Risk of major congenital malformations associated with first-trimester exposure to propulsives: A health administrative database study in Japan.

PURPOSE: To evaluate the risk of major congenital malformations (MCMs) associated with first-trimester exposure to propulsives with a special focus on domperidone using a large administrative database in Japan. METHODS: A large claims database was used from January 2005 to August 2016. The dates of pregnancy onset and delivery were estimated using the developed algorithms. MCMs were defined according to the International Classification of Diseases, 10th revision codes. We compared the infants' risk of overall MCMs between women with or without first-trimester prescriptions of propulsives and estimated the odds ratios (ORs) with unadjusted and adjusted analyses. We also compared the risk of overall MCMs between women with domperidone prescriptions and those with other propulsive prescriptions during the first trimester. RESULTS: Among 38 270 women, propulsives were prescribed to 3197 women (8.4%) in the first trimester, including domperidone to 371 women (1.0%). Propulsive prescriptions in the first trimester were not significantly associated with an increased risk of overall MCMs (adjusted OR [aOR] 1.030, 95% confidence interval [CI] 0.843-1.257). Compared to the prescription of other propulsives in the first trimester, the prescription of domperidone in the first trimester was not associated with an increased risk of overall MCMs (aOR 0.724, 95% CI 0.363-1.447). CONCLUSIONS: The first-trimester prescription of propulsives, including domperidone, was not associated with an increased risk of overall MCMs.

Domperidone and the risks of sudden cardiac death and ventricular arrhythmia: A systematic review and meta-analysis of observational studies.

AIMS: Concerns exist regarding the cardiovascular safety of domperidone. However, many of the previous studies addressing this issue had important limitations. We aimed to examine domperidone and the risks of sudden cardiac death and ventricular arrhythmia through a systematic review and meta-analysis of observational studies, including an in-depth methodological assessment. METHODS: We systematically searched MEDLINE, PubMed, EMBASE, Scopus and CINAHL Plus to identify observational studies examining the association of domperidone and sudden cardiac death and/or ventricular arrhythmia. We assessed study quality in duplicate using the ROBINS-I tool supplemented by an assessment of specific biases and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. Data were pooled across studies using DerSimonian and Laird random-effects models. RESULTS: Six case-control studies, 1 case-crossover study and 1 retrospective cohort study were included (n = 480 395). Based on ROBINS-I, 3 studies had moderate risk of bias, 4 had serious risk, and 1 had critical risk. The overall GRADE rating is moderate. When data were pooled across nonoverlapping studies, domperidone was associated with an increased risk of composite endpoint of sudden cardiac death or ventricular arrhythmia compared to nonuse (adjusted odds ratio: 1.69; 95% confidence interval: 1.46, 1.95; I2 : 0%; τ2 : 0). This association persisted when restricted to higher-quality studies (odds ratio: 1.60; 95% confidence interval: 1.30, 1.97; I2 : 0%; τ2 : 0). CONCLUSION: Domperidone is associated with an increased risk of sudden cardiac death and ventricular arrhythmia compared to nonuse. Further investigation comparing domperidone to an active comparator and in younger populations are warranted.

Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.

AIM: To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control. METHODS: Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors. RESULTS: The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183). CONCLUSIONS: This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.

Association between domperidone use and adverse cardiovascular events: A nested case-control and case-time-control study.

