MONOGRAPH FOR UKPID CHLORPROMAZINE HYDROCHLORIDE 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 Chlorpromazine hydrochloride Chemical group Phenothiazine Origin Synthetic Name UK Brand name(s) Largactil(R), Chloractil(R) Synonyms Common names Product licence number Largactil(R) 10mg: 0012/5108R Largactil(R) 25mg: 0012/5109R Largactil(R) 50mg: 0012/5110R Largactil(R) 100mg: 0012/5111R Largactil(R) injection solution 2.5%: 0012/5308R Largactil(R) syrup: 0012/5083R Largactil(R) Forte Suspension: 0012/5001R CAS number 69-09-0 Manufacturer Rhône-Poulenc Rorer Ltd, RPR House, 50 Kings Hill Ave., Kings Hill, West Malling, Kent, ME19 4AH. Tel. no. 01732 584000 Fax. no. 01732 584086 Available as Largactil(R) from Rhône-Poulenc Rorer, and as generics or branded generics from Antigen, APS, DDSA (Chloractil(R)), Hillcross, Rosemont and Norton. Form Tablets Oral liquids Injection Suppositories Formulation details Tablets of 10 mg, 25 mg, 50 mg, and 100 mg Syrup containing 25 mg / 5 ml Forte suspension equivalent to 100 mg/5 ml (as chlorpromazine embonate) Injection of 25 mg / ml. Suppositories of 100 mg (unlicensed product) Pack size Largactil tabs 10 mg, 25 mg, 50 mg, and 100 mg - blister packs of 56 Largactil syrup - 100ml pack Largactil forte suspension - 100ml pack Largactil injection - ampoules of 1 ml and 2 ml Pack sizes may differ for generics and branded generics. Packaging Largactil(R) tabs 10mg - white tablets marked LG10 Largactil(R) tabs 25mg - white tablets marked LG25 Largactil(R) tabs 50mg - white tablets marked LG50 Largactil(R) tabs 100mg - white tablets marked LG100 Chemical structure C17H19ClN2S.HCl Chemical name 3-(2-Chlorophenothiazin-10-yl)propyldimethylamine hydrochloride Indication Schizophrenia and other psychoses, (especially paranoid and hypomania); short-term adjunctive management of anxiety, psychomotor agitation, excitement, and violent or dangerously impulsive behaviour; intractable hiccup; nausea and vomiting of terminal illness (where other drugs have failed or are not available); induction of hypothermia; childhood schizophrenia and autism. Therapeutic dosage - adults BY MOUTH: 75-300 mg daily in divided doses (doses up to 1 g used in psychoses). BY DEEP IM INJECTION: 25-50 mg every 6-8 hours. BY RECTUM (unlicensed route): 100 mg every 6-8 hours. For equivalent therapeutic effect: 100 mg by rectum ° 20-25 mg by IM injection ° 40-50 mg by mouth Therapeutic dosage - children BY MOUTH: 1-5 years: 500 micrograms/kg 4-6 hourly (maximum 40 mg daily). 6-12 years: _ to ´ adult dose (maximum 75 mg daily). BY DEEP IM INJECTION: 500 micrograms/kg 6-8 hourly with maximum daily dose as for oral dose. BY RECTUM (unlicensed route): 1-4 years: 12.5 mg 3-4 hourly. 5-12 years: 25 mg 3-4 hourly. over 12 years: 50-100 mg 3-4 hourly. Contra-indications Coma caused by CNS depressants, bone marrow depression, phaeochromocytoma. Abuses Epidemiology Although the phenothiazines show similar toxic properties to the tricyclic antidepressants, overdoses tend to be less serious, with severe hypotension and cardiotoxicity being less common. (Ellenhorn 1997). ADVERSE EFFECTS There are a large number of adverse effects associated with therapeutic use including changes in hepatic, cardiovascular, respiratory, haematologic, ocular and endocrine functions, besides extrapyramidal reactions and the risk of neuroleptic malignant syndrome. Postural hypotension commonly occurs, especially after intramuscular administration. INTERACTIONS PHARMACODYNAMIC 1. Chlorpromazine enhances the central nervous system depression produced by other CNS DEPRESSANT drugs. 2. The hypotensive effect of ANTIHYPERTENSIVE AGENTS is likely to be enhanced, the exception being GUANETHIDINE where chlorpromazine may antagonise its hypotensive effect (Fruncillo 1985, Janowsky 1973). 3. There is an increased risk of ventricular arrhythmias when chlorpromazine is taken with drugs that increase the QT interval e.g. ASTEMIZOLE, TERFENADINE, or ANTI-ARRHYTHMIC AGENTS. 