Trimipramine


Concise Prescribing Info
Indications/Uses
Depression.
Dosage/Direction for Use
Adult : PO Initial: 50-75 mg/day, increased gradually as necessary to 150-300 mg daily. Maintenance: 75-150 mg/day. May be given in divided doses during the day or as a single dose at night.
Dosage Details
Oral
Depression
Adult: Initially, 50-75 mg daily, increased gradually as necessary to 150-300 mg daily. Maintenance: 75-150 mg daily. May be given in divided doses during the day or as a single dose at night.
Elderly: Initially, 50 mg daily, increased gradually according to response and tolerability. Maintenance: Lowest effective dose at bedtime. Max: 100 mg daily.
Special Patient Group
Pharmacogenomics:

Tertiary amines such as trimipramine are mainly metabolised by CYP2C19 to active metabolites. CYP2D6 metabolises both tertiary and secondary amines to less active metabolites. Trimipramine is metabolised to desmethyltrimipramine (major and active metabolite). Both CYP2D6 and CYP2C19 genes are known to be polymorphic, which may affect the response to and efficacy of trimipramine. TCAs have similar pharmacokinetic properties, applying Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations for amitriptyline and CYP2C19 and CYP2D6 to other tricyclics including trimipramine may be appropriate.

Recommendations based on 2016 Update CPIC Guideline:

CYP2D6 phenotype

CYP2D6 ultrarapid metabolisers
Carriers of duplication of functional alleles [e.g. (*1/*1)xN, <I>(*1/*2)xN, (*2/*2)xN] with activity score of >2.0 have increased metabolism of TCAs to less active compounds resulting to lower plasma concentrations of active drug and may increase pharmacotherapy failure. Avoid trimipramine and consider an alternative drug not metabolised by CYP2D6. If treatment with TCA is necessary, consider titrating to a higher target dose than normal metabolisers. Use therapeutic drug monitoring to guide dose adjustments.

CYP2D6 normal metabolisers
Carriers of 2 normal function alleles or 2 decreased function alleles or 1 normal and no function allele or 1 normal function and decreased function allele (e.g. *1/*1, *1/*2, *2/*2, *1/*5, *1/*9, *1/*41, *41/*41, *1/*4) with activity score of 1.0-2.0 have normal metabolism of TCAs. Start treatment with the recommended initial dose.

CYP2D6 intermediate metabolisers
Carriers of 1 decreased function and 1 no function allele (e.g. *4/*41, *5/*9, *4/*10) with activity score of 0.5 may have reduced metabolism of TCAs to less active compounds resulting to higher plasma concentrations of active drug and may increase risk of adverse effects. Consider 25% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.

CYP2D6 poor metabolisers
Carriers of no function alleles [e.g. *4/*4, (*4/*4)xN, *3/*4, *5/*5, *5/*6] with activity score of 0 have greatly reduced metabolism of TCAs to less active compounds resulting to higher plasma concentrations of active drug and increased risk of adverse effects. Avoid TCA use and consider alternative drug not metabolised by CYP2D6. If treatment with TCA is necessary, consider 50% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.

CYP2C19 phenotype

CYP2C19 ultrarapid metabolisers
Carriers of 2 increased function alleles (e.g. *17/*17) have increased metabolism of tertiary amines thereby greater conversion of tertiary amines to secondary amines may affect response and adverse effects. Avoid tertiary amine use and consider an alternative drug not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). If treatment with tertiary amine is necessary, use therapeutic drug monitoring to guide dose adjustments.

CYP2C19 rapid metabolisers
Carriers of 1 normal function allele and 1 increased function allele (e.g. *1/*17) have increased metabolism of tertiary amines thereby greater conversion of tertiary amines to secondary amines which may affect response or adverse effects. Avoid tertiary amine use and consider an alternative drug not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). If tertiary amine is necessary, use therapeutic drug monitoring to guide dose adjustments.

CYP2C19 normal metabolisers
Carriers of 2 normal function alleles (e.g. *1/*1) have normal metabolism of tertiary amines. Start treatment with the recommended initial dose.

