Doxylamine

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Doxylamine
Skeletal formula of the doxylamine molecule
Ball-and-stick model of the doxylamine molecule
Clinical data
Trade names Unisom
AHFS/Drugs.com Monograph
MedlinePlus a682537
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
  • A (Briggs)
Routes of
administration		 Oral
ATC code R06AA09 (WHO)
Legal status
Legal status
  • AU: S3 (Pharmacist only)
  • US: OTC
Pharmacokinetic data
Bioavailability Oral: 24.7%, Intranasal: 70.8%[1]
Metabolism Hepatic (CYP3A4-meditated)
Biological half-life 6–12 hours
Excretion Urine (60%), feces (40%)[2]
Identifiers
CAS Number 469-21-6 YesY
PubChem (CID) 3162
IUPHAR/BPS 7171
DrugBank DB00366 YesY
ChemSpider 3050 YesY
UNII 95QB77JKPL YesY
KEGG D07878 YesY
ChEBI CHEBI:51380 YesY
ChEMBL CHEMBL1004 YesY
ECHA InfoCard 100.006.742
Chemical and physical data
Formula C17H22N2O
Molar mass 270.369 g/mol
3D model (Jmol) Interactive image
  (verify)

Doxylamine is a first-generation antihistamine. It can be used by itself as a short-term sedative and in combination with other drugs to provide night-time allergy and cold relief. Doxylamine is also used in combination with the analgesics paracetamol (acetaminophen) and codeine as an analgesic/calmative preparation, and is prescribed in combination with vitamin B6 (pyridoxine) to prevent morning sickness in pregnant women. Its fetal safety is "A" in Briggs’ Reference Guide to Foetal and Neonatal Risk.[3]

Medical uses[edit]

It is used in the combination drug Pyridoxine/doxylamine to treat nausea and vomiting of pregnancy.[4][5]

As of 2004, doxylamine and diphenhydramine were the agents most commonly used to treat short term insomnia.[6] As of 2008, 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.".[7]

Metabolites[edit]

The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide.[8][9]

Side effects[edit]

Doxylamine succinate is a potent anticholinergic and has a side-effect profile common to such drugs, including dry mouth, ataxia, urinary retention, drowsiness, memory problems, inability to concentrate, hallucinations, psychosis, and a marked increased sensitivity to external stimuli. Like many hypnotics, it should not be combined with other antihistamines,[citation needed] such as cetirizine (Zyrtec) or diphenhydramine (Benadryl), as this combination can increase the risk of serious side effects. Using doxylamine over a long period of time is not recommended. However, the drug is not addictive, and withdrawal effects are unlikely to be experienced with prolonged use.

Toxicity[edit]

Doxylamine succinate is generally safe for administration to healthy adults. The median lethal dose (LD50) is estimated to be 50–500 mg/kg in humans.[10] Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death.[11] Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic (or grand mal) seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory 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.[citation needed] Rarely, an overdose results in rhabdomyolysis and acute renal failure.[12]

Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse.[13] The carcinogenicity of the drug in humans is not well studied, and the IARC lists the drug as "not classifiable as to its carcinogenicity to humans".[14]

History[edit]

Doxylamine is a first-generation antihistamine, first reported in 1949.[15][third-party source needed]

Society and culture[edit]

Formulations[edit]

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 (UK version no longer contains doxylamine as of 2015), 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 (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2 and Sleep Aid (generic, Australia).
  • In the United States:
    • doxylamine succinate is the active ingredient in the over-the-counter sleep-aid tablets branded as Unisom SleepTabs; however, all other Unisom products contain diphenhydramine hydrochloride instead.[16]
    • doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA in April 2013 as the only drug for morning sickness with a class A safety rating for pregnancy.[17]
  • In Canada:
    • doxylamine succinate was the active ingredient in the over-the-counter sleep-aid marketed as Unisom-2 tablets (no longer available). Unisom now solely markets products containing diphenhydramine hydrochloride as the active ingredient.[18]
    • 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)[where?].

It is marketed under the names Restavit and Dozile), Russia (Valocordin-Doxylamine) and India (Vomentin).

See also[edit]

References[edit]

  1. ^ Pelser, Andries; Müller, Douw G.; du Plessis, Jeanetta; du Preez, Jan L.; Goosen, Colleen (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. 
  2. ^ "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. 
  3. ^ Briggs, Gerald G.; Freeman, Roger K.; Yaffe, Sumner J. (2008). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. doi:10.1258/om.2009.090002. ISBN 978-0-7817-7876-3. 
  4. ^ 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 4030125Freely accessible. PMID 24574047. 
  5. ^ Cada, DJ; Demaris, K; Levien, TL; Baker, DE (October 2013). "Doxylamine succinate/pyridoxine hydrochloride.". Hospital pharmacy. 48 (9): 762–6. doi:10.1310/hpj4809-762. PMC 3857125Freely accessible. PMID 24421551. 
  6. ^ Ringdahl, EN; Pereira, SL; Delzell JE, Jr (2004). "Treatment of primary insomnia.". The Journal of the American Board of Family Practice. 17 (3): 212–9. PMID 15226287. 
  7. ^ Schutte-Rodin, S; Broch, L; Buysse, D; Dorsey, C; Sateia, M (15 October 2008). "Clinical guideline for the evaluation and management of chronic insomnia in adults." (PDF). Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 4 (5): 487–504. PMID 18853708. 
  8. ^ Holder, C. L.; Korfmacher, W. A.; Slikker Jr, W.; Thompson Jr, H. C.; Gosnell, A. B. (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. 
  9. ^ rxlist.com, Khedezla.
  10. ^ DOXYLAMINE SUCCINATE. hazard.com
  11. ^ Syed, Husnain; Sumit Som; Nazia Khan; Wael Faltas (17 March 2009). "Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone". BMJ Case Reports. BMJ Group. 2003 (90): 845. doi:10.1136/bcr.09.2008.0879. PMID 21686586. 
  12. ^ Leybishkis B, B; Fasseas P; Ryan KF. (2001). "Doxylamine overdose as a potential cause of rhabdomyolysis". American Journal of the Medical Sciences. Lippincott Williams & Wilkins. 322 (1): 48–9. doi:10.1097/00000441-200107000-00009. PMID 11465247. 
  13. ^ Doxylamine succinate (CAS 562-10-7). berkeley.edu
  14. ^ DOXYLAMINE SUCCINATE. International Agency for Research on Cancer (IARC) - Summaries & Evaluations
  15. ^ Sperber, Nathan.; Papa, Domenick.; Schwenk, Erwin.; Sherlock, Margaret. (1949). "Pyridyl-Substituted Alkamine Ethers as Antihistaminic Agents". Journal of the American Chemical Society. 71 (3): 887–890. doi:10.1021/ja01171a034. PMID 18113525. 
  16. ^ chattem.com, UNISOM Drug facts
  17. ^ Slaughter, Shelley R.; Hearns-Stokes, Rhonda; van der Vlugt, Theresa; Joffe, Hylton V. (2014). "FDA Approval of Doxylamine–Pyridoxine Therapy for Use in Pregnancy". New England Journal of Medicine. 370 (12): 1081–1083. doi:10.1056/NEJMp1316042. PMID 24645939. 
  18. ^ unisom.ca product page
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