PURPOSE: To assess the association between domperidone and adverse cardiovascular events. METHODS: We conducted nested case-control and case-time-control studies using Korea's healthcare database (2002-2015). We identified patients without history of hospitalization, cancer, or cardiovascular diseases in 2002. From our cohort, those diagnosed with an adverse cardiovascular event (case), composite of arrhythmia, hypertension, or acute myocardial infarction were matched to two controls using risk-set sampling on various sociodemographic variables. Exposure was assessed in the 1 to 7 days, or in the 1 to 7 days (hazard period) and 91 to 97 days (control period) prior to index date, in nested case-control and case-time control studies, respectively. We compared domperidone to metoclopramide or non-use and estimated odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression. RESULTS: From 627 799 patients, we identified 71 555 cases and 141 833 controls. In the nested case-control study, while the risk of cardiovascular events was increased with domperidone (OR 1.38, 95% CI 1.28-1.47) compared to non-use, the risk was reduced (0.64, 0.57-0.72) compared to metoclopramide. In the case-time-control study, similar increased risk was found when compared to non-use (1.40, 1.29-1.52) but a reduced risk as compared with metoclopramide (0.63, 0.54-0.72). Risk of myocardial infarction associated with domperidone was highest (nested case-control: 1.94, 1.33-2.83; case-time-control: 1.91, 1.01-3.62) when compared to non-use but did not indicate an increased risk when compared to metoclopramide (nested case-control: 0.60, 0.32-1.13; case-time-control: 0.70, 0.25-1.98). CONCLUSION: Our findings support a positive association between domperidone and adverse cardiovascular events. However, domperidone may have a safer cardiovascular profile than metoclopramide.

Data variability across Canadian administrative health databases: Differences in content, coding, and completeness.

PURPOSE: The Canadian Network for Observational Drug Effect Studies (CNODES) is a network of Canadian research centres using administrative data to conduct distributed drug safety and effectiveness studies. In this study, we compare the provincial administrative databases and illustrate the potential impact of database differences on a CNODES study about domperidone and the risk of ventricular tachyarrhythmia and sudden cardiac death (VT/SCD). METHODS: We assessed the impact of varying versions and precision of the International Classification of Diseases coding system in physician claims data, and the content and completeness of hospital discharge abstracts across CNODES sites, as these variations can introduce differences in the study cohorts formed and affect study results. RESULTS: In our study of 214 962 patients, hospital diagnosis type (such as most responsible, admitting, or secondary diagnosis) was missing in some provinces, resulting in misclassification of the outcome and variation in rates and risk estimates. Incidence rates of VT/SCD ranged from 19.8 (95% confidence interval [CI] 17.7-22.2) per 10 000 person-years in British Columbia to 53.4 (95% CI 50.3-56.5) in Quebec. While most provinces reported an increased risk of VT/SCD, a null effect was observed in Quebec (rate ratio 1.06; 95% CI 0.79-1.41). CONCLUSIONS: Distributed analyses allow for rapid responses to drug safety signals. However, variation in characteristics of the administrative data across research centres can influence study results. By identifying the sources of database heterogeneity, one can evaluate the potential biases these differences may introduce, highlighting the importance of considering such variation in distributed networks.

Oral galactagogues (natural therapies or drugs) for increasing breast milk production in mothers of non-hospitalised term infants.

