Domperidone

Not to be confused with Droperidol.

Domperidone
Names
Trade namesMotilium, others
IUPAC name
  • 5-Chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
Clinical data
Drug classD2 receptor antagonist; Prolactin releaser
Main usesNausea, gastroparesis[1]
Pregnancy
category
  • AU: B2
  • US: N (Not classified yet)
    Routes of
    use    		By mouth, intramuscular, rectal[1]
    External links
    AHFS/Drugs.comMicromedex Detailed Consumer Information
    Legal
    Legal status
    • UK: POM (Prescription only)
    • US: Not approved for use or sale
    • Prescription medicine (Rx only):Pakistan, India, Australia, Canada, Israel, Belgium, France, Netherlands; over-the-counter: Egypt, Ireland, Italy, Japan, South Africa, Switzerland, Kuwait, China, Russia, Slovakia, Ukraine[2] Mexico, Thailand, Malta, South Korea, and Romania[3]
    Pharmacokinetics
    BioavailabilityBy mouth: 13–17%[1][4]
    Intramuscular: 90%[1]
    Protein binding~92%[1]
    MetabolismLiver (CYP3A4/5) and intestinal (first-pass)[1][5]
    MetabolitesAll inactive[1][5]
    Elimination half-life7.5 hours[1][4]
    ExcretionFeces: 66%[1]
    Urine: 32%[1]
    Breast milk: small quantities[1]
    Chemical and physical data
    FormulaC22H24ClN5O2
    Molar mass425.92 g·mol−1
    3D model (JSmol)
    Melting point242.5 °C (468.5 °F)
    SMILES
    • Clc1cc2c(cc1)N(C(=O)N2)C5CCN(CCCN4c3ccccc3NC4=O)CC5
    InChI
    • InChI=1S/C22H24ClN5O2/c23-15-6-7-20-18(14-15)25-22(30)28(20)16-8-12-26(13-9-16)10-3-11-27-19-5-2-1-4-17(19)24-21(27)29/h1-2,4-7,14,16H,3,8-13H2,(H,24,29)(H,25,30) checkY
    • Key:FGXWKSZFVQUSTL-UHFFFAOYSA-N checkY

    Domperidone, sold under the brand name Motilium among others, is a medication used to relieve nausea, increase the transit of food through the stomach, treat migraines, and to promote breast milk production.[1][6][7] It is taken by mouth.[8] Due to the risk of side effects, use is recommended for less than a week and it is not recommended to increase breast milk.[8][9]

    Common side effects include a dry mouth.[8] Other side effects include anxiety, diarrhea, and sexual dysfunction.[8] Its use is not recommended in those with heart disease due to the risk of arrhythmias and sudden cardiac arrest.[8][10] Use during breastfeeding is believed safe for the baby.[8][11] Domperidone is a peripherally selective dopamine D2 receptor antagonist.[1]

    Domperidone was developed in 1974 by Janssen Pharmaceutica.[12] It is available as a generic medication.[8] In the United Kingdom a months supply costs the NHS about 3 pounds.[8] While available in many countries, it is only available in the United States under compassionate use for severe gastrointestinal motility disorders not manageable by other treatments.[1][9]

    Medical uses

    Nausea and vomiting

    Domperidone is indicated for nausea and vomiting.[13] It is recommended by the Canadian Headache Society for treatment of nausea associated with acute migraine.[14]

    Gastroparesis

    Gastroparesis is a medical condition characterised by delayed emptying of the stomach when there is no mechanical gastric outlet obstruction. Its cause is most commonly idiopathic, a diabetic complication or a result of abdominal surgery. The condition causes nausea, vomiting, fullness after eating, early satiety (feeling full before the meal is finished), abdominal pain and bloating.

