JHLXXX10.1177/0890334414561265Journal of Human LactationPaul et al research-article5612652014

Review

Journal of Human 2015, Vol. 31(1) 57­–63 Use of as a Galactagogue © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav Drug: A Systematic Review of the DOI: 10.1177/0890334414561265 Benefit-Risk Ratio jhl.sagepub.com

Catherine Paul, PharmD1, Marie Zénut, MD, PhD2,3, Agnès Dorut, CPM4, Marie-Ange Coudoré, PharmD, PhD5,6, Julie Vein, DVM, PhD7, Jean-Michel Cardot, PharmD, PhD8,9, and David Balayssac, PharmD, PhD7,10

Abstract is the optimal method for feeding a newborn. However, some mothers may have difficulties lactating. Domperidone is widely used as a galactagogue but to the best of our knowledge has not been approved by any health authority. The objective of this review was to assess the benefit-risk ratio of domperidone for stimulating lactation. The benefit-risk ratio of domperidone as a galactagogue was assessed following a literature search of the PubMed database up to July 2013. Four studies were selected to assess domperidone efficacy and demonstrated an increased milk production. The limited data (60 mother-baby pairs) and the moderate methodological quality of 1 study remain insufficient to conclude on domperidone efficacy. Regarding the safety of domperidone, 7 studies were selected that exposed 113 infants to domperidone through breastfeeding. No adverse effects were observed in 85 infants, and no information was provided for the remaining 28. The limited data available remain in favor of a safe domperidone profile in infants and mothers. However, in large studies focused on gastrointestinal disorders, domperidone is responsible for drug-induced long QT syndrome and sudden cardiac death. The use of domperidone as a galactagogue is worrisome as drug-induced long QT syndrome occurred mostly in women. In these circumstances, an improvement of breastfeeding practices seems to be more effective and safer than the use of an off-label domperidone treatment.

Keywords benefit-risk ratio, breastfeeding, domperidone

Background 1Université d’Auvergne, Faculté de Pharmacie, Clermont-Ferrand, France Mothers who delivered preterm infants often have difficul- 2CHU Clermont-Ferrand, Centre Regional de Pharmacovigilance, 1 Clermont-Ferrand, France ties producing sufficient amounts of milk. Additionally, 3 mothers of term infants can have, under certain circum- EA 4681 PEPRADE, Université d'Auvergne, Clermont-Ferrand, France 4CHU Clermont-Ferrand, Service d’Obstétrique, Clermont-Ferrand, France stances, difficulties with producing enough milk for their 5Université d’Auvergne, Faculté de Pharmacie, Laboratoire de Physiologie, infants (eg, maternal illness, cesarean delivery, maternal Clermont-Ferrand, France smoking, previous breast surgery, mother-infant separation, 6CHU Clermont-Ferrand, Hématologie Biologique, Clermont-Ferrand, France 7 and psychosomatic disorders).2,3 Women and clinicians often INSERM U1107, NEURO-DOL, Université d’Auvergne, Clermont- Ferrand, France turn to galactogogue drugs or supplements to try and increase 8 3 Université d’Auvergne, Faculté de Pharmacie, Laboratoire de supply. The use of receptor antagonists, such as Biopharmacie, Clermont-Ferrand, France or domperidone, is probably the most wide- 9CHU Clermont-Ferrand, INSERM CIC 1405, Centre de Pharmacologie spread pharmacological strategy.4 Clinique, Clermont-Ferrand, France 10 Domperidone is a prokinetic and antiemetic drug for the CHU Clermont-Ferrand, Délégation à la Recherche Clinique et à treatment of gastroparesis, nausea, and vomiting, approved l’Innovation, Clermont-Ferrand, France worldwide with the exception of the US (mainly due to car- FastTrack papers are considered high impact. After peer review, we diotoxicity).5,6 Antiemetic activity results from the associa- speed up their publication so JHL readers can access important new tion of peripheral effects on gastric motility and dopaminergic information as soon as possible. FastTrack papers may not always be related to themed content in special issues. antagonism of the chemoreceptors in the trigger zone, which 7 is outside the blood brain barrier in the area postrema. Date submitted: April 29, 2014; Date accepted: November 3, 2014. Domperidone has a strong affinity for dopaminergic D2 receptors in the peripheral nervous system and the gastroin- Corresponding Author: testinal system.7 Despite its antidopaminergic effect, dom- David Balayssac, PharmD, PhD, INSERM U1107, NEURO-DOL, Laboratoire de Toxicologie, Faculté de Pharmacie, 28 place Henri Dunant, peridone is rarely responsible for extrapyramidal side 63000 Clermont-Ferrand, France. 8 effects because it hardly crosses the blood brain barrier. Email: [email protected]

