ChlorproMAZINE

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

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; V_d: 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)

Metabolism

Extensively hepatic by demethylation (followed by glucuronide conjugation) and amine oxidation to active and inactive metabolites

Excretion

Urine (<1% as unchanged drug) within 24 hours

Onset of Action

IM: 15 minutes; Oral: 30 to 60 minutes; Antipsychotic effects: Gradual, may take up to several weeks; Maximum antipsychotic effect: 6 weeks to 6 months

Duration of Action

Oral: 4 to 6 hours

Half-Life Elimination

Biphasic: Initial: Children: 1.1 hours; Adults: ~2 hours; Terminal: Children: 7.7 hours; Adults: ~30 hours

Protein Binding

92% to 97%

Use: Labeled Indications

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: 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/Vomiting: Management of nausea and vomiting.

Porphyria, acute intermittent: Treatment of acute intermittent porphyria.

Schizophrenia/Psychotic disorders: Treatment of schizophrenia and psychotic disorders.

Surgery: Management of restlessness and apprehension prior to surgery.

Tetanus: Adjunctive therapy in the treatment of tetanus.

Use: Off Label

Nausea and vomiting of pregnancyyes

Based on the American College of Obstetricians and Gynecologists (ACOG) Nausea and Vomiting in Pregnancy guidelines, the use of chlorpromazine may be considered for adjunctive treatment of nausea and vomiting in pregnant women. Use is reserved for women with dehydration when symptoms persist following preferred pharmacologic therapies.

Psychosis/agitation associated with dementiayes

Based on the American Psychiatric Association (APA) practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia, antipsychotics, such as chlorpromazine, may be considered for the treatment of agitation and psychosis in certain patients with dementia; however evidence for efficacy is modest and use should be limited to patients whose symptoms are dangerous, severe, or cause significant patient distress due to safety risks associated with antipsychotic use. Additionally, the guidelines recommend giving preference to second generation antipsychotics over first generation antipsychotics like chlorpromazine in elderly patients with dementia-related psychosis due to a potentially greater risk of harm relative to second generation antipsychotics.

Contraindications

Hypersensitivity to phenothiazines (cross-reactivity between phenothiazines may occur); concomitant use with large amounts of CNS depressants (alcohol, barbiturates, opioids, etc); comatose states

Dosage and Administration

Dosing: Adult

Bipolar disorder/psychotic disorders/schizophrenia:

Oral: Range: 30 to 800 mg daily in 2 to 4 divided doses, initiate at lower doses and titrate as needed; usual dose: 200 to 800 mg daily; some patients may require 1 to 2 g daily, however, therapeutic gain is limited at doses >1 g daily

IM: Initial: 25 mg, may give additional 25 to 50 mg in 1 hour if needed. Based on response and tolerability, may gradually increase subsequent IM doses over several days; usual dosage 200 mg/day (Man 1973)

Intractable hiccups:

Oral: 25 to 50 mg 3 to 4 times daily

IM (refractory to oral treatment): 25 to 50 mg; Note: If symptoms persist after one dose, administer IV dose.

IV (refractory to oral or IM treatment): 25 to 50 mg via slow IV infusion with patients lying flat in bed. Monitor blood pressure.

Nausea and vomiting:

Oral: 10 to 25 mg every 4 to 6 hours as needed

IM: Initial: 25 mg; if no hypotension occurs, can administer 25 to 50 mg every 3 to 4 hours as needed until vomiting stops

During surgery: Initial: 12.5 mg; repeat in 30 minutes if necessary and if no hypotension occurs

IV (during surgery): 2 mg per fractional injection at 2 minute intervals using a 1 mg/mL solution; do not exceed 25 mg

Nausea and vomiting of pregnancy, refractory (off-label use) (ACOG 189 2018):

IV, IM: 25 to 50 mg every 4 to 6 hours

Oral: 10 to 25 mg every 4 to 6 hours

Porphyria, acute intermittent:

Oral: 25 to 50 mg 3 to 4 times daily; usually may be discontinued after several weeks although maintenance therapy may be necessary

IM: 25 mg 3 or 4 times daily (until patient can tolerate oral administration)

Presurgical apprehension:

Oral: 25 to 50 mg 2 to 3 hours prior to surgery

IM: 12.5 to 25 mg 1 to 2 hours prior to surgery

Tetanus:

IM: 25 to 50 mg 3 or 4 times daily; titrate to response

IV: 25 to 50 mg

Discontinuation of therapy: The manufacturer and American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (APA [Lehman 2004]; Cerovecki 2013; CPA [Addington 2005]; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). 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 (APA [Lehman 2004]; CPA [Addington 2005]). Continuing anti-parkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). 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 (Cerovecki 2013; Remington 2005).

