Haloperidol
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS |
| 1.4.2 Other numbers |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, Importers |
| 1.7 Presentation, Formulation |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Properties of the substance |
| 3.3.1.1 Colour |
| 3.3.1.2 State/Form |
| 3.3.1.3 Description |
| 3.3.2 Properties of the locally available formulation(s) |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of the locally available formulation |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 4. USES |
| 4.1 Indications |
| 4.1.1 Indications |
| 4.1.2 Description |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Macroscopic and microscopic analysis |
| 8.1.1.2 Toxicological analyses |
| 8.1.1.3 Biological analyses |
| 8.1.1.4 Arterial blood gas analysis |
| 8.1.1.5 Haematological analyses |
| 8.1.1.6 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Macroscopic and microscopic analysis |
| 8.1.2.2 Toxicological analyses |
| 8.1.2.3 Biochemical analyses |
| 8.1.2.4 Arterial blood gas analysis |
| 8.1.2.5 Haematological analyses |
| 8.1.2.6 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Macroscopic and microscopic analysis |
| 8.1.3.2 Toxicological analyses |
| 8.1.3.3 Biochemical analyses |
| 8.1.3.4 Arterial blood gas analysis |
| 8.1.3.5 Haematological analyses |
| 8.1.3.6 Other (unspecified) analyses |
| 8.2 Toxicological analyses and their interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple qualitative test(s) |
| 8.2.1.2 Advanced qualitative confirmation test(s) |
| 8.2.1.3 Simple quantitative method(s) |
| 8.2.1.4 Advanced quantitative method(s) |
| 8.2.2 Tests on biological specimens |
| 8.2.2.1 Simple qualitative test(s) |
| 8.2.2.2 Advanced qualitative confirmation test(s) |
| 8.2.2.3 Simple quantitative method(s) |
| 8.2.2.4 Advanced quantitative method(s) |
| 8.2.2.5 Other dedicated method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central nervous system (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
1. NAME
1.1 Substance
Haloperidol (INN)
(WHO, 1992)
1.2 Group
ATC classification index
Psycholeptics (N05)/Antipsychotics (N05A)/Butyrophone
derivatives (N05AD).
(WHO, 1992)
1.3 Synonyms
Aloperidolo
Haloperidolum
(Reynolds, 1993)
(To be completed by each Centre using local data)
1.4 Identification numbers
1.4.1 CAS
52-86-8
1.4.2 Other numbers
RTECS
EU 1575000
1.5 Brand names, Trade names
Monocomponent products
Haldol (UK,Belg., Canad., Fr., Ger., Neth., Norw., Swed.,
Switz., USA)
Halopidol (Arg.)
Peridol (Canad.)
Serenace (UK, Austral., Jap., S.Afr.)
Serenase (Denm., Ital.)
Halosten (Jap.)
Sigaperidol (Ger.)
Combination products
Vesadol (Fr.)
Vesalium (Ital)
(To be completed by each Centre using local data)
1.6 Manufacturers, Importers
Lando Lab
Janssen Lab (France, UK)
Searle (Australia, UK)
Technilab (Canada)
(To be completed by each Centre using local data)
1.7 Presentation, Formulation
Oral solution
2 mg/mL
Sterile solution for injection
5 mg/5 mL
Ampoules for injection
5 mg/mL
Tablets
1.5 mg, 5 mg, 10 mg, and 20 mg.
Capsules
0.5 mg
(To be completed by each Centre using local data)
2. SUMMARY
2.1 Main risks and target organs
The main features of severe overdosage are extrapyramidal
reactions, hypotension, respiratory difficulty and impairment
of consciousness.
Haloperidol acts mainly as a dopamine antagonist.
2.2 Summary of clinical effects
Consciousness may be depressed, progressing to coma;
paradoxically, some patients manifest confusion, excitement
and restlessness. Tremor or muscle twitching, muscle spasm,
rigidity and convulsions are seen.
Extrapyramidal signs can include dystonia, sometimes severe
enough to impair swallowing or breathing; torticollis,
oculogyric crises and opisthotonos. The pupils may be
constricted or dilated.
Hypotension and tachycardia are common. Sometimes there can
be cardiac arrhythmias, including ventricular fibrillation,
conduction defects and cardiac arrest.
2.3 Diagnosis
Diagnosis is usually on the basis of history and typical
extrapyramidal features.
Collect urine and blood samples for biological test.
Qualitative drug screens require urine samples.
2.4 First aid measures and management principles
Although ipecac syrup is said to be effective in promoting
vomiting even after overdoses of phenothiazine
tranquillizers, it should not be administered if the patient
is already drowsy. Gastric lavage should be considered up to
2 hours after ingestion because gastric motility is greatly
reduced. Use precautions against aspiration. 50 to 100 g of
activated charcoal may be administered.