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Domperidone is rapidly absorbed after oral intake, with a For the assessment of domperidone efficacy and maternal peak plasma concentration between 30 and 60 minutes. safety, only the publications measuring the production of However, the oral bioavailability is low (15%) due to milk in lactating women and comparing a domperidone hepatic first pass metabolism. Food intake delays the peak treated group to a control group were selected for the review. plasma concentration but increases the bioavailability. For the assessment of domperidone safety in infants, publi- Domperidone binds strongly to plasma protein (91%-93%) cations were selected if the infants were exposed to domperi- and is widely distributed in tissues, with the exception of done through breastfeeding. the central nervous system. After oral administration, dom- peridone is rapidly and intensively metabolized by hydrox- Results ylation and N-dealkylation by CYP3A enzymes in the gut wall and the liver.9 Two-thirds of the administrated dose Bibliographic Results are eliminated in feces and the remaining third in urine, The literature search collected 89 references, and the mainly as metabolites (90%). Plasma half-life after oral selection of the references for the review is presented in intake is about 7 to 9 hours and increases in cases of renal 8 the Figure 1. Two meta-analyses assessing domperidone failure. efficacy as a galactagogue have been identified and The use of domperidone as a galactagogue was first 14,15 10 selected. Seven clinical studies focusing on domperi- described in 1983. This property results from its antidopa- done and lactation have been identified.12,13,16-20 Among the minergic effect on D2 receptors of the lactotropic cells of remaining 7 publications, 4 studies fulfilled the inclusion the anterior pituitary gland, bearing in mind that dopamine 12,18-20 13,16,17 11 criteria of domperidone efficacy, and 3 studies is the main inhibitor of release. In a randomized were excluded due to methodological bias (absence of con- clinical trial, the prolactinemia of treated women (n = 24) trol groups or irrelevant comparator). The domperidone increased by 302% compared to 85% in control women (n = safety in infants was assessed from the 7 publications cor- 21) (P = .03) after 4 days of domperidone treatment (10 mg, responding to infants exposed to domperidone through 3 times a day). After 14 days of domperidone treatment, the 12,13,16-20 breastfeeding. increase of the prolactinemia was only 107% in treated women compared to 17% in control women (P = .07).12 following domperidone treatment remains, Domperidone Efficacy as a Galactagogue however, a rare adverse drug reaction (frequency: > 1/10 All 4 studies selected from the literature search were con- 8 000 and < 1/1000). trolled double-blind studies,12,18-20 and 3 studies12,18,20 were To the best of our knowledge, the use of domperidone as randomized (Table 1). Women were included due to an inad- 13 a galactagogue has not been approved by any authority. equate postpartum milk production12,18,19 or after a cesarean Consequently, an adequate assessment of the benefit-risk birth.20 All definitions of lactation insufficiency were ratio of domperidone is essential before prescribing this accepted, the most frequent definition being a milk produc- drug for lactation failure. The objective of this systematic tion insufficient for the daily needs of the infant. All the review of the literature was to conduct an assessment of the mothers who delivered vaginally were included a few weeks benefit-risk ratio of domperidone use as a galactagogue, after the delivery, leaving a sufficient period necessary for with regards to milk production, excretion of domperidone the initiation of lactation, with lactation support if required. in milk, quality of milk, and safety of the mothers and However, only 1 study19 mentioned that advice on improv- infants during domperidone treatment. ing lactation had been given before inclusion into the trial. For the mothers who delivered by cesarean section, the Methods domperidone treatment was initiated as soon as they were able to take liquid beverages, namely, 24 hours after the A single author performed a literature search of the PubMed delivery. In these 3 studies, the doses of domperidone were database (up to July 2013) in order to assess the benefit-risk approximately 30 to 40 mg/day (10 mg, 3-4 times per os). A ratio of domperidone. The search used the keywords dom- double-blind procedure was used for the administration of peridone associated with lactation, galactagogue, milk, or the drug. Treatment duration was between 7 and 14 days. In breastfeeding. The bibliographic analysis was limited to the study by Petraglia et al,19 the mothers breastfed their clinical trials and meta-analyses published in French or in infants born at full term. The quantity of milk produced was English. Exclusion criteria were chosen as follows: nonclin- estimated every day by weighing the infants before and after ical study, non-English or French publication, review, letter, breastfeeding.19 In the others 3 studies, the mothers who case report, study protocol, guideline, different topic than gave birth prematurely12,18 or by cesarean section at term20 lactation (eg, digestive pathology, galactorrhoea, analytical fed their babies with milk collected using a pump. In these method), low quality study (eg, observational study, meth- studies, the quantities of produced milk were assessed after odological bias). collection.12,18,20

