CLINICAL PHARMACOLOGY

Pharmacodynamics Properties

• Pharmacotherapeutic Group: Intestinal, Anti-Infective - Antibiotics. Rifaximin is a Non-Aminoglycoside Semi-Synthetic, Non-Systemic Antibiotic derived from Rifamycin SV
• Mechanism of Action: Rifaximin is an antibacterial drug of the Rifamycin class that irreversibly binds the beta sub-unit of the bacterial enzyme DNA-dependent RNA polymerase and consequently inhibits bacterial RNA synthesis. Rifaximin has a broad antimicrobial spectrum against most of the Gram-positive and negative, aerobic and anaerobic bacteria, including ammonia producing species. Rifaximin may inhibit the division of Urea-Delaminating Bacteria, thereby reducing the production of Ammonia and other compounds that are believed to be important to the pathogenesis of Hepatic Encephalopathy.
• Mechanism of Resistance: The development of resistance to Rifaximin is primarily a reversible chromosomal one-step alteration in the rpoB gene encoding the bacterial RNA polymerase. Clinical studies that investigated changes in the susceptibility of intestinal flora of patients affected by Traveler’s Diarrhea failed to detect the emergence of drug resistant Gram-positive (e.g. Enterococci) and Gram-negative (E. coli) organisms during a three-day course of treatment with Rifaximin.
• Development of resistance in the normal intestinal bacterial flora was investigated with repeated, high doses of Rifaximin in healthy volunteers and Inflammatory Bowel Disease patients. Strains resistant to Rifaximin developed, but were unstable and did not Colonized the gastrointestinal tract or replace Rifaximin-sensitive strains. When treatment was discontinued resistant strains disappeared rapidly. Experimental and clinical data suggest that the treatment with Rifaximin of patients Harbouring strains of Mycobacterium Tuberculosis or Neisseria Meningitides will not select for Rifampicin Resistance.
• Susceptibility: Rifaximin is a Non-Absorbed Antibacterial agent. In vitro susceptibility testing cannot be used to reliably establish susceptibility or resistance of bacteria to Rifaximin. There are currently insufficient data available to support the setting of a clinical breakpoint for susceptibility testing. Rifaximin has been evaluated in vitro on several pathogens including Ammonia producing bacteria as Escherichia coli spp, Clostridium spp, Enterobacteriaceae, Bactericides spp. Due to the very low absorption from the gastro-intestinal tract Rifaximin is not clinically effective against invasive pathogens, even though these bacteria are susceptible in vitro.

Pharmacokinetic Properties

• Absorption: Pharmacokinetic studies in Rats, Dogs and Humans demonstrated that after oral administration Rifaximin in the polymorph α form is poorly absorbed (less than 1%). After repeated administration of therapeutic doses of Rifaximin in healthy volunteers and patients with damaged intestinal mucosa (Inflammatory Bowel Disease), plasma levels are negligible (less than 10 ng/mL). In HE patients, administration of Rifaximin 550 mg twice a day showed mean Rifaximin exposure approximately 12-fold higher than that observed in healthy volunteers following the same dosing regimen. A clinically irrelevant increase of Rifaximin systemic absorption was observed when administered within 30 minutes of a high-fat breakfast.
• Distribution: 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.
• Biotransformation: Analysis of faecal extracts demonstrated that Rifaximin is found as the intact molecule, implying that it is neither degraded nor metabolized during its passage through the Gastrointestinal Tract. In a study using radio-labelled Rifaximin, Urinary recovery of Rifaximin was 0.025% of the administered dose, while < 0.01% of the dose was recovered as 25-Desacetylrifaximin, the only Rifaximin metabolite that has been identified in Humans.
• Elimination: A study with radio-labelled Rifaximin suggested that Rifaximin is almost exclusively and completely excreted in faeces (96.9 % of the administered dose). The urinary recovery of Rifaximin does not exceed 0.4% of the administered dose.
• Linearity/Non-Linearity: The rate and extent of systemic exposure of humans to Rifaximin appeared to be characterized by non-linear (dose-dependent) kinetic which is consistent with the possibility of dissolution-rate-limited absorption of Rifaximin.

