Version January 2024
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 and 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was approximately 4.5%, compared with a rate of approximately 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Chlorpromazine is not approved for the treatment of patients with dementia-related psychosis.
Dosage guidance:
Clinical considerations: Generally not a first- or second-line agent due to availability of safer, equally effective alternatives for most indications (Ref).
Agitation/aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia, bipolar disorder) (alternative agent):
Note: Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression; however, chlorpromazine should be reserved for settings where safer parenteral antipsychotics are unavailable (Ref). Avoid in suspected or confirmed intoxications with anticholinergic substances, alcohol withdrawal, or other withdrawal syndromes. Depending on presentation, may combine with a benzodiazepine (Ref). To reduce risk of orthostatic hypotension, patient should be in a supine position with regular BP monitoring during and 30 minutes after administration.
IM: Initial: 25 mg single dose; may give additional 25 to 50 mg in 1 hour based on response and tolerability; may repeat every 4 to 6 hours as needed up to 200 mg/day. Switch to oral therapy as soon as possible.
Bipolar disorder: Acute manic episodes (alternative agent):
Note: Other better tolerated agents are generally preferred; may be considered if preferred agents are unavailable (Ref).
Oral: Initial: 30 to 75 mg/day in 2 to 4 divided doses; may increase dose based on response and tolerability in increments of 20 to 50 mg every ≥3 days to a usual range of 400 to 800 mg/day. Although the manufacturer's labeling states that some patients may require up to 2 g/day, most experts consider 1 g/day to be the maximum dose for this indication (Ref).
Hiccups, prolonged or intractable (alternative agent):
Note: Used for hiccups lasting >48 hours despite physical maneuvers; other better tolerated options may be preferred initially (Ref).
Oral: Initial: 25 mg 3 to 4 times daily; may increase to 50 mg 3 to 4 times daily if needed and tolerated; maximum dose: 200 mg/day (Ref). In patients who may be sensitive to adverse effects (hypotension, sedation) some experts suggest a lower initial dose of 10 mg 3 times daily (Ref).
IM, IV:
Note: If symptoms persist after 2 to 3 days, may consider IM or IV administration. To reduce risk of orthostatic hypotension with IM/IV administration, patient should be in a supine position with regular BP monitoring during and 30 minutes after administration.
IM (refractory to oral route): 25 to 50 mg single dose. Note: If symptoms persist after one IM dose, consider IV route.
IV (refractory to oral and IM route): 25 to 50 mg single dose as a slow IV infusion (maximum rate: 1 mg/minute).
Migraine, severe, acute treatment (alternative agent) (off-label use):
Note: To reduce risk of orthostatic hypotension, patient should be in a supine position with regular BP monitoring during and 30 minutes after infusion. Some experts suggest adjunctive use of an anticholinergic drug (eg, IV diphenhydramine) to prevent akathisia and dystonic reactions (Ref).
IV: 0.1 mg/kg or 12.5 mg single dose as a slow IV infusion (maximum rate: 1 mg/minute); may repeat after 20 minutes if needed and tolerated; maximum cumulative dose: 25 mg (Ref).
Nausea and vomiting, acute self-limiting (alternative agent):
Note: May be considered if preferred agents are unavailable (Ref).
Oral: 10 to 25 mg every 4 to 8 hours as needed; maximum dose: 150 mg/day (Ref).
IM, IV:
Note: To reduce risk of orthostatic hypotension with parenteral administration, patient should be in a supine position with regular BP monitoring during and 30 minutes after administration.
IM: 25 mg single dose; if tolerated, may administer 10 to 25 mg every 3 to 4 hours as needed; maximum dose: 200 mg/day (Ref).
IV (off-label route): 10 to 25 mg by slow infusion (maximum rate: 1 mg/minute); if tolerated, may repeat dose every 3 to 4 hours as needed; maximum dose: 200 mg/day (Ref).
Nausea and vomiting of pregnancy, refractory (alternative agent) (off-label use):
Note: Some experts use short-term in a monitored setting, in conjunction with other agents and supportive measures, as an alternative to corticosteroids in patients in whom steroid side effects may be more serious (Ref).
IM, IV: 25 to 50 mg every 4 to 6 hours; maximum dose: 300 mg/day (Ref). Note: To reduce risk of orthostatic hypotension, patient should be in a supine position with regular BP monitoring during and 30 minutes after infusion.
Oral: 10 to 25 mg every 4 to 6 hours; maximum dose: 150 mg/day (Ref).
Presurgical apprehension (alternative agent):
Note: No longer used due to risk of prolonged sedation and refractory hypotension (Ref) and availability of safer, more rapid-acting sedatives (Ref).
IM: 12.5 to 25 mg, administered 1 to 2 hours before procedure.
Oral: 25 to 50 mg, administered 2 to 3 hours before procedure.
Schizophrenia (alternative agent):
Note: Rarely indicated; may be considered if preferred agents are unavailable (Ref).
Oral: Initial: 25 to 200 mg/day in 2 to 4 divided doses; may increase dose based on response and tolerability in increments of 20 to 50 mg every ≥3 days up to 800 mg/day in 2 to 4 divided doses (Ref). According to the manufacturer's labeling, some patients may require up to 1 to 2 g/day; however, adverse effects may be greater (Ref). Due to safety concerns, some experts consider 800 mg/day to be the maximum acceptable dose for this indication (Ref).
