Succinato de doxilamina

Doxylamine Succinate

1. Identity and Chemical Characterization

Doxylamine succinate is a synthetic organic compound and the pharmaceutical salt form of doxylamine, formed by combining the free base doxylamine with succinic acid in a 1:1 ratio. Its IUPAC name is butanedioic acid; dimethyl({2-[1-phenyl-1-(pyridin-2-yl)ethoxy]ethyl})amine, and it carries the CAS Registry Number 562-10-7. Its molecular formula is C₂₁H₂₈N₂O₅, with a molecular weight of 388.46 g/mol. The free base component of the salt, doxylamine itself, carries the systematic name (RS)-N,N-dimethyl-2-(1-phenyl-1-pyridin-2-yl-ethoxy)-ethanamine.

The acid succinate salt of doxylamine is a white to creamy-white powder with a characteristic odor, soluble in water (1:1) and alcohol (1:2). Doxylamine succinate is one of the first-generation H₁ receptor antagonists of the ethanolamine chemical class. It is a member of the ethanolamine class of antihistamines; other members of this group include bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, orphenadrine, and phenyltoloxamine.

Doxylamine has no natural botanical or herbal source. It is a fully synthetic compound with no plant, fungal, or animal origin. As a pharmaceutical agent, the medication is delivered chemically by the salt doxylamine succinate and is taken by mouth.

Common Forms and Preparations

• Doxylamine succinate comes as a tablet for oral administration.
• It is also administered orally in liquid form.
• To treat nausea and vomiting during pregnancy, doxylamine is often co-administered with pyridoxine (vitamin B6) as an extended-release oral tablet, in a formulation containing doxylamine succinate 10 mg and pyridoxine HCl 10 mg per tablet.
• It is sold under brand names such as Equate and Unisom, among others, and is used in nighttime cold medicines (e.g., NyQuil) and pain medications containing paracetamol (acetaminophen) or codeine to help with sleep.
• In Commonwealth countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared with paracetamol (acetaminophen) and codeine under brand names including Dolased, Propain Plus, Syndol, or Mersyndol, as a treatment for tension headache and other types of pain.
• The doxylamine-pyridoxine combination is available as Diclegis® in the USA and Diclectin® in Canada.

2. Historical and Regulatory Background

Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues, and was first reported in 1948 or 1949. It belongs to the ethanolamine class of antihistamines and was approved for use in the United States in 1948. Doxylamine is a first-generation antihistamine used to treat the symptoms of allergic rhinitis and the common cold, including sneezing, cough, runny nose, watery eyes, and itching; because of its sedating side effects, it is also used as a mild sleeping aid and sedative.

Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an anticholinergic antispasmodic agent), was marketed for the treatment of morning sickness in 1956. In 1976, an eight-way study of doxylamine, pyridoxine HCl, and dicyclomine showed that dicyclomine had no independent antiemetic effect, and therefore, Bendectin was reformulated to contain 10 mg doxylamine succinate and 10 mg pyridoxine HCl. 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; however, these concerns have not been supported by studies.

Courtroom testimony claiming that Bendectin was a human teratogen was markedly devoid of evidence-based corroboration. Merrell Dow indicated that its decision to withdraw Bendectin was based not on safety issues but on financial concerns. The International Federation of Gynecology and Obstetrics described the removal of Bendectin as "the worst example in history of women being denied medication without a cause." For the next 30 years after 1983, there were no medications that had been approved by the Food and Drug Administration (FDA) for the treatment of nausea and vomiting of pregnancy.

In April 2013, the FDA approved the delayed-release combination of doxylamine succinate and pyridoxine hydrochloride (Diclegis®) for nausea and vomiting of pregnancy (NVP), following a Phase 3 randomized trial in pregnant women. Doxylamine has been the antihistamine component of NyQuil since 1966. Doxylamine and other first-generation antihistamines are the most widely used sleep medications in the world.

3. Active Constituents and Pharmacological Identity

Doxylamine succinate contains a single pharmacologically active moiety: the doxylamine free base. The succinate counterion (derived from succinic acid, also known as butanedioic acid) serves as a pharmaceutically acceptable salt-forming acid that improves stability and solubility. Doxylamine is primarily used as the succinic acid salt, doxylamine succinate. The compound is therefore fully synthetic and its "key constituent" is the doxylamine molecule itself, which carries all known pharmacological activity.