In severe shock, plasma expanders and if necessary dopamine
infusion.
Fluid and electrolyte therapy; oxygen and artificial
respiration whenever necessary.
Sodium dantrolene, or possibly bromocriptine, may be useful
in the malignant neuroleptic syndrome.
Continuously monitor the ECG.
For relief of extrapyramidal signs, antihistaminic/
anticholinergics have been suggested for use in adults
(Ellenhorn & Barceloux, 1988). Diphenhydramine (10 to 50 mg)
intravenously is said to provide relief from extrapyramidal
signs. The maximum 24 hour dose is 400 mg in children.
Diphenhydramine intravenously is effective in children but
should not exceed 400 mg in 24 hours.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
It is a synthetic product. Haloperidol is the first of the
butyrophenone series of major tranquillizers.
3.2 Chemical structure
Structural formula
Molecular formula
C21H23C1FNO2
Molecular weight
375.9
Structural Chemical names
4-[4-(4-Chlorophenyl)-4-hydroxypiperidino]-4'-
fluorobutyrophenone.
4[4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-
fluorophenyl)-1-butanone.
4[4-(p-Chlorophenyl)-4-hydroxypiperidino]-4'-
fluorobutyrophenone.
(Reynolds, 1993; Budavari, 1989)
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
White to faintly yellowish
3.3.1.2 State/Form
Amorphous or microcrystalline powder
3.3.1.3 Description
Odourless
Practically insoluble in water; soluble in
approximately 1:60 in alcohol, 1:20 in
chloroform and slightly soluble in ether.
Freely soluble in methanol-acetone, benzene and
acids.
pKa 8.3
The B.P. injection has a pH of 2.8 to 3.6
3.3.2 Properties of the locally available formulation(s)
To be completed by each Centre using local data.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
3.4.2 Shelf-life of the locally available formulation
To be completed by each Centre using local data.
3.4.3 Storage conditions
Store in airtight containers. Protect from light.
3.4.4 Bioavailability
To be completed by each Centre using local data.
3.4.5 Specific properties and composition
To be completed by each Centre using local data.
4. USES
4.1 Indications
4.1.1 Indications
Haloperidol is indicated for use in the management of
manifestations of psychotic disorders such as
schizophrenia and mania.
It is indicated for the control of tics and vocal
utterances of Tourette's Disorder in children and
adults.
It is effective for the treatment of severe behaviour
problems in children of combative, explosive
hyperexcitability.
It is also used in the management of Gilles de La
Tourette's syndrome, intractable hiccup and as an anti-
emetic.
((Physician's Desk Reference, 1987)
4.1.2 Description
Not relevant.
4.2 Therapeutic dosage
4.2.1 Adults
Oral
Psychoses and associated behavioural disorders
0.5 to 5 mg twice or three times daily.
Severe psychoses
Up to 100 mg daily.
In very high dose therapy, 200 mg daily has been used.
Parenteral
Intramuscular
Doses vary from 2 to 30 mg depending on the condition
being treated.
Long-acting decanoate ester may be given in doses
ranging from 100 to 300 mg.
Intravenous
Up to 30 mg for emergency control of disturbed
patients.
(Reynolds, 1993)
4.2.2 Children
Oral
A suggested dose in children over 3 years of age is 25
to 50 ug/kg per bodyweight daily, and increased
cautiously, if necessary up to 150 ug/kg daily.
(Reynolds, 1993)
4.3 Contraindications
Severe dystonic reactions have followed the use of
haloperidol, particularly in children and adolescents. It
should therefore be used with extreme care in children.
Haloperidol may also cause severe neurotoxic reactions in
patients with hyperthyroidism and in patients receiving
lithium.
(Reynolds, 1989)
Haloperidol is contraindicated in severe toxic central
nervous system depression or comatose states from any cause
and individuals who are hypersensitive to this drug or have
Parkinson's disease (Physician's Desk Reference, 1987).
Also contraindicated in late pregnancy because of dystonic
reaction in the neonate. Infants should not be nursed during
drug treatment (Physician's Desk Reference, 1987).
5. ROUTES OF ENTRY
5.1 Oral
It is the main route of administration.
5.2 Inhalation
Not relevant.
5.3 Dermal
Not relevant.
5.4 Eye
Not relevant.
5.5 Parenteral
Through intravenous and intramuscular injection.
5.6 Other
Not relevant.
6. KINETICS
6.1 Absorption by route of exposure
Haloperidol is readily absorbed from the gastrointestinal
tract. Owing to the first-pass effect of metabolism in the
liver, plasma concentrations following oral administration
are lower than those following intramuscular administration.