Discontinuation of therapy: In the treatment of chronic psychiatric disease, switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).
Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Ref). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment likely to be necessary for any degree of kidney dysfunction (<1% parent drug excreted unchanged; 21% to 33% excreted as active and inactive metabolites [4% to 8% unconjugated, 14% to 29% conjugated] over a 24-hour period after a single dose (Ref)); use with caution (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (large Vd, highly protein bound): No supplemental dose or dosage adjustment necessary; use with caution (Ref).
Peritoneal dialysis: Unlikely to be dialyzed (large Vd, highly protein bound): No dosage adjustment likely to be necessary (Ref); use with caution.
CRRT: No dosage adjustment likely to be necessary; use with caution (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment likely to be necessary; use with caution (Ref).
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
Oral, IM, IV: Dosages in the lower range of recommended adult dosing are generally sufficient. Titrate dosage slowly and monitor carefully.
Alternative dosing: Psychotic disorders: Routine use is not recommended; however, if used, the following doses have been used:
Oral: Initial: 10 to 25 mg 3 times daily (Ref); titrate dose slowly. Usual dosage range: 50 to 200 mg/day in divided doses (Ref). Mean dosage range: 25 to 75 mg/day in divided doses (Ref). Doses greater than 300 to 400 mg/day are rarely necessary (Ref).
Note: IM administration may be used in the very acutely disturbed patient (Ref). IM doses are approximately 4 times more potent than comparable oral doses (ie, 25 mg IM is approximately equivalent to 100 mg oral) (Ref).
(For additional information see "Chlorpromazine: Pediatric drug information")
Behavior problems; severe (acute agitation): Limited data in adolescents:
Note: Begin with low doses and gradually titrate as needed to lowest effective dose; route of administration should be determined by severity of symptoms.
Recommended for psychiatric emergencies in patients with developmental delay or who have been diagnosed with autism for severe or refractory agitation, in patients with oppositional defiant or conduct disorder, or in suspected ethanol or benzodiazepine intoxication; parenteral may also be appropriate for mania or psychosis (Ref).
Children and Adolescents:
Oral: Initial: 0.55 mg/kg/dose every 4 to 6 hours as needed; however, in trials, most patients responded to a single dose for acute agitation; one trial reported a mean initial dose of 0.53 ± 0.24 mg/kg/dose in patients 6 to 16 years of age (Ref). Hospitalized patients may require dose titration; in severe cases, higher doses may be required in younger children: 50 to 100 mg/day,(Ref) and in older children or adolescents, per manufacturer labeling, higher daily doses (200 mg/day or higher) may be necessary; maximum daily dose: 500 mg/day; daily doses >500 mg have not been shown to further improve behavior in pediatric patients with severe mental impairment.
IM, IV: Initial: 0.28 to 0.55 mg/kg/dose, dose may be repeated every 6 to 8 hours as needed; however, in trials, most patients responded to a single dose for acute agitation (Ref); in adolescents, a usual single dose is 25 mg.
Maximum recommended daily doses:
Children <5 years or weighing <22.7 kg: 40 mg/day.
Children ≥5 years and Adolescents or weighing ≥22.7 kg: 75 mg/day; a maximum total dose of 100 mg has been used (Ref).
Chemotherapy-induced nausea and vomiting (CINV); prevention; adjunctive: Limited data available: Note: Current expert guidelines do not consider chlorpromazine a therapeutic option in the management of chemotherapy induced nausea and vomiting; efficacy data of use in combination with 5-HT3 antagonists is lacking (Ref).
Infants ≥6 months, Children, and Adolescents: IV: Initial: 0.5 mg/kg/dose every 6 hours; if not controlled, may increase up to 1 mg/kg/dose; monitor for sedation, maximum dose: 50 mg; recommended in situations where corticosteroids are contraindicated (Ref).
Cyclic vomiting syndrome; treatment, adjunct therapy: Limited data available: Children, and Adolescents: Oral, IV: 0.5 to 1 mg/kg/dose every 6 to 8 hours; maximum dose: 50 mg; in combination with diphenhydramine (for possible dystonic reactions) (Ref).
Nausea and vomiting, treatment (non-CINV): Note: Current consensus guidelines do not consider chlorpromazine a therapeutic option in the management of postoperative nausea and vomiting (Ref).
Infants ≥6 months, Children, and Adolescents weighing ≤45.5 kg: Oral, IM, IV: 0.55 mg/kg/dose every 6 to 8 hours as needed; in severe cases, higher doses may be needed.
Usual maximum daily dose: IM, IV:
Children <5 years or weighing <22.7 kg: 40 mg/day.
Children ≥5 years and Adolescents or weighing 22.7 to 45.5 kg: 75 mg/day.
Adolescents weighing >45.5 kg:
Oral: 10 to 25 mg every 4 to 6 hours as needed.
IM, IV: Initial: 25 mg; if tolerated (no hypotension), then may give 25 to 50 mg every 4 to 6 hours as needed.