BACKGROUND: Many women express concern about their ability to produce enough milk, and insufficient milk is frequently cited as the reason for supplementation and early termination of breastfeeding. When addressing this concern, it is important first to consider the influence of maternal and neonatal health, infant suck, proper latch, and feeding frequency on milk production, and that steps be taken to correct or compensate for any contributing issues. Oral galactagogues are substances that stimulate milk production. They may be pharmacological or non-pharmacological (natural). Natural galactagogues are usually botanical or other food agents. The choice between pharmacological or natural galactagogues is often influenced by familiarity and local customs. Evidence for the possible benefits and harms of galactagogues is important for making an informed decision on their use. OBJECTIVES: To assess the effect of oral galactagogues for increasing milk production in non-hospitalised breastfeeding mother-term infant pairs. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), Health Research and Development Network - Phillippines (HERDIN), Natural Products Alert (Napralert), the personal reference collection of author LM, and reference lists of retrieved studies (4 November 2019). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) comparing oral galactagogues with placebo, no treatment, or another oral galactagogue in mothers breastfeeding healthy term infants. We also included cluster-randomised trials but excluded cross-over trials. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two to four review authors independently selected the studies, assessed the risk of bias, extracted data for analysis and checked accuracy. Where necessary, we contacted the study authors for clarification. MAIN RESULTS: Forty-one RCTs involving 3005 mothers and 3006 infants from at least 17 countries met the inclusion criteria. Studies were conducted either in hospitals immediately postpartum or in the community. There was considerable variation in mothers, particularly in parity and whether or not they had lactation insufficiency. Infants' ages at commencement of the studies ranged from newborn to 6 months. The overall certainty of evidence was low to very low because of high risk of biases (mainly due to lack of blinding), substantial clinical and statistical heterogeneity, and imprecision of measurements. Pharmacological galactagogues Nine studies compared a pharmacological galactagogue (domperidone, metoclopramide, sulpiride, thyrotropin-releasing hormone) with placebo or no treatment. The primary outcome of proportion of mothers who continued breastfeeding at 3, 4 and 6 months was not reported. Only one study (metoclopramide) reported on the outcome of infant weight, finding little or no difference (mean difference (MD) 23.0 grams, 95% confidence interval (CI) -47.71 to 93.71; 1 study, 20 participants; low-certainty evidence). Three studies (metoclopramide, domperidone, sulpiride) reported on milk volume, finding pharmacological galactagogues may increase milk volume (MD 63.82 mL, 95% CI 25.91 to 101.72; I² = 34%; 3 studies, 151 participants; low-certainty evidence). Subgroup analysis indicates there may be increased milk volume with each drug, but with varying CIs. There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints, such as tiredness, nausea, headache and dry mouth (very low-certainty evidence). No adverse effects were reported for infants. Natural galactagogues Twenty-seven studies compared natural oral galactagogues (banana flower, fennel, fenugreek, ginger, ixbut, levant cotton, moringa, palm dates, pork knuckle, shatavari, silymarin, torbangun leaves or other natural mixtures) with placebo or no treatment. One study (Mother's Milk Tea) reported breastfeeding rates at six months with a concluding statement of "no significant difference" (no data and no measure of significance provided, 60 participants, very low-certainty evidence). Three studies (fennel, fenugreek, moringa, mixed botanical tea) reported infant weight but could not be meta-analysed due to substantial clinical and statistical heterogeneity (I2 = 60%, 275 participants, very low-certainty evidence). Subgroup analysis shows we are very uncertain whether fennel or fenugreek improves infant weight, whereas moringa and mixed botanical tea may increase infant weight compared to placebo. Thirteen studies (Bu Xue Sheng Ru, Chanbao, Cui Ru, banana flower, fenugreek, ginger, moringa, fenugreek, ginger and turmeric mix, ixbut, mixed botanical tea, Sheng Ru He Ji, silymarin, Xian Tong Ru, palm dates; 962 participants) reported on milk volume, but meta-analysis was not possible due to substantial heterogeneity (I2 = 99%). The subgroup analysis for each intervention suggested either benefit or little or no difference (very low-certainty evidence). There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints such as mothers with urine that smelled like maple syrup and urticaria in infants (very low-certainty evidence). Galactagogue versus galactagogue Eight studies (Chanbao; Bue Xue Sheng Ru, domperidone, moringa, fenugreek, palm dates, torbangun, moloco, Mu Er Wu You, Kun Yuan Tong Ru) compared one oral galactagogue with another. We were unable to perform meta-analysis because there was only one small study for each match-up, so we do not know if one galactagogue is better than another for any outcome. AUTHORS' CONCLUSIONS: Due to extremely limited, very low certainty evidence, we do not know whether galactagogues have any effect on proportion of mothers who continued breastfeeding at 3, 4 and 6 months. There is low-certainty evidence that pharmacological galactagogues may increase milk volume. There is some evidence from subgroup analyses that natural galactagogues may benefit infant weight and milk volume in mothers with healthy, term infants, but due to substantial heterogeneity of the studies, imprecision of measurements and incomplete reporting, we are very uncertain about the magnitude of the effect. We are also uncertain if one galactagogue performs better than another. With limited data on adverse effects, we are uncertain if there are any concerning adverse effects with any particular galactagogue; those reported were minor complaints. High-quality RCTs on the efficacy and safety of galactagogues are urgently needed. A set of core outcomes to standardise infant weight and milk volume measurement is also needed, as well as a strong basis for the dose and dosage form used.

Domperidone prescribing patterns in pediatric patients before and after safety warning in South Korea.

