Prescription medicine (Rx only):Pakistan, India, Australia, Canada, Israel, Belgium, France, Netherlands; over-the-counter: Egypt, Ireland, Italy, Japan, South Africa, Switzerland, China, Russia, Slovakia, Ukraine Mexico, Thailand, Malta, South Korea, and Romania
However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate (equate) well with relief of symptoms.
Parkinson's disease is a chronic neurological condition where a decrease in dopamine in the brain leads to rigidity (stiffness of movement), tremor and other symptoms and signs. Poor gastrointestinal function, nausea and vomiting is a major problem for people with Parkinson's disease because most medications used to treat Parkinson's disease are given by mouth. These medications, such as levodopa, can cause nausea as a side effect. Furthermore, anti-nausea drugs, such as metoclopramide, which do cross the blood–brain barrier may worsen the extra-pyramidal symptoms of Parkinson's disease.
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. In addition to this, domperidone may enhance the bioavailability (effect) of levodopa (one of the main treatments in Parkinson's disease).
Although these features make domperidone a useful drug in Parkinson's disease, caution is needed due to the cardiotoxic side effects of domperidone especially when given intravenously, in elderly people and in high doses (> 30 mg per day). A clinical sign of domperidone's potential toxicity to the heart is the prolongation (lengthening) of the QT interval (a segment of the heart's electrical pattern).
The hormone prolactin stimulates lactation (production of breast milk). Dopamine, released by the hypothalamus stops the release of prolactin from the pituitary gland. Domperidone, by acting as an anti-dopaminergic agent, results in increased prolactin secretion, and thus promotes lactation (that is, it is a galactogogue). Domperidone moderately increases the volume of expressed breast milk in mothers of preterm babies where breast milk expression was inadequate, and appears to be safe for short-term use for this purpose. In the United States, domperidone is not approved for this or any other use.
A study called the EMPOWER trial was designed to assess the effectiveness and safety of domperidone in assisting mothers of preterm babies to supply breast milk for their infants. The study randomized 90 mothers of preterm babies to receive either domperidone 10 mg orally three times daily for 28 days (Group A) or placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days (Group B). Mean milk volumes at the beginning of the intervention were similar between the 2 groups. After the first 14 days, 78% of mothers receiving domperidone (Group A) achieved a 50% increase in milk volume, while 58% of mothers receiving placebo (Group B) achieved a 50% increase in milk volume.
To induce lactation, domperidone is used at a dosage of 10 to 20 mg 3 or 4 times per day by mouth. Effects may be seen within 24 hours or may not be seen for 3 or 4 days. The maximum effect occurs after 2 or 3 weeks of treatment, and the treatment period generally lasts for 3 to 8 weeks. A 2012 review shows that no studies support prophylactic use of a galactagogue medication at any gestation including domperidone.
Reflux in children
Domperidone has been found effective in the treatment of reflux in children. However some specialists consider its risks prohibitory of the treatment of infantile reflux.
UK drug regulatory authorities (MHRA) have issued 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:
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.
Domperidone is almost exclusively metabolized by CYP3A4, and for this reason, inhibitors and inducers of this enzyme may alter the metabolism and concentrations of domperidone. Moreover, domperidone has been identified as a modest mechanism-based (irreversible) inhibitor of CYP3A4 (Ki = 12 μM), and it has been estimated that it may increase the serum concentrations of CYP3A4 substrates by approximately 50%.
Itraconazole and ketoconazole, both used to treat fungal infections, are potent CYP3A4 inhibitors and increase the plasma concentration of domperidone. In healthy volunteers, ketoconazole increased the Cmax and AUC concentrations of domperidone by 3- to 10-fold. 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. As such, domperidone with ketoconazole or other CYP3A4 inhibitors is a potentially dangerous combination.
Erythromycin and certain other macrolide antibiotics are CYP3A4 inhibitors and inhibit the metabolism of domperidone (in vitro), thus increasing the concentration of domperidone and potential side effects of the drug. This is of concern as both drugs may be used to treat gastroparesis.
There is evidence that domperidone should not be taken with grapefruitjuice, which is a known CYP3A4 inhibitor.
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). 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). 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). 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. The mechanism of the difference is unknown. The increase in prolactin levels observed with the two drugs was, as expected, much greater in women than in men. This appears to be due to the higher estrogen levels in women, as estrogen stimulates prolactin secretion.
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.
Effects on TSH levels
Along with prolactin, domperidone has, to a lesser extent, been found to increase the secretion of thyroid-stimulating hormone (TSH), even in patients with hypothyroidism. A single 4 mg intravenous dose of domperidone produced peak TSH levels of 1.9-fold above baseline and peak prolactin levels of 23-fold above baseline (which occurred at 30 minutes post-administration) in women with hypothyroidism. Levels of TSH and prolactin decreased to 1.6-fold and 17-fold above baseline, respectively, at 120 minutes post-administration.
