Domperidone

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Not to be confused with Droperidol.

Domperidone
Names
Trade namesMotilium, others
  • 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)
  • Clc1cc2c(cc1)N(C(=O)N2)C5CCN(CCCN4c3ccccc3NC4=O)CC5
  • 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
Australia Janssen–Cilag Motilium 10 mg scored tablets[30]
Belgium and the Netherlands - Motilium From 2013 only by prescription in Belgium.[76]
Bangladesh Square Motigut 10 mg scored tablets
Bangladesh Orion Pharma Cosy 10 mg scored tablets
Bangladesh Astra Pharma Domperon 10 mg scored tablets
Bangladesh - Ridon -
Canada - Motilium (1985–2002) Generic brands available
France Janssen Motilium 10 mg tablets only with prescription generic domperidone available
Greece Johnson & Johnson Hellas Cilroton 10 mg scored tablets
India Salius Pharma Escacid DXR pantoprazole 40 mg and domperidone SR 30 mg
India FDC Pharmaceuticals Pepcia-D Rabeprazole 20 mg and Domperidone SR 30 mg
India Rhubarb pharmaceuticals - domperidone 5, 10 and 20 mg tablets.
India Ipca Laboratories, Mumbai Domperi suspension domperidone 1 mg/ml, 30 ml suspension.[77]
India Torrent pharmaceuticals Domstal -[78]
India Ozone pharmaceuticals and chemicals Pantazone-D 10 mg domperidone and 40 mg pantoprazole
India Chimak Health Care Pancert D 10 mg Domperidone and 40 mg pantoprazole
India Draavin Pharma Draaci-XD Pantaprazole 40 mg and Domperione 30 mg
Iran Abidi Pharmaceutical Co. MOTiDON 10 mg tablet
Ireland McNeil Healthcare Motilium 10 mg orally disintegrating tablet (ODT)
Italy - Peridon domperidone 10 mg tablets; 30 ml suspension
Lithuania Johnson & Johnson Motilium -
Pakistan Barrett Hodgson Pakistan Domel
Pakistan Johnson & Johnson Pakistan Motilium-v domperidone 10 mg tablets; 30 ml suspension
Pakistan ATCO Laboratories Limited Vomilux domperidone 10 mg tablets
Pakistan Aspin Pharma (Pvt) Limited Motilium domperidone 10 mg tablets
Philippines Health Saver Pharma Abdopen -
Philippines United Laboratories, Inc. GI Norm -
Portugal Medinfar Cinet domperidone 1 mg/ml oral suspension (200 ml)
Russia Janssen Pharmaceutica Motilium domperidone 10 mg film-coated tablets & ODT; 1 mg/ml suspension (100 ml)
- OBL Pharm Passagix domperidone 10 mg film-coated tablets & chewable tablets
- Dr. Reddy's Laboratories Omez D domperidone/omeprazole (10 mg/10 mg)
Saudi Arabia JamJoom Pharmaceuticals Dompy Domperidone 10 mg tablets
Spain Laboratorios Dr. Esteve, SA Motilium domperidone 1 mg/ml oral suspension (200 ml)
Sweden Ebb medical Domperidon Ebb (2013) domperidone 10 mg ODT and peppermint
Taiwan - Dotitone -
Thailand - Motilium M -
Turkey Saba Motinorm -
- GlaxoSmithKline Motinorm -

Research

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

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 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. ↑ 4.0 4.1 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. ↑ 5.0 5.1 5.2 5.3 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. ↑ 6.0 6.1 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. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 BNF 79 : March 2020. London: Royal Pharmaceutical Society. 2020. p. 444. ISBN 9780857113658.
  9. ↑ 9.0 9.1 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.
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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.
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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.
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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. ↑ 30.0 30.1 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. ↑ 32.0 32.1 32.2 32.3 32.4 32.5 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. ↑ 33.0 33.1 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. ↑ 34.0 34.1 34.2 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.
  39. ↑ Rossi M, Giorgi G (2010). "Domperidone and long QT syndrome". Curr Drug Saf. 5 (3): 257–62. doi:10.2174/157488610791698334. PMID 20394569.
  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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