OBJECTIVE: In 2014, the Korean Ministry of Food and Drug Safety (MFDS) issued a safety warning to carefully consider adverse cardiac effects when prescribing domperidone for children. We conducted this study to compare the trends of domperidone prescription in pediatrics before and after the MFDS safety warning. MATERIALS: This study included patients < 18 years old who used national health insurance services within the year 2011 and the year 2016, sampled from Health Insurance Review Agency data. METHODS: We analyzed domperidone prescribing patterns including prescribed daily dosage, maximum period of continuous prescription, and number and types of co-prescribed medications and compared two different years pre and post safety warning. RESULTS: A total of 16,614 pediatric patients (1.74%) received domperidone prescriptions in 2011, and 11,317 patients (1.23%) in 2016. The probability of receiving at least one prescription in 2016 has been reduced by 30% compared to 2011. Gastritis was the most common indication in both years. The number of prescriptions containing a maximum daily dosage of over 30 mg was significantly lower in 2016. In the same time period, the number of cases with a maximum continuous prescription period of more than 7 days significantly decreased (p < 0.001). In addition, from 2011 to 2016, comorbid diseases of domperidone-treated patients were similar, but the number of co-prescriptions of interacting medication to domperidone decreased (p < 0.001). CONCLUSION: After the 2014 safety letter was released, the pattern of prescribing domperidone in pediatrics has enhanced drug safety for children in terms of frequency of prescriptions, maximum duration of domperidone use, and the prescription of drugs interacting with domperidone.

Effect of Chronic Domperidone Use on QT Interval: A Large Single Center Study.

GOALS: The goal of this study was to determine the effect and safety of domperidone on QTc interval at the commonly prescribed doses of 30 to 80 mg daily. BACKGROUND: Domperidone is a dopamine receptor antagonist used for the treatment of gastroparesis. However, it has been associated with QT prolongation, ventricular arrhythmias, and sudden cardiac death. STUDY: This study analyzed patients prescribed domperidone for treatment of gastroparesis between January 2012 and September 2017 at a single center. This study reviewed EKGs, primarily the QTc interval, taken at baseline, 2 to 6 months after initiation of domperidone, 6 to 12 months after initiation, and ≥12 months after initiation. Concurrent QTc prolonging medications were recorded for each patient. The primary endpoint was QTc prolongation >500 ms. Secondary endpoints were QTc >450 ms for males, a QTc>470 ms for females, QTc prolongation ≥20 ms above baseline, and QTc prolongation >60 ms above baseline. RESULTS: In total, 246 patients were included for analysis (age, 46.3±17.4 y; F 209). EKGs were available for all 246 patients before treatment, 170 patients at 2 to 6 months, 135 at 6 to 12 months, and 152 patients at least 1 year after domperidone initiation.Of 246 subjects, 15 patients (6.1%, 9 female) had clinically important QTc prolongation; 11 had QTc >450 ms for males or >470 ms for females; none had QTc prolongation >500 ms; 5 (2.0%) had >60 ms over baseline and 61 (24.7%) patients had QTc increase of ≥20 ms but <60 ms from baseline. CONCLUSIONS: Domperidone at the conventionally used doses to treat gastroparesis (30 to 80 mg/d) was associated with QTc prolongation in only 6% of patients with no QT interval reaching the point considered to be clinically significant. These data suggest that domperidone can be safely prescribed at doses of 30 to 80 mg daily for the treatment of gastroparesis.

Prescription pattern & adverse drug reactions of prokinetics.

