Metoclopramide

Metoclopramide is a medication used for stomach and esophageal problems.[4] It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease.[5] It is also used to treat migraine headaches.[6]

Metoclopramide
Clinical data
Pronunciation/ˌmɛtəˈklɒprəmaɪd/
Trade namesPrimperan, Reglan, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa684035
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous, intramuscular, nasal spray
Drug classD2 receptor antagonist; 5-HT3 receptor antagonist; 5-HT4 receptor agonist; Prolactin releaser
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80 ± 15% (by mouth)
MetabolismLiver
Elimination half-life5–6 hours
ExcretionUrine: 70–85%
Feces: 2%
Identifiers
IUPAC name
  • 4-Amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.006.058
Chemical and physical data
FormulaC14H22ClN3O2
Molar mass299.80 g·mol−1
3D model (JSmol)
Melting point147.3 °C (297.1 °F)
SMILES
  • Clc1cc(c(OC)cc1N)C(=O)NCCN(CC)CC
InChI
  • InChI=1S/C14H22ClN3O2/c1-4-18(5-2)7-6-17-14(19)10-8-11(15)12(16)9-13(10)20-3/h8-9H,4-7,16H2,1-3H3,(H,17,19) Y
  • Key:TTWJBBZEZQICBI-UHFFFAOYSA-N Y
  (verify)

Common side effects include: feeling tired, diarrhea, and feeling restless. More serious side effects include: movement disorder like tardive dyskinesia, a condition called neuroleptic malignant syndrome, and depression.[5] It is thus rarely recommended that people take the medication for longer than twelve weeks.[5] No evidence of harm has been found after being taken by many pregnant women.[5][7] It belongs to the group of medications known as dopamine-receptor antagonists and works as a prokinetic.[5]

In 2012, metoclopramide was one of the top 100 most prescribed medications in the United States.[8] It is available as a generic medication.[5] It is on the World Health Organization's List of Essential Medicines.[9] In 2017, it was the 253rd most commonly prescribed medication in the United States, with more than one million prescriptions.[10][11]

Medical uses
Metoclopramide 5-mg tablets

Nausea

Metoclopramide is commonly used to treat nausea and vomiting associated with conditions such as uremia, radiation sickness, cancer and the effects of chemotherapy, labor, infection, and emetogenic drugs.[5][12][13][14] As a perioperative anti-emetic, the effective dose is usually 25 to 50 mg (compared to the usual 10 mg dose).

It is also used in pregnancy as a second choice for treatment of hyperemesis gravidarum (severe nausea and vomiting of pregnancy).[5]

It is also used preventatively by some EMS providers when transporting people who are conscious and spinally immobilized.[15]

Migraine

In migraine headaches, metoclopramide may be used in combination with paracetamol (acetaminophen) or in combination with aspirin.[16]

Gastroparesis

Evidence also supports its use for gastroparesis, a condition that causes the stomach to empty poorly, and as of 2010 it was the only drug approved by the FDA for that condition.[5][17]

It is also used in gastroesophageal reflux disease.[5][3]

Lactation

While metoclopramide is used to try to increase breast milk production, evidence for its effectiveness for this is poor.[18] Its safety for this use is also unclear.[19]

Procedures

Intravenous metoclopramide is used in small-bowel follow-through, small-bowel enema, and radionuclide gastric-emptying studies to reduce the time taken for barium to go through the intestines, thus reducing the total time needed for the procedures. Metoclopramide also prevents vomiting after oral ingestion of barium.[20]

Contraindications

Metoclopramide is contraindicated in pheochromocytoma. It should be used with caution in Parkinson's disease since, as a dopamine antagonist, it may worsen symptoms. Long-term use should be avoided in people with clinical depression, as it may worsen one's mental state.[13] It is contraindicated for people with a suspected bowel obstruction,[5] in epilepsy, if a stomach operation has been performed in the previous three or four days, if the person has ever had bleeding, perforation or blockage of the stomach, and in newborn babies.[14]

