What are the primary uses of doxylamine. How does doxylamine work in the body. What are the potential side effects of taking doxylamine. Is doxylamine safe during pregnancy.

Understanding Doxylamine: A Versatile Medication

Doxylamine is a widely used medication that belongs to the first-generation antihistamine class. It has gained popularity due to its multiple therapeutic applications, particularly in managing nausea and vomiting during pregnancy, alleviating allergic rhinitis symptoms, and aiding in sleep disorders. Let’s delve deeper into the various aspects of this versatile drug.

Primary Indications for Doxylamine Use

Doxylamine has several approved uses in medical practice. Here are the main indications:

• Nausea and Vomiting of Pregnancy (NVP)
• Allergic Rhinitis
• Insomnia

Is doxylamine effective for treating nausea during pregnancy. Yes, when combined with pyridoxine (vitamin B6), doxylamine is FDA-approved as a first-line treatment for nausea and vomiting of pregnancy (NVP). This condition affects up to 85% of pregnant women, making it the most prevalent medical issue during pregnancy.

Can doxylamine help with allergies. Indeed, like other antihistamines, doxylamine is indicated for managing allergic rhinitis symptoms such as nasal congestion, sneezing, rhinorrhea, and nasal itching.

Does doxylamine aid in sleep. Yes, doxylamine tablets are available over-the-counter as an approved sleep aid for insomnia in the USA. Its sedative effects make it an effective option for those struggling with sleep issues.

Mechanism of Action: How Doxylamine Works

Understanding how doxylamine functions in the body is crucial for appreciating its therapeutic effects. Here’s a breakdown of its mechanism of action:

Antihistamine Effects

How does doxylamine combat histamine in the body. Doxylamine acts as a competitive antagonist at h2-receptor binding sites. It effectively blocks the action of histamine in various parts of the body, including:

• Uterus
• Gastrointestinal tract
• Large blood vessels
• Bronchial muscles

Central and Peripheral Effects

Why does doxylamine cause drowsiness. Doxylamine binds non-selectively to h2-receptors both centrally and peripherally. This non-selective binding contributes to its sedative effects, making it useful as a sleep aid. However, this same action can also lead to some of its side effects.

Anticholinergic Activity

Does doxylamine have effects beyond histamine blockade. Yes, due to its interaction with highly conserved receptor residues across aminergic receptors, doxylamine can produce anticholinergic effects. These effects include:

• Depression of labyrinthine function
• Blocking of the chemoreceptor trigger zone
• Diminished vestibular stimulation

Antiemetic Action

How does doxylamine reduce nausea and vomiting. Doxylamine inhibits histaminergic signaling to the vomiting center in the medulla, effectively reducing nausea and vomiting. This action is particularly beneficial in treating NVP.

Administration and Dosage Guidelines

Proper administration of doxylamine is crucial for its effectiveness and safety. Here are the general guidelines:

For Nausea and Vomiting of Pregnancy

What is the recommended dosage for NVP. Doxylamine is often co-administered with pyridoxine as an extended-release oral tablet (10 mg doxylamine succinate / 10 mg pyridoxine-HCl). The initial recommended dose is two tablets before bed, taken with water on an empty stomach. Dosage can be adjusted based on symptom control, with a maximum of four tablets per day.

For Insomnia

How should doxylamine be taken for sleep issues. For adults and children 12 and older, the recommended dose is 25 to 50 mg orally at bedtime as needed, taken 30 minutes before sleep.

For Allergy Symptoms

What is the proper dosage for allergic rhinitis. Adults and children 12 and older can take 12.5 mg orally every 4 to 6 hours as needed, with a maximum daily dosage of 75 mg.

Potential Side Effects and Precautions

While doxylamine is generally safe when used as directed, it can cause some side effects. Being aware of these potential adverse effects is important for safe use.

Common Side Effects

What are the most frequently reported side effects of doxylamine. Common adverse effects include:

• Impaired vigilance
• Atropine-like effects (dry mouth, blurred vision)
• Drowsiness
• Dizziness
• Constipation

Serious Side Effects

Are there any severe adverse reactions associated with doxylamine use. While rare, some serious side effects can occur, including:

• Hypersensitivity reactions (hypotension, urticaria, decreased oxygen saturation)
• Severe drowsiness or dizziness
• Difficulty urinating
• Fast or irregular heartbeat

Precautions and Contraindications

Who should avoid taking doxylamine. Doxylamine should be used with caution in:

• Elderly patients
• Patients with a history of asthma
• Individuals with narrow-angle glaucoma
• Those with severe hepatic impairment

Is doxylamine safe during pregnancy. While doxylamine is FDA-approved for use in pregnancy to treat NVP, it should always be used under medical supervision. The need for continued therapy should be reassessed throughout the pregnancy.