4. Mechanisms of Action

Primary Mechanism: H₁ Receptor Antagonism

Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H₁ receptor. This action is responsible for its antihistamine and sedative properties. As a first-generation antihistamine, it typically crosses the blood–brain barrier into the brain, thereby producing a suite of sedative and hypnotic effects mediated by the central nervous system. It is categorized as a first-generation antihistamine because it can cross the blood-brain barrier, which newer antihistamines generally do not do.

Histamine is a neurotransmitter involved in the regulation of sleep and wakefulness; when histamine binds to H₁ receptors, it promotes wakefulness and alertness. By blocking these receptors, doxylamine succinate inhibits the action of histamine, leading to a sedative effect that makes it easier to fall asleep and stay asleep.

Anticholinergic / Antimuscarinic Activity

Doxylamine is also a potent anticholinergic, meaning that it causes delirium at high doses (at much higher doses than recommended). Specifically, it is an antagonist of the muscarinic acetylcholine receptors M1 through M5. The antagonistic activity on muscarinic receptors is primarily responsible for anticholinergic adverse effects, including blurred vision, dry mouth, and constipation.

Antiemetic Mechanism

Doxylamine reduces nausea and vomiting by inhibiting histaminergic signaling to the vomiting center in the medulla. This activity also depresses labyrinthine function, blocks the chemoreceptor trigger zone, and diminishes vestibular stimulation. The mechanism of action of doxylamine succinate and pyridoxine hydrochloride in treating nausea and vomiting in pregnant women is specifically unknown.

Additional Receptor Targets

The neuropharmacological relevance of doxylamine primarily stems from its antagonism of histamine H₁ receptors within the central nervous system, which is associated with sedative effects and decreased alertness. Alongside its H₁ receptor antagonism, doxylamine exerts additional antagonistic actions at muscarinic cholinergic and adrenergic receptors.

5. Pharmacokinetics

Absorption and Distribution

Doxylamine succinate is rapidly absorbed in the gastrointestinal tract after oral administration. Both doxylamine and pyridoxine (in the combination formulation) are absorbed in the gastrointestinal tract, mainly in the jejunum. In a study of 16 healthy male volunteers who received a single oral dose of 25 mg doxylamine succinate, mean kinetic variables were: peak plasma level, 99 ng/mL; time of peak, 2.4 hours post-dose; and elimination half-life, 10.1 hours. For the delayed-release formulation, peak plasma concentrations of doxylamine occur within 7.5 hours, and the half-life of doxylamine was 10.1 hours following a single dose and 11.9 hours following multiple doses.

The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration.

Metabolism and Excretion

Doxylamine is metabolized by the liver to N-desmethyl-doxylamine and N,N-didesmethyldoxylamine. Both of these metabolites are excreted by the kidney. Doxylamine is converted to demethylated metabolites and their N-acetylated derivatives in humans, monkeys, and rats. In rats, doxylamine is also metabolized via N-oxidation, aromatic hydroxylation, and ether cleavage pathways. Doxylamine undergoes hepatic metabolism via a dealkylation reaction, so clinicians should consider the patient's liver function. Additionally, doxylamine and its respective metabolites are excreted by the kidneys, so clinicians should consider the patient's renal function when administering this drug.

Half-Life and Duration of Effects

Doxylamine has a half-life of approximately 10 hours, which increases to 12 to 15 hours in the elderly. The relatively long half-life of doxylamine may confer benefits for maintenance of insomnia but also increases the potential for next-morning residual sedation. 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.

6. Body Systems and Health Areas

Doxylamine succinate has documented activity across several body systems:

• Central Nervous System: Sedation, hypnotic effect, suppression of wakefulness via H₁ receptor blockade in the brain.
• Immune/Inflammatory System: Attenuation of allergic inflammatory cascades mediated by histamine at peripheral H₁ receptors.
• Gastrointestinal System: Inhibition of the chemoreceptor trigger zone and vomiting center in the medulla; antiemetic activity.
• Vestibular System: Depression of labyrinthine function and vestibular stimulation.
• Autonomic Nervous System: Anticholinergic effects on smooth muscle, glandular secretion, and the urinary tract via muscarinic receptor blockade.

7. Scientific Evidence by Area of Use

7.1 Insomnia and Short-Term Sleep Disturbance

Doxylamine is a medication used to manage and treat insomnia, allergic rhinitis, and nausea and vomiting of pregnancy (NVP). Its use for self-medication for short-term management of insomnia is established; however, the FDA states that, pending further accumulation of data, doxylamine-containing nighttime sleep aids approved for this use may continue to be marketed in the US.

Doxylamine succinate 25 mg was studied in a trial of 83 insomniacs (mean age 46 ± 14 years) who completed the study. Patient ratings were significantly more positive for doxylamine with regard to sleep latency (P < .001), nocturnal awakenings (P < .001), sleep duration (P < .001), sleep quality (P < .001), and morning restfulness (P < .001).

