg/ml 0242/0094
Haldol(R) Decanoate 100mg/ml 0242/0095
CAS number
74050-97-8
Manufacturer
Janssen-Cilag Limited, PO Box 79, Saunderton, High Wycombe, Bucks HP14
4HJ
Tel no. 01494 567567
Form
Intramuscular depot injection.
NOTE: a separate entry exists for other haloperidol formulations - see
under 'Haloperidol'.
Formulation details
Injection of haloperidol decanoate equivalent to 50mg/ml or 100mg/ml
of haloperidol for intramuscular administration. Solutions contain
sesame oil and benzyl alcohol as inactive ingredients.
Pack size
50 mg/ml: 5x1ml ampoules
100mg/ml: 5x1ml ampoules
Packaging
Chemical structure
C31H41ClFNO3
Molecular weight = 530.1
Chemical name
4-[4-(4-Chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone
decanoate
Indication
Long term maintenance in schizophrenia, psychoses especially paranoid,
and other mental and behavioural problems.
Therapeutic dosage - adults
By deep IM injection:
50-300 mg every 4 weeks (reduced doses in elderly)
Therapeutic dosage - children
Not recommended
Contra-indications
Use in children, confusional states, coma caused by CNS depressants,
parkinsonism, hypersensitivity to haloperidol, lesions of the basal
ganglia, and during lactation.
Abuses
Epidemiology
Overdose with haloperidol decanoate tends to be limited to accidental
administration and dosage errors.
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
Haloperidol decanoate has no intrinsic activity. The pharmacological
effects are those of haloperidol which is released by bioconversion.
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.
Haloperidol 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, orthostatic hypotension, a reduction of
seizure threshold, hypothermia, QT and PR prolongation on the ECG,
sedation, and antimuscarinic effects.
Pharmacokinetics
ABSORPTION
Haloperidol decanoate is slowly released into the circulation where it
is hydrolysed releasing active haloperidol. Peak plasma concentrations
occur within 3-9 days, then decrease slowly (Beresford & Ward 1987).
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 18 L/kg (Holley et al. 1983).
METABOLISM
Haloperidol decanoate undergoes hydrolysis by plasma and/or tissue
esterases to form haloperidol and decanoic acid (Beresford & Ward
1987).
Subsequently, haloperidol is metabolised in the liver, the main routes
of metabolism being oxidative N-dealkylation, and reduction of the
ketone group to form reduced haloperidol (Forsman & Larsson 1978).
Reduced haloperidol is much less active than haloperidol but undergoes
re-oxidation to haloperidol (Chakraborty et al. 1989, Cheng & Jusko
1993). The cytochrome P4502D6 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). There
is evidence of enterohepatic recycling (Chakraborty et al. 1989).
Half-life - substance
Haloperidol decanoate: 3 weeks
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 in breast milk.
Toxicokinetics
Absorption
Distribution
Metabolism
Elimination
Half-life - substance
Half-life - metabolites
Special populations
Breast milk
Summary
TYPE OF PRODUCT
Intramuscular antipsychotic depot injection.
INGREDIENTS
Haloperidol decanoate equivalent to 50mg/ml, or 100mg/ml of
haloperidol.
Formulated in benzyl alcohol and sesame oil.
NOTE: a separate entry exists for other haloperidol formulations - see
under 'Haloperidol'.
SUMMARY OF TOXICITY
Plasma concentrations of haloperidol will be greatest during the first
week after injection. It will be during this period that there is the
greatest risk of acute toxicity. Any symptoms occurring may take
several weeks to resolve. Accidental injection or dose errors tend to
be in patients on long term therapy which carries a risk of
neuroleptic malignant syndrome and tardive dyskinesia in addition to
acute symptoms.
FEATURES
Rigidity, dystonic reactions, drowsiness, and tremor.
UNCOMMON FEATURES
Cardiac arrhythmias, neuroleptic malignant syndrome, tardive
dyskinesia.
SUMMARY OF MANAGEMENT: SUPPORTIVE
1. Check heart rhythm and blood pressure.
2. Acute dystonic reactions can be managed with IV procyclidine or
benztropine, followed by oral doses to prevent recurrence.
3. Other measures as required by the patients clinical condition.
Peak plasma concentrations occur within 3-9 days of
administration and it is during this time that symptoms are most
likely to occur.
Features - acute
Ingestion
Inhalation
Dermal
Ocular
Other routes
BY INJECTION:
Erythema, swelling, or tender lumps at the site of injection. 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).
Features - chronic
Ingestion
Inhalation
Dermal
Ocular
Other routes
BY INJECTION: as for acute injection.
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 oral 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
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
NA
Supportive care
MANAGEMENT OF THE SYMPTOMATIC PATIENT: SUPPORTIVE
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 1996).
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 or dopamine) should not be used as they may aggravate
hypotension.
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 beta 2-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 39°C) 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 40°C 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
Check the heart rate and rhythm, blood pressure, and body temperature
during the first 7-10 days after administration. Correct any
electrolyte abnormalities.
Antidotes
None available.
Elimination techniques
None.
Investigations
Management controversies
Case data
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).
Peak concentrations following depot injection have been in the range
0.001-0.050 mg/L with steady-state concentrations around 0.008 mg/L
(Nayak et al. 1987).
Conversion factors
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
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