XIFAXAN

Rifaximin is an oral rifamycin antibiotic structurally related to rifampin. The drug is indicated to treat patients with traveler's diarrhea caused by noninvasive strains of Escherichia coli and to reduce the risk of hepatic encephalopathy recurrence. The antimicrobial spectrum of activity includes various gram-positive and gram-negative aerobes and anaerobes. Coverage against gram-positive cocci is better than its coverage against Enterobacteriaceae. Rifaximin is also approved to treat irritable bowel syndrome with diarrhea (IBS-D). Guidelines strongly recommend rifaximin to treat global IBS-D symptoms. Rifaximin has virtually no systemic bioavailability after oral administration; thus, unlike other rifamycins, rifaximin is unlikely to cause metabolic-based drug interactions in vivo.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Rifaximin tablets may be taken with or without food.

Extemporaneous Compounding-Oral
Extemporaneous 20 mg/ml rifaximin oral suspension:
NOTE: Rifaximin oral suspension is not an FDA approved formulation.
-With a mortar and pestle, crush six 200 mg rifaximin tablets into a fine powder.
-Mix 30 ml Ora-Plus with either 30 ml Ora-Sweet or 30 ml Ora-Sweet Sugar Free and stir vigorously.
-Levigate 30 ml of the Ora-Plus/Ora-Sweet mixture into the rifaximin powder via geometric dilution until a smooth suspension is formed.
-Transfer the mixture into a 2 ounce amber plastic bottle.
-Rinse the mortar with the remainder of the Ora-Plus/Ora-Sweet mixture and add to the amber plastic bottle to bring the final volume to 60 ml.
-Shake well before each use. This suspension is stable 60 days at room temperature (23-25 degrees C).

Some of the most common adverse events associated with rifaximin during clinical trials were gastrointestinal-related. Gastrointestinal adverse reactions reported in subjects receiving rifaximin include abdominal pain (6% to 9%), ascites (7% to 11%), constipation (16%), decreased appetite/anorexia (7%), diarrhea (5%), nausea (2% to 15%), and vomiting (6%). Discontinuations due to adverse reactions occurred in 0.4% of subjects; gastrointestinal adverse reactions leading to discontinuation include ageusia, anorexia, dysentery, and weight loss.

Adverse reactions associated with the skin and subcutaneous tissues during clinical trials with rifaximin include pruritus (9% to 10%) and rash (5%). Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN), have been reported with rifaximin in persons with cirrhosis in postmarketing reports. Discontinue rifaximin at the first sign or symptom of a severe cutaneous adverse reaction.

Hypersensitivity reactions including anaphylaxis (anaphylactoid reactions), exfoliative dermatitis, rash, angioedema (swelling of face and tongue and difficulty swallowing), flushing, urticaria, and pruritus have been reported during postmarketing use of rifaximin. These adverse reactions have occurred as early as within 15 minutes after rifaximin administration.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis (less than 5%) has been reported with rifaximin. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Urinary tract infection has been reported with rifaximin in 12% of subjects during clinical trials.

Musculoskeletal adverse events reported with rifaximin during clinical trials include arthralgia (6%) and muscle spasms (8% to 9%). Myalgia and increased serum creatine phosphokinase have been reported with rifaximin in less than 5% of subjects during clinical trials. Rhabdomyolysis has been reported during postmarketing use of rifaximin in persons with cirrhosis, with and without concomitant statin use.

Central nervous system and psychiatric adverse reactions reported with rifaximin during clinical trials include anxiety (5%), depression (7%), dizziness (13%), headache (7% to 10%), and insomnia (12%).

Respiratory adverse events reported with rifaximin during clinical trials include cough (6%), dyspnea (6% to 7%), and naso-pharyngitis (7%). Discontinuations due to adverse reactions occurred in 0.4% of subjects; respiratory adverse reactions leading to discontinuation include nasal passage irritation.

General adverse events reported with rifaximin during clinical trials include fatigue (12% to 14%) and fever (6%).