DRUG-DRUG INTERACTIONS

• In vitro studies have shown that Rifaximin did not inhibit cytochrome P450 Isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations up to 200 ng/mL (at least 10 times the clinical Cmax). Rifaximin is not expected to inhibit these enzymes in clinical use.
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• In healthy subjects, clinical drug interaction studies demonstrated that Rifaximin did not significantly affect the pharmacokinetics of CYP3A4 substrates, however, in Hepatic Impaired patients it cannot be excluded that Rifaximin may decrease the exposure of concomitant CYP3A4 substrates administered (e.g. Warfarin, Antiepileptic’s, Antiarrhythmic and Oral Contraceptives), due to the higher systemic exposure with respect to healthy subjects.
• An in vitro study suggested that Rifaximin is a moderate substrate of P-glycoprotein (P-gp) and metabolized by CYP3A4. It is unknown whether concomitant drugs which inhibit CYP3A4 can increase the systemic exposure of Rifaximin.
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• In healthy subjects, co-administration of a single dose of Ciclosporin (600 mg), a potent P-Glycoprotein inhibitor, with a single dose of Rifaximin (550 mg) resulted in 83-fold and 124-fold increases in Rifaximin mean Cmax and AUC. Ciclosporin is also an inhibitor of OATP, Breast Cancer Resistance Protein (BCRP) and a weak inhibitor of CYP3A4; the relative contribution of inhibition of each transporter by Ciclosporin to the increase in Rifaximin exposure is unknown. The clinical significance of this increase in systemic exposure is unknown.
• The potential for drug-drug interactions to occur at the level of transporter systems has been evaluated in vitro and these studies suggest that a clinical interaction between Rifaximin and other compounds that undergo efflux via P-gp and other transport proteins is unlikely (MRP2, MRP4, BCRP and BSEP).
• Both decreases and increases in international normalized ratio have been reported in patients maintained on Warfarin and prescribed Rifaximin. If co-administration is necessary, the international normalized ratio should be carefully monitored with the addition or withdrawal of Rifaximin. Adjustments in the dose of Oral Anticoagulants may be necessary.
• There is no experience regarding administration of Rifaximin to subjects who are taking another Rifamycin Antibacterial agent to treat a systemic bacterial infection.

INDICATIONS

• 200 mg is used to treat Traveler’s Diarrhea that is caused by bacteria that do not invade the gut wall, in people aged 12 years and older. It is not effective for diarrhea caused by bacteria that invade the gut wall.
• Prevention of the recurrence of Hepatic Encephalopathy where other treatments have failed or are contraindicated.

DOSAGE AND METHOD OF ADMINISTRATION:

• For Traveler’s Diarrhea: The recommended dosage of RIFAZEX Tablets is one 200 mg tablet three times a day for three days (a total of 9 doses).
• For Hepatic Encephalopathy: Recommended dose is 550 mg twice a day. The clinical benefit was established from a controlled study in which subjects were treated for 6 months. Treatment beyond 6 months should take into consideration the individual balance between benefits and risks, including those associated with the progression of Hepatic Dysfunction.
• Pediatrics Population: The safety and efficacy of Rifaximin in pediatric patients (aged less than 18 years) have not been established.
• Elderly: No dosage adjustment is necessary as the safety and efficacy data of Rifaximin showed no differences between the elderly and the younger patients.
• Hepatic Impairment: No dosage adjustment is necessary for patients with Hepatic Insufficiency.
• Renal Impairment: Although dosing change is not anticipated, caution should be used in patients with Impaired Renal Function.
• Method of Administration: Orally with a glass of water. Rifaximin can be administered with or without food.

SIDE-EFFECTS

Common side effects and they worry you:

• Dizziness, Headache
• Wind, Abdominal Bloating, Abdominal Pain, Constipation,
• Diarrhea
• Involuntary, Painful, or Ineffective Straining on the Toilet
• Nausea, Vomiting
• Fever

Less common side effects include:

• Thrush, Cold sore, Swollen Throat, Inflammation or
• Infection of the Nose or Throat.
• Loss of Appetite, Dehydration.
• Depressed Mood, Sleeplessness, Nervousness
• Earache
• Cough, Dry or Sore Throat, Runny Nose,
• Shortness of Breath, Blocked Nose
• Muscle Cramps, Muscle Pain, Back or Neck Pain
• Chills, cold sweats, perspiration, flu-like illness
• Rash, Blotchy Skin, Hot Flushes.

Tell your doctor as soon as possible if you notice any of the following:

• Diarrhea: Rifaximin like nearly