Side Effects of Xifaxan (rifaximin)

Xifaxan(rifaximin) is an antibiotic used to treattraveler'sdiarrheaandhepatic encephalopathy.It is derived from rifamycin, a naturally occurring chemical produced by a bacterium calledStreptomyces mediterranei.

Xifaxan is active againstEscherichia coli(E. coli) bacterialstrainsthat causetraveler'sdiarrhea,preventing growth of the bacteria by preventing them from manufacturing proteins needed for their replication and survival. By suppressing growth of the bacteria, Xifaxan reduces symptoms of traveler'sdiarrhea.

Hepatic encephalopathyis a serious neurologic complication of advancedliver diseasethat affects the brain. It is believed to be caused by the absorption of ammonia and other chemicals produced by bacteria in the intestine. It is believed that Xifaxan prevents and treats hepaticencephalopathy通过减少肠道细菌产生mmonia.

Common side effects of Xifaxan include

• nausea,
• vomiting,
• constipation,
• urge to defecate,
• dizziness,
• fatigue,
• headache,
• abdominal pain,
• fever,
• gas(flatulence), and
• fluid retention (水肿).

Many of these side effects are also symptoms of traveler's diarrhea, which Xifaxan is used for treating. Xifaxan also causesallergicreactions,rash, anditching.

Serious side effectsof Xifaxan include alteration of the normal bacteria in the colon which encourages overgrowth of some bacteria such asClostridium difficileand causes inflammation of the colon (pseudomembranouscolitis). Signs of pseudomembranous colitis include diarrhea,fever,abdominal pain, and possiblyshock.

Xifaxan has a low risk ofdrug interactionsbecause it is poorly absorbed into the blood stream, and it does not significantly affectliver enzymesthat break down mostdrugs.

The safety of Xifaxan inpregnantwomen has not been adequately evaluated. It is unknown if Xifaxan passes intobreast milk. Consult your doctor beforebreastfeeding.

Common side effects associated with rifaximin include:

• nausea,
• vomiting,
• constipation,
• urge to defecate,
• dizziness,
• fatigue,
• headache,
• abdominal pain,
• fever,
• flatulence, and
• fluid retention (edema).

Many of these side effects are also symptoms of traveler's diarrhea which rifaximin is used for treating. Rifaximin also causes allergic reactions,rash, anditching.

Like other antibiotics rifaximin can alter the normal bacteria in the colon and encourage overgrowth of some bacteria such asClostridium difficilewhich causes inflammation of the colon (pseudomembranous colitis).

Patients who develop signs of pseudomembranous colitis after starting rifaximin (diarrhea, fever, abdominalpain, and possibly shock,) should contact their physician immediately.

Clinical Studies Experience

Becauseclinical trialsare conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Travelers' Diarrhea

The safety of Xifaxan 200 mg taken three times a day was evaluated in patients withtravelers' diarrhea consisting of 320 patients in two placebo-controlled clinical trials with 95% of patients receiving three or four days of treatment with Xifaxan.

The population studied had a mean age of 31.3 (18-79) years of which approximately 3% were ≥65 years old, 53% were male and

• 84% were White,
• 11% were Hispanic.

Discontinuations due to adverse reactions occurred in 0.4% of patients. The adverse reactions leading to discontinuation were taste loss, dysentery, weight decrease,anorexia, nausea and nasal passage irritation.

The adverse reaction that occurred at a frequency ≥2% in Xifaxan-treated patients (n=320) at a higher rate than placebo (n=228) in the two placebo-controlled trials of TD was:

• headache(10% Xifaxan, 9% placebo)

肝性脑病

The data described below reflect exposure to Xifaxan in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days).

The safety of Xifaxan 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n=140) and in a long term followup study (n=280).

The population studied had a mean age of 56 (range: 21 to 82) years; approximately 20% of the patients were ≥65 years old, and

• 61% were male,
• 86% were White, and
• 4% were Black.

Ninety-one percent of patients in the trial were takinglactuloseconcomitantly. The most common adverse reactions that occurred at an incidence ≥5% and at a higher incidence in Xifaxan-treated subjects than in the placebo group in the 6-month trial are provided in Table 1.

