Rifaximin

Medical uses

Travelers' diarrhea

Rifaximin is used to treat travelers' diarrhea caused by E. coli bacteria in people aged twelve years of age and older. It treats travelers' diarrhea by stopping the growth of the bacteria that cause diarrhea. Rifaximin will not work to treat travelers' diarrhea that is bloody or occurs with fever.

Irritable bowel syndrome

Rifaximin is used for the treatment of irritable bowel syndrome (IBS). It possesses anti-inflammatory and antibacterial properties, and is a non-absorbable antibiotic that acts locally in the gut. These properties make it efficacious in relieving chronic functional symptoms of non-constipation type irritable bowel syndrome. It appears to retain its therapeutic properties for this indication, even after repeated courses. It is particularly indicated where small intestine bacterial overgrowth is suspected of involvement in irritable bowel syndrome. Symptom relief or improvement can be obtained for global irritable bowel syndrome symptoms, including: abdominal pain, flatulence, bloating, and stool consistency. A drawback is that repeated courses may be necessary for remission of symptoms.

''Clostridioides difficile'' infection

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

Hepatic encephalopathy

Rifaximin is used to prevent episodes of hepatic encephalopathy (changes in thinking, behavior, and personality caused by a build-up of toxins in the brain in adults who have liver disease). It treats hepatic encephalopathy by stopping the growth of bacteria that produce toxins and that may worsen the liver disease. Although high-quality evidence is lacking, it 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. It 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. The drawbacks are increased cost, and lack of robust clinical trials for hepatic encephalopathy without combination lactulose therapy.

Other uses

Other uses include treatment of: infectious diarrhea, small intestinal bacterial overgrowth, inflammatory bowel disease, and diverticular disease. It is effective in treating small intestinal bacterial overgrowth regardless of whether it is associated with irritable bowel syndrome or not. It has also shown efficacy with rosacea, ocular rosacea which also presents as dry eyes for patients with co-occurrence with small intestinal bacterial overgrowth (SIBO).

Veterinary uses

Rifaximin is used to treat cattle mastitis intramammarily and post-partum metritis intrauterinally.

Special caution

People should avoid rifaximin if they are allergic either rifabutin, rifampin, or rifapentine. It may cause attenuated vaccines (such as typhoid vaccine) not to work well. Health-care professionals should be informed about its usage before giving immunizations. Pregnant or breastfeeding women should avoid rifaximin: it can harm the fetus. Caution is required in people with cirrhosis who have a Child–Pugh score of C.

Side effects

Rifaximin has an excellent safety profile due to its lack of systemic absorption. Clinical trials did not show any serious adverse events while using rifaximin. There were no deaths while using it in the clinical trials.

The most common side effects include nausea, stomach pain, dizziness, fatigue, headaches, muscle tightening, and joint pain. It may also cause reddish discoloration of urine.

The most serious side effects of rifaximin are:

1. Clostridioides difficile-associated diarrhea
2. Drug-resistant bacterial superinfection
3. Severe allergic reactions including hives, rashes and itching

Interactions

As rifaximin is not significantly absorbed from the gut, the great majority of this drug's interactions are negligible in people with healthy liver function, so healthcare providers usually do not worry about drug interactions unless liver impairment is present. It may decrease the effectiveness of warfarin, a commonly prescribed anticoagulant, in people with liver problems.

Pharmacology

Rifaximin is a semisynthetic broad spectrum antibacterial drug, derived through chemical modification of the natural antibiotic rifamycin. It has very low bioavailability due to its poor absorption after oral administration. Because of this local action within the gut and the lack of horizontal transfer of resistance genes, the development of bacterial resistance is rare, and most of the drug taken orally stays in the gastrointestinal tract where the infection takes place.

Mechanism of action

Rifaximin interferes with transcription by binding to the β-subunit of bacterial RNA polymerase. 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. 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. A resetting of the bacterial composition has also been suggested as a possible mechanism of action for relief of irritable bowel syndrome symptoms. Additionally, rifaximin may have a direct anti-inflammatory effect on gut mucosa via modulation of the pregnane X receptor. 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.

Availability

In the United States, Salix Pharmaceuticals holds a US Patent for rifaximin and markets it under the brand name Xifaxan. In addition to receiving FDA approval for travelers' diarrhea and (marketing approved for) hepatic encephalopathy, rifaximin received FDA approval for irritable bowel syndrome in May 2015. 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 24 March 2017. 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.

Rifaximin is approved in many countries for the treatment of certain gastrointestinal disorders. In August 2013, Health Canada issued a Notice of Compliance to Salix Pharmaceuticals for the drug product Zaxine. In India, it is available under the brand names Ciboz and Xifapill. In Russia and Ukraine the drug is sold under the name Alfa Normix (Альфа Нормикс), and under the name Flonorm in Mexico, produced by Alfa Wassermann S.p.A. (Italy). In 2018, the FDA approved a similar drug by Cosmos Pharmaceuticals called Aemcolo for traveler's diarrhea.

Physicochemical properties

Rifaximin can exist in different crystalline forms depending on the degree of hydration. They drastically differ in water solubility, which has to be taken into account during the manufacturing process. Wet rifaximin exists in the β-form, which can be dehydrated to obtain forms α and δ. ε-Form can be only obtained by dehydrating δ-form. Amongst them, γ-form is the most stable and is resistant to high humidity levels.

