Rifaximin

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Rifaximin
Names
Trade namesXifaxan, Xifaxanta, Normix, others
  • (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro
    [4,5-e]pyrido[1,2-a]-benzimida-zole-1,15(2H)-dione,25-acetate
Clinical data
Main usesHepatic encephalopathy, irritable bowel syndrome, traveler's diarrhea[1]
Side effectsNausea, headache, abdominal discomfort[1]
WHO AWaRe
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
use		By mouth
External links
AHFS/Drugs.comMonograph
MedlinePlusa604027
Legal
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability< 0.4%
MetabolismLiver
Elimination half-life6 hours
ExcretionFecal (97%)
Chemical and physical data
FormulaC43H51N3O11
Molar mass785.891 g·mol−1
3D model (JSmol)
  • CC(=O)O[C@H]3[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(\C)C(=O)Nc6c2c(nc1cc(C)ccn12)c5c4C(=O)[C@@](C)(O/C=C/[C@H](OC)[C@H]3C)Oc4c(C)c(O)c5c6O
  • InChI=1S/C43H51N3O11/c1-19-14-16-46-28(18-19)44-32-29-30-37(50)25(7)40-31(29)41(52)43(9,57-40)55-17-15-27(54-10)22(4)39(56-26(8)47)24(6)36(49)23(5)35(48)20(2)12-11-13-21(3)42(53)45-33(34(32)46)38(30)51/h11-18,20,22-24,27,35-36,39,48-51H,1-10H3,(H,45,53)/b12-11+,17-15+,21-13-/t20-,22+,23+,24+,27-,35-,36+,39+,43-/m0/s1 checkY
  • Key:NZCRJKRKKOLAOJ-XRCRFVBUSA-N checkY

Rifaximin, sold under the trade name Xifaxan among others, is an antibiotic used to treat hepatic encephalopathy, irritable bowel syndrome, and traveler's diarrhea.[1] Specifically it can be used to decrease the number of episodes of hepatic encephalopathy.[2] It is not effective for a number of types of diarrhea including Salmonella.[1] It is taken by mouth.[2]

Common side effects include nausea, headache, and abdominal discomfort.[1] Other side effects may include joint pain, mood changes, swelling, skin rash, and Clostridium difficile colitis.[2][1] Use in pregnancy is not recommended while use during breastfeeding is believed to be safe for the baby.[2] It is in the rifamycin family of medications.[2]

Rifaximin was approved for medical use in the United States in 2004.[1] In United States the dose for hepatic encephalopathy costs $1,864 per month as of January 2017.[3] In the UK, 56 tablets of the 550mg dose costs the NHS around 260 pounds as of 2020.[2] As of 2020 no generic version is available in the United States.[4]

Medical uses

Hepatic encephalopathy

In the United States, rifaximin has orphan drug status for the treatment of hepatic encephalopathy.[5] Although high-quality evidence is still lacking, rifaximin appears to be as effective as or more effective than other available treatments for hepatic encephalopathy (such as lactulose), is better tolerated, and may work faster.[6] Rifaximin is taken by mouth. It has minimal side effects, prevents reoccurring encephalopathy, and is associated with high patient satisfaction. People are more compliant and satisfied to take this medication than any other due to minimal side effects, prolonged remission, and overall cost.[7] It reduces the levels of intestinal ammonia-producing bacteria thus alleviating the symptoms of hepatic encephalopathy and reducing mortality.[8] The drawbacks to rifaximin are increased cost and lack of robust clinical trials for HE without combination lactulose therapy.

Irritable bowel syndrome

Rifaximin is approved in the United States for the treatment of irritable bowel syndrome.[9] It possesses anti-inflammatory and antibacterial properties and additionally, it is a nonabsorbable antibiotic that acts locally in the gut. These properties make it efficacious in relieving chronic functional symptoms of non-constipation type irritable bowel syndrome (IBS). It appears to retain its therapeutic properties for this indication, even after repeated courses.[10][11] Rifaximin is particularly indicated where small intestine bacterial overgrowth is suspected of involvement in a person's IBS. Symptom relief or improvement can be obtained for global IBS symptoms including: abdominal pain, flatulence, bloating, and stool consistency. A drawback is that repeated courses may be necessary for relapse of symptoms.[11][8] There is evidence that rifaximin can be curative in some people with IBS.[12]

C. difficile infection

Rifaximin may also be a useful addition to vancomycin when treating patients with relapsing C. difficile infection.[13][14] However the quality of evidence of these studies was judged to be low.[15] Although exposure to rifamycins in the past may increase risk for resistance, so rifaximin should be avoided in such cases.