Background & objectives: Prokinetics are extensively prescribed leading to several adverse events (AEs). The aim of this study was to assess the prescription pattern in patients receiving prokinetics, and characteristics of adverse drug reactions (ADRs) in an outpatient department set up in a tertiary care hospital in western India. Methods: Patients attending outpatient departments of a tertiary care hospital and who had received prokinetic agent for at least seven days over the last one month were enrolled. Causality assessment of AEs was done and assessed for severity, preventability, seriousness and predictability. Results: A total of 304 patients [161 males (52.96%); 143 females (47.04%)] were enrolled. Most prescriptions (299/304, 98%) included domperidone, most commonly prescribed as fixed-dose combination (FDC) with pantoprazole (274/304, 90%). Prokinetic dose was not mentioned in 251/304 (83%) prescriptions, and 18/304 (6%) did not mention frequency. Of the 378 AEs reported from 179 patients (47.35%), 306 (81%) were mild, all non-serious; 272 (72%) not preventable and 291 (77%) predictable in nature. Decreased appetite (n=31, 8.2%) and fatigue (n=27,7.14%) were most commonly reported. Causality assessment by the World Health Organization-Uppsala Monitoring Centre scale showed that 180 AEs were related to suspected drug (17 probable and 163 possible ADRs). Significant correlation was observed for AEs with increasing number of drugs per prescription (Spearman's R=+0.8, P =0.05) and with increasing therapy duration (Spearman's R=+1.00, P <0.001). Interpretation & conclusions: Our findings showed that prokinetics were often prescribed as FDCs, with incomplete prescriptions. Domperidone was found to be associated with multiple AEs. It is suggested that regular prescription monitoring should be done in hospitals to encourage rational use of drugs.

Increased risk of all-cause mortality associated with domperidone use in Parkinson's patients: a population-based cohort study in the UK.

AIMS: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease (PD) and is linked to an increased risk of mortality. We sought to examine the risk of all-cause mortality associated with domperidone exposure in PD. METHODS: We conducted a cohort study using data from the Clinical Practice Research Datalink database (1987-2011). The first recorded PD diagnosis defined index date. Time-dependent Cox proportional hazards models estimated hazard ratios (HRs) of all-cause mortality associated with domperidone use. PD patients were stratified by domperidone use (current/recent/past), with never used as the referent. Current domperidone users were stratified by daily dose, domperidone duration and other anti-Parkinson's medications. A secondary analysis compared PD patients to matched (1:1) non-PD patients. RESULTS: A total of 5114 PD patients were identified. Current use of domperidone among PD patients was associated with a two-fold increase in all-cause mortality (HRadj  = 2.00, 95% confidence interval [CI]: 1.64-2.45), as compared to patients never exposed to domperidone. All-cause mortality risk was highest in those starting domperidone in the previous month [HRadj  = 2.97, 95% CI: 2.06-4.27]. When compared to matched non-PD patients, PD was associated with a 43% increased risk of all-cause mortality, yet this increased to a 2.4-fold increased risk among PD patients currently using domperidone. CONCLUSION: Current use of domperidone was associated with a two-fold increased mortality risk in PD patients, as compared to PD patients that never used domperidone. The risk is highest in the first month of use and does not appear to be attributable to PD alone.

Domperidone for insufficient lactation in England 2002-2015: A drug utilization study with interrupted time series analysis.

PURPOSE: Our aim was to describe trends in the prescription of domperidone for insufficient lactation in England, the characteristics of women prescribed it postpartum, and the impact of a 2014 European Medicines Agency (EMA) recommendation to restrict its use due to a potential increased risk of sudden cardiac death associated with its use. METHODS: We conducted a population-based cohort study with interrupted time series analysis using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified women with live births from 2002 to 2015, excluding those with nonlactation indications for domperidone (n = 247 349). We evaluated trends in the prescription rate of domperidone in the 6 months postpartum and differences in this rate before and after the EMA recommendation. RESULTS: Domperidone was prescribed among 1438 deliveries at a rate of 1.24 per 100 person-years. This rate increased from 0.56 to 2.1 per 100 person-years between 2002-2004 and 2011-2013 (rate ratio: 3.8; 95% confidence interval [CI], 3.2-4.6). Prescribing decreased in level by 0.35 (95% CI, -0.86 to 0.16) per 100 person-years immediately following the recommendation with little change in trend (0.003; 95% CI, -0.059 to 0.065 per 100 person-years). Following the recommendation, prescription of doses >30 mg and coprescription of drugs with a risk of torsade de pointes decreased. No arrhythmic events were observed among domperidone users. CONCLUSIONS: Although we observed an important increase in prescribing during the study period, domperidone remains infrequently prescribed postpartum in England. While overall prescribing changed little, some prescribing practices became more restricted following the EMA's recommendation.

