Adult: Initiate at a low dose, then increase gradually based on patient response and tolerance. Usual dose: 25 mg 3 or 4 times daily. Alternatively, the total dose may be given once daily, usually at night. Max: 150 mg daily. Dosage and treatment recommendations may vary among individual products and between countries (refer to specific product guidelines). Elderly: Initiate at a low dose, then increase gradually based on patient response and tolerance to 30-50 mg daily in divided doses. Dosage and treatment recommendations may vary among individual products and between countries (refer to specific product guidelines).
What are the brands available for Nortriptyline in Malaysia?
Nortriptyline Remedica
Special Patient Group
Pharmacogenomics:
Metabolism of nortriptyline into 10-hydroxynortriptyline (less active metabolite) via hydroxylation is mainly mediated by CYP2D6 isoenzyme. The CYP2D6 gene is highly polymorphic, and genetic variation in this gene may predispose patients to treatment failure or adverse effects.
CYP2D6 isoenzyme activity is reduced in a subset of Caucasians, and approx 7-10% of this population are classified as CYP2D6 poor metabolisers. Reliable estimates of the prevalence of reduced CYP2D6 isoenzyme activity among Asians, Africans, and other populations are not yet available. Genetic testing may be considered to help identify patients at risk of nortriptyline adverse effects or treatment failure.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2016:
Phenotype and Genotype
Implications
Recommendations
CYP2D6 ultrarapid metaboliser (activity score of >2)
Patients carrying duplications of functional alleles e.g. (*1/*1)xN, (*1/*2)xN, (*2/*2)xN (where xN represents the number of CYP2D6 gene copies)
Increased TCA metabolism to less active metabolites as compared to normal metabolisers. Lower plasma concentrations of the active drug may increase the possibility of pharmacotherapy failure.
Avoid TCA use and consider an alternative drug not metabolised by CYP2D6. If TCA use is warranted, consider titrating to a higher target dose compared to normal metabolisers. Therapeutic drug monitoring is strongly recommended to guide dose adjustments.
CYP2D6 intermediate metaboliser (activity score of 0.5 or 1)
Patients carrying 1 decreased function and 1 non-functional allele e.g. *4/*41, *5/*9, *4/*10
CPIC update as of October 2019: Phenotype assignment for activity score of 1 has been changed from CYP2D6 normal metaboliser to CYP2D6 intermediate metaboliser.
Decreased TCA metabolism to less active metabolites as compared to normal metabolisers. Higher plasma concentrations of the active drug may increase the risk of adverse effects.
Consider a 25% reduction of the recommended initial dose. Use therapeutic drug monitoring to guide dose adjustments.
CYP2D6 poor metaboliser (activity score of 0)
Patients carrying non-functional alleles only e.g. *4/*4, (*4/*4)xN, *3/*4, *5/*5, *5/*6
Significantly decreased TCA metabolism to less active metabolites as compared to normal metabolisers. Higher plasma concentrations of the active drug may increase the risk of adverse effects.
Avoid TCA use and consider an alternative drug not metabolised by CYP2D6. If TCA use is warranted, consider a 50% reduction of the recommended initial dose. Therapeutic drug monitoring is strongly recommended to guide subsequent dose adjustments.
In addition, patients taking strong CYP2D6 inhibitors are suggested to be treated similarly to CYP2D6 poor metabolisers. Consider drug-drug interactions and patient characteristics alongside the gene-based dosing recommendations mentioned above.
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:
Phenotype
Description
Recommendations
CYP2D6 ultrarapid metaboliser
Decreased plasma concentration of nortriptyline and increased plasma concentration of the cardiotoxic metabolite Z-10-hydroxynortriptyline. May increase the risk of therapeutic failure and cardiotoxicity.
Use 1.7 times the standard dose. Monitor nortriptyline and Z-10-hydroxynortriptyline plasma concentrations or the therapeutic and adverse effects. Avoid nortriptyline use if a dose increase is not wanted due to cardiotoxic hydroxy metabolite. Other antidepressant drugs that are not metabolised (or to a lesser extent) by CYP2D6 include citalopram and sertraline.
CYP2D6 intermediate metaboliser
Increased plasma concentration of nortriptyline, which may increase the risk of adverse effects.
Use 60% of the standard dose. Monitor nortriptyline plasma concentrations or the therapeutic and adverse effects to determine the maintenance dose.
CYP2D6 poor metaboliser
Increased plasma concentration of nortriptyline, which may increase the risk of adverse effects.
Use 40% of the standard dose. Monitor nortriptyline plasma concentrations or the therapeutic and adverse effects to determine the maintenance dose.
Dosage or treatment recommendations may vary among countries. Refer to local guidelines for the appropriate clinical recommendations.
Hepatic Impairment
Severe: Contraindicated.
Administration
Nortriptyline May be taken with or without food.
Contraindications
Recent MI, any degree of heart block or cardiac arrhythmias, manic phase of bipolar disorder. Severe hepatic impairment. Concomitant use with MAOIs or within 14 days of discontinuing MAOIs. Concomitant use with IV methylthioninium chloride.