Objective polysomnographic data present a more nuanced picture. Subjective reports indicate that doxylamine decreases sleep latency and increases sleep continuity, although polysomnographic data suggest that sleep latency and total sleep time may be unaffected or only slightly improved, with rapid eye movement (REM) sleep typically decreased. There is a lack of placebo-controlled trials evaluating long-term safety and efficacy in insomnia.

The American College of Physicians (ACP) and American Academy of Sleep Medicine (AASM) guidelines do not recommend doxylamine as a first-line or even well-supported second-line agent for insomnia treatment; Cognitive Behavioral Therapy for Insomnia (CBT-I) is the first-line treatment for chronic insomnia disorder. Overall, the evidence for doxylamine in insomnia is limited to short-term subjective outcomes in small trials; no robust polysomnographic or long-term randomized controlled trial evidence exists to support use beyond occasional, transient sleep disturbance.

7.2 Nausea and Vomiting of Pregnancy (NVP)

This is the area with the strongest clinical evidence base for doxylamine succinate. Doxylamine-pyridoxine is recommended as a first-line treatment for nausea and vomiting during pregnancy and is commonly prescribed. Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers.

The pivotal clinical trial that supported FDA approval was a randomized, double-blind, multicenter, placebo-controlled trial studying pregnant women suffering from nausea and vomiting of pregnancy, analyzed by intention to treat. Women received Diclectin (n = 131) or placebo (n = 125) for 14 days. NVP symptoms were evaluated daily using the pregnancy unique quantification of emesis (PUQE) scale. Diclectin use resulted in a significantly larger improvement in symptoms compared with placebo based on the PUQE score (−4.8 ± 2.7 vs. −3.9 ± 2.6; P = .006) and quality of life. After the trial, 64 (48.9%) women receiving Diclectin asked to continue compassionate use of their medication, compared with 41 (32.8%) of placebo-treated women (P = .009).

A secondary analysis examined the time course of symptom improvement. The use of delayed-release doxylamine succinate and pyridoxine hydrochloride tablets showed improved NVP symptom control compared to placebo on Days 3, 4, and 5, with sustained efficacy until the end of the trial. A four-day study drug dosing trial was sufficient to document efficacy, as the results were similar to those achieved after 14 study drug dosing days.

In a randomized, placebo-controlled safety trial, doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal, or cardiovascular involvement. The delayed-release combination was safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy.

The FDA's approval of Diclegis was based on efficacy and safety data from a randomized, placebo-controlled clinical trial and also took into account extensive data showing that combined treatment with doxylamine succinate and pyridoxine hydrochloride is not teratogenic. These data reveal a favorable risk–benefit profile for Diclegis in the treatment of nausea and vomiting of pregnancy that has been refractory to nonpharmacologic treatment.

7.3 Teratogenicity and Pregnancy Safety: The Bendectin Evidence Base

The question of teratogenicity was the subject of one of the most extensive pharmacoepidemiology investigations in history. Since the mid-1950s, over 33 million women have used the combination drug of pyridoxine/doxylamine in pregnancy, and scientific analysis on more than 200,000 exposed pregnancies has been conducted to determine if the combination is harmful to the unborn baby. No epidemiological studies have found any teratogenic effect.

Two separate meta-analyses assessed pregnancy outcomes following the use of a combination of pyridoxine and doxylamine with or without dicyclomine during the first trimester. The initial meta-analysis, published in 1988, combined data from 12 cohort and 5 case-control studies, and the subsequent meta-analysis, published in 1994, combined data from 16 cohort studies and 11 case-control studies. These studies included over 200,000 Bendectin-exposed pregnancies and did not observe an increased risk for major malformations. Separate analyses were conducted for specific defects including cardiac defects, limb reduction defects, oral clefts, and genital tract malformations; no increased risks for these defects were found.

In a prospective cohort study of 50,282 gravidas and their offspring, congenital malformation rates were similar in the children of over 1,000 women exposed and those not exposed to doxylamine succinate and dicyclomine hydrochloride during the first four lunar months of pregnancy. Mean birth weight and perinatal mortality rates were similarly not significantly different according to exposure, as were intelligence quotient scores measured at four years of age.

