Up to 10% of Caucasian individuals show substantially reduced metabolism of doxepin that can result in up to 8-fold elevated plasma concentrations of the drug compared to normal.Nordoxepin is a mixture of (E) and (Z) stereoisomers similarly to doxepin. Whereas pharmaceutical doxepin is supplied in an approximate 85:15 ratio mixture of (E)- and (Z)-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the (E)- and (Z)-stereoisomers of nordoxepin, due to stereoselective metabolism of doxepin by cytochrome P450 enzymes, are approximately 1:1. Elimination
Doxepin is eliminated primarily in the urine and predominantly in the form of glucuronide conjugates, with less than 3% of a dose excreted unchanged as doxepin or nordoxepin. Pharmacogenetics
Since doxepin is mainly metabolized by CYP2D6, CYP2C9, and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of doxepin may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drugs efficacy. Individuals can be categorized into different types of cytochrome P450 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most people are extensive metabolizers, and have "normal" metabolism of doxepin. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects.
The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely. The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4. History
Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969. It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010. Society and culture
Generic names
Doxepin is the generic name of the drug in English and German and its INN and BAN, while doxepin hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are doxepina, in French and its DCF are doxépine, and in Latin is doxepinum.The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its INN while cidoxepin hydrochloride is its USAN. Brand names
It was introduced under the brand names Quitaxon and Aponal by Boehringer and as Sinequan by Pfizer.Doxepin is marketed under many brand names worldwide, including: Adnor, Anten, Antidoxe, Colian, Deptran, Dofu, Doneurin, Dospin, Doxal, Doxepini, Doxesom, Doxiderm, Flake, Gilex, Ichderm, Li Ke Ning, Mareen, Noctaderm, Oxpin, Patoderm, Prudoxin, Qualiquan, Quitaxon, Sagalon, Silenor, Sinepin, Sinequan, Sinquan, and Zonalon. It is also marketed as a combination drug with levomenthol under the brand name Doxure. Approvals
The oral formulations of doxepin are FDA-approved for the treatment of depression and sleep-maintenance insomnia, and its topical formulations are FDA-approved the short-term management for some itchy skin conditions.