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Doxylamine


Doxylamine

Article Author:
Nathan Brott
Article Editor:
Anil Kumar Reddy Reddivari
Updated:
6/10/2020 4:20:39 PM
For CME on this topic:
Doxylamine CME
PubMed Link:
Doxylamine

Indications

Doxylamine succinate with pyridoxine has approval from the U.S. Food and Drug Administration for the first-line treatment of nausea and vomiting of pregnancy (NVP).[1]  NVP affects up to 85% of women during pregnancy—it is the most prevalent medical condition during pregnancy.[2] Most patients with NVP are manageable by making alterations to diet and lifestyle factors; however, more than 30% might need fluids, vitamin supplementation, and additional treatment with an antiemetic such as doxylamine.[3]

Like other antihistamines, it also has utility for the management of allergic rhinitis.[4] Allergic rhinitis is the most prevalent atopic disorder, and symptoms consist of nasal congestion, sneezing, rhinorrhea, and nasal itching.[5] Doxylamine tablets are also available over-the-counter as an approved sleep aid for insomnia.[6] Insomnia is among the most commonly encountered patient concerns, and it can have significant adverse effects on mental and physical health.[7]

Mechanism of Action

As a member of the first-generation class of antihistamines, doxylamine exerts its effects by competitively antagonizing the binding of free histamine at the H1-receptor binding sites. It antagonizes the effects of histamine in the uterus, GI tract, large blood vessels, and bronchial muscles. Doxylamine binds non-selectively to H1-receptors, both centrally and peripherally, contributing to the sedative effects that also make it an effective sleeping aid. However, due to their interactions with receptor residues that remain highly conserved across the aminergic receptors, H1 receptor antagonists can produce several off-target effects, which are anticholinergic. This activity also depresses labyrinthine function, blocks the chemoreceptor trigger zone, and diminishes vestibular stimulation.[8] Furthermore, doxylamine reduces nausea and vomiting by inhibiting histaminergic signaling to the vomiting center in the medulla.[9] The mechanism of action of pyridoxine while treating NVP is unknown.

Administration

Doxylamine is often co-administered with pyridoxine (vitamin B6) as an extended-release oral tablet (doxylamine succinate 10 mg/ pyridoxine-HCl 10 mg). The tablets should not be crushed, chewed, or split to maintain the extended-release effects.[10] For NVP, the recommended dose is two tablets before bed with water on an empty stomach. If symptoms continue on the second day, the patient can take one tablet after waking in the morning and two at night. If, on the third day, symptoms are still inadequately controlled with a three tablet regimen, the dose could increase to four tablets per day: one in the morning, one mid-afternoon, and two before bed. The maximum daily limit is four tablets.

Patients should not take doxylamine/pyridoxine as needed while treating NVP. The need for continued therapy requires reassessment throughout the pregnancy.[11][12][13] Doxylamine as a standalone medication is also available as doxylamine succinate 25 mg oral tablets under both brand and generic forms. These serve as a sleep aid, so the medication should be administered 30 minutes before bedtime.[14]

Adverse Effects

Because doxylamine is available over the counter, the risk of overdose is a concern.[4] Adverse effects due to hypersensitivity to the drug include hypotension, urticaria, and decreased oxygen saturation.[15] Common adverse effects include impaired vigilance, atropine-like effects, and drowsiness during the day—all of which could pose problems for high-risk fall patients and those operating heavy machinery.[16] 

Doxylamine and other first-generation histamine H1 receptor antagonists can bind to and inhibit muscarinic receptor signaling in other organ systems, resulting in systemic anticholinergic effects. This non-selective receptor binding can lead to various adverse effects such as flushing of the skin, anhidrosis, hyperthermia, hallucinations, mydriasis, delirium, and urinary retention.[17] Doxylamine is safe for use in breastfeeding in small, occasional doses. In longer-term or higher doses, doxylamine might decrease lactation, and it could cause drowsiness or other adverse effects on the breastfed infant.[18] Doxylamine is safe for use in pregnancy, as it is not teratogenic.[3]

Contraindications

One contraindication to treatment with doxylamine includes concurrent use of a monoamine oxidase inhibitor (MAOI).[13] Hypersensitivity to doxylamine is a contraindication to its use.[15] Concomitant alcohol use is contraindicated due to its effect of causing pronounced somnolence when combined with doxylamine. Doxylamine contraindications also include patients with the following conditions: elevated intraocular pressure, narrow-angle glaucoma, asthma, stenosing peptic ulcer disease, urinary bladder neck obstruction, gastric outlet obstruction.[11]

Monitoring

Researchers have mostly studied the pharmacokinetics of doxylamine in healthy nonpregnant women. Doxylamine is absorbed in the gastrointestinal tract, mainly the jejunum. With extended-release formulation, peak plasma concentrations occur within 7.5 hours.[13] Doxylamine is highly lipophilic; therefore, it circulates as 98% protein-bound. The volume of distribution is between 0.5 and 30 L/kg. Doxylamine undergoes hepatic metabolism via a dealkylation reaction, so the clinician should consider the patient's liver function.[17] Additionally, doxylamine and its respective metabolites get excreted by the kidneys, so clinicians should consider the patient's renal function when administering this drug. The half-life of doxylamine is 11.9 hours, and the half-life of coadministered pyridoxine is 0.4 hours.[11]

Toxicity

Toxicity associated with antihistamine use is due to overdose following oral ingestion, either unintentional or intentional suicide attempt—most commonly in young and elderly populations. Toxicity from intravenous, intramuscular, or topical routes of administration rarely occurs in the household setting. Toxicity presents as antimuscarinic and hallucinogenic effects. The mnemonic 'dry as a bone, hot as a hare, red as a beet, blind as a bat, full as a flask, and mad as a hatter' has been used to remember the presentation of acute anticholinergic toxicity. This mnemonic represents the findings of anhidrosis, hyperthermia, reddening of the skin, mydriasis, hallucinations, urinary retention, and delirium, respectively.