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Figure 1. Flow Chart of the Literature Search in the PubMed Database (up to July 2013) for Domperidone Efficacy.

Pubmed search 89 references

48 references 36 references 5 references Human Animal research Foreign language

16 references 2 references 11 references 11 references 5 references 2 references 1 reference Clinical studies Meta-analyses Reviews Leers Case reports Study protocols Guideline

9 references 3 references 3 references 1 reference Lactaon Digesve pathologies Galactorrhoea Analycal method

4 references 3 references 2 references Lactaon Methodological bias Observaonal study

The search used the keywords domperidone associated with lactation, galactagogue, milk, or breastfeeding. The references in grey have been excluded from the review according to inclusion/exclusion criteria.

The methodological quality of the studies by Campbell- and control group was 3.9 ± 4.6 ml/day and 3.4 ± 9.3 ml/day, Yeo et al,12 Da Silva et al,18 and Petraglia et al19 were assessed respectively.20 by meta-analysis.15 For the studies by Campbell-Yeo et al12 The prolactin concentrations in the blood of patients and Da Silva et al,8 the randomization, blinding procedures, have been assessed in 3 of these studies, and they report a and results were judged satisfactory. However, in the study significant increase of prolactin concentrations between by Da Silva et al,18 data were missing for 3 of the 11 partici- 300% and 800% compared to baseline values.12,18,19 After 5 pants (domperidone group). Despite this missing data, the 2 days of domperidone treatment (10 mg 3 times daily), studies were considered of good quality and without serious serum prolactin levels were about 119.3 ± 97.3 μg/L in the bias. Conversely, the study by Petraglia et al19 did not give domperidone group compared to 18.1 ± 14.7 μg/L in the sufficient information about the blinding procedure. This placebo group (P = .008).18 study is defined as a double-blind trial. However, neither was In conclusion, these studies demonstrated an increased it stated if the appearance and taste of the active and placebo milk production after domperidone treatment in mothers at forms were similar nor if the initially randomized mothers risk of lactation failure, as well as in mothers after a cesarean participated until the end of the trial. Considering these delivery at full term. The recent meta-analysis by Donovan methodological issues, this study was judged to be of moder- and Buchanan demonstrated a modest increase in expressed ate quality. of 99.49 mL/day (95% confidence interval, –1.94 Da Silva et al18 found that between the first and the sev- to 200.92); random-effects, T2 3511.62, I2 63%).14 The meta- enth day of treatment, the volume of milk produced increased analysis by Osadchy et al15 was more encouraging and by 49.5 ± 29.4 ml/day (44.5%) in the domperidone group reported a significant increase in daily milk production of compared to 8.0 ± 39.5 ml/day (16.6%) in the control group 74.72% (95% confidence interval, 54.57-94.86). However, (P < .05). Petraglia et al19 showed that after 10 days of treat- considering the limited data (only 60 mother-baby pairs ment, the daily milk production increased for the domperi- treated with domperidone in the 4 selected studies) and the done treated mothers, with a mean increase of 326 ml/day moderate methodological quality of the Petraglia et al19 compared to 63 ml/day in the control group (P < .01). study, scientific proofs remain insufficient to conclude on the Campbell-Yeo et al12 demonstrated an increase in daily milk clinical efficacy of domperidone as a galactagogue. production of 267% after 14 days of domperidone treatment A multicenter, double-blind, and randomized clinical trial compared to 18.5% in the control group (P = .005). Finally, to assess domperidone efficacy in breastfeeding deficiency, Jantarasaengaram et al20 showed that the volume of collected with a planned inclusion of 560 mothers of preterm neonates milk was approximately 191.0 ± 136.1 ml/day after 4 days of and funded by the Canadian Institutes of Health Research, is domperidone treatment compared to 91.4 ± 60.3 ml/day in currently ongoing.21 The results are expected in 2016 and the control group (P = .003). The mean volume of milk pro- should give sufficient information on the galactagogue prop- duced before the beginning of treatment in the domperidone erties of domperidone and its efficacy and safety.

