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FAMOTIDINE

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FAMOTIDINE

76824-35-6

3-(2-Guanidinothiazol-4-ylmethylthio)-N-sulfamoylpropanamidine

MK-208
YM-11170
YM-1170

Histamine H2 Receptor Antagonists

Gastroesophageal Reflux Disease,

Agents forGastric Antisecretory Drugs (GERD)

Astellas Pharma (Innovaator)Launched – 1985

Systematic (IUPAC) name
3-[({2-[(diaminomethylidene)amino]-1,3-thiazol-4-yl}methyl)sulfanyl]-N’-sulfamoylpropanimidamide
Clinical data
Trade names Pepcid
AHFS/Drugs.com monograph
MedlinePlus a687011
Licence data US FDA:link
Pregnancy cat.
Legal status
  • Pharmacist only S3/S4(AU), General Availability (OTC)(UK),
    Over the Counter(US)
Routes Oral (tablet form)
Pharmacokinetic data
Bioavailability 40-45% (Oral)[1]
Protein binding 15-20%[1]
Metabolism hepatic
Half-life 2.5-3.5 hours[1]
Excretion Renal (25-30% unchanged [Oral])[1]
Identifiers
CAS number 76824-35-6 Yes
ATC code A02BA03
PubChem CID 3325
DrugBank DB00927
ChemSpider 3208 Yes
UNII 5QZO15J2Z8 Yes
Chemical data
Formula C8H15N7O2S3 
Mol. mass 337.449 g/mol
3-[[[2-[(Aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-(aminosulfonyl)propanimidamide
Additional Names: [1-amino-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propylidene]sulfamide; N-sulfamoyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamide
Manufacturers’ Codes: YM-11170; MK-208
Trademarks: Amfamox (Merck & Co.); Fadul (Hexal); Famodil (Sigma-Tau); Famosan (ProMed); Famoxal (Silanes); Ganor (Boehringer, Ing.); Gaster (Yamanouchi); Gastridin (Merck & Co.); Gastropen (Schwarz); Lecedil (Zdravlje); Motiax (Neopharmed); Muclox (Sigma-Tau); Pepcid (Merck & Co.); Pepcidac (McNeil); Pepcidine (Merck & Co.); Pepdine (Merck & Co.); Pepdul (Merck & Co.); Peptan (Merck & Co.); Ulfamid (Krka)
Molecular Formula: C8H15N7O2S3
Molecular Weight: 337.45
Percent Composition: C 28.47%, H 4.48%, N 29.06%, O 9.48%, S 28.51%
Properties: mp 163-164°. Soly at 20° (%, w/v): 80 in DMF; 50 in acetic acid; 0.3 in methanol; 0.1 in water; <0.01 in ethanol, ethyl acetate, chloroform. LD50 i.v. in mice: 244.4 mg/kg (Yasufumi).
Melting point: mp 163-164°
Toxicity data: LD50 i.v. in mice: 244.4 mg/kg (Yasufumi)
Therap-Cat: Antiulcerative.

Famotidine is an H2-histamine antagonist that was first launched by Astellas Pharma (formerly Yamanouchi) in Japan in 1985 as an injectable for the treatment of upper gastrointestinal hemorrhage and for the treatment of Zollinger-Ellison syndrome. In 1986, the drug was launched pursuant to a collaboration between Merck Sharp & Dohme and Sigma-Tau for the oral prevention and treatment of gastroesophageal reflux disease (GERD).

Famotidine (INN) /fəˈmɒtɪdn/ is a histamine H2-receptor antagonist that inhibits stomach acid production, and it is commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD/GORD). It is commonly marketed byJohnson & Johnson/Merck under the trade names Pepcidine and Pepcid and by Astellas under the trade name Gaster. Unlikecimetidine, the first H2 antagonist, famotidine has no effect on the cytochrome P450 enzyme system, and does not appear to interact with other drugs.[2]

Medical use

Certain preparations of famotidine are available over the counter (OTC) in various countries. In the US 20 or more mg, sometimes in combination with a more traditional antacid, are available OTC. Larger doses still require a prescription.