    Domperidone may be useful in diabetic and idiopathic gastroparesis.[15][16]

    However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate (equate) well with relief of symptoms.[17]

    Domperidone can be used to relieve gastrointestinal symptoms in Parkinson's disease; it blocks peripheral D2 receptors but does not cross the blood–brain barrier in normal doses (the barrier between the blood circulation of the brain and the rest of the body) so has no effect on the extrapyramidal symptoms of the disease.[18]

    Breastfeeding

    There is evidence that domperidone moderately increases the volume of breast milk in mothers of preterm babies where breast milk expression was inadequate.[19][20][21]

    Recommends on the safety of its use; however, are variable.[6][22] The FDA recommended against such use in 2004.[23] The NHS and Australia say use is okay, but recommends it only short term.[24][25]

    A 2012 review found no studies support preventative use of medication at any gestation including domperidone.[26]

    Other

    Domperidone has been found effective in the treatment of reflux in children.[27] However some specialists consider its risks prohibitory of the treatment of infantile reflux.[28]

    Domperidone may be used in functional dyspepsia.[29]

    Dosage

    The dose in those who weight more than 35 kg is generally 10 mg by mouth up to three times per day.[8] In those who weight less than that the dose is 0.25 mg per kg up to three times per day.[8]

    Contraindications

    Side effects

    Side effects associated with domperidone include dry mouth, abdominal cramps, diarrhea, nausea, rash, itching, hives, and hyperprolactinemia (the symptoms of which may include breast enlargement, galactorrhea, breast pain/tenderness, gynecomastia, hypogonadism, and menstrual irregularities).[31] Due to blockade of D2 receptors in the central nervous system, D2 receptor antagonists like metoclopramide can also produce a variety of additional side effects including drowsiness, akathisia, restlessness, insomnia, lassitude, fatigue, extrapyramidal symptoms, dystonia, Parkinsonian symptoms, tardive dyskinesia, and depression.[1][32] However, this is not the case with domperidone, because, unlike other D2 receptor antagonists, it minimally crosses the blood-brain-barrier, and for this reason, is rarely associated with such side effects.[1][32]

    Excess prolactin levels

    Due to D2 receptor blockade, domperidone causes hyperprolactinemia.[33] Hyperprolactinemia can suppress the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, in turn suppressing the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and resulting in hypogonadism (low sex hormone (e.g., testosterone, estradiol) levels).[34] As such, male patients may experience low libido, erectile dysfunction, and impaired spermatogenesis.[34] Also in accordance with hyperprolactinemia, 10–15% of female patients have been reported to experience mammoplasia (breast enlargement), mastodynia (breast pain/tenderness), galactorrhea (inappropriate or excessive milk production/secretion), and amenorrhea (cessation of menstrual cycles) with domperidone treatment.[33] Gynecomastia has been reported in males treated with domperidone,[35] and galactorrhea could occur in males as well.[34]

    Rare reactions

    Heart

    Domperidone use is associated with an increased risk of sudden cardiac death (by 70%)[36] most likely through its prolonging effect of the cardiac QT interval and ventricular arrhythmias.[37][38] The cause is thought to be blockade of hERG voltage-gated potassium channels.[39][40] The risks are dose-dependent, and appear to be greatest with high/very high doses via intravenous administration and in the elderly, as well as with drugs that interact with domperidone and increase its circulating concentrations (namely CYP3A4 inhibitors).[41][42] Conflicting reports exist, however.[43] In neonates and infants, QT prolongation is controversial and uncertain.[44][45]

    UK drug regulatory authorities (MHRA) have issued Archived 25 August 2018 at the Wayback Machine the following restriction on domperidone in 2014 due to increased risk of adverse cardiac effects:

    Domperidone (Motilium) is associated with a small increased risk of serious cardiac side effects. Its use is now restricted to the relief of nausea and vomiting and the dosage and duration of use have been reduced. It should no longer be used for the treatment of bloating and heartburn. Domperidone is now contraindicated in those with underlying cardiac conditions and other risk factors. Patients with these conditions and patients receiving long-term treatment with domperidone should be reassessed at a routine appointment, in light of the new advice.