Peripheral edema has been reported with rifaximin in 15% to 17% of subjects during clinical trials.

Anemia has been reported with rifaximin in 8% to 10% of subjects during clinical trials.

Elevated hepatic enzymes (i.e., increased ALT) have been reported with rifaximin in 2% of subjects during clinical trials.

Acute renal failure has been reported with rifaximin in 6% of subjects during clinical trials.

Rifaximin is contraindicated in patients with a history of rifamycin hypersensitivity, rifaximin hypersensitivity, or hypersensitivity to any of the components of rifaximin.

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 E. coli. Discontinue rifaximin if diarrhea symptoms get worse or persist more than 24 to 48 hours and consider alternative antibiotic therapy. Do not use rifaximin in patients where Campylobacter jejuni, Shigella sp., or Salmonella sp. may be suspected as causative pathogens. Rifaximin is not effective in cases of travelers' diarrhea due to Campylobacter jejuni. The effectiveness of rifaximin in travelers' diarrhea caused by Shigella sp. and Salmonella sp. has not been proven. Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including rifaximin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Use caution when administering rifaximin to persons with severe hepatic disease (Child-Pugh class C). There is increased rifaximin systemic exposure in persons with severe hepatic impairment. Clinical trials were limited to subjects with MELD (Model for End-Stage Liver Disease) scores less than 25. Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN), as well as cases of rhabdomyolysis have been associated with the use of rifaximin in patients with biliary cirrhosis in postmarketing reports.

Clinical studies with rifaximin for travelers' diarrhea did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

There are no available data on rifaximin use in human pregnancy to inform any drug associated risks. However, because systemic absorption of rifaximin after oral administration is minimal, rifaximin is suggested as an alternative agent for travelers' diarrhea in pregnant women in whom quinolones are contraindicated. Pregnant women have a higher risk of experiencing travelers' diarrhea due to decreased gastric acidity and increased GI transit time, and the consequences of fluid loss may be more severe (e.g., premature labor, shock). Teratogenic effects were observed in animal reproduction studies after 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 to 1,650 mg/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. Advise pregnant women of the potential risk to a fetus.

There is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breast-fed infant, or the effects of rifaximin on milk production. Consider the development and health benefits of breast-feeding along with the mother's clinical need for rifaximin and any potential adverse effects on the breast-fed infant from rifaximin or from the underlying maternal condition.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Escherichia coli
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Clostridioides difficile
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of traveler's diarrhea due to noninvasive strains of E. coli:
Oral dosage:
Adults: 200 mg PO 3 times daily for 3 days. Rifaximin is an alternative treatment for severe, nondysenteric diarrhea in areas where invasive pathogens are not common. May reserve use for patients unable to take a quinolone or azithromycin. Antibiotic treatment is not recommended for mild cases, may be considered for moderate cases, and should be used for severe cases.
Children and Adolescents 12 to 17 years: 200 mg PO 3 times daily for 3 days.

For traveler's diarrhea prophylaxis*:
Oral dosage:
Adults: 200 to 1,100 mg/day PO in 1 to 3 divided doses for travelers at high risk of health-related complications of traveler's diarrhea.

For reduction in risk of overt hepatic encephalopathy recurrence:
Oral dosage:
Adults: 550 mg PO twice daily. In clinical trials, 91% of subjects were using lactulose concomitantly. Differences in the treatment effect of those subjects not using lactulose concomitantly could not be assessed.

For the treatment of active Crohn's disease*:
Oral dosage:
Adults: In an open-label study, patients ranging in age from 18 to 80 years with active Crohn's disease received rifaximin 200 mg PO three times per day for 16 weeks. At the conclusion of the study, rifaximin was well tolerated and resulted in clinical improvement in patients with active Crohn's disease. Due to the open-label design, a randomized, double-blind, placebo-controlled study is needed to confirm the effectiveness of rifaximin in active Crohn's disease.
Geriatric: See adult dosage.
Children and Adolescents: Safety and efficacy have not been established.

