Doxepin

Source: Wikipedia, the free encyclopedia.
Doxepin
Clinical data
Trade namesSinequan, Quitaxon, Aponal, others[1]
Other namesNSC-108160[2]
AHFS/Drugs.comMonograph
MedlinePlusa682390
License data
Pregnancy
category
  • AU: C
Drug classTricyclic antidepressant (TCA)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability13–45% (mean 29%)[5][6]
Protein binding76%[7]
MetabolismLiver (CYP2D6, CYP2C19)[8][5]
MetabolitesNordoxepin, glucuronide conjugates[8]
Elimination half-lifeDoxepin: 8–24 hours (mean 17 hours)[7]
Nordoxepin: 28–31 hours[7][9]
ExcretionKidney: ~50%[8][5]
Feces: minor[5]
Identifiers
  • (E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
JSmol)
  • CN(C)CC/C=C1C2=C(C=CC=C2)OCC3=C/1C=CC=C3
  • InChI=1S/C19H21NO/c1-20(2)13-7-11-17-16-9-4-3-8-15(16)14-21-19-12-6-5-10-18(17)19/h3-6,8-12H,7,13-14H2,1-2H3 checkY
  • Key:ODQWQRRAPPTVAG-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Doxepin is a

cream for itchiness due to atopic dermatitis or lichen simplex chronicus.[13]

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.

generic medication.[14][16][17] In 2020, it was the 252nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[18][19]

Medical uses

Doxepin is used as a pill to treat

anxiety disorders, and chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia).[10][7][11] As a cream it is used for short-term treatment of itchiness caused by atopic dermatitis or lichen simplex chronicus.[13]

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

orexin receptor antagonists, such as suvorexant, were more similar (SMDs of 0.23 to 0.44).[23]

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]

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.

respiratory depression in association with maternal doxepin use have been reported.[30]

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).

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 effects of low-dose doxepin for insomnia[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

Haemodialysis is not recommended due to the high degree of protein binding with doxepin.[7] ECG monitoring is recommended for several days after doxepin overdose due to the potential for cardiac conduction abnormalities.[7]

Interactions

Doxepin should not be used within 14 days of using a

thyroid hormones may also increase the potential for adverse reactions.[7]

Pharmacology

Doxepin is a

Pharmacodynamics

Doxepin[35]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter 68–95
210 (
IC50
Tooltip Half-maximal inhibitory concentration)
Human [36][34]
[8]
NETTooltip Norepinephrine transporter 30–58
13 (IC50)
Human [36][34]
[8]
DATTooltip Dopamine transporter >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]
mAChTooltip Muscarinic acetylcholine receptor 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
Tooltip Human Ether-à-go-go-Related Gene
6,500 (
IC50
Tooltip Half-maximal inhibitory concentration)
Human [45]
Values are Ki, unless otherwise specified. The smaller the value, the more strongly the drug binds to the site.

Doxepin is a

H2 receptors, the serotonin 5-HT2A and 5-HT2C receptors, the α1-adrenergic receptor, and the muscarinic acetylcholine receptors (M1M5).[35] Similarly to other tricyclic antidepressants, doxepin is often prescribed as an effective alternative to SSRI medications. Doxepin is also a potent blocker of voltage-gated sodium channels, and this action is thought to be involved in both its lethality in overdose[46] and its effectiveness as an analgesic (including in the treatment of neuropathic pain,[47] and as a local anesthetic).[48] The potencies of doxepin in terms of its receptor antagonism specifically are as follows:[48][49]

Based on its

5-HT2A serotonin receptor subtype. There is negligible influence on dopamine reuptake.[36][34]

The major

tertiary amine TCAs like nordoxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities.[50][51][52]

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

stereoisomers with an approximate ratio of 85:15.[5] When doxepin was developed, no effort was made to separate or balance the mixture following its synthesis, resulting in the asymmetric ratio.[5] (Z)-Doxepin is more active as an inhibitor of serotonin and norepinephrine reuptake than (E)-doxepin.[5] The selectivity of doxepin for inhibition of norepinephrine reuptake over that of serotonin is likely due to the 85% presence of (E)-doxepin in the mixture.[5] Most other tertiary amine TCAs like amitriptyline and imipramine do not exhibit E-Z isomerism or such mixture asymmetry and are comparatively more balanced inhibitors of serotonin and norepinephrine reuptake.[5][36]

As a hypnotic


TCAs and TeCAs at H1
and mACh receptors[56][43]
Drug
H1
mAChTooltip Muscarinic acetylcholine receptor 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.

memory impairment, unlike most other sedating antihistamines, and similarly has no effect on other receptors such as adrenergic and serotonin receptors.[53][8][12]

The H1 receptor antagonism of doxepin is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses.