Other uses

Rifaximin may be used to treat and prevent traveler's diarrhea,[16][17] where there is no fever or bloody diarrhea.[2]

Other uses include treatment of: infectious diarrhea, small intestinal bacterial overgrowth, inflammatory bowel disease, and diverticular disease.[8] Rifaximin is effective in treating small intestinal bacterial overgrowth regardless of whether it is associated with irritable bowel syndrome or not.[18]

Dosage

The recommended dose in hepatic encephalopathy is 550 mg two times per day while for traveler's diarrhea 200 mg three times per day for three days is used.[2]

Side effects

Rifaximin has few side effects.[11] Side effects are generally mild and uncommon;[10] this is largely because very little of the drug is absorbed from the gut meaning systemic side effects are absent.[11] Clostridium difficile infection does not typically result from rifaximin therapy unless risk factors such as immunosuppression and hospitalisation are present. Rifaximin is active against Clostridium difficile.[10]

Caution

Cautious use is required in individuals with cirrhosis of the liver who have a Child-Pugh score of class C severity.[8]

Interactions

Rifaximin is not significantly absorbed from the gut and therefore does not have much significant interactions with other drugs in people with normal liver function.[10]

Pharmacology

Mechanisms of action of pharmacological treatments in IBS-D( Rifaximin, targets the luminal gut microbiome because of its non-absorbable properties[19]

Rifaximin is a semisynthetic broad spectrum antibacterial drug,[12][20] that has very low bioavailability due to its poor absorption after oral administration.[11] Because of this local action within the gut and the lack of horizontal transfer of resistant genes the development of bacterial resistance is rare.[10] Because of this poor absorption, most of the drug taken orally stays in the gastrointestinal tract where the infection takes place.[21] However, due to drug polymorphisms and differences between crystalline and amorphous forms of the compounds, certain generic drug versions are more readily absorbable than the original brand name version.[8]

Mechanism of action

Rifaximin interferes with transcription by binding to the β-subunit of bacterial RNA polymerase.[8] This results in the blockage of the translocation step that normally follows the formation of the first phosphodiester bond, which occurs in the transcription process.[22] This in turn results in a reduction of bacteria populations, including gas producing bacteria, which may reduce mucosal inflammation, epithelial dysfunction and visceral hypersensitivity. Rifaximin has broad spectrum antibacterial properties against both gram positive and gram negative anaerobic and aerobic bacteria. As a result of bile acid solubility, its antibacterial action is limited mostly to the small intestine and less so the colon.[8] A resetting of the bacteria composition has also been suggested as a possible mechanism of action for relief of IBS symptoms.[12] Additionally, rifaximin may have a direct anti-inflammatory effect on gut mucosa via modulation of the pregnane X receptor.[12]

Other mechanisms for its therapeutic properties include inhibition of bacterial translocation across the epithelial lining of the intestine, inhibition of adherence of bacteria to the epithelial cells and a reduction in the expression of proinflammatory cytokines.[23]

Society and culture

Availability

In the United States, Salix Pharmaceuticals holds a US Patent for rifaximin and markets the drug under the name Xifaxan.[24][25] In addition to receiving FDA approval for traveler's diarrhea and (marketing approved for)[25] hepatic encephalopathy, rifaximin received FDA approval for IBS in May 2015.[26] No generic formulation is available in the US and none has appeared due to the fact that the FDA approval process was ongoing. If rifaximin receives full FDA approval for hepatic encephalopathy it is likely that Salix will maintain marketing exclusivity and be protected from generic formulations until March 24, 2017.[25] In 2018, a patent dispute with Teva was settled which delayed a generic in the United States, with the patent set to expire in 2029.[27]

Rifaximin is approved in 33 countries for GI disorders.[28][29] On August 13, 2013, Health Canada issued a Notice of Compliance to Salix Pharmaceuticals Inc. for the drug product Zaxine.[30] In India it is available under the brand names Ciboz and Xifapill.[citation needed] In Russia and Ukraine the drug is sold under the name Alfa Normix (Альфа Нормикс), produced by Alfa Wassermann S.p.A (Italy).[31]

