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 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 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. 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See Also: HALOPERIDOL (PIM 253)