CYP2C19 intermediate metabolisers
Carriers of 1 normal function allele and 1 no function allele or 1 no function allele and 1 increased function allele (e.g. *1/*2, *1/*3, *2/*17) have reduced metabolism of tertiary amines. Start treatment with the recommended initial dose.

CYP2C19 poor metabolisers
Carriers of 2 no function alleles (e.g. *2/*2, *2/*3, *3/*3) have greatly reduced metabolism of tertiary amines thereby decreased conversion of tertiary amines to secondary amines which may affect response and adverse effects. Avoid tertiary amine use and consider an alternative drug which is not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). Consider a 50% reduction of the recommended initial dose for tertiary amines. Use therapeutic drug monitoring to guide dose adjustments.
Hepatic Impairment
Severe: Contraindicated.
Administration
May be taken with or without food.
Contraindications
Recent MI, heart block or other cardiac arrhythmias, mania. Severe liver impairment. Lactation. Concurrent or within 14 days of MAOI therapy (e.g. linezolid or IV methylene blue).
Special Precautions
Patient with major depressive disorder and history of suicide. Patient with decreased gastrointestinal motility, paralytic ileus, urinary retention, benign prostatic hyperplasia, xerostomia, narrow-angle glaucoma or other visual problems. Patient at risk of orthostatic hypotension (cerebrovascular disease, hypovolaemia). Patient with CV disease (e.g. stroke, tachycardia, conduction abnormalities). Patient with diabetes mellitus, at risk of QT interval prolongation (e.g. congenital long QT syndrome, bradycardia, uncorrected electrolyte imbalance), history of seizure disorder. Avoid abrupt withdrawal. Discontinue treatment prior to electroconvulsive therapy or elective surgery. Renal and hepatic impairment. Elderly. Pregnancy. 
Adverse Reactions
Significant: Anticholinergic effects (e.g. constipation, xerostomia, blurred vision, urinary retention), fractures, QT interval prolongation, orthostatic hypotension, withdrawal symptoms (e.g. insomnia, irritability, excessive perspiration), syndrome of inappropriate antidiuretic hormone secretion and hyponatremia (elderly).
Blood and lymphatic system disorders: Rarely, bone marrow depression (e.g. agranulocytosis, eosinophilia, purpura, thrombocytopenia).
Cardiac disorders: Hypotension, hypertension, tachycardia, palpitation, MI, arrhythmias, heart block, stroke, torsade de pointes.
Gastrointestinal disorders: Nausea, vomiting, anorexia, epigastric distress, diarrhoea, peculiar taste, stomatitis, abdominal cramps, black tongue, parotid swelling.
General disorders and administration site conditions: Weakness, fatigue.
Hepatobiliary disorders: Jaundice (simulating obstructive), altered liver function. Rarely, cholestatic jaundice.
Investigations: Blood sugar elevation or depression, weight gain or loss.
Nervous system disorders: Drowsiness, tremor, dizziness, headache. Rarely, peripheral neuropathy, seizure.
Psychiatric disorders: Confusional states (elderly) with hallucinations, disorientation, delusions, anxiety, restlessness, agitation, insomnia, nightmares, exacerbation of psychosis (e.g. mania or hypomania, psychosis, paranoid delusions).
Renal and urinary disorders: Urinary frequency.
Reproductive system and breast disorders: Interfered sexual function, gynecomastia (male), breast enlargement and galactorrhoea (female), increased or decreased libido, impotence, testicular swelling.
Skin and subcutaneous tissue disorders: Rash, sweating, alopecia.
Vascular disorders: Flushing.
Potentially Fatal: Suicidal ideation and behaviour.
Patient Counseling Information
This drug may impair alertness, if affected, do not drive or operate machinery.
MonitoringParameters
Closely monitor for clinical worsening, suicidality, or unusual changes in behaviour. Monitor for signs of serotonin syndrome such as mental status changes (e.g. agitation, hallucinations, delirium, coma); autonomic instability (e.g. tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (e.g. tremor, rigidity, myoclonus); gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Monitor electrolytes, LFTs, blood glucose, weight and BMI. Monitor ECG, heart rate and blood pressure of patient at risk.
Overdosage
Symptoms: Severe hypotension, convulsions, coma, respiratory failure, QT interval prolongation, torsade de pointes, dry mouth, dilated pupils, urinary retention, hypothermia, hyperreflexia. Management: Protect patient’s airway and secure an IV line and initiate gastric decontamination. Perform gastric lavage followed by administration of activated charcoal as soon as possible; may pass an endotracheal tube in unconscious patients before starting gastric lavage. Perform ECG test and monitor cardiac function. Administer Na lactate via slow IV inj for treatment of acidosis. Ventilation and intubation are necessary. Administer diazepam IV for convulsions. Administer pyridostigmine bromide IV or propranolol for supraventricular tachycardia. Continue treatment for at least 3 days.
Drug Interactions
May increase risk of arrhythmia and hypotension with concurrent use of anaesthetics. May decrease the antihypertensive activity of guanethidine, debrisoquine, bethanidine and clonidine. May increase metabolism rate with barbiturates. Increased risk of developing other adverse effects with agents known to prolong QT interval (e.g. class IA and III antiarrhythmics, macrolide antibiotics, fluoroquinolones, antifungals, antipsychotics).
Potentially Fatal: Increased risk of serotonin syndrome with MAOIs (e.g. IV methylene blue, linezolid) and serotonergic agents (e.g. triptans, TCAs, fentanyl, lithium, tramadol, buspirone, tryptophan).
Food Interaction
Potentiates CNS depressant effect of alcohol. Increased risk of serotonin syndrome with St. John’s wort.
Action
Description: Trimipramine is a dibenzazepine tricyclic antidepressant with antimuscarinic and sedative properties. It acts by postsynaptic sensitisation to serotonin.
Pharmacokinetics:
Absorption: Bioavailability: 18-63%. Time to peak plasma concentration: 1-6 hours.
Distribution: Plasma protein binding: Approx 95%. Volume of distribution: 31 L/kg.
Metabolism: Undergoes first-pass effect in the liver to major active metabolite, desmethylimipramine.
Excretion: Via urine. Elimination half-life: 7-40 hours.
Chemical Structure