Downloaded from jhl.sagepub.com at MCGILL UNIVERSITY LIBRARY on November 24, 2015 Infant Safety effect effect information effect No adverse No adverse

No No adverse Safety Maternal effect effect (7 mothers) effect effect abdominal cramp (1 mother) No adverse No adverse D: Dry mouth C: No adverse D: No adverse C: Mild Measure µg/L, mean ± SD; Day of C: 65.4 ± 13.6; day 5 C: 18.1 ± 14.7; day 5 information C: 36.0 ± 26.2; day 14 Prolactin Values, D: 146.9 ± 14.8; D: 119.3 ± 97.3; No D: 81.3 ± 70.8;

Measure ± SD; Day of C: 398 ± 45; day 10 C: 66.0 ± 61.7; day 7 day 14 C: 91.4 ± 60.3; day 4 C: 250.8 ± 171.6; Milk Volume, mL/day, mean D: 673 ± 44; D: 183.5 ± 138.5; D: 191.3 ± 136.1; D: 380.2 ± 201.6; Dose times daily for 10 days times daily for 7 days times daily for 4 days times daily for 2 weeks Domperidone 10 mg orally 3 10 mg orally 3 10 mg orally 4 10 mg orally 3 Study Design controlled trial randomized controlled trial randomized controlled trial randomized controlled trial Double-blind Double-blind Double-blind Double-blind

Participants Domperidone/ Delivery; Term term infants preterm infants delivery; term cesarean delivery, C: 50% cesarean delivery; preterm infants < 31 weeks gestation infants Control, n; Type of 9/8; vaginal delivery; 7/9; unknown; 22/23; 100% cesarean 22/24; D: 45.5% Study Location gynecology department, Italy intensive care unit, Canada gynecology department, Thailand intensive care unit, Canada Obstetrics and Neonatal Obstetrics and Neonatal 18 Main Features of the 4 Included Studies. 20

12 19 2010 1985 al, 2012 Da Silva et al, 2001 Campbell-Yeo et al, Petraglia et al, Jantarasaengaram et Table 1. Study Abbreviations: C, control; D, domperidone.