Dosing: Geriatric

Oral, IM, IV: Dosages in the lower range of recommended adult dosing are generally sufficient. Titrate dosage slowly and monitor carefully.

Alternate dosing: Psychotic disorders: Oral: Routine use is not recommended; however, if used, the following doses have been used: Initial: 10 to 25 mg 3 times daily (Denham 1980; Gareri 2003; Salzman 2005); titrate dose slowly. Usual dosage range: 50 to 200 mg daily in divided doses (Salzman 2005). Mean dosage range: 25 to 75 mg daily in divided doses (Gareri 2003). Doses greater than 300 to 400 mg/day are rarely necessary (Denham 1980). Note: IM administration may be used in the very acutely disturbed patient (Denham 1980). IM doses are approximately 4 times more potent than comparable oral doses (ie, 25 mg IM is approximately equivalent to 100 mg oral) (Salzman 2005).

Psychosis/agitation associated with dementia (off-label use): Oral: Initial: One-third to one-half the usual dose to treat psychosis in younger adults or the smallest available dosage. In patients without a clinically significant response after 4 weeks, taper and withdraw therapy. In patients with an adequate response, attempt to taper and withdraw therapy within 4 months, unless symptoms recurred with a previous taper attempt. Assess symptoms at least monthly during taper and for at least 4 months after withdrawal of therapy (APA [Reus 2016]).

Dosing: Pediatric

Behavior problems; severe: Note: Begin with low doses and gradually titrate as needed to lowest effective dose; route of administration should be determined by severity of symptoms.

Infants ≥6 months, Children, and Adolescents weighing ≤45.5 kg:

Oral: Initial: 0.55 mg/kg/dose every 4 to 6 hours as needed; may titrate as required; in severe cases, higher doses may be required (50 to 100 mg/day); in older children, 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: 0.55 mg/kg/dose every 6 to 8 hours as needed; may titrate as required in severe cases (Kliegman 2007)

Maximum recommended daily doses:

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: Range: 30 to 800 mg/day in 2 to 4 divided doses, initiate at lower doses and titrate as needed; usual dose is 200 mg/day

IM, IV: 25 mg initially, may repeat (25 to 50 mg) in 1 to 4 hours, gradually increase to a maximum of 400 mg/dose every 4 to 6 hours until patient controlled; usual dose 200 to 800 mg/day (Kliegman 2007)

Nausea and vomiting, treatment (non-CINV):

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

Chemotherapy-induced nausea and vomiting (CINV); prevention: 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 (Dupuis 2013)

Cyclic vomiting syndrome; abortive therapy: Infants ≥6 months, Children, and Adolescents: IV: 0.5 to 1 mg/kg/dose every 6 hours; maximum dose: 50 mg; in combination with diphenhydramine (for possible dystonic reactions) (Li 2008)

Delirium, ICU associated: Limited data available (Silver 2010): Infants ≥6 months, Children, and Adolescents:

Oral: 2.5 to 6 mg/kg/day divided every 4 to 6 hours

Maximum daily dose:

Children ≤5 years: 50 mg/day

Children >5 years and Adolescents: 200 mg/day

IM: 2.5 to 4 mg/kg/day divided every 6 to 8 hours; maximum daily dose: 40 mg/day

Preoperative sedation, anxiety: Infants ≥6 months, Children, and Adolescents:

Oral: 0.55 mg/kg/dose once 2 to 3 hours before surgery; maximum dose: 50 mg

IM: 0.55 mg/kg/dose once 1 to 2 hours before surgery; maximum dose: 25 mg

Tetanus:

Infants ≥6 months, Children, and Adolescents weighing ≤45.5 kg: IM, IV: 0.55 mg/kg/dose every 6 to 8 hours; in severe cases higher doses may be needed

Usual maximum daily dose:

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: IM, IV: 25 to 50 mg every 6 to 8 hours; begin with low dose and increase gradually based upon patient response

Discontinuation of pyschosis/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 (AACAP [McClellan 2007]; APA [Lehman 2004]; Cerovecki 2013; CPA 2005; NICE 2013; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). 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 (APA [Lehman 2004]; CPA 2005). Continuing antiparkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). 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 (Cerovecki 2013; Remington 2005).