For the treatment of irritable bowel syndrome (IBS) with diarrhea:
Oral dosage:
Adults: 550 mg PO 3 times daily for 14 days. May repeat course up to twice for persons experiencing a recurrence of symptoms (maximum of 3 total treatment cycles). Data from 2 clinical trials showed more subjects receiving rifaximin experienced adequate relief of IBS symptoms compared to placebo (41% vs. 31%, p= 0.0125 and 41% vs. 32%, p = 0.0263).

For the treatment of pseudomembranous colitis* due to C. difficile infection*:
Oral dosage:
Adults: 400 mg PO 3 times daily for 20 days after 10 days of oral vancomycin for patients with second or subsequent recurrences.

For the treatment of small intestinal bacterial overgrowth*:
Oral dosage:
Adults: 550 mg PO 3 times daily or 800 to 1,600 mg/day PO divided 3 times daily for 7 to 10 days.
Children and Adolescents 8 to 17 years: 200 to 550 mg PO 3 times daily for 7 to 10 days.
Children 3 to 7 years: 200 mg PO 3 times daily for 7 to 10 days.

Maximum Dosage Limits:
-Adults
600 mg/day PO for traveler's diarrhea; 1100 mg/day PO for hepatic encephalopathy; 1650 mg/day for irritable bowel syndrome with diarrhea.
-Geriatric
600 mg/day PO for traveler's diarrhea; 1100 mg/day PO for hepatic encephalopathy; 1650 mg/day for irritable bowel syndrome with diarrhea.
-Adolescents
600 mg/day PO for traveler's diarrhea.
-Children
>= 12 years: 600 mg/day PO for traveler's diarrhea.
< 12 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
There is increased systemic exposure in patients with severe hepatic impairment. Pharmacokinetic trials showed increased Cmax and AUC in patients with Child-Pugh Class A, B, and C (see Pharmacokinetics). Clinical trials were limited to patients with MELD (Model for End-Stage Liver Disease) scores < 25; therefore, caution should be exercised when administering rifaximin to patients with severe hepatic impairment (Child-Pugh class C).

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Abrocitinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with abrocitinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and abrocitinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Adagrasib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with adagrasib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and adagrasib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Amiodarone: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with amiodarone is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and clarithromycin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Asciminib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with asciminib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and asciminib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Atazanavir; Cobicistat: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cobicistat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Brigatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with brigatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and brigatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Cabozantinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cabozantinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cabozantinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Cannabidiol: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cannabidiol is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cannabidiol is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Capmatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with capmatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and capmatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Carvedilol: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with carvedilol is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and carvedilol is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Clarithromycin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and clarithromycin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Cobicistat: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cobicistat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Conivaptan: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with conivaptan is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and conivaptan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Cyclosporine: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cyclosporine is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cyclosporine is a P-gp inhibitor. Coadministration with cyclosporine increased rifaximin overall exposure by 124-fold.