Based upon animal-model studies, bioavailability (Cmax, tmax, AUC0-24, AUC∞) increases in the following order: β, α, ε, δ, γ. Thus, structures with lower bioavailability exert their antimicrobial activity more locally in the gastrointestinal tract, whereas δ- and γ-forms are more suitable for systemic treatment (however the problem with cross-resistance with rifampicin in Mycobacterium tuberculosis might lead to multidrug-resistant strain selection).

References

References

1. (2 November 2020). "Rifaximin international".
2. (February 2024). "Product monograph brand safety updates".
3. (1 October 2019). "Xifaxan- rifaximin tablet".
4. (January 2010). "Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases". Current Opinion in Gastroenterology.
5. "Drug Approval Package: Xifaxan (Nfaximin) NDA #021361".
6. (26 July 2011). "Drug Approval Package: Xifaxan (rifaximin) NDA #022554".
7. (July 2007). "Therapy for and prevention of traveler's diarrhea". Clinical Infectious Diseases.
8. (2016). "Rifaximin for the treatment of diarrhea-predominant irritable bowel syndrome". Expert Review of Gastroenterology & Hepatology.
9. (July 2016). "Rifaximin for the treatment of irritable bowel syndrome - a drug safety evaluation". Expert Opinion on Drug Safety.
10. (April 2018). "Clinical Practice Guidelines for Irritable Bowel Syndrome in Korea, 2017 Revised Edition". Journal of Neurogastroenterology and Motility.
11. (March 2007). "Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin". Clinical Infectious Diseases.
12. (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.
13. (March 2017). "Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults". The Cochrane Database of Systematic Reviews.
14. (June 2013). "Use of rifamycin drugs and development of infection by rifamycin-resistant strains of Clostridium difficile". Antimicrobial Agents and Chemotherapy.
15. (August 2008). "Rifaximin for the treatment of hepatic encephalopathy". Pharmacotherapy.
16. (March 2014). "Safety, efficacy, and patient acceptability of rifaximin for hepatic encephalopathy". Patient Preference and Adherence.
17. (August 2014). "Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver". Hepatology.
18. (February 2023). "Diverticular Disease and Rifaximin: An Evidence-Based Review". Antibiotics.
19. (April 2011). "Meta-analysis: long-term therapy with rifaximin in the management of uncomplicated diverticular disease". Alimentary Pharmacology & Therapeutics.
20. (April 2015). "Prevention and Conservative Therapy of Diverticular Disease". Viszeralmedizin.
21. (2015). "Rifaximin: The Revolutionary Antibiotic Approach for Irritable Bowel Syndrome". Mini Reviews in Medicinal Chemistry.
22. (May 2013). "Rosacea and small intestinal bacterial overgrowth: prevalence and response to rifaximin". Journal of the American Academy of Dermatology.
23. (May 1988). "Rifaximin (Extension to topical use) Summary Report (3) (EMEA/MRL/443/98-FINAL)".
24. "Rifaxules Dry Period".
25. "Rifaximin Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing".
26. (August 2006). "Fertility and pregnancy in the patient with inflammatory bowel disease". Gut.
27. (2022). "Rifaximin". StatPearls Publishing.
28. "Rifaximin Side Effects". U.S. National Library of Medicine.
29. (May 2011). "Probable interaction between warfarin and rifaximin in a patient treated for small intestine bacterial overgrowth". The Annals of Pharmacotherapy.
30. (December 1984). "The synthesis of 4-deoxypyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV derivatives". The Journal of Antibiotics.
31. (December 2005). "Poorly absorbed antibiotics for the treatment of traveler's diarrhea". Clinical Infectious Diseases.
32. (2015). "Profile of rifaximin and its potential in the treatment of irritable bowel syndrome". Clinical and Experimental Gastroenterology.
33. (22 March 2017). "Rifaximin". DrugBank.
34. (January 2016). "Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea". Alimentary Pharmacology & Therapeutics.
35. (October 2015). "Pharmacologic Agents for Chronic Diarrhea". Intestinal Research.
36. "Product Details for NDA 022554". U.S. [[Food and Drug Administration]] (FDA).
37. "FDA approves two therapies to treat IBS-D". U.S. [[Food and Drug Administration]] (FDA).
38. (12 September 2018). "Bausch Health stock soars 8.6% premarket on news of patent settlement".
39. "Investors | Salix Pharmaceuticals".
40. (7 November 2013). "Zaxine product information".
41. "Brands".
42. (20 March 2017). "Trade Marks Journal". The Government of India, Trade Mark Registry.
43. "Alfa Normix". Russian medical server.
44. (20 November 2018). "Cosmo to give Bausch Health a run for its money with FDA nod for Xifaxan rival".
45. (August 2022). "The Relevance of Crystal Forms in the Pharmaceutical Field: Sword of Damocles or Innovation Tools?". International Journal of Molecular Sciences.
46. (2012). "The structure–property relationship of four crystal forms of rifaximin". CrystEngComm.
47. (2008). "Crystal forms of rifaximin and their effect on pharmaceutical properties". CrystEngComm.
48. (August 2022). "The Relevance of Crystal Forms in the Pharmaceutical Field: Sword of Damocles or Innovation Tools?". International Journal of Molecular Sciences.
49. (2012). "The structure–property relationship of four crystal forms of rifaximin". CrystEngComm.
50. (July 2002). "Impact of resistance to anti-tuberculosis drugs on treatment outcome using World Health Organization standard regimens". Transactions of the Royal Society of Tropical Medicine and Hygiene.