The safety of the drug was reviewed by the European Medicines Agency in 2011, which determined that it should not be prescribed in high doses, for periods of more than five days, or given to children below 1 year of age. They suggested its use in older children should be restricted to treating post-chemotherapy or post-surgery nausea and vomiting, and even then only for patients where other treatments have failed. For adults, they recommended its use be restricted to treating migraines and post-chemotherapy or post-surgery patients.[21][22]

Pregnancy

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or foetus.[23] A large cohort study of babies born to Israeli women exposed to metoclopramide during pregnancy found no evidence that the drug increases the risk of congenital malformations, low birth weight, preterm birth, or perinatal mortality.[24] A large cohort study in Denmark found, in addition, no association between metoclopramide exposure and miscarriage.[25] Metoclopramide is excreted into milk.[23]

Infants

A systematic review found a wide range of reported outcomes for treatment of gastroesophageal reflux disease (GERD) in infants and concluded a "poor" rating of evidence and "inconclusive" rating of safety and efficacy for the treatment of GERD in infants.[26]

Side effects
Plastic ampoule of metoclopramide

Common adverse drug reactions (ADRs) associated with metoclopramide therapy include restlessness (akathisia), and focal dystonia. Infrequent ADRs include hypertension, hypotension, hyperprolactinaemia leading to galactorrhea, headache, and extrapyramidal effects such as oculogyric crisis.[13][3]

Metoclopramide may be the most common cause of drug-induced movement disorders.[27] The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy.[12][13] Tardive dyskinesia may be persistent and irreversible in some people. The majority of reports of tardive dyskinesia occur in people who have used metoclopramide for more than three months.[27] Consequently, the US Food and Drug Administration (FDA) recommends that metoclopramide be used for short-term treatment, preferably less than 12 weeks. In 2009, the FDA required all manufacturers of metoclopramide to issue a black box warning regarding the risk of tardive dyskinesia with chronic or high-dose use of the drug.[27]

Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with diphenhydramine injected intramuscularly.[3] Agents in the benzodiazepine class of drugs may be helpful, but benefits are usually modest and side effects of sedation and weakness can be problematic.[28]

In some cases, the akathisia effects of metoclopramide are directly related to the infusion rate when the drug is administered intravenously. Side effects were usually seen in the first 15 min after the dose of metoclopramide.[29]

Rare side effects

Diabetes, age, and female gender are risk factors that increase the likelihood of experiencing a neuropsychiatric side effect of metoclopramide.[30]

Pharmacology

Pharmacodynamics

Metoclopramide appears to bind to dopamine D2 receptors with nanomolar affinity (Ki = 28.8 nM),[32] where it is a receptor antagonist, and is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist.[30]

Mechanism of action

The antiemetic action of metoclopramide is due to its antagonist activity at D2 receptors in the chemoreceptor trigger zone in the central nervous system — this action prevents nausea and vomiting triggered by most stimuli.[33] At higher doses, 5-HT3 antagonist activity may also contribute to the antiemetic effect.[34]

The gastroprokinetic activity of metoclopramide is mediated by muscarinic activity, D2 receptor antagonist activity, and 5-HT4 receptor agonist activity.[35][36] The gastroprokinetic effect itself may also contribute to the antiemetic effect. Metoclopramide also increases the tone of the lower esophageal sphincter.[37]

Metoclopramide might influence on mood because of its blockade action on 5-HT4 and 5-HT3.[30]

Chemistry

Metoclopramide is a substituted benzamide; cisapride and mosapride are structurally related.[34]

History

Metoclopramide was first described by Louis Justin-Besançon and Charles Laville in 1964, while working to improve the anti-dysrhythmic properties of procainamide.[38][39][40][41] That research project also produced the product sulpiride.[38] The first clinical trials were published by Tourneu et al. in 1964 and by Boisson and Albot in 1966.[41] Justin-Besançon and Laville worked for Laboratoires Delagrange[38] and that company introduced the drug as Primperan in 1964.[42][43] Laboratoires Delagrange was acquired by Synthelabo in 1991[44][45] which eventually became part of Sanofi.[46]

