TABLE OF CONTENTS
Rifaximin tablets is a semi-synthetic, non-systemic antibiotic. The chemical name for rifaximin is (2S,16Z, 18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-α]-benzimidazole-1,15(2H)-dione,25-acetate. The empirical formula is C43H51N3O11 and its molecular weight is 785.9. The chemical structure is represented below:
Rifaximin tablets for oral administration are film-coated and contain 200 mg or 550 mg of rifaximin. Inactive ingredients are colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose, microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide.
|2. INDICATIONS AND USAGE|
To reduce the development of drug-resistant bacteria and maintain the effectiveness of rifaximin and other antibacterial drugs, rifaximin 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.
2.1 Travelers’ Diarrhea
Rifaximin 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].
Limitations of Use
Rifaximin 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.
2.2 Hepatic Encephalopathy
Rifaximin 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age.
In the trials of rifaximin 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.
Rifaximin 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, Use in Specific Populations].
|3. DOSAGE AND ADMINISTRATION|
3.1 Dosage for Travelers’ Diarrhea
The recommended dose of rifaximin is one 200 mg tablet taken orally three times a day for 3 days. Rifaximin can be administered orally, with or without food.
3.2 Dosage for Hepatic Encephalopathy
The recommended dose of rifaximin is one 550 mg tablet taken orally two times a day, with or without food.
Rifaximin tablets are contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in rifaximin tablets.
Rifaximin acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis.
Escherichia coli has been shown to develop resistance to rifaximin in vitro. However, the clinical significance of such an effect has not been studied.
Rifaximin is a structural analog of rifampin. Organisms with high rifaximin minimum inhibitory concentration (MIC) values also have elevated MIC values against rifampin. Cross-resistance between rifaximin and other classes of antimicrobials has not been studied.
|6. USE IN SPECIFIC POPULATIONS|
6.1 Usage in Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies in pregnant women. Rifaximin tablets should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
6.2 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 rifaximin tablets, 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.
6.3 Pediatric Use
The safety and effectiveness of rifaximin 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established.
The safety and effectiveness of rifaximin 550 mg for HE have not been established in patients less than 18 years of age.
6.4 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 rifaximin 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.
6.5 Renal Impairment
The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.
6.6 Hepatic Impairment
Following administration of rifaximin 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUCt) 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 rifaximin is administered to patients with severe hepatic impairment.
|7. WARNINGS AND PRECAUTIONS|
7.1 Travelers’ Diarrhea Not Caused by Escherichia coli
Rifaximin 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 rifaximin if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered.
Rifaximin is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of rifaximin in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. Rifaximin should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.
7.2 Clostridium difficile-Associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including rifaximin, 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.
7.3 Development of Drug Resistant Bacteria
Prescribing rifaximin 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.
7.4 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 less than 25. Therefore, caution should be exercised when administering rifaximin to patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations].
|8. ADVERSE REACTIONS|
8.1 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.
The safety of rifaximin 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 rifaximin. The population studied had a mean age of 31.3 (18-79) years of which approximately 3% were greaer than or equal to 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 irrigation.
All adverse reactions for rifaximin 200 mg three times daily that occurred at a frequency greater than or equal to 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 Rifaximin Tablets, 200 mg Three Times Daily, in Placebo-Controlled Studies
* NOS: Not otherwise specified
The data described below reflect exposure to rifaximin 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 rifaximin 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 greater than or equal to 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 greater than or equal to 5% and at a higher incidence in rifaximin 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 Rifaximin and at a Higher Incidence Than Placebo
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 rifaximin 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
8.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of rifaximin. 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 rifaximin.
Infections and Infestations
Cases of C. difficile-associated colitis have been reported [see Warnings and Precautions].
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.
No specific information is available on the treatment of overdosage with rifaximin. In clinical studies at doses higher than the recommended dose (> 600 mg/day for travelers’ diarrhea or > 1100 mg/day for hepatic encephalopathy), adverse reactions were similar in subjects who received doses higher than the recommended dose and placebo. In the case of overdosage, discontinue rifaximin, treat symptomatically, and institute supportive measures as required.
|10. 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. Rifaximin is not expected to inhibit these enzymes in clinical use.