Drug Interactions and Special Considerations

Understanding potential drug interactions is crucial for safe use of doxylamine. Here are some important considerations:

Interactions with Other Medications

What drugs may interact with doxylamine. Doxylamine can interact with several types of medications, including:

• Other antihistamines
• Central nervous system depressants
• Monoamine oxidase inhibitors (MAOIs)
• Anticholinergic drugs

These interactions can potentially increase side effects or alter the effectiveness of doxylamine or the interacting drug.

Alcohol Consumption

Can alcohol be consumed while taking doxylamine. It’s advisable to avoid alcohol consumption while taking doxylamine. Alcohol can enhance the sedative effects of the medication, potentially leading to excessive drowsiness and impaired coordination.

Driving and Operating Machinery

Is it safe to drive while taking doxylamine. Due to its sedative effects, patients should be cautioned about driving or operating heavy machinery while taking doxylamine, especially when first starting the medication or after dosage increases.

Pharmacokinetics of Doxylamine

Understanding how doxylamine is processed in the body can provide insights into its effects and duration of action.

Absorption and Distribution

How quickly does doxylamine take effect. Doxylamine is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations are typically reached within 2 to 3 hours after oral administration.

Metabolism and Excretion

How is doxylamine eliminated from the body. Doxylamine undergoes extensive hepatic metabolism and is primarily excreted in the urine. Its half-life is approximately 10 hours in adults, increasing to 12 to 15 hours in elderly patients.

Duration of Action

How long do the effects of doxylamine last. The duration of action can vary depending on the individual and the specific use. For sleep aid purposes, effects typically last 6 to 8 hours. For allergy symptoms, relief may last 4 to 6 hours.

Comparison with Other Antihistamines

How does doxylamine compare to other antihistamines. Doxylamine belongs to the first-generation antihistamine class, which means it can cross the blood-brain barrier more readily than second-generation antihistamines. This property contributes to its sedative effects but also increases the risk of side effects.

Doxylamine vs. Diphenhydramine

What are the differences between doxylamine and diphenhydramine. Both are first-generation antihistamines with similar uses, but doxylamine tends to have a longer duration of action. Diphenhydramine is more commonly used as a sleep aid, while doxylamine is more frequently employed for NVP when combined with pyridoxine.

Doxylamine vs. Loratadine

How does doxylamine differ from loratadine. Loratadine is a second-generation antihistamine that causes less sedation and has fewer anticholinergic side effects compared to doxylamine. However, doxylamine may be more effective for some individuals in managing allergy symptoms.

In conclusion, doxylamine is a versatile medication with multiple therapeutic applications. Its effectiveness in treating nausea and vomiting of pregnancy, allergic rhinitis, and insomnia makes it a valuable option in various clinical scenarios. However, like all medications, it should be used judiciously and under appropriate medical supervision to maximize benefits and minimize potential risks. As research continues, our understanding of doxylamine’s mechanisms and applications may further expand, potentially opening new avenues for its use in medical practice.

Doxylamine – StatPearls – NCBI Bookshelf

Continuing Education Activity

Doxylamine is a medication used to manage and treat nausea and vomiting of pregnancy (NVP), allergic rhinitis, and insomnia. It is in the first-generation histamine receptor h2 antagonist class of medications. In the USA, it is available as an over-the-counter medication. This activity reviews the indications, action, and contraindications for doxylamine as a valuable agent in managing nausea and vomiting of pregnancy (NVP), allergic rhinitis, and insomnia.

Objectives:

• Identify the mechanism of action of doxylamine.

• Describe the potential adverse effects of doxylamine.

• Summarize the indications for doxylamine use.

• Review interprofessional team strategies for improving care coordination and communication to advance doxylamine and improve outcomes.

Access free multiple choice questions on this topic.

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]  Nausea and vomiting of pregnancy 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 is also indicated 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 in the USA.[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 h2-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 h2-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, h2 receptor antagonists can produce several off-target effects; these 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 nausea and vomiting during pregnancy is unknown.

The drug undergoes extensive hepatic metabolism and is excreted primarily in the urine. It has a half-life of approximately 10 hours, which increases to 12 to 15 hours in the elderly.

Administration

To treat nausea and vomiting during pregnancy, 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 symptoms remain inadequately controlled with a three tablet regimen on the third day, 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. Adult dosing for doxylamine is as follows:

• For insomnia (adults and children 12 and older): 25 to 50 mg orally at bedtime as needed, dosed 30 minutes before sleep.[14]

• For allergy symptoms (adults and children 12 and older): 12.5 mg orally every 4 to 6 hours as needed, with a maximum dosage of 75 mg daily.

Hepatic and renal dosing adjustments are not defined.