A.H. Robins introduced the drug in the US under the brand name Reglan in 1979[47] as an injectable[48] and an oral form was approved in 1980.[49] in 1989 A.H. Robins was acquired by American Home Products,[50] which changed its name to Wyeth in 2002.[51]

The drugs were initially used to control nausea for people with severe headaches or migraines, and later uses for nausea caused by radiation therapy and chemotherapy, and later yet for treating nausea caused by anesthesia.[41] In the US the injectable form was labelled for chemotherapy-induced nausea and the oral form was eventually labelled for gastroesophageal reflux disease.[52]

It became widely used in the 1980s, becoming the most commonly used drug to treat anesthesia-induced nausea[41] and for treating gastritis in emergency rooms.[53]

The first generics were introduced in 1985.[52][54]

In the early 1980s signs began to emerge in pharmacovigilance studies from Sweden that the drug was causing tardive dyskinesia in some patients.[55] The FDA required a warning about tardive dyskinesia to be added to the drug label in 1985 stating that: "tardive dyskinesia . . . may develop in patients treated with metoclopramide,” and warned against use longer than 12 weeks, as that was how long the drug has been tested.[56][57] In 2009 the FDA required that a black box warning be added to the label.[17][27]

The emergence of this severe side effect led to a wave of product liability litigation against generic manufacturers as well as Wyeth.[58] The litigation was complicated since there was a lack of clarity in jurisdiction between state laws, where product liability is determined, and federal law, which determines how drugs are labelled, as well as between generics companies, which had no control over labelling, and the originator company, which did.[58][59] The litigation yielded at least two important cases. In Conte v. Wyeth in the California state courts, the claims of the plaintiff against the generic companies Pliva, Teva, and Purepac that had sold the drugs that the plaintiff actually took, and the claims against Wyeth, whose product the plaintiff never took, were all dismissed by the trial court, but the case was appealed, and in 2008 the appellate court upheld the dismissal of the cases against the generic companies, but reversed on Wyeth, allowing the case against Wyeth to proceed.[58][59][60] This established an "innovator liability" or "pioneer liability" for pharmaceutical companies.[58] The precedent was not widely followed in California nor in other states.[59] Litigation over the same issues related to metoclopramide also reached the US Supreme Court in PLIVA, Inc. v. Mensing,[61] in which the court held in 2011 that generic companies cannot be held liable for information, or the lack of information, on the originator's label.[57][59][62] As of August 2015 there were about 5000 suits pending across the US and efforts to consolidate them into a class action had failed.

Shortly following the Pliva decision, the FDA proposed a rule change that would allow generics manufacturers to update the label if the originating drug had been withdrawn from the market for reasons other than safety.[63] As of May 2016 the rule, which turned out to be controversial since it would open generic companies to product liability suits, was still not finalized, and the FDA had stated the final rule would be issued in April 2017.[64] The FDA issued a draft guidance for generic companies to update labels in July 2016.[65]

