Amitriptyline


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Depression Initial: 25 mg bid, gradually increase by 25 mg every other day up to 150 mg daily in divided doses. Alternatively, initiate therapy with 50-100 mg at bedtime, may be increased by 25-50 mg as necessary to a total dose of 150mg/day. For hospitalized patients: Initial: 100 mg/day, may be increased to 200 mg/day as necessary, up to 300mg/day. Duration of treatment: 2-4 weeks, up to 6 months after recovery to prevent relapse. Neuropathic pain; Prophylaxis of migraine Initial: 10-25 mg preferably in the evening. May gradually increase to 10-25 mg every 3-7 days as tolerated. Recommended doses: 25-75 mg/day preferably in the evening.
Dosage Details
Oral
Nocturnal enuresis
Child: 6-10 years 10-20 mg daily. 11-16 years 25-50 mg at bedtime. Duration of treatment: Not to exceed 3 months.

Oral
Depression
Adult: Initially, 25 mg bid, then gradually increase by 25 mg every other day up to 150 mg daily in divided doses. Alternatively, initiate therapy with 50-100 mg at bedtime, may be increased by 25-50 mg as necessary to a total dose of 150 mg daily. For hospitalized patients: Initially, 100 mg daily, may be increased to 200 mg daily as necessary, up to 300 mg daily. Duration of treatment: 2-4 weeks, up to 6 months after recovery to prevent relapse.
Elderly: 10-25 mg daily preferably in the evening. May increase gradually to 100-150 mg daily, according to patient tolerability and response. Doses above 100 mg should be used with caution.

Oral
Neuropathic pain, Prophylaxis of migraine
Adult: Initially, 10-25 mg preferably in the evening. May increase gradually to 10-25 mg every 3-7 days as tolerated.  Recommended doses: 25-75 mg daily preferably in the evening. Doses above 75 mg may be given in divided dose. Doses above 100 mg should be used with caution.
Elderly: Initially, 10-25 mg preferably in the evening. May increase gradually according to patient response and tolerability. Doses above 75 mg should be used with caution.
Special Patient Group
Patient with CV disease: 10-25 mg daily preferably in the evening. May increase gradually to 100-150 mg daily, according to patient tolerability and response.

Pharmacogenomics:

Amitriptyline is primarily metabolised by CYP2C19 via demethylation and CYP2D6 via hydroxylation into active metabolite. Available studies show that approx 7-10% of Caucasians cannot metabolise CYP2D6 substrates and are classified as poor CYP2D6 metabolisers. CYP2C19 may vary among individuals of different ethnic background, approx 15% of Asian population has an allele frequency. It affects variability on pharmacokinetics, clinical efficacy and adverse effects. Genetic variation in CYP2D6 altering drug clearance or in CYP2C19 altering the ratio of parent drug to metabolites.

Monitor for amitriptyline serum concentration and genetic testing for CYP2D6 and CYP2C19 is recommended prior to initiation of treatment.

CYP2D6 Ultrarapid metaboliser (carrier of more than 2 copies of functional alleles e.g. *1/*1xN, *1/*2xN)
Increased metabolism reduces amitriptyline plasma concentrations resulting to pharmacotherapy failure. Avoid use and consider alternative drugs (e.g. citalopram and sertraline) that are not metabolised by CYP2D6. Titration to higher dose should be considered if TCA is necessary for the patient. Monitor therapy with therapeutic drug monitoring.

CYP2D6 Normal metaboliser (carrier of 2 normal function 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 dosage adjustment needed.

CYP2D6 Intermediate metaboliser (carrier of 1 decreased and 1 no function allele e.g. *4/*41, *5/*9, *4/*10)
Increased plasma concentrations and increased risk of adverse effects (e.g. arrhythmia, tachycardia) of amitriptyline. Initiate therapy with 25% dose reduction of recommended starting dose or use of alternative drugs (e.g. citalopram, sertraline). Monitor therapy with therapeutic drug monitoring.

CYP2D6 Poor metaboliser (carrier of no function alleles e.g. *4/*4, *4/*4xN, *3/*4, *5/*5, *5/*6)
Increased serum concentration and increased risk of adverse effects (e.g. arrhythmia, tachycardia) of amitriptyline. Avoid use and consider alternative drugs (e.g. citalopram, sertraline) that are not metabolised by CYP2D6. Dose reduction by 50% should considered if TCA is necessary for the patient. Monitor therapy with therapeutic drug monitoring.