Special Precautions
Patient with history of suicide-related events or exhibiting significant degree of suicidal ideation; bipolar disorder; history of seizure disorder; CV disease (e.g. stroke, tachycardia, significant bradycardia, uncompensated heart failure), electrolyte disturbances (e.g. hypokalaemia, hyperkalaemia, hypomagnesaemia), diabetes mellitus, hyperthyroidism, paralytic ileus, urinary retention, prostatic hypertrophy, increased IOP or angle-closure glaucoma. Patient undergoing surgery; discontinue treatment several days before elective surgery, if possible. CYP2D6 ultrarapid, intermediate, and poor metabolisers. Avoid abrupt withdrawal. Avoid use in patients with Brugada syndrome or suspected of having Brugada syndrome. Renal and mild to moderate hepatic impairment. Elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Increased risk of suicidal thoughts and behaviour (particularly in young adults); MI, stroke, cardiac arrhythmias, unmasking of Brugada syndrome; anticholinergic effects (e.g. constipation, dry mouth, blurred vision, palpitations, tachycardia, urinary retention), CNS depression, orthostatic hypotension, withdrawal symptoms (upon abrupt discontinuation). Rarely, SIADH and/or hyponatraemia. Cardiac disorders: AV block, bundle branch block. Eye disorders: Accommodation disorder, mydriasis, cycloplegia. Gastrointestinal disorders: Nausea, dysgeusia. General disorders and administration site conditions: Fatigue. Investigations: Increased weight, abnormal ECG (e.g. prolonged QT and QRS complex). Nervous system disorders: Dizziness, headache, drowsiness, ataxia, tremor, paraesthesia, disturbance in attention. Psychiatric disorders: Aggression, agitation, confusional state. Renal and urinary disorders: Micturition disorders. Reproductive system and breast disorders: Decreased libido, erectile dysfunction. Skin and subcutaneous tissue disorders: Hyperhidrosis.
Patient Counseling Information
This drug may cause drowsiness and impair physical or mental abilities, if affected, do not drive or operate machinery.
Monitoring Parameters
Screen for family history of suicide, bipolar disorder, and depression before treatment initiation. Monitor blood glucose, weight, BMI; blood pressure, heart rate, ECG (particularly in elderly with pre-existing cardiac disease); serum Na (in at-risk populations, as clinically indicated); mental alertness. Closely monitor for clinical worsening, suicidal behaviour or thoughts, psychosis, and unusual changes in behaviour (particularly at 1-2 months of treatment initiation or during dose adjustments).
Overdosage
Symptoms: Vomiting, dry mouth, fever, decreased bowel motility, urinary retention, blurred vision, dizziness, confusion, restlessness, hypothermia, hyperthermia, agitation, hyperactive reflexes, dilated pupils, rapid heart rate, myoclonic jerks, convulsions, respiratory depression, myoglobinuric renal failure, nystagmus, ataxia, dysarthria, choreoathetosis, hypotension, shock, coma, cardiac arrhythmias or conduction defects, arrhythmias (including ventricular tachyarrhythmias, torsades de pointes, ventricular fibrillation), Brugada syndrome unmasking and Brugada ECG patterns. Management: Symptomatic and supportive treatment. Protect patient's airway and establish an IV access. Perform gastric lavage and administer activated charcoal to reduce absorption. If the patient is unconscious, secure the airway before initiating lavage. Obtain an ECG and immediately start cardiac monitoring. Administer IV Na bicarbonate to maintain the serum pH in the range of 7.45-7.55; hyperventilation may also be used if the pH response is inadequate. Lidocaine, phenytoin, or bretylium tosilate may be used in patients with dysrhythmias unresponsive to hyperventilation or Na bicarbonate. Early intubation is advised in patients with CNS depression. Control seizures with benzodiazepines (e.g. diazepam) or, if ineffective, other anticonvulsants (e.g. phenobarbital, phenytoin).
Drug Interactions
May diminish the antihypertensive effects of adrenergic neuron blockers (e.g. guanethidine). Concomitant use with anticholinergic agents may result in additive anticholinergic effects. May increase the risk of arrhythmias with agents that prolong QT interval, including anaesthetics, antiarrhythmics (e.g. quinidine) and certain antipsychotics (e.g. pimozide). Increased risk of cardiac adverse effects with thioridazine. May enhance the sedative effects of barbiturates and other CNS depressants. May increase serum concentration with fluvoxamine, cimetidine, valproic acid, antifungals (e.g. fluconazole, terbinafine), and strong CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, quinidine). May reduce plasma concentration with rifampicin, barbiturates, and carbamazepine. Potentially Fatal: Increased risk of serotonin syndrome with MAOIs (including linezolid and IV methylthioninium chloride) and other serotonergic agents (e.g. triptans, opioids, lithium, buspirone, tryptophan, SSRIs, other TCAs).
Food Interaction
May enhance the sedative effect of alcohol. May increase the risk of serotonin syndrome and reduce plasma concentrations with St. John's wort.
Action
Description: Mechanism of Action: Nortriptyline, a dibenzocycloheptadiene tricyclic antidepressant, is the main active metabolite of amitriptyline. It is believed to inhibit the reuptake of norepinephrine and/or serotonin at the presynaptic neuronal membrane, thereby increasing their synaptic concentration in the CNS. Additionally, it blocks the action of histamine, 5-hydroxytryptamine, and acetylcholine, and enhances the pressor effect of norepinephrine but inhibits the pressor effect of phenethylamine. Onset: Antidepressant effect: 1-2 weeks. Pharmacokinetics: Absorption: Rapidly absorbed. Bioavailability: 46-70%. Time to peak plasma concentration: 4-9 hours. Distribution: Widely distributed throughout the body. Crosses the placenta and detected in cord blood; enters breast milk. Volume of distribution: 21.1-31.1 L/kg. Metabolism: Metabolised mainly in the liver via demethylation and hydroxylation followed by conjugation with glucuronic acid; undergoes extensive first-pass metabolism into the less active metabolite, 10-hydroxynortriptyline. Excretion: Via urine (as metabolites and small amounts of unchanged drug). Elimination half-life: 14-51 hours.
Chemical Structure
Nortriptyline Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 4543, Nortriptyline. https://pubchem.ncbi.nlm.nih.gov/compound/Nortriptyline. Accessed May 28, 2025.
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