Diclegis: a new pill for morning sickness

Key Points

• Approved: April 8, 2013
• Generic ingredients: 10mg Doxylamine succinate and 10mg pyridoxine hydrocholoride
• Indication: Nausea and Vomiting associated with pregnancy in women whose symptoms do not improve with conservative management strategies
• Dosage instructions: two tablets (20mg) at bedtime on an empty stomach with a full glass of water
• Maximum dosage: 4 tablets a day (40mg)
• Safety information: Pregnancy category A
• Major side effect – Somnolence

Introduction
During pregnancy, 70% to 85% of women experience ‘morning sickness’ which manifest in form of nausea and vomiting. About 0.5% to 2% of these women develop a more severe form of morning sickness known as hyperemesis gravidarum, a condition that causes extreme, persistent nausea often associated with dehydration. Hyperemesis gravidarum causes weight loss and hospitalization during pregnancy and is the second most common cause of hospitalization during pregnancy. Early treatment of nausea and vomiting in pregnancy may help prevent progression to hyperemesis gravidarum.

Diclegis (doxylamine succinate and pyridoxine hydrochloride)  is the only FDA approved medication for nausea and vomiting associated with pregnancy. However its components have actually already been used for many years (as early as the 70’s) for the same purpose. As a matter of fact, in its 2004 practice bulletin, doxylamine was recommended as a first-line therapy in combination with pyridoxine by the American College of Obstetrics and Gynecology (ACOG) for the management of nausea and vomiting of pregnancy .

It is important to note that Diclegis is only approved for nausea and vomiting associated with pregnancy and not for hyperemesis gravidarum.

Dosing and Administration
Diclegis is a delayed release tablet that contains 10mg of both doxylamine and pyridoxine and should be administered on an empty stomach with a glass of water. Patients are advised to swallow tablets whole; do not crush, chew, or split.

The initial dosage is two tablets (20mg) at bedtime on day 1, to be titrated in one tablet (10mg) increments first in the morning, then another 10mg midafternoon, if symptoms persist. Maximum dosage is 40mg per day.

Pharmacology and pharmacokinetics
Doxylamine is an antihistamine, while pyridoxine is a vitamin B6 analog. However, the mechanism of action of doxylamine/pyridoxine for nausea and vomiting in pregnancy is unknown.

Doxylamine and pyridoxine are both absorbed mainly in the jejunum, reaching peak plasma concentration (Cmax) in 7.5 and 5.5 hours, respectively. Elimination half-life is 12.5 hours for doxylamine and 0.5 hours for pyridoxine, and steady state concentrations of doxylamine are reached within 24 to 48 hours while pyridoxine’s short half life does not allow it to reach steady-state concentrations. They are both primarily metabolized in the liver and excreted by the kidneys.

The administration of food delays the absorption of both doxylamine and pyridoxine due to the lower Cmax of doxylamine, however the extent of absorption is not affected. Pharmacokinetic studies in special populations such as renal and hepatic impaired patients have not yet been studied.

Clinical trial
Two meta-analyses evaluated the result of several case studies between 1961 and 1985, and failed to detect any teratogenicity to the components of Diclegis as related to its use during the first trimester of pregnancy.

In a clinical trial of pregnant adult women between 7 and 14 weeks gestation, 131 patients received between 2 and 4 tablets dailym while 125 received placebo for 14 days. A survey known as the “Pregnancy Unique-Quantification of Emesis” (PUQE) was used to evaluate the degree of nausea in the study subjects. This survey rated the degree of emesis from 3 (no emesis) to 15 (6 or more hours of nausea, 7 or more instances of vomiting, and 7 or more instances of dry heaves daily). Treatment with placebo led to a 3.9-point mean decrease in the PUQE score by day 15, while patients treated with Diclegis experienced an additional 0.7-point mean decline in PUQE scores over patients treated with placebo (95% CI:0.2 – 1.2; P , 0.0006)

Safety information
Diclegis is contraindicated in patients with a hypersensitivity to ethanolamine-based antihistamines, pyridoxine hydrochloride, or any inactive components of Diclegis. Drowsiness may occur so patients should avoid tasks such as operating machinery, driving or drinking alcohol which may increase the sedation potential of Diclegis. Doxylamine has some anticholinergic properties therefore medical conditions such as asthma, increased intraocular pressure, narrow-angle glaucoma, certain stomach problems, and bladder obstruction problems should be discussed with a health care professional before initiating treatment with Diclegis.

Clinical trials showed that 14.3% of patients using Diclegis experienced somnolence versus 11.7% of patients using placebo. Other adverse events observed during post market surveillance include urinary retention, tachycardia, vertigo, blurred vision, rash, irritability, and migraine.

Finally, although Diclegis is a category A medication for use in pregnancy, it should not be used during breastfeeding because the doxylamine component may cause sedation and worsening of respiratory conditions in infants.

Cost

Most patients with commercial insurance should expect to pay no more than $30 for up to a 30-day supply of Diclegis (restrictions apply). More information on cost savings can be found at the Diclegis website

Sources

• American College of Obstetrics and Gynecology. American College of Obstetrics and Gynecology (ACOG) Practice Bulletin: nausea and vomiting of pregnancy. Obstet Gynecol. 2004;103(4):803-814. PubMed
• Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 8th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008.
• Diclegis [package insert]. Bryn Mawr, PA: Duchesnay USA; April 2013.