Preoperative sedation, anxiety: Note: Although FDA approved as a preoperative sedative for restlessness and apprehension, use has been replaced by other agents (Ref).
Infants ≥6 months, Children, and Adolescents:
Oral: 0.55 mg/kg/dose once 2 to 3 hours before surgery; maximum dose: 50 mg/dose.
IM: 0.55 mg/kg/dose once 1 to 2 hours before surgery; maximum dose: 25 mg/dose.
Tetanus:
Infants ≥6 months, Children, and Adolescents: IM, IV: 0.55 mg/kg/dose every 6 to 8 hours; usual doses should not exceed 25 to 50 mg/dose; in severe cases, higher doses may be necessary.
Maximum daily dose (usual), weight-directed:
Weight <22.7 kg: 40 mg/day.
Weight 22.7 to 45.5 kg: 75 mg/day.
Adolescents weighing >45.5 kg: 200 mg/day.
Discontinuation of psychosis/severe behavior therapy: Infants ≥6 months, Children, and Adolescents: The manufacturer and American Academy of Child and Adolescent Psychiatry (AACAP), American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), National Institute for Health and Care Excellence (NICE), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (Ref); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Ref). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months and the APA guidelines recommend reducing the dose by 10% each month (Ref). Continuing antiparkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Ref). When switching antipsychotics, three strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited and results are conflicting (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Not dialyzable (0 to 5%).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Chlorpromazine is associated with altered cardiac conduction, including ECG abnormality (nonspecific QT changes), atrial fibrillation, and atrial flutter (Ref).
Mechanism:
• Atrial fibrillation/flutter: Increases cardiac muscarinic blockage causing atrial conduction abnormalities and alters autonomic tone (Ref).
• QT changes: Inhibits the delayed rectifier potassium channel (IKr), which is encoded by the human ether-à-go-go related gene 1 (hERG1), causing lengthening of the action potential of cardiac myocytes, prolonging the QT interval (Ref).
Risk factors:
Drug-induced QTc prolongation/torsades de pointes (TdP) (in general)
• High doses (Ref)
• Females (Ref)
• Age >65 years (Ref)
• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction) (Ref)
• Genetic defects of cardiac ion channels (Ref)
• History of drug-induced TdP (Ref)
• Congenital long QT syndrome (Ref)
• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 milliseconds (Ref)
• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, or hypomagnesemia) (Ref)
• Bradycardia (Ref)
• Hepatic impairment (Ref)
• Kidney impairment (Ref)
• Loop diuretic use (Ref)
• Sepsis (Ref)
Phenothiazines, including chlorpromazine, may cause anticholinergic adverse effects such as cognitive impairment, constipation, mydriasis, urinary retention, and xerostomia. Relative to other antipsychotics, chlorpromazine has a moderate-to-high potency of cholinergic blockade (Ref). Chlorpromazine is included in the Beers Criteria of Potentially Inappropriate Medication Use in Older Adults due to its anticholinergic properties (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, muscarinic receptor antagonism) (Ref).
Risk factors:
• Age ≥65 years (Ref)
• Concurrent use of other anticholinergic agents (Ref)
Skin photosensitivity, photoallergic contact dermatitis, and skin pigmentation (purple to gray pigmentation of sun-exposed areas) have been reported with chlorpromazine. These effects may be transient (photosensitivity, dermatitis) or permanent (some cases of hyperpigmentation) and may lead to nonadherence (Ref).
Mechanism: Photosensitivity is a non-immunologic response resulting in direct tissue injury; photoallergic contact dermatitis is a delayed, immune-mediated hypersensitivity reaction (Ref); hyperpigmentation is thought to be due to deposits of complexes of chlorpromazine and melanin within macrophages in superficial layers of dermis (Ref).
Risk factors:
• Sun exposure (Ref)
• Prolonged therapy with high doses (hyperpigmentation) (Ref)
Drug-induced liver injury, specifically cholestatic jaundice, has been reported with chlorpromazine (Ref). The estimated incidence of chlorpromazine-induced liver injury has been estimated as >100 per 100,000 users (Ref).
Mechanism: Etiologies vary; peripheral eosinophilia and eosinophils on liver biopsy with or without fever and recurrence upon rechallenge have been observed, which suggests an allergic component in some cases (Ref). Liver injury may manifest as a true idiosyncratic reaction; isolated obstructive jaundice or mixed cholestatic and hepatocellular injury may manifest through direct mitochondrial damage by chlorpromazine (Ref).
Onset: Varied; most cases of jaundice were reported between 2 and 5 weeks following therapy initiation (Ref).
Risk factors:
• History of phenothiazine-induced jaundice
• Concurrent use with hepatotoxic agents (Ref)
• Age >70 years (Ref)
• Underlying liver disease (hepatitis, non-alcohol-related fatty liver disease) (Ref)
Extrapyramidal symptoms (EPS), including akathisia, acute dystonia, drug-induced parkinsonism, and tardive dyskinesia, have occurred with the use of chlorpromazine and other dopamine receptor antagonist neuroleptic agents in adults and pediatric patients. Relative to other antipsychotics, chlorpromazine carries a moderate risk of causing EPS (Ref). Symptoms of EPS may be confused with other conditions, such as Reye syndrome or other encephalopathy. EPS presenting as dysphagia, esophageal dysmotility, or aspiration have also been reported with antipsychotics, which may not be recognized as EPS (Ref).
