Rifaximin

Rifaximin is a Rifamycin-based non-systemic antibiotic belonging to Gastrointestinal agent.

Rifaximin is a rifamycin-based non-systemic antibiotic used for the treatment of gastrointestinal bacterial infections, such as traveler's diarrhea and irritable bowel syndrome, and reduction of overt hepatic encephalopathy recurrence in adults.

Rifaximin nonabsorbed from the gastrointestinal tract having bioavailability is abot <0.4%. Time to peak plasma concentration is approximately 1 hour.Rifaximin is moderately bound to human plasma proteins. In vivo, the mean protein binding ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when Rifaximinwas administered.Rifaximin is extensively metabolised in the liver and mainly by CYP3A4. It is excreted via faeces in (96.6% as unchanged drug)and in urine (0.32% as metabolites).

Rifaximin shows side effects like Nausea, stomach pain, dizziness, excessive tiredness, headache, muscle tightening, joint pain.

Rifaximin is available in the form of Oral Tablet.

Rifaximin is available in India, US, UK, Singapore, Malaysia, Canada, France, Italy, Spain, and Australia.

Rifaximin belongs to the Gastrointestinal agent acts as a Rifamycin-based non-systemic antibiotic.

Rifaximin acts by inhibiting RNA synthesis in susceptible bacteria by binding to the beta-subunit of bacterial deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase enzyme. This binding blocks translocation, which stops transcription.

The Data of Onset and duration of action of Rifaximin is not clinically established.

The Tmax of Rifaximin is approximately 1 hour.

Rifaximin is available in the form of Oral Tablet.

Rifaximin tablet is taken orally, usually three times daily.

Rifaximin is an effective medicine used to treat bacterial infections of the intestine. It is used for the treatment of traveler's diarrhea, irritable bowel syndrome with diarrhea caused due to certain specific strains of bacteria.

Rifaximin is a Rifamycin-based non-systemic antibiotic belonging to Gastrointestinal agent.

Rifaximin inhibits bacterial RNA synthesis by binding to bacterial DNA-dependent RNA polymerase.

Rifaximin is approved for use in the following clinical indications

Adult indication

• Clostridioides difficile infection
• Hepatic encephalopathy, treatment, or prevention
• Irritable bowel syndrome, moderate to severe, without constipation
• Pouchitis, acute refractory disease
• Small intestinal bacterial overgrowth
• Travelers’ diarrhea

Pediatric indication

• Clostridioides difficile infection
• Inflammatory bowel disease
• Small intestinal bacterial overgrowth
• Travelers' diarrhea, treatment

Adult indication

• Clostridioides difficile infection

Oral: 400 mg 3 times daily for 20 days; administer after a 10-day course of oral vancomycin.

• Hepatic encephalopathy, treatment, or prevention

Oral: 550 mg twice daily or 400 mg 3 times daily.

• Irritable bowel syndrome, moderate to severe, without constipation

Oral: 550 mg 3 times daily for 14 days.

• Pouchitis, acute refractory disease

Oral: 550 mg to 1 g every 12 hours in combination with ciprofloxacin for 28 days.

• Small intestinal bacterial overgrowth

Oral: 550 mg 3 times daily for 14 days.

• Travelers’ diarrhea

Prophylaxis (off-label use

Oral: 200 mg 1 to 3 times daily for the duration of travel; optimal dose and duration not well established.

Treatment, moderate to severe (alternative agent)

Oral: 200 mg 3 times daily for 3 days.

Pediatric indication

• Clostridioides difficile infection

Children <12 years

Oral: 15 to 30 mg/kg/day in divided doses 3 times daily for 20 days; usual adult dose: 400 mg/dose; administer after a 10-day course of oral vancomycin.

Children ≥12 years and Adolescents

Oral: 400 mg 3 times daily for 20 days; administer after a 10-day course of oral vancomycin.

• Inflammatory bowel disease

Children ≥8 years and Adolescents

Oral: 10 to 30 mg/kg/day in divided doses; maximum daily dose: 1,200 mg/day.

• Small intestinal bacterial overgrowth

Children 3 to <8 years: Oral: 200 mg 3 times daily for 7 to 14 days.

Children ≥8 years and Adolescents: Oral: 200 to 550 mg 3 times daily for 7 to 14 days.

• Travelers' diarrhea, treatment

Children 3 to 11 years

Oral: 100 mg 4 times daily for up to 5 days has been used in 38 children (age range: 3 to 8 years) to treat infectious diarrhea.

Children ≥12 years and Adolescents

Oral: 200 mg 3 times daily for 3 days.

Rifaximin is available in various strengths as 550mg and 200mg.

Rifaximin is available in the form of Oral Tablet.

• Dosage Adjustment in Kidney Patient

Mild to severe impairment: No dosage adjustment necessary.

Rifaximin is contraindicated in patients with

• Rifaximin is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in rifaximin. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

• Travelers’ Diarrhea Not Caused by Escherichia coli

Rifaximin was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. Discontinue Rifaximin if diarrhea symptoms get worse or persist more than 24 to 48 hours and alternative antibiotic therapy should be considered. Rifaximin is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of Rifaximin in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. Rifaximin should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

• Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Rifaximin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

• Development of Drug-Resistant Bacteria

Prescribing Rifaximin for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

• Severe (Child-Pugh Class C) Hepatic Impairment

There is increased systemic exposure in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering Rifaximin to patients with severe hepatic impairment (Child-Pugh Class C)

• Concomitant Use with P-glycoprotein Inhibitors

Concomitant administration of drugs that are P-glycoprotein (P-gp) inhibitors with Rifaximin can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of Rifaximin and a P-gp inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to rifaximin.

