Metoclopramide

Metoclopramide
Clinical data
Pronunciation /ˌmɛtəˈklɒprəmaɪd/
Trade names Primperan, Reglan, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a684035
License data
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
Routes of
administration		 By mouth, intravenous, intramuscular
ATC code A03FA01 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 80±15% (by mouth)
Metabolism Liver
Biological half-life 5 h to 6 h
Excretion 70–85% kidney, 2% faecal
Identifiers
CAS Number 364-62-5 YesY
PubChem (CID) 4168
IUPHAR/BPS 241
DrugBank DB01233 YesY
ChemSpider 4024 YesY
UNII L4YEB44I46 YesY
KEGG D00726 YesY
ChEBI CHEBI:107736 YesY
ChEMBL CHEMBL86 YesY
Chemical and physical data
Formula C14H22ClN3O2
Molar mass 299.80 g/mol
3D model (Jmol) Interactive image
Melting point 147.3 °C (297.1 °F)
  (verify)

Metoclopramide is a medication used mostly for stomach and esophageal problems.[2] It is commonly used to treat nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying due to either diabetes or following surgery, and to help with gastroesophageal reflux disease.[3] It is also used to treat migraine headaches.[4]

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.[3] It is thus rarely recommended that people take the medication for longer than twelve weeks.[3] It is pregnancy category B in the United States and category A in Australia, meaning no evidence of harm has been found after being taken by many pregnant women.[3][5] It belongs to the group of medications known as dopamine-receptor antagonists.[3]

In 2012, metoclopramide was one of the top 100 most prescribed medications in the United States.[6] It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[7] It is avaliable as a generic medication.[3] The wholesale cost in the developing world as of 2014 is 0.003 to 0.08 USD per pill.[8] In the United States a month worth of medication is generally less than 25 USD.[9]

Medical uses

Metoclopramide 5-mg tablets

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, migraine headaches, and emetogenic drugs.[3][10][11][12] In the setting of painful conditions such as migraine headaches, metoclopramide may be used in combination with paracetamol (acetaminophen) or in combination with aspirin. It is also used preventatively by some EMS providers when transporting people who are conscious and spinally immobilized.[13]

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.[3][14] Evidence also supports its use for gastroesophageal reflux disease.[3] It is also used in pregnancy as a second choice for treatment of hyperemesis gravidarum (severe nausea and vomiting of pregnancy).[3]

It increases peristalsis of the duodenum and jejunum, increases tone and amplitude of gastric contractions, and relaxes the pyloric sphincter and duodenal bulb, while simultaneously increasing lower esophageal sphincter tone. These gastroprokinetic effects make metoclopramide useful in the treatment of gastric stasis (for example: after gastric surgery or diabetic gastroparesis), as an aid in gastrointestinal radiographic studies by accelerating transit through the gastrointestinal system in barium studies, and as an aid in difficult intubation of the small intestine. It is also used in gastroesophageal reflux disease.[15]

Adverse 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, constipation, depression, headache, and extrapyramidal effects such as oculogyric crisis. Rare but serious ADRs associated with metoclopramide therapy include agranulocytosis, supraventricular tachycardia, hyperaldosteronism, neuroleptic malignant syndrome, akathisia and tardive dyskinesia.[11][16]

Metoclopramide may be the most common cause of drug-induced movement disorders.[17] The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy.[10][11] 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.[17] 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.[17]

Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with diphenhydramine injected intramuscularly.[18] 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.[19]

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.[20]

Cautions and 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.[11] It is contraindicated for people with a suspected bowel obstruction[3] and 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, in cases of pheochromocytoma, and in newborn babies.[12]

People with a history of ADHD, restless legs syndrome, hyperprolactinaemia, and Parkinson's disease should be closely monitored when using dopamine antagonists for treatment of emesis. People who take antipsychotics are recommended not to take metoclopramide.

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]

Pregnancy

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or unborn baby.[22] In the USA, it has been assigned to pregnancy category B by the US FDA.[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.[22]

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]

Mechanism of action

It appears to bind to dopamine D2 receptors with nanomolar affinity (Ki 28.8 nM),[27] where it is a receptor antagonist, and is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist.