Society and culture

Brand names
List of brand names for metoclopramide[1][66]
AAdco-Contromet, Aeroflat (metoclopramide and dimeticone), Afipran, Anaflat Compuesto (metoclopramide and simeticone; pancreatin), Anagraine (metoclopramide and paracetamol),[67] Anausin Métoclopramide, Anolexinon, Antiementin, Antigram (Metoclopramide and Acetylsalicylic Acid), Aswell
BBalon, Betaclopramide, Bio-Metaclopramide, Bitecain AA
CCarnotprim, Carnotprim, Cephalgan (metoclopramide and carbasalate calcium), Cerucal, Chiaowelgen, Chitou, Clifar (Metoclopramide and Simeticone), Clodaset (metoclopramide and ondansetron), Clodoxin (metoclopramide and pyridoxine), Clomitene, Clopamon, Clopan, Cloperan, Cloprame, Clopramel, Clozil
DDamaben, Degan, Delipramil, Di-Aero OM (metoclopramide and simeticone), Dibertil, Digenor (Metoclopramide and Dimeticone), Digespar (Metoclopramide and Simeticone), Digestivo S. Pellegrino, Dikinex Repe (Metoclopramide and Pancreatin), Dirpasid, Doperan, Dringen
EEgityl (metoclopramide and acetylsalicylic Acid), Elieten, Eline, Elitan, Emenil, Emeprid (veterinary use), Emeran, Emetal, Emoject, Emperal, Enakur, Enteran, Enzimar, Espaven M.D. (Metoclopramide and Dimethicone), Ethiferan, Eucil
FFactorine (Metoclopramide and Simeticone)
GGastro-Timelets, Gastrocalm, Gastronerton, Gastrosil, Geneprami
HH-Peran, Hawkperan, Hemibe, Horompelin
IImperan, Isaprandil, Itan
J
KK.B. Meta, Klometol, Klopra
LLexapram, Linperan, Linwels
MMalon, Manosil, Maril, Matolon, Maxeran, Maxolon, Maxolone, Meclam, Meclid, Meclomid, Meclopstad, Meniperan, Mepram, Met-Sil, Metajex, Metalon, Metamide, Metilprednisolona Richet, Metoceolat, Metoclor, Metoco, Metocol, Metocontin, Metomide (veterinary use), Metonia, Metopar (Metoclopramide and Paracetamol), Metopar (Metoclopramide and Paracetamol), Metopelan, Metoperan, Metoperon, Metopran, Metotag, Metozolv, Metpamid, Metsil, Mevaperan, Midatenk, Migaura (Metoclopramide and Paracetamol), Migpriv (Metoclopramide and Acetylsalicylic Acid), Migracid (Metoclopramide and Paracetamol), Migraeflux MCP (Metoclopramide and Paracetamol), Migrafin (Metoclopramide and Aspirin), Migralave + MCP (Metoclopramide and Paracetamol), MigraMax (Metoclopramide and Acetylsalicylic Acid), Migräne-Neuridal (Metoclopramide and Paracetamol), Migränerton (Metoclopramide and Paracetamol), Motilon
NN-Metoclopramid, Nastifran, Nausil, Nevomitan, Nilatika, Novomit
OOpram
PPacimol-M (Metoclopramide and Paracetamol), Pangastren (Metoclopramide and Simeticone), Paramax (Metoclopramide and Paracetamol), Paspertin, Peraprin, Perinorm, Perinorm-MPS (Metoclopramide and Dimeticone), Perone, Piralen, Plamide, Plamine, Plasil, PMS-Metoclopramide, Podokedon, Polun, Poriran, Pradis, Pramidin, Pramidyl, Pramin, Praux, Premig (Metoclopramide and Acetylsalicylic Acid), Premosan, Prenderon, Prevomic, Primadol (Metoclopramide and Paracetamol), Primavera-N, Premier, Primlan, Primperan, Primperil, Primperoxane (Metoclopramide and Dimeticone), Primram, Primran, Primsel, Pripram, Prokinyl, Promeran, Prometin, Prowel, Pulin, Pulinpelin, Pulperan, Pusuan, Putelome, Pylomid
Q
RR-J, Raclonid, Randum, Reglan, Reglomar, Reliveran, Remetin, Riamide, Rilaquin, Rowelcon
SSabax Metoclopramide, Sinprim, Sinthato, Soho, Indonesia, Sotatic, Stomallin, Suweilan
TTalex (Metoclopramide and Pancreatin), Tivomit, Tomit, Torowilon
U
VVertivom, Vilapon, Vitamet, Vomend (veterinary use), Vomesea, Vomiles, Vomipram, Vomitrol, Vosea
WWei Lian, Winperan
X
Y
ZZudaw

Veterinary use

Metoclopramide is commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits.[68]