Table 1: Most Common Adverse Reactions in HE Trial

MedDRA Preferred Term	Number (%) of Patients
	Xifaxan Tablets 550 mg Twice Daily n=140	Placebo n=159
Peripheral edema	21 (15%)	13 (8%)
Nausea	20 (14%)	21 (13%)
Dizziness	18 (13%)	13 (8%)
Fatigue	17 (12%)	18 (11%)
一个scites	16 (11%)	15 (9%)
Muscle spasms	13 (9%)	11 (7%)
Pruritus	13 (9%)	10 (6%)
一个bdominal pain	12 (9%)	13 (8%)
一个nemia	11 (8%)	6 (4%)
Depression	10 (7%)	8 (5%)
Nasopharyngitis	10 (7%)	10 (6%)
一个bdominal pain upper	9 (6%)	8 (5%)
一个rthralgia	9 (6%)	4 (3%)
Dyspnea	9 (6%)	7 (4%)
Pyrexia	9 (6%)	5 (3%)
Rash	7 (5%)	6 (4%)
* reported in ≥5% of Patients Receiving Xifaxan and at a higher incidence than placebo

Irritable Bowel Syndrome With Diarrhea

The safety of Xifaxan for the treatment ofIBS-Dwas evaluated in 3 placebo-controlled studies in which 952 patients were randomized to Xifaxan 550 mg three times a day for 14 days.

在研究中,96%的患者接受least 14 days of treatment with Xifaxan. In Trials 1 and 2, 624 patients received only one 14-day treatment.

Trial 3 evaluated the safety of Xifaxan in 328 patients who received 1 open-label treatment and 2 double-blind repeat treatments of 14 days each over a period of up to 46 weeks.

The combined population studied had a mean age of 47 (range: 18 to 88) years of whom approximately

• 11% of the patients were ≥65 years old,
• 72% were female,
• 88% were White,
• 9% were Black and
• 12% were Hispanic.

The adverse reaction that occurred at a frequency ≥2% in Xifaxan-treated patients at a higher rate than placebo in Trials 1 and 2 forIBS-Dwas:

• nausea (3% Xifaxan, 2% placebo)

The adverse reactions that occurred at a frequency >2% in Xifaxan-treated patients (n=328) at a higher rate than placebo (n=308) in Trial 3 forIBS-Dduring the double-blind treatment phase were:

一个LT increased (Xifaxan 2%, placebo 1%)

• nausea (Xifaxan 2%, placebo 1%)

Less Common Adverse Reactions

The following adverse reactions, presented by body system, were reported in less than 2% of patients in clinical trials of TD andIBS-D and in less than 5% of patients in clinical trials of HE:

Hepatobiliary disorders:Clostridium colitis

Investigations:Increased blood creatine phosphokinase

Musculoskeletal and connective tissue disorders:myalgia

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, reported in ≥5% of Patients Receiving Xifaxan and at a higher incidence than placebo frequency of reporting or causal connection to Xifaxan.

Infections And Infestations

Cases ofC. difficile-associated colitis have been reported.

General

Hypersensitivity reactions, including exfoliativedermatitis, rash, angioneurotic edema (swelling of face and tongue anddifficulty swallowing),urticaria, flushing, pruritus andanaphylaxishave been reported. These events occurred as early as within 15 minutes of drug administration.

Effects Of Xifaxan On Other Drugs

Substrates Of Cytochrome P450 enzymes

Rifaximin is not expected to inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 in clinical use based on in vitro studies.

一个n in vitro study has suggested that rifaximin induces CYP3A4. However, in patients with normalliver function, Xifaxan 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 reducedliverfunction who have elevated rifaximin concentrations.

Effects Of Other Drugs On Xifaxan

In vitro studies suggested that rifaximin is a substrate of P-glycoprotein, OATP1A2, OATP1B1 and OATP1B3. Concomitantcyclosporine, an inhibitor of P-glycoprotein and OATPs, significantly increased the systemic exposure to rifaximin.

Cyclosporine

Co-administration of cyclosporine, with Xifaxan resulted in 83-fold and 124-fold increases in rifaximin mean Cmax and AUC8 in healthy subjects. The clinical significance of this increase in systemic exposure is unknown.