Share to: share facebook share twitter share wa share telegram print page

 

Doxylamine

Doxylamine
Skeletal formula of the doxylamine molecule
Ball-and-stick model of the doxylamine molecule
Clinical data
Trade namesUnisom, Vicks Formula 44 (in combination with Dextromethorphan), others
AHFS/Drugs.comMonograph
MedlinePlusa682537
Pregnancy
category
  • AU: A
  • A (Briggs)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S3 (Pharmacist only)
  • US: OTC
Pharmacokinetic data
BioavailabilityOral: 24.7%[1]
Intranasal: 70.8%[1]
MetabolismHepatic (CYP2D6, CYP1A2, CYP2C9)[2]
Elimination half-life10–12 hours (range 7–15 hours)[2][3][4]
ExcretionUrine (60%), feces (40%)[5]
Identifiers
  • (RS)-N,N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl)ethoxy]ethan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.006.742 Edit this at Wikidata
Chemical and physical data
FormulaC17H22N2O
Molar mass270.376 g·mol−1
3D model (JSmol)
  • n1ccccc1C(c1ccccc1)(C)OCCN(C)C
  • InChI=1S/C17H22N2O/c1-17(20-14-13-19(2)3,15-9-5-4-6-10-15)16-11-7-8-12-18-16/h4-12H,13-14H2,1-3H3 checkY
  • Key:HCFDWZZGGLSKEP-UHFFFAOYSA-N checkY
  (verify)

Doxylamine is an antihistamine medication used to treat insomnia and allergies, and—in combination with pyridoxine (vitamin B6)—to treat morning sickness in pregnant women. It is available over-the-counter and is typically sold under such brand names as Equate or Unisom, among others; and it is used in nighttime cold medicines (e.g., NyQuil) and pain medications containing acetaminophen and/or codeine to help with sleep. The medication is delivered chemically by the salt doxylamine succinate and is taken by mouth. Doxylamine and other first-generation antihistamines are the most widely used sleep medications in the world.[6] Typical side effects of doxylamine (at recommended doses) include dizziness, drowsiness, grogginess, and dry mouth, among others.[7][4]

As an antihistamine, doxylamine is an inverse agonist of the histamine H1 receptor. As a first-generation antihistamine, it typically crosses the blood–brain barrier into the brain, thereby producing a suite of sedative and hypnotic effects that are mediated by the central nervous system. (N.b.: An agonist is a molecule that activates certain receptors (i.e., specific cellular proteins) in a cell to produce a specific pharmacological response, causing the cell to modify its activity—while an inverse agonist targets the same receptors as those of a given agonist, but causes a response opposite to that caused by the agonist. An antagonist blocks the action of a given agonist.)

Doxylamine is also a potent anticholinergic, meaning that it causes delirum at high doses—i.e., at much higher doses than recommended.[8] (Specifically it is an antagonist of the muscarinic acetylcholine receptors M1 through M5.) These sedative and deliriant effects have in some cases led to using the drug recreationally. Doxylamine was first described in 1948 or 1949.[9]

Medical uses

Doxylamine is an antihistamine used to treat sneezing, runny nose, watery eyes, hives, skin rash, itching, and other cold or allergy symptoms. It is also used as a short-term treatment for insomnia.[10]

Insomnia

The first-generation sedating antihistamines diphenhydramine, doxepin, doxylamine, and pyrilamine are the most widely used medications in the world for preventing and treating insomnia.[6] As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia.[11] As of 2008 and 2017, over-the-counter antihistamines were not recommended by the American Academy of Sleep Medicine for treatment of chronic insomnia "due to the relative lack of efficacy and safety data".[12][13] Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed.[12][13] A 2015 systematic review of over-the-counter sleep aids including doxylamine found little evidence to inform the use of doxylamine for treatment of insomnia.[4]

A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that doxylamine had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.47 (95% CITooltip confidence interval 0.06 to 0.89).[14] The certainty of evidence was rated as moderate.[14] No data were available for doxylamine in terms of longer-term treatment (3 months).[14] For comparison, the other sedating medicines assessed, doxepin and trimipramine (both of which are tricyclic antidepressants) had effect sizes (SMD) at 4 weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence), respectively.[14]