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.[28] At higher doses, 5-HT3 antagonist activity may also contribute to the antiemetic effect.[29]

The gastroprokinetic activity of metoclopramide is mediated by muscarinic activity, D2 receptor antagonist activity and 5-HT4 receptor agonist activity.[30][31] The gastroprokinetic effect itself may also contribute to the antiemetic effect. Metoclopramide also increases the tone of the lower esophageal sphincter.[32]

Chemistry

Metoclopramide is a substituted benzamide; cisapride and mosapride are structurally related.[29]

History

Metoclopramide was first described by Justin-Besançon and C. Laville in 1964, while working to improve the anti-dysrhythmic properties of procainamide.[33][34][35][36] That research project also produced the product sulpiride.[33] The first clinical trials were published by Tourneu et al. in 1964 and by Boisson and Albot in 1966.[36] Justin-Besançon and Laville worked for Laboratoires Delagrange[33] and that company introduced the drug as Primperan in 1964.[37][38] Laboratoires Delagrange was acquired by Synthelabo in 1991[39][40] which eventually became part of Sanofi.[41]

A.H. Robins introduced the drug in the US under the tradename Reglan in 1979[42] as an injectable[43] and an oral form was approved in 1980.[44] in 1989 A.H. Robins was acquired by American Home Products,[45] which changed its name to Wyeth in 2002.[46]

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.[36] In the US the injectable form was labelled for chemotherapy-induced nausea and the oral form was eventually labelled for gastroesophageal reflux disease.[47]

It became widely used in 1980s, becoming the most commonly used drug to treat anesthesia-induced nausea[36] and for treating gastritis in emergency rooms.[48]

The first generics were introduced in 1985.[47][49]

In the early 1980s signs began to emerge in pharmacovigilance studies from Sweden that the drug was causing tardive dyskinesia in some patients.[50] 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.[51][52] In 2009 the FDA required that a black box warning be added to the label.[14][53]

The emergence of this severe side effect led to a wave of product liability litigation against generic manufacturers as well as Wyeth.[54] 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.[54][55] 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.[54][55][56] This established an "innovator liability" or "pioneer liability" for pharmaceutical companies.[54] The precedent was not widely followed in California nor in other states.[55] Litigation over the same issues related to metoclopramide also reached the US Supreme Court in PLIVA, Inc. v. Mensing,[57][58] 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.[52][55][59] As of August 2015 there were about 5000 suits pending across the US, efforts to consolidate them into a class action had failed, and "companies have paid millions in compensation to those suffering from tardive dyskinesia after taking Reglan/metoclopramide."[60]

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.[61] 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.[62] The FDA issued a draft guidance for generic companies to update labels in July 2016.[63]

Brand names

List of trade names for metoclopramide[1][64]
AAdco-Contromet, Aeroflat (Metoclopramide and Dimeticone), Afipran, Anaflat Compuesto (Metoclopramide and Simeticone; Pancreatin), 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 Dimeticone), 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), 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, Primier, 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 also commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits.[65]

