XIFAXAN

XIFAXAN- rifaximin tablet
Dispensing Solutions, Inc.

1 INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN when used to treat infection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

1.1 Travelers’ Diarrhea

XIFAXAN 200 mg is indicated for the treatment of patients (≥ 12 years of age) with travelers’ diarrhea caused by noninvasive strains of Escherichia coli [ see Warnings and Precautions (5) , Clinical Pharmacology (12.4) and Clinical Studies (14.1)].

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.

1.2 Hepatic Encephalopathy

XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age.

In the trials 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 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)].

2 DOSAGE AND ADMINISTRATION

2.1 Dosage for Travelers’ Diarrhea

The recommended dose of XIFAXAN is one 200 mg tablet taken orally three times a day for 3 days. XIFAXAN can be administered orally, with or without food [see Clinical Pharmacology (12.3)].

2.2 Dosage for Hepatic Encephalopathy

The recommended dose of XIFAXAN is one 550 mg tablet taken orally two times a day, with or without food[see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

XIFAXAN is a pink-colored biconvex tablet and is available in the following strengths:

• 200 mg – a round tablet debossed with “Sx” on one side.
• 550 mg – an oval tablet debossed with “rfx” on one side.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis [see Adverse Reactions ( 6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 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 24-48 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 Shigella spp. and Salmonella spp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

5.2 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. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause 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. difficile may 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.

5.3 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.

5.4 Severe (Child-Pugh C) Hepatic Impairment

There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen 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 C)

[see Use in Specific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].

6 ADVERSE REACTIONS

6.1 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.

All adverse reactions for XIFAXAN 200 mg three times daily that occurred at a frequency ≥ 2% in the two placebo-controlled trials combined are provided in Table 1. (These include adverse reactions that may be attributable to the underlying disease.)

Table 1. All Adverse Reactions With an Incidence ≥2% Among Patients Receiving XIFAXAN Tablets, 200 mg Three Times Daily, in Placebo-Controlled Studies

MedDRA Preferred Term	Number (%) of Patients
	XIFAXANTablets, 600 mg/day (N = 320)	Placebo N = 228
*NOS: Not otherwise specified
Flatulence	36 (11%)	45 (20%)
Headache	31 (10%)	21 (9%)
Abdominal Pain NOS*	23 (7%)	23 (10%)
Rectal Tenesmus	23 (7%)	20 (9%)
Defecation Urgency	19 (6%)	21 (9%)
Nausea	17 (5%)	19 (8%)
Constipation	12 (4%)	8 (4%)
Pyrexia	10 (3%)	10 (4%)
Vomiting NOS	7 (2%)	4 (2%)

The following adverse reactions, presented by body system, have also been reported in <2% of patients taking XIFAXAN in the two placebo-controlled clinical trials where the 200 mg tablet was taken three times a day for travelers’ diarrhea. The following includes adverse reactions regardless of causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Lymphocytosis, monocytosis, neutropenia

Ear and Labyrinth Disorders: Ear pain, motion sickness, tinnitus

Gastrointestinal Disorders: Abdominal distension, diarrhea NOS, dry throat, fecal abnormality NOS, gingival disorder NOS, inguinal hernia NOS, dry lips, stomach discomfort

General Disorders and Administration Site Conditions: Chest pain, fatigue, malaise, pain NOS, weakness

Infections and Infestations: Dysentery NOS, respiratory tract infection NOS, upper respiratory tract infection NOS

Injury and Poisoning: Sunburn

Investigations: Aspartate aminotransferase increased, blood in stool, blood in urine, weight decreased

Metabolic and Nutritional Disorders: Anorexia, dehydration

Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, muscle spasms, myalgia, neck pain

Nervous System Disorders: Abnormal dreams, dizziness, migraine NOS, syncope, loss of taste

Psychiatric Disorders: Insomnia

Renal and Urinary Disorders: Choluria, dysuria, hematuria, polyuria, proteinuria, urinary frequency

Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea NOS, nasal passage irritation, nasopharyngitis, pharyngitis, pharyngolaryngeal pain, rhinitis NOS, rhinorrhea

Skin and Subcutaneous Tissue Disorders: Clamminess, rash NOS, sweating increased

Vascular Disorders: Hot flashes NOS

Hepatic Encephalopathy

The data described below reflect exposure to XIFAXAN 550 mg 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 follow-up study (n = 280). The population studied had a mean age of 56.26 (range: 21-82) years; approximately 20% of the patients were ≥ 65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. All adverse reactions that occurred at an incidence ≥ 5% and at a higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).

Table 2: Adverse Reactions Occurring in ≥ 5% of Patients Receiving XIFAXAN and at a Higher Incidence Than Placebo

	Number (%) of Patients
MedDRA Preferred Term	XIFAXAN Tablets 550 mg TWICE DAILY N = 140	Pla ceboN = 159
	Edema peripheral	21 (15%)	13 (8%)
Nausea	20 (14%)	21 (13%)
Dizziness	18 (13%)	13 (8%)
Fatigue	17 (12%)	18 (11%)
Ascites	16 (11%)	15 (9%)
Muscle spasms	13 (9%)	11 (7%)
Pruritus	13 (9%)	10 (6%)
Abdominal pain	12 (9%)	13 (8%)
Abdominal distension	11 (8%)	12 (8%)
Anemia	11 (8%)	6 (4%)
Cough	10 (7%)	11 (7%)
Depression	10 (7%)	8 (5%)
Insomnia	10 (7%)	11 (7%)
Nasopharyngitis	10 (7%)	10 (6%)
Abdominal pain upper	9 (6%)	8 (5%)
Arthralgia	9 (6%)	4 (3%)
Back pain	9 (6%)	10 (6%)
Constipation	9 (6%)	10 (6%)
Dyspnea	9 (6%)	7 (4%)
Pyrexia	9 (6%)	5 (3%)
Rash	7 (5%)	6 (4%)

The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure.

Ear and Labyrinth Disorders: Vertigo

Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort

General Disorders and Administration Site Conditions: Chest pain, generalized edema, influenza like illness, pain NOS

Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS

Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain

Investigations: Weight increased

Metabolic and Nutritional Disorders: Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia

Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia, pain in extremity

Nervous System Disorders: Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor

Psychiatric Disorders: Confusional state

Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis

Vascular Disorders: Hypotension