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.
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.
It was reported in 2007 that domperidone is available in 58 countries, including Canada, but the uses or 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. 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 a legally marketed human drug and it is not approved for sale in the U.S. On 7 June 2004, FDA issued a public warning that distributing any domperidone-containing products is illegal.
Domperidone is not generally approved for use in the United States. There is an exception for use in people with treatment-refractory gastrointestinal symptoms under an FDA Investigational New Drug application.
^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. PMID23968886.
^Stevens JE, Jones KL, Rayner CK, Horowitz M (June 2013). "Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives". Expert Opinion on Pharmacotherapy. 14 (9): 1171–86. doi:10.1517/14656566.2013.795948. PMID23663133.
^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. PMID9663360.
^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. PMID24005344.
^Nishikawa N, Nagai M, Tsujii T, Iwaki H, Yabe H, Nomoto M (2012). "Coadministration of domperidone increases plasma levodopa concentration in patients with Parkinson disease". Clinical Neuropharmacology. 35 (4): 182–4. doi:10.1097/WNF.0b013e3182575cdb. PMID22751085.
^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. PMID23656449.
^Malek NM, Grosset KA, Stewart D, Macphee GJ, Grosset DG (June 2013). "Prescription of drugs with potential adverse effects on cardiac conduction in Parkinson's disease". Parkinsonism & Related Disorders. 19 (6): 586–9. doi:10.1016/j.parkreldis.2013.02.004. PMID23522959.
^Xiao M, Qiu X, Yue D, Cai Y, Mo Q (2013). "Influence of hippophae rhamnoides on two appetite factors, gastric emptying and metabolic parameters, in children with functional dyspepsia". Hellenic Journal of Nuclear Medicine. 16 (1): 38–43. PMID23529392.
^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. PMID29469929.
^Grzeskowiak LE, Lim SW, Thomas AE, Ritchie U, Gordon AL (February 2013). "Audit of domperidone use as a galactogogue at an Australian tertiary teaching hospital". Journal of Human Lactation. 29 (1): 32–7. doi:10.1177/0890334412459804. hdl:2440/94368. PMID23015150.
^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. PMID22419310.
^Asztalos EV, Campbell-Yeo M, da Silva OP, Ito S, Kiss A, Knoppert D, et al. (EMPOWER Study Collaborative Group) (2017). "Enhancing human milk production with Domperidone in mothers of preterm infants". Journal of Human Lactation. 33 (1): 181–187. doi:10.1177/0890334416680176. PMID28107101.
^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. PMID26649742.
^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. PMID20925438.
^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. PMID20652862.
^ abBuffery PJ, Strother RM (2015). "Domperidone safety: a mini-review of the science of QT prolongation and clinical implications of recent global regulatory recommendations". N. Z. Med. J. 128 (1416): 66–74. PMID26117678.
^Sakamoto Y, Kato S, Sekino Y, Sakai E, Uchiyama T, Iida H, Hosono K, Endo H, Fujita K, Koide T, Takahashi H, Yoneda M, Tokoro C, Goto A, Abe Y, Kobayashi N, Kubota K, Maeda S, Nakajima A, Inamori M (2011). "Effects of domperidone on gastric emptying: a crossover study using a continuous real-time 13C breath test (BreathID system)". Hepato-gastroenterology. 58 (106): 637–41. PMID21661445.
^Parkman HP, Jacobs MR, Mishra A, Hurdle JA, Sachdeva P, Gaughan JP, Krynetskiy E (January 2011). "Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects". Digestive Diseases and Sciences. 56 (1): 115–24. doi:10.1007/s10620-010-1472-2. PMID21063774.
^ abcdefBrouwers JR, Assies J, Wiersinga WM, Huizing G, Tytgat GN (1980). "Plasma prolactin levels after acute and subchronic oral administration of domperidone and of metoclopramide: a cross-over study in healthy volunteers". Clin. Endocrinol. 12 (5): 435–40. doi:10.1111/j.1365-2265.1980.tb02733.x. PMID7428183.
^Fujino T, Kato H, Yamashita S, Aramaki S, Morioka H, Koresawa M, Miyauchi F, Toyoshima H, Torigoe T (1980). "Effects of domperidone on serum prolactin levels in human beings". Endocrinol. Jpn. 27 (4): 521–5. doi:10.1507/endocrj1954.27.521. PMID7460861.
^Hofmeyr, G. J.; Van Iddekinge, B.; Van Der Walt, L. A. (2009). "Effect of domperidone-induced hyperprolactinaemia on the menstrual cycle; a placebo-controlled study". Journal of Obstetrics and Gynaecology. 5 (4): 263–264. doi:10.3109/01443618509067772. ISSN0144-3615.