safety.[12][61] Aside from diphenhydramine and doxylamine, which have historical approval as hypnotics, doxepin is the only H1 receptor antagonist that is specifically approved for the treatment of insomnia in the United States.[61][62]

The

Z-drug) hypnotics, which are additionally effective in improving sleep onset latency.[12] However, it is also in contrast to higher doses of doxepin (50 to 300 mg/day), which have been found to significantly reduce latency to sleep onset.[12] A positive dose–response relationship on sleep measures was observed for doses of doxepin between 1 and 6 mg in clinical studies, whereas the incidence of adverse effects remained constant across this dose range in both young and older adults.[12] However, the incidence of adverse effects appeared to increase with longer treatment duration.[12] A dose of doxepin as low as 1 mg/day was found to significantly improve most of the assessed sleep measures, but unlike the 3 and 6 mg/day doses, was not able to improve wake time during sleep.[12] This, along with greater effect sizes with the higher doses, was likely the basis for the approval of the 3 and 6 mg doses of doxepin for insomnia and not the 1 mg dose.[12]

At very low doses, doxepin has not shown discontinuation or

dependence (by day 3 or 4 of continuous dosing) and loss of hypnotic effectiveness.[61] It is for this reason that, unlike doxepin, they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e., 1 week).[61] It is not entirely clear why doxepin and first-generation antihistamines are different in this regard, but it has been suggested that it may have to do with the lack of selectivity for the H1 receptor of the latter or may have to do with the use of optimal doses.[57] Unlike very-low-dose doxepin, most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion.[61] This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65.[61] Anticholinergic activity notably may interfere with the sleep-promoting effects of H1 receptor blockade.[34]

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

circadian sleep–wake cycle may be involved in the beneficial effects of doxepin on sleep and insomnia.[8][48]

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

Pharmacokinetics of doxepin (25 mg)[7][28]
Parameters Doxepin Nordoxepin
Tmax
Tooltip Time to peak concentrations (hours)
Mean: 2.9
Range: 2–4
Mean: ND
Range: 2–10
Cmax
Tooltip Peak concentrations (ng/mL)
Mean: ND
Range: 8.8–45.8
Mean: 9.7
Range: 4.8–14.5
VDTooltip Volume of distribution (L/kg) 20 ND
Protein bindingTooltip Plasma protein binding 76% ND
t1/2
Tooltip Terminal half-life (hours)
Mean: 17
Range: 8–24
Mean: 31
Range: ND
Metabolic
enzymes
Major: CYP2D6, CYP2C19
Minor: CYP1A2, CYP2C9, CYP3A4
Metabolic
pathways
N-

Absorption

Doxepin is well-

Area-under-curve levels of the drug are increased significantly when it is taken with food.[8]

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

elimination half-life of doxepin is about 15–18 hours, whereas that of nordoxepin is around 28–31 hours.[8][9] 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.[49][48]

Nordoxepin is a

stereoisomers similarly to doxepin.[5] 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.[5]

Elimination

Doxepin is

glucuronide conjugates, with less than 3% of a dose excreted unchanged as doxepin or nordoxepin.[8]

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

Area-under-the-curve (0–48 hour) levels of nordoxepin were dependent on the genotype of CYP2D6 with median values of 1.28, 1.35, and 5.28 nM•L/hour in CYP2D6 extensive, intermediate, and poor metabolizers, respectively (~4-fold difference between extensive and poor).[69] Taken together, doxepin metabolism appears to be highly stereoselective, and CYP2D6 genotype has a major influence on the pharmacokinetics of (E)-doxepin.[69] Moreover, CYP2D6 poor metabolizers, as well as patients taking potent CYP2D6 inhibitors (which can potentially convert a CYP2D6 extensive metabolizer into a poor metabolizer), may be at an increased risk for adverse effects of doxepin due to their slower clearance of the drug.[69]

Another study assessed doxepin and nordoxepin metabolism in CYP2D6

ultra-rapid, extensive, and poor metabolizers following a single 75 mg oral dose.[71] They found up to more than 10-fold variation in total exposure to doxepin and nordoxepin between the different groups.[71] The researchers suggested that in order to achieve equivalent exposure, based on an average dose of 100%, the dosage of doxepin might be adjusted to 250% in ultra-rapid metabolizers, 150% in extensive metabolizers, 50% in intermediate metabolizers, and 30% in poor metabolizers.[71]

Chemistry

Doxepin is a

molecular weight of 279.376 g/mol.[76] The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely.[2][77] The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4.[2][77]

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

Latin is doxepinum.[1]

The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its

INNTooltip International Nonproprietary Name while cidoxepin hydrochloride is its USANTooltip United States Adopted Name.[2]

Brand 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.

levomenthol under the brand name Doxure.[1]