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, impaired coordination, and drowsiness during the day—all of which could pose problems for high-risk fall patients and those operating heavy machinery or who drive a vehicle.[16] 

Other common reactions to doxylamine include constipation, dysuria, urinary retention, blurred vision, and diplopia. Many of these can be attributed to the drug’s anticholinergic effects.

Doxylamine and other first-generation histamine h2 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. No known fetal harm exists based on human data when it was studied in combination therapy with pyridoxine. 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 also a contraindication to its use.[15] Concomitant alcohol use is contraindicated due to its effect of causing pronounced somnolence when combined with doxylamine. It should be used with caution when given concurrently with CNS depressant drugs. Doxylamine contraindications also include patients with the following conditions: elevated intraocular pressure, narrow-angle glaucoma, asthma, stenosing peptic ulcer disease, urinary bladder neck obstruction, and gastric outlet obstruction.[11]

Doxylamine should not be used in children under two years of age.

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. If the patient experiences toxicity, the healthcare team should continually 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 h2 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 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 because of cumulative effects. 

An interprofessional healthcare team, including clinicians (MDs, DOs, NPS, and PAs), 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 the patient regarding 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. If any one member of the interprofessional team notes an adverse event or therapeutic failure, it should be documented in the patient’s health record and communicated to all other team members so appropriate action can take place. These examples of interprofessional collaboration show how to optimize doxylamine therapy for the best clinical results with the fewest adverse events. [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, which eventually resulted in the 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. 

In summary, doxylamine is a generally safe, effective over-the-counter medication that can provide patient benefit with minimal adverse events when used correctly.

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

Persaud N, Chin J, Walker M. Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy? J Obstet Gynaecol Can. 2014 Apr;36(4):343-348. [PubMed: 24798673]

2.

Koren G. Safety considerations surrounding use of treatment options for nausea and vomiting in pregnancy. Expert Opin Drug Saf. 2017 Nov;16(11):1227-1234. [PubMed: 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. Nat Rev Dis Primers. 2019 Sep 12;5(1):62. [PubMed: 31515515]

4.

Derinöz-Güleryüz O. Doxylamine succinate overdose: Slurred speech and visual hallucination. Turk J Pediatr. 2018;60(4):439-442. [PubMed: 30859772]

5.

Kakli HA, Riley TD. Allergic Rhinitis. Prim Care. 2016 Sep;43(3):465-75. [PubMed: 27545735]

6.

Allison M, Hale C. A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment. Drugs R D. 2018 Jun;18(2):129-136. [PMC free article: PMC5995792] [PubMed: 29671128]

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Buysse DJ. Insomnia. JAMA. 2013 Feb 20;309(7):706-16. [PubMed: 23423416]

8.

Shiroishi M, Kobayashi T. Structural Analysis of the Histamine H₁ Receptor. Handb Exp Pharmacol. 2017;241:21-30. [PubMed: 27826702]

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Simons FE, Simons KJ. h2 antihistamines: current status and future directions. World Allergy Organ J. 2008 Sep;1(9):145-55. [PMC free article: PMC3650962] [PubMed: 23282578]

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. Paediatr Drugs. 2014 Jun;16(3):199-211. [PMC free article: PMC4030125] [PubMed: 24574047]

11.

Mospan C, Mospan G, Byland E, Whitaker WB, Xiong L, Dunlap J, Canupp K. Drug updates and approvals: 2018 in review. Nurse Pract. 2018 Dec;43(12):23-32. [PubMed: 30379711]

12.

Fantasia HC. A new pharmacologic treatment for nausea and vomiting of pregnancy. Nurs Womens Health. 2014 Feb-Mar;18(1):73-77. [PubMed: 24548499]

13.

Cada DJ, Demaris K, Levien TL, Baker DE. Doxylamine succinate/pyridoxine hydrochloride. Hosp Pharm. 2013 Oct;48(9):762-6. [PMC free article: PMC3857125] [PubMed: 24421551]

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Drugs for chronic insomnia. Med Lett Drugs Ther. 2018 Dec 17;60(1562):201-205. [PubMed: 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. J Investig Allergol Clin Immunol. 2018 Dec;28(6):433-434. [PubMed: 30530395]

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Sleep complaints: Whenever possible, avoid the use of sleeping pills. Prescrire Int. 2008 Oct;17(97):206-12. [PubMed: 19536941]

17.

Borowy CS, Mukherji P. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Mar 10, 2023. Antihistamine Toxicity. [PubMed: 29493943]

18.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Sep 20, 2021. Doxylamine. [PubMed: 29999680]

19.

Doshi HH, Giudici MC. The EKG in hypothermia and hyperthermia. J Electrocardiol. 2015 Mar-Apr;48(2):203-9. [PubMed: 25537312]

Disclosure: Nathan Brott declares no relevant financial relationships with ineligible companies.