Mechanism: Dose-related; due to antagonism of dopaminergic D2 receptors in nigrostriatal pathways (Ref).
Onset:
Antipsychotics in general:
Acute dystonia: Rapid; in the majority of cases, dystonia usually occurs within the first 5 days after initiating antipsychotic therapy (and even with the first dose, particularly in patients receiving parenteral antipsychotics) or a dosage increase (Ref).
Akathisia: Varied; may begin within several days after antipsychotic initiation but usually increases with treatment duration, occurring within 1 month in up to 50% of cases, and within 3 months in 90% of cases (Ref).
Drug-induced parkinsonism: Varied; onset may be delayed from days to weeks, with 50% to 75% of cases occurring within 1 month and 90% within 3 months of antipsychotic initiation, a dosage increase, or a change in the medication regimen (such as adding another antipsychotic agent or discontinuing an anticholinergic medication) (Ref).
Tardive dyskinesia: Delayed; symptoms usually appear after 1 to 2 years of continuous exposure to a D2 receptor antagonist, and almost never before 3 months, with an insidious onset, evolving into a full syndrome over days and weeks, followed by symptom plateau, and then a chronic waxing and waning of symptoms (Ref).
Esophageal dysfunction (associated with extrapyramidal symptoms): Varied; ranges from weeks to months following initiation (Ref)
Risk factors:
Antipsychotics in general:
EPS (in general):
• Higher doses (Ref)
• Prior history of EPS (Ref)
Acute dystonia:
• Males (Ref)
• Young age (Ref)
• Use of agents with high dopamine D2 receptor affinity (Ref)
• History of acute dystonia (Ref)
• Cocaine use (Ref)
• Pediatric:
- Acute illness (eg, chickenpox, CNS infections, measles, gastroenteritis)
- Dehydration
Akathisia:
• Mood disorders (Ref)
• Females (Ref)
• Older patients (Ref)
Drug-induced parkinsonism:
• Older patients (Ref)
• Females (Ref)
• Dementia (Ref)
• Preexisting movement disorder (Ref)
Tardive dyskinesia:
• Greater total antipsychotic exposure (especially first-generation antipsychotics) (Ref)
• Concomitant treatment with anticholinergic medications (Ref)
• Substance misuse or dependence (Ref)
• Age >55 years (Ref)
• Cognitive impairment (Ref)
• Diabetes (Ref)
• Diagnosis of schizophrenia or affective disorders (Ref)
• Females (Ref)
• History of extrapyramidal symptoms (Ref)
Esophageal dysfunction (associated with EPS):
• Certain comorbidities such as neurologic degenerative disease, dementia, stroke, Parkinson disease, or myasthenia gravis (Ref)
• Older adults >75 years of age (may be risk factor due to age-related muscle atrophy, cognitive impairment, reduced esophageal peristalsis) (Ref)
Leukopenia, neutropenia, and agranulocytosis have been reported rarely with chlorpromazine (Ref).
Mechanism: Not well understood; proposed mechanisms include peripheral cytotoxicity, cell division-mediated bone marrow suppression, and immunologic effects (Ref).
Onset: Varied; most cases have occurred between 4 and 10 weeks following therapy initiation; however, onset may be insidious. In one case report, neutropenia developed within one week (Ref).
Risk factors:
• Preexisting low WBC
• History of drug-induced leukopenia/neutropenia
All antipsychotics are associated with metabolic syndrome, which is comprised of significant weight gain (increase of ≥7% from baseline), hyperglycemia, diabetes mellitus, dyslipidemia, and hypertension. Although metabolic abnormalities are usually associated with second generation (atypical) antipsychotics, the syndrome also occurs in varying degrees with first generation (typical) antipsychotics, including chlorpromazine (Ref).
Mechanism: Not entirely understood; likely multifactorial. Multiple mechanisms have been proposed, including actions at serotonin, dopamine, histamine, and muscarinic receptors, with differing effects explained by variations in affinity of antipsychotics at these receptors (Ref).
Onset: Weight gain: Varied; antipsychotic-induced weight gain usually occurs rapidly in the initial period following initiation, then rate of weight gain gradually decreases and plateaus over several months with patients continuing to gain weight in the long term (Ref).
Risk factors:
Weight gain:
• Family history of obesity (Ref)
• Parental BMI (Ref)
• Children and adolescents (Ref)
• Rapid weight gain in the initial period: Younger age, lower baseline BMI, more robust response to antipsychotic and increase in appetite; rapid weight gain of >5% in the first month has been observed as the best predictor for significant long-term weight gain (Ref)
• Duration of therapy (although weight gain plateaus, patients continue to gain weight over time) (Ref)
• Schizophrenia, regardless of medication, is associated with a higher prevalence of obesity compared to the general population (Ref)
• Specific antipsychotic: Chlorpromazine is associated with a moderate to high propensity for causing weight gain (Ref)
Lipid/glucose metabolism abnormalities:
• Specific antipsychotic: Chlorpromazine is associated with a high risk of causing lipid and/or glucose metabolism abnormalities (Ref)
Older adults treated with antipsychotics are at an increased risk of death compared to placebo. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infections (eg, pneumonia) in nature (Ref).
