Pantoprazole

Pantoprazole
Names
Trade namesProtonix, others[1]
IUPAC name
  • (RS)-6-(Difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzo[d]imidazole
Clinical data
Drug classProton pump inhibitor (PPI)[2]
Main usesStomach ulcers, erosive esophagitis, gastroesophageal reflux disease (GERD), Zollinger–Ellison syndrome[2]
Side effectsHeadaches, diarrhea, vomiting, abdominal pain, joint pain[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3[3]
  • US: N (Not classified yet)[3]
    Routes of
    use    		By mouth and intravenous
    Defined daily dose40 mg[4]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa601246
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only) / S2
    • UK: POM (Prescription only) [5]
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability77%
    MetabolismLiver (CYP2C19)
    Elimination half-life1-2 hours
    ExcretionUrine, Feces
    Chemical and physical data
    FormulaC16H15F2N3O4S
    Molar mass383.37 g·mol−1
    3D model (JSmol)
    ChiralityRacemic
    SMILES
    • FC(F)Oc1ccc2[nH]c(nc2c1)S(=O)Cc3nccc(OC)c3OC
    InChI
    • InChI=1S/C16H15F2N3O4S/c1-23-13-5-6-19-12(14(13)24-2)8-26(22)16-20-10-4-3-9(25-15(17)18)7-11(10)21-16/h3-7,15H,8H2,1-2H3,(H,20,21) checkY
    • Key:IQPSEEYGBUAQFF-UHFFFAOYSA-N checkY

    Pantoprazole, sold under the brand name Protonix among others, is a medication used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger–Ellison syndrome.[2] It may also be used along with other medications to eliminate Helicobacter pylori.[6] Effectiveness is similar to other proton pump inhibitors (PPIs).[7] It is available by mouth and by injection into a vein.[2]

    Common side effects include headaches, diarrhea, vomiting, abdominal pain, and joint pain.[2] More serious side effects may include severe allergic reactions, a type of chronic inflammation known as atrophic gastritis, Clostridium difficile colitis, low magnesium, and vitamin B12 deficiency.[2] Use in pregnancy appears to be safe.[2] Pantoprazole is a proton pump inhibitor that decreases gastric acid secretion.[2] It works by inactivating (H+/K+)-ATPase function in the stomach.[8][2]

    Study of pantoprazole began in 1985, and it came into medical use in Germany in 1994.[9] It is available as a generic medication.[2] As of 2018, the wholesale cost of the pills in the United States is less than US$0.10 per dose.[10] In the United Kingdom, this amount costs less than 0.05 pounds, while the intravenous formulation costs about five pounds per dose.[6] In 2017, it was the 19th most commonly prescribed medication in the United States, with more than 27 million prescriptions.[11][12]

    Medical uses

    Pantoprazole is used for short-term treatment of erosion and ulceration of the esophagus for adults and children five years of age and older caused by gastroesophageal reflux disease.[13] It can be used as a maintenance therapy for long-term use after initial response is obtained, but there have not been any controlled studies about the use of pantoprazole past a duration of 12 months.[13] Pantoprazole may also be used in combination with antibiotics to treat ulcers caused by Helicobacter pylori.[14] It can also be used for long-term treatment of Zollinger-Ellison syndrome.[13] It may be used to prevent gastric ulcers in those taking NSAIDs.[6]

    Pantoprazole is only indicated for the short-term treatment of erosive esophagitis in children ages seven and older; and the safety and effectiveness of pantoprazole have only been established in the treatment of erosive esophagitis in children.[13]

    Dosage

    In upper gastrointestinal bleeding 80 mg intravenous followed by 8 mg/hr for 72 hours maybe used.[15]

    The defined daily dose is 40 mg by mouth or by injection.[4] Higher doses may be used (40 to 80 mg two to three times per day) for Zollinger Ellison syndrome.[2]

    Treatment for GERD is generally 7 to 10 days, while that for esophagitis is typically 8 to 16 weeks, and Zollinger Ellison syndrome may be for years.[2]

    • Wyeth pantoprazole 20-mg
      Wyeth pantoprazole 20-mg
    • Vial of pantoprazole for intravenous use
      Vial of pantoprazole for intravenous use

    Side effects

    Infection: Stomach acid plays a role in killing ingested bacteria. Use of pantoprazole may increase the chance of developing infections such as pneumonia, particularly in hospitalized patients.[16]