Committees assembled by both the FDA and Health Canada supported these findings, stating that the drug combination of doxylamine succinate and pyridoxine HCl does not increase malformation risk. One large observational study published in 2022 raised a signal of possible increased risk of major congenital malformations; results of this large observational study suggested that exposure to doxylamine-pyridoxine during the first trimester of pregnancy was associated with a significantly increased risk of overall and specific major congenital malformations, though other evidence continues to confirm that doxylamine-pyridoxine is not a teratogen. This new signal has been the subject of ongoing scientific scrutiny and debate, and the broader existing body of evidence remains supportive of safety.

7.4 Allergic Rhinitis and Common Cold Symptoms

Doxylamine is a first-generation ethanolamine H₁-antihistamine. H₁-antihistamines interfere with the agonist action of histamine at the H₁ receptor and are administered to attenuate inflammatory processes in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Doxylamine is widely used in combination with other agents such as dextromethorphan, pseudoephedrine, aspirin, and acetaminophen in over-the-counter products for relief of symptoms of the common cold and allergic rhinitis. The clinical evidence base for doxylamine as a standalone antiallergic agent is sparse; its antihistaminic use in cold and allergy formulations is primarily supported by class-level evidence for first-generation H₁ antagonists rather than doxylamine-specific randomized controlled trials.

8. Dosage Forms and Reported Dosages

The following dosages are drawn directly from published clinical sources and official product labeling:

• Insomnia (OTC, adults): The standard dosage for treating insomnia in adults is 25 mg, taken approximately 30 minutes before bedtime.
• Nausea and Vomiting of Pregnancy (combination tablet): The standard recommended dose of Diclegis/Diclectin is typically up to four tablets daily: two tablets at bedtime, one in the morning, and one in the mid-afternoon. Each tablet contains doxylamine 10 mg and pyridoxine 10 mg.
• Pharmacokinetic study reference dose: Sixteen healthy male volunteers received a single oral dose of 25 mg doxylamine succinate in a published pharmacokinetic study.
• Bioavailability study: Doxylamine succinate 25 mg tablets were evaluated in healthy subjects, giving a mean maximum plasma drug concentration (Cmax) of 118.21 ng/mL in the fasting state.
• Duration of use: Healthcare providers usually advise a course no longer than two weeks for treating insomnia.

9. Safety Considerations and Drug Interactions

General Adverse Effect Profile

Typical side effects of doxylamine include dizziness, drowsiness, grogginess, and dry mouth, among others. 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 — sometimes described as a "hangover effect."

Anticholinergic Burden and Special Populations

Therapy with antihistamines should be administered cautiously, if at all, in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction, angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma, and gastrointestinal obstructive disorders.

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. The half-life of doxylamine increases to 12 to 15 hours in the elderly, prolonging potential adverse effects in that population. Older adults over the age of 65 may be more likely to experience certain side effects of doxylamine. Drowsiness and unsteadiness may be more likely in this population and can increase the risk of falls or accidents. Anticholinergic medications are also linked to impaired cognition and an increased risk of dementia in this age group.

Paediatric Risk

Children appear to be at high risk for cardiopulmonary arrest with doxylamine overdose. A toxic dose for children of more than 1.8 mg/kg has been reported. A three-year-old child died 18 hours after ingesting 1,000 mg doxylamine succinate. Children may be more susceptible to experiencing side effects than adults. Doxylamine should not be used by children under the age of 12, unless instructed by a doctor.

Overdose and Toxicity

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. Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death. Rarely, an overdose results in rhabdomyolysis and acute kidney injury.

Drug–Drug Interactions

• CNS depressants: Using doxylamine with CNS depressants, such as alcohol, benzodiazepines, and opioids, can increase CNS depressant effects and the risk of oversedation and overdose.
• Monoamine oxidase inhibitors (MAOIs): MAOIs prolong and intensify the anticholinergic effects of antihistamines. This combination is generally contraindicated.
• Other anticholinergic agents: Conventional, first-generation antihistamines such as the ethanolamines, including doxylamine, tend to exhibit substantial anticholinergic effects, and combining doxylamine with other anticholinergic drugs would be expected to compound this burden.
• Hepatic enzyme interactions: Doxylamine is a potent, phenobarbital-type inducer of cytochrome P450 enzymes in mice. No evidence of enzyme induction has been found in humans.

Hepatic and Renal Considerations

Despite widespread use over many decades, doxylamine has not been linked to liver test abnormalities or to clinically apparent liver injury. The reason for its safety may relate to its short half-life and limited duration of use. NIH LiverTox assigns it a likelihood score of E (unlikely to be a cause of clinically apparent liver injury). In animal studies, however, studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse. 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." No evidence of enzyme induction has been found in humans despite the rodent findings. Patients with renal and/or liver disease may be at greater risk for adverse effects from antihistamines due to drug and metabolite accumulation.

