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Drugs in R&D Jun 2013Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose... (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetic dose proportionality between two strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate film-coated tablets in fasting state: a single-dose, randomized, two-period crossover study in healthy volunteers.
BACKGROUND
Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years.
OBJECTIVE
The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects.
STUDY DESIGN
This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study.
SETTING
The study was conducted in a phase I clinical unit.
SUBJECTS AND METHODS
A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration-time curve (AUCt normalized). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG).
RESULTS
In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (Cmax) and area under the concentration-time curve from time zero to time t (AUCt ) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2%; mean AUCt 817.33 ng·h/mL, CV 27.4%; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7%; mean AUCt 1630.85 ng·h/mL, CV 22.8%]. Mean AUCt normalized was 815.43 ng·h/mL, CV 22.8% for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUCt was 98.92 (90% CI: 92.46, 105.83). The most common adverse event was somnolence.
CONCLUSIONS
Exposure to doxylamine was proportional over the therapeutic dose range of 12.5-25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.
Topics: Adult; Biological Availability; Cross-Over Studies; Dose-Response Relationship, Drug; Doxylamine; Fasting; Female; Healthy Volunteers; Histamine H1 Antagonists; Humans; Male; Medication Adherence; Middle Aged; Tablets
PubMed: 23633146
DOI: 10.1007/s40268-013-0015-7 -
The Israel Medical Association Journal... Jan 2013Diclectin (pyridoxine 10 mg and doxylamine 10 mg) has traditionally been used to treat nausea and vomiting of pregnancy (NVP); however, this drug is unavailable in many... (Comparative Study)
Comparative Study
BACKGROUND
Diclectin (pyridoxine 10 mg and doxylamine 10 mg) has traditionally been used to treat nausea and vomiting of pregnancy (NVP); however, this drug is unavailable in many countries.
OBJECTIVES
To evaluate the efficacy and safety of a simple bi-daily treatment regimen with the combination of pyridoxine (50 mg twice daily) and doxylamine (25-50 mg) as an alternative treatment for NVP.
METHODS
A prospective case-controlled observational study of mother-infant pairs was conducted between February 2008 and December 2010. All women who contacted the Beilinson Teratology Information Service (BELTIS) regarding treatment of NVP were eligible for inclusion. Using data on NVP severity, treatment efficacy and outcomes, we compared the two groups of women: those treated with the combination of pyridoxine and doxylamine (treatment group, n=29) and those treated with metoclopramide (control group, n=29).
RESULTS
Moderate to severe symptoms were present in 97% of the treatment group women vs. 69% of control group women (P < 0.01). Despite increased symptom severity in the treatment group, the combination regimen was efficacious: 20/29 (69%) vs. 18/25 (72%) in the treatment vs. control women respectively (P = 0.65). There were no congenital anomalies in the treatment group. Follow-up was normal for all infants.
CONCLUSIONS
Bi-daily combination therapy with pyridoxine and doxylamine for NVP is safe, has comparable efficacy to metoclopramide, and is a treatment alternative in countries where Diclectin is not available. Despite symptoms warranting counseling by a teratology information service, more than a third of women do not take the suggested treatment.
Topics: Administration, Oral; Adult; Antiemetics; Case-Control Studies; Dicyclomine; Dose-Response Relationship, Drug; Doxylamine; Drug Administration Schedule; Drug Combinations; Female; Humans; Nausea; Pregnancy; Pregnancy Complications; Prospective Studies; Pyridoxine; Surveys and Questionnaires; Treatment Outcome; Vitamin B Complex; Vomiting
PubMed: 23484234
DOI: No ID Found -
Drugs in R&D Dec 2012Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. The data available on the... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
BACKGROUND
Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. The data available on the pharmacokinetic profile of doxylamine in humans are limited, notwithstanding that this drug has been marketed in European countries for more than 50 years. In fact, no data on the effect of food on the pharmacokinetic parameters of doxylamine are available.