Disclosure: Anil Kumar Reddy Reddivari declares no relevant financial relationships with ineligible companies.

Doxylamine Succinate Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing

Uses

Doxylamine is an antihistamine, used to relieve symptoms of allergy, hay fever, and the common cold. This medication works by blocking certain natural substances (histamine, acetylcholine) that your body makes. This effect helps to relieve allergy/cold symptoms such as watery eyes, runny nose, and sneezing. Doxylamine is also used to help you relax and fall asleep.Cough-and-cold products have not been shown to be safe or effective in children younger than 6 years. Do not use this product to treat cold symptoms in children younger than 6 years unless specifically directed by the doctor. Also, do not give the 25 milligram tablets to children younger than 12 years, unless directed by the doctor. Ask your doctor or pharmacist for more details about using your product safely. These products do not cure or shorten the length of the common cold and may cause serious side effects. To decrease the risk for serious side effects, carefully follow all dosage directions. Do not use this product to make a child sleepy. Do not give other cough-and-cold medication that might contain the same or similar ingredients (see also Drug Interactions section). Ask the doctor or pharmacist about other ways to relieve cough and cold symptoms (such as drinking enough fluids, using a humidifier or saline nose drops/spray).

How to use Doxylamine Succinate Tablet

Follow all directions on the product package. If your doctor has prescribed this medication, take it as directed. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with or without food. This medication may be taken with food or milk if stomach upset occurs.

If you are using the chewable form of this medication, chew thoroughly and then swallow.

If you are using the liquid form of this medication, measure the dose carefully using a special measuring device/spoon. Do not use a household spoon because you may not get the correct dose.

The dosage is based on your age, medical condition, and response to treatment. Do not increase your dose or take this medication more often than directed.

To help you sleep, take this medication about 30 minutes before bedtime. If you continue to have difficulty sleeping for longer than 2 weeks, contact your doctor.

If your condition lasts or gets worse, or if you think you may have a serious medical problem, get medical help right away.

Side Effects

Drowsiness, dizziness, headache, constipation, stomach upset, blurred vision, decreased coordination, or dry mouth/nose/throat may occur. If any of these effects last or get worse, contact your doctor or pharmacist promptly.

If your doctor has directed you to use this medication, remember that your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: mental/mood changes (such as hallucinations, irritability, nervousness, confusion), ringing in the ears, trouble urinating, easy bruising/bleeding, fast/irregular heartbeat.

Get medical help right away if you have any very serious side effects, including: seizure.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US – Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

Before taking doxylamine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: breathing problems (such as asthma, emphysema), a certain eye problem (glaucoma), heart problems, high blood pressure, liver disease, seizures, stomach problems (such as ulcers, blockage), overactive thyroid (hyperthyroidism), urination problems (such as trouble urinating due to enlarged prostate, urinary retention).

This drug may make you dizzy or drowsy or blur your vision. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness or clear vision until you can do it safely. Avoid alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).

To minimize dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Liquid products may contain sugar. Caution is advised if you have diabetes. Ask your doctor or pharmacist about using this product safely.

Older adults may be more sensitive to the side effects of this drug, especially drowsiness, dizziness, low blood pressure, confusion, constipation, or trouble urinating. Drowsiness, dizziness, and confusion can increase the risk of falling.

Children may be more sensitive to the effects of antihistamines. In young children, this medication may cause agitation/excitement instead of drowsiness.

This product is safe to use during pregnancy.

Based on information from related drugs, this medication may pass into breast milk. Consult your doctor before breast-feeding.

Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug include: antihistamines applied to the skin (such as diphenhydramine cream, ointment, spray).

Tell your doctor or pharmacist if you are taking other products that cause drowsiness such as opioid pain or cough relievers (such as codeine, hydrocodone), alcohol, marijuana (cannabis), drugs for sleep or anxiety (such as alprazolam, lorazepam, zolpidem), muscle relaxants (such as carisoprodol, cyclobenzaprine), or other antihistamines (such as cetirizine, diphenhydramine).

Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

This medication may interfere with certain lab tests (such as urine drug screening tests), possibly causing false test results. Make sure lab personnel and all your doctors know you use this drug.

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Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: large pupils, flushing, fever, hallucinations, weakness, shaking (tremor), muscle twitching, loss of consciousness, seizures. In children, excitement may occur first, and may be followed by loss of coordination, drowsiness, loss of consciousness, seizures.

Do not take for several days before allergy testing because test results can be affected.

Keep all medical and lab appointments.

Not applicable.

Refer to storage information printed on the package. If you have any questions about storage, ask your pharmacist. Keep all products away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

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CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment.

