Systemic bioavailability and pharmacokinetics of the doxylamine-pyridoxine delayed-release combination (Diclectin).

BACKGROUND: Diclectin, composed of 10 mg doxylamine succinate (DOX) and 10 mg pyridoxine hydrochloride, is the drug combination of choice for the management of nausea and vomiting during pregnancy in Canada. However, there is large variability in its onset and duration of action among women. To understand and improve its effectiveness, the variability in the pharmacokinetics of the ingredients in this doxylamine succinate/pyridoxine hydrochloride combination must be studied. OBJECTIVES: To determine the pharmacokinetics of DOX and pyridoxine after oral administration of two tablets of this drug combination in the form of Diclectin and to calculate their respective relative bioavailability by comparison with intravenous administration in another population. METHODS: Eighteen nonpregnant, nonlactating, healthy females between 18 and 45 years of age were administered two tablets of Diclectin with 240 mL of water under empty stomach conditions. Blood samples were analyzed for DOX and pyridoxine along with its four active metabolites: pyridoxal, pyridoxal-5'-phosphate (PLP), pyridoxamine, and pyridoxamine-5'-phosphate using tandem mass spectrometry. For the purpose of this study, pharmacokinetic values for DOX and PLP were adjusted for body weight. RESULTS: The mean DOX-AUC0→∞ was calculated to be 3137.22 ± 633.57 ng·hr/mL (range, 2056.59-4376.06 ng·hr/mL). The mean PLP-AUC0→∞ was calculated to be 5513.10 ± 2362.35 ng·hr/mL (range, 1572.56-10,153.77 ng·hr/mL). Based on literature values of the PLP-AUC0→∞ after intravenous administration and data from the current study, the relative bioavailability of pyridoxine in Diclectin was calculated at 100%. CONCLUSION: There was a 2.1-fold variability in the DOX-AUC0→∞ and 6.5-fold variability in the PLP-AUC0→∞ after oral administration of 20 mg Diclectin. Using literature values and data from the current study, we estimated the oral bioavailability of pyridoxine to be 100%. Therefore, interindividual differences in metabolism, and not in bioavailability, may be important sources of variability that need to be addressed in dosing guidelines.

The effect of Acid-reducing pharmacotherapy on the severity of nausea and vomiting of pregnancy.

Background. Heartburn and acid reflux (HB/RF) are associated with increased severity of nausea and vomiting. The ability of acid-reducing drugs to reduce symptoms of nausea and vomiting of pregnancy has not been previously tested. Objective. To determine whether acid-reducing pharmacotherapy decreases the severity of NVP symptoms. Methods. We studied a cohort of women experiencing NVP, who were also experiencing HB/RF. Women were counseled to commence acid-reducing pharmacotherapy. The effectiveness of the acid-reducing medication in decreasing symptoms of both HB/RF and NVP was measured. Results. Acid-reducing drugs resulted in significant decreases in PUQE (9.6 +/- 3.0 to 6.5 +/- 2.5, P < .0001) and well-being scores from the initial (4.0 +/- 2.0) to the follow-up interview (6.8 +/- 1.6, P < .0001). After intervention with acid-reducing pharmacotherapy, a reduction in acid symptoms correlated significantly with reduction in NVP (R(2) = 0.72, P < .001). Conclusion. This is the first study to demonstrate that management of HB/RF can reduce the severity of NVP.

The effect of heartburn and acid reflux on the severity of nausea and vomiting of pregnancy.

BACKGROUND: Heartburn (HB) and acid reflux (RF) in the nonpregnant population can cause nausea and vomiting; therefore, it is plausible that in women with nausea and vomiting of pregnancy (NVP), HB/RF may increase the severity of symptoms. OBJECTIVE: To determine whether HB/RF during pregnancy contribute to increased severity of NVP. METHODS: A prospectively collected cohort of women who were experiencing NVP and HB, RF or both (n=194) was studied. The Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scale and its Well-being scale was used to compare the severity of the study cohort's symptoms. This cohort was compared with a group of women experiencing NVP but no HB/RF (n=188). Multiple linear regression was used to control for the effects of confounding factors. RESULTS: Women with HB/RF reported higher PUQE scores (9.6+/-2.6) compared with controls (8.9+/-2.6) (P=0.02). Similarly, Well-being scores for women experiencing HB/RF were lower (4.3+/-2.1) compared with controls (4.9+/-2.0) (P=0.01). Multiple linear regression analysis demonstrated that increased PUQE scores (P=0.003) and decreased Well-being scores (P=0.005) were due to the presence of HB/RF as opposed to confounding factors such as pre-existing gastrointestinal conditions/symptoms, hyperemesis gravidarum in previous pregnancies and comorbidities. CONCLUSION: The present cohort study is the first to demonstrate that HB/RF are associated with increased severity of NVP. Managing HB/RF may improve the severity of NVP.

The safety of histamine 2 (H2) blockers in pregnancy: a meta-analysis.

Heartburn and acid reflux increase the severity of nausea and vomiting of pregnancy, and may lead to more serious medical conditions. The fetal safety of histamine 2 (H2) blockers, the most common antireflux medication, during pregnancy needs to be determined. The aim herein is to determine the fetal safety of H2 blockers during pregnancy through systematic review. All original research assessing the safety of H2 blockers in pregnancy was sought. Data included congenital malformations, spontaneous abortions, preterm delivery, and small for gestational age. A random-effects model combined results. With data from 2,398 exposed and 119,892 nonexposed to H2 blockers, overall odds ratio was 1.14 [0.89, 1.45]. Further analysis revealed no increased risks for spontaneous abortions, preterm delivery, and small for gestational age with odds ratios and 95% confidence intervals (CIs) of 0.62 [0.36-1.05], 1.17 [0.94, 1.147], and 0.28 [0.06, 1.22], respectively. H2 blockers can be used safely in pregnancy.

Is the use of letrozole to induce ovulation teratogenic?

QUESTION: A patient of mine has been prescribed letrozole to induce ovulation; however, a recent release from the Food and Drug Administration contraindicates the use of letrozole in premenopausal women owing to teratogenicity. Does the use of letrozole increase the risk of a child being born with a birth defect? ANSWER: The use of letrozole to induce ovulation has not been associated with an increased risk of a child being born with a birth defect; in contrast, the use of clomiphene citrate in pregnancy is associated with intrauterine growth restriction.