Moreover, there is wide intersubject variation in plasma
concentration of haloperidol and its therapeutic effects.
The decanoate ester of haloperidol is very slowly absorbed
from the site of injection and is therefore suitable for
depot injection. It is gradually released into the
bloodstream where it is rapidly hydrolysed to haloperidol.
(Reynolds, 1989)
6.2 Distribution by route of exposure
Haloperidol is very extensively bound to plasma proteins
(90%). It is widely distributed in body and crosses the
bloodbrain barrier. The volume of distribution is 18 L/kg).
(Reynolds, 1989; Gilman et al., 1990)
6.3 Biological half-life by route of exposure
The plasma half-life in therapeutic doses is reported to
range from about 13 to nearly 40 hours (Reynolds, 1989), with
a mean of 20 hours. Gilman et al.(1990) gives a similar
average value of 18 hours.
6.4 Metabolism
Haloperidol is metabolized in the liver and the paths of
metabolism include oxidative N-dealkylation (Reynolds, 1989).
6.5 Elimination by route of exposure
The total systemic clearance of the drug from plasma is
11.8 mL/min/kg. This rate increases in children and decreases
in aged patients (Gilman et al., 1990).
After metabolism, haloperidol is excreted in the urine, via
the bile and in the faeces, there is evidence of
enterohepatic recycling by 40%. About 26% was excreted in
the urine by the healthy subjects and 20% by the patients in
the first 5 days; by the third day about 15% had been
excreted in the faeces (Johnson, 1967). It takes 28 days to
fully eliminate a single oral dose.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
The same mechanism of action applies to both
pharmacodynamics and toxicodynamics.
7.1.2 Pharmacodynamics
Dopamine receptors currently are classified as D-
1(stimulate adenylate cyclase) and D-2(inhibit
adenylate cyclase). Neuroleptic drugs block both D-1
and D-2 receptors but the significance of the ratio
remains unclear. The therapeutic dose of neuroleptic
drug appears to correlate with its affinity for brain
dopamine D-2 receptors (Richelson, 1984).
Neuroleptic drugs also block a number of other
receptors including H1 and H2 histamine, alfa 1 and
alfa 2 adrenergic, muscarinic and serotoninergic
receptors.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Deaths from massive haloperidol ingestion have
not been reported (Ellenhorn & Barceloux,
1988).
Three cases of sudden death after taking 20 to
140 mg daily for one to four days (Gosselin et
al., 1984).
7.2.1.2 Children
A 29-month-old girl and an 11 month old boy who
divided 265 mg of haloperidol between them
developed lethargy, hypothermia, hyperreflexia,
neuromuscular rigidity, unsteady gait and
intention tremors (Scialli, 1978).
7.2.2 Relevant animal data
LD50 (oral) rat 850 mg/kg (Gosselin, 1984).
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
Carcinogenicity studies using oral haloperidol were conducted
in Wistar rats (dosed at up to 5 mg/kg daily for 24 months)
and in Albino swiss mice (dosed at up to 5 mg/kg daily for 18
months).
In the rat study, survival was less than optimal in all dose
groups, reducing the number of rats at risk for developing
tumours. However, although a relatively greater number of
rats survived to the end of the study in high dose male and
female groups, these animals did not have a greater incidence
of tumours than control animals.
Therefore, although not optimal, this study does suggest the
absence of haloperidol related increase in the incidence of
neoplasia in rats at doses up to 20 times the usual daily
human dose for chronic patients.
In female mice at 5 to 20 times the highest initial daily
dose for chronic patients, there was a statistically
significant increase in mammary gland neoplasia and total
tumour incidence; at 20 times the same daily dose there was
a statistically significant increase in pituitary gland
neoplasia. In male mice, no statistically significant
differences in incidence of total tumours or specific
tumour types were noted. Neuroleptic drugs elevate
prolactin levels; the elevation persists during chronic
administration. Tissue culture experiment indicate that
approximately one-third of human breast cancers are
prolactin dependent "in vitro", a factor of potential
importance if the prescription of these drugs is
contemplated in a patient with a previously detected breast
cancer. Although disturbances such as galactorrhoea,
amenorrhea, gynaecomastia, and impotence have been
reported, the clinical significance of elevated serum
prolactin levels is unknown for most patients. An increase
in mammary neoplasms has been found in rodents after
chronic administration of neuroleptic drugs. Neither
clinical studies nor epidemiological studies conducted to
date, however, have shown an association between chronic
administration of these drugs and mammary tumorigenesis;
the available evidence is considered too limited to be
conclusive at this time (Physician's Desk Reference, 1987).