Doxylamine – description of the substance, pharmacology, use, contraindications, formula

Contents

• Structural formula

• Russian name

• English name

• Latin name

• chemical name

• Gross formula

• Pharmacological group of the substance Doxylamine

• Nosological classification

• CAS code

• pharmachologic effect

• Characteristic

• Pharmacology

• Application of the substance Doxylamine

• Contraindications

• Use during pregnancy and lactation

• side effects of doxylamine

• Interaction

• Overdose

• Dosage and administration

• Precautionary measures

• special instructions

• Trade names with the active substance Doxylamine

Structural formula

Russian name

Doxylamine

English name

Doxylamine

Latin name

Doxylaminum ( genus Doxylamini)

Chemical name

90 054 N,N-Dimethyl-2-[1-phenyl-1-(2-pyridinyl) ethoxy]ethanamine

Gross formula

C ₁₇ H ₂₂ N ₂ O

Pharmacological group of the substance Doxylamine

h2 antihistamines

Sleeping pills

Nosological classification

ICD-10 code list

• G47. 0 Disorders of initiation and maintenance of sleep [insomnia]

• J06 Acute infections of the upper respiratory tract, multiple and unspecified

• L29 Itching

• R05 Cough

• T78. 4 Allergy, unspecified

CAS code

469-21-6

Pharmacological action

Pharmacological action –

antiallergic , sedative , hypnotic .

Description

Blocker of H ₁ – histamine receptors from the group of ethanolamines.

Pharmacology

Blocks H ₁ -histamine receptors, has an m-anticholinergic effect. Reduces the time to fall asleep, increases the duration and quality of sleep, does not change the phase of sleep.

Well absorbed from the gastrointestinal tract. Passes histohematic barriers (including the BBB) and is distributed to tissues and organs. Metabolized in the liver. It is excreted by the kidneys (60% unchanged) and partially – with faeces.

Use of the substance Doxylamine

Sleep disorders; allergic reactions, skin itching; colds and cough (as part of combined preparations).

Contraindications

Hypersensitivity, angle-closure glaucoma, prostatic hyperplasia, urination disorders of various origins, pregnancy, breast-feeding, age up to 6 years (as an antihistamine drug), up to 15 years (as a sedative-hypnotic).

Use in pregnancy and lactation

Contraindicated in pregnancy. At the time of treatment should stop breastfeeding.

Side effects of the substance Doxylamine

Daytime drowsiness, lethargy, dry mouth, accommodation paresis, constipation, urinary retention.

Interaction

Enhances (mutually) depriming effect of barbiturates, benzodiazepines, clonidine, opioid analgesics, neuroleptics, ethanol, etc. m-Cholinoblockers increase the likelihood of side effects (dry mouth, urinary retention).

Overdose

Symptoms: daytime sleepiness, depression, anxiety, incoordination, tremor, athetosis, convulsive syndrome, coma with cardiorespiratory collapse; mydriasis, flushing of the skin of the face, hyperthermia.

Treatment: symptomatic, if necessary, anticonvulsants, mechanical ventilation.

Dosage and administration

Inside. For insomnia – 15-30 minutes before the expected bedtime, 7.5-30 mg, for the elderly – 7.5-15 mg; course of treatment up to 2 weeks. In case of allergic reactions – in a single dose up to 25 mg with an interval of 4-6 hours, the maximum daily dose is 150 mg.

Precautions

Should not be used by drivers of vehicles and people whose profession is associated with increased concentration of attention. Care must be taken when awakening at night while taking the drug (possible lethargy or dizziness). At the time of treatment, you should stop taking alcohol.

Special instructions

When following a low-salt diet, the effervescent tablet contains 484 mg sodium bicarbonate.

Brand names with active substance Doxylamine

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Lek. form
All lek. drop forms for oral administration substance powder substance tablets dispersible film-coated tablets

Dosage
All dosages 15 mg 25 mg/ml No dosage

Manufacturer
All manufacturers Alium JSC BERAHIM Ltd. Biocom JSC Biocom JSC Biochemist JSC Krka Crevel Meuselbach GmbH Obolenskoye – pharmaceutical company JSC Ozon Ltd. Organika JSC R.L. Fine Chem North Star NAO UPSA PharmVILAR NPO Pharmproekt JSC

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efficacy, safety and place in clinical practice uMEDp

Doxylamine is a competitive h2-histamine receptor agonist with a sedative effect. It has been used as a treatment for insomnia and nausea in pregnancy since the middle of the 20th century. The article analyzes the currently available data on the efficacy, safety and characteristics of the use of doxylamine in individuals with a high risk of developing adverse events. Its place in clinical recommendations and guidelines, as well as in real clinical practice, is discussed.

