Nortriptyline


Concise Prescribing Info
Indications/Uses
Depression.
Dosage/Direction for Use
Adult : PO Initiate at a low dose then increase as necessary to 75-100 mg/day in 3-4 divided doses or as a single dose. Max: 150 mg/day. Doses are usually given at night.
Dosage Details
Oral
Depression
Adult: Initiate at a low dose then increase as necessary to 75-100 mg daily in 3-4 divided doses or as a single dose. Max: 150 mg daily. Doses are usually given at night.
Elderly: Initiate at a low dose then increase as necessary to 30-50 mg daily in divided doses. Max: 50 mg daily.

Oral
Nocturnal enuresis
Child: For patients who have failed on previous therapies: 6-7 years 20-25 kg: 10 mg daily; 8-11 years 25-35 kg: 10-20 mg daily; >11 years 35-54 kg: 25-35 mg daily. All doses should be given 30 minutes before bedtime. Treatment duration: ≤3 months.
Special Patient Group
Pharmacogenomics:

Nortriptyline is metabolised by CYP2D6 via hydroxylation to 10-hydroxy nortriptyline metabolite (less-active). Available studies show that approx 7-10% of Caucasians cannot metabolise CYP2D6 substrates and are classified as poor CYP2D6 metabolisers.

Monitor for nortriptyline serum concentration and genetic testing for CYP2D6 is recommended prior to initiation of treatment.

CYP2D6 ultrarapid metabolisers (carriers of more than 2 copies of functional alleles e.g. *1/*1xN, *1/*2xN)
Increased metabolism reduces the plasma concentration of nortriptyline resulting in ineffectiveness of therapy; may also result to increased risk of cardiotoxic effects due to an increase in the plasma concentration of the cardiotoxic metabolite, Z-10-hydroxynortriptyline. Avoid use and consider an alternative drug not metabolised by CYP2D6 (e.g. citalopram, sertraline). Titration to a higher dose should be considered if TCA is necessary for the patient. Use therapeutic dose monitoring to guide succeeding dose adjustments. Observe clinical response with symptom improvement and minimal side effects.

CYP2D6 normal metabolisers (approx. 72-88% of patients with activity score of 1.0-2.0; carriers of 2 normal function alleles or 2 decreased function alleles or 1 normal and no function allele or 1 normal and decreased function allele or combinations of duplicated alleles e.g. *1/*1, *1/*2, *2/*2, *1/*9, *1/*41, *41/*41, *1/*4, *1/*5)
Initiate therapy with recommended starting dose. No dose adjustment.

CYP2D6 intermediate metabolisers (carriers of 1 decreased and 1 no function allele e.g. *4/*41, *5/*9, *4/*10)
Reduced metabolism of nortriptyline resulting to increased plasma concentration and increased risk of adverse effects. Consider 25% dose reduction of recommended starting dose. Titrate dose according to observed clinical response with improvement of symptom and minimal side effects. Use therapeutic dose monitoring to guide succeeding dose adjustments.