    However, a 2015 Australian review concluded the following:[42]

    Based on the results of the two TQT (the regulatory agency gold standard for assessment of QT prolongation) domperidone does not appear to be strongly associated with QT prolongation at oral doses of 20 mg QID in healthy volunteers. Further, there are limited case reports supporting an association with cardiac dysfunction, and the frequently cited case-control studies have significant flaws. While there remains an ill-defined risk at higher systemic concentrations, especially in patients with a higher baseline risk of QT prolongation, our review does not support the view that domperidone presents intolerable risk.

    Babies

    In Britain a legal case involved the death of two children of a mother whose three children had all had hypernatraemia. She was charged with poisoning the children with salt. One of the children, who was born at 28 weeks gestation with respiratory complications and had a fundoplication for gastroesophageal reflux and failure to thrive was prescribed domperidone. An advocate for the mother suggested the child may have suffered neuroleptic malignant syndrome as a side effect of domperidone due to the drug crossing the child's immature blood-brain-barrier.[46]

    Interactions

    In healthy volunteers, ketoconazole increased the Cmax and AUC concentrations of domperidone by 3- to 10-fold.[47] This was accompanied by a QT interval prolongation of about 10–20 milliseconds when domperidone 10 mg four times daily and ketoconazole 200 mg twice daily were administered, whereas domperidone by itself at the dosage assessed produced no such effect.[47] As such, domperidone with ketoconazole or other CYP3A4 inhibitors is a potentially dangerous combination.[47]

    Pharmacology

    Pharmacodynamics

    Domperidone is a peripherally selective dopamine D2 and D3 receptor antagonist.[32] It has no clinically significant interaction with the D1 receptor, unlike metoclopramide.[32] The medication provides relief from nausea by blocking D receptors.[48] It blocks dopamine receptors in the anterior pituitary gland increasing release of prolactin which in turn increases lactation.[49][50] Domperidone may be more useful in some patients and cause harm in others by way of the genetics of the person, such as polymorphisms in the drug transporter gene ABCB1 (which encodes P-glycoprotein), the voltage-gated potassium channel KCNH2 gene (hERG/Kv11.1), and the α1D—adrenoceptor ADRA1D gene.[51]

    Effects on prolactin levels

    A single 20 mg oral dose of domperidone has been found to increase mean serum prolactin levels (measured 90 minutes post-administration) in non-lactating women from 8.1 ng/mL to 110.9 ng/mL (a 13.7-fold increase).[32][52][53][54] This was similar to the increase in prolactin levels produced by a single 20 mg oral dose of metoclopramide (7.4 ng/mL to 124.1 ng/mL; 16.7-fold increase).[53][54] After two weeks of chronic administration (30 mg/day in both cases), the increase in prolactin levels produced by domperidone was reduced (53.2 ng/mL; 6.6-fold above baseline), but the increase in prolactin levels produced by metoclopramide, conversely, was heightened (179.6 ng/mL; 24.3-fold above baseline).[32][54] This indicates that acute and chronic administration of both domperidone and metoclopramide is effective in increasing prolactin levels, but that there are differential effects on the secretion of prolactin with chronic treatment.[53][54] The mechanism of the difference is unknown.[54] The increase in prolactin levels observed with the two drugs was, as expected, much greater in women than in men.[53][54] This appears to be due to the higher estrogen levels in women, as estrogen stimulates prolactin secretion.[55]

    For comparison, normal prolactin levels in women are less than 20 ng/mL, prolactin levels peak at 100 to 300 ng/mL at parturition in pregnant women, and in lactating women, prolactin levels have been found to be 90 ng/mL at 10 days postpartum and 44 ng/mL at 180 days postpartum.[56][57]

    Pharmacokinetics

    With oral administration, domperidone is extensively metabolized in the liver (almost exclusively by CYP3A4/5, though minor contributions by CYP1A2, CYP2D6, and CYP2C8 have also been reported)[58] and in the intestines.[5] Due to the marked first-pass effect via this route, the oral bioavailability of domperidone is low (13–17%);[1] conversely, its bioavailability is high via intramuscular injection (90%).[1] The terminal half-life of domperidone is 7.5 hours in healthy individuals, but can be prolonged to 20 hours in people with severe kidney dysfunction.[1] All of the metabolites of domperidone are inactive as D2 receptor ligands.[1][5] The drug is a substrate for the P-glycoprotein (ABCB1) transporter, and animal studies suggest that this is the reason for the low central nervous system penetration of domperidone.[59]