Daclatasvir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with daclatasvir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and daclatasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Daridorexant: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with daridorexant is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and daridorexant is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Darunavir; Cobicistat: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cobicistat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cobicistat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with quinidine is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and quinidine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Dronedarone: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with dronedarone is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and dronedarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Elacestrant: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with elacestrant is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and elacestrant is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Elagolix: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with elagolix is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and elagolix is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with elagolix is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and elagolix is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ivacaftor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Eliglustat: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with eliglustat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and eliglustat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cobicistat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cobicistat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Enasidenib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Erdafitinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with erdafitinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and erdafitinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Erythromycin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with erythromycin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and erythromycin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Etravirine: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with etravirine is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and etravirine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Flibanserin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with flibanserin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and flibanserin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Fostamatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with fostamatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and fostamatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Futibatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with futibatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Gilteritinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with gilteritinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and gilteritinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with glecaprevir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and glecaprevir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold. (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with pibrentasvir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and pibrentasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Ibrutinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ibrutinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ibrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Isavuconazonium: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with isavuconazonium is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and isavuconazonium is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Istradefylline: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with istradefylline is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and istradefylline is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Itraconazole: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with itraconazole is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and itraconazole is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Ivacaftor: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ivacaftor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Ketoconazole: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ketoconazole is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ketoconazole is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and clarithromycin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Lapatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lapatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and lapatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Lasmiditan: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lasmiditan is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and lasmiditan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Ledipasvir; Sofosbuvir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ledipasvir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ledipasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Lenacapavir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lenacapavir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and lenacapavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Levoketoconazole: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ketoconazole is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ketoconazole is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Lomitapide: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lomitapide is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and lomitapide is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Lonafarnib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lonafarnib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and lonafarnib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Lopinavir; Ritonavir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ritonavir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ritonavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Lumacaftor; Ivacaftor: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ivacaftor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Maribavir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with maribavir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and maribavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Mefloquine: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with mefloquine is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and mefloquine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Mifepristone: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with mifepristone is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and mifepristone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Mitapivat: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with mitapivat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and mitapivat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Nelfinavir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with nelfinavir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and nelfinavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Neratinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with neratinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and neratinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Nirmatrelvir; Ritonavir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ritonavir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ritonavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Osimertinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and osimertinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Pacritinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with pacritinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and pacritinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Pirtobrutinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with pirtobrutinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Posaconazole: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with posaconazole is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and posaconazole is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Pretomanid: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with pretomanid is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and pretomanid is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Propafenone: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with propafenone is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and propafenone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Quinidine: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with quinidine is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and quinidine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Quinine: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with quinine is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and quinine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Ranolazine: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ranolazine is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ranolazine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Ritonavir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ritonavir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ritonavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Rolapitant: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with rolapitant is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and rolapitant is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Saquinavir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with saquinavir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and saquinavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Sarecycline: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with sarecycline is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and sarecycline is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Selpercatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with selpercatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and selpercatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with taurursodiol is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and taurursodiol is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with velpatasvir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and velpatasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with velpatasvir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and velpatasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold. (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with voxilaprevir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and voxilaprevir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Sorafenib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with sorafenib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and sorafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Sotorasib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with sotorasib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and sotorasib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Sparsentan: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with sparsentan is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and sparsentan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Stiripentol: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with stiripentol is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and stiripentol is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Temsirolimus: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with temsirolimus is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and temsirolimus is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Tepotinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with tepotinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and tepotinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Tezacaftor; Ivacaftor: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ivacaftor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Ticagrelor: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ticagrelor is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ticagrelor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Trandolapril; Verapamil: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with verapamil is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and verapamil is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Tucatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with tucatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and tucatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Vemurafenib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with vemurafenib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and vemurafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Venetoclax: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with venetoclax is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and venetoclax is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Verapamil: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with verapamil is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and verapamil is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Voclosporin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with voclosporin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and voclosporin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and clarithromycin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Zonisamide: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with zonisamide is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and zonisamide is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Rifaximin is a semi-synthetic derivative of rifampin and acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase thereby blocking 1 of the steps in transcription. This results in inhibition of bacterial protein synthesis and consequently inhibits bacterial growth.

Resistance to rifaximin is caused primarily by mutations in the rpoB gene. This changes the binding site on DNA-dependent RNA polymerase and decreases rifaximin binding affinity, thereby reducing efficacy.

Since oral rifaximin is minimally absorbed, it is concentrated in the gastrointestinal tract, where it exerts its effects. In general, oral antibiotics have been used for hepatic encephalopathy to reduce ammonia-producing enteric bacteria.

