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Levomepromazine (methotrimeprazine) (United States: Not available): Drug information

Levomepromazine (methotrimeprazine) (United States: Not available): Drug information
(For additional information see "Levomepromazine (methotrimeprazine) (United States: Not available): Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: Canada
  • Methoprazine;
  • Nozinan
Pharmacologic Category
  • Analgesic, Nonopioid;
  • Antimanic Agent;
  • First Generation (Typical) Antipsychotic
Dosing: Adult

Note: Patients receiving parenteral therapy should be switched to oral therapy as soon as possible. If pronounced sedation occurs, administer smaller doses during the day and higher doses at night.

Anxiety

Anxiety: Oral: Initial: 6 to 25 mg/day in 3 divided doses with meals; may increase based on response and tolerability.

Bipolar disorder

Bipolar disorder:

IM: 25 mg, 3 or 4 times per day.

Oral: Initial: 50 to 75 mg/day in 2 or 3 divided doses; may increase based on response and tolerability. Patients requiring higher initial doses (100 to 200 mg/day in divided doses) should remain in bed for the first few days of therapy. Doses ≥1 g/day may be needed in some patients with psychosis.

Insomnia

Insomnia:

Note: Limit long-term use (>4 weeks) to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (ACP [Qaseem 2016]).

Oral: Single dose of 10 to 25 mg at bedtime.

IM: Single dose of 25 mg at bedtime.

SUBQ (off-label route): Palliative care:

Continuous infusion: 6.25 to 250 mg/day in sterile water or NS (via syringe pump) (Adam 1997; Nozinan datasheet, Sanofi Aventis New Zealand limited 2010).

Bolus administration: Median dose: 6.25 mg/day (range: 3.12 to 25 mg/day) administered as 1 to 2 divided doses (Adam 1997; Eisenchlas 2005).

Nausea/vomiting

Nausea/vomiting:

IM: 25 mg, 3 or 4 times per day.

Oral: Initial: 6 to 25 mg/day in 3 divided doses with meals; may increase based on response and tolerability.

SUBQ (off-label route): Palliative care:

Continuous infusion: 6.25 to 250 mg/day in sterile water or NS (via syringe pump) (Adam 1997; Nozinan datasheet, Sanofi Aventis New Zealand limited 2010).

Bolus administration: Median dose: 6.25 mg/day (range: 3.12 to 25 mg/day) administered as 1 to 2 divided doses (Adam 1997; Eisenchlas 2005).

Pain

Pain:

IM: 25 mg, 3 or 4 times per day. For postoperative adjunctive analgesia: 10 to 25 mg every 8 hours (equivalent to oral dose of 20 to 40 mg); consider additional dose reduction if administered in combination with narcotics.

Oral:

Mild conditions: Initial: 6 to 25 mg/day in 3 divided doses with meals; may increase based on response and tolerability.

Severe conditions: Initial: 50 to 75 mg/day in 2 or 3 divided doses; may increase based on response and tolerability. Patients requiring higher initial doses (100 to 200 mg/day in divided doses) should remain in bed for the first few days of therapy.

Schizophrenia

Schizophrenia:

IM: 25 mg, 3 or 4 times per day.

Oral: Initial: 50 to 75 mg/day in 2 or 3 divided doses; may increase based on response and tolerability. Patients requiring higher initial doses (100 to 200 mg/day in divided doses) should remain in bed for the first few days of therapy. Doses ≥1 g/day may be needed in some patients with psychosis.

Discontinuation of therapy: In the treatment of chronic psychiatric disease switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (APA [Keepers 2020]; Lambert 2007; Moncrieff 2020; Post 2020).

Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Stroup 2022).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Avoid parenteral use in patients with renal impairment.

Dosing: Hepatic Impairment: Adult

Use is contraindicated.

Dosing: Pediatric

Note: Patients receiving parenteral therapy should be switched to oral therapy as soon as possible. If pronounced sedation occurs, administer smaller doses during the day and higher doses at night.

Insomnia, nausea/vomiting, pain, psychotic disorders

Insomnia, nausea/vomiting, pain, psychotic disorders (ie, schizophrenia and/or manic-depressive syndromes):

Children and Adolescents:

Oral: 0.25 mg/kg/day in 2 to 3 divided doses; may titrate to effect (maximum dose for children <12 years of age: 40 mg/day). Note: May also be used for anxiety/tension disorders.

Parenteral:

IM: 0.0625 to 0.125 mg/kg/day as a single dose or in several divided doses.