    Chemistry

    Domperidone is a benzimidazole derivative and is structurally related to butyrophenone neuroleptics like haloperidol.[60][61]

    History

    • 1974 – Domperidone synthesized at Janssen Pharmaceutica[62] following the research on antipsychotic drugs.[63] Janssen pharmacologists discovered that some of antipsychotic drugs had a significant effect on dopamine receptors in the central chemoreceptor trigger zone that regulated vomiting and started searching for a dopamine antagonist that would not pass the blood–brain barrier, thereby being free of the extrapyramidal side effects that were associated with drugs of this type.[63] This led to the discovery of domperidone as a strong anti-emetic with minimal central effects.[63][64]
    • 1978 – On 3 January 1978 Domperidone was patented in the United States under patent US4066772 A. The application has been filed on 17 May 1976. Jan Vandenberk, Ludo E. J. Kennis, Marcel J. M. C. Van der Aa and others has been cited as the inventors.
    • 1979 – Domperidone marketed under trade name "Motilium" in Switzerland and (Western) Germany.[65]
    • 1999 – Domperidone was introduced in the forms of orally disintegrating tablets (based on Zydis technology).[66]
    • Janssen Pharmaceutical has brought domperidone before the United States Federal Drug Administration (FDA) several times, including in the 1990s.
    • 2014 – In April 2014 Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) published official press-release suggesting to restrict the use of domperidone-containing medicines. It also approved earlier published suggestions by Pharmacovigilance Risk Assessment Committee (PRAC) to use domperidone only for curing nausea and vomiting and reduce maximum daily dosage to 10 mg.[67]

    Society and culture

    Generic names

    Domperidone is the generic name of the drug and its INN, USAN, BAN, and JAN.[68][69][70]

    Regulatory approval

    In 2007 domperidone was available in 58 countries, including Canada.[71] The approved indications of domperidone vary between nations. In Italy it is used in the treatment of gastroesophageal reflux disease and in Canada, the drug is indicated in upper gastrointestinal motility disorders and to prevent gastrointestinal symptoms associated with the use of dopamine agonist antiparkinsonian agents.[72] In the United Kingdom, domperidone is only indicated for the treatment of nausea and vomiting and the treatment duration is usually limited to 1 week.

    In the United States, domperidone is not currently generally approved for medical use. On 7 June 2004, FDA issued a public warning that distributing any domperidone-containing products is illegal.[73] There is an exception for use in people with treatment-refractory gastrointestinal symptoms under an FDA Investigational New Drug application.[1]

    It is available over-the-counter to treat gastroesophageal reflux and functional dyspepsia in many countries, such as Ireland, the Netherlands, Italy, South Africa, Mexico, Chile, and China.[74]

    Formulations

    It and is available as a tablet, orally disintegrating tablets,[75] suspension, and suppositories.[67]

