Side Effects of Xifaxan (rifaximin)

Xifaxan (rifaximin) is an antibiotic used to treat traveler's diarrhea and hepatic encephalopathy. It is derived from rifamycin, a naturally occurring chemical produced by a bacterium called Streptomyces mediterranei.

Xifaxan is active against Escherichia coli (E. coli) bacterial strains that cause traveler's diarrhea, 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's diarrhea.

Hepatic encephalopathy is a serious neurologic complication of advanced liver disease that 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 hepatic encephalopathy by reducing the intestinal bacteria that produce ammonia. 

Common side effects of Xifaxan include

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

Many of these side effects are also symptoms of traveler's diarrhea, which Xifaxan is used for treating. Xifaxan also causes allergic reactions, rash, and itching. 

Serious side effects of Xifaxan include alteration of the normal bacteria in the colon which encourages overgrowth of some bacteria such as Clostridium difficile and causes inflammation of the colon (pseudomembranous colitis). Signs of pseudomembranous colitis include diarrhea, fever, abdominal pain, and possibly shock.

Xifaxan has a low risk of drug interactions because it is poorly absorbed into the blood stream, and it does not significantly affect liver enzymes that break down most drugs.

The safety of Xifaxan in pregnant women has not been adequately evaluated. It is unknown if Xifaxan passes into breast milk. Consult your doctor before breastfeeding.

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, and itching.

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

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

Clinical Studies Experience

Because clinical trials are 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 with travelers' 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)

Hepatic Encephalopathy

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 taking lactulose concomitantly. 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

Irritable Bowel Syndrome With Diarrhea

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

Across the 3 studies, 96% of patients received at 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 for IBS-D was:

• 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 for IBS-D during the double-blind treatment phase were:

ALT 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 and IBS-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 of C. difficile-associated colitis have been reported.

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.

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.

An in vitro study has suggested that rifaximin induces CYP3A4. However, in patients with normal liver 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 reduced liver function 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. Concomitant cyclosporine, 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.