Adult: As cap/soln: Initially, 75 mg daily, adjusted according to individual response. May increase up to 300 mg daily in severe cases. Doses up to 100 mg daily may be given as single dose at bedtime or in divided doses. Doses >100 mg should be given in 3 divided doses. Elderly: Initiate at lower doses and monitor closely.
Adult: As tab: 3-6 mg once daily, taken within 30 minutes of bedtime and not within 3 hours of a meal. Max: 6 mg daily. Re-evaluate patient after 7-10 days if insomnia persists. Elderly: ≥65 years 3 mg once daily, may be increased to 6 mg daily if necessary.
Topical/Cutaneous Pruritic skin disorders
Adult: As 5% cream: Apply a thinly to the affected area 3-4 times daily, with at least 3-4 hours interval between application, for up to 8 days. Max coverage area: <10% of BSA. Child: >12 years Same as adult dose.
Special Patient Group
Patients with very mild cases or emotional symptoms accompanying organic disease: As oral solution: Initiate at lower doses (e.g. 25-50 mg daily).
Doxepin is mainly metabolised via demethylation, N-oxidation and hydroxylation by CYP2D6 and CYP2C19 isoenzymes, and to a lesser extent by CYP3A4 and CYP1A2 isoenzymes. Genetic variations in CYP2D6 and CYP2C19 may influence the pharmacokinetic parameters, treatment outcomes, and safety of doxepin. Pharmacogenetic testing for may be considered prior to initiation of therapy.
CYP2D6 ultrarapid metabolisers (carriers of >2 copies of functional alleles e.g. *1/*1xN, *1/*2xN, *2/*2xN)
Patients may have increased metabolism as compared with normal metabolisers and decreased plasma concentrations which increases the risk of treatment failure.
CPIC strongly recommends avoiding the use of doxepin due to possible lack of efficacy. Consider the use of an alternative drug not metabolised by CYP2D6 (e.g. anticholinergic, CNS or cardiac effects). If doxepin use is necessary, may consider titrating to a higher target dose (as compared to the dosage of normal metabolisers) and adjust the dose according to therapeutic drug monitoring.
CYP2D6 normal metabolisers (carriers of 2 normal function alleles, or 2 decreased function alleles, or 1 normal and 1 non-functional allele, or 1 normal and 1 decreased function allele, or combinations of duplicated alleles resulting in activity score of 1-2 e.g. *1/*1, *1/*2, *2/*2, *1/*9, *1/*41, *41/*41, *1/*4, *1/*5).
Initiate treatment with the recommended starting dose. No dosage adjustment needed.
CYP2D6 intermediate metabolisers (carriers of 1 decreased function and 1 non-functional allele e.g. *4/*41, *5/*9, *4/*10)
Patients may have reduced metabolism as compared with normal metabolisers, and increased plasma concentrations resulting in increased risk of adverse effects (e.g. anticholinergic, CNS or cardiac effects).
Consider a 25% reduction of the recommended starting dose and adjust the dose according to therapeutic drug monitoring.
CYP2D6 poor metabolisers (carriers of only non-functional alleles e.g. *4/*4, *4/*4xN, *3/*4, *5/*5, *5/*6)
Patient may have greatly reduced metabolism as compared with normal metabolisers, and increased doxepin plasma concentrations which increases the risk of adverse effects (e.g. anticholinergic, CNS or cardiac effects). The prevalence of this variant allele is estimated in approx 7-10% in Caucasians, while reliable estimates among Asians, Africans and other populations are not yet available.
CPIC strongly suggests avoiding the use of doxepin. Consider the use of an alternative drug not metabolised by CYP2D6. If the doxepin use is necessary, may consider a 50% reduction of the recommended starting dose and adjust the dose according to therapeutic drug monitoring.
CYP2C19 ultrarapid metabolisers (carriers of 2 increased function alleles e.g. *17/*17) and CYP2C19 rapid metabolisers (carriers of 1 normal and 1 increased function allele e.g. *1/*17)
Patients may have increased doxepin metabolism as compared to normal metabolisers, and increased the risk of suboptimal response or adverse effects (e.g. anticholinergic, CNS or cardiac effects). Avoid the use of doxepin, or consider an alternative drug not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). If the doxepin use is necessary, adjust dose according to the therapeutic drug monitoring.
