Doxepin
Clinical data | |
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Trade names | Sinequan, Quitaxon, Aponal, others[1] |
Other names | NSC-108160[2] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682390 |
License data | |
Pregnancy category |
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intravenous, intramuscular injection[3] | |
Drug class | Tricyclic antidepressant (TCA) |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 13–45% (mean 29%)[5][6] |
Protein binding | 76%[7] |
Metabolism | Liver (CYP2D6, CYP2C19)[8][5] |
Metabolites | Nordoxepin, glucuronide conjugates[8] |
Elimination half-life | Doxepin: 8–24 hours (mean 17 hours)[7] Nordoxepin: 28–31 hours[7][9] |
Excretion | Kidney: ~50%[8][5] Feces: minor[5] |
Identifiers | |
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JSmol) | |
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Doxepin is a
Common side effects include sleepiness, dry mouth, constipation, nausea, and blurry vision.[10] Serious side effects may include increased risk of suicide in those under the age of 25, mania, and urinary retention.[10] A withdrawal syndrome may occur if the dose is rapidly decreased.[10] Use during pregnancy and breastfeeding is not generally recommended.[14][15] Although how it works for treating depression remains an area of active inquiry, it may involve increasing the levels of norepinephrine, along with blocking histamine, acetylcholine, and serotonin.[10]
Doxepin was approved for medical use in the United States in 1969.
Medical uses
Doxepin is used as a pill to treat
Insomnia
Doxepin is used in the treatment of insomnia.[11] In 2016, the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short-term help maintaining sleep, on the basis of weak evidence.[20][21] The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar.[20] A 2015 Agency for Healthcare Research and Quality review of treatments for insomnia had similar findings.[22]
A major
Doses of doxepin used for sleep normally range from 3 to 6 mg, but high doses of up to 25 to 50 mg may be used as well.[24][25]
Other uses
A 2010 review found that topical doxepin is useful to treat itchiness.[26]
A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second-line treatment.[27]
Contraindications
Known contraindications include:[28]
- Hypersensitivities to doxepin, other TCAs, or any of the excipients inside the product used
- Glaucoma
- A predisposition to developing urinary retention such as in benign prostatic hyperplasia
- Use of monoamine oxidase inhibitors in last 14 days[29]
Pregnancy and lactation
Its use in pregnant and lactating women is advised against, although the available evidence suggests it is unlikely to cause negative effects on fetal development.
Side effects
Doxepin's side effects profile may differ from the list below in some countries where it is licensed to be used in much smaller doses (viz., 3 mg and 6 mg).
- Central nervous system: extrapyramidal side effects (rarely), abuse in patients with polytoxicomania (rarely), ringing in the ears (tinnitus)
- Anticholinergic: dry mouth, constipation, even ileus (rarely), difficulties in urinating, sweating, precipitation of glaucoma
- )
- Allergic/toxic: skin rash, photosensitivity, liver damage of the cholestatic type (rarely), hepatitis (extremely rare), leuko- or thrombocytopenia (rarely), agranulocytosis (very rarely), hypoplastic anemia (rarely)
- Others: frequently increased appetite and weight gain, rarely nausea, rarely high blood pressure. May increase or decrease liver enzyme levels in the blood of some people.[31]
The side effects of low-dose doxepin for insomnia in long-term clinical trials (28 to 85 days) in adults and elderly people were as follows:[11]
Side effect | Placebo (N=278) |
Doxepin 3 mg (N=157) |
Doxepin 6 mg (N=203) |
---|---|---|---|
Somnolence/sedation | 4% | 6% | 9% |
nasopharyngitis |
2% | 4% | 2% |
Gastroenteritis | 0% | 2% | 0% |
Nausea | 1% | 2% | 2% |
Hypertension | 0% | 3% | <1% |
Note: Includes reactions that occurred at a rate of ≥ 2% in any doxepin-treated group and at a higher rate than placebo. |
Overdose
Like other TCAs, doxepin is highly
Interactions
Doxepin should not be used within 14 days of using a
Pharmacology
Doxepin is a
Pharmacodynamics
Site | Ki (nM) | Species | Ref |
---|---|---|---|
SERT | 68–95 210 ( IC50 ) |
Human | [36][34] [8] |
NET | 30–58 13 (IC50) |
Human | [36][34] [8] |
DAT | >10,000 4,600 (IC50) |
Human | [36] [8] |
5-HT1A | 276 | Human | [37] |
5-HT2A | 11–27 | Human | [34][37] |
5-HT2B | ND | ND | ND |
5-HT2C | 200 8.8 |
Human Rat |
[34] [38] |
5-HT3 | ND | Human | [39] |
5-HT6 | 136 | Rat | [40] |
5-HT7 | ND | ND | ND |
α1 | 24 | Human | [34] |
α1B | 12 | Human | [34] |
α2A | 1,100–1,270 | Human | [34][37] |
α2B | 28 | Human | [34] |
α2C | 96 | Human | [34] |
D2 |
360 | Human | [37] |
H1 | 0.09–1.23 | Human | [41][37][34] |
H2 | 174 | Human | [41] |
H3 | 39,800 | Human | [41][34] |
H4 | 15,100 | Human | [41][42] |
mACh | 23–80 | Human | [37][43] |
M1 | 18–38 | Human | [34][44] |
M2 | 160–230 | Human | [34][44] |
M3 | 25–52 | Human | [34][44] |
M4 | 20–82 | Human | [34][44] |
M5 | 5.6–75 | Human | [34][44] |
hERG |
6,500 ( IC50 ) |
Human | [45] |
Values are Ki, unless otherwise specified. The smaller the value, the more strongly the drug binds to the site. |
Doxepin is a
- Extremely strong: H1 receptor
- Strong: α1-adrenergic receptor, 5-HT2A and muscarinic acetylcholine receptors
- Moderate: 5-HT1A receptors
- Weak: D2 receptors