60

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Domperidone Doses and Treatment Duration for No side effect was reported in 3 of these studies.12,18,19 Only 20 Stimulating Lactation the study by Jantarasaengaram et al reported some events of dry mouth in 31.8% of the domperidone treated group and In the summary of product characteristics (regulatory drug no adverse reaction in the placebo group. These 4 studies information for professionals), the approved domperidone assumed that the use of domperidone during breastfeeding dose for the treatment of gastroparesis, nausea, and vomiting was safe, but with a limited number of 60 treated mothers. is 10 to 20 mg 3 to 4 times daily, with a maximal daily dose of 80 mg.8 However, as a galactagogue, no study has been designed to determine the best dose and treatment duration of Domperidone Safety for the Infants domperidone that ensures both efficacy and patients’ safety. In Among the 7 studies retained,12,13,16-20 4 compared the effects the majority of studies, the domperidone doses used to stimu- of domperidone (30-40 mg/day) to a placebo,12,18-20 and 5 12,16,18,19 late lactation were about 10 or 20 mg 3 times a day. studies12,16-19 monitored adverse drug reactions in infants. However, we must be cautious because some institutions sug- One hundred and thirteen infants were exposed to domperi- gest increasing the daily domperidone doses to as high as 120 done through breastfeeding. No adverse effects were observed 22,23 mg or 160 mg, without any clinical validation, and this is in 85 infants, and no information was provided for the remain- 8 twice the maximum daily dose recommended in France. No ing 28. The exposure of the 85 infants was heterogenic, treatment duration can be defined since they were quite differ- according to the dose and the duration of the mother’s dom- 20 16 ent among the studies, from 4 days to 6 weeks. peridone treatment. The main dose was approximately 10 mg 3 times a day with a treatment duration between 4 days and 4 Domperidone Excretion in Milk weeks. Seven mothers were treated with a dose of 20 mg 3 times a day for 4 weeks.16 Moreover, infant exposure to dom- After a maternal oral dose of 10 mg 3 times a day, an infant peridone varied according to different factors. Drug concen- would receive a daily dose of 0.2 µg/kg from a daily milk tration in milk is higher at the beginning of lactation, but the intake of 150 mL/kg and a milk concentration of domperi- mothers included in the studies presented various levels of 18 done of 1.2 ng/mL. After an oral domperidone dose of 10 lactation according to the duration of the pregnancy, the type mg 3 times daily, concentrations in the milk varied from 0.24 of delivery, and the length of time since the delivery.26 Drug ng/mL (1 hour) to 1.1 ng/mL (4 hours) and 2.6 ng/mL (4 exposure through milk depends on the volume of milk 24 days). According to the summary of product characteristics ingested, which increases with the age of the infant. Metabolic (regulatory drug information for professionals), the concen- clearance increases in infants from birth and is equivalent to tration of domperidone in the milk of lactating women repre- an adult after 68 weeks post conception.27 The ages of the sents 10% to 50% of the plasma concentrations and is rarely infants in the studies varied between 1 day and several weeks. 8,25 higher than 10 ng/mL. After oral doses of 80 mg daily (the Bibliographic analysis did not identify any risk for the highest recommended dose for authorized indications in infants from exposure to domperidone. These studies France), the total quantity of domperidone excreted into milk assumed that the use of domperidone during breastfeeding 8 is less than 7 µg per day. was safe for the infants. However, these conclusions must be nuanced due to the small number of patients included and the Milk Quality after Domperidone Treatment short and disparate duration of treatment (4 days to 6 weeks). In a randomized controlled trial that included 46 lactating women (22 women treated with 10 mg domperidone 3 times Conclusion a day for 14 days and 24 controls), the quality of the milk The off-label use of domperidone as a galactagogue is fre- (energy value and quantities of proteins, fats, sodium and quent and possibly encouraged by specialists.4 In an Australian 12 phosphate) remained unchanged. Prolactin and carbohy- tertiary teaching hospital, dispensation of domperidone to drate concentrations were slightly increased (P < .07) and the mothers increased from 0.5% in 2000 to more than 5% in calcium concentration was significantly increased (P = .02) 2010, with a mean treatment duration of 12 days for most 12 among those receiving domperidone. Consequently, the women (80%).4 More worrisome is the fact that in most cases impact of domperidone on milk quality seems to be limited, (60%), women were not assessed by a lactation consultant.4 except for increased calcium concentration. However, the This review aimed to assess the benefit-risk ratio of dom- health consequences of this increase are currently unknown. peridone to improve milk production. Domperidone treatment (10 or 20 mg 3 times a day) seems to modestly increase milk Maternal Safety of Domperidone production based on the limited data available. The few exist- ing trials seem to demonstrate that maternal treatment with As mentioned previously, 4 controlled double-blind studies domperidone does not expose breastfed infants to any risk. were selected to assess domperidone efficacy (Table 1). The presented trials focused on breastfeeding did not report Maternal safety was assessed from these 4 publications.12,18-20 significant adverse drug reactions in the treated mothers.

