8.20.2018 by Isaac Mercer

Equilibrium dialysis indicate a mean protein binding of 75.5% for doxepin and 76.0% for desmethyldoxepin.

* Oral: * - Indicated for the treatment of depression and/or anxiety. - Indicated for the treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders. - Indicated for the treatment of insomnia characterized by difficulties with sleep maintenance.

Doxepin is widely distributed throughout the body tissues. The mean apparent volume of distribution following a single 6 mg oral dose of Silenor to healthy subjects was 11,930 L.

In a thorough QTc prolongation clinical study in healthy subjects, doxepin had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 50 mg.

Doxepin, a tricyclic antidepressant of the dibenzoxepin type, is used to treat depression and anxiety and, topically, pruritus associated with eczema. Doxepin has substantial anticholinergic and sedative effects. The E (trans)-isomer is more active as a serotonin reuptake inhibitor while the Z-isomer acts as a sedative.

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

Doxepin 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.


Oral LD50 values in mouse and rat are 180 mg/kg and 147 mg/kg, respectively. 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.

Luigi Schioppi, Brian Talmadge Dorsey, Michael Skinner, John Carter, Robert Mansbach, Philip Jochelson, Roberta L. Rogowski, Cara Casseday, Meredith Perry, Bryan Knox, "LOW-DOSE DOXEPIN FORMULATIONS AND METHODS OF MAKING AND USING THE SAME." U.S. Patent US, issued March 19, 2009.

The mechanism of action of doxepin is not compley understood. It is thought that like amitriptyline, doxepin enhances the actions of norepinephrine and serotonin by blocking their reuptake at the neuronal membrane. However, doxepin weakly inhibits the reuptake of dopamine. Doxepin may also act on histamine H 1 -receptors, resulting in sedative effects, and β-adrenergic receptors. It is also an antagonist of 5-hydroxytryptamine (serotonin) receptors, alpha-1 adrenergic receptor, and muscarinic cholinergic receptors.

Doxepin is a dibenzoxepin-derivative tricyclic antidepressant (TCA). Structurally similar to phenothiazines, TCAs contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, doxepin does not affect mood or arousal, but may cause sedation. In depressed individuals, doxepin exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Tertiary amine TCAs, such as doxepin and amitriptyline, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline and desipramine. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H 1 receptors, α 1 -adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. Doxepin has less sedative and anticholinergic effects than amitriptyline. See toxicity section below for a complete listing of side effects. When orally administered, doxepin may be used to treat depression and insomnia. Unlabeled indications of oral doxepin also include chronic and neuropathic pain, and anxiety. Doxepin may also be used as a second line agent to treat idiopathic urticaria. As a topical agent, doxepin may be used relieve itching in patients with certain types of eczema. It may be used for the management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus.

Doxepin is reported to be well-absorbed from the GI tract. Peak plasma concentrations (Cmax) occur within 1-2 hours of oral administration. The AUC and Cmax are expected to increase when administered with a high fat meal. Doxepin is also a lipophillic drug and may be capable of crossing the blood-brain-barrier.

No evidence of carcinogenic potential was observed in mice studies. Doxepin was negative in in vitro (bacterial reverse mutation, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays, indicating it is unlikely to be mutagenic compound. The effects of doxepin on fertility were investigated in male and female rats. Adverse effects on fertility (increased copulatory interval and decreased corpora lutea, implantation, viable embryos and litter size) and sperm parameters (increased percentages of abnormal sperm and decreased sperm motility) were observed. However the AUC for doxepin and nordoxepin at the no-effect dose for adverse effects on reproductive performance and fertility in rats (10 mg/kg/day) are less than those in humans at the maximum recommended human dose of 6 mg/day.

Extensively metabolized in the liver via the same pathways as other TCAs. Following oral administration, doxepin undergoes extensive oxidation and demethylation. In vitro studies have shown that CYP2C19 and CYP2D6 are the major enzymes involved in doxepin metabolism, and that CYP1A2 and CYP2C9 are involved to a lesser extent. N-demethylation produces a primary active metabolite, N-desmethyldoxepin (nordoxepin). The primary metabolite undergoes further biotransformation to glucuronide conjugates.

This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British Columbia, and Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with funding from the federal government. Maintenance, support, and commercial licensing is provided by OMx Personal Health Analytics, Inc. Designed by Educe Design & Innovation Inc.

Topical: - Indicated for the short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus.

Half life of doxepin ranges from 6 to 24.5 hours. The mean distribution half-life of doxepin was 2.0 hrs and the mean elimination half-life ranges from 15.3 to 17.9 hrs. The apparent terminal half-life of desmethyldoxepin was 31 hours.

Drug created on June 13, 2005 07:24 / Updated on September 15, 2018 18:14.