References
  1. "International names for metoclopramide". Drugs.com. Retrieved 28 March 2016.
  2. "Metoclopramide Use During Pregnancy". Drugs.com. 27 February 2020. Retrieved 22 November 2020.
  3. "Reglan- metoclopramide hydrochloride tablet". DailyMed. 19 June 2020. Retrieved 22 November 2020.
  4. "Metoclopramide". MedlinePlus. Retrieved 22 November 2020.
  5. "Metoclopramide hydrochloride". Monograph. The American Society of Health-System Pharmacists. Retrieved 27 September 2014.
  6. Becker WJ (June 2015). "Acute Migraine Treatment in Adults". Headache. 55 (6): 778–793. doi:10.1111/head.12550. PMID 25877672. S2CID 23327034.
  7. "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Retrieved 22 April 2014.
  8. Bartholow M. "Top 200 Drugs of 2012". Pharmacy Times. Archived from the original on 17 May 2014. Retrieved 22 April 2014.
  9. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  10. "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
  11. "Metoclopramide Hydrochloride - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 11 April 2020.
  12. "Maxolon (Australian Approved Product Information)". Valeant Pharmaceuticals. 2000. Archived from the original on 7 November 2011.
  13. Rossi S., ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 978-0-9757919-2-9.
  14. "Metoclopramide Hydrochloride 5mg/5ml Oral Solution - - (eMC)". xpil.medicines.org.uk. Archived from the original on 3 March 2016. Retrieved 22 July 2013.
  15. "Ambulance Victoria Clinical Guideline A0701""Oxygen Therapy" (PDF). Ambulance Victoria. 2013. Archived from the original (PDF) on 12 March 2015. Retrieved 5 December 2014.
  16. Derry S, Moore RA (April 2013). "Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults". The Cochrane Database of Systematic Reviews (4): CD008040. doi:10.1002/14651858.CD008040.pub3. PMC 4161111. PMID 23633349.
  17. Rao AS, Camilleri M (January 2010). "Review article: metoclopramide and tardive dyskinesia". Alimentary Pharmacology & Therapeutics. 31 (1): 11–19. doi:10.1111/j.1365-2036.2009.04189.x. PMID 19886950. S2CID 22847205.
  18. Bazzano AN, Hofer R, Thibeau S, Gillispie V, Jacobs M, Theall KP (2016). "A Review of Herbal and Pharmaceutical Galactagogues for Breast-Feeding". The Ochsner Journal. 16 (4): 511–524. PMC 5158159. PMID 27999511.
  19. Forinash AB, Yancey AM, Barnes KN, Myles TD (October 2012). "The use of galactogogues in the breastfeeding mother". The Annals of Pharmacotherapy. 46 (10): 1392–1404. doi:10.1345/aph.1R167. PMID 23012383. S2CID 207264697.
  20. Watson N, Jones H (2018). Chapman and Nakielny's Guide to Radiological Procedures. Elsevier. pp. 48, 55, 87. ISBN 9780702071669.
  21. "Metoclopramide-containing medicines". European Medicines Agency.
  22. "Metoclopramide only containing medicinal products" (PDF). EMA/753989/2013 Assessment report. European Medicines Agency. 20 December 2013.
  23. Briggs GG, Freeman RK, Yaffe SJ (2008). Drugs in Pregnancy and Lactation (8th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 1197–1200. ISBN 978-0-7817-7876-3. Retrieved 11 June 2009.
  24. Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Levy A (June 2009). "The safety of metoclopramide use in the first trimester of pregnancy". The New England Journal of Medicine. 360 (24): 2528–2535. doi:10.1056/NEJMoa0807154. PMID 19516033.
  25. Pasternak B, Svanström H, Mølgaard-Nielsen D, Melbye M, Hviid A (October 2013). "Metoclopramide in pregnancy and risk of major congenital malformations and fetal death". JAMA. 310 (15): 1601–1611. doi:10.1001/jama.2013.278343. PMID 24129464.