    The incidence of side effects occurring in people aged 65 years and older was similar to that in people aged 65 years and less.[13]

    Common

    • Gastrointestinal: abdominal pain (6%), diarrhea (9%), flatulence (4%), nausea (7%), vomiting (4%)[13]
    • Neurologic: headache (12%), dizziness (3%)[13]
    • Neuromuscular and skeletal: arthralgia (3%)[13]

    Rare

    Long-term use

    • Osteoporosis and bone fracture have been observed in people on high-dose and/or long-term (over one year) prescription proton pump inhibitors.[19]
    • Hypomagnesia has been observed in people on medications like pantoprazole when taken for longer periods of time (generally one year or more, although cases have been reported with regimens as short as three months).[20]

    Discontinuation

    In people taking PPIs for longer than six months, a dose taper should be considered prior to discontinuation. For those on a moderate- to high-dose this can be done by 50 percent every week until on the lowest dose. After a week it can then be stopped.[21]

    Pregnancy and breastfeeding

    In reproductive studies using doses largely greater than the recommended doses performed on rats and rabbits, there was no evident harm on the development of the baby.[13][3]

    Pantoprazole has been found to pass through the breast milk. However, in rodent cancer studies, pantoprazole has been shown to potentially cause tumor growth. The clinical relevance of the finding is unknown, but risks and benefits are recommended for consideration in determining the use of therapy for the mother and child.[13][3]

    Interactions

    Acidity: Due to its effect of reducing stomach acidity, use of pantoprazole can affect absorption of drugs that are pH-sensitive such as ampicillin esters, ketoconazole, atazanavir, iron salts, amphetamine and mycophenolate mofetil.[13]

    Pharmacology

    The mechanism of action of pantoprazole is to inhibit the final step in gastric acid production.[13] In the gastric parietal cell of the stomach, pantoprazole covalently binds to the H+/K+ ATP pump to inhibit gastric acid and basal acid secretion.[13] The covalent binding prevents acid secretion for up to 24 hours and longer.[13]

    Pantoprazole is metabolized in the liver by the cytochrome P450 system.[22] Metabolism mainly consists of demethylation by CYP2C19 followed by sulfation. Another metabolic pathway is oxidation by CYP3A4. Pantoprazole metabolites are not thought to have any pharmacological significance. It is usually given with a prokinetic drug because of inactivity in the acidic environment of the stomach. Pantoprazole binds irreversibly to H+K+ATPase (proton pumps) to suppress the secretion of acid. Due to irreversible binding of the pumps, new pumps have to be made before acid production can be resumed.[8] The drug's plasma half-life is about two hours.[23]

    History

    Pantoprazole was discovered by scientists at Byk Gulden, a subsidiary of Altana; the drug discovery program started in 1980 and which produced pantoprazole in 1985 - the compound was actually created by chemists working on scaleup of a different chemical that had been chosen as a development candidate.[24]: 117, 129  Byk Gulden partnered with Smith Kline & French in 1984.[24]: 124  The compound's development names were BY1029 and SK&F96022.[24]: 123  By 1986 the companies had created the sodium salt, pantoprazole sodium sesquihydrate, and decided to develop it as it was more soluble and stable, and was more compatible with other ingredients used in the formulation.[24]: 130  It was first marketed in Germany in 1994.[24]: 130  Wyeth licensed the US patent from Altana,[25] and obtained marketing approval from the US FDA in 2000 under the trade name Protonix.[26][27]

    In 2004, worldwide sales of the drug were $3.65 billion, about half of which were in the US.[25]

    In 2007, Altana's drug business was acquired by Nycomed.[28] Nycomed was in turn acquired by Takeda in 2011[29] and Wyeth was acquired by Pfizer in 2009.[30]

    The patent protecting the drug was set to expire in 2010, but Teva Pharmaceuticals filed an Abbreviated New Drug Application (ANDA) in 2007, and Wyeth and Nycomed sued Teva for patent infringement, but Teva decided to launch its generic drug "at risk" that year, before the patent had been invalidated.[31][32] Wyeth launched an authorized generic in 2008.[28] Pfizer and Takeda's patent exclusivity expired in 2010, and an administrative exclusivity they had for pediatric use expired in January 2011, and full generic competition began.[33] The litigation between Teva and Pfizer/Takeda was settled in 2013, with Teva paying the patent holders $2.15 billion in damages for its early launch.[34]