Prokinetics for functional dyspepsia.

BACKGROUND: Dyspepsia is a common condition associated with gastrointestinal (GI) disease. Prokinetics are the treatment of choice for functional dyspepsia (FD). However, the role of prokinetics in FD treatment is still controversial. OBJECTIVES: We conducted a systematic review and meta-analysis of randomised control trials (RCTs) examining the efficacy of prokinetics in the treatment of FD. The primary outcome was overall absence of or improvement of symptoms and symptom scores at the end of treatment. We also evaluated quality of life (QoL) and adverse events as secondary outcomes. SEARCH METHODS: We performed a systematic search of MEDLINE, Embase, the Cochrane Library, and CINAHL, from 1946 until September 2017. RevMan 5.3 was used to calculate pooled risk ratios (RR) of symptoms persisting or without improved QoL or adverse events, mean difference (MD) or standardised mean difference (SMD) of post-treatment symptoms scores, changes of symptom scores, and QoL, when appropriate with 95% confidence intervals (CI), using a random-effects model. Quality of evidence was evaluated using GRADE methodology. SELECTION CRITERIA: We included studies that were parallel group RCTs comparing one prokinetic with either placebo or another prokinetic of the same or different class for the treatment of FD. Studies involved adults who presented with dyspepsia symptoms and who had negative or insignificant findings on endoscopy as well as no other organic and metabolic disorders. Studies only including participants with primarily reflux or heartburn symptoms were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, study quality and performed data extraction. MAIN RESULTS: From an initial 1388 citations, we identified 43 studies in 40 papers. Of those, 29 studies with 10,044 participants compared six prokinetics with placebo for the outcome of absence of symptoms or symptom improvement. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR of remaining dyspeptic = 0.81, 95% CI 0.74 to 0.89; number needed to treat for an additional beneficial outcome (NNTB) =7, very low-quality evidence) with considerable heterogeneity; I2 = 91% (P < 0.00001). After removing cisapride from the analysis, the effect of prokinetics in global symptom improvement still persisted, compared to placebo (RR 0.87, 95% CI 0.80 to 0.94), but was still based on very low-quality evidence. The result showed persistence of significant improvement in subgroups of studies at unclear or at low risk of bias (RR 0.86, 95% CI 0.80-0.92), and in subgroups by molecules of cisapride (RR 0.71, 95% CI 0.54 to 0.93; NNTB = 4), acotiamide (RR 0.94, 95% CI 0.91 to 0.98; NNTB = 20) and tegaserod(RR 0.89, 95% CI 0.82 to 0.96; NNTB = 14).Ten studies compared different types of prokinetics with each other and the most commonly used comparator was domperidone, 10 mg three times a day (eight of the 10 studies). There was a significantly better post-treatment symptom score in other prokinetics, compared to domperidone (SMD -0.19, 95% CI -0.35 to -0.03, very low-quality evidence), but no difference in reducing global symptom (RR 0.94, 95% CI 0.83 to 1.07), and mean difference symptom scores (SMD -0.13, 95% CI -0.31 to 0.05). We found five studies that assessed quality of life, but there was no benefit in improving quality of life with prokinetic treatment (SMD 0.11, 95% CI -0.10 to 0.33; participants = 1774). The adverse events in individual prokinetics was not different from placebo (RR 1.09, 95% CI 0.95 to 1.25; participants = 3811; studies = 17). However, when we looked at the adverse effects by each prokinetic, there were overall greater adverse effects in the active treatment group with cisapride (RR 1.31, 95% CI 1.03 to 1.65; P = 0.03). The most common side effects were diarrhoea, abdominal discomfort and nausea. The funnel plot was asymmetric (Egger's test, P = 0.02) implying reporting bias or other small-study effects may be, in part, driving the benefit of prokinetics compared to placebo in this meta-analysis. The GRADE assessment of the quality of the evidence in each outcome are mostly low or very low due to concerns around risk of bias in study design, unexplained heterogeneity and possible publication bias. AUTHORS' CONCLUSIONS: Due to low, or very low, quality of evidence, we are unable to say whether prokinetics are effective for the treatment of functional dyspepsia . We are uncertain which of the individual prokinetic drugs is the most effective as well as whether prokinetics can improve quality of life. Apart from cisapride, prokinetics are well-tolerated. Good quality RCTs are needed to verify the efficacy of prokinetics.

