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 References AHFS. AHFS, (American Hospital Formulary Service), Drug Information. Bethesda MD: American Society of Health-System Pharmacists, 1996. Aunsholt NA. Prolonged Q-T interval and hypokalemia caused by haloperidol. Acta Psychiatr Scand 1989; 79: 411-412. Beresford R, Ward A. 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