Doses of doxylamine that have been used for sleep range from 5 to 50 mg, with 25 mg being the typical dose.[15][16][17][18]

Morning sickness

Doxylamine is used in the combination drug pyridoxine/doxylamine to treat morning sickness (nausea and vomiting of pregnancy).[19][20][21] It is the only medication approved by the United States Food and Drug Administration for the treatment of morning sickness.[19][20]

Available forms

See also: Pyridoxine/doxylamine

Doxylamine is used medically as doxylamine succinate, the succinate salt of doxylamine, and is available both alone (brand names Decapryn, Doxy-Sleep-Aid, Unisom) and in combination with pyridoxine (a form of vitamin B6) (brand names Bendectin, Bonjesta, Diclegis).[22] Doxylamine is available alone as immediate-release oral tablets containing 25 mg doxylamine succinate.[22] Oral tablets containing 12.5 mg doxylamine succinate as well as oral capsules containing 25 mg doxylamine succinate were also previously available but were discontinued.[22] The combination of doxylamine and pyridoxine is available in the form of extended- and delayed-release oral tablets containing 10 to 20 mg doxylamine succinate and 10 to 20 mg pyridoxine hydrochloride.[22] Doxylamine alone is available over-the-counter, whereas doxylamine in combination with pyridoxine is a prescription-only medication.[22] Doxylamine is also available in over-the-counter nighttime cold medicine products such as NyQuil Cold & Flu (contains acetaminophen, doxylamine succinate 6.25 to 12.5 mg, and dextromethorphan hydrobromide), where it serves as the sedating component.[23][24]

Contraindications

The fetal safety rating of doxylamine is "A" (no evidence of risk).[25]

Side effects

Side effects of doxylamine include dizziness, drowsiness, and dry mouth, among others.[4] Doxylamine is a potent anticholinergic and has a side-effect profile common to such drugs, including blurred vision, dry mouth, constipation, muscle incoordination, urinary retention, mental confusion, and delirium.[18][7]

Because of its relatively long elimination half-life (10–12 hours), doxylamine is associated with next-day effects including sedation, drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic.[26][18] This may be described as a "hangover effect".[18] The shorter elimination half-life of diphenhydramine (4–8 hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard.[27]

Antihistamines like doxylamine are sedating initially but tolerance occurs with repeated use and can result in rebound insomnia upon discontinuation.[7][28]

Occasional case reports of coma and rhabdomyolysis have been reported with doxylamine.[2] This is in contrast to diphenhydramine.[2]

Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse.[29] The carcinogenicity of the drug in humans is not well-studied, and the International Agency for Research on Cancer lists the drug as "not classifiable as to its carcinogenicity to humans".[30]

Continuous and/or cumulative use of anticholinergic medications, including first-generation antihistamines, is associated with a higher risk of cognitive decline and dementia in older people.[31][32]

Overdose

Doxylamine is generally safe for administration to healthy adults. Doses of doxylamine of up to 1,600 mg/day for 6 months have been given to adults with schizophrenia, with little toxicity encountered.[33] The median lethal dose (LD50) is estimated to be 50–500 mg/kg in humans.[34] Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death.[35] Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic (or grand mal) seizures and cardiopulmonary arrest. Children appear to be at a high risk for cardiopulmonary arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000 mg doxylamine succinate.[5] Rarely, an overdose results in rhabdomyolysis and acute kidney injury.[36]

Pharmacology

Pharmacodynamics

Doxylamine[37]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter >10,000 Human [38]
NETTooltip Norepinephrine transporter >10,000 Human [38]
DATTooltip Dopamine transporter >10,000 Human [38]
5-HT2A >10,000 Human [38]
5-HT2C >10,000 Human [38]
α1B >10,000 Human [38]
α2A >10,000 Human [38]
α2B >10,000 Human [38]
α2C >10,000 Human [38]
H1 42 Human [38]
H2 ND ND ND
H3 >10,000 Human [38]
H4 ND ND ND
M1 490 Human [38]
M2 2,100 Human [38]
M3 650 Human [38]
M4 380 Human [38]
M5 180 Human [38]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor.[39][38] This action is responsible for its antihistamine and sedative properties.[39][38] To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors,[39][38] an action responsible for its anticholinergic and (at high doses) deliriant effects.[39][38]