Case report: domperidone use as a galactagogue resulting in withdrawal symptoms upon discontinuation.

We present a case of domperidone withdrawal in a woman using the medication as a galactagogue. Our primary goal is to increase the literature available to providers who work with women who are breastfeeding. We evaluated a woman presenting to our reproductive psychiatry clinic for consultation regarding anxiety and agitation in the context of domperidone discontinuation. We evaluated the available literature regarding domperidone as a galactagogue, as well as the literature regarding adverse effects. The patient presented with withdrawal symptoms after gradual taper and discontinuation of domperidone. After restarting the medication, her symptoms resolved. She was able to successfully discontinue domperidone with a slow, gradual taper. Domperidone is occasionally used as a galactagogue in women with inadequate milk supply. We report a case in which a woman experienced withdrawal symptoms after domperidone discontinuation.

Domperidone is Commonly Prescribed With QT-Interacting Drugs: Review of a Community-based Practice and a Postmarketing Adverse Drug Event Reporting Database.

INTRODUCTION: Domperidone, a peripheral D2 dopamine receptor antagonist, has efficacy for treatment of nausea, dyspepsia, and gastroparesis. Domperidone prolongs the QT interval (QTc), and may cause life-threatening arrhythmias. METHODS: Electronic medical records for all patients receiving domperidone in the NorthShore University HealthSystem from January 1, 2008 to December 1, 2013 were reviewed. All concomitant medications were noted. The coadministration of QT-interacting medications was determined. Electrocardiogram (EKG) evaluation before and during domperidone therapy was noted. A query of the FDA Adverse Event Reporting System (FAERS) database was also performed. Individual reports from the FAERS Web site from January 2008 to June 2014 were downloaded and analyzed. The database was queried for all reports of adverse events with domperidone. Coadministration of QT-interacting medications was noted. Cardiac events that potentially were related to prolongation of the QTc were examined. RESULTS: In total, 108 of 155 patients (69.7%) were coprescribed QT-interacting drugs along with domperidone. Fifty-nine of 155 patients (38.1%) underwent a baseline EKG and 9 (15.3%) had prolongation of the QTc at initiation. Forty patients (25.8%) had a follow-up EKG and 13 (32.5%) had prolongation of the QTc. All 13 were coprescribed QT-interacting medications. On the FAERS, 221 nonfatal cardiac events were reported in domperidone patients; of these, 162 (73.3%) occurred in patients receiving QT-interacting medications. Coprescription occurred in 53 of 151 deaths (35.1%) and in 16 of 61 cardiac arrests (26.2%). CONCLUSIONS: Coprescribing of QT-prolonging medications and inconsistent EKG monitoring occur in patients receiving domperidone, placing these patients at risk for arrhythmias.

Media attention regarding sudden cardiac death associated with domperidone use does not affect in hospital ECG recording.

PURPOSE: In March 2013, regulatory warnings concerning the potential risks of domperidone caused considerable media attention in the Netherlands. The aim of the study was to assess the effect of regulatory warnings and the resulting media hype on the frequency of electrocardiogram (ECG) monitoring of inpatients using domperidone. We also studied the effect on the frequency of prescribing domperidone by physicians. METHODS: A 2-centre, observational, retrospective cohort study was performed. Inpatients using domperidone in 2 hospitals in the Netherlands during a period of 384 days before and after the media hype were included. The main outcomes were (1) the proportion of domperidone users with ECGs before and/or during domperidone treatment, (2) the proportion of patients with an ECG before and during treatment, and (3) the proportion of patients with an ECG during treatment. Secondary outcome was the proportion of domperidone prescriptions comparing the before- and after-period. RESULTS: Four hundred twenty-eight patients were included. The main outcomes [respectively (1) relative risk (RR) 1.02, 95% confidence interval (CI), 0.85-1.21; (2) RR 1.06, 95% CI, 0.60-1.85; and (3) RR 1.27, 95% CI, 0.80-2.01) were not different. After stratifying for hospital, no significant differences were found. A statistically significant decrease (RR 0.40, 95% CI, 0.35-0.45) in numbers of prescriptions was found for the university medical centre only. CONCLUSIONS: No effect of the media hype was found on the intensity of ECG monitoring in domperidone users. In the university medical centre, domperidone prescriptions were reduced.