There is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breastfed infant, or the effects of rifaximin on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rifaximin and any potential adverse effects on the breastfed infant from Rifaximin or from the underlying maternal condition.

There are no available data on Rifaximin use in pregnant women to inform any drug associated risks. Teratogenic effects were observed in animal reproduction studies following administration of rifaximin to pregnant rats and rabbits during organogenesis at doses approximately 0.9 to 5 times and 0.7 to 33 times, respectively of the recommended human doses of 600 mg to 1650 mg per day. In rabbits, ocular, oral and maxillofacial, cardiac, and lumbar spine malformations were observed. Ocular malformations were observed in both rats and rabbits at doses that caused reduced maternal body weight gain. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise pregnant women of the potential risk to a fetus.

Common

• Peripheral edema, Nausea (14%; irritable bowel syndrome with diarrhea: 3%), Ascites , Dizziness, fatigue, Pruritus, skin rash, Abdominal pain, Clostridioides difficile colitis (<5%), Anemia, Depression, headache, Arthralgia, increased creatine phosphokinase in blood specimen, muscle spasm, myalgia, Dyspnea, nasopharyngitis

Rare

• Flushing, Exfoliative dermatitis, urticaria, Clostridioides difficile-associated diarrhea, Anaphylaxis, angioedema, hypersensitivity reaction.

• P-glycoprotein Inhibitors

Concomitant administration of cyclosporine, an inhibitor of P-gp and OATPs significantly increased the systemic exposure of rifaximin. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of Rifaximin and a P-gp inhibitor such as cyclosporine is needed.

• Warfarin

Changes in INR have been reported postmarketing in patients receiving rifaximin and warfarin concomitantly. Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.

• CYP3A4 Substrates

An in vitro study has suggested that rifaximin induces CYP3A4. However, in patients with normal liver function, Rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.

The common side effects of Rifaximin include the following

Common side effects

• Nausea, stomach pain, dizziness, excessive tiredness, headache, muscle tightening, joint pain.

Rare side effects

• Watery or bloody diarrhea that may occur along with stomach cramps and fever during your treatment or for 2 months afterward, hives, rash, itching, difficulty breathing or swallowing, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, Hoarseness.

• Pregnancy

There are no available data on Rifaximin use in pregnant women to inform any drug associated risks. Teratogenic effects were observed in animal reproduction studies following administration of rifaximin to pregnant rats and rabbits during organogenesis at doses approximately 0.9 to 5 times and 0.7 to 33 times, respectively of the recommended human doses of 600 mg to 1650 mg per day. In rabbits, ocular, oral and maxillofacial, cardiac, and lumbar spine malformations were observed. Ocular malformations were observed in both rats and rabbits at doses that caused reduced maternal body weight gain. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise pregnant women of the potential risk to a fetus.

• Nursing Mothers

There is no information regarding the presence of Rifaximin in human milk, the effects of Rifaximin on the breastfed infant, or the effects of Rifaximin on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rifaximin and any potential adverse effects on the breastfed infant from Rifaximin  or from the underlying maternal condition.

• Pediatric Use

The safety and effectiveness of Rifaximin has not been established in pediatric patients less than 12 years of age with TD or in patients less than 18 years of age for HE and IBS-D.

• Geriatric Use

Of the total number of patients in the clinical study of Rifaximin for HE, 19% of patients were 65 and over, while 2% were 75 and over. In the clinical studies of IBS-D, 11% of patients were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either indication. Clinical studies with Rifaximin for TD did not include enough patients aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No specific information is available on the treatment of overdosage with Rifaximin. In clinical studies at doses higher than the recommended dose (greater than 600 mg per day for TD, greater than 1100 mg per day for HE or greater than 1650 mg per day for IBS-D), adverse reactions were similar in subjects who received doses higher than the recommended dose and placebo. In the case of overdosage, discontinue Rifaximin, treat symptomatically, and institute supportive measures as required.

Pharmacodynamic

Rifaximin is a structural analog of rifampin and a non-systemic, gastrointestinal site-specific antibiotic. This non-systemic property of the drug is due to the addition of a pyridoimidazole ring, which renders it non-absorbable. Rifaximin acts by inhibiting bacterial ribonucleic acid (RNA) synthesis and contributes to restore intestinal microflora imbalance. Other studies have also shown rifaximin to be a pregnane X receptor (PXR) activator. As PXR is responsible for inhibiting the proinflammatory transcription factor NF-kappa B (NF-κB) and is inhibited in inflammatory bowel disease (IBD), Rifaximinwas proven to be effective for the treatment of IBS-D.

Pharmacokinetics

• Absorption

Rifaximin nonabsorbed from the gastrointestinal tract having bioavailability is abot <0.4%. Time to peak plasma concentration is approximately 1 hour.

• Distribution

Rifaximin is moderately bound to human plasma proteins. In vivo, the mean protein binding ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when Rifaximin was administered.

• Metabolism and Excretion

Rifaximin is extensively metabolized in the liver and mainly by CYP3A4. It is excreted via faeces in (96.6% as unchanged drug)and in urine (0.32% as metabolites).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021361s023lbl.pdf
• https://www.uptodate.com/contents/rifaximin-drug-information#F218484
• https://www.mims.com/philippines/drug/info/rifaximin?mtype=generic
• https://www.practo.com/medicine-info/rifaximin-244-api
• https://go.drugbank.com/drugs/DB01220
• https://www.drugs.com/dosage/rifaximin.html