In 2018, the FDA approved a similar drug by Cosmos Pharmaceuticals called Aemcolo for traveler's diarrhea.[32]

Cost

In United States the dose for hepatic encephalopathy costs $1,864 per month as of January 2017.[3] This amount in the United Kingdom costs the NHS about 260 pounds as of 2020.[2] In Russia, as of 2016, a daily dose costs 231.25 RUB (approximately US$4), Colombia as 2019, it is 6286 COP (approximately US $2).[33] A course of treatment for travelers diarrhea in the UK costs about 15 pounds.[2]

  • Rifaximin costs (US)

    Rifaximin costs (US)

  • Rifaximin prescriptions (US)

    Rifaximin prescriptions (US)

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Rifaximin". The American Society of Health-System Pharmacists. Archived from the original on 25 June 2012. Retrieved 8 January 2017.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 BNF (80 ed.). London: BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 609. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
  3. ↑ 3.0 3.1 "NADAC as of 2017-01-25". Centers for Medicare and Medicaid Services. Archived from the original on 2017-02-02. Retrieved 25 January 2017.
  4. ↑ "Generic Xifaxan Availability". Drugs.com. Archived from the original on 5 June 2016. Retrieved 8 October 2020.
  5. ↑ Wolf, David C. (2007-01-09). "Hepatic Encephalopathy". eMedicine. WebMD. Archived from the original on 2007-03-06. Retrieved 2007-02-15.
  6. ↑ Lawrence KR, Klee JA (August 2008). "Rifaximin for the treatment of hepatic encephalopathy". Pharmacotherapy. 28 (8): 1019–32. doi:10.1592/phco.28.8.1019. PMID 18657018. Free full text with registration Archived 2011-02-09 at the Wayback Machine at Medscape.
  7. ↑ Kimer N, Krag A, Gluud LL (March 2014). "Safety, efficacy, and patient acceptability of rifaximin for hepatic encephalopathy". Patient Preference and Adherence. 8: 331–8. doi:10.2147/PPA.S41565. PMC 3964161. PMID 24672227.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 Iorio N, Malik Z, Schey R (2015). "Profile of rifaximin and its potential in the treatment of irritable bowel syndrome". Clin Exp Gastroenterol. 8: 159–67. doi:10.2147/CEG.S67231. PMC 4467648. PMID 26089696.
  9. ↑ Kane JS, Ford AC (2016). "Rifaximin for the treatment of diarrhea-predominant irritable bowel syndrome". Expert Rev Gastroenterol Hepatol. 10 (4): 431–42. doi:10.1586/17474124.2016.1140571. PMID 26753693.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 Ponziani FR, Pecere S, Lopetuso L, Scaldaferri F, Cammarota G, Gasbarrini A (July 2016). "Rifaximin for the treatment of irritable bowel syndrome - a drug safety evaluation". Expert Opinion on Drug Safety. 15 (7): 983–91. doi:10.1080/14740338.2016.1186639. PMID 27149541.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 Song KH, Jung HK, Kim HJ, Koo HS, Kwon YH, Shin HD, et al. (April 2018). "Clinical Practice Guidelines for Irritable Bowel Syndrome in Korea, 2017 Revised Edition". Journal of Neurogastroenterology and Motility. 24 (2): 197–215. doi:10.5056/jnm17145. PMC 5885719. PMID 29605976.
  12. ↑ 12.0 12.1 12.2 12.3 Pimentel M (January 2016). "Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea". Aliment. Pharmacol. Ther. 43 Suppl 1: 37–49. doi:10.1111/apt.13437. PMID 26618924.
  13. ↑ Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN (March 2007). "Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin". Clinical Infectious Diseases. 44 (6): 846–8. doi:10.1086/511870. PMID 17304459.
  14. ↑ Garey KW, Ghantoji SS, Shah DN, Habib M, Arora V, Jiang ZD, DuPont HL (December 2011). "A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection". The Journal of Antimicrobial Chemotherapy. 66 (12): 2850–5. doi:10.1093/jac/dkr377. PMID 21948965.