Breastfeeding

Other doxylamine products are deemed safe to use as a short-term or infrequent treatment while breastfeeding. High dose or prolonged treatment can result in decreased lactation and some side effects in the infant.

Respiratory Disease

Oral anxiolytic, sedative, and hypnotic agents may cause respiratory depression and apnea when given in high dosages or following acute overdose. Some patients may be susceptible at commonly used dosages, including the elderly, debilitated or severely ill patients, those receiving other CNS depressants, and those with limited ventilatory reserve, chronic pulmonary insufficiency, or other respiratory disorders.

10. Evidence Strength Summary

• Nausea and vomiting of pregnancy: The strongest evidence base. Supported by a Phase 3 randomized, double-blind, placebo-controlled trial, multiple prior cohort studies, two independent meta-analyses, and FDA and Health Canada regulatory approval. Evidence quality: high for short-term efficacy; high for fetal safety.
• Insomnia / sleep-onset: Supported by small-to-moderate randomized controlled trials using primarily subjective endpoints. Objective polysomnographic evidence is limited and mixed. The FDA permits continued marketing pending further data accumulation. Evidence quality: moderate for subjective outcomes; weak for objective polysomnographic measures; no long-term safety/efficacy data.
• Allergic rhinitis / common cold symptoms: Used on the basis of class-level H₁-antihistamine pharmacology. No doxylamine-specific large randomized controlled trials identified in this indication. Evidence quality: indirect / class-based.

References

• Brott NR, Reddivari AKR. Doxylamine. StatPearls. NIH/NCBI Bookshelf.
• Doxylamine. LiverTox®: Clinical and Research Information on Drug-Induced Liver Injury. NIH/NCBI Bookshelf.
• Nulman I et al. Doxylamine Succinate/Pyridoxine Hydrochloride. PMC/NCBI.
• Koren G et al. Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial. BMC Pregnancy Childbirth. PMC.
• Koren G et al. Demonstration of early efficacy results of the delayed-release combination of doxylamine-pyridoxine for the treatment of nausea and vomiting of pregnancy. PMC/NCBI.
• Madjunkova S et al. The Delayed-Release Combination of Doxylamine and Pyridoxine (Diclegis®/Diclectin®) for the Treatment of Nausea and Vomiting of Pregnancy. PMC/NCBI.
• Koren G et al. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. American Journal of Obstetrics & Gynecology.
• FDA Approval of Doxylamine–Pyridoxine Therapy for Use in Pregnancy. New England Journal of Medicine.
• Cheung KL, Lafayette RA. Doxylamine-pyridoxine for nausea and vomiting of pregnancy randomized placebo controlled trial: Prespecified analyses and reanalysis. PLOS One.
• Doxylamine. Wikipedia (with referenced citations to primary sources).
• Doxylamine: Uses, Interactions, Mechanism of Action. DrugBank.
• Friedman H et al. The pharmacokinetics of doxylamine: use of automated gas chromatography with nitrogen-phosphorus detection. PubMed.
• Novell A et al. Food Effects on the Pharmacokinetics of Doxylamine Hydrogen Succinate 25 mg Film-Coated Tablets: A Single-Dose, Randomized, Two-Period Crossover Study in Healthy Volunteers. PMC/NCBI.
• Doxylamine succinate. IARC Summary & Evaluation, Volume 79, 2001. INCHEM.
• American Academy of Sleep Medicine: Clinical Practice Review — Treatment of Primary Insomnia (AASM).
• Morin CM, Benca R. Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review. The Primary Care Companion for CNS Disorders.
• Doxylamine. MedlinePlus Drug Information. U.S. National Library of Medicine.
• Doxylamine Disease Interactions. Drugs.com.
• BONJESTA (doxylamine succinate and pyridoxine hydrochloride) Prescribing Information. U.S. FDA.
• FDA Center for Drug Evaluation and Research: NDA Application 021876 — Diclegis Cross-Discipline Team Leader Review.
• APO-DOXYLAMINE/B6 Product Monograph. Health Canada.
• Pyridoxine/doxylamine. Wikipedia (with referenced primary source citations).
• Milkovich L, van den Berg BJ. Antenatal exposure to doxylamine succinate and dicyclomine hydrochloride (Bendectin) in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score. ScienceDirect.
• NCATS Inxight Drugs — Doxylamine Succinate. National Center for Advancing Translational Sciences, NIH.
• Doxylamine H1-Antihistamine Immune Response Action Pathway. Small Molecule Pathway Database (SMPDB).