OBJECTIVE
The objective of this study was to evaluate the pharmacokinetic parameters of doxylamine following a single oral dose of doxylamine hydrogen succinate 25 mg in healthy human subjects under fed and fasting conditions.
STUDY DESIGN
This was a single-center, randomized, single-dose, laboratory-blinded, two-period, two-sequence, crossover study.
SETTING
The study was conducted in a phase I clinical unit.
SUBJECTS AND METHODS
A single oral dose of doxylamine hydrogen succinate 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under either fed conditions (high-fat, high-calorie food intake) or fasting conditions in each study period. The drug administrations were separated by a wash-out period of seven calendar days. Plasma samples were collected for up to 60 hours postdose, and plasma doxylamine concentrations were determined by a high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography.
RESULTS
In total, 24 healthy subjects (12 male and 12 female) were included in the study. Doxylamine succinate 25 mg tablets exhibited similar oral bioavailability of doxylamine in the fasting state (mean maximum plasma drug concentration [C(max)] 118.21 ng/mL, coefficient of variation [CV] 19.2%; mean area under the plasma concentration time curve from time zero to time t [AUC(t)] 1746.97 ng · h/mL, CV 31.6%) and in the fed state (mean C(max) 120.99 ng/mL, CV 15.0%; mean AUC(t) 1712.20 ng · h/mL, CV 26.7%). No statistically significant between-treatment differences were observed for any of the pharmacokinetic parameters under study. The fed : fasting ratios of the geometric least squares means with corresponding 90% confidence intervals for C(max) and AUC(t) were within the range of 80-125%.
CONCLUSION
High-fat, high-calorie food intake does not affect the kinetics of doxylamine in healthy subjects. The drug was safe and well tolerated by the subjects in this study.
Topics: Administration, Oral; Adult; Area Under Curve; Biological Availability; Cross-Over Studies; Doxylamine; Fasting; Female; Food-Drug Interactions; Half-Life; Humans; Male; Middle Aged; Tablets; Tablets, Enteric-Coated; Young Adult
PubMed: 23230999
DOI: 10.2165/11641640-000000000-00000 -
BMJ Case Reports Nov 2012Doxylamine succinate, an H(1)-antihistamine drug, is commonly used as sleep-inducing agent as well as therapy for nausea and vomiting in pregnancy. At usual doses, it...
Doxylamine succinate, an H(1)-antihistamine drug, is commonly used as sleep-inducing agent as well as therapy for nausea and vomiting in pregnancy. At usual doses, it may cause impairment of cognitive and psychomotor performance, anticholinergic effects, agitation and postural hypotension. Besides, since this drug is frequently involved in either accidental or intentional overdoses, it seems relevant to bear in mind other possible toxic effects. We report a case of acute severe hyponatremia in the setting of a syndrome of inappropriate antidiuresis (SIAD), an apparent new adverse effect linked to doxylamine overdose. The Naranjo adverse drug reaction probability scale indicated a probable relationship between doxylamine intake and SIAD development. SIAD may be considered as a potential, serious adverse reaction of doxylamine overdose. Clinicians should consider this aetiological possibility when attending patients suffering from hyponatremia.
Topics: Aged; Dose-Response Relationship, Drug; Doxylamine; Drug Overdose; Female; Glasgow Coma Scale; Humans; Hypnotics and Sedatives; Hyponatremia; Inappropriate ADH Syndrome; Saline Solution, Hypertonic; Sleep Initiation and Maintenance Disorders
PubMed: 23166178
DOI: 10.1136/bcr-2012-007428 -
Canadian Family Physician Medecin de... Oct 2012While I usually prescribe doxylamine-pyridoxine for morning sickness, some of my patients with severe nausea and vomiting of pregnancy (NVP) receive ondansetron in...
QUESTION
While I usually prescribe doxylamine-pyridoxine for morning sickness, some of my patients with severe nausea and vomiting of pregnancy (NVP) receive ondansetron in hospital. I have read some new precautions recommended by the US Food and Drug Administration (FDA). Is ondansetron safe to use during pregnancy?