Approvals

The oral formulations of doxepin are FDATooltip Food and Drug Administration-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

urticaria (hives).[82] As of 2017, it is in phase II clinical trials for this indication.[82] The drug was also under investigation for the treatment of allergic rhinitis, atopic dermatitis, and contact dermatitis, but development for these indications was discontinued.[82]

Headache

Doxepin was under development by Winston Pharmaceuticals in an

intranasal formulation for the treatment of headache.[83] As of August 2015, it was in phase II clinical trials for this indication.[83]

Neuropathic pain

As of 2017, there was no good evidence that topical doxepin was useful to treat localized neuropathic pain.[84]

References

  1. ^ a b c d e "International brands of doxepin". Drugs.com. Retrieved 25 October 2017.
  2. ^ .
  3. ^ a b "Doxepin Hydrochloride". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. 30 January 2013. Retrieved 3 December 2013.
  4. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  5. ^ .
  6. ^ .
  7. ^ a b c d e f g h i j k l m n o p "Sinepin Capsules 25mg - Summary of Product Characteristics (SPC)". UK Electronic Medicines Compendium. 22 January 2014. Retrieved 24 October 2017.
  8. ^
    S2CID 26739281
    .
  9. ^ .
  10. ^ a b c d e f g h i j "Doxepin Hydrochloride". Drugs.com. American Society of Health-System Pharmacists. Retrieved 20 March 2019.
  11. ^ a b c d e "Silenor (doxepin) label" (PDF). FDA. 17 March 2010. Retrieved 25 October 2017. For label updates see FDA index page for NDA 022036
  12. ^
    PMID 25047681
    .
  13. ^ a b "Doxepin hydrochloride cream" (PDF). FDA. 20 December 2002. Retrieved 25 October 2017. For label updates see FDA index page for NDA 020126
  14. ^ .
  15. ^ "Doxepin Use During Pregnancy". Drugs.com. Retrieved 21 March 2019.
  16. ^ "Competitive Generic Therapy Approvals". U.S. Food and Drug Administration (FDA). 29 June 2023. Archived from the original on 29 June 2023. Retrieved 29 June 2023.
  17. ^ "First Generic Drug Approvals 2023". U.S. Food and Drug Administration (FDA). 30 May 2023. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
  18. ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  19. ^ "Doxepin - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  20. ^
    PMID 27998379
    .
  21. .
  22. .
  23. ^ .
  24. .
  25. .
  26. .
  27. PMID 20369115. Archived from the original
    (PDF) on 2018-11-24. Retrieved 2017-10-25.
  28. ^ a b c d e f g h i j k "Deptran Doxepin (as hydrochloride)" (PDF). TGA eBusiness Services. Alphapharm Pty Ltd. 6 May 2013. Retrieved 3 December 2013.
  29. ^ "Silenor (doxepin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 3 December 2013.
  30. ^ .
  31. ^ Lippincott "nursing 2007 drug handbook" LWW press. 2007
  32. PMID 19031375
    .
  33. .
  34. ^ .
  35. ^ a b c d Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  36. ^
    PMID 9537821
    .
  37. ^ .
  38. .
  39. .
  40. .
  41. ^ .
  42. .
  43. ^ .
  44. ^ .
  45. .
  46. .
  47. .
  48. ^ .
  49. ^ .
  50. ^ .
  51. ^ .
  52. .
  53. ^ .
  54. ^ .
  55. .
  56. .
  57. ^ .
  58. .
  59. .
  60. .
  61. ^ .
  62. ^ "Sleep Disorder (Sedative-Hypnotic) Drug Information - U.S. FDA". Food and Drug Administration. 13 June 2017. Retrieved 9 August 2017.
  63. ^
    PMC 4027305
    . In general, sedating properties of anti-depressant agents are related to antagonism of serotonin 5HT2, histamines, and α-1 adrenergic receptors[14]–[16].
  64. .
  65. .
  66. ^ .
  67. .
  68. .
  69. ^ .
  70. .
  71. ^ .
  72. .
  73. .
  74. .
  75. .
  76. ^ a b Chambers M. "Doxepin [INN:BAN] - Similar structures search, synonyms, formulas, resource links, and other chemical information". ChemIDplus. U.S. National Library of Medicine. Retrieved 16 March 2019.
  77. ^ .
  78. .
  79. .
  80. ^ "PRUDOXIN (doxepin hydrochloride) cream". DailyMed. August 2010. Retrieved 3 December 2013.
  81. .
  82. ^ a b c "Cidoxepin". Adisinsight.springer.com. Retrieved 16 March 2019.
  83. ^ a b "Doxepin intranasal - Winston Pharmaceuticals". Adisinsight.springer.com. Retrieved 16 March 2019.
  84. PMID 28271334
    .

External links

  • Media related to Doxepin at Wikimedia Commons