Comparative characteristics of first generation h2-histamine receptor antagonists

Introduction

The histaminergic system is one of the main activating systems in the mammalian brain. Its structure was described in 1983–1984. And in 1988, M. Jouvet discovered its inherent activating effect. The projections of the histaminergic system go from the tuberomamillary nucleus to the neurohypophysis, to the striatum, hippocampus, amygdala, neocortex and many other brain structures. Functionally, the histaminergic system is associated with the orexinergic (activating) and GABAergic (inhibitory) systems. This interaction is supposed to make the whole mechanism responsible for the sleep-wake cycle more stable [1].

Antihistamines were first synthesized in 1949. Since the early 1950s. and to this day, some of them, especially diphenhydramine and doxylamine, are used to treat sleep disorders. From a biochemical point of view, antihistamines are not histamine receptor antagonists, but inverse competitive agonists that bind to the receptor and stabilize it in an inactive state. As a result, the activity of the histaminergic system decreases, and soon drowsiness occurs. This effect is most pronounced when blocking H ₁ – histamine receptors.

The sedative potential of first and second generation antihistamines differs. First-generation drugs, having a high lipophilicity, easily penetrate the blood-brain barrier. This group includes chlorpheniramine, chloropyramine, clemastine, cyproheptadine, diphenhydramine, doxylamine, hydroxyzine, meclozine, and promethazine (table). Their ability to occupy receptors reaches 60%. In addition to antihistamine, these substances have M-anticholinergic and alpha-adrenergic blocking effects, and also affect 5HT-mediated transmission [2, 3].

Second-generation antihistamines are hydrophilic molecules that do not readily enter the central nervous system. This group includes cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine. They are much more selective, but their ability to occupy receptors ranges from negligible for fexofenadine to 30% for cetirizine [4]. Second-generation drugs are used mainly for the treatment of allergies, as sedatives they are ineffective.

Doxylamine study

Compared to other modern sleeping pills, doxylamine has been relatively little studied. There are several reasons for this. First of all, it was registered in 1956, when there was no generally accepted three-stage procedure for evaluating efficacy and safety today.

Since entering the market in the US and Europe, doxylamine has been sold without a prescription. As you know, such drugs, unlike prescription drugs, do not need active marketing support, so they are relatively rarely studied in post-marketing studies. There are exceptions when a manufacturer or distributor is looking for a new niche for a drug, but in the case of doxylamine, the list of indications for use was not expanded. The fact that drugs based on diphenhydramine are more popular in the United States both then and now also played a role.

In the last decades of the 20th century, that is, in the period of the formation of evidence-based medicine, there were already several drugs of doxylamine on the market. Accordingly, a qualitative study on one of them would become a tool for promoting all brands, which did not suit any of the interested companies.

Another reason for the relatively low level of study of doxylamine-hypnotics is the court history associated with another drug, which included doxylamine. Between 1956 to 1983, Bendectin, a brand-name drug containing a combination of pyridoxine and doxylamine, was widely used to treat pregnancy vomiting. However, in the early 1980s, A series of lawsuits took place in the United States. The prosecution insisted that Bendectin causes various types of birth defects. Despite a number of studies that denied such a connection, the manufacturing company withdrew the drug from the market. This decision was dictated by financial considerations: the amount of claims for lawsuits exceeded the proceeds from the sale of the drug by more than three times. Already at 1990s additional research has confirmed that doxylamine is safe. And only in 2013, 30 years after the recall, the drug containing doxylamine and pyridoxine returned to medical practice. Its effectiveness and safety are still being studied [5].

Thus, for various reasons, doxylamine has not often become the subject of research and therefore is rarely mentioned in clinical guidelines (we will return to this issue). It is necessary to note the injustice of the current situation, since doxylamine, with the proper approach, remains an effective and safe remedy.

K.N. Strygin (2018) presented a comprehensive analysis of studies on the effectiveness of doxylamine in the treatment of sleep disorders. This review concluded that doxylamine has hypnotic properties comparable to those of zolpidem. At the same time, the effectiveness of doxylamine is selective – not all patients respond equally to the drug. Important advantages of doxylamine are good tolerability and safety. At the same time, the value of the studies reviewed from the standpoint of evidence-based medicine is limited, since for the assessment of sleep, subjective methods were mainly used, and subjects without sleep disorders were often recruited into the studied groups [6].

Doxylamine Safety

The pharmacokinetics and metabolism of doxylamine in humans and other mammals, in particular rats, are different. It is known that doxylamine is metabolized by the enzymes CYP 2D6, CYP 1A2, CYP 2C9. First-generation antihistamines serve not only as a substrate, but also as an inhibitor of CYP 2D6. This should be taken into account when prescribing drugs that involve this metabolic pathway: metoprolol, tramadol, antipsychotic or antiarrhythmic drugs, tricyclic antidepressants.