CYP2C19 normal metabolisers (carriers of 2 normal function alleles e.g. *1/*1)
Initiate treatment with the recommended starting dose. No dosage adjustment needed.
CYP2C19 intermediate metabolisers (carriers of 1 normal and 1 non-functional allele, or 1 non-functional and 1 increased function allele e.g. *1/*2, *1/*3, *2/*17)
Patients may have reduced doxepin metabolism as compared with normal metabolisers. The prevalence of *3 allele is low among most ethnic groups but has approx 15% frequency in some Asian populations. No dosage adjustment needed. Initiate treatment with the recommended starting dose.
CYP2C19 poor metabolisers (carriers of 2 non-functional alleles e.g. *2/*2, *2/*3, *3/*3)
Patients may have greatly reduced doxepin metabolism as compared to normal metabolisers, thereby increasing the risk of suboptimal response or adverse effects (e.g. anticholinergic, CNS or cardiac effects). Avoid the use of doxepin, or consider an alternative drug not metabolised by CYP2C19 (e.g. nortriptyline, desipramine). Alternatively, reduce the recommended starting dose by 50% and adjust the dose according to therapeutic drug monitoring.
Dose reduction may be necessary.
Initially, 3 mg once daily.
Dose reduction may be necessary. Severe: Contraindicated.
May be taken with or without food.
Hướng dẫn pha thuốc
Oral soln: Mix with approx 120 mL of water, whole or skimmed milk, or orange, grapefruit, tomato, prune or pineapple juice immediately before administration.
Oral solution: Incompatible with carbonated beverages.
Chống chỉ định
Mania, narrow-angle glaucoma, tendency to urinary retention. Severe liver impairment. Lactation. Concomitant use or within 14 days of discontinuing MAOIs.
Patient with bipolar disorder; history of suicide-related events, epilepsy, risk factors of seizures (e.g. head trauma, brain damage, alcoholism), CV disease (e.g. recent MI, heart block, tachycardia, cardiac arrhythmia, conduction abnormalities), cerebrovascular disease, hypovolaemia, compromised respiratory function, sleep apnoea, decreased gastrointestinal motility, paralytic ileus, benign prostatic hyperplasia, xerostomia, visual problems, diabetes mellitus, hyperthyroidism. Patient undergoing elective surgery. Concomitant electroconvulsive therapy. Avoid abrupt withdrawal. Renal and mild to moderate hepatic impairment. Children and elderly. Pregnancy. CYP2D6 ultrarapid, intermediate and poor metabolisers. CYP2C19 ultrarapid, rapid and poor metabolisers.
Phản ứng phụ
Significant: Suicidal ideation and behaviour, precipitation of mania or hypomania, anticholinergic effects (e.g. constipation, dry mouth, blurred vision, urinary retention), CNS depression, bone fractures, mild pupillary dilation, orthostatic hypotension, QT prolongation, sleep-related activities (e.g. sleep-driving, cooking, eating or making phone calls while asleep), amnesia, hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), withdrawal symptoms, contact sensitisation (topical). Blood and lymphatic system disorders: Rarely, eosinophilia, purpura, leucopenia, agranulocytosis, thrombocytopenia. Endocrine disorders: Extrapyramidal symptoms. Gastrointestinal disorders: Nausea, vomiting, indigestion, diarrhoea, taste disturbances. General disorders and administration site conditions: Fatigue, weakness, chills, facial oedema; application site reactions (e.g. burning, or stinging sensation, irritation). Immune system disorders: Urticaria. Investigations: Weight gain, increased or decreased blood sugar levels. Metabolism and nutrition disorders: Anorexia. Nervous system disorders: Drowsiness, tremors, paraesthesia, headache, dizziness. Rarely, convulsions. Psychiatric disorders: Insomnia, nightmares, confusion, disorientation, agitation. Reproductive system and breast disorders: Testicular swelling, gynecomastia. Respiratory, thoracic and mediastinal disorders: Nasopharyngitis. Skin and subcutaneous tissue disorders: Rash, sweating, pruritus, photosensitisation, alopecia. Vascular disorders: Flushing.