CYP2D6 poor metabolisers (carriers of only no function alleles e.g. *4/*4, *4/*4xN, *3/*4, *5/*5, *5/*6)
Increased plasma concentration and risk of adverse effects because of greatly reduced metabolism of nortriptyline. Avoid use and consider an alternative drug not metabolised by CYP2D6. If TCA is necessary for the patient, consider 50% dose reduction of initial dose. Titrate dose according to observed clinical response with improvement of symptom and minimal side effects. Use therapeutic dose monitoring to guide succeeding dose adjustments.
Hepatic Impairment
Depression: Severe: Contraindicated.
Administration
May be taken with or without food.
Contraindications
Recent MI, arrythmias, heart block or other cardiac arrhythmias, manic phase of bipolar disorder, known or suspected Brugada syndrome. Concomitant or within 14 days of MAOI therapy (e.g. linezolid, IV methylene blue). Severe hepatic impairment. Children <6 years. Lactation.
Special Precautions
Patients with major depressive disorder, history of suicide, bipolar disorder. Patients with CV disease (e.g. stroke, tachycardia, conduction abnormalities), diabetes, history of seizures and narrow-angle glaucoma. Patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, benign prostatic hyperplasia, xerostomia and visual problems. Concurrent electroconvulsive therapy and elective surgery. CYP2D6 ultrarapid, intermediate and poor metabolisers. Avoid abrupt withdrawal. Elderly and children. Renal and mild to moderate hepatic impairment. Pregnancy.
Adverse Reactions
Significant: CNS depression, behavioural changes, bone marrow suppression (e.g. aplastic anaemia, agranulocytosis), pupillary dilation, orthostatic hypotension (at risk patient), syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia, bone fractures, anticholinergic effects (e.g. blurred vision, xerostomia, constipation, urinary retention).
Cardiac disorders: Hypotension, hypertension, tachycardia, palpitation, MI, arrythmias, heart block, stroke.
Ear and labyrinth disorders: Tinnitus.
Eye disorders: Disturbance of accommodation, mydriasis.
Gastrointestinal disorders: Paralytic ileus, nausea, vomiting, anorexia, epigastric distress, diarrhoea, peculiar taste, stomatitis, abdominal cramps, parotid gland swelling.
General disorders and administration site conditions: Drug fever, weakness, fatigue.
Hepatobiliary disorders: Jaundice, altered liver function.
Immune system disorders: Cross-sensitivity with other TCAs.
Investigations: Blood sugar levels elevation or depression, weight gain or loss.
Nervous system disorders: Numbness, tingling, paraesthesia of extremities, incoordination, ataxia, tremors, peripheral neuropathy, extrapyramidal symptoms, seizures, alteration in EEG patterns, drowsiness, dizziness, headache.
Psychiatric disorders: Confusional states (especially in elderly), hallucinations, disorientation, delusions, anxiety, restlessness, agitation, insomnia, panic, nightmares, hypomania, exacerbation of psychosis.
Renal and urinary disorders: Delayed micturition, dilation of urinary tract, urinary frequency, nocturia.
Reproductive system and breast disorders: Gynecomastia; breast enlargement and galactorrhea (female); increased or decreased libido, impotence, testicular swelling.
Skin and subcutaneous tissue disorders: Skin rash, petechiae, urticaria, itching, photosensitisation.
Vascular disorders: Flushing, alopecia.
Potentially Fatal: Suicidal ideation and behaviour.
Patient Counseling Information
This drug may impair mental or physical abilities, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor plasma concentration. Monitor for signs of serotonin syndrome (e.g. agitation, hallucinations, delirium, coma). Monitor blood pressure, pulse rate and ECG in patient at risk. Monitor blood glucose, weight and BMI. Monitor TCA plasma levels on concomitant use with CYP2D6 inhibitor. Monitor CBC. Assess mental status, suicidal ideation, anxiety, social functioning, mania, panic attacks or other unusual changes in behaviour.
Overdosage
Symptoms: Blurred vision, confusion, restlessness, dizziness, agitation, vomiting, dry mouth, hypo- or hyperthermia, Severe hypotension, cardiac dysrhythmias, shock, CHF, pulmonary oedema, convulsions, and CNS depression, including coma; changes in ECG. Management: Symptomatic and supportive treatment. Secure airway and establish an IV line. Gastric lavage followed by activated charcoal may be given to reduce absorption. Emesis is contraindicated. Initiate cardiac monitoring and observe for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures. Na bicarbonate may be given to treat ventricular arrhythmias while refractory arrhythmias may respond to bretylium, propranolol or lignocaine. In case of seizures, diazepam or phenytoin may be administered.
Drug Interactions
Increased plasma concentration with cimetidine. Increased risk of hypoglycaemia with chlorpropamide in type II diabetic patient. May decrease the antihypertensive effect of guanethidine, debrisoquine, bethanidine and clonidine. Barbiturates may increase the rate of metabolism of nortriptyline. Risk of arrythmias and hypotension may be increased when given with anaesthetics. CYP2D6 inhibitors (e.g. quinidine) may increase nortriptyline toxicity.
Potentially Fatal: Increased risk of serotonin syndrome with MAOIs (e.g. linezolid, IV methylene blue).
Food Interaction
Increased risk of serotonin syndrome with St John's wort. May potentiate the CNS depressant effect of alcohol.
Action
Description: Nortriptyline, a dibenzocycloheptadiene tricyclic antidepressant, is the primary active metabolite of amitriptyline. It increases synaptic concentration of serotonin and/or norepinephrine in the CNS by blocking the neuronal reuptake of norepinephrine and serotonin. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. Additionally, it increases the pressor effect of norepinephrine but interferes with the transport, release, and storage of catecholamines.
Pharmacokinetics:
Absorption: Rapidly absorbed. Bioavailability: 46-70%. Time to peak plasma concentration: 4-9 hours.
Distribution: Crosses the placenta and detected in cord blood. Enters breast milk. Volume of distribution: 21.1-31.1 L/kg. Plasma protein binding: Extensive.
Metabolism: Metabolised in the liver via extensive first-pass effect to active metabolite, 10-hydroxynortriptyline.
Excretion: Via urine (as metabolites and small amounts as unchanged drug). Half-life elimination: Mean: 26 hours (range: 14-51 hours).
Chemical Structure

Chemical Structure Image
Nortriptyline

Source: National Center for Biotechnology Information. PubChem Database. Nortriptyline, CID=4543, https://pubchem.ncbi.nlm.nih.gov/compound/Nortriptyline (accessed on Jan. 22, 2020)

Storage
Store between 20-25°C. Protect from light.
MIMS Class
ATC Classification
N06AA10 - nortriptyline ; Belongs to the class of non-selective monoamine reuptake inhibitors. Used in the management of depression.
References
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 08/08/2019

Annotation of CPIC Guideline for Nortriptyline and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 08/08/2019.

Annotation of DPWG Guideline for Nortriptyline and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 08/08/2019.

Anon. CYP2D6 - Nortriptyline. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 08/08/2019.

Anon. Nortriptyline. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 08/08/2019.

Buckingham R (ed). Nortriptyline hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/08/2019.

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 08/08/2019.

Joint Formulary Committee. Nortriptyline. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/08/2019.

McEvoy GK, Snow EK, Miller J et al (eds). Nortriptyline hydrochloride. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 30/07/2014.

Nortriptyline Hydrochloride Capsule (Taro Pharmaceuticals U.S.A., Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 08/08/2019.

Nortriptyline Tablets (Eucogen Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 08/08/2019.

Pamelor Capsule (Mallinckrodt, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 30/07/2014.

Disclaimer: This information is independently developed by MIMS based on Nortriptyline 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
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in