Reconstitution

Direct IV injection: Dilute with NS to a maximum concentration of 1 mg/mL.

IV: For treatment of intractable hiccups the manufacturer recommends diluting 25 to 50 mg of chlorpromazine in 500 to 1000 mL NS.

Administration

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.

Storage

Oral: Store at 20°C to 25°C (68°F to 77°F); protect from light and moisture.

Injection solution: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light and freezing. A slightly yellowed solution does not indicate potency loss, but a markedly discolored solution should be discarded.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). 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. Consider therapy modification

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Antimalarial Agents: May increase the serum concentration of Antipsychotic Agents (Phenothiazines). Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). 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. Consider therapy modification

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. Consider therapy modification

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). 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. Consider therapy modification

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. Consider therapy modification

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bepridil: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Bepridil. 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. Consider therapy modification

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. Exceptions: Atenolol; Levobunolol; Metipranolol; Nadolol. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. 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. 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. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of Antipsychotic Agents (Phenothiazines). Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Avoid combination

Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Avoid combination

CloBAZam: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

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. Consider therapy modification

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. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

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. Consider therapy modification

Desmopressin: ChlorproMAZINE may enhance the adverse/toxic effect of Desmopressin. 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. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. 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. 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. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dronedarone: May enhance the QTc-prolonging effect of ChlorproMAZINE. 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. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. 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. Consider therapy modification

Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Avoid combination

Erythromycin (Systemic): QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Erythromycin (Systemic). Erythromycin (Systemic) 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. Consider therapy modification

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. Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). 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. 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. Consider therapy modification

Fluconazole: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluconazole. Fluconazole 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. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Avoid combination

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. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). 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. 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. Consider therapy modification

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. 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. 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. Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

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. 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 anticonvulsants. 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 anticonvulsants. 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 anticonvulsants. Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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. 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. Consider therapy modification

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. 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. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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. 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. 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 adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. 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. Consider therapy modification

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. 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. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. 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. 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. Consider therapy modification

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. 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. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. 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. Consider therapy modification

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

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. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

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. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. 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. Avoid combination

Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. 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. Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. 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. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Avoid combination

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. Consider therapy modification

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. 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. 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. 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. Exceptions: Dronedarone. 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. 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. Exceptions: Arsenic Trioxide; Astemizole; Bedaquiline; Bepridil. Consider therapy modification

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration 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. Exceptions: Erythromycin (Systemic); Fluconazole; Nilotinib; Ribociclib. 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). Exceptions: Clarithromycin. Avoid combination

QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Avoid combination

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Avoid combination

Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. 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. Consider therapy modification

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. 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. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

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. Monitor therapy

Serotonin Reuptake Inhibitor/Antagonists: Antipsychotic Agents (Phenothiazines) may enhance the adverse/toxic effect of Serotonin Reuptake Inhibitor/Antagonists. Specifically, this may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Serotonin Reuptake Inhibitor/Antagonists may enhance the hypotensive effect of Antipsychotic Agents (Phenothiazines). Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sodium Stibogluconate: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sodium Stibogluconate. 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. Consider therapy modification

Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Avoid combination

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination

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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thiopental: Antipsychotic Agents (Phenothiazines) may enhance the adverse/toxic effect of Thiopental. Monitor therapy

Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Avoid combination

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Tobacco (Smoked): May decrease the serum concentration of ChlorproMAZINE. Monitor therapy

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Valproate Products: ChlorproMAZINE may increase the serum concentration of Valproate Products. 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. Consider therapy modification

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. 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. Consider therapy modification

Test Interactions

False-positives for phenylketonuria, amylase, uroporphyrins, urobilinogen. May cause false-positive pregnancy test. May interfere with urine detection of amphetamine/methamphetamine and methadone (false-positives).

Adverse Reactions

Frequency not defined.