Mechanism: Unknown; possible mechanisms include arrhythmia, cardiac arrest, stroke, and extrapyramidal effects that may increase the risk of falls, aspirations, and pneumonia (Ref).
Risk factors:
• Antipsychotic class (a higher risk of mortality has been observed for first-generation antipsychotics compared to second-generation antipsychotics (Ref)
• Higher antipsychotic dosage (Ref)
• Dementia-related psychosis (eg, Lewy body dementia, Parkinson disease dementia)
All antipsychotics have been associated with neuroleptic malignant syndrome (NMS) in all ages. First-generation antipsychotic-associated NMS seems to occur at a higher frequency, severity, and lethality compared to second-generation antipsychotic-associated NMS (Ref). There are numerous reports of NMS occurring with chlorpromazine, either as monotherapy or in combination with other medications (Ref).
Mechanism: Non–dose-related; idiosyncratic. Believed to be due to antagonism of D2 receptors within the nigrostriatal, hypothalamic, and mesolimbic pathways, along with the dysregulation of autonomous nervous system activity (Ref).
Onset: In general, most patients develop NMS within 2 weeks of initiating an antipsychotic, and in some patients, prodromal symptoms emerge within hours of initiation; once the syndrome starts, the full syndrome usually develops in 3 to 5 days (Ref).
Risk factors
• Antipsychotic class: First-generation antipsychotics seem to have a higher risk of NMS compared to second-generation antipsychotics (Ref)
• Males (twice as likely to develop NMS compared to females) (Ref)
• Prolonged heat exposure, dehydration (Ref)
• High-dose antipsychotic treatment (Ref)
• Rapid dose escalation (Ref)
• Concomitant lithium or benzodiazepine (Ref)
• Catatonia (Ref)
• Polypharmacy (Ref)
• Pharmacokinetic interactions (Ref)
• Parenteral administration (Ref)
• Psychomotor agitation (Ref)
Phenothiazines, including chlorpromazine, may cause orthostatic hypotension (Ref). Orthostatic hypotension may increase the risk for falls in older patients; this risk may be augmented by the sedative effects of chlorpromazine. Symptoms typically last for up to 2 hours, although occasionally, effects may be more severe and prolonged.
Mechanism: Dose-related; related to the pharmacologic action (ie, alpha-1 adrenergic receptor blockade) (Ref).
Onset: Rapid; may occur after the first oral or parenteral dose, and may continue to occur occasionally after subsequent parenteral doses.
Risk factors:
• Higher doses (Ref)
• Parenteral administration (Ref)
• Concurrent use of thiazide diuretics or other medications which increase risk of orthostatic hypotension
• Concomitant alcohol use
• Older patients (Ref)
• Mitral insufficiency
• Pheochromocytoma
Sedated state and drowsiness are common with chlorpromazine and may cause nonadherence, impair physical and/or mental abilities, and may result in subsequent falling (Ref). Most patients tolerate sedation within one week of therapy initiation (Ref).
Mechanism: Sedation is primarily attributed to H1 antagonism; chlorpromazine is thought to have high affinity for H1 receptors (Ref).
Onset: Rapid; within 15 minutes following parenteral administration and within 2 hours following oral administration has been reported (Ref).
Risk factors:
• Higher doses (Ref)
• Concomitant use of other agents which cause CNS depression
Chlorpromazine is associated with dose-dependent seizure, including tonic-clonic seizure, and may cause EEG pattern changes (Ref). Compared to other first-generation (typical) antipsychotics, chlorpromazine has a high risk of inducing seizures (Ref).
Mechanism: Dose-related (exact dose-relationship is unclear); exact mechanism is unknown, although a role of dopamine has been suggested (Ref)
Onset: Varied; EEG pattern changes occurring 15 minutes following injection have been reported (Ref). Seizures have been reported within 3 to 36 days following oral administration (Ref).
Risk factors:
Antipsychotics in general:
• High doses (Ref)
• Drug-drug interactions (Ref)
• Concurrent use of other drugs that lower the seizure threshold (Ref)
• Rapid dose titration or sudden increase in dose (Ref)
• History of seizure activity or abnormal EEG (Ref)
• Organic brain disorders (Ref)
• Metabolic factors (Ref)
• Preexisting risk factors for seizures (ie, alcoholism, head trauma, brain damage) (Ref)
Antipsychotics may impair the body's ability to regulate core body temperature, which may cause a potentially life-threatening heat stroke during predisposing conditions, such as heat wave or strenuous exercise.