Famotidine is given to surgery patients before operations to prevent postoperative nausea and to reduce the risk of aspiration pneumonitis. Famotidine is also given to some patients taking NSAIDs, to prevent peptic ulcers.[3] It serves as an alternative toproton-pump inhibitors.[4]

It is also given to dogs and cats with acid reflux.

Famotidine has also been used in combination with an H1 antagonist to treat and prevent urticaria caused by an acute allergic reaction.[5]

Side-effects

Side-effects are associated with famotidine use. In clinical trials, the most common adverse effects were headache, dizziness, andconstipation or diarrhea.[6]

History

Famotidine was developed by Yamanouchi Pharmaceutical Co.[7] It was licensed in the mid-80s by Merck & Co.[8] and is marketed by a joint venture between Merck and Johnson & Johnson. The imidazole-ring of cimetidine was replaced with a 2-guanidinothiazole ring. Famotidine proved to be 30 times more active than cimetidine.[citation needed]

It was first marketed in 1981. Pepcid RPD orally-disintegrating tablets were released in 1999. Generic preparations became available in 2001, e.g.Fluxid (Schwarz) or Quamatel (Gedeon Richter Ltd.).

In the United States and Canada, a product called Pepcid Complete, which combines famotidine with an antacid in a chewable tablet to quickly relieve the symptoms of excess stomach acid, is available. In the UK, this product is known as Pepcidtwo.

Famotidine suffers from poor bioavailability (50%), as it is poorly soluble in the low pH of the stomach. Famotidine used in combination with antacids promotes local delivery of these drugs to the receptor of the parietal cell wall. Therefore, researchers are developing innovative formulations of tablets, such as gastroretentive drug delivery systems. Such tablets are retained in the stomach for a longer period of time, thereby improving the bioavailability of drugs. Local delivery also increases bioavailability at the stomach wall receptor site and increases the efficacy of drugs to reduce acid secretion.[9]

Research

Famotidine has been investigated as an adjunct in treatment-resistant schizophrenia. In one trial it caused a 10% reduction in schizophrenic symptom severity in treatment-resistant patients.[10]

Famotidine is also indicated in the treatment of duodenal and benign gastric ulcers, for the prevention of relapse of duodenal ulceration, for the treatment of gastric mucosal lesions associated with acute gastritis and acute exacerbation of chronic gastritis, for the treatment of heartburn associated with acid indigestion and sour stomach, for the prevention of meal-induced heartburn, and for the treatment of reflux esophagitis due to GERD, including ulcerative disease as diagnosed by endoscopy. The drug is currently marketed in tablet, film-coated tablet, orally-disintegrating tablet, powder, lyophilized powder for injection solution and injectable formulations. The compound had been in development for the treatment of non-erosive reflux disease (NERD), however, Astellas Pharma discontinued development for this indication in 2007.

Famotidine was developed by replacing the imidazole ring of GlaxoSmithKline’s cimetidine with a 2-guanidinothiazole ring, a modification proven to increase the activity of the drug 30-fold. Famotidine competitively inhibits the action of histamine at the histamine H2 receptors of the parietal cells. It suppresses the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid by two mechanisms: by blocking histamine released by enterochromaffin-like (ECL) cells in the stomach from binding to H2 receptors and stimulating acid secretion, and by reducing the effect that other compounds (such as gastrin, pentagastrin, caffeine, insulin and acetylcholine) have on the promotion of acid secretion due to H2 receptor blockade.

Famotidine was originally developed at Astellas Pharma. It was subsequently licensed in the U.S. to Merck & Co., known outside the U.S. and Canada as Merck Sharp & Dohme. In 2007, Salix acquired the U.S. rights to famotidine oral solution (Pepcid[R]) for the treatment of GERD and peptic ulcer. Sigma-Tau holds rights to the drug and is responsible for marketing activities in Italy. Famotidine is sold in over 110 countries worldwide, including France, Germany, Italy, Japan, the U.S. and the U.K.

……………………………..