Cardiovascular: ECG abnormality (nonspecific QT changes), orthostatic hypotension, syncope, tachycardia

Central nervous system: Brain edema, catatonic-like state, dizziness, drowsiness, dystonia, extrapyramidal reaction, hyperpyrexia, neuroleptic malignant syndrome, parkinsonism, psychotic symptoms, restlessness, tardive dyskinesia, tardive dystonia

Dermatologic: Contact dermatitis, cutaneous lupus erythematosus (Pavlidakey 1985), skin photosensitivity, skin pigmentation (slate gray)

Endocrine & metabolic: Weight gain

Gastrointestinal: Atony of colon, constipation, increased appetite, nausea, obstipation, paralytic ileus, xerostomia

Genitourinary: Breast engorgement, ejaculatory disorder, false positive pregnancy test, impotence, lactation, priapism, urinary retention

Hematologic & oncologic: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, immune thrombocytopenia, leukopenia

Hepatic: Jaundice

Hypersensitivity: Nonimmune anaphylaxis

Neuromuscular & skeletal: Lupus-like syndrome (Pavlidakey 1985)

Ophthalmic: Corneal deposits, lens disease (deposits), miosis, mydriasis, star-shaped cataract, visual impairment

Respiratory: Nasal congestion

Miscellaneous: Low fever

Postmarketing: Abnormal proteins in cerebrospinal fluid, amenorrhea, angioedema, asthma, epithelial keratopathy, exfoliative dermatitis, glycosuria, gynecomastia, hyperglycemia, hypoglycemia, laryngeal edema, pancytopenia, peripheral edema, retinitis pigmentosa, seizure

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: May alter cardiac conduction (life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines). May cause QT prolongation and subsequent torsade de pointes; avoid use in patients with diagnosed or suspected congenital long QT syndrome.
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. Relative to other neuroleptics, chlorpromazine has a moderate potency of cholinergic blockade (Richelson 1999).
• Aspiration of vomit: Because chlorpromazine can suppress the cough reflex, aspiration of vomit is possible.
• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm³.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).
• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical disorders such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman] 2004; Soares-Weisner 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.
• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases, conditions, or on medications that may increase fall risk.
• Hyperprolactinemia: Use associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.
• Hypotension: Significant hypotension may occur, particularly with parenteral administration. May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Neuroleptic malignant syndrome (NMS): May be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability.
• Ocular effects: May cause pigmentary retinopathy, and lenticular and corneal deposits, particularly with prolonged therapy.
• Photosensitivity: Mild urticarial-type rash or photosensitivity may occur; avoid undue exposure to the sun. More severe reactions, including exfoliative dermatitis, have been reported occasionally.
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease.
• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. The APA recommends giving preference to second generation antipsychotics over first generation antipsychotics such as chlorpromazine in elderly patients with dementia-related psychosis due to a potentially greater risk of harm relative to second generation antipsychotics (APA [Reus 2016]). Chlorpromazine is not approved for the treatment of dementia-related psychosis.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• 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.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).

Monitoring Parameters

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/HbA_1c (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).

Pregnancy

Pregnancy Considerations

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).

Patient Education

What is this drug used for?

• It is used to treat hiccups.
• It is used to treat tetanus.
• It is used to treat problems with how one acts.
• It is used to treat acute intermittent porphyria.
• It is used to treat mania.
• It is used to treat upset stomach and throwing up.
• It is used to treat schizophrenia.
• It is used to ease anxiety before surgery.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Constipation
• Dry mouth
• Fatigue
• Stuffy nose
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Neuroleptic malignant syndrome like fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot.
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating.
• Tardive dyskinesia like unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; or puffing cheeks.
• Fast heartbeat
• Yellow skin
• Abnormal heartbeat
• Erection that lasts more than 4 hours
• Abnormal movements
• Twitching
• Change in balance
• Agitation
• Muscle weakness
• Difficulty swallowing
• Difficulty speaking
• Dizziness
• Passing out
• Tremors
• Difficulty moving
• Rigidity
• Drooling
• Behavioral changes
• Seizures
• Swelling of arms or legs
• Vision changes
• Bruising
• Bleeding
• Enlarged breasts
• Nipple discharge
• Sexual dysfunction
• No menstrual periods
• Difficult urination
• Unable to pass urine
• Severe loss of strength and energy
• Trouble sleeping
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.