    Formulations
    Nation Manufacturer Brand Formulations
    AustraliaJanssen–CilagMotilium10 mg scored tablets[30]
    Belgium and the Netherlands-MotiliumFrom 2013 only by prescription in Belgium.[76]
    BangladeshSquareMotigut10 mg scored tablets
    BangladeshOrion PharmaCosy10 mg scored tablets
    BangladeshAstra PharmaDomperon10 mg scored tablets
    Bangladesh-Ridon-
    Canada-Motilium (1985–2002)Generic brands available
    FranceJanssenMotilium10 mg tablets only with prescription generic domperidone available
    GreeceJohnson & Johnson HellasCilroton10 mg scored tablets
    IndiaSalius PharmaEscacid DXRpantoprazole 40 mg and domperidone SR 30 mg
    IndiaFDC PharmaceuticalsPepcia-DRabeprazole 20 mg and Domperidone SR 30 mg
    IndiaRhubarb pharmaceuticals-domperidone 5, 10 and 20 mg tablets.
    IndiaIpca Laboratories, MumbaiDomperi suspensiondomperidone 1 mg/ml, 30 ml suspension.[77]
    IndiaTorrent pharmaceuticalsDomstal-[78]
    IndiaOzone pharmaceuticals and chemicalsPantazone-D10 mg domperidone and 40 mg pantoprazole
    IndiaChimak Health CarePancert D10 mg Domperidone and 40 mg pantoprazole
    IndiaDraavin PharmaDraaci-XDPantaprazole 40 mg and Domperione 30 mg
    IranAbidi Pharmaceutical Co.MOTiDON10 mg tablet
    IrelandMcNeil HealthcareMotilium10 mg orally disintegrating tablet (ODT)
    Italy-Peridondomperidone 10 mg tablets; 30 ml suspension
    LithuaniaJohnson & JohnsonMotilium-
    PakistanBarrett Hodgson PakistanDomel
    PakistanJohnson & Johnson PakistanMotilium-vdomperidone 10 mg tablets; 30 ml suspension
    PakistanATCO Laboratories LimitedVomiluxdomperidone 10 mg tablets
    PakistanAspin Pharma (Pvt) LimitedMotiliumdomperidone 10 mg tablets
    PhilippinesHealth Saver PharmaAbdopen-
    PhilippinesUnited Laboratories, Inc.GI Norm-
    PortugalMedinfarCinetdomperidone 1 mg/ml oral suspension (200 ml)
    RussiaJanssen PharmaceuticaMotiliumdomperidone 10 mg film-coated tablets & ODT; 1 mg/ml suspension (100 ml)
    -OBL PharmPassagixdomperidone 10 mg film-coated tablets & chewable tablets
    -Dr. Reddy's LaboratoriesOmez Ddomperidone/omeprazole (10 mg/10 mg)
    Saudi ArabiaJamJoom PharmaceuticalsDompyDomperidone 10 mg tablets
    Spain Laboratorios Dr. Esteve, SA Motilium domperidone 1 mg/ml oral suspension (200 ml)
    SwedenEbb medicalDomperidon Ebb (2013)domperidone 10 mg ODT and peppermint
    Taiwan-Dotitone-
    Thailand-Motilium M-
    TurkeySabaMotinorm-
    -GlaxoSmithKlineMotinorm-