4. Combination with other antidopaminergic agents such as METOCLOPRAMIDE or PROCHLORPERAZINE increases the risk of extrapyramidal effects. PHARMACOKINETIC 1. The metabolism of TRICYCLIC ANTIDEPRESSANTS is impaired by chlorpromazine, increasing the risk of toxicity (Balant-Gorgia & Balant 1987). OTHER An interaction between phenothiazine drugs and 'caffeinated' beverages has been reported. A precipitation occurs when these drugs are diluted in tea or coffee (including decaffeinated varieties) which is considered to be a nonspecific reaction between the nitrogen-containing organic bases and tannic acid. The reaction is reversible in the acid environment of the stomach (Curry et al. 1991). ETHANOL The administration of ethanol with chlorpromazine results in potentiated sedative effects and impaired co-ordination (Lieber 1994, Milner & Landauer 1971, Zirkle 1959). MECHANISM OF ACTION Chlorpromazine blocks post-synaptic D2 dopamine receptors. It is considered that dopamine receptor blockade in the mesolimbic area accounts for the antipsychotic effect, whilst blockade in the nigrostriatal system produces the extrapyramidal effects associated with chlorpromazine use. The anti-emetic effect results from dopamine antagonism in the chemoreceptor trigger zone. Chlorpromazine also possesses antimuscarinic properties. It is an antagonist at histamine (H1), serotonin and alpha-1-adrenergic receptors (Dollery 1991). MECHANISM OF TOXICITY The extrapyramidal, anticholinergic, sedative, and hypotensive features of toxicity result from the blockade of dopaminergic, muscarinic, histaminic, and alpha adrenergic receptors respectively. The cardiotoxic effects of phenothiazines in overdose are similar to that of the tricyclic antidepressants. (Ellenhorn 1997). Cardiac arrhythmia and apparent 'sudden death' have been associated with therapeutic doses of chlorpromazine, the sudden cardiovascular collapse being attributed to ventricular dysrhythmia (Fowler et al. 1976, Hollister & Kosec 1965). Pharmacokinetics ABSORPTION Peak plasma concentrations occur on average 2-3 hours (range 1.5-8 hours) after an oral dose (Midha et al. 1989, Yeung et al. 1993). After intramuscular injection chlorpromazine is slowly absorbed from the injection site, with the peak plasma concentration occurring 6-24 hours after administration (Dahl & Strandjord 1977). The oral bioavailability of chlorpromazine is about 30% that of intramuscular doses (Dahl & Strandjord 1977) and about 10% that of intravenous doses (Yeung et al. 1993) as a result of pre-systemic metabolism. DISTRIBUTION Chlorpromazine is highly lipid soluble and is 98% bound to plasma proteins (Dollery 1991). It is extensively distributed throughout the body and has a mean volume of distribution of 17 L/kg (Yeung et al. 1993). METABOLISM Chlorpromazine is subject to significant pre-systemic metabolism attributed to first passage through the gut wall, liver and lung (Yeung et al. 1993). It is extensively metabolised involving cytochrome P450 microsomal pathways (Lieber 1994) with more than 100 metabolites being theoretically possible (Javaid 1994). The major routes of metabolism include hydroxylation, N-oxidation, sulphoxidation, demethylation, deamination and conjugation (Dollery 1991). A number of the metabolites may contribute to the pharmacological effects of chlorpromazine including 7-hydroxychlorpromazine, chlorpromazine-N-oxide, 3-hydroxychlorpromazine and desmethylchlorpromazine (Chetty et al. 1994). Although the metabolite chlorpromazine-N-oxide does not possess activity in vitro, it exerts an indirect pharmacological effect in vivo by reverting to chlorpromazine (Cheng & Jusko 1993). It is considered that one of the metabolites produced (chlorpromazine-sulphoxide) may oppose the alpha-adrenergic blocking action of chlorpromazine (Chetty et al. 1994). There is limited evidence to suggest that following multiple doses, the metabolism of chlorpromazine may be increased due to induction of microsomal liver enzymes (Dahl & Strandjord 1977). ELIMINATION Excretion is primarily via the kidneys with less than 1% of a dose excreted as unchanged drug in the urine, and 20-70% as conjugated or unconjugated metabolites (Dollery 1991). 