ANSWER
During the past decade ondansetron has been increasingly used in the United States for NVP, owing to the lack of an FDA-approved drug for this condition. While fetal safety data for doxylamine-pyridoxine are based on more than a quarter of a million pregnancies, the fetal safety data for ondansetron are based on fewer than 200 births. Moreover, a recent case-control study suggested there was an increased risk of cleft palate associated with ondansetron. Recently, the FDA issued a warning about potentially serious QT prolongation and torsade de pointes associated with ondansetron use; the warning included a list of precautions and tests that must be followed. The drug is not labeled for use in NVP in either the United States or Canada. Based on the data available today, ondansetron use cannot be assumed to be safe during pregnancy.
Topics: Antiemetics; Canada; Cleft Palate; Female; Fetus; Humans; Long QT Syndrome; Morning Sickness; Nausea; Ondansetron; Pregnancy; Pregnancy Complications, Cardiovascular; United States; Vomiting
PubMed: 23064917
DOI: No ID Found -
Therapeutic Drug Monitoring Oct 2012Women often hesitate to take medications in pregnancy due to fears of perceived potential fetal damage. The authors' objective is to identify the determinants of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Women often hesitate to take medications in pregnancy due to fears of perceived potential fetal damage. The authors' objective is to identify the determinants of adherence to delayed-release doxylamine-pyridoxine (Diclectin) in patients with nausea and vomiting of pregnancy (NVP).
METHODS
The authors performed a prespecified secondary analysis of a multicenter double-blind randomized controlled trial of Diclectin versus placebo for the treatment of NVP. Data on adherence to study medication were collected in all patients. The primary outcome of this analysis was adherence to study medication, which was determined by pill counting and patient diaries. The treatment regimen in the original trial was not fixed and depended on patient's symptoms. There was no difference in the adherence rates between subjects in the Diclectin or placebo arms of the study, so the 2 arms were analyzed as one cohort. The degree of adherence was analyzed in the various subgroups. Subsequently, a multiple linear regression model was constructed to identify predictors to adherence.
RESULTS
Two hundred fifty-eight women were included in this analysis. There were no differences in adherence rates according to ethnicity, race, or the presence of adverse events. Gravidity, average number of prescribed tablets per day, site of enrollment, and change in NVP severity measured by the pregnancy unique-quantification of emesis score were associated with adherence. In multivariable analysis, average number of tablets per day, change in pregnancy unique-quantification of emesis, number of treatment days, site of enrollment were significantly predictive of adherence, with the former being negatively correlated.
CONCLUSION
Adherence to antinauseants for NVP is affected by number of tablets prescribed per day, and treatment duration and effectiveness.
Topics: Adult; Antiemetics; Cohort Studies; Delayed-Action Preparations; Dicyclomine; Double-Blind Method; Doxylamine; Drug Combinations; Female; Humans; Medication Adherence; Nausea; Pregnancy; Pregnancy Complications; Pyridoxine; Vomiting
PubMed: 22972538
DOI: 10.1097/FTD.0b013e31826e7997 -
Case Reports in Neurological Medicine 2012Paroxysmal hypnogenic dyskinesia is a rare clinical entity characterized by intermittent dystonia and choreoathetoid movements that begin exclusively during sleep, often...
Paroxysmal hypnogenic dyskinesia is a rare clinical entity characterized by intermittent dystonia and choreoathetoid movements that begin exclusively during sleep, often with consciousness preserved once the patient is awakened during the episodes. They occur almost every night and are often misdiagnosed as sleeping disorders. Paroxysmal hypnogenic dyskinesia is currently known to be a form of frontal lobe epilepsy, but not in all cases. We present a 19-year-old male patient with paroxysmal hypnogenic dyskinesia who responded to antihistamines. This supports an alternative theory from 1977 (before the cases had been adequately described) that the disorder lies in dysregulation in the basal ganglia. This description now appears similar to acute dystonic reactions such as extrapyramidal symptoms from antipsychotic medications, which also respond to antihistamines.