    Research

    Domperidone has been studied as a potential hormonal contraceptive to prevent pregnancy in women.[79]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Reddymasu, Savio C.; Soykan, Irfan; McCallum, Richard W. (2007). "Domperidone: Review of Pharmacology and Clinical Applications in Gastroenterology". The American Journal of Gastroenterology. 102 (9): 2036–2045. ISSN 0002-9270. PMID 17488253.
    2. ↑ "БРЮЛІУМ ЛІНГВАТАБС" [BRULIUM LINGUATABS]. Нормативно-директивні документи МОЗ України (in українська). 18 March 2014. Archived from the original on 30 May 2015. Retrieved 29 May 2015.
    3. ↑ "Domperidone". Archived from the original on 22 May 2013. Retrieved 30 June 2013.
    4. 1 2 Suzanne Rose (October 2004). Gastrointestinal and Hepatobiliary Pathophysiology. Hayes Barton Press. pp. 523–. ISBN 978-1-59377-181-2.{{cite book}}: CS1 maint: url-status (link)
    5. 1 2 3 4 Simard, C.; Michaud, V.; Gibbs, B.; Massé, R.; Lessard, É; Turgeon, J. (2008). "Identification of the cytochrome P450 enzymes involved in the metabolism of domperidone". Xenobiotica. 34 (11–12): 1013–1023. doi:10.1080/00498250400015301. ISSN 0049-8254. PMID 15801545. S2CID 27426219.
    6. 1 2 Paul, C; Zénut, M; Dorut, A; Coudoré, MA; Vein, J; Cardot, JM; Balayssac, D (February 2015). "Use of domperidone as a galactagogue drug: a systematic review of the benefit-risk ratio". Journal of human lactation : official journal of International Lactation Consultant Association. 31 (1): 57–63. doi:10.1177/0890334414561265. PMID 25475074.
    7. ↑ Becker, WJ (June 2015). "Acute Migraine Treatment in Adults". Headache. 55 (6): 778–93. doi:10.1111/head.12550. PMID 25877672.
    8. 1 2 3 4 5 6 7 8 9 10 BNF 79 : March 2020. London: Royal Pharmaceutical Society. 2020. p. 444. ISBN 9780857113658.
    9. 1 2 Research, Center for Drug Evaluation and (3 August 2020). "How to Request Domperidone for Expanded Access Use". FDA. Archived from the original on 5 October 2020. Retrieved 6 October 2020.
    10. ↑ Leelakanok, N; Holcombe, A; Schweizer, ML (February 2016). "Domperidone and Risk of Ventricular Arrhythmia and Cardiac Death: A Systematic Review and Meta-analysis". Clinical drug investigation. 36 (2): 97–107. doi:10.1007/s40261-015-0360-0. PMID 26649742.
    11. ↑ "Domperidone". Drugs and Lactation Database (LactMed). National Library of Medicine (US). Archived from the original on 9 July 2021. Retrieved 6 October 2020.
    12. ↑ Zarros, Apostolos; Tansey, Tilli (2019). Pharmaceutical Innovation After World War II: From Rational Drug Discovery to Biopharmaceuticals. Frontiers Media SA. p. 49. ISBN 978-2-88963-223-7. Archived from the original on 9 July 2021. Retrieved 6 October 2020.
    13. ↑ Wiffen, Philip; Stoner, Nicola (2017). "15. Therapy-related issues: gastrointestinal". Oxford Handbook of Clinical Pharmacy. Oxford: Oxford University Press. p. 309. ISBN 978-0-19-873582-3. LCCN 2016945512. Archived from the original on 9 October 2021. Retrieved 13 October 2021.
    14. ↑ Worthington I, Pringsheim T, Gawel MJ, Gladstone J, Cooper P, Dilli E, Aube M, Leroux E, Becker WJ (September 2013). "Canadian Headache Society Guideline: acute drug therapy for migraine headache". The Canadian Journal of Neurological Sciences. 40 (5 Suppl 3): S1–S80. doi:10.1017/S0317167100118943. PMID 23968886.
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    16. ↑ Silvers D, Kipnes M, Broadstone V, Patterson D, Quigley EM, McCallum R, Leidy NK, Farup C, Liu Y, Joslyn A (1998). "Domperidone in the management of symptoms of diabetic gastroparesis: efficacy, tolerability, and quality-of-life outcomes in a multicenter controlled trial. DOM-USA-5 Study Group". Clinical Therapeutics. 20 (3): 438–53. doi:10.1016/S0149-2918(98)80054-4. PMID 9663360.
    17. ↑ Janssen P, Harris MS, Jones M, Masaoka T, Farré R, Törnblom H, Van Oudenhove L, Simrén M, Tack J (September 2013). "The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis". The American Journal of Gastroenterology. 108 (9): 1382–91. doi:10.1038/ajg.2013.118. PMID 24005344. S2CID 32835351.