This drug may cause drowsiness, if affected, do not drive or operate machinery. Topical: Avoid use of occlusive dressing.
Monitor ECG, heart rate and blood pressure in at risk patients; serum electrolytes (e.g. K, Na, magnesium), LFTs, blood glucose, weight and BMI at baseline, at periodic intervals and as clinically indicated. Closely monitor CNS status for signs of suicidal ideation, clinical worsening, and unusual behavioural changes especially at the start of therapy or when doses are increased or decreased; local skin reactions, excessive drowsiness or other systemic effects.
Symptoms: Mild: Drowsiness, stupor, blurred vision, excessive dryness of mouth. Severe: Bladder atony, paralytic ileus, hypothermia, dilated pupils, hyperactive reflexes, hyper- or hypotension, tachycardia, cardiac arrhythmias, convulsion, respiratory depression, or coma. Management: Symptomatic and supportive treatment. Perform continuous gastric lavage using saline for 24 hours or more. Administer activated charcoal; Na bicarbonate IV to maintain serum pH; appropriate antiarrhythmic agent for arrhythmias; 1-3 mg of physostigmine salicylate via slow IV inj for severe CV and CNS symptoms (repeated as necessary); standard anti-convulsant therapy for convulsions, however, barbiturates may potentiate respiratory depression. Monitor ECG for possible relapse. Establish adequate airway and assisted ventilation for comatose patients.
Increased plasma concentrations with CYP2D6 inhibitors (e.g. quinidine, SSRIs). Increased risk of arrhythmias, hypo- or hypertension with anaesthetics, sympathomimetic agents (e.g. ephedrine, isoprenaline). May decrease antihypertensive effects of debrisoquine, bethanidine, guanethidine, clonidine. Increased rate of metabolism with barbiturates. Cimetidine may fluctuate steady-serum concentration of doxepin. May reduce effect of sublingual nitrates owing to dry mouth. Increased risk of severe hypoglycaemia with tolazamide. Potentially Fatal: Increased risk of serotonin syndrome with MAOIs.
Increased risk of serotonin syndrome with St. John’s wort. May potentiate sedative effects of alcohol. Increased bioavailability and delayed peak plasma concentration with high-fat meals (tablet).
Description: Doxepin, a dibenzoxepin derivative TCA, inhibits the re-uptake of serotonin and norepinephrine by the presynaptic neuronal membrane, thereby increasing their concentrations in the CNS. The exact mechanism for its anti-pruritic activity is still unknown; however, doxepin has potent histamine H1 and H2 receptor blocking effects. Pharmacokinetics: Absorption: Readily absorbed from the gastrointestinal tract. Food, particularly high-fat meals may increase bioavailability and may delay peak plasma levels. Bioavailability: 27%. Time to peak plasma concentration: Approx 2-4 hours (capsule); 3.5 hours (tablet). Distribution: Widely distributed throughout the body. Crosses the blood-brain barrier and placenta, enters breast milk. Volume of distribution: Approx 20 L/kg. Plasma protein binding: Approx 80%. Metabolism: Undergoes extensive first-pass metabolism in the liver via demethylation to form the active metabolite, N-desmethyldoxepin (nordoxepin); further metabolise via demethylation, N-oxidation, hydroxylation and glucuronide formation primarily by CYP2D6 and CYP2C19 isoenzymes. Excretion: Mainly via urine (<3% as unchanged drug or N-desmethyldoxepin). Elimination half-life: Oral: Approx 15 hours (doxepin); 31-51 hours (N-desmethyldoxepin). Topical: 28-52 hours (N-desmethyldoxepin).
Tab/cap/oral soln: Store between 20-25°C. Protect from light. Cream: Store below 27°C.