  26. Hibbs AM, Lorch SA (August 2006). "Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic review". Pediatrics. 118 (2): 746–752. doi:10.1542/peds.2005-2664. PMID 16882832. S2CID 21568481.
  27. "FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs" (Press release). U.S. Food and Drug Administration. 26 February 2009. Retrieved 11 June 2009. "Lay Summary – WebMD".
  28. Olanow C, Schapira AV (2012). "Chapter 372. Parkinson's Disease and Other Movement Disorders.". In Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J (eds.). Harrison's Principles of Internal Medicine (18th ed.). New York, NY: McGraw-Hill.
  29. Dobbs MR (2009). Clinical Neurotoxicology E-Book: Syndromes, Substances, Environments. Elsevier Health Sciences. p. 393. ISBN 978-0-323-07099-7.
  30. Surawski RJ, Quinn DK (2011). "Metoclopramide and homicidal ideation: a case report and literature review". Psychosomatics. 52 (5): 403–409. doi:10.1016/j.psym.2011.02.001. PMID 21907057.
  31. Isola S, Adams N (2020). "Metoclopramide". Statpearls. PMID 30137802.
  32. Matsui A, Matsuo H, Takanaga H, Sasaki S, Maeda M, Sawada Y (November 1998). "Prediction of catalepsies induced by amiodarone, aprindine and procaine: similarity in conformation of diethylaminoethyl side chain" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 287 (2): 725–732. PMID 9808703. Retrieved 21 January 2018.
  33. Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4.
  34. Fischer J, Gere A (2006). "Timing of Analog Research in Medicinal Chemistry. Chapter 6". In Chorghade MS (ed.). Drug Discovery and Development. Drug Discovery. Vol. 1. John Wiley & Sons. pp. 203–205. ISBN 9780471780090.
  35. Sweetman S., ed. (2004). Martindale: The Complete Drug Reference (34th ed.). London: Pharmaceutical Press. ISBN 978-0-85369-550-9.
  36. Tonini M, Candura SM, Messori E, Rizzi CA (May 1995). "Therapeutic potential of drugs with mixed 5-HT4 agonist/5-HT3 antagonist action in the control of emesis". Pharmacological Research. 31 (5): 257–260. doi:10.1016/1043-6618(95)80029-8. PMID 7479521.
  37. Feldman M, Friedman LS, Brandt LJ, eds. (2010). "Ch. 43: Gastroesophageal Reflux Disease". Sleisenger and Fordtran's Gastrointestinal and Liver Disease (9th ed.). Philadelphia: Saunders. ISBN 978-1-4160-6189-2.
  38. Sneader W (31 October 2005). Drug Discovery: A History. John Wiley & Sons. pp. 205–. ISBN 978-0-470-01552-0.
  39. Sanger GJ (December 2009). "Translating 5-HT receptor pharmacology". Neurogastroenterology and Motility. 21 (12): 1235–1238. doi:10.1111/j.1365-2982.2009.01425.x. PMID 19906028. S2CID 35544028.
  40. Justin-Besancon L, Laville C (1964). "[Antiemetic Action of Metoclopramide with Respect to Apomorphine and Hydergine]". Comptes Rendus des Séances de la Société de Biologie et de ses Filiales (in French). 158: 723–727. PMID 14186927.
  41. Henzi I, Tramèr MR (2003). "Metoclopramide for the Control of Postoperative Nausea and Vomiting". In Donnerer J (ed.). Antiemetic Therapy. pp. 161–168. doi:10.1159/000071415. ISBN 3-8055-7547-5.
  42. Landry Y (2011). Petite histoire des médicaments: De l'Antiquité à nos jours. Dunod. p. 182. ISBN 9782100571307.
  43. Lefebvre T, Raynal C (2007). "La mystérieuse bonbonne des Laboratoires Delagrange [Q265, Usage des bonbonnes]". Revue d'Histoire de la Pharmacie. 94 (353): 160–162.