PubMed: 22937351
DOI: 10.1155/2012/484689 -
Obstetrics and Gynecology International 2012NVP occurs in 50-90% of pregnancies, making it a common medical condition in pregnancy. Women present differently with any combination of signs and symptoms. It is...
NVP occurs in 50-90% of pregnancies, making it a common medical condition in pregnancy. Women present differently with any combination of signs and symptoms. It is appropriate to take the pregnancy-related versus nonpregnancy-related approach when determining the cause of nausea and vomiting but other causes should be considered. The most common etiologies for NVP include the hormonal changes associated with pregnancy, the physiologic changes in the gastrointestinal tract, and a genetic predisposition. Up to 10% of women will require pharmacotherapy to treat the symptoms of NVP despite conservative measures. ACOG currently recommends that a combination of oral pyridoxine hydrochloride and doxylamine succinate be used as first-line treatment for NVP if pyridoxine monotherapy does not relieve symptoms. A review of NVP and early pharmacotherapeutic management is presented due to the fact that NVP is largely undertreated, and investigations into the safe and effective pharmacotherapies available to treat NVP are lacking.
PubMed: 22190950
DOI: 10.1155/2012/252676 -
Brazilian Journal of Microbiology :... Jul 2011Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics...
Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics belonging to both old and new generations using multiresistant Gram-positive and Gram-negative clinical isolates. The bacteriostatic activity of antihistaminics was investigated by determining their MIC both by broth and agar dilution techniques against 29 bacterial strains. Azelastine, cyproheptadine, mequitazine and promethazine were the most active among the tested drugs. Diphenhydramine and cetirizine possessed weaker activity whereas doxylamine, fexofenadine and loratadine were inactive even at the highest tested concentration (1 mg/ml). The MIC of meclozine could not be determined as it precipitated with the used culture media. The MBC values of antihistaminics were almost identical to the corresponding MIC values. The bactericidal activity of antihistaminics was also studied by the viable count technique in sterile saline solution. Evident killing effects were exerted by mequitazine, meclozine, azelastine and cyproheptadine. Moreover, the dynamics of bactericidal activity of azelastine were studied by the viable count technique in nutrient broth. This activity was found to be concentration-dependant. This effect was reduced on increasing the inoculum size while it was increased on raising the pH. The post-antimicrobial effect of 100 μg/ml azelastine was also determined and reached up to 3.36 h.
PubMed: 24031715
DOI: 10.1590/S1517-838220110003000018 -
International Journal of Women's Health Aug 2010Nausea and vomiting of pregnancy (NVP) is a common medical condition in pregnancy with significant physical and psychological morbidity. Up to 90% of women will suffer...
Nausea and vomiting of pregnancy (NVP) is a common medical condition in pregnancy with significant physical and psychological morbidity. Up to 90% of women will suffer from NVP symptoms in the first trimester of pregnancy with up to 2% developing hyperemesis gravidarum which is NVP at its worst, leading to hospitalization and even death in extreme cases. Optimal management of NVP begins with nonpharmacological approaches, use of ginger, acupressure, vitamin B6, and dietary adjustments. The positive impact of these noninvasive, inexpensive and safe methods has been demonstrated. Pharmacological treatments are available with varying effectiveness; however, the only drug marketed specifically for the treatment of NVP in pregnancy is Diclectin(®) (vitamin B6 and doxylamine). In addition, the Motherisk algorithm provides a guideline for use of safe and effective drugs for the treatment of NVP. Optimal medical management of symptoms will ensure the mental and physical wellbeing of expecting mothers and their developing babies during this often stressful and difficult time period. Dismissing NVP as an inconsequential part of pregnancy can have serious ramifications for both mother and baby.
PubMed: 21151729
DOI: 10.2147/ijwh.s6794