IV: Palliative care: 0.0625 mg/kg in D5W 250 mL infused slowly at a rate of 20 to 40 drops/minute.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

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

Dosing: Hepatic Impairment: Pediatric

Use is contraindicated.

Dosing: Older Adult

Refer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis. Titrate dosage slowly and monitor carefully (Howard 2000).

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

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

Solution, Injection:

Nozinan: 25 mg/mL (1 mL) [contains sodium sulfite]

Tablet, Oral:

Generic: 2 mg, 5 mg, 25 mg, 50 mg

Product Availability

Not available in the US

Administration: Adult

Oral: Administer with meals.

Injection may be administered parenterally by slow IV infusion at a rate of 20 to 40 drops/minute, deep IM injection, subcutaneously (off-label route) as bolus injection (Adam 1997; Eisenchlas 2005), or as continuous infusion over 24 hours (Adam 1997; Nozinan datasheet, Sanofi Aventis New Zealand limited 2010). Patients should remain lying down for ≥1 hour (to reduce risk of hypotension).

For intermittent dosing, may administer smaller doses during day and higher doses at night if pronounced sedation occurs.

Administration: Pediatric

IM: May be administered by deep IM injection into a large muscle. May administer smaller doses during day and higher doses at night if pronounced sedation occurs.

IV: Palliative care: May be administered by slow IV infusion at a rate of 20 to 40 drops/minute.

Use: Labeled Indications

Note: Not approved in the United States.

Anxiety (tablet only): Treatment of conditions associated with anxiety.

Bipolar disorder: Treatment of bipolar disorder.

Insomnia: Management of insomnia, including for sedation in palliative care settings.

Nausea/vomiting: Management of nausea and vomiting.

Pain: Management of pain, including pain caused by neuralgia, cancer, or muscular discomforts, and as adjunct to general anesthesia (pre- and postoperatively).

Schizophrenia: Treatment of schizophrenia and psychotic disorders.

Medication Safety Issues
Safety concerns:

ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See "Warnings/Precautions" section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.

Older Adult: High-Risk Medication:

Beers Criteria: Based on pharmacologic class concerns for antipsychotics in the Beers Criteria, methotrimeprazine may be a potentially inappropriate medication to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reactions listed are based on reports for other agents in this same pharmacologic class, and may not be specifically reported for methotrimeprazine.

Postmarketing:

Cardiovascular: Atrioventricular block, cardiac arrhythmia (including atrial arrhythmia, cardiac fibrillation, tachycardia, ventricular arrhythmia, ventricular tachycardia), deep vein thrombosis, ECG changes (depression of ST segment on ECG, prolonged QT interval on ECG, T-wave changes, U-wave changes), orthostatic hypotension, pulmonary embolism, torsades de pointes, venous thromboembolism

Dermatologic: Dyschromia, skin photosensitivity, skin rash, Stevens-Johnson syndrome (Moubayed 2017), urticaria

Endocrine & metabolic: Amenorrhea, change in libido, decreased glucose tolerance, diabetic ketoacidosis, galactorrhea not associated with childbirth, gynecomastia, hyperglycemia, hyperprolactinemia, hyponatremia, menstrual disease, SIADH, weight gain

Gastrointestinal: Constipation, necrotizing enterocolitis, paralytic ileus, xerostomia

Genitourinary: Ejaculatory disorder (including inhibited ejaculation), lactation, priapism, urinary retention

Hematologic & oncologic: Agranulocytosis (Ananth 1970), eosinophilia, granulocytopenia, immune thrombocytopenia, leukopenia, neutropenia, thrombocytopenia

Hepatic: Abnormal hepatic function tests, cholestatic jaundice, hepatic injury

Hypersensitivity: Angioedema, hypersensitivity reaction

Local: Irritation at injection site (Moubayed 2017), skin ulceration at injection site (Moubayed 2017)

Nervous system: Anxiety, apathy, confusion, delirium, disruption of body temperature regulation, dizziness, drowsiness, extrapyramidal reaction (including akathisia, akinesia [with or without hypertonia], dystonia ([oculogyric crisis, spasmodic torticollis, trismus], hyperkinetic muscle activity, neuromuscular excitability, parkinsonism), insomnia, mood changes, neonatal withdrawal, neuroleptic malignant syndrome (Hayashida 2013), seizure, withdrawal syndrome (with abrupt discontinuation of high dose therapy; including gastritis, nausea, tremor, and vomiting)

Neuromuscular & skeletal: Tardive dyskinesia

Ophthalmic: Accommodation disturbance, cataract (Kim 2010), deposits on or around the surface of the eye (brownish deposits due to accumulation of the drug) (Kim 2010), myopia (Kashani 2005)

Respiratory: Nasal congestion, respiratory depression

Contraindications

Hypersensitivity to methotrimeprazine, phenothiazines, or any component of the formulation; hepatic disease; hematologic disorders (blood dyscrasia); coma or CNS depression due to ethanol, hypnotics, analgesics, or opioids.