CYP2C19 Ultrarapid metaboliser (carrier of 2 increased function alleles e.g. *17/*17)
Increased metabolism reduces amitriptyline plasma concentration resulting to pharmacotherapy failure. Consider use of alternative drug not metabolised by CYP2C19 (e.g. nortriptyline and desipramine) or adjust dose according to therapeutic drug monitoring, if tertiary amine is necessary.

CYP2C19 Rapid metaboliser (carrier of 1 normal and 1 increased function allele e.g. *1/*17)
Increased metabolism reduces amitriptyline plasma concentration resulting to pharmacotherapy failure. Consider use of alternative drug not metabolised by CYP2C19 (e.g. nortriptyline and desipramine) or adjust dose according to therapeutic drug monitoring, if tertiary amine is necessary.

CYP2C19 Normal metaboliser (carrier of 2 normal function alleles e.g. *1/*1)
Initiate therapy with recommended starting dose. No dosage adjustment needed.

CYP2C19 Intermediate metaboliser (carrier of 1 normal function allele and 1 no function allele e.g. *1/*2, *1/*3, *2/*17)
Reduced metabolism compared to normal metabolisers. Initiate therapy with recommended starting dose. No dosage adjustment needed.

CYP2C19 Poor metabolisers (carrier of 2 no function alleles e.g. *2/*2, *2/*3, *3/*3)
Increased plasma concentration due to greatly reduced metabolism of amitriptyline which may result in increased risk of adverse effect e.g. arrhythmia, tachycardia. Avoid tertiary amine use and consider 50% dose reduction of recommended starting dose or use alternative drug not metabolised by CYP2C19 (e.g. nortriptyline and desipramine). Monitor therapy with therapeutic drug monitoring.
Hepatic Impairment
Depression
Severe: Contraindicated.

Neuropathic pain; Prophylaxis of migraine
Severe: Contraindicated.