The time to reach the maximum concentration of doxylamine in the blood plasma is 2.4 hours, the half-life is 10.3 hours. The main part is excreted in the urine. The pharmacodynamics of doxylamine is dose-dependent, intranasal administration is not superior to oral administration. The semi-lethal dose (average dose that kills 50% of test animals) is estimated to be in the range of 50–500 mg/kg body weight, i.e. at least 3500 mg for an adult human weighing 70 kg. When poisoning with doxylamine, convulsions, confusion, rhabdomyolysis can occur [7].

Children are probably more sensitive to doxylamine: a case of a fatal overdose in a three-year-old boy who took about 100 doxylamine/pyridoxine tablets has been described. However, such a risk exists only with extremely severe poisoning. F. Cantrell et al. (2015) found that the symptoms of doxylamine poisoning in children from six months to five years old, who took the drug at a dose of up to 37 mg/kg, went away on their own and only in isolated cases required the use of activated charcoal [8].

The LiverTox database does not contain information about the toxic effect of doxylamine on the liver. According to the classification adopted in this database, it is unlikely that this drug is toxic [9]. However, in patients with impaired liver function, the dose of doxylamine should be reduced.

Doxylamine alone and in combination with pyridoxine is safe to use throughout pregnancy. According to a meta-analysis of 24 controlled studies (about 200,000 women), taking antihistamines in the first trimester did not increase the risk of congenital anomalies or even had a protective effect (odds ratio 0.76.95% CI 0.60–0.94) [10]. Doxylamine, the only antihistamine of all antihistamines, has been declared safe during pregnancy by the U.S. Food and Drug Administration (Category A). Combined drugs containing doxylamine and pyridoxine are not registered in the Russian Federation, therefore, for the treatment of sleep disorders and vomiting of pregnant women, it is permissible to prescribe drugs separately. It is advisable not to combine doxylamine with antidepressants.

According to the LactMed database dedicated to pharmacotherapy during lactation, adverse events are unlikely with episodic use of doxylamine in small doses [11]. However, doxylamine preparations available in the Russian Federation are prohibited during breastfeeding due to the limited data available.

Risk of developing tolerance and dependence while taking doxylamine

The mechanism of addiction to antihistamines is not known. Special studies that would have studied the development of addiction and dependence on the background of the use of doxylamine could not be found in the literature. In one double-blind, randomized, cross-over study, 15 healthy men 18 to 50 years of age received 50 mg diphenhydramine or placebo. In the first days, the level of drowsiness in the diphenhydramine group was higher than in the placebo group, but by the fourth day the results were equal. Thus, with the use of 50 mg of diphenhydramine, complete addiction occurred in three full days [12]. According to clinical experience, the effectiveness of doxylamine decreases after five to seven days. However, as with all antihistamines, the response of different patients to therapy is variable.

Doxylamine itself is not addictive, but the abuse of several drugs at the same time can lead to negative consequences. So, in Australia, a study was conducted, during which the medical data of the population of three states, that is, approximately 18.6 million people, were analyzed [13]. There were 441 cases of unintentional death associated with the abuse of codeine in various combinations with other drugs. In 79% of cases, the deceased people took alcohol, other opiates, benzodiazepines, illicit drugs, psychotropic drugs. In the total sample, doxylamine was detected in 102 (23%) cases. The authors point out that the combined use of doxylamine and codeine can increase the inhibitory effect on the respiratory center. At the same time, it is obvious that the leading role in this process belongs to codeine, access to which, like other opiates, must be controlled. The authors do not provide arguments in favor of the hypothesis of the addictive potential of doxylamine. Thus, when recommending doxylamine, one should adhere to the instructions and use it with caution in patients at risk for substance abuse.

Special uses of doxylamine

Antihistamines have practically no effect on the synthesis and release of histamine. Therefore, potential adverse events associated with the use of doxylamine arise due to their action on receptors. Dryness of the oral mucosa, exacerbation of glaucoma, and a potential decrease in cognitive functions are associated with an M-anticholinergic effect, and worsening of the course of prostate hyperplasia is associated with an alpha-adrenergic blocking effect. Disturbances in sensory and motor reactions are caused by histaminergic and M-anticholinergic effects.

Analyzing data on the safety of doxylamine, one has to rely on information about first-generation antihistamines in general. All of them affect the ability to drive vehicles and mechanisms. At the same time, there are no data on doxylamine in the literature [14]. One way or another, when prescribing doxylamine, patients should be advised to refrain from driving in the morning.

Histamine is involved in sensory and motor responses, so the suppression of its activity is associated with an increased risk of falls. H. Cho et al. (2018) indicate that antihistamines increase the risk of traumatic falls and fractures in the elderly. Based on a meta-analysis of five studies, the odds ratio was 2.03 (95% CI 1.49–2.76, p = 0.41, I2 = 0%) [15]. The data obtained are sufficient to limit the use of first-generation antihistamines in elderly patients with a high risk of falling.