US 4283408

http://www.google.co.in/patents/US4283408

The reaction ot S-(2-aminothiazol-4-ylmethyl)isothiourea (I) with 3-chloropropionitrile (II) by means of NaOH in ethanol – water gives 3-(2-aminothiazol-4-ylmethylthio)propionitrile (III), which is condensed with benzoyl isothiocyanate (IV) in refluxing acetone to afford 3-[2-(3-benzoylthioureido)thiazol-4-ylmethylthio]propionitrile (V). The hydrolysis of (V) with K2CO3 in acetone – methanol – water yields 3-(2-thioureidothiazonl-4-ylmethylthio)propionitrile (VI), which by methylation with methyl iodide in refluxing ethanol is converted into 3-[2-(S-methylisothioureido)thiazol-4-ylmethylthio]propionitrile hydroiodide (VII). The reaction of (VII) with NH3 and NH4Cl in methanol at 90 C in a pressure vessel affords 3-(2-guanidinothiazol-4-ylmethylthio)propionitrile (VIII), which by partial alcoholysis with methanol by means of dry HCl in CHCl3 is converted into methyl 3-(2-guanidinothiazol-4-ylmethylthio)propionimidate (IX). Finally, this compound is treated with sulfamide in refluxing methanol.

Drugs Fut 1983, 8, 1, 14

US 4283408

DOS 2 951 675 (Yamanouchi; appl. 21.12.1979; J-prior. 2.8.1979).

DOS 3 008 056 (Yamanouchi; appl. 3.3.1980; J-prior. 6.3.1979, 23.6.1979).

GB 2 052 478 (Yamanouchi; appl. 6.3.1980; J-prior. 6.3.1979, 23.6.1979).

GB 2 055 800 (Yamanouchi; appl. 20.12.1979; J-prior. 2.8.1979).

synthesis of S-[2-aminothiazol-4-ylmethyl]isothiourea:

Spragne, J.M.; Lund, A.H.; Ziegler, C.: J. Am. Chem. Soc. (JACSAT) 68, 2155 (1946).

Figure 1: FTIR spectra of famotidine

FT IR OF FAMOTIDINE

http://link.springer.com/article/10.1007%2Fs00216-011-5599-6

[1H,13C] 2D NMR Spectrum

………………………..

DSC OF FAMOTIDINE

WILL BE ADDED

heating rate of 10C/min, and was run from 100 to 190C.The compound was found to melt at 166.4C

 

……………………………

 

…………………..

UV – range

Conditions : Concentration – 1 mg / 100 ml
The solvent designation graphics Methanol
Water
0.1М HCl
0.1M NaOH
Maximum absorption 287 nm 265 nm 286 nm
465 309 440
e 15700 10400 14850

 

FIG WILL BE ADDED

 

Ultraviolet spectroscopy
The UV spectrum of famotidine (5mg/ml) in methanol is shown inFig.ABOVE
. The spectrum was recorded using a Shimadzu UV–vis Spectro-photometer 1601 PC. Famotidine exhibited three maxima wavelengths
TABLE WILL BE ADDED

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

…………..

Synthesis pathway

Synthesis of a)


Trade names

Country Trade name Manufacturer
Germany Fadul Hexal
Famobeta betapharm
Famonerton Dolorgiet
Pepdul TEOFARMA
various generic drugs
France Peptsidak McNeil
Peptsidduo McNeil
Pepdin Merck Sharp & Dohme-Chibret
Great Britain Peptsid Merck Sharp & Dohme
Italy Famoudou Sigma-Tau
Gastridin Merck Sharp & Dohme
Motiaks Neopharmed
Japan Gaster Astellas
United States Peptsid Merck, 1986
– “- Johnson & Johnson; Merck
Ukraine Ulfamid Krka, dd, Novo mesto, Slovenia
Kvamatel JSC “Gedeon Richter”, Hungary
Famasan ABM. MED. CA AT Prague, Czech Republic
FamodinGeksal Salyutas Pharma GmbH, Germany, venture hexane AG, Germany
various generic drugs

Formulations

  • ampoule 10 mg, 20 mg;
  • Tablets coated with 10 mg, 20 mg, 40 mg;
  • oral suspension, 40 mg / 5 ml;
  • 2% powder, 10%;
  • 10 mg tablets, 20 mg;
  • vials (lyophilisate) 20 mg

Reference for above

  • DOS 2,951,675 (Yamanouchi; appl. 21.12.1979; J-prior. 2.8.1979).
  • DOS 3,008,056 (Yamanouchi; appl. 3.3.1980; J-prior. 6.3.1979, 23.6.1979).
  • GB 2052478 (Yamanouchi; appl. 6.3.1980; J-prior. 6.3.1979, 23.6.1979).
  • GB 2055800 (Yamanouchi; appl. 20.12.1979; J-prior. 2.8.1979).
  • US 4,283,408 (Yamanouchi; 11.8.1981; J-prior. 2.8.1979).