7.4 Teratogenicity
Rodents given 2 to 20 times the usual maximum human dose of
haloperidol by oral or parenteral routes showed an increase
in incidence of resorption, reduced fertility, delayed
delivery and pup mortality. No teratogenic effect has been
reported in rats, rabbits or dogs at dosages within this
range, but cleft palate has been observed in mice given 15
times the usual maximum human dose. Cleft palate in mice
appears to be a non-specific response to stress or
nutritional imbalance as well as to a variety of drugs, and
there is no evidence to relate this phenomenon to predictable
human risk for most of this agents (Physician's Desk
Reference, 1987).
There are no well controlled studies with haloperidol in
pregnant women. There are reports, however, of cases of limb
malformations observed following maternal use of haloperidol
along with other drugs which have suspected teratogenic
potential during the first trimester of pregnancy. Causal
relationships were not established in these cases. Since
such experience does not exclude the possibility of fetal
damage due to haloperidol; this drug should be used during
pregnancy or in women likely to become pregnant only if the
benefit clearly justifies a potential risk to the fetus
(Physician's Desk Reference, 1987).
7.5 Mutagenicity
No mutagenic potential of haloperidol was found in the Ames
Salmonella microsomal activation assay (Physicians Desk
Reference, 1987).
7.6 Interactions
The use of alcohol with this drug should be avoided due to
possible additive effects and hypotension.
An encephalopathic syndrome (characterised by weakness,
lethargy, fever, tremulousness and confusion, extrapyramidal
symptoms, leucocytosis, elevated serum enzymes, BUN, and FBS)
followed by irreversible brain damage has occurred in a few
patients treated with lithium plus haloperidol. A casual
relationship between these events and the concomitant
administration of lithium and haloperidol has not been
established; however, patients receiving such combination
therapy should be monitored closely for early evidence of
neurological toxicity and treatment discontinued promptly if
such signs appear (Physician's Desk Reference, 1987).
Other reported interactions involve the following drugs and
adverse effects:
Beta-blockers (Severe hypotension or pulmonary arrest).
Methyldopa (Dementia, psychomotor retardation, memory
impairment and inability to concentrate)
Indomethacin (Severe drowsiness and confusion).
(Reynolds, 1989; Ellenhorn & Barceloux, 1988)
7.7 Main adverse effects
In general, the symptoms of overdose would be an exaggeration
of known pharmacological effects and adverse reactions.
Anticholinergic side effects and sedation occur less often
than with aliphatic phenothiazines, but extrapyramidal
reactions are more common. Administration of antidopaminergic
and anticholinergics may worsen or bring forward the onset of
extrapyramidal effects.
Idiosyncratic reaction producing severe drowsiness when used
with indomethacin (Reynolds, 1989; Ellenhorn & Barceloux,
1988).
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
Blood levels do not correlate well with clinical effects in
part because of the large number of active metabolites.
Chlorpromazine appears unstable in plasma but more stable in
erythrocytes.
8.1.1 Sampling and specimen collection
8.1.1.1 Macroscopic and microscopic analysis
8.1.1.2 Toxicological analyses
8.1.1.3 Biological analyses
8.1.1.4 Arterial blood gas analysis
8.1.1.5 Haematological analyses
8.1.1.6 Other (unspecified)
analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Macroscopic and microscopic analysis
8.1.2.2 Toxicological analyses
8.1.2.3 Biochemical analyses
8.1.2.4 Arterial blood gas analysis
8.1.2.5 Haematological analyses
8.1.2.6 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Macroscopic and microscopic analysis
8.1.3.2 Toxicological analyses
8.1.3.3 Biochemical analyses
8.1.3.4 Arterial blood gas analysis
8.1.3.5 Haematological analyses
8.1.3.6 Other (unspecified) analyses
8.2 Toxicological analyses and their interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple qualitative test(s)
8.2.1.2 Advanced qualitative confirmation test(s)
8.2.1.3 Simple quantitative method(s)
8.2.1.4 Advanced quantitative method(s)
8.2.2 Tests on biological specimens
8.2.2.1 Simple qualitative test(s)
Phenistix testing of the urine also may suggest
the presence of phenothiazines. The
persistence of the positive violet colour upon
addition of 50% H2SO4 to the strip confirms the
presence of phenothiazines.
The ferric chloride urine test also is a quick
qualitative screen for phenothiazines (25 mg of
phenothiazine per 100 ml of urine is necessary
for a positive reaction). The 10% ferric
chloride solution should be kept in a dark
bottle in a dark cabinet.
One millilitre of urine added to 10 to 15 drops
of 10% ferric chloride solution will yield a
deep burgundy, port wine colour if sufficient
phenothiazines are present.
8.2.2.2 Advanced qualitative confirmation test(s)
8.2.2.3 Simple quantitative method(s)
The Forrest colorimetric test provides a
relative quick semi-quantitative urine
screening test for phenothiazines (test
solution: 20 parts 5% ferric chloride; 80 parts
10% sulphuric acid).