Risk factors:
Heat stroke (antipsychotics in general):
• Psychiatric illness (regardless of medication use) (Ref)
• Dehydration (Ref)
• Strenuous exercise (Ref)
• Heat exposure (Ref)
• Concomitant medications possessing anticholinergic effects (Ref)
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Frequency not defined:
Gastrointestinal: Atony of colon, constipation, nausea, obstipation, paralytic ileus, xerostomia
Genitourinary: Ejaculatory disorder, impotence, priapism, urinary retention
Nervous system: Parkinsonism, restlessness
Neuromuscular & skeletal: Dystonia, tardive dyskinesia, tardive dystonia
Ophthalmic: Miosis, mydriasis
Respiratory: Nasal congestion
Postmarketing:
Cardiovascular: Atrial fibrillation (Chou 2017), atrial flutter (Chou 2017), ECG abnormality (nonspecific QT changes), orthostatic hypotension (White 1986), peripheral edema, syncope (White 1986)
Dermatologic: Contact dermatitis (Esteve-Martinez 2015), cutaneous lupus erythematosus (Pavlidakey 1985), exfoliative dermatitis, skin photosensitivity (Montgomery 2022), skin pigmentation (Greiner 1964), toxic epidermal necrolysis (Purcell 1996)
Endocrine & metabolic: Amenorrhea, diabetes mellitus (Cooperberg 1956), gynecomastia, hyperglycemia (Lambert 1972), hypoglycemia, weight gain (Baptista 2004)
Genitourinary: Glycosuria
Hematologic & oncologic: Agranulocytosis (Lambert 2022), aplastic anemia, eosinophilia (Hartnett 1955), hemolytic anemia (Cooperberg 1956), immune thrombocytopenia, leukopenia (Lambert 2022), neutropenia (Burckart 1982), pancytopenia (McKinney 1967)
Hepatic: Jaundice (including cholestatic jaundice) (Dusi 2019)
Hypersensitivity: Angioedema, drug reaction with eosinophilia and systemic symptoms (Gowda 2020), nonimmune anaphylaxis
Nervous system: Abnormal proteins in cerebrospinal fluid, brain edema, catatonic-like state, cognitive impairment (Solmi 2017), drowsiness (Solmi 2017), EEG pattern changes (Fabisch 1957), hyperpyrexia, neuroleptic malignant syndrome (Mahmood 1989), psychotic symptoms, sedated state (Solmi 2017), seizure (Hedges 2003)
Neuromuscular & skeletal: Akathisia (Solmi 2017), lupus-like syndrome (Pavlidakey 1985)
Ophthalmic: Corneal deposits (Molina-Ruiz 2016), corneal opacity (Molina-Ruiz 2016), epithelial keratopathy (Johnson 1966), lens disease (deposits) (Molina-Ruiz 2016), retinitis pigmentosa, star-shaped cataract
Respiratory: Asthma, laryngeal edema
Hypersensitivity to phenothiazines (cross-reactivity between phenothiazines may occur); concomitant use with large amounts of CNS depressants (alcohol, barbiturates, opioids, etc); comatose states
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Hyperprolactinemia: Use associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.
Disease-related concerns:
• GI motility: Use with caution in patients with decreased GI motility or pyloroduodenal obstruction as anticholinergic effects may exacerbate underlying condition.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Mehrizi 2012).
• Ophthalmic conditions: Use with caution in patients with certain ophthalmic conditions (eg, narrow angle glaucoma, visual problems) as anticholinergic effects may exacerbate underlying condition.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution in patients with respiratory disease (eg, severe asthma, emphysema) due to potential for CNS effects.
• Reye syndrome: Avoid use in patients with signs/symptoms suggestive of Reye syndrome.
• Urinary tract conditions: Use with caution in patients with urinary retention, benign prostatic hyperplasia (BPH), or bladder neck obstruction, as anticholinergic effects may exacerbate underlying condition.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
• Sulfites: Injection contains sulfites.
Other warnings/precautions:
• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).
EPS occurring with chlorpromazine should be differentiated from possible CNS syndromes which may also cause vomiting (eg, Reye’s syndrome, encephalopathy); avoid use in pediatric patients whose clinical presentation is suggestive of Reye's syndrome.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Concentrate, Oral:
Generic: 30 mg/mL (120 mL); 100 mg/mL (240 mL)
Solution, Injection, as hydrochloride:
Generic: 25 mg/mL (1 mL); 50 mg/2 mL (2 mL)
Tablet, Oral, as hydrochloride:
Generic: 10 mg, 25 mg, 50 mg, 100 mg, 200 mg
Yes
Concentrate (chlorproMAZINE HCl Oral)
30 mg/mL (per mL): $5.04 - $5.25
100 mg/mL (per mL): $10.80 - $11.25
Solution (chlorproMAZINE HCl Injection)
25 mg/mL (per mL): $34.67
50 mg/2 mL (per mL): $19.86
Tablets (chlorproMAZINE HCl Oral)
10 mg (per each): $4.20 - $5.25
25 mg (per each): $6.25 - $11.10
50 mg (per each): $9.46 - $15.05
100 mg (per each): $14.62 - $22.25
200 mg (per each): $18.31 - $33.12
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Generic: 25 mg, 50 mg, 100 mg
IV: For direct IV injection, administer diluted solution slow IV at a rate not to exceed 1 mg/minute. For the treatment of intractable hiccups, infuse as a slow IV infusion. To reduce the risk of hypotension, patients receiving IV chlorpromazine must remain lying down during and for 30 minutes after the injection.