Pharmacokinetics

The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration.[1] The Tmax of doxylamine is 1.5 to 2.5 hours.[2] Its elimination half-life is 10 to 12 hours (range 7 to 15 hours).[2][3][4] Doxylamine is metabolized in the liver primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9.[2][40] The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide.[41] Doxylamine is eliminated 60% in the urine and 40% in feces.[5]

Doxylamine concentrations after a single 25 mg oral dose of doxylamine in healthy volunteers. X-axis represents the time in hours after initial dose.[3]

Chemistry

Doxylamine is a member of the ethanolamine class of antihistamines.[6] Other antihistamines from this group include bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, orphenadrine, and phenyltoloxamine.[6][42]

History

Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.[43][9][44] It has been the antihistamine component of NyQuil since 1966.[43]

Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an anticholinergic antispasmodic agent), was marketed for treatment of morning sickness in 1956.[45] This product was reformulated in 1976 to remove dicyclomine.[45] The reformulated product was voluntarily discontinued by the manufacturer in the United States in 1983 due to concerns about an alleged association with congenital limb defects.[45] However, these concerns have not been supported by studies.[19][20] In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis.[19][20] The combination was not removed from the market in Canada, where it had been marketed since 1979.[19][20]

Society and culture

Formulations

Doxylamine is primarily used as the succinic acid salt, doxylamine succinate.

  • It is the sedating ingredient of NyQuil (generally in combination with dextromethorphan and acetaminophen).
  • In Commonwealth countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared with paracetamol (acetaminophen) and codeine under the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment for tension headache and other types of pain.
  • Doxylamine succinate is used in general over-the-counter sleep-aids branded as Somnil (South Africa), Dozile, Donormyl, Lidène (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2, Sominar (Thailand), Sleep Aid (generic, Australia) and Dorminox (Poland).
  • In the United States:
    • Doxylamine succinate is the active ingredient in many over-the-counter sleep aids branded under various names.
    • Doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA in April 2013 becoming the only drug approved for morning sickness[46] with a class A safety rating for pregnancy (no evidence of risk).
  • In Canada:
    • Doxylamine succinate and pyridoxine (vitamin B6) are the ingredients of Diclectin, which is used to prevent morning sickness.
    • It is also available in combination with vitamin B6 and folic acid under the brand name Evanorm (marketed by Ion Healthcare).
  • In India
    • Doxylamine preparations are available typically in combination with pyridoxine which may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.