Performance of test: mix 1 ml urine with 1 ml
test solution: read within 20 seconds.
Resulting test colours and daily dosage (mg)
Pink Purple Dark blue Dark grey
+ ++ +++ ++++
100-300 300-600 600-900 > 900
8.2.2.4 Advanced quantitative method(s)
8.2.2.5 Other dedicated method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Blood, plasma or serum
Serum electrolytes, glucose, creatine kinase should be
performed in symptomatic patients.
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.2 Urine
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
Monitor arterial blood gases in particular with
respiratory symptoms with malignant hyperthermia.
8.3.3 Haematological analyses
Serial blood counts should be performed, especially in
patients who have history of prolonged use.
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
Continuous ECG monitoring should be performed for patients
with suspected or overt cardiac arrhythmia.
8.5 Overall interpretation of all toxicological analyses and
toxicological investigations
Chlorpromazine has produced haematological disorders,
including agranulocytosis, eosinophilia, leucopenia,
haemolytic anaemia, aplastic anaemia, thrombocytopenic
purpura and pancytopenia.
Hyperglycaemia, hypoglycaemia and glycosuria have also been
reported.
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
In general, the symptoms of overdosage would be an
exaggeration of known pharmacologic effects and adverse
reactions, the most prominent of which would be as
follows:
Coma with respiratory depression and hypotension which
could be severe enough to produce a shock-like state.
The extrapyramidal reaction would be manifest by
muscular weakness or rigidity and a generalized or
localized tremor.
Paradoxical effects such as hypertension or agitation
may occur, especially in children.
(Physician's Desk Reference, 1987)
Note: While overdosage is likely to occur with a
parenteral rather than with an oral medication,
information pertaining to haloperidol is presented,
modified only to reflect the extended duration of
action of haloperidol decanoate.
9.1.2 Inhalation
Not relevant
9.1.3 Skin exposure
Not relevant
9.1.4 Eye contact
Not relevant
9.1.5 Parenteral exposure
Usually iatrogenic with signs and symptoms similar to
oral except that the decanoate salt has a prolonged
duration of action.
9.1.6 Other
9.2 Chronic poisoning
9.2.1 Ingestion
Chronic poisoning by ingestion may induce neurological
syndromes, the most severe of which are parkinsonism,
akathisia and tardive dyskinesia (Reynolds, 1989).
9.2.2 Inhalation
Not relevant
9.2.3 Skin exposure
Not relevant
9.2.4 Eye contact
Not relevant
9.2.5 Parenteral exposure
No data available
9.2.6 Other
Not relevant
9.3 Course, prognosis, cause of death
Cases of sudden and unexpected death have been reported in
association with the administration of haloperidol. The
nature of the evidence makes it impossible to determine
definitively what role, if any, haloperidol played in the
outcome of the reported cases. The possibility that
haloperidol caused death cannot, of course, be excluded, but
it is to be kept in mind that sudden and unexpected death may
occur in psychotic patients when they go untreated or when
they are treated with other neuroleptic drugs (Reynolds,
1993).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Cardiac arrhythmia, hypotension, hypertension and ECG
changes are usually secondary to acute overdose
(Reynolds, 1989; Physician's Desk Reference, 1987).
9.4.2 Respiratory
In acute overdose, respiratory depression secondary to
CNS depression is common.
Laryngospasm and bronchospasm have been reported
(Physician's Desk Reference, 1987).
Bronchopneumonia can occur and is commonly due to
aspiration.
It has been postulated that lethargy and decreased
sensation of thirst due to central inhibition may lead
to dehydration, haemoconcentration and reduced
pulmonary ventilation.
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
Acute
Acute effects include CNS depression, coma,
acute dystonia. Neuroleptic malignant syndrome
can occur after acute overdose or chronic
therapy.
Extrapyramidal reactions
Neuromuscular (extrapyramidal) reactions during
the administration of haloperidol have been
reported frequently, often during the first few
days of treatment.
In most patients, these reactions involved
Parkinson-like symptoms which, when first
observed, were usually reversible. Other types
of neuromuscular reactions such as motor
restlessness, dystonia and tardive dystonia,
akathisia, hyperreflexia, opisthotonos,
oculogyric crises have been reported far less
frequently, but were often more severe.
Severe extrapyramidal reactions have been
reported to occur at relatively low doses.
Generally the occurrence and severity of most
extrapyramidal symptoms are dose related since
they occur at relatively high doses and have
been shown to disappear or become less severe
when the dose is reduced.
As with all antipsychotic agents haloperidol
has been associated with persistent dyskinesia.