    Society and culture

    As of 2017, the drug was marketed under many brands worldwide, including as a combination drug with domperidone, a combination with itopride, in combination with both clarithromycin and amoxicillin, in combination with levosulpiride, and in combination with naproxen.[1]

    List of brand names

    As of 2017, it was marketed under many brands worldwide, including: Acernix, Aciban, Acida, Acido-X, Acidrol, Acidwell, Acilib, Acilibre, Acillect, Acipan, Acrid, Alapanzol, Amphoter, Anagastra, Anesteloc, Antaxid, Antopral, Anulacid, Anxel, Apazol, Appryo, Aptizole, Apton, Armcid, Asoprazole, Aspan, Aurizol-P, Awamed, Azatol, Biotop V, Brandocare, Branzol, Buffet, Buscopan Reflusso, Caprol, Ciprazol, Citrel, Clessol, Comenazol, Conoran, Contix, Contracid, Contraflux, Contro-Cap, Controloc, Controloc, Cool Pan, Delpanto EC, Digene Total, Digespan, Dosanloc, Empaflun, Eracid, Erprazol, Esopan, Eupantol, Exopan, Extream, Extreme, F-Pan, Farmazol, Fenix, Fexmor, Fu Shi Tan, Fulpan, Fupan, Gastblok, Gastenz, Gastrazol-L, Gastriwin, Gastrolan, Gastroloc, Gastromax, Gastronorm, Gastroprozal, Gastrostad, Gastrowell, Gastrozol, Gerdamegh, Gerprazol, Gesoflux, Gondea, Gopan, Hansazol, Hasanloc, Helix, Iboprot, Inipant, Inipepsia, Inipomp, IPP, Ippracid, Ipraalox, Kaiji, Kairol, Letopra, Loxanto, Luoxu, Lupipan, Maalox, Mag, Manez, Marozel, Monpan, Nelgast, Nexpan, Noacid, Noacid, Nolpaza, Nolpaza, Normogastrol, Noxadif, Ntap, Nuosen, Nupenta, Oritop, Osipan, Ozepran, Ozpan, Ozzion, P-20, P-40, P-Bit, P-OD, P-PPI, P-Zole, Pacid, Paciddia, Palio, Palmy, Pamel, Pamtrazol, Pamyl, Pan, Panbloc, Pancleus, Pancrazio, Pandev, Pane, Panfast, Pangest, Panglen, Panlan, Panlisu, Panloc, Panloz, Panmeilu, Panocer, Panogastin, Panopaz, Panor, Panoral, Panore, Panpot, Panpra, Panprabene, Panprax, Panprazol, Panprazox, Panpro, Panproton, Panpure, Panrazol, Panrazole, Panrbe, Panref, Pansa, Pansec, Panso, Pantac, Pantacid, Pantact, Pantagi, Pantakind, Pantaltius, Pantap, Pantasur, Pantaz, Pantazol, Pantecta, Pantex, Pantexel, Pantezol, Panthec, Panthron, Pantid, Pantin, Pantip, Pantium, Panto, Panto-Denk, Panto-Gas, Pantobex, Pantoc, Pantocal, Pantocar, Pantocare, Pantocas, Pantocer, Pantocid, Pantocim, Pantocom, Pantocure, Pantodac, Pantodar, Pantofin, Pantofir, Pantogastrix, Pantogen, Pantogerolan, PantoJenson, Pantokem, Pantokool, Pantolax, Pantoline, Pantoloc, Pantolok, Pantolup, Pantomax, Pantomed, Pantometylentina, Pantomyl, Pantonis, Pantonix, Pantop, Pantopacid, Pantopan, Pantopaz, Pantopep, Pantopi, Pantopra-Q, Pantopraz, Pantoprazal, Pantoprazol, Pantoprazole, Pantoprazolo, Pantoprazolum, Pantoprem, Pantoprix, Pantoprol, Pantopump, Pantor, Pantorc, Pantoren, Pantorica, Pantosal, Pantosan, Pantosec, Pantosid, Pantostad, Pantotab, Pantotis, Pantover, Pantoz, Pantozim, Pantozol, Pantozole, Pantpas, Pantra, Pantrol, Pantroz, Pantul, Pantune, Pantus, Panveda, Panvell, Panz, Panzat, Panzel, Panzilan, Panzilan, Panzol, Panzole, Panzor, Parastamic, Paz, Peblo, Penkool, Penlip, Pentalink, Pentastar, Pentowin, Pentoz, Pentozed, Peploc, Peptac, Peptazol, Peptazole, Pepticaid, Pepticool, Peptix, Peptoloc, Pepzol, Perloc, Pipanzin, Pozola, Praize, Pranza, Praz-Up, Prazobloc, Prazocid, Prazolacid, Prazolan, Prazole, Prazolpan, Prazopant, Pregel, Prevacid, Previfect, Previfect, Progen, Prolex, Promtec, Propanz, Protech, Protinum, Protium, Protocent, Protocid, Protofix, Protoloc, Proton, Proton-P, Protonex, Protonil, Protonix, Protopan, PTA, Pulcet, Pumpisel, Ranloc, Razon, Rcpan, Redacib, Refluxine, Refluxopan, rifun, Ripane, Roxitrol, Sedipanto, Segregam, Seltraz, Sipar, Sodac, Somac, Sozol, Stamic, Stomafor, Stripole, Sumipral, Supacid, Super OM, Suppi, Supracam, Supracid, Surmera, Tai Mei Ni Ke, Tecta, Tonval, Topazol, Topra, Topraz, Topzole, Toraflux, Tropaz, Trupan, Ulceron, Ulcoreks, Ulcotenal, Ulprix, Ulsepan, Ulstop, Ultop, Ultoz, Unigastrozol, Vencid, Ventro-Pant, Vomizole, Wei Di, Wei Ke An, Wonon, Xotepic, Yoevid, Zamotil, Zaprol, Zencopan, Zgaton, Zimpax, Zipant, Zipantol, Zipantola, Ziprol, Zolan, Zolemer, Zolpan, Zolpanz, Zolpra, Zoltex, Zoltum, Zontop, Zoprax, Zovanta, Zurcal, and Zurcazol.[1]