Based on its
The major
Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day.[53][12] Antihistamine doses, including for dermatological uses and as a sedative/hypnotic for insomnia, are considered to be 3 to 25 mg,[54][12] although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia.[55] At low doses, below 25 mg, doxepin is a pure antihistamine and has more of a sedative effect.[53] At antidepressant doses of above 75 mg, doxepin is more stimulating with antiadrenergic, antiserotonergic, and anticholinergic effects, and these activities contribute to its side effects.[54][53][12]
Doxepin is a
As a hypnotic
Drug | H1 |
mACh | Ratio |
---|---|---|---|
Amitriptyline | 1.1 | 18 | 1:16 |
Amoxapine | 25 | 1,000 | 1:40 |
Clomipramine | 31 | 37 | 1:1.2 |
Desipramine | 110 | 196 | 1:1.8 |
Dosulepin[54] | 4.0 | 38 | 1:9.5 |
Doxepin | 0.24 | 83 | 1:346 |
Imipramine | 11 | 91 | 1:8.3 |
Lofepramine[37] | 360 | 67 | 1:0.2 |
Maprotiline | 2.0 | 560 | 1:280 |
Mianserin | 0.40 | 820 | 1:2050 |
Mirtazapine | 0.14 | 670 | 1:4786 |
Nortriptyline | 10 | 149 | 1:15 |
Protriptyline | 25 | 25 | 1:1 |
Trimipramine | 0.27 | 58 | 1:215 |
Values are Ki (nM). |
Doxepin is a highly potent antihistamine, with this being its strongest activity.
The H1 receptor antagonism of doxepin is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses.
The
At very low doses, doxepin has not shown discontinuation or
Antagonism of the H1, 5-HT2A, 5-HT2C, and α1-adrenergic receptors is thought to have sleep-promoting effects and to be responsible for the sedative effects of TCAs including those of doxepin.[63][64][65] Although doxepin is selective for the H1 receptor at doses lower than 25 mg, blockade of serotonin and adrenergic receptors may also be involved in the hypnotic effects of doxepin at higher doses.[63] However, in contrast to very low doses of doxepin, rebound insomnia and daytime sedation are significantly more frequent than placebo with moderate doses (25 to 50 mg/day) of the drug.[12] In addition, one study found that although such doses of doxepin improved sleep measures initially, most of the benefits were lost with chronic treatment (by 4 weeks).[12] Due to limited data however, more research on potential tolerance and withdrawal effects of moderate doses of doxepin is needed.[12] At these doses of doxepin, dry mouth, an anticholinergic effect, was common (71%), and other side effects such as headache (25%), increased appetite (21%), and dizziness (21%) were also frequently observed, although these adverse effects were notably not significantly more frequent than with placebo in the study in question.[12] In any case, taken together, higher doses of doxepin than very low doses are associated with an increased rate of side effects as well as apparent loss of hypnotic effectiveness with chronic treatment.[57]
Doxepin at a dose of 25 mg/day for 3 weeks has been found to decrease
CYP2D6 inhibition
Doxepin has been identified as an inhibitor of CYP2D6 in vivo in a study of human patients being treated with 75 to 250 mg/day for depression.[66] While it significantly altered metabolic ratios for sparteine and its metabolites, doxepin did not convert any of the patients to a different metabolizer phenotype (e.g., extensive to intermediate or poor).[66] Nonetheless, inhibition of CYP2D6 by doxepin could be of clinical importance.[66]
Pharmacokinetics
Parameters | Doxepin | Nordoxepin |
---|---|---|
Tmax (hours) |
Mean: 2.9 Range: 2–4 |
Mean: ND Range: 2–10 |
Cmax (ng/mL) |
Mean: ND Range: 8.8–45.8 |
Mean: 9.7 Range: 4.8–14.5 |
VD (L/kg) | 20 | ND |
Protein binding | 76% | ND |
t1/2 (hours) |
Mean: 17 Range: 8–24 |
Mean: 31 Range: ND |
Metabolic enzymes |
Major: CYP2D6, CYP2C19 Minor: CYP1A2, CYP2C9, CYP3A4 | |
Metabolic pathways |
N- oxidation, hydroxylation, glucuronidation
|
Absorption
Doxepin is well-
Distribution
Doxepin is widely distributed throughout the body and is approximately 80% plasma protein-bound, specifically to albumin and α1-acid glycoprotein.[8][68]
Metabolism
Doxepin is extensively
Nordoxepin is a
Elimination
Doxepin is
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 drug's 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. Ultrarapid metabolizers break down doxepin much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.
A study assessed the metabolism of a single 75 mg oral dose of doxepin in healthy volunteers with
Another study assessed doxepin and nordoxepin metabolism in CYP2D6
Chemistry
Doxepin is a
History
Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969.[48] It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.[12][77]
Society and culture
Generic names
Doxepin is the
The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its
while cidoxepin hydrochloride is itsBrand names
It was introduced under the brand names Quitaxon and Aponal by Boehringer and as Sinequan by Pfizer.[79]
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.
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.[80] In Australia and the United Kingdom, the only licensed indications are in the treatment of major depression and pruritus in eczema.[30][81]
Research
Antihistamine
Headache
Doxepin was under development by Winston Pharmaceuticals in an
Neuropathic pain
As of 2017, there was no good evidence that topical doxepin was useful to treat localized neuropathic pain.[84]
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External links
- Media related to Doxepin at Wikimedia Commons