References

  1. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Oct 10]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  2.  Humphries TJ, Merritt GJ (August 1999). “Review article: drug interactions with agents used to treat acid-related diseases” (pdf). Aliment. Pharmacol. Ther. 13 (Suppl 3): 18–26.doi:10.1046/j.1365-2036.1999.00021.x. PMID 10491725.
  3. “Horizon Pharma, Inc. Announces FDA Approval of DUEXIS(R) for the Relief of the Signs and Symptoms of Rheumatoid Arthritis and Osteoarthritis and to Decrease the Risk of Developing Upper Gastrointestinal Ulcers” (Press release). Horizon Pharma. 2011-04-25.
  4.  Brauser D (Jul 13, 2009). “Famotidine May Prevent Peptic Ulcers, Esophagitis in Patients Taking Low-Dose Aspirin”. Medscape.
  5.  Fogg TB, Semple D (29 November 2007). “Combination therapy with H2 and H1 antihistamines in acute, non compromising allergic reactions”. BestBets. Manchester, England: Manchester Royal Infirmary. Retrieved 26 April 2011.
  6.  “Pepcid Side Effects & Drug Interactions”. RxList.com. 2008. Retrieved 2008-07-31.
  7.  US patent 4283408, HIRATA YASUFUMI; YANAGISAWA ISAO; ISHII YOSHIO; TSUKAMOTO SHINICHI; ITO NORIKI; ISOMURA YASUO; TAKEDA MASAAKI, “Guanidinothiazole compounds, process for preparation and gastric inhibiting compositions containing them”, issued 1981-08-11
  8.  “Sankyo Pharma”. Skyscape Mediwire. 2002. Retrieved 2009-10-30.[dead link]
  9.  “Formulation and Evaluation of Gastroretentive Floating Tablets of Famotidine”. Farmavita.Net. 2008. Retrieved 2009-01-30.
  10.  Meskanen, K; Ekelund, H; Laitinen, J; Neuvonen, PJ; Haukka, J; Panula, P; Ekelund, J (August 2013). “A randomized clinical trial of histamine 2 receptor antagonism in treatment-resistant schizophrenia.”. Journal of Clinical Psychopharmacology 33 (4): 472–478. doi:10.1097/JCP.0b013e3182970490. PMID 23764683.
References:
Histamine H2-receptor antagonist. Prepn, NMR and mass spectral data: H. Yasufumi et al., BE 882071;eidem, US 4283408; JP Kokai 81 55383, C.A. 95, 203930n (1980, 1981, 1981 all to Yamanouchi).
Inhibition of gastric acid and pepsin secretion in rats: M. Takeda et al., Arzneim.-Forsch. 32, 734 (1982); in man: M. Miwa et al., Int. J. Clin. Pharmacol. Ther. Toxicol. 22, 214 (1984).
Effect on disposition of antipyrine in liver: Ch. Staiger et al., Arzneim.-Forsch. 34, 1041 (1984). Chromatographic determn in plasma and urine: W. C. Vincek et al., J. Chromatogr. 338, 438 (1985). Pharmacokinetics: T. Takabatke et al., Eur. J. Clin. Pharmacol. 28, 327 (1985).
Clinical trial in Zollinger-Ellison syndrome: J. M. Howard et al.,Gastroenterology 88, 1026 (1985). Symposia on pharmacology and clinical efficacy: Am. J. Med. 81, Suppl. 4B, 1-64 (1986);Scand. J. Gastroenterol. 22, Suppl. 134, 1-62 (1987).
Web information on Famotidine
Mechanism of Action
H2-receptor antagonist
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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