5-6% of a dose is excreted in faeces via biliary elimination (Dollery 1991). Some metabolites can still be detected up to 18 months after discontinuation of long-term therapy (Dollery 1991). HALF-LIFE The half-life of chlorpromazine is usually within the range 8-35 hours (Dollery 1991), although it is as short as 2 hours or as long as 60 hours in some individuals (Midha et al. 1989). The half-lives of the primary metabolites are generally within the same range (Yeung et al. 1993). Special populations ELDERLY: it has been suggested that the elderly metabolise antipsychotic drugs more slowly than do the non-elderly adult population (Balant-Gorgia & Balant 1987). RENAL IMPAIRMENT: the effects of renal disease on chlorpromazine pharmacokinetics are not known, but since it is extensively metabolised in the liver, they are not anticipated to be great. HEPATIC IMPAIRMENT: it is considered that hepatic dysfunction will increase the bioavailability of chlorpromazine and delay its elimination (Dollery 1991). GENDER: Breast milk Chlorpromazine has been identified in the milk of nursing mothers receiving the drug. In one study (Blacker et al. 1962) the peak milk concentration of chlorpromazine (0.29 mg/L) occurred 2 hours after a single oral dose of 1200 mg, although in this report the assay design was relatively nonspecific and no account was taken of active metabolites. In a later study chlorpromazine and several metabolites were identified in the breast milk of four nursing mothers receiving the drug (doses not specified). The milk concentrations ranged from 0.007-0.098 mg/L, with maternal serum levels ranging from 0.016-0.052 mg/L. In two of the four patients the milk concentrations of chlorpromazine were higher than the maternal plasma concentrations. One of the babies was reported to be drowsy and lethargic (the milk chlorpromazine level in this case was 0.092 mg/L) (Wiles et al. 1978). Toxicokinetics Absorption Distribution Metabolism Elimination HALF-LIFE HALF-LIFE - METABOLITES Special populations ELDERLY: RENAL IMPAIRMENT: HEPATIC IMPAIRMENT: GENDER: Breast milk Summary TYPE OF PRODUCT A phenothiazine antipsychotic. INGREDIENTS Tablets of 10 mg, 25 mg, 50 mg, and 100 mg. Oral liquids containing 25 mg / 5 ml, and 100 mg / 5 ml. Injection of 25 mg / ml. Suppositories of 100 mg (unlicensed product). SUMMARY OF TOXICITY Central nervous system depression is the most common feature of toxicity and usually begins 1-2 hours after ingestion. Hypotension and anticholinergic symptoms are also common. Acute dystonic reactions and cardiac arrhythmias may occur. Chlorpromazine lowers the seizure threshold (a dose-related effect) so convulsions may occur in patients not previously known to be epileptic. Individual response to chlorpromazine overdose is variable - an ingestion of 20 g has been survived, whilst 2 g has proved fatal. In children, hypotension and drowsiness can follow doses ranging from 100-375 mg, with severe central nervous system depression resulting from higher doses. Fatalities have been reported in children, the doses ingested ranging from 20-74 mg/kg. In mixed drug ingestions chlorpromazine enhances the sedation produced by other central nervous system depressants including ethanol. FEATURES Drowsiness, hypotension, anticholinergic symptoms (e.g. dry mouth, dilated pupils, urinary retention, visual disturbances), acute dystonic reactions, and cardiac arrhythmias. UNCOMMON FEATURES Acute pulmonary oedema, and neuroleptic malignant syndrome. SUMMARY OF MANAGEMENT 1. Maintain a clear airway and adequate ventilation if consciousness is impaired. 2. If within 1 hour of the ingestion and more than 500mg has been ingested by an adult, or more than 4mg/kg by a child, give oral activated charcoal. 3. Monitor the cardiac rhythm. 4. Manage hypotension with IV fluids. 5. Treat acute dystonic reactions with IV procyclidine or benztropine. Clinical Features Features - acute Ingestion Hypotension, sinus tachycardia, varying degrees of CNS depression, blurred vision, dry mouth, urinary retention, acute dystonic reactions, akathisia, parkinsonism, ECG changes including prolonged PR and QT intervals, ventricular tachyarrhythmias, convulsions, hypothermia (or occasionally hyperthermia), pulmonary oedema, and respiratory depression (Allen et al. 1980, Barry et al. 1973, Ellenhorn 1997, Li & Gefter 1992, Reid & Harrower 1984). Inhalation Dermal Contact dermatitis. 