Tardive dyskinesia, a syndrome consisting of
potentially irreversible, involuntary,
dyskinetic movements, may appear in some
patients on long-term therapy or may occur
after drug therapy has been discontinued. The
risk appears to be greater in elderly patients
on high dose therapy, especially females. The
symptoms are persistent and in some patients
appear irreversible. The syndrome is
characterized by rhythmical involuntary
movements of tongue, face, mouth or jaw (e.g.
protrusion of tongue, puffing of cheeks of
mouth, chewing movements). Sometimes these may
be accompanied by involuntary movements of
extremities.
It has been reported that fine vermicular
movement of the tongue may be an early sign of
the syndrome and if the medication is stopped
at that time the syndrome may not develop.
9.4.3.2 Peripheral nervous system
Not relevant
9.4.3.3 Autonomic nervous system
Dry mouth, blurred vision, urinary retention
and diaphoresis. This is an important
component of neuroleptic malignant syndrome.
9.4.3.4 Skeletal and smooth muscle
(see 9.4.3.1 and 9.4.14)
9.4.4 Gastrointestinal
Anorexia, constipation, hypersalivation, dyspepsia,
nausea and vomiting.
9.4.5 Hepatic
Impaired liver function and/or jaundice have been
reported.
9.4.6 Urinary
9.4.6.1 Renal
Urinary retention can occur in acute overdose
and chronic haloperidol administration.
9.4.6.2 Other
No data available
9.4.7 Endocrine and reproductive systems
Endocrine disorders may occur with chronic treatment.
Lactation, breast engorgement, mastalgia, menstrual
irregularities, gynaecomastia, impotence, increased
libido, hyperglycaemia, hypoglycaemia and
hyponatraemia.
9.4.8 Dermatological
Maculopapular and acneiform skin reactions and isolated
cases of photosensitivity and loss of hair have been
reported in chronic therapy.
9.4.9 Eye, ear, nose, throat: local effects
Cataracts, retinopathy and visual disturbances (PDR,
1987).
9.4.10 Haematological
In chronic therapy there are rare reports of mild
haematological abnormalities, usually transient
leucopenia or leucocytosis.
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available
9.4.12.2 Fluid and electrolyte disturbances
No data available
9.4.12.3 Others
Decreased serum cholesterol has been reported
(Physician's Desk Reference, 1987).
9.4.13 Allergic reactions
Maculopapular and acneiform skin reactions and
isolated cases of photosensitivity.
9.4.14 Other clinical effects
Neuroleptic Malignant Syndrome
As with other neuroleptic drugs, a symptom complex
sometimes referred to as neuroleptic malignant syndrome
(NMS) has been reported. Cardinal features of NMS are
hyperpyrexia, muscle rigidity, altered mental status
(including catatonic signs), and evidence of autonomic
instability (irregular pulse or blood pressure).
Additional signs may include elevated CPK,
myoglobinuria (rhabdomyolysis) and acute renal failure.
NMS is potentially fatal, requires intensive
symptomatic treatment discontinuation of neuroleptic
treatment.
Hyperpyrexia and heat stroke, not associated with the
above symptom complex, have also been reported.
Cases of photosensitivity have been reported.
9.4.15 Special risks
Pregnancy
There are no adequate well-controlled studies in
pregnant women. There are reports, however, of two
cases of limb malformations observed following
maternal use of haloperidol along with other drugs
which have suspected teratogenic potential during the
first trimester of pregnancy. Use with caution in
pregnancy or in women likely to become pregnant only
if the benefit clearly justifies a potential risk to
the fetus.
Breast-feeding
Since haloperidol is excreted in human breast milk,
infants should not be nursed during drug treatment
with haloperidol.
9.5 Other
Withdrawal Emergent Neurological Signs
Generally, patients receiving short term therapy
experience no problems with abrupt discontinuation of
antipsychotic drugs. However, some patients on maintenance
treatment experience transient dyskinetic signs after abrupt
withdrawal. In certain of these cases the dyskinetic
movements are indistinguishable from the syndrome described
under "Tardive Dyskinesia" except for duration. It is not
known whether gradual withdrawal of antipsychotic drugs will
reduce the rate of occurrence of withdrawal emergent
neurological signs but until further evidence becomes
available, it seems reasonable to withdraw the use of
haloperidol gradually.
Insomnia, restlessness, anxiety, euphoria, agitation,
drowsiness, depression, lethargy, headache, confusion,
vertigo, grand mal seizures, exacerbation of psychotic
symptoms including hallucinations, and catatonic-like
behavioural states may occur which may be responsive to drug
withdrawal and/or treatment with anticholinergic drugs.
9.6 Summary
Not relevant.