Rifaximin is administered orally, although it is largely unabsorbed by the GI tract. Rifaximin is 67.5% bound to plasma proteins in healthy subjects and 62% bound to plasma proteins in patients with hepatic impairment. In an in vitro study, rifaximin was metabolized mainly by CYP3A4. Rifaximin accounted for 18% of radioactivity in plasma suggesting that the absorbed rifaximin undergoes extensive metabolism. After administration of radiolabeled rifaximin to healthy volunteers, 96.62% of the administered radioactivity was recovered in the feces mostly as unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug. Biliary excretion of rifaximin was suggested in a study in which rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa. The mean half-life in healthy subjects at steady-state is 5.63 hours and 6.08 hours in patients with irritable bowel syndrome with diarrhea.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp, OATP1A2, OAPT1B1, and OATP1B3
In vitro studies show that rifaximin is a substrate of CYP3A4, P-gp, and OATP1A2, OAPT1B1, and OATP1B3. In vitro drug interaction studies of rifaximin show that it does not inhibit the CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 isoenzymes. In vitro studies show rifaximin is an inhibitor of P-gp, OATP1A2, OAPT1B1, and OATP1B3. The clinical significance of potential interaction with substrates of these drug transporters is unknown.


-Route-Specific Pharmacokinetics
Oral Route
In healthy volunteers treated with rifaximin 550 mg 3 times daily for 14 days, the median Tmax was 1 hour. The mean Cmax was 4.04 ng/mL after a single dose on day 1 and 2.39 ng/mL on day 14. The mean AUC was 10.4 ng x hour/mL after a single dose on day 1 and 9.3 ng x hour/mL on day 14. A high-fat meal consumed 30 minutes before a 550 mg dose resulted in a delay in the mean Cmax from 0.75 to 0.8 hours to 1.5 hours and increased systemic AUC by 2-fold. The Cmax of rifaximin was unchanged in the fasting vs. the fed state.

After oral administration of rifaximin 200 mg, 400 mg, and 600 mg, systemic exposure increased dose-dependently by approximately 2-fold for both AUC and Cmax from 200 to 400 mg, but with a less than dose-proportional increase of 1.3-fold for both AUC and Cmax from 400 to 600 mg.

In patients with irritable bowel syndrome with diarrhea treated with rifaximin 550 mg 3 times daily for 14 days, the median Tmax was 1 hour. The mean Cmax was 3.49 ng/mL after a single dose on day 1 and 4.22 ng/mL on day 14. The mean AUC was 9.69 ng x hour/mL after a single dose on day 1 and 16 ng x hour/mL on day 14.

Systemic absorption of rifaximin 200 mg 3 times daily was evaluated in 13 shigellosis patients on days 1 and 3 of a 3-day treatment course. Rifaximin plasma concentrations were low and variable and there was no evidence of drug accumulation after repeated administration for 3 days. Peak plasma concentrations (Cmax) on day 1 and day 3 ranged from 0.81 to 3.4 ng/mL and 0.68 to 2.26 ng/mL, respectively. The AUC estimates were 6.95 +/- 5.15 ng x hour/mL and 7.83 +/- 4.94 ng x hour/mL, on day 1 and day 3 respectively. Rifaximin is not suitable for treating systemic bacterial infections because of the limited systemic exposure after oral rifaximin administration.


-Special Populations
Hepatic Impairment
Rifaximin is 62% bound to plasma in patients with hepatic impairment. The systemic exposure is markedly elevated in patients with hepatic impairment compared to healthy subjects. In patients with a history of hepatic encephalopathy, the pharmacokinetic parameters were associated with a high variability. Mean rifaximin exposure (AUC) in patients with a history of hepatic encephalopathy was approximately 12-fold higher than that observed in healthy subjects. Among patients with a history of hepatic encephalopathy, the mean AUC in patients with hepatic impairment of Child-Pugh Class C was 2-fold higher than in patients with hepatic impairment of Child-Pugh Class A. The mean AUC in patients with hepatic impairment of Child-Pugh Class A, B, and C was 10-, 14-, and 21-folder higher, respectively, compared to that in healthy subjects. The Cmax was also increased from that in normal subjects (3.4 +/- 1.6 ng/mL) in patients with hepatic impairment of Child-Pugh Class A (19.5 +/- 11.4 ng/mL), Class B (25.4 +/- 11.9 ng/mL), and Class C (39.7 +/- 13.4 ng/mL).

Renal Impairment
The pharmacokinetics of rifaximin in patients with impaired renal function have not been studied.