  44. Conard D (17 October 1991). "Synthélabo rachète les laboratoires Delagrange". Lesechos.fr. Les Echos.
  45. "Laboratoires Delagrange (1932) - Organisation - Resources from the BnF". Data.bnf.fr. Retrieved 21 January 2018.
  46. Meek T (24 May 2013). "A look back at Sanofi's merger with Synthélabo". PMLiVE. Pmlive.com.
  47. "Metoclopramide hydrochloride". Pharmaceutical Manufacturing Encyclopedia. Vol. 1–4 (3rd ed.). Elsevier. 2013. pp. 179m. ISBN 9780815518563.
  48. "New Drug Application (NDA): 017862 - Approval history - Hikma Metoclopramide Hydrochloride". U.S. Food and Drug Administration.
  49. "New Drug Application (NDA): 017854: Approval history - Ani Pharms Metoclopramide Hydrochloride". U.S. Food and Drug Administration.
  50. "Virginia Historical Society A Guide to the A. H. Robins Company Records, 1885–2004". Vahistorical.org. Archived from the original on 1 December 2017. Retrieved 21 January 2018.
  51. Petersen M (11 March 2002). "American Home Is Changing Name to Wyeth". The New York Times.
  52. Staff (29 September 1986). "FDA's Oral Verapamil ANDA Approvals on Eve of Exclusivity Expiration Pit Five Generic Products V. Calan, Isoptin; Inderal, Reglan Indications No Longer Exclusive". The Pink Sheet. Archived from the original on 10 May 2017.
  53. "All About Metoclopramide (Reglan)". Emergency Physicians Monthly. EPMonthly.com. 15 August 2014. Retrieved 21 January 2018.
  54. "TEVA Metoclopramide Hydrochloride". Abbreviated New Drug Application (ANDA): 070184. U.S. Food and Drug Administration.
  55. Wiholm BE, Mortimer O, Boethius G, Häggström JE (February 1984). "Tardive dyskinesia associated with metoclopramide". British Medical Journal. 288 (6416): 545–547. doi:10.1136/bmj.288.6416.545. PMC 1444584. PMID 6421373.
  56. Stoddart A (2012). "Missing After Mensing: A Remedy for Generic Drug Consumers". Boston College Law Review. 53: 1967–2001.
  57. Casey S (24 October 2012). "Generic Pharmaceutical Liability: Challenges And Changes". Law360.com
  58. Noah L (Spring–Summer 2010). "Adding Insult to Injury: Paying For Harms Caused by a Competitor's Copycat Product" (PDF). Tort Trial & Insurance Practice Law Journal. 45 (3–4): 673–695. JSTOR 41059447.
  59. Rothschild E (16 March 2016). "Calif. Asks Innovator Drug Brands To Do The Impossible". Pepper Hamilton LLP's Insight Center. Archived from the original on 5 August 2016.
  60. Conte v. Wyeth, Inc., A116707, A117353 (Court of Appeal, First District, Division 3, California.).
  61. PLIVA, Inc. v. Mensing (U.S. Supreme Court 23 June 2011).Text
  62. Liptak A (23 June 2011). "Drug Makers Win Two Supreme Court Decisions". The New York Times.
  63. Rossen J, Patel A. "FDA moves to make generic drugmakers more accountable". Today.com. Retrieved 21 January 2018.
  64. Silverman E (19 May 2016). "FDA delays rule to allow generic drug makers to change labels". Pharmalot. Statnews.com. Retrieved 21 January 2018.
  65. Brennan Z (8 July 2016). "Generic Drug Labels: FDA Offers Draft Guidance on Updates After Reference Products are Withdrawn". Regulatory Focus.
  66. Hamilton RJ (2010). Tarascon Pharmacopoeia 2010 Library Edition. Jones & Bartlett Learning. p. 170. ISBN 9780763777685.
  67. "Anagraine - Drugs.com". Drugs.com. Retrieved 10 May 2020.
  68. Mikota SK, Plumb DC (June 2003). "Metoclopramide HCl". The Elephant Formulary. Elephant Care International. Archived from the original on 29 December 2003.
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