Injection: Additional contraindications: Bone marrow depression; brain damage; pheochromocytoma; circulatory collapse/severe hypotension or severe heart disorders; myasthenia gravis; regional or spinal anesthesia; patients at risk of closed-angle glaucoma or urinary retention related to urethroprostatic disorders; history of agranulocytosis; concomitant use of neuroleptics (eg, dopaminergics); pediatric patients <1 year of age.

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines. QT prolongation has been reported rarely with use.

• Anticholinergic effects: Phenothiazines may cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, benign prostatic hyperplasia, xerostomia, glaucoma, or visual problems.

• Blood dyscrasias: Agranulocytosis, neutropenia, and granulocytopenia have been reported with use of antipsychotics. Monitor for any signs of infection and obtain CBC if symptoms (eg, fever, sore throat) evident.

• 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, 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 (ie, Alzheimer disease), particularly in patients >75 years of age (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 diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Keepers 2020]; Soares-Weiser 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 (Landi 2005; Seppala 2018).

• GI effects: Paralytic ileus may occur and should be treated as an emergency. Fatal necrotizing enterocolitis (rare) has been reported.

• Hyperglycemia: Hyperglycemia or glucose intolerance has been reported with use; diabetic ketoacidosis has been observed in patients without a prior history of hyperglycemia. Assess glucose prior to initiating therapy and periodically thereafter; patients with diabetes or those at risk for diabetes should be monitored for loss of glucose control during therapy.

• Hyperprolactinemia: Antipsychotic use has been associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown (APA [Keepers 2020]; Pollack 1993; Wang 2002). Prolonged hyperprolactinemia in association with hypogonadism may result in decreased bone mineral density in females and males.

• Neuroleptic malignant syndrome: May be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability. Discontinue use immediately for signs/symptoms of NMS and treat appropriately.

• Ocular effects: Antipsychotic use has been associated with pigmentary retinopathy, and lenticular and corneal deposits, particularly with prolonged therapy (Oshika 1995).

• Orthostatic hypotension: May cause orthostatic hypotension, particularly following parenteral administration or with high dosages; use with caution in patients at risk of hypotension or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Patients should remain in bed for the first few days following initiation of parenteral therapy or with high oral doses.

• Photosensitivity: May cause photosensitization; avoid prolonged exposure to sunlight and use high SPF sunscreen.

• Priapism: Rare cases of priapism have been reported with use; effects appear to be independent of dose and duration of therapy.

• Temperature regulation: Antipsychotic use has been associated with impaired core body temperature regulation; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Kerwin 2004; Kwok 2005; Martinez 2002).

• Venous thromboembolism: Cases of venous thromboembolism (some fatal) have been reported; use with caution in patients at risk for thromboembolism.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease. Dose reductions may be necessary when initiating therapy. Avoid use in patients with heart failure.

• Dementia: [Canadian Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to those treated with placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. An increased risk of cerebrovascular events including stroke has been observed with atypical antipsychotic use in elderly patients with dementia; risk with methotrimeprazine has not been established but cannot be ruled out. Methotrimeprazine is not indicated for the treatment of dementia or dementia-related psychosis in elderly patients.

• Hypothyroidism: Avoid use in patients with hypothyroidism.

• Parkinson disease: Avoid use in patients with Parkinson disease.

• Prostatic hypertrophy: Avoid use in patients with prostatic hypertrophy.

• Respiratory disease: Use with caution in patients with respiratory disease (eg, severe asthma, emphysema) due to potential for CNS depression effects.

• Seizure disorder: Use with caution in patients with seizure disorders; appropriate antiseizure therapy should be administered. Phenothiazines may lower seizure threshold.

Other warnings/precautions :

• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).