Miscellaneous Drugs and Male Reproduction.

In addition to main categories of medications believed to have negative impacts on male reproduction, there are a number of miscellaneous drugs with some evidence for such adverse reactions. Because of its widespread use and over-the-counter availability, the H2 receptor antagonist cimetidine is most concerning. As a competitive antagonist at androgen receptors, it can impact the HPG axis and semen quality. In this chapter, we review the studies of this drug and other histamine H2 receptor antagonists in men and experimental species. Several other medications are concerning and the evidence for negative effects on reproduction are covered: colchicine, domperidone, hydroxyurea, metformin, metoclopramide, mifepristone, retinoids, and statins.

[Antiemetics and cardiac effects potentially linked to prolongation of the QT interval: Case/non-case analysis in the national pharmacovigilance database]. / Antiémétiques et effets cardiaques potentiellement liés à un allongement de l'intervalle QT : analyse cas/non-cas dans la Base nationale de pharmacovigilance.

OBJECTIVES: Observational retrospective studies have linked domperidone and prolonged QT interval, ventricular arrhythmias and risk of sudden death. Since then, antiemetic prescription was applied to other molecules (including metopimazine). The aim of this study was to evaluate the profile of adverse cardiac effects associated with QT prolongation for each antiemetic available in France. METHODS: We conducted disproportionality analyses (case/non-case method), based on the observations recorded consecutively in the French national pharmacovigilance database between 2004 and 2013. Cases were defined by following MedDRA terms: prolongation of the QT interval, syncope, sudden death, cardiac arrest, ventricular arrhythmias including torsades de pointes; non-cases were other adverse events reported during the same period. We analyzed the presence of each antiemetic among cases and non-cases and measured the disproportionality by reporting odds ratios (ROR). We validate the assay with a positive control (methadone) and a negative control (acetaminophen). RESULTS: We compared 2093 cases (94 with antiemetics) to 253,665 non-cases (7015 with antiemetics). Among antiemetics, adverse cardiac effects studied were more frequently found with notifications including domperidone (ROR=2.0, 95% CI=[1.3; 3.0]), ondansetron (ROR=1.8, 95% CI=[1.3; 2.6]) and granisetron (ROR=3.4, 95% CI=[1.5; 7.6]). Metopimazine was not statistically associated with that risk (ROR=2.0; 95% CI=[0.8; 4.8]). CONCLUSION: We confirmed a risk of cardiac adverse event related to prolongation of the QT interval with domperidone and setrons. These results suggest caution when prescribing antiemetics and encourage systematic reporting of adverse cardiac effects observed with these molecules.

Modulation of gastrointestinal motility beyond metoclopramide and domperidone : Pharmacological and clinical evidence for phytotherapy in functional gastrointestinal disorders.

The prokinetic cisapride, an important therapeutic option in functional gastrointestinal (GI) disorders, was withdrawn from the market 15 years ago due to rare severe side effects. Likewise in 2014, the use of metoclopramide (MCP) and domperidone in functional GI disorders (FGID) was restricted, consequently leaving a therapeutic gap in clinical practice. A systematic review revealed that the herbal medicinal product (HMP) STW 5 presents a therapeutic option equivalent to MCP and cisapride. STW 5 is the only HMP for which efficacy has been shown in randomized controlled clinical trials (RCTs) in functional dyspepsia and irritable bowel syndrome, based on its multitarget effect on numerous etiological factors. Due to an outstanding favorable safety profile, STW 5 allows an effective and safe use in FGID without a limitation of the duration of the treatment.