Xifaxan

Travelers’ Diarrhea

XIFAXAN is indicated for the treatment of travelers’ diarrhea (TD) caused by noninvasive strains of Escherichia coliin adults and pediatric patients 12 years of age and older.

Limitations of Use

XIFAXAN should not be used in patients with diarrhea complicated by fever or blood in the stool or diarrhea due to pathogens other than Escherichia coli [see Warnings and Precautions ( 5.1), Clinical Pharmacology ( 12.4), Clinical Studies ( 14.1)].

Hepatic Encephalopathy

XIFAXAN is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults.

In the placebo-controlled trial of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed.

XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores >25, and only 8.6% of patients in the placebo-controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction [see Warnings and Precautions ( 5.4), Use in Specific Populations ( 8.7), Clinical Pharmacology ( 12.3)].

Irritable Bowel Syndrome with Diarrhea

XIFAXAN is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

Dosage for Travelers’ Diarrhea

The recommended dosage of XIFAXAN is 200 mg taken orally three times a day for 3 days.

Dosage for Hepatic Encephalopathy

The recommended dosage of XIFAXAN is 550 mg taken orally two times a day.

Dosage for Irritable Bowel Syndrome with Diarrhea

The recommended dosage of XIFAXAN is 550 mg taken orally three times a day for 14 days. Patients who experience a recurrence of symptoms can be retreated up to two times with the same dosage regimen.

Administration

XIFAXAN can be taken with or without food [see Clinical Pharmacology ( 12.3)].

Pregnancy

Risk Summary

There are no available data on XIFAXAN 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 1,650 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 [see Data]. 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.

Data

Animal Data

Rifaximin was teratogenic in rats at doses of 150 to 300 mg/kg (approximately 2.5 to 5 times the recommended dose for TD [600 mg per day], and approximately 1.3 to 2.6 times the recommended dose for HE [1,100 mg per day], and approximately 0.9 to 1.8 times the recommended dose for IBS-D [1,650 mg per day] adjusted for body surface area). Rifaximin was teratogenic in rabbits at doses of 62.5 to 1,000 mg/kg (approximately 2 to 33 times the recommended dose for TD [600 mg per day], and approximately 1.1 to 18 times the recommended dose for HE [1,100 mg per day], and approximately 0.7 to 12 times the recommended dose for IBS-D [1,650 mg per day] adjusted for body surface area). These effects include cleft palate, agnathia, jaw shortening, hemorrhage, eye partially open, small eyes, brachygnathia, incomplete ossification, and increased thoracolumbar vertebrae.

A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses of rifaximin up to 300 mg/kg per day (approximately 5 times the recommended dose for TD [600 mg per day], and approximately 2.6 times the recommended dose for HE [1,100 mg per day], and approximately 1.8 times the recommended dose for IBS-D [1,650 mg per day] adjusted for body surface area).

Lactation

Risk Summary

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 XIFAXAN and any potential adverse effects on the breastfed infant from XIFAXAN or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of XIFAXAN 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 XIFAXAN 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 XIFAXAN for TD did not include sufficient numbers of 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.

Renal Impairment

The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.

Hepatic Impairment

Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC τ) of rifaximin was about 10-, 14-, and 21-fold higher in those patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment [see Warnings and Precautions ( 5.4), Clinical Pharmacology ( 12.3), Clinical Studies ( 14.2)] .

Travelers’ Diarrhea Not Caused by Escherichia coli

XIFAXAN 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 XIFAXAN if diarrhea symptoms get worse or persist more than 24 to 48 hours and alternative antibiotic therapy should be considered.

XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea caused by Shigellaspp. and Salmonellaspp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigellaspp., or Salmonellaspp. may be suspected as causative pathogens [ see Indications and Usage ( 1.1)].

Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, 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. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficilecause 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. difficilemay 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 XIFAXAN 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 XIFAXAN to patients with severe hepatic impairment (Child-Pugh Class C) [ see Use in Specific Populations ( 8.7), Clinical Studies ( 14.2)].

Concomitant Use with P-glycoprotein Inhibitors

Concomitant administration of drugs that are P-glycoprotein (P-gp) inhibitors with XIFAXAN can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of XIFAXAN 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 [see Drug Interactions ( 7.1), Clinical Pharmacology ( 12.3)].