Major complications of doxylamine toxicity include arrhythmias, respiratory failure, seizures, hyperthermia, rhabdomyolysis, and coma. In the event of toxicity, the healthcare team should constantly monitor cardiac activity, and IV access is necessary. Patients who only recently ingested the toxic dose can receive activated charcoal.[17][19]

Enhancing Healthcare Team Outcomes

Doxylamine is available both over-the-counter and through a consultation with a physician. It is a first-generation histamine H1 receptor antagonist that can lead to various adverse outcomes if consumed inappropriately. Over-the-counter availability of doxylamine to consumers demands the need to educate patients and the general public on appropriate antihistamine consumption and how to recognize signs of toxicity. Individuals taking doxylamine should understand the potential adverse effects, and they should receive instruction to store this medication in a secure location where children or other individuals at risk of ingesting a toxic dose (intentionally or unintentionally) cannot access it. Patients should also be counseled on the potential drug interactions with doxylamine, such as increased somnolence and sedation when consumed with alcohol or other central nervous system depressants. 

An interprofessional healthcare team should be well-versed in recognizing the symptoms of doxylamine toxicity. They should be aware of the potential complications that can manifest, such as multiorgan failure and coma. Although most patients experience a full recovery following doxylamine toxicity, it is still vital that healthcare teams are knowledgeable and up to date on the presentation of doxylamine toxicity.[17] The prescribing clinician, along with a pharmacist, should educate about dosing and interactions. The pharmacist (as well as nursing) can counsel the patient on administration and potential adverse effects. Nursing can also perform follow-up monitoring and also act as a bridge between the prescriber and the patient. These examples of interprofessional collaboration show how to optimize doxylamine therapy for the best clinical results. [Level 5]

Historically, there has been significant debate around a reported correlation between using a combination product containing doxylamine and pyridoxine in the 1970s and congenital disabilities. Media and law firms launched publicity campaigns against the older formulation, eventually resulted in discontinuation of the drug for decades until the newer formulation received approval in 2013 for treating NVP refractory to other nonpharmacological management. Approval of the newer formulation was based on randomized, placebo-controlled clinical trials supporting its efficacy and safety. It also considered extensive data concluding that combined treatment with doxylamine succinate and pyridoxine hydrochloride in pregnancy is not teratogenic. This decades-long debate and evidence reinforce the importance of evidence-based medicine. 


References

[1] Persaud N,Chin J,Walker M, Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy? Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2014 Apr;     [PubMed PMID: 24798673]
[2] Koren G, Safety considerations surrounding use of treatment options for nausea and vomiting in pregnancy. Expert opinion on drug safety. 2017 Nov;     [PubMed PMID: 28749713]
[3] Fejzo MS,Trovik J,Grooten IJ,Sridharan K,Roseboom TJ,Vikanes Å,Painter RC,Mullin PM, Nausea and vomiting of pregnancy and hyperemesis gravidarum. Nature reviews. Disease primers. 2019 Sep 12;     [PubMed PMID: 31515515]
[4] Derinöz-Güleryüz O, Doxylamine succinate overdose: Slurred speech and visual hallucination. The Turkish journal of pediatrics. 2018;     [PubMed PMID: 30859772]
[5] Kakli HA,Riley TD, Allergic Rhinitis. Primary care. 2016 Sep;     [PubMed PMID: 27545735]
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[10] Madjunkova S,Maltepe C,Koren G, The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy. Paediatric drugs. 2014 Jun;     [PubMed PMID: 24574047]
[11] Mospan C,Mospan G,Byland E,Whitaker WB,Xiong L,Dunlap J,Canupp K, Drug updates and approvals: 2018 in review. The Nurse practitioner. 2018 Dec;     [PubMed PMID: 30379711]
[12] Fantasia HC, A new pharmacologic treatment for nausea and vomiting of pregnancy. Nursing for women's health. 2014 Feb-Mar;     [PubMed PMID: 24548499]
[13] Cada DJ,Demaris K,Levien TL,Baker DE, Doxylamine succinate/pyridoxine hydrochloride. Hospital pharmacy. 2013 Oct;     [PubMed PMID: 24421551]
[14] Drugs for chronic insomnia. The Medical letter on drugs and therapeutics. 2018 Dec 17;     [PubMed PMID: 30625122]
[15] Rial MJ,Fernández-Nieto M,Rodrigo-Muñoz JM,Sastre B,Sastre J,Del Pozo V, Doxylamine Allergy in a Pregnant Woman: Suitability of the Basophil Activation Test. Journal of investigational allergology     [PubMed PMID: 30530395]
[16] Sleep complaints: Whenever possible, avoid the use of sleeping pills. Prescrire international. 2008 Oct;     [PubMed PMID: 19536941]
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[18] Doxylamine 2006;     [PubMed PMID: 29999680]
[19] Doshi HH,Giudici MC, The EKG in hypothermia and hyperthermia. Journal of electrocardiology. 2015 Mar-Apr;     [PubMed PMID: 25537312]