Metabolism/Transport Effects

Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

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

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

Agents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased. Management: Avoid alcohol in patients treated with methotrimeprazine. Risk X: Avoid combination

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

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

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

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy

Amphetamines: Antipsychotic Agents may enhance the adverse/toxic effect of Amphetamines. Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy

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

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

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Methotrimeprazine may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Methotrimeprazine. Risk X: Avoid combination

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Beta-Blockers: Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

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

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

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

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy

Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

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

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

CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification

CNS Depressants: May enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Dexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

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

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

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

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

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

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

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

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

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

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

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification

Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy

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

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

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

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

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

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Methotrimeprazine. Specifically, monoamine oxidase inhibitors may enhance dopamine blockade, possible increasing the risk for neuroleptic malignant syndrome. Methotrimeprazine may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

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

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

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

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

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

Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid combination

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

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Products Containing Ethanol: May enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid combination

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

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

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

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

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

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

Saquinavir: Antipsychotic Agents (Phenothiazines) may enhance the arrhythmogenic effect of Saquinavir. Risk X: Avoid combination

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modification

Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: 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. Risk D: Consider therapy modification

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

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

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

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

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Reproductive Considerations

Hyperprolactinemia associated with methotrimeprazine may lead to impaired fertility in women. Limited data suggest that methotrimeprazine may also be associated with impaired fertility in men.

If treatment with an antipsychotic is needed in a woman planning a pregnancy, other agents are preferred (Larsen 2015).

Pregnancy Considerations

Information related to use in pregnancy is limited (Callaghan 1966; DeKornfeld 1964; Heazell 2005). 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. Delayed meconium passage, abdominal bloating, and initial feeding difficulties due to the atropinic properties of the phenothiazines may also occur.

If treatment with an antipsychotic is initiated during pregnancy, use of other agents is preferred (Larsen 2015). Methotrimeprazine is not one of the treatments recommended for nausea and vomiting associated with pregnancy (Campbell 2016).

Breastfeeding Considerations

Methotrimeprazine is present in breast milk.

According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should consider the risk of exposure to the infant and the benefits of treatment to the mother. If treatment with an antipsychotic is needed in a breastfeeding woman, other agents are preferred (Larsen 2015).

Monitoring Parameters

Mental status; vital signs, including body weight (as clinically indicated); BMI; LFTs (baseline and periodically thereafter); renal function tests (baseline and periodically thereafter); CBC (baseline, during the first 2 to 3 months of therapy, and regularly thereafter); plasma glucose (patients with or at risk of diabetes); abnormal involuntary movement scale; extrapyramidal symptoms; ECG (if clinically indicated); fall risk (baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk) (Landi 2005; Seppala 2018).

Schizophrenia (additional monitoring recommendations): BMI, waist circumference (baseline; at every visit for the first 6 months; quarterly with stable antipsychotic dose); electrolytes (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); fasting lipid panel (baseline; repeat every 2 years if low-density lipoprotein (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 (baseline, monthly for 3 months after initiation, and then yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for ≥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 of age; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004).

Mechanism of Action

Aliphatic phenothiazine that antagonizes D1 and D2 dopamine receptor subtypes; also binds alpha-1, alpha-2, serotonin (5-HT1 and 5-HT2), and muscarinic (M1 and M2) receptors (Lal 1993)

Pharmacokinetics

Onset of action:

Anxiety/tension: Injection: 1 hour (Nozinan datasheet, Sanofi Aventis New Zealand limited 2010).

Bipolar disorder, acute mania: Oral: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).

Schizophrenia: Oral: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).

Duration: 2 to 4 hours (Nozinan datasheet, Sanofi Aventis New Zealand limited 2010)

Distribution: Vd: 23 to 42 L/kg (Dahl 1976)

Bioavailability: 50% (Dahl 1976)

Time to peak, serum: IM: 0.5 to 1.5 hours; Oral: 1 to 3 hours (Nozinan datasheet, Sanofi Aventis New Zealand limited 2010)

Half-life elimination: 15 to 30 hours (Dahl 1976)

Excretion: Urine; feces (Nozinan datasheet, Sanofi Aventis New Zealand limited 2010)

Brand Names: International
  • Detenler (AR);
  • Hirnamin (TW);
  • Neozine (BR);
  • Nidrane (UY);
  • Nozinan (AR, AT, BE, BG, CH, CZ, DK, EE, FR, GB, GR, HN, HR, ID, IE, IL, IS, IT, LU, MT, NL, NO, NZ, PH, PL, PT, PY, RU, SE, SI, SK, TR, UY);
  • Ronexine (IL);
  • Sinogan (CL, CO, ES, MX, PE, VE);
  • Tiscerin (KR);
  • Tisercin (HU, RU, UA, VN)


For country code abbreviations (show table)
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