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 muscle rigidity, hyperthermia, altered consciousness, and autonomic instability), and tardive dyskinesia (involuntary movements of the tongue, face, jaw, or mouth) (Rosenberg & Green 1989). Inhalation Dermal Contact dermatitis. Ocular Other routes BY INJECTION: as for chronic ingestion. At risk groups ELDERLY Elderly and volume depleted subjects are particularly susceptible to postural hypotension. PREGNANCY The administration of chlorpromazine near term has been associated with unpredictable falls in maternal blood pressure which could be dangerous to the mother and the foetus. Administration near term has also resulted in an extrapyramidal syndrome in some infants, characterised by tremors, increased muscle tone, and hyperactive deep tendon reflexes persisting some months (Briggs 1994). One psychiatric patient who ingested 8 g of chlorpromazine in the last ten days of pregnancy, delivered a hypotonic, lethargic infant with depressed reflexes and jaundice (Hammond & Toseland 1970). CHILDREN ENZYME DEFICIENCIES ENZYME INDUCED Occupations Pharmacists, nurses, and other health workers should avoid direct contact with chlorpromazine due to a risk of contact sensitisation. Tablets should not be crushed and solutions handled with care (BNF 1998). Others RENAL IMPAIRMENT: renal impairment is unlikely to increase the risk of toxicity. HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired metabolism and hepatotoxic potential. 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 the ingestion, and more than 500mg has been ingested by an adult, or 100mg by a child, oral activated charcoal may be given to reduce drug absorption. ADULT DOSE: 50g; CHILD DOSE; 1g/kg. If the patient is drowsy this should be administered via a nasogastric tube, and if there is no gag reflex present, using an endotracheal tube to protect the airway. Supportive care GENERAL MANAGEMENT OF THE SYMPTOMATIC PATIENT Clear and maintain airway, and give cardiopulmonary resuscitation if necessary. Evaluate the patient's condition and provide support for vital functions. The aim is to maintain vital bodily functions with minimal intervention whilst the elimination of chlorpromazine takes place. Particular care should be given to the prevention of hypoxia and acidosis, and the correction of any electrolyte imbalance. SPECIFIC MANAGEMENT OF THE SYMPTOMATIC PATIENT 1. 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) 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: vasopressors with mixed alpha and beta adrenergic effects (e.g. adrenaline, dopamine) should not be used as hypotension may be exacerbated. 2. COMA Good supportive care is essential. 3. CARDIOTOXICITY In practice it is seldom necessary or advisable to use specific drug treatment for arrhythmias. If hypoxia and acidosis are reversed, and adequate serum potassium levels maintained, then the majority of patients will show improvement with supportive measures. Where these measures fail and life-threatening arrhythmias persist, intravenous sodium bicarbonate should be given (even in the absence of acidosis) before considering antiarrhythmic drug therapy. Where an antiarrhythmic is considered necessary, lignocaine is the preferred drug. ADULT DOSE: 50-100 mg lignocaine by IV bolus given over a few minutes, followed by an infusion of 4 mg/minute for 30 minutes, 2 mg/minute for 2 hours, then 1 mg/minute (BNF 1998). NOTE: the use of quinidine, procainamide, flecainide, or disopyramide, is contraindicated as these agents further depress cardiac conduction and contractility. The use of beta-blockers and calcium channel blockers should also be avoided as they decrease cardiac output and exacerbate hypotension. The ventricular arrhythmia, TORSADE DE POINTES, may prove difficult to manage. The preferred treatment is cardiac overdrive pacing, but in cases where cardiac pacemaker insertion is not readily available, intravenous magnesium sulphate has been shown to be effective (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). Torsade de pointes has also been successfully managed in adults by the intravenous administration of 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). However it should be used with caution as its beta-2-adrenergic agonist effects exacerbate hypotension. 4. 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, and oral: ADULT DOSE: 5-10 mg (use lower end of dose range in elderly), CHILD DOSE under 2 years: 500 micrograms-2 mg (unlicensed indication) 2-10 years: 2-5 mg (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). 5. SEIZURES/MUSCLE SPASMS Diazepam by slow intravenous injection preferably in emulsion form, may be given to control muscle spasms and convulsions not remitting spontaneously. ADULT DOSE: 10 mg repeated as required depending upon clinical condition; CHILD DOSE: 200 - 300 micrograms/kg. 6. 