References

  1. ^ a b c Pelser A, Müller DG, du Plessis J, du Preez JL, Goosen C (September 2002). "Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats". Biopharmaceutics & Drug Disposition. 23 (6): 239–244. doi:10.1002/bdd.314. PMID 12214324. S2CID 32126626.
  2. ^ a b c d e f g Kryger MH, Roth T, Dement WC (1 November 2010). Principles and Practice of Sleep Medicine E-Book. Elsevier Health Sciences. p. 925. ISBN 978-1-4377-2773-9.
  3. ^ a b c Allison M, Hale C (June 2018). "A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment". Drugs in R&D. 18 (2): 129–136. doi:10.1007/s40268-018-0232-1. PMC 5995792. PMID 29671128.
  4. ^ a b c d e Culpepper L, Wingertzahn MA (2015). "Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety". The Primary Care Companion for CNS Disorders. 17 (6). doi:10.4088/PCC.15r01798. PMC 4805417. PMID 27057416.
  5. ^ a b c "New Zealand Datasheet: Doxylamine Succinate" (PDF). Medsafe, New Zealand Medicines and Medical Devices Safety Authority. 16 July 2008. Archived from the original on 22 March 2016.
  6. ^ a b c d Simons FE, Simons KJ (December 2011). "Histamine and H1-antihistamines: celebrating a century of progress". The Journal of Allergy and Clinical Immunology. 128 (6): 1139–1150.e4. doi:10.1016/j.jaci.2011.09.005. PMID 22035879.
  7. ^ a b c Neubauer DN (August 2007). "The evolution and development of insomnia pharmacotherapies". Journal of Clinical Sleep Medicine. 3 (5 Suppl): S11–S15. doi:10.5664/jcsm.26930. PMC 1978321. PMID 17824496.
  8. ^ "Doxylamine - PsychonautWiki".
  9. ^ a b Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 546. ISBN 9783527607495.
  10. ^ "Doxylamine: MedlinePlus Drug Information".
  11. ^ Ringdahl EN, Pereira SL, Delzell JE (2004). "Treatment of primary insomnia". The Journal of the American Board of Family Practice. 17 (3): 212–219. doi:10.3122/jabfm.17.3.212. PMID 15226287.
  12. ^ a b Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M (October 2008). "Clinical guideline for the evaluation and management of chronic insomnia in adults". Journal of Clinical Sleep Medicine. 4 (5): 487–504. doi:10.5664/jcsm.27286. PMC 2576317. PMID 18853708.
  13. ^ a b Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL (February 2017). "Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline". Journal of Clinical Sleep Medicine. 13 (2): 307–349. doi:10.5664/jcsm.6470. PMC 5263087. PMID 27998379.
  14. ^ a b c d De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, et al. (July 2022). "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet. 400 (10347): 170–184. doi:10.1016/S0140-6736(22)00878-9. hdl:11380/1288245. PMID 35843245. S2CID 250536370.
  15. ^ Perry PJ (2007). Psychotropic Drug Handbook. Lippincott Williams & Wilkins. ISBN 9780781762731.
  16. ^ Dupuis G, Vaugeois JM (February 2020). "[The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin]" [The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin]. L'Encephale (in French). 46 (1): 80–82. doi:10.1016/j.encep.2019.01.006. PMID 30879783. S2CID 151085176.
  17. ^ Lie JD, Tu KN, Shen DD, Wong BM (November 2015). "Pharmacological Treatment of Insomnia". P & T. 40 (11): 759–771. PMC 4634348. PMID 26609210.
  18. ^ a b c d Shirley DW, Sterrett J, Haga N, Durham C (February 2020). "The therapeutic versatility of antihistamines: A comprehensive review". The Nurse Practitioner. 45 (2): 8–21. doi:10.1097/01.NPR.0000651112.76528.ed. PMID 31913218. S2CID 210086511.
  19. ^ a b c d e Nuangchamnong N, Niebyl J (2014). "Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview". International Journal of Women's Health. 6: 401–409. doi:10.2147/IJWH.S46653. PMC 3990370. PMID 24748822.
  20. ^ a b c d e Madjunkova S, Maltepe C, Koren G (June 2014). "The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy". Paediatric Drugs. 16 (3): 199–211. doi:10.1007/s40272-014-0065-5. PMC 4030125. PMID 24574047.
  21. ^ Cada DJ, Demaris K, Levien TL, Baker DE (October 2013). "Doxylamine succinate/pyridoxine hydrochloride". Hospital Pharmacy. 48 (9): 762–766. doi:10.1310/hpj4809-762. PMC 3857125. PMID 24421551.
  22. ^ a b c d e "Drugs@FDA: FDA-Approved Drugs". accessdata.fda.gov. Retrieved 23 August 2022.
  23. ^ "VICKS NYQUIL COLD AND FLU - acetaminophen, dextromethorphan hydrobromide, and doxylamine succinate capsule, liquid filled". DailyMed. U.S. National Library of Medicine.