    It was marketed as a combination drug with domperidone under the brand names Aciban-DSR, Acillect-DSR, Asoprazole-D, Buffet-DXR, Depam, Domelong P, Dycizol, Eracid-D, F-Pan DSR, Fulpan-D, Fulpan-DSR, Gerdom, Gi-Fri, Gopan-D, Gopan-DSR, GR8-OD, Kurepane-DSR, Latop-D, Monpan-D, Monpan-DSR, Nupenta-DSR, Odipan-DSR, Oritop-D, Oritop-DSR, P-Bit-D, P-Bit-DSR, P-Zole DSR, P-Zole-D, PAA-DSR, Palio-D, Pamtrazol-D, Pan-D, Pancrazio-DSR, Pandiff, Pandostal, Pandostal-OD, Panfast-DSR, Panopaz-D, Panor-D, Panpot-DSR, Pansa-D, Pantact-D, Pantin-D, Pantin-RD, Pantocar-D, Pantocom-D, Pantoflux, Pantojoy-DXR, Pantokool-D, Pantolex-DS, Pantopacid-D, Pantopacid-SR, Pantorica-D, Pantozol-D, Pantozol-DSR, Pantra-D, Pantune-D, Panveda-D, Panzo-D, Panzol Plus, Panzol-D, Paz-DN, Peblo-D, Peblo-DSR, Penkool-DSR, Penlip-D, Pentalink-D, Pentastar-D, Pentozed-D, Peptac D, Peptac DSR, Pepticool-DXR, Pintel-DSR, Pop-DSR, Praize-D, Praize-D Forte, Prazole Plus, Prazosan-DSR, Predom, Predom-OD, Prolex-DSR, Prolus-DSR, Protocent-DSR, Protopan-D, Protopan-H, Ripane-D, Ripane-DSR, Trazol-DSR, PTA-D, Ulcicap-PD, Ultop DSR, Ultoz-D, Wonon-D, Wonon-DSR, and Zovanta-D.[1]

    It was marketed in combination with itopride under the brand names Ganaton Total, Kurepan-IT, Nupenta-ITR, P-Bit-ISR, Pepnil-ITO, Prolus-ISR, and Protopan-I.[1]

    It was marketed in combination with clarithromycin and amoxicillin as Gastrocomb, Klacid Hp7, Panclamox, and ZacPac.[1]

    It was marketed in combination with levosulpiride as Panlife-LS and in combination with naproxen as Arthopan.[1]

    Cost

    As of 2018, the wholesale cost of the pills in the United States is less than US$0.10 per dose.[10] In the United Kingdom, this amount costs less than 0.05 pounds, while the intravenous formulation costs about five pounds per dose.[6] In 2017, it was the 19th most commonly prescribed medication in the United States, with more than 27 million prescriptions.[11][12]