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However, in larger studies focused on gastrointestinal disor- 5. Barone JA. Domperidone: a peripherally acting dopamine2- ders, the use of domperidone is not devoid of risks for the receptor antagonist. Ann Pharmacother. 1999;33(4):429-440. patients. Domperidone is now well defined as a blocker of the 6. Ahmad N, Keith-Ferris J, Gooden E, Abell T. Making a case rapid component of the delayed rectifier potassium current for domperidone in the treatment of gastrointestinal motility (I ; HERG), which in turn is responsible for drug-induced disorders. Curr Opin Pharmacol. 2006;6(6):571-576. Kr 7. Reddymasu SC, Soykan I, McCallum RW. Domperidone: long QT syndrome, arrhythmias, and sudden cardiac death. review of pharmacology and clinical applications in gastroen- From the analysis of 5 population-based studies focused on terology. Am J Gastroenterol. 2007;102(9):2036-2045. domperidone and cardiac adverse effects, domperidone 8. Agence Nationale de Sécurité du Médicament et des produits de increased the odds ratio for sudden cardiac death (2.8, 95% Santé. Résumé des caractéristiques du produit – Domperidone 28 confidence interval, 1.53-6.10). The risk of sudden cardiac Motilium 10 mg, comprimé pelliculé. Saint Denis, France: death seems to be dose dependent, with an odds ratio of 2.57 Agence Nationale de Sécurité du Médicament et des produits (95% confidence interval, 0.79-8.36) for patients using 30 mg/ de Santé; 2011. http://agence-prd.ansm.sante.fr/php/ecodex/ day and an odds ratio of 16 (95% confidence interval, 3.49- frames.php?specid=63679194&typedoc=R&ref=R0186787. 73.6) for patients using more than 30 mg/day.29 Moreover, the htm. Accessed December 18, 2013. use of domperidone as a galactagogue is worrisome as drug- 9. Ward BA, Morocho A, Kandil A, Galinsky RE, Flockhart DA, induced long QT syndrome occurred mostly in women.28,30 Desta Z. Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in The introduction of a drug in these breastfeeding mothers vitro. Br J Clin Pharmacol. 2004;58(3):277-287. raises other issues that have not been assessed in this specific 10. Hofmeyr GJ, van Iddekinge B. Domperidone and lactation. population. Domperidone is a substrate of the drug metabo- Lancet. 1983;1(8325):647. lizing enzyme CYP3A and of the drug transporter 11. Caron MG, Beaulieu M, Raymond V, et al. Dopaminergic 28 P-glycoprotein, which can lead to drug-drug interactions. receptors in the anterior pituitary gland. Correlation of [3H] CYP3A inhibitors could increase the domperidone exposi- dihydroergocryptine binding with the dopaminergic control of tion and lead to adverse drug reaction, notably cardiac prolactin release. J Biol Chem. 1978;253(7):2244-2253. adverse drug reactions.9 Inhibition of P-glycoprotein can 12. Campbell-Yeo ML, Allen AC, Joseph KS, et al. 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