  24. ^ "Nyquil Cold and Flu: Basics, Side Effects & Reviews".
  25. ^ Briggs GG, Freeman RK, Yaffe SJ (2008). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Obstetric Medicine. Vol. 2. Lippincott Williams & Wilkins. p. 89. doi:10.1258/om.2009.090002. ISBN 978-0-7817-7876-3. PMC 4989726.
  26. ^ Avidan AY (2017). Review of Sleep Medicine E-Book. Elsevier Health Sciences. p. 394. ISBN 978-0-323-47349-1.
  27. ^ Rutter P, Newby D (11 September 2015). Community Pharmacy ANZ – eBook: Symptoms, Diagnosis and Treatment. Elsevier Health Sciences. p. 99. ISBN 978-0-7295-8345-9.
  28. ^ Stahl SM (December 2008). "Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines". CNS Spectrums. 13 (12): 1027–1038. doi:10.1017/s1092852900017089. PMID 19179941. S2CID 6849261.
  29. ^ Doxylamine succinate (CAS 562-10-7) Archived 1 May 2012 at the Wayback Machine. berkeley.edu.
  30. ^ DOXYLAMINE SUCCINATE. International Agency for Research on Cancer (IARC) – Summaries & Evaluations.
  31. ^ Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, et al. (March 2015). "Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study". JAMA Internal Medicine. 175 (3): 401–407. doi:10.1001/jamainternmed.2014.7663. PMC 4358759. PMID 25621434.
  32. ^ Carrière I, Fourrier-Reglat A, Dartigues JF, Rouaud O, Pasquier F, Ritchie K, Ancelin ML (July 2009). "Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study". Archives of Internal Medicine. 169 (14): 1317–1324. doi:10.1001/archinternmed.2009.229. PMC 2933398. PMID 19636034.
  33. ^ Federal Register, Volume 43, Issues 114-121. Office of the Federal Register, National Archives and Records Service, General Services Administration. 1978. p. 25584. OCLC 1768512.
  34. ^ "DOXYLAMINE SUCCINATE". hazard.com. Archived from the original on 17 January 2022.{{cite web}}: CS1 maint: unfit URL (link)
  35. ^ Syed H, Som S, Khan N, Faltas W (17 March 2009). "Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone". BMJ Case Reports. 2009 (90): 845. doi:10.1136/bcr.09.2008.0879. PMC 3028279. PMID 21686586.
  36. ^ Leybishkis B, Fasseas P, Ryan KF (July 2001). "Doxylamine overdose as a potential cause of rhabdomyolysis". The American Journal of the Medical Sciences. 322 (1): 48–49. doi:10.1097/00000441-200107000-00009. PMID 11465247.
  37. ^ 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.
  38. ^ a b c d e f g h i j k l m n o p q r s t Krystal AD, Richelson E, Roth T (August 2013). "Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications". Sleep Medicine Reviews. 17 (4): 263–272. doi:10.1016/j.smrv.2012.08.001. PMID 23357028.
  39. ^ a b c d Vande Griend JP, Anderson SL (2012). "Histamine-1 receptor antagonism for treatment of insomnia". Journal of the American Pharmacists Association. 52 (6): e210–e219. doi:10.1331/JAPhA.2012.12051. PMID 23229983.
  40. ^ Krystal AD (August 2009). "A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice". Sleep Medicine Reviews. 13 (4): 265–274. doi:10.1016/j.smrv.2008.08.001. PMID 19153052.
  41. ^ Holder CL, Korfmacher WA, Slikker W, Thompson HC, Gosnell AB (April 1985). "Mass spectral characterization of doxylamine and its rhesus monkey urinary metabolites". Biomedical Mass Spectrometry. 12 (4): 151–158. doi:10.1002/bms.1200120403. PMID 2861861. S2CID 6020605.
  42. ^ Kalpaklioglu F, Baccioglu A (2012). "Efficacy and safety of H1-antihistamines: an update". Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry. 11 (3): 230–237. doi:10.2174/1871523011202030230. PMID 23173575.
  43. ^ a b Atta-ur-Rahman, ed. (11 July 2018). Frontiers in Clinical Drug Research - Anti-Allergy Agents, Volume 3. Bentham Science Publishers. p. 30. ISBN 978-1-68108-337-7. OCLC 1048922805.
  44. ^ Sperber N, Papa D (March 1949). "Pyridyl-substituted alkamine ethers as antihistaminic agents". Journal of the American Chemical Society. 71 (3): 887–890. doi:10.1021/ja01171a034. PMID 18113525.
  45. ^ a b c Briggs GG, Freeman RK, Yaffe SJ (28 March 2012). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk (9 ed.). Lippincott Williams & Wilkins. p. 453. ISBN 978-1-4511-5359-0. OCLC 1232803849.
  46. ^ Slaughter SR, Hearns-Stokes R, van der Vlugt T, Joffe HV (March 2014). "FDA approval of doxylamine-pyridoxine therapy for use in pregnancy". The New England Journal of Medicine. 370 (12): 1081–1083. doi:10.1056/NEJMp1316042. PMID 24645939.
Kembali kehalaman sebelumnya