10. MANAGEMENT
10.1 General principles
In acute overdosage the mainstay of treatment is supportive
care. Patients with a history of significant neuroleptic
ingestion should receive gut decontamination, and
monitoring of vital signs and ECG. Symptomatic patients
(e.g. hypotension, conduction delay, dysrhythmia) should be
admitted until the ECG is normal for 24 hours. Asymptomatic
patients can be released after a 4 hour observation period.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Collect urine and blood samples for toxicology and
biomedical analysis.
10.2.2 Biomedical analysis
10.2.3 Toxicological analysis
Blood levels do not correlate well with clinical
effects.
10.2.4 Other investigations
ECG monitoring.
10.3 Life supportive procedures and symptomatic/specific
treatment
Patients with vital signs or cardiac abnormalities should
receive cardiac monitoring. Hypotension is the most common
sign and should initially be treated with plasma expanders.
Additional appropriately titrated doses of dopamine may be
required. Pure beta agonists are contraindicated because
they may worsen the hypotension.
In cases of arrhythmia, correction of acidosis,
hypokalaemia and hypoxia should be done. Intractable
ventricular dysrhytmias ("torsades de pointes") may require
overdrive pacing, or isoprenaline infusion if precipitated
by bradycardia.
Tardive Dyskinesia
Once this syndrome has developed, treatment is difficult.
About 50% of patients may eventually recover if the
neuroleptics are withdrawn. Anticholinergic drugs used in
acute dystonic reactions do not improve this condition and
in fact may worsen it. The use of diltiazem in doses up to
360 mg daily has been associated with immediate clinical
improvement lasting for weeks in an initial study (Ross et
al., 1987).
Thermal Dysregulation
Hypothermia invariably is mild unless the patient has been
exposed to low ambient temperature; it is usually
responsive to measures used to correct other vital signs
and to passive rewarming. True hyperthermia represents a
greater risk and the development of the neuroleptic
malignant syndrome requires prompt treatment. Careful
attention should be directed toward maintaining fluid and
electrolyte balance and controlling seizures. Cooling
blankets or ice packs are helpful but antipyretics probably
are not. Haloperidol and other anticholinergic drugs
should be stopped. The development of myoglobinuria
indicates the need for alkaline diuresis to prevent acute
tubular necrosis.
For malignant hyperthermia, dantrolene may be administered
at an initial intravenous dose of 2.5 mg/kg up to a maximum
of 10 mg/kg/day. (See the IPCS antidote monograph on
dantrolene for more details). Monitor arterial blood gases
(PO2, pH) serum electrolytes, glucose and creatine kinase
carefully. Bromocriptine may be required. Patients should
receive appropriate hydration.
Seizures
Diazepam and phenytoin are the anticonvulsant drugs of
choice. Persistence of seizures for an hour is an
indication for intubation, curarization, and thiopental
general anaesthesia. Urine myoglobin and serum muscle
enzyme levels should be checked in all patients with
prolonged muscle rigidity or seizures.
Acute Dystonic reactions
Intravenous diphenhydramine (2 mg/kg up to 50 mg over
several minutes) and intramuscular benztropine mesylate (2
mg in adults) are the drugs of choice and should relieve
symptoms in 5 and 15 to 20 minutes respectively. Mild
sedation is the main side effect. Follow up treatment with
an anticholinergic agent (e.g. diphenhydramine 50 mg oral
three times daily or trihexylphenidyl 2 mg oral twice
daily) should be given over 2 to 3 days because of the long
half-life of major tranquillizers. Doses of benztropine
mesylate exceeding 8 mg in one day should be avoided
because of the possibility of severe anticholinergic
symptoms. Haloperidol should be discontinued.
Akathisias and Parkinsonianlike syndrome
These may be relieved by reduction of the dose, or addition
or antiparkinsonian drugs (e.g. benztropine). Often
akathisias appear resistant to anticholinergic drugs and
benzodiazepines. Recent trial of low dose propranolol
suggest that beta adrenergic blockers may be efficacious
(Adler, 1986).
10.4 Decontamination
Haloperidol delays gastric emptying. Obtunded patients
theoretically may benefit from gastric decontamination up
to several hours post-ingestion. However, lavage is
generally not recommended later than 2 hours following
ingestion. Instead, activated charcoal should be given and
may be repeated later.
10.5 Elimination
Because of the high protein binding and large volumes of
distribution, haemodialysis and forced diuresis are
ineffective. Haemoperfusion has not been well studied, but
is unlikely to be efficacious.
10.6 Antidote treatment
10.6.1 Adults
There are no antidotes.
10.6.2 Children
There are no antidotes.
10.7 Management discussion
In the absence of any specific antidote the mainstay of
treatment is supportive care. Physostigmine has been used
to treat the effects of mixed phenothiazine and tricyclic
antidepressants (Weisdorf, 1978), but its use is
controversial and is not recommended, due to serious
adverse reactions.