Chemical Structure Image
Trimipramine

Source: National Center for Biotechnology Information. PubChem Database. Trimipramine, CID=5584, https://pubchem.ncbi.nlm.nih.gov/compound/Trimipramine (accessed on Jan. 23, 2020)

Storage
Store between 20-25°C.
MIMS Class
ATC Classification
N06AA06 - trimipramine ; Belongs to the class of non-selective monoamine reuptake inhibitors. Used in the management of depression.
References
Dean, L. Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype. Medical Genetics Summaries. Accessed 17/12/2019. PMID: 28520380

Hicks JK, Sangkuhl K, Swen JJ et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clinical Pharmacology & Therapeutics. 2017 Jul;102(1):37-44. doi: 10.1002/cpt.597. Accessed 28/11/2019

Kirchheiner J, Muller G, Meineke I et al. Effects of Polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on Trimipramine Pharmacokinetics. Journal of Clinical Psychopharmacology. 2003 Oct;23(5):459-466. doi: 10.1097/01.jcp.0000088909.24613.92. Accessed 28/11/2019. PMID: 14520122

Annotation of CPIC Guideline for trimipramine and CYP2C19, CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 12/12/2019.

Annotation of FDA Label for Trimipramine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 28/11/2019.

Anon. CYP2C19 - Trimipramine (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 28/11/2019.

Anon. CYP2D6 - Trimipramine (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 28/11/2019.

Anon. Trimipramine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 28/11/2019.

Buckingham R (ed). Trimipramine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 28/11/2019.

Clinical Annotation for CYP2C19*1, CYP2C19*2; Trimipramine. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 28/11/2019.

Clinical Annotation for CYP2D6*1, CYP2D6*2xN, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6; Trimipramine. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 28/11/2019.

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 28/11/2019.

Joint Formulary Committee. Trimipramine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 28/11/2019.

Surmontil Capsules (Zentiva Pharma UK Limited). MHRA. https://products.mhra.gov.uk/. Accessed 28/11/2019.

Trimipramine Capsule (Breckenridge Pharmaceutical, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 28/11/2019.

Disclaimer: This information is independently developed by MIMS based on Trimipramine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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