    18. ↑ Lertxundi, U; Domingo-Echaburu, S; Soraluce, A; García, M; Ruiz-Osante, B; Aguirre, C (February 2013). "Domperidone in Parkinson's disease: a perilous arrhythmogenic or the gold standard?". Current drug safety. 8 (1): 63–8. doi:10.2174/1574886311308010009. PMID 23656449.
    19. ↑ Grzeskowiak LE, Smithers LG, Amir LH, Grivell RM (October 2018). "Domperidone for increasing breast milk volume in mothers expressing breast milk for their preterm infants: a systematic review and meta-analysis". BJOG. 125 (11): 1371–1378. doi:10.1111/1471-0528.15177. hdl:2440/114203. PMID 29469929.
    20. ↑ Donovan TJ, Buchanan K (2012). "Medications for increasing milk supply in mothers expressing breastmilk for their preterm hospitalised infants". The Cochrane Database of Systematic Reviews. 3 (3): CD005544. doi:10.1002/14651858.CD005544.pub2. PMID 22419310.
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    25. ↑ Queensland, Children's Health (17 June 2019). "Domperidone for improving breast milk supply fact sheet | CHQ". Children’s Health Queensland. Archived from the original on 30 May 2023. Retrieved 15 June 2023.
    26. ↑ Donovan, Timothy J; Buchanan, Kerry (14 March 2012). "Medications for increasing milk supply in mothers expressing breastmilk for their preterm hospitalised infants". Cochrane Database of Systematic Reviews (3): CD005544. doi:10.1002/14651858.cd005544.pub2. PMID 22419310.
    27. ↑ Kapoor, A.K.; Raju, S.M. (2013). "7.2 Gastrointestinal Drugs". Illustrated Medical Pharmacology. JP Medical Ltd. p. 677. ISBN 978-9350906552. Retrieved 31 October 2014. (Google Books)
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    29. ↑ Huang X, Lv B, Zhang S, Fan YH, Meng LN (December 2012). "Itopride therapy for functional dyspepsia: a meta-analysis". World Journal of Gastroenterology. 18 (48): 7371–7. doi:10.3748/wjg.v18.i48.7371. PMC 3544044. PMID 23326147.
    30. 1 2 Swannick G. (ed.) "MIMS Australia." December 2013
    31. ↑ Henderson, Amanda (2003). "Domperidone: Discovering New Choices for Lactating Mothers". AWHONN Lifelines. 7 (1): 54–60. doi:10.1177/1091592303251726. ISSN 1091-5923. PMID 12674062.
    32. 1 2 3 4 5 6 Barone JA (1999). "Domperidone: a peripherally acting dopamine2-receptor antagonist". The Annals of Pharmacotherapy. 33 (4): 429–40. doi:10.1345/aph.18003. PMID 10332535. S2CID 39279569.
    33. 1 2 Elliott Proctor Joslin; C. Ronald Kahn (2005). Joslin's Diabetes Mellitus: Edited by C. Ronald Kahn ... [et Al.]. Lippincott Williams & Wilkins. pp. 1084–. ISBN 978-0-7817-2796-9. Archived from the original on 23 December 2018. Retrieved 22 September 2016.
    34. 1 2 3 Edmund S. Sabanegh, Jr. (20 October 2010). Male Infertility: Problems and Solutions. Springer Science & Business Media. pp. 83–. ISBN 978-1-60761-193-6. Archived from the original on 20 May 2016. Retrieved 22 September 2016.
    35. ↑ Gerald G. Briggs; Roger K. Freeman; Sumner J. Yaffe (28 March 2012). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. pp. 442–. ISBN 978-1-4511-5359-0.
    36. ↑ Leelakanok N, Holcombe A, Schweizer ML (2015). "Domperidone and Risk of Ventricular Arrhythmia and Cardiac Death: A Systematic Review and Meta-analysis". Clin Drug Investig. 36 (2): 97–107. doi:10.1007/s40261-015-0360-0. PMID 26649742. S2CID 25601738.
    37. ↑ van Noord C, Dieleman JP, van Herpen G, Verhamme K, Sturkenboom MC (November 2010). "Domperidone and ventricular arrhythmia or sudden cardiac death: a population-based case-control study in the Netherlands". Drug Safety. 33 (11): 1003–14. doi:10.2165/11536840-000000000-00000. PMID 20925438. S2CID 21177240.
    38. ↑ Johannes CB, Varas-Lorenzo C, McQuay LJ, Midkiff KD, Fife D (September 2010). "Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: a nested case-control study". Pharmacoepidemiology and Drug Safety. 19 (9): 881–8. doi:10.1002/pds.2016. PMID 20652862.
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    40. ↑ Doggrell SA, Hancox JC (2014). "Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine" (PDF). Expert Opin Drug Saf. 13 (1): 131–8. doi:10.1517/14740338.2014.851193. PMID 24147629. S2CID 30668496. Archived (PDF) from the original on 22 September 2017. Retrieved 27 October 2018.
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