XIFAXAN (Page 2 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN.

Infections and Infestations

Cases of C. difficile -associated colitis have been reported [see Warnings and Precautions (5.2)].

General

Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.

7 DRUG INTERACTIONS

In vitro studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from 2 to 200 ng/mL [see Clinical Pharmacology (12.3)]. Rifaximin is not expected to inhibit these enzymes in clinical use.

An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. 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.

An in vitro study suggested that rifaximin is a substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein can increase the systemic exposure of rifaximin [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium.

The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients or less than 0.1 times the dose in patients with hepatic encephalopathy, based upon plasma AUC comparisons.

Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.

8.3 Nursing Mothers

It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of XIFAXAN 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established.

The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients < 18 years of age.

8.5 Geriatric Use

Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects.

In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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.

8.6 Renal Impairment

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

8.7 Hepatic Impairment

Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUCτ ) of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh 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 ), Nonclinical Toxicology ( 13.2 ), and Clinical Studies ( 14.2 )].

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