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ChlorproMAZINE

Pronunciation

Pronunciation

(klor PROE ma zeen)

Index Terms

  • Chlorpromazine HCl
  • Chlorpromazine Hydrochloride
  • CPZ
  • Thorazine

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

Pharmacologic Category

  • Antimanic Agent
  • First Generation (Typical) Antipsychotic
  • Phenothiazine Derivative

Pharmacology

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

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)

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: Unlabeled

Behavioral symptoms associated with dementia (elderly); Huntington's disease; psychosis/agitation related to Alzheimer's dementia

Contraindications

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

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 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 is controlled; usual dose: 200 to 800 mg daily

Intractable hiccups:

Oral, IM: 25 to 50 mg 3 to 4 times/day

IV (refractory to oral or IM treatment): 25 to 50 mg via slow IV infusion

Nausea and vomiting:

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

IM: 25 to 50 mg every 3 to 4 hours as needed

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

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

Dosing: Geriatric

Manufacturer’s labeling: 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).

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 daily); in older children, higher daily doses (200 mg daily 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 (off-label): Initial: 0.55 mg/kg/dose every 6-8 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 daily in 2 to 4 divided doses, initiate at lower doses and titrate as needed; usual dose is 200 mg daily

IM, IV (off-label): 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 daily (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

Prevention of chemotherapy-associated nausea and vomiting (Pediatric Oncology Group of Ontario [POGO] dosing recommendation): Highly or moderately emetogenic chemotherapy (patients who cannot receive corticosteroids): Infants ≥6 months, Children, and Adolescents: IV: 0.5 mg/kg/dose every 6 hours (in combination with ondansetron or granisetron); if not controlled, may increase up to 1 mg/kg/dose; monitor for sedation, maximum dose: 50 mg (Dupuis, 2013)

Presurgical apprehension: Infants ≥6 months, Children, and Adolescents:

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

IM: 0.55 mg/kg/dose 1 to 2 hours prior to 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 titrate to response

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Not dialyzable (0% to 5%)

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

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

SubQ: Do not administer SubQ (tissue damage and irritation may occur).

IV: For direct IV injection, administer diluted solution slow IV at a rate not to exceed 0.5 mg/minute in children and 1 mg/minute in adults. 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.

Note: Avoid skin contact with solution; may cause contact dermatitis.

Compatibility

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D51/4NS, D51/2NS, D5NS, D5W, D10W, LR, 1/2NS, NS.

Y-site administration: Incompatible with allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, aztreonam, bivalirudin, cefepime, etoposide phosphate, fludarabine, furosemide, linezolid, melphalan, methotrexate, paclitaxel, pantoprazole, pemetrexed, piperacillin/tazobactam, sargramostim, tigecycline.

Compatibility in syringe: Incompatible with cimetidine, pantoprazole, pentobarbital, thiopental.

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. 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. 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

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

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

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: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

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

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

Analgesics (Opioid): Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Analgesics (Opioid). Monitor therapy

Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Antacids: May decrease the absorption of Antipsychotic Agents (Phenothiazines). Monitor therapy

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

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

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

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

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

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

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

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

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

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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

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

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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

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

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

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: Antipsychotic Agents (Phenothiazines) may enhance the arrhythmogenic effect of Dronedarone. Avoid combination

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. 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

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

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

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

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

Haloperidol: ChlorproMAZINE may enhance the QTc-prolonging effect of Haloperidol. Haloperidol may increase the serum concentration of ChlorproMAZINE. ChlorproMAZINE may increase the serum concentration of Haloperidol. Management: Consider alternatives to combined treatment with these agents. If combined treatment cannot be avoided, monitor for signs and symptoms of prolonged QTc interval (e.g. arrhythmias). Consider therapy modification

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

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. 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. Monitor therapy

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

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

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

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

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

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

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

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

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

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

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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

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

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

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

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

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

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

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

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

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 may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Piribedil [INT]: Antipsychotic Agents may diminish the therapeutic effect of Piribedil [INT]. Piribedil [INT] 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

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

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

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

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 using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to 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

Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. 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

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: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: 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

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

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

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

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

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, tachycardia

Central nervous system: Akathisia, dizziness, drowsiness, dystonia, neuroleptic malignant syndrome, parkinsonian-like syndrome, seizure, tardive dyskinesia

Dermatologic: Dermatitis, skin photosensitivity, skin pigmentation (slate gray)

Endocrine & metabolic: Amenorrhea, gynecomastia, hyperglycemia, hypoglycemia

Gastrointestinal: Constipation, nausea, xerostomia

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

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

Hepatic: Jaundice

Ophthalmic: Blurred vision, corneal changes, epithelial keratopathy, retinitis pigmentosa

ALERT: U.S. Boxed Warning

Increased mortality in elderly patients with dementia-related psychosis:

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.

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.

• 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 <1000/mm3.

• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer's disease).

• Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. Risk of dystonia (and possibly other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Risk of tardive dyskinesia and potential for irreversibility may be increased in elderly patients (particularly women), prolonged therapy, and higher total cumulative dose; antipsychotics may also mask signs/symptoms of tardive dyskinesia. Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• 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.

• 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.

• Orthostatic hypotension: 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).

• Sedation: Highly sedating which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• 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 severe 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. Chlorpromazine is not approved for the treatment of dementia-related psychosis.

• Glaucoma: Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Parkinson's disease: Use with caution in patients with Parkinson's disease; they may be more sensitive to adverse effects.

• 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.

• 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:

• Antiemetic effects: May mask toxicity of other drugs or conditions (eg, intestinal obstruction, Reye's syndrome, brain tumor) due to antiemetic effects.

• 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.

Special populations:

• Elderly: Increased risk for developing tardive dyskinesia, particularly in elderly women.

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.

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/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).

Pregnancy Considerations

Embryotoxicity was observed in animal reproduction studies. 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.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, dry mouth, fatigue, rhinitis, or nausea. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot), signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; and puffing cheeks), priapism, abnormal movements, twitching, change in balance, dysphagia, difficulty speaking, severe dizziness, passing out, tremors, difficulty moving, rigidity, drooling, seizures, swelling of arm or leg, vision changes, bruising, bleeding, enlarged breasts, nipple discharge, sexual dysfunction, amenorrhea, urinary retention, loss of strength and energy, or insomnia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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