A surrogate marker for the risk of prescribing antihistamines can be considered age over 65 years. According to the instructions for drugs containing doxylamine, they should be used with caution in patients of this age. However, in women, due to the high prevalence of postmenopausal osteoporosis, the risk may be significantly higher even at a younger age. That is why it is important to ask the patient if there have been episodes of falling in the last year, and if there were two or more, then limit the use of antihistamines if possible.

First-generation antihistamines can affect cognitive functions. However, the strength of this effect and its clinical relevance remain controversial. One large prospective study evaluated the possible relationship between the use of cholinergic drugs and the risk of dementia. It turned out that this relationship really existed and was noted mainly against the background of taking tricyclic antidepressants, first-generation antihistamines and drugs for the treatment of overactive bladder. At the same time, the strength of this connection was moderate, and the effect itself appeared only as a cumulative effect with constant and long-term therapy (for three or more years). An association has been convincingly shown for drugs such as chlorpheniramine, meclozine, doxepin, oxybutine, and olanzapine [16]. Doxylamine is not among them. In addition, it should be taken into account that tolerance during doxylamine therapy develops within a few days, so its ability to negatively affect cognitive functions is unlikely. However, when recommending doxylamine, it is necessary to warn the patient about the importance of a short course of taking the drug.

It must be remembered that antihistamines can exacerbate the course of glaucoma, a condition associated with increased intraocular pressure. In particular, there are cases of increased intraocular pressure associated with the use of promethazine, cimetidine, ranitidine [17]. The mechanism of this effect is associated with a pupillary block due to anticholinergic action. For this reason, doxylamine, like other drugs with a similar effect, is contraindicated in angle-closure glaucoma. In case the patient has not been examined by an ophthalmologist, it is useful to know the risk factors (old age, female gender, farsightedness) and recommend a specialist consultation.

It is believed that first-generation antihistamines can adversely affect cardiac function. However, it was only in 2015 that the first representative review was published, combining pharmacovigilance data from various European countries and aiming to find out which of the antihistamines pose a relatively greater or lesser risk to the cardiovascular system. The data for 2004-2011 were analyzed. in all cases of “pirouette tachycardia” (torsades des pointes), QT anomalies, ventricular arrhythmias and cardiac arrest and death associated with it. It turned out that most of the non-fatal arrhythmias are associated with diphenhydramine. It was concluded that doxylamine belongs to active substances with a relatively lower level of danger to the cardiovascular system [18].

Doxylamine is contraindicated in prostate diseases that interfere with the outflow of urine. In the literature, it was not possible to find direct indications of the connection of doxylamine with the aggravation of this disease. Doxylamine is banned along with other first-generation antihistamines, especially diphenhydramine and chlorpheniramine [19].

Doxylamine in clinical practice worldwide

In separate clinical recommendations there are indications for the use of doxylamine, despite the weak evidence base. For example, in a review of insomnia treatment methods by E. Ringdahl et al. (2004), mentions that diphenhydramine and doxylamine are widely available over-the-counter drugs, which, however, should take into account the risks in the elderly.

The position of the British Association for Psychopharmacology (2010) points to the limited place of antihistamines in the treatment of insomnia. It is noted that psychiatrists and first-line physicians can prescribe them, especially for insomnia caused by alcohol or drug withdrawal syndrome. In addition, they can be used in order to avoid the risk of cross-dependence [20].

Experts from the European Guidelines for the Treatment of Insomnia (2017) note the low quality of the evidence base for the effectiveness of antihistamines. In this regard, they are not recommended for use in insomnia [21]. In this manual, relatively little attention is paid to the treatment of acute insomnia and does not cover the issue of sleep disorders in pregnant women.

The American College of Physicians (2016) guideline for the treatment of chronic insomnia briefly states that long-standing antihistamines, in particular diphenhydramine and trazodone, have not been adequately studied and are not considered further [22].

As for domestic recommendations for the treatment of insomnia, they position doxylamine as a more modern drug compared to diphenhydramine. In clinical practice, it is assigned the role of a means for correcting short-term sleep disorders and sleep disorders in pregnant women [23].

The American Academy of Sleep Medicine (2017) guidelines also point to the low quality of the evidence base for antihistamines. The guidelines include a recommendation not to use diphenhydramine in the treatment of insomnia. Doxylamine is not mentioned in the guidelines because, as mentioned above, in the USA it is prescribed much less frequently than diphenhydramine [24].

Thus, a number of indications for the use of doxylamine can be distinguished.

1. Acute insomnia caused by one or more stress factors: conflict at work and in interpersonal relationships, a serious illness in the person himself or his immediate environment, loss or change of job, loss, etc. [25].