IM: Inject slowly, deep into upper outer quadrant of buttock. Do not administer SubQ (tissue damage and irritation may occur).
Note: Avoid skin contact with solution; may cause contact dermatitis.
Oral concentrate: Mix with ≥60 mL of a carbonated beverage, coffee, fruit or tomato juice, milk, orange syrup, simple syrup, tea, or water; may also add to semisolid food (eg, pudding, soup).
Oral: Administer with water, food, or milk to decrease GI upset; brown precipitate may occur when chlorpromazine is mixed with caffeine-containing liquids.
Parenteral: Administer IM or IV. Do not administer SubQ (tissue damage and irritation may occur). Note: Avoid skin contact with solution; may cause contact dermatitis.
IM: Administer undiluted as deep IM injection into outer buttock quadrant.
IV: Administer diluted solution slow IV at a rate not to exceed 0.5 mg/minute in children and 1 mg/minute in adults. To reduce the risk of hypotension, patients receiving IV chlorpromazine must remain lying down during and for 30 minutes after the injection.
Agitation/aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia, bipolar disorder): Treatment of agitation and aggression related to bipolar disorder, schizophrenia, and other psychotic disorders.
Behavioral problems: Treatment of severe behavioral problems in children 1 to 12 years of age marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations).
Bipolar disorder: Treatment of manic episodes associated with bipolar disorder.
Hiccups, prolonged or intractable: Treatment of intractable hiccups.
Hyperactivity: Short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressiveness, mood lability, and poor frustration tolerance.
Nausea and vomiting, acute self-limiting: Management of nausea and vomiting. Also used off label as an alternative agent for refractory nausea and vomiting of pregnancy (ACOG 2018).
Presurgical apprehension: Relief of restlessness and apprehension prior to surgery.
Schizophrenia: Treatment of schizophrenia and psychotic disorders.
Tetanus: Adjunctive therapy in the treatment of tetanus.
Limitation of use: Generally not a first- or second-line agent due to availability of safer, equally effective alternatives for most indications (Jibson 2020).
Migraine, severe, acute treatment; Nausea and vomiting of pregnancy
ChlorproMAZINE may be confused with chlordiazePOXIDE, chlorproPAMIDE, clomiPRAMINE, prochlorperazine, promethazine
Thorazine may be confused with thiamine, thioridazine
Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years due to an increased risk of stroke and a greater rate of cognitive decline and mortality in patients with dementia. Evidence also suggests there may be an increased risk of mortality with use independent of dementia. Avoid antipsychotics for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. In addition, antipsychotics should be used with caution in older adults because of their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults. Use of antipsychotics may be appropriate for labeled indications including schizophrenia, bipolar disorder, Parkinson disease psychosis, adjunctive therapy in major depressive disorder, or for short-term use as an antiemetic (Beers Criteria [AGS 2023]).
KIDs List: Dopamine antagonists, when used in pediatric patients <18 years of age, are identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided in infants and used with caution in children and adolescents due to risk of acute dystonia (dyskinesia), and with intravenous administration an increased risk of respiratory depression, extravasation, and death (strong recommendation; moderate quality of evidence) (PPA [Meyers 2020]).
Substrate of CYP1A2 (minor), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Agents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Amiodarone: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Amiodarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Amisulpride (Oral): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride (Oral). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even greater risk. Risk D: Consider therapy modification
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antimalarial Agents: May increase the serum concentration of ChlorproMAZINE. Risk C: Monitor therapy
Anti-Parkinson Agents (Dopamine Agonist): May diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible. If antipsychotic use is necessary, consider using atypical antipsychotics such as clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Arsenic Trioxide: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Arsenic Trioxide. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Asenapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Astemizole: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Astemizole. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bedaquiline: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Bedaquiline. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Beta-Blockers: Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy
Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination
Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Carbetocin: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Cariprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Chlorprothixene: Anticholinergic Agents may enhance the anticholinergic effect of Chlorprothixene. Risk C: Monitor therapy
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination
Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Risk X: Avoid combination
Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Risk X: Avoid combination
Clofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
ClomiPRAMINE: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Clothiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
CloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Dabrafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Dasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Desmopressin: ChlorproMAZINE may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Risk X: Avoid combination
Doxepin-Containing Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Doxepin-Containing Products. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy
Dronedarone: May enhance the QTc-prolonging effect of ChlorproMAZINE. Risk X: Avoid combination
DroPERidol: May enhance the CNS depressant effect of ChlorproMAZINE. DroPERidol may enhance the QTc-prolonging effect of ChlorproMAZINE. Management: Consider alternatives to this drug combination. If combined, dose reductions are recommended. Monitor for additive toxicities such as QTc interval prolongation, ventricular arrhythmias, and CNS depression. Risk D: Consider therapy modification
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
Escitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Etelcalcetide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Fexinidazole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
Fingolimod: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Flecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Fluconazole: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluconazole. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fluorouracil Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Risk X: Avoid combination
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
Gemifloxacin: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Gilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modification
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination
Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy
Halofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Haloperidol: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Iloperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Imipramine: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Levofloxacin-Containing Products (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Levoketoconazole: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination
Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapy
Lofexidine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Lofexidine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Loxapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lumateperone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lurasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Meglumine Antimoniate: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modification
Methadone: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for extrapyramidal symptoms and excessive sedation may be increased. Risk C: Monitor therapy
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Midostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: Monitor therapy
Mivacurium: ChlorproMAZINE may enhance the therapeutic effect of Mivacurium. Risk C: Monitor therapy
Molindone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Risk X: Avoid combination
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. Risk X: Avoid combination
Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
OLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Ondansetron: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Osimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Oxytocin: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Pacritinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pacritinib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Paliperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
PAZOPanib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of PAZOPanib. Risk X: Avoid combination
Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Periciazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Perphenazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Pimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk X: Avoid combination
Pipamperone [INT]: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pipamperone [INT]. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Risk X: Avoid combination
Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid combination
Polyethylene Glycol-Electrolyte Solution: ChlorproMAZINE may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Polyethylene Glycol-Electrolyte Solution may decrease the absorption of ChlorproMAZINE. Management: Give oral chlorpromazine at least 2 hours before or at least 6 hours after polyethylene glycol-electrolyte solutions that contain magnesium sulfate (Suflave brand). Other products without magnesium do not require dose separation. Monitor for seizures. Risk D: Consider therapy modification
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid combination
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination
Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Risk X: Avoid combination
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Promazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Propafenone: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Propofol: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Miscellaneous Agents (Highest Risk): May enhance the QTc-prolonging effect of ChlorproMAZINE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Risk X: Avoid combination
QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Risk X: Avoid combination
Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quizartinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination
Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Risk X: Avoid combination
RisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modification
Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Risk X: Avoid combination
Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: Avoid combination
SUNItinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of SUNItinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Terbutaline: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for NMS and extrapyramidal symptoms may be increased. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Thiopental: Antipsychotic Agents (Phenothiazines) may enhance the adverse/toxic effect of Thiopental. Risk C: Monitor therapy
Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Thiothixene: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination
Tobacco (Smoked): May decrease the serum concentration of ChlorproMAZINE. Risk C: Monitor therapy
Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy
Toremifene: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Toremifene. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Triptorelin: Hyperprolactinemic Agents may diminish the therapeutic effect of Triptorelin. Risk X: Avoid combination
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valproate Products: ChlorproMAZINE may increase the serum concentration of Valproate Products. Risk C: Monitor therapy
Vemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Jaundice or hyper- or hyporeflexia have been reported in newborn infants following maternal use of phenothiazines. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.
Chlorpromazine may be considered for the adjunctive treatment of nausea and vomiting in pregnant women. Use is reserved for women with dehydration when symptoms persist following preferred pharmacologic therapies (ACOG 189 2018).
Chlorpromazine and its metabolites are present in breast milk; concentrations may be higher than what is in the maternal plasma. Drowsiness and lethargy were observed in a breastfed infant (Wiles 1978). Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.
Mental status; vital signs (as clinically indicated); weight, height, BMI, waist circumference (baseline; at every visit for the first 6 months; quarterly with stable antipsychotic dose); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); fasting plasma glucose level/HbA1c (baseline, then yearly; in patients with diabetes risk factors or if gaining weight, repeat 4 months after starting antipsychotic, then yearly); lipid panel (baseline; repeat every 2 years if LDL level is normal; repeat every 6 months if LDL level is >130 mg/dL); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (at each visit for the first 12 weeks after the antipsychotic is initiated or until the dose is stable, then yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 6 months; high-risk patients every 3 months); visual changes (inquire yearly); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA, 2004; Lehman, 2004; Marder, 2004); fall risk (baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk); symptoms of neuroleptic malignant syndrome (eg, fever, muscle rigidity, autonomic instability).
Timing of serum samples: Draw trough just before next dose (Hiemke 2018).
Therapeutic reference range: 30 to 300 ng/mL (SI: 94.2 to 942 nmol/L) (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations; however, therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).
Laboratory alert level: 600 ng/mL (SI 1,884 nmol/L) (Hiemke 2018).
Chlorpromazine is an aliphatic phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits a strong alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones; believed to depress the reticular activating system, thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis
Onset of action: Oral:
Bipolar disorder, acute mania: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).
Schizophrenia: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).
Duration: Oral: 4 to 6 hours
Absorption: Oral: Rapid and virtually complete; large first-pass effect due to metabolism during absorption in the GI mucosa
Distribution: Widely distributed into most body tissues and fluids; crosses blood-brain barrier
Vd: IV (Yeung 1993):
Single dose: Mean: 15.7 L/kg (range: 9.03 to 37.1 L/kg)
Steady state: Mean: 8.38 L/kg (range: 5.08 to 14 L/kg)
Protein binding: 92% to 97%
Metabolism: Extensively hepatic by demethylation (followed by glucuronide conjugation) and amine oxidation to active and inactive metabolites
Bioavailability: Oral: ~32%
Half-life, biphasic: Initial: Children: 1.1 hours; Adults: ~2 hours; Terminal: Children: 7.7 hours; Adults: ~30 hours
Excretion: Urine (<1% as unchanged drug) within 24 hours
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