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. 7. NEUROLEPTIC MALIGNANT SYNDROME The development of neuroleptic malignant syndrome 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: 1 mg/kg body weight by rapid IV injection repeated as required to a cumulative maximum of 10 mg/kg (BNF 1998). 8. OTHER MEASURES Pulmonary oedema typically resolves with conventional supportive management within 18-40 hours of ingestion (Li & Gefter 1992). Monitoring Monitor the heart rate and rhythm, blood pressure, arterial blood gases, serum electrolytes, body temperature, respiratory rate and depth, and urinary output. Observe for a minimum of 4 hours post-ingestion where: i) more than 4 mg/kg has been ingested by a child (or more than the child's normal therapeutic dose, if this is greater), ii) more than 500 mg is known to have been ingested by an adult (or more than the patients's normal therapeutic dose, if this is greater), iii) the patient is symptomatic. Where symptoms develop following overdose, they may persist for 24 hours. Complications following severe toxicity may require the patient to be hospitalised for several days. Antidotes None available. Elimination techniques Haemodialysis and diuresis are ineffective as ways of increasing drug elimination due to the large volume of distribution and high lipid solubility of chlorpromazine. It is not considered that haemoperfusion will be of benefit (Ellenhorn 1997). Investigations Where there is evidence of severe toxicity a chest radiograph should be performed within 24 hours of the ingestion to exclude pulmonary complications. 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 A 27 year old woman was admitted 12 hours after ingesting 8 g chlorpromazine and 150 mg flurazepam. After 18 hours she was fully alert and normotensive. Six hours later she sustained a cardiac arrest and was successfully resuscitated. Subsequent ventricular tachycardia responded to intravenous lignocaine, and a prolonged QT interval shortened progressively to normal over the next three days (Reid & Harrower 1984). Analysis Agent/toxin/metabolite Several studies to determine the relationship between plasma concentration and therapeutic response have been performed. The majority of studies showed large individual variations in chlorpromazine concentration relative to dose, and no clear association between plasma concentration and therapeutic response has been made (Dahl & Strandjord 1977). As a consequence the measurement of plasma chlorpromazine concentrations following overdose is not routinely advised. Sample container Storage conditions Transport Interpretation of data Although no clear relationship exists between plasma concentration and therapeutic effect, it has been suggested that therapeutic response may be associated with the plasma concentration range 0.05-0.30 mg/L (Rivera-Calimlim et al. 1976). In a study of unexplained deaths in patients receiving multiple antipsychotic therapy, five cases had concentrations of antipsychotic drugs which were considered 'probably' toxic and were implicated in the development of ventricular fibrillation. The plasma chlorpromazine concentrations in these cases were in the range 0.5-7.0 mg/L (Jusic & Lader 1994). Conversion factors 1 mg/L = 2.817 micromoles/L 1 micromole/L = 0.355 mg/L The molecular weight of chlorpromazine hydrochloride is 355.3 Others Toxicological data Carcinogenicity Genotoxicity Mutagenicity Reprotoxicity Teratogenicity Chlorpromazine readily crosses the placenta. Although one study found an increased incidence of malformations in first trimester phenothiazine-exposed infants compared to non-exposed controls (3.5%compared to 1.6%), most reports describing the use of phenothiazines in pregnancy (during all stages of gestation) conclude that they do not adversely affect the foetus or newborn (Briggs 1994). 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 November 1996 Updated May 1998 References Allen MD, Greenblatt DJ, Noel BJ. Overdosage with antipsychotic agents. Am J Psychiatry 1980; 137: 234-236. Balant-Gorgia AE, Balant L. Antipsychotic drugs - clinical pharmacokinetics of potential candidates for plasma concentration monitoring. Clin Pharmacokinet 1987; 13: 65-90. Barry D, Meyskens FL, Becker CE. 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