References

  1. 1 2 Drugs.com International names for metoclopramide Page accessed March 28, 2016
  2. ↑ "Metoclopramide". nlm.nih.gov. Retrieved 28 September 2014.
  3. 1 2 3 4 5 6 7 8 9 10 11 "Metoclopramide hydrochloride". Monograph. The American Society of Health-System Pharmacists. Retrieved 2014-09-27.
  4. ↑ Derry, S; Moore, RA (30 April 2013). "Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults.". The Cochrane database of systematic reviews (4): CD008040. PMID 23633349.
  5. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Retrieved 22 April 2014.
  6. ↑ Bartholow, Michael. "Top 200 Drugs of 2012". Pharmacy Times. Retrieved 22 April 2014.
  7. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  8. ↑ "Metoclopramide HCL". International Drug Price Indicator Guide. Retrieved 23 August 2016.
  9. ↑ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 262. ISBN 9781284057560.
  10. 1 2 "Maxolon (Australian Approved Product Information)". Valeant Pharmaceuticals. 2000.
  11. 1 2 3 4 Rossi S., ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3.
  12. 1 2 http://xpil.medicines.org.uk/ViewPil.aspx?DocID=8068
  13. ↑ "Ambulance Victoria Clinical Guideline A0701"http://www.ambulance.vic.gov.au/media/docs/Adult%20CPG%20wm-a01f0e1e-4fc0-405c-bc83-3136adf4a723-0.pdf
  14. 1 2 Rao AS, Camilleri M. Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther. 2010 Jan;31(1):11-9. PMID 19886950 Free full text
  15. ↑ "METOCLOPRAMIDE (metoclopramide hydrochloride) injection, solution [Hospira, Inc.]" http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=373ba08b-33ad-49fc-28a7-928e89a65314#nlm34089-3
  16. ↑ FDA reglan tablets Label Page accessed August 24, 2016
  17. 1 2 3 "FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs" (Press release). U.S. Food and Drug Administration. 2009-02-26. Retrieved 2009-06-11. "Lay Summary – WebMD".
  18. ↑ "Metoclopramide (metoclopramide hydrochloride) injection, solution [Hospira, Inc.]" http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=373ba08b-33ad-49fc-28a7-928e89a65314#nlm34089-3
  19. ↑ Olanow C, Schapira AV. 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, 18e. New York, NY: McGraw-Hill; 2012.
  20. ↑ Parlak, I; Atilla, R; Cicek, M; Parlak, M; Erdur, B; Guryay, M; Sever, M; Karaduman, S (Sep 2005). "Rate of metoclopramide infusion affects the severity and incidence of akathisia.". Emergency medicine journal : EMJ. 22 (9): 621–4. doi:10.1136/emj.2004.014712. PMC 1726928Freely accessible. PMID 16113179.
  21. ↑ EMA. Summary Page and EMA/753989/2013 Assessment report. Metoclopramide only containing medicinal products December 20, 2013
  22. 1 2 Briggs, G. G.; Freeman, R. K.; Yaffe, S. J. (2008). Drugs in Pregnancy and Lactation (8th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 1197–1200. ISBN 0-7817-7876-X. Retrieved 2009-06-11.
  23. ↑ http://www.drugs.com/metoclopramide.html
  24. ↑ Matok, I.; Gorodischer, R.; Koren, G.; Sheiner, E.; Wiznitzer, A.; Levy, A. (2009). "The Safety of Metoclopramide Use in the First Trimester of Pregnancy" (pdf). New England Journal of Medicine. 360 (24): 2528–2535. doi:10.1056/NEJMoa0807154. PMID 19516033.
  25. ↑ Pasternak, B. R.; Svanström, H.; Mølgaard-Nielsen, D.; Melbye, M.; Hviid, A. (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 (Aug 2006). "Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic review.". Pediatrics. 118 (2): 746–52. doi:10.1542/peds.2005-2664. PMID 16882832.
  27. ↑ Prediction of Catalepsies Induced by Amiodarone, Aprindine and Procaine: Similarity in Conformation of Diethylaminoethyl Side Chain http://jpet.aspetjournals.org/content/287/2/725.full.pdf
  28. ↑ Rang, H. P.; Dale, M. M.; Ritter, J. M.; Moore, P. K. (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
  29. 1 2 Janos Fischer and Aniko Gere. Timing of Analog Research in Medicinal Chemistry. Chapter 6 in Drug Discovery and Development, Volume 1: Drug Discovery. Ed, Mukund S. Chorghade. John Wiley & Sons, 2006. ISBN 9780471780090 pp 203-205
  30. ↑ Sweetman S., ed. (2004). Martindale: The Complete Drug Reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4.
  31. ↑ Tonini, M.; Candura, S. M.; Messori, E.; Rizzi, C. A. (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. ISSN 1043-6618. PMID 7479521.
  32. ↑ Feldman, M.; Friedman, L. S.; Brandt, L. J., 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.
  33. 1 2 3 Walter Sneader (31 October 2005). Drug Discovery: A History. John Wiley & Sons. pp. 205–. ISBN 978-0-470-01552-0.
  34. ↑ Sanger GJ Translating 5-HT receptor pharmacology. Neurogastroenterol Motil. 2009 Dec;21(12):1235-8. PMID 19906028 Free full text
  35. ↑ 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.
  36. 1 2 3 4 Henzi I, Tramèr MR, Metoclopramide for the Control of Postoperative Nausea and Vomiting. pp 161-168 in Antiemetic Therapy. Donnerer J (ed). Karger, 2003. ISBN 9783805575478. doi:10.1159/000071415
  37. ↑ Yves Landry. Petite histoire des médicaments: De l'Antiquité à nos jours. Dunod, 2011 ISBN 9782100571307 p. 182
  38. ↑ Thierry Lefèbvresem and Cécile Raynalsem. (2007) La mystérieuse bonbonne des Laboratoires Delagrange Revue d'histoire de la pharmacie 94(353):160-162
  39. ↑ Denis Conard for Les Echos. Oct 17, 1991 Synthélabo rachète les laboratoires Delagrange
  40. ↑ Bibliothèque nationale de France Laboratoires Delagrange Page accessed Aug 24, 2016
  41. ↑ Tom Meek for PMLiVE May 24, 2013 A look back at Sanofi's merger with Synthélabo
  42. ↑ Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Volumes 1-4. Elsevier, 2013 ISBN 9780815518563 p. 179m
  43. ↑ FDA NDA no. 017862 - Approval history
  44. ↑ FDA NDA 017854 History of Approvals
  45. ↑ Staff, Virginia Historical Society. A.H. Robins Company Page accessed August 24, 2016
  46. ↑ Melody Petersen for the New York Times. March 11, 2002 American Home Is Changing Name to Wyeth
  47. 1 2 Staff, The Pink Sheet. Sep 29, 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
  48. ↑ Staff, Emergency Physician Monthly. All About Metoclopramide (Reglan) Page accessed August 24, 2016
  49. ↑ FDA ANDA 070184 - History
  50. ↑ Wiholm BE, Mortimer O, Boethius G, Häggström JE. Tardive dyskinesia associated with metoclopramide. Br Med J (Clin Res Ed). 1984 Feb 18;288(6416):545-7. PMID 6421373 Free full text
  51. ↑ Allison Stoddart, Missing After Mensing: A Remedy for Generic Drug Consumers, 53 B.C.L. Rev. 1967 (2012)
  52. 1 2 Steven Casey for Law360. October 24, 2012 Generic Pharmaceutical Liability: Challenges And Changes
  53. ↑ FDA Feb. 26, 2009 FDA Press Release: FDA Requires Boxed Warning and Risk Mitigation Strategy for Metoclopramide-Containing Drugs Agency warns against chronic use of these products to treat gastrointestinal disorders
  54. 1 2 3 4 Lars Noah Adding Insult to Injury: Paying For Harms Caused by a Competitor’s Copycat Product Tort Trial & Insurance Practice Law Journal, Spring/Summer 2010 (45:3-4)
  55. 1 2 3 4 Eric Rothschild for Pepper Hamilton LLP's Insight Center. March 16, 2016 Calif. Asks Innovator Drug Brands To Do The Impossible
  56. ↑ Conte v. Wyeth, Inc., 85 Cal. Rptr. 3d 299, 304–05 (Ct. App. 2008).
  57. ↑ Scotus Blog: PLIVA, Inc. v. Mensing
  58. ↑ Supreme Court of the United States 564 PLIVA, Inc. v. Mensing U. S. ____ (2011)
  59. ↑ Adam Liptak for the New York Times. June 23, 2011 Drug Makers Win Two Supreme Court Decisions
  60. ↑ DrugWatch. Reglan & Tardive Dyskinesia Last updated, August 21, 2015
  61. ↑ Staff, Today. Nov. 8, 2013 FDA moves to make generic drugmakers more accountable
  62. ↑ Ed Silverman for Pharmalot. May 19, 2016 FDA again delays rule to allow generic drug makers to change labels
  63. ↑ Zachary Brennan for Regulatory Focus. July 8, 2016 Generic Drug Labels: FDA Offers Draft Guidance on Updates After Reference Products are Withdrawn
  64. ↑ Hamilton, Richard J. (2010). Tarascon Pharmacopoeia 2010 Library Edition. Jones & Bartlett Learning. p. 170. ISBN 9780763777685.
  65. ↑ Mikota, S. K.; Plumb, D. C. (June 2003). "Metoclopramide HCl". The Elephant Formulary. Elephant Care International.
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