  15. ↑ Nelson RL, Suda KJ, Evans CT (March 2017). "Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults". The Cochrane Database of Systematic Reviews. 3: CD004610. doi:10.1002/14651858.CD004610.pub5. PMC 6464548. PMID 28257555.
  16. ↑ "Xifaxan label information" (PDF). Archived (PDF) from the original on 8 April 2020. Retrieved 15 November 2008.
  17. ↑ DuPont HL (July 2007). "Therapy for and prevention of traveler's diarrhea". Clinical Infectious Diseases. 45 (Suppl 1): S78-84. doi:10.1086/518155. PMID 17582576.
  18. ↑ Triantafyllou K, Sioulas AD, Giamarellos-Bourboulis EJ (2015). "Rifaximin: The Revolutionary Antibiotic Approach for Irritable Bowel Syndrome". Mini Rev Med Chem. 16 (3): 186–92. doi:10.2174/1389557515666150722105340. PMID 26202193.
  19. ↑ Colomier, Esther; Algera, Joost; Melchior, Chloé (2021). "Pharmacological Therapies and Their Clinical Targets in Irritable Bowel Syndrome With Diarrhea". Frontiers in Pharmacology. 11. doi:10.3389/fphar.2020.629026/full. ISSN 1663-9812.
  20. ↑ Laterza L, Ianiro G, Scoleri I, Landi R, Bruno G, Scaldaferri F, Gaetani E, Campanale M, Gasbarrini A (March 2015). "Rifaximin for the treatment of diarrhoea-predominant irritable bowel syndrome". Expert Opin Pharmacother. 16 (4): 607–15. doi:10.1517/14656566.2015.1007951. PMID 25641072.
  21. ↑ Taylor DN (December 2005). "Poorly absorbed antibiotics for the treatment of traveler's diarrhea". Clinical Infectious Diseases. 41 Suppl 8 (Supplement_8): S564-70. doi:10.1086/432953. PMID 16267720.
  22. ↑ "Rifaximin". DrugBank. 22 March 2017. Archived from the original on 11 July 2017. Retrieved 9 December 2011.
  23. ↑ Lee KJ (October 2015). "Pharmacologic Agents for Chronic Diarrhea". Intest Res. 13 (4): 306–12. doi:10.5217/ir.2015.13.4.306. PMC 4641856. PMID 26576135.
  24. ↑ "XIFAXAN (Rifaximin) 550 mg - Reduce Overt Hepatic Encephalopathy Recurrences". Salix Pharmaceuticals. Archived from the original on 2013-03-06. Retrieved 2013-02-22.
  25. ↑ 25.0 25.1 25.2 "Product Details for NDA 022554". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration. Archived from the original on 2020-02-23. Retrieved 2018-10-05.
  26. ↑ "Press Announcements - FDA approves two therapies to treat IBS-D". U.S. Food and Drug Administration. Archived from the original on 2018-01-26. Retrieved 2019-12-16.
  27. ↑ Linnane, Ciara. "Bausch Health stock soars 8.6% premarket on news of patent settlement". MarketWatch. Archived from the original on 2019-05-14. Retrieved 2019-05-14.
  28. ↑ "Xifaxan® (rifaximin) Tablets 550 mg for Hepatic Encephalopathy" (PDF). United States Food and Drug Administration Gastrointestinal Drugs Advisory Committee. 23 February 2010. Archived from the original (PDF) on 9 May 2017. Retrieved 16 December 2019.
  29. ↑ "Pharmaceutical News & Media - Salix Pharmaceuticals". Archived from the original on 2013-07-02. Retrieved 2013-02-22.
  30. ↑ "Summary Basis of Decision (SBD): Zaxine". Government of Canada, Health Canada, Health Products and Food Branch, Therapeutic Products Directorate, Bureau of Gastroenterology Infection and Viral Diseases. 2013. Archived from the original on 2014-04-08. Retrieved 2014-04-08.
  31. ↑ "Alfa Normix". Russian medical server. Archived from the original on 2017-02-16. Retrieved 2017-02-16.
  32. ↑ "Cosmo to give Bausch Health a run for its money with FDA nod for Xifaxan rival". FiercePharma. Archived from the original on 2019-05-14. Retrieved 2019-05-14.
  33. ↑ "Drug prices archive of the administration of the city of Krasnodar" (in Russian). Archived from the original on 2017-02-16. Retrieved 2017-02-16.{{cite web}}: CS1 maint: unrecognized language (link)

External links

Identifiers:
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