Doxylamine is a first-generation antihistamine used as a short-term sedative and hypnotic or in combination formulations to provide night-time allergy and cold relief. It provides a calmative effect in preparations containing the analgesics paracetamol and codeine. It is prescribed in combination with vitamin B6 to prevent morning sickness in pregnant women. Its fetalsafety rating is "A" in Briggs' Reference Guide to Fetal and Neonatal Risk. It was first described in 1948.
Doxylamine succinate is a potent anticholinergic and has a side-effect profile common to such drugs, including dry mouth, ataxia, urinary retention, drowsiness, memory problems, inability to concentrate, hallucinations, psychosis, and a marked increased sensitivity to external stimuli. Like many hypnotics, it should not be combined with other antihistamines, such as cetirizine or diphenhydramine, as this combination can increase the risk of serious side effects. Some people can have a different reaction: instead of sedating, it stimulates. Using doxylamine over a long period of time is not recommended. However, the drug is not addictive. It can be mildly psychologically addictive to some people. If used for longer periods of time, withdrawal effects are unlikely to be experienced with prolonged use, but mild withdrawal symptoms are likely if taken long-term. Because of its relatively long elimination half-life, doxylamine is associated with daytime/next-day drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic. The shorter elimination half-life of diphenhydramine may give it an advantage over doxylamine in this regard. Unlike with diphenhydramine, case reports of coma and rhabdomyolysis have been reported with doxylamine.
Toxicity
Doxylamine succinate is generally safe for administration to healthy adults. The median lethal dose is estimated to be 50–500 mg/kg in humans. Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death. Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1000 mg doxylamine succinate. Rarely, an overdose results in rhabdomyolysis and acute kidney injury. 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 IARC lists the drug as "not classifiable as to its carcinogenicity to humans".
Pharmacology
Pharmacodynamics
Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor. This action is responsible for its antihistamine and sedative properties. To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors, an action responsible for its minor hypnotic, anticholinergic, and deliriant effects.
Doxylamine succinate is used in general over-the-counter sleep-aids branded as Somnil, Dozile, Donormyl, Lidène, Dormidina, Restavit, Unisom-2, Sominar, and Sleep Aid.
* Doxylamine preparations are available typically in combination with Pyridoxine that may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.