An in vitro study has suggested that rifaximin induces CYP3A4. 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
Systemic absorption of rifaximin (200 mg three times daily) was evaluated in 13 subjects challenged with shigellosis on Days 1 and 3 of a three-day course of treatment. Rifaximin plasma concentrations and exposures were low and variable. There was no evidence of accumulation of rifaximin following repeated administration for 3 days (9 doses). Peak plasma rifaximin concentrations after 3 and 9 consecutive doses ranged from 0.81 to 3.4 ng/mL on Day 1 and 0.68 to 2.26 ng/mL on Day 3. Similarly, AUC0-last estimates were 6.95 ± 5.15 ng•h/mL on Day 1 and 7.83 ± 4.94 ng•h/mL on Day 3. Rifaximin is not suitable for treating systemic bacterial infections because of limited systemic exposure after oral administration [see Warnings and Precautions].
After a single dose and multiple doses of rifaximin 550 mg in healthy subjects, the mean time to reach peak plasma concentrations was about an hour. The pharmacokinetic (PK) parameters were highly variable and the accumulation ratio based on AUC was 1.37.
The PK of rifaximin in patients with a history of HE was evaluated after administration of rifaximin, 550 mg two times a day. The PK parameters were associated with a high variability and mean rifaximin exposure (AUCt) in patients with a history of HE (147 ng•h/mL) was approximately 12-fold higher than that observed in healthy subjects following the same dosing regimen (12.3 ng•h/ mL). When PK parameters were analyzed based on Child-Pugh Class A, B, and C, the mean AUCτ was 10-, 13-, and 20-fold higher, respectively, compared to that in healthy subjects (Table 3).
Table 3. Mean (± SD) Pharmacokinetic Parameters of Rifaximin at Steady-State in Patients with a History of Hepatic Encephalopathy by Child-Pugh Class1
1 Cross-study comparison with PK parameters in healthy subjects
2 Median (range)
Food Effect in Healthy Subjects
A high-fat meal consumed 30 minutes prior to rifaximin dosing in healthy subjects delayed the mean time to peak plasma concentration from 0.75 to 1.5 hours and increased the systemic exposure (AUC) of rifaximin by 2-fold (Table 4).
Table 4. Mean (± SD) Pharmacokinetic Parameters After Single-Dose Administration of Rifaximin Tablets 550 mg in Healthy Subjects Under Fasting and Fed Conditions (N = 12)
1 Median (range)
Rifaximin can be administered with or without food [see Dosage and Administration].
Rifaximin is moderately bound to human plasma proteins. In vivo, the mean protein binding ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when rifaximin 550 mg was administered.
Metabolism and Excretion
In a mass balance study, after administration of 400 mg 14C-rifaximin orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces almost exclusively as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug. Rifaximin accounted for 18% of radioactivity in plasma. This suggests that the absorbed rifaximin undergoes metabolism with minimal renal excretion of the unchanged drug. The enzymes responsible for metabolizing rifaximin are unknown.
In a separate study, rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa, suggesting biliary excretion of rifaximin.
Renal Insufficiency: The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.
Hepatic Insufficiency: The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy subjects. The mean AUC in patients with Child-Pugh Class C hepatic impairment was 2-fold higher than in patients with Child-Pugh Class A hepatic impairment (see Table 3), [see Warnings and Precautions and Use in Specific Populations].
|12. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: XIFAXAN, by SALIX PHARMS.
b) Generic drugs: None.
2) How Supplied:
XIFAXAN® Tablets are available as:
200 mg tablet is a pink-colored, round, biconvex tablet with “Sx” debossed on one side. It is available in the following presentations:
The 550 mg tablet is a pink-colored, oval, biconvex tablet with “rfx” debossed on one side. It is available in the following presentations:
3) Storage: Store XIFAXAN® Tablets at 20–25°C (68–77°F); excursions permitted to 15–30°C (59-86°F). See USP Controlled Room Temperature.