Doxepin

Uses

Doxepin Tablet is used for Anxiety disorders, Depression, Insomnia and Doxepin cream is used for the short-term (upto 8 days) management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus.

Doxepin is also used to associated treatment for these conditions: Anxiety, Bipolar Affective Disorders, Depression, Depression, Involutional, Insomnia, Lichen simplex chronicus, Neuropathic Pain, Neurotic depression, Pruritus, Psychotic depressive disorder

How Doxepin works

Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker. This effect on histamine receptors indicates effectiveness in skin conditions.

Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites. It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors.

It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area.

Dosage

Doxepin dosage

Cream: Adult and child over 12 years: apply thinly 3–4 times daily; usual max. 3 g per application; usual total max. 12 g daily; coverage should be less than 10% of body surface area.

Oral: Adult: As hydrochloride: Initially, 75 mg daily adjusted according to response; up to 300 mg daily in severely depressed patients; 25-50 mg daily in mildly affected patients. Total daily dose 100 mg should be given in divided doses.

May be taken with or without food.

Side Effects

For Cream: Drowsiness, local burning, stinging, irritation, tingling, rash; systemic side-effects such as antimuscarinic effects, headache, fever, dizziness, gastro-intestinal disturbances has been reported.

For Oral: Sedation, fatigue, weakness, lethargy, Dry mouth, Constipation, Blurred vision, Headache, Agitation, Insomnia, Anxiety, Nausea, vomiting, Sweating, Confusion, extrapyramidal symptoms (EPS), dizziness, paresthesia, Orthostatic hypotension, ECG changes, tachycardia, Increased LFTs, Tinnitus, Sexual dysfunction, Rash, Seizure, Agranulocytosis, Thrombocytopenia, Eosinophilia.

Toxicity

Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively. In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed.

On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential.

Precaution

Cautions should be exercised if there is susceptibility to angle-closure glaucoma, urinary retention, severe liver impairment, mania and also in pregnancy and breast-feeding. Drowsiness may affect performance of skilled tasks (e.g. driving) so patient should be careful.

Interaction

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 like MAO inhibitors, cimetidine, alcohol may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with Doxepin cream.

Methylphenidate may increase plasma doxepin levels. Potentially Fatal: Potentiates hypertensive action of sympathomimetics. Increased anticholinergic effects with MAOIs. Additive CNS effects with anticholinergics, CNS depressants and alcohol.

Food Interaction

• Avoid alcohol. Co-administration may enhance CNS adverse effects such as drowsiness and sedation.
• Avoid St. John's Wort. Co-administration may lead to decreased serum concentrations of doxepin.

Doxepin Alcohol interaction

[Moderate] GENERALLY AVOID:

Concomitant use of ethanol and a tricyclic antidepressant (TCA) may result altered TCA plasma levels and efficacy, and additive impairment of motor skills, especially driving skills.

Acute ethanol ingestion may inhibit TCA metabolism, while chronic ingestion of large amounts of ethanol may induce hepatic TCA metabolism.

Patients should be advised to avoid alcohol during TCA therapy.

Alcoholics who have undergone detoxification should be monitored for decreased TCA efficacy.

Dosage adjustments may be required.

Doxepin Drug Interaction

Major: duloxetine, duloxetine, sertraline, sertralineModerate: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, zolpidem, zolpidem, clonazepam, clonazepam, pregabalin, pregabalin, quetiapine, quetiapine, alprazolam, alprazolam, cetirizine, cetirizineUnknown: cholecalciferol, cholecalciferol

Doxepin Disease Interaction

Major: depression, anticholinergic effects, anticholinergic effects, cardiovascular disease, pheochromocytoma, acute myocardial infarction recovery, cardiovascular disease, depression, seizure disordersModerate: glaucoma, liver disease, renal/liver disease, bipolar screening, bone marrow suppression, diabetes, renal/liver disease, schizophrenia/bipolar disorder, tardive dyskinesia, acute alcohol intoxication, bipolar disorder screening, glaucoma, hyper/hypoglycemia, liver/renal disease, neutropenia, schizophrenia, thyroid disorders, urinary retention

Volume of Distribution

The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg.

Elimination Route

Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal.

Half Life

The mean elimination half-life is reported to be of 15 hours.

Clearance

The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg.

Elimination Route

The elimination profile of doxepin is presented as biphasic. It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin.

Pregnancy & Breastfeeding use

Pregnancy: Category B- There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Doxepin is excreted in human milk after oral administration. It is possible that doxepin may also be excreted in human milk following topical application of Doxepin cream.

Contraindication

Patients with untreated narrow angle glaucoma or a tendency to urinary retention because doxepin has an anticholinergic effect. Individuals who have shown previous sensitivity to any of its components. Hypersensitivity; mania, glaucoma, neonates (topical); lactation.

Special Warning

Use in Children: The use of Doxepin cream in pediatric patients is not recommended. Safe conditions for use of cream in children have not been established.

Use in Elderly Patients: Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Acute Overdose

If overdosage with topical application of Doxepin cream occur, the signs and symptoms may include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia.

Storage Condition

Store at 15-30°C.

Innovators Monograph

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