Gut decontamination (where appropriate), and monitoring
vital signs and ECG are recommended. Symptomatic patients
(e.g. hypotension, conduction delay, dysrthythmia) should
be admitted until the ECG is normal for 24 hours.
Appropriate therapy (as per section 10.3) to counter the
adverse effects is also recommended.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Case 1
A 29-month-old girl ingested an indeterminate amount out of
53 x 5 mg haloperidol tablets and was admitted with
impaired consciousness, hypotension, and general
hypotonia.Intravenous mannitol was given to increase
diuresis. 12 hours after admission she showed signs of
bradycardia, sinus arrhythmia and hypothermia, as well as
tremor and rigidity of the upper extremities, unsteady gait
and dystonic movements around the eyelids and mouth.
Diphenhydramine intravenously partly relieved the dystonic
movements. Symptoms resolved without sequelae 4 days after
admission. (Scialli et al, 1978).
Case 2
11-month-old boy (brother of girl in Case 1) also ingested
an indeterminate amount out of 53 x 5 mg haloperidol
tablets and showed symptoms of bradycardia, arrhythmia,
hypothermia and hypotension as well as impaired
consciousness and rigidity of the extremities with
hyperreflexia. Generalised tremors developed, with
flushing, hypersalivation and cogwheel rigidity in all
extremities. Intravenous diphenhydramine improved the
symptomology and the patient was symptom free after 7
days.(Scialli & Thornton, 1978).
Case 3
Report of severe arrhythmia and mild parkinsonism in a
patient treated for mania with high dose haloperidol (90 mg
the first day, 60 mg second day and 10 mg the third day).
The patient was treated with lidocaine (lignocaine),
followed by procainamide and on day 13 the ECG was normal
and mild parkinsonism was still evident. (Mehta et al.,
1979)
Case 4
Brief clinical report of latent onset of hypertension in
22-month-old girl who had swallowed 15 to 20 mg of
haloperidol and had developed systolic pressures up to 180
mm Hg after 8 hours after admission. After 5 days of
antihypertensive therapy (hydrallazine) the patient had
recovered. (Cummingham & Challapalli, 1979)
Case 4
Sinaniotis et al. (1978) describe 3 cases of young children
(3.5-year-old girl, 6-year-old boy and 5-year-old girl who
had ingested unknown quantities of haloperidol (later
confirmed by spectrophotometric analysis of the blood).
Prominent toxicity features were dysarthric speech,
difficulty in swallowing and extrapyramidal symptoms.
Akathisia was present in one child. Biperiden was
administered to all three patients and in each case the
extrapyramidal symptoms subsided in a few hours.
Case 5
Adverse drug report by the Australian Adverse Drug Reaction
Advisory Committee (ADRAC) of malignant ventricular
tachycardia in a 46-year-old woman treated in hospital with
haloperidol 60 to 100 mg daily for 10 days. Antiarrhythmic
drug (lignocaine) was unsuccessful against the tachycardia
and cardioversion was required. (Bett & Holt, 1983).
Case 6
Report of a 54-year-old hospitalised male who developed the
syndrome of inappropriate secretion of antidiuretic hormone
(SIADH), after taking clinical doses of haloperidol which
led to significant hyponatraemia (Peck & Shenkman, 1979).
Case 7
Suspected idiosyncratic neuroleptic malignant syndrome in a
58-year-old woman who developed sinus tachycardia and
hyperthermia (above 40 0C) accompanied by muscle rigidity
and opisthotonos after a single intramuscular injection of
5 mg of haloperidol. Treatment with oral dantrolene (25 to
150 mg daily) had to be withdrawn after 6 days due to
hepatotoxicity, whilst supportive treatment was continued.
Complete recovery from suspected syndrome after 29 days
(Konikoff et al., 1984)
Case 8
Brief clinical report of a 60-year-old woman with no
history of cardiac disease seen in a hospital emergency
department 30 minutes after ingesting 1000 mg of
haloperidol. Eighteen hours after admission she had several
episodes of torsades de pointes which was successfully
controlled with ventricular overdrive pacing (Zee-Cheng et
al., 1985)
11.2 Internally extracted data on cases
No data available.
11.3 Internal cases
To be completed by each Centre using local data.
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
No antidote is available.
12.2 Specific preventive measures
No data available.
12.3 Other
Not relevant.
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author Dr Julia Higa de Landoni
Division Toxicologia
Hospital de Clinicas San Martin
Avda. Cordoba 2351
1120-Buenos Aires
Argentina
Date 13 August 1992
Peer Review Drs Deng, Ferner, Landoni, Maramba, Shintani &
Wickstrom.
Date and 10 September 1992,
Place