Administration
May be taken with or without food.
Contraindications
Recent MI, arrythmia (e.g. heart block), coronary artery insufficiency. Concomitant use within 14 days of MAOIs use and cisapride. Severe hepatic impairment. Children <6 years.
Special Precautions
Patient with CV disease (e.g. previous MI, stroke, tachycardia, or conduction abnormalities), head trauma, brain damage, alcoholism, history of seizures, diabetes mellitus, bipolar disorder, narrow angle glaucoma, urinary retention, prostatic hypertrophy, paranoid symptomology, pylorus stenosis, paralytic ileus, hyperthyroidism. Behavioural changes and increased risk of suicidal thinking. Concomitant electroconvulsive therapy and elective surgery. CYP2D6 ultrarapid, intermediate and poor metabolisers. CYP2C19 ultrarapid, rapid and poor metabolisers. Elderly and children. Renal and mild to moderate hepatic impairment. Pregnancy and lactation.
Adverse Reactions
Significant: Serotonin syndrome e.g. CNS depression, bone fractures, bone marrow suppression, mild pupillary dilation, orthostatic hypotension, QT interval prolongation.
Blood and lymphatic system disorders: Agranulocytosis, leukopenia, thrombocytopenia, purpura, eosinophilia.
Cardiac disorders: MI, heart block, arrythmias, tachycardia, palpitation.
Ear and labyrinth disorders: Tinnitus.
Eye disorders: Mydriasis, blurred vision, increased intraocular pressure, accommodation disorder.
Gastrointestinal disorders: Dry mouth, constipation, nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhoea, parotid swelling, black tongue.
General disorders and administration site conditions: Fever, hyperthermia, ataxia.
Investigations: Increase or decrease of blood sugar, weight gain or loss.
Metabolism and nutrition disorders: Oedema.
Nervous system disorders: Headache, seizures, incoordination, tremors, peripheral neuropathy, numbness, paraesthesia, extrapyramidal symptoms (e.g. speech difficulties), involuntary movements, tardive dyskinesia, disturbed concentration, excitement, insomnia, stroke, restlessness, drowsiness, agitation, dysgeusia.
Psychiatric disorders: Confusional states, hallucinations, disorientation, delusions, nightmares, dysarthria, anxiety, delirium, hypomania, mania.
Renal and urinary disorders: Urinary retention, frequency.
Reproductive system and breast disorders: Testicular swelling, gynecomastia, breast enlargement, galactorrhea, libido decreased, impotence.
Skin and subcutaneous tissue disorders: Rash, urticaria, photosensitivity, alopecia.
Vascular disorders: Syncope, hypertension, hypotension.
Patient Counseling Information
This drug may cause dizziness, drowsiness, and visual disturbances, if affected, do not drive or operate machinery. Avoid abrupt withdrawal.
MonitoringParameters
Obtain blood glucose, heart rate, blood pressure, weight, BMI, ECG, electrolyte levels (as indicated). Assess mental status, suicidal ideation, anxiety, social functioning, mania, panic attacks or other unusual changes in behaviour. Monitor TCA plasma levels when co-administered with a CYP2D6 inhibitor drug.
Overdosage
Symptoms: CNS depression, respiratory depression, cardiac dysrhythmias, convulsions, excitement, restlessness with marked antimuscarinic effects including dry mouth, intestinal stasis mydriasis, tachycardia, urinary retention, dry mucous membranes, reduced bowel motility; fever, severe hypotension, coma, hyperreflexia with extensor plantar reflexes, hypothermia. Management: Symptomatic and supportive treatment. Ensure adequate airway and IV access. Perform gastric lavage followed by activated charcoal within one hour of ingestion to reduce absorption. Obtain ECG and initiate cardiac monitoring. Intubation is advised for abrupt deterioration. Administer benzodiazepines or anticonvulsants (e.g. phenobarbital, phenytoin) to control seizures.
Drug Interactions
May potentiate CV effects of sympathomimetic agents (e.g. adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, phenylpropanolamine). May enhance sedative effects of barbiturates and other CNS depressants. May reduce antihypertensive effects of adrenergic neuron blockers (e.g. guanethidine, betanidine, reserpine, clonidine, methyldopa). May increase ventricular arrythmias with antiarrhythmics (e.g. quinidine, amiodarone), antihistamines (e.g. astemizole, terfenadine), halofantrine, sotalol. Diuretics (e.g. furosemide) may increase risk of hypokalaemia. May increase serum concentrations with antifungals (e.ag. fluconazole, terbinafine). Risk of delirium with disulfiram. Increased rate of metabolism with barbiturates. Increased plasma concentration with cimetidine, methylphenidate, antipsychotics, and Ca-channel blockers. Decreased rate of metabolism with CYP2D6 inhibitors.
Potentially Fatal: Increased risk of serotonin syndrome with MAOIs e.g. selegiline, fluoxetine. Increased risk of QT interval prolongation, cardiac arrhythmias with cisapride.
Food Interaction
May enhance CNS depressant effects of alcohol. Avoid alcohol. May increase risk of serotonin syndrome with St John’s wort.
Action
Description: Amitriptyline is a dibenzocycloheptadiene tricyclic antidepressant. It inhibits the neuronal reuptake of serotonin (5-HT) and/or norepinephrine by the presynaptic neuronal membrane, hence increasing the synaptic concentration in the CNS. It also possesses affinity for muscarinic and histamine (H1) receptors to varying degrees.
Pharmacokinetics:
Absorption: Readily absorbed from the gastrointestinal tract. Bioavailability: Approx 43-46%. Time to peak plasma concentration: Approx 6 hours.
Distribution: Crosses placenta and enters breast milk. Volume of distribution: Approx 18-22 L/kg. Plasma protein binding: Approx 96%.
Metabolism: Extensively metabolised in the liver via N-demethylation to nortriptyline (active metabolite), hydroxy derivatives and conjugated derivatives.
Excretion: Via urine (as glucuronide or sulfate conjugate metabolite; 18% as unchanged drug); faeces (small amounts). Elimination half-life: Approx 13-36 hours.
Chemical Structure

Chemical Structure Image
Amitriptyline

Source: National Center for Biotechnology Information. PubChem Database. Amitriptyline, CID=2160, https://pubchem.ncbi.nlm.nih.gov/compound/Amitriptyline (accessed on Jan. 20, 2020)

Storage
Store below 25°C. Protect from light.
MIMS Class
ATC Classification
N06AA09 - amitriptyline ; 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 29/04/2019

Amitriptyline Hydrochloride Film-Coated Tablet (Accord Healthcare Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/04/2019.

Annotation of CPIC Guideline for Amitriptyline and CYP2C19, CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 29/04/2019.

Annotation of DPWG Guideline for Amitriptyline and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 29/04/2019.

Annotation of FDA Label for Amitriptyline and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 29/04/2019.

Anon. Amitriptyline. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/04/2019.

Buckingham R (ed). Amitriptyline. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/04/2019.

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 29/04/2019.

Joint Formulary Committee. Amitriptyline Hydrochloride. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/04/2019.

Supplement to: Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6 and CYP2C19 Genotypes and Tricyclic Antidepressants: 2016 Update. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 28/05/2019.

Disclaimer: This information is independently developed by MIMS based on Amitriptyline 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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