    • Pantoprazole costs (US)
      Pantoprazole costs (US)
    • Pantoprazole prescriptions (US)
      Pantoprazole prescriptions (US)

    Other animals

    Pantoprazole has been demonstrated to increase the 3rd compartment pH in alpacas.[35] It has been shown to be generally safe to use in cattle, sheep and goats.[36]

    References

    1. 1 2 3 4 5 6 7 "Pantoprazole international brand names". Drugs.com. Archived from the original on 15 March 2017. Retrieved 15 March 2017.
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Pantoprazole Sodium Monograph for Professionals - Drugs.com". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 29 October 2018. Retrieved 28 October 2018.
    3. 1 2 3 4 "Pantoprazole Use During Pregnancy". Drugs.com. 26 June 2018. Archived from the original on 24 June 2019. Retrieved 20 February 2020.
    4. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 21 January 2021. Retrieved 9 September 2020.
    5. ↑ "Pantoprazole 20mg gastro-resistant tablets - Summary of Product Characteristics (SmPC)". (emc). 25 November 2019. Archived from the original on 20 February 2020. Retrieved 20 February 2020.
    6. 1 2 3 4 British national formulary : BNF 74 (74 ed.). British Medical Association. 2017. p. 79. ISBN 978-0857112989.
    7. ↑ "[99] Comparative effectiveness of proton pump inhibitors". Therapeutics Initiative. 28 June 2016. Archived from the original on 30 October 2020. Retrieved 14 July 2016.
    8. 1 2 Richardson P, Hawkey CJ, Stack WA (September 1998). "Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders". Drugs. 56 (3): 307–35. doi:10.2165/00003495-199856030-00002. PMID 9777309. S2CID 46962618.
    9. ↑ Fischer, János; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 130. ISBN 9783527607495. Archived from the original on 8 November 2020. Retrieved 30 June 2020.
    10. 1 2 "NADAC as of 2018-10-24". Centers for Medicare and Medicaid Services. Archived from the original on 24 June 2019. Retrieved 28 October 2018.
    11. 1 2 "The Top 300 of 2020". ClinCalc. Archived from the original on 12 February 2021. Retrieved 11 April 2020.
    12. 1 2 "Pantoprazole Sodium - Drug Usage Statistics". ClinCalc. 23 December 2019. Archived from the original on 28 February 2020. Retrieved 11 April 2020.
    13. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 "Protonix delayed-release- pantoprazole sodium tablet, delayed release Protonix delayed-release- pantoprazole sodium granule, delayed release". DailyMed. 2 May 2019. Archived from the original on 20 February 2020. Retrieved 20 February 2020.
    14. ↑ Dammann HG, Fölsch UR, Hahn EG, von Kleist DH, Klör HU, Kirchner T, et al. (March 2000). "Eradication of H. pylori with pantoprazole, clarithromycin, and metronidazole in duodenal ulcer patients: a head-to-head comparison between two regimens of different duration". Helicobacter. 5 (1): 41–51. doi:10.1046/j.1523-5378.2000.00006.x. PMID 10672051.
    15. ↑ van Rensburg, CJ; Cheer, S (2012). "Pantoprazole for the treatment of peptic ulcer bleeding and prevention of rebleeding". Clinical medicine insights. Gastroenterology. 5: 51–60. doi:10.4137/CGast.S9893. PMID 24833934.
    16. ↑ Herzig SJ, Doughty C, Lahoti S, Marchina S, Sanan N, Feng W, Kumar S (November 2014). "Acid-suppressive medication use in acute stroke and hospital-acquired pneumonia". Annals of Neurology. 76 (5): 712–8. doi:10.1002/ana.24262. PMC 4214881. PMID 25164323.
    17. ↑ Ricketson J, Kimel G, Spence J, Weir R (March 2009). "Acute allergic interstitial nephritis after use of pantoprazole". CMAJ. 180 (5): 535–8. doi:10.1503/cmaj.080456. PMC 2645468. PMID 19255077.
    18. ↑ [Dr. John Cooke, chair of Methodist Hospital's cardiovascular services] [Houston Chronicle Health Zone dated Thursday, July 11, 2013 chron.com/refluxmeds] (Journal: Circulation)
    19. ↑ Center for Drug Evaluation and Research. "Postmarket Drug Safety Information for Patients and Providers - FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors". U.S. Food and Drug Administration (FDA). Archived from the original on 20 January 2017. Retrieved 3 November 2015.
    20. ↑ Center for Drug Evaluation and Research. "Drug Safety and Availability - FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs)". U.S. Food and Drug Administration (FDA). Archived from the original on 12 May 2020. Retrieved 3 November 2015.
    21. ↑ Wolfe MM, Sachs G (February 2000). "Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome". Gastroenterology. 118 (2 Suppl 1): S9-31. doi:10.1016/s0016-5085(00)70004-7. PMID 10868896.
    22. ↑ Meyer UA (October 1996). "Metabolic interactions of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole with other drugs". European Journal of Gastroenterology & Hepatology. 8 Suppl 1 (Suppl 1): S21-5. doi:10.1097/00042737-199610001-00005. PMID 8930576.
    23. ↑ Sachs G, Shin JM, Hunt R (December 2010). "Novel approaches to inhibition of gastric acid secretion". Current Gastroenterology Reports. 12 (6): 437–47. doi:10.1007/s11894-010-0149-5. PMC 2974194. PMID 20924727.
    24. 1 2 3 4 5 Senn-Bilfinger, Jörg; Sturm, Ernst (2006). "6. The Development of a New Proton-Pump Inhibitor: The Case History of Pantoprazole". In Fischer, János; Ganellin, C. Robin (eds.). Analogue-based drug discovery. Weinheim: Wiley-VCH. pp. 115–136. ISBN 9783527608003.
    25. 1 2 Daly, Erin Marie (20 May 2008). "Wyeth, Nycomed Take Aim At Sandoz Over Protonix". Law360. Archived from the original on 16 March 2017. Retrieved 15 March 2017.
    26. ↑ Mathews S, Reid A, Tian C, Cai Q (2010). "An update on the use of pantoprazole as a treatment for gastroesophageal reflux disease". Clinical and Experimental Gastroenterology. 3: 11–6. doi:10.2147/ceg.s6355. PMC 3108659. PMID 21694841.
    27. ↑ "Drug Approval Package: Protonix (Pantoprazole Sodium) NDA 20987". U.S. Food and Drug Administration (FDA). 24 December 1999. Archived from the original on 20 February 2020. Retrieved 20 February 2020.
    28. 1 2 Goldstein, Jacob (30 January 2008). "Generic Protonix and Wyeth as Takeover Bait". WSJ. Archived from the original on 15 March 2017. Retrieved 4 August 2017.
    29. ↑ "Takeda to Buy Nycomed for $13.7 Billion". DealBook. 19 May 2011. Archived from the original on 6 September 2018. Retrieved 15 March 2017.
    30. ↑ Davis, Alexander (23 January 2009). "Pfizer in talks to acquire Wyeth in $60 billion deal: WSJ". MarketWatch. Archived from the original on 20 February 2020. Retrieved 11 August 2012.
    31. ↑ Saul, Stephanie (7 September 2007). "Wyeth Faces Generic Rival to a Heartburn Drug". The New York Times. Archived from the original on 15 March 2017. Retrieved 7 September 2017.
    32. ↑ Curtiss FR (April 2008). "Perspectives on the "generic cliff"--pushing and falling". Journal of Managed Care Pharmacy. 14 (3): 318–21. doi:10.18553/jmcp.2008.14.3.318. PMID 18439056.
    33. ↑ "Protonix - Big Patent Expirations of 2010". FiercePharma. Archived from the original on 15 March 2017. Retrieved 15 March 2017.
    34. ↑ Helfand, Carly (12 June 2013). "Teva loses $2B gamble on generic of Pfizer's Protonix". FiercePharma. Archived from the original on 15 March 2017. Retrieved 15 March 2017.
    35. ↑ Smith, G.W.; Davis, J.L.; Smith, S.M.; Gerard, M.P.; Campbell, N.B.; Foster, D.M. (July 2010). "Efficacy and Pharmacokinetics of Pantoprazole in Alpacas". Journal of Veterinary Internal Medicine. 24 (4): 949–955. doi:10.1111/j.1939-1676.2010.0508.x. PMID 20384953.
    36. ↑ Smith, Joseph S.; Kosusnik, Austin R.; Mochel, Jonathan P. (2020). "A Retrospective Clinical Investigation of the Safety and Adverse Effects of Pantoprazole in Hospitalized Ruminants". Frontiers in Veterinary Science. 7: 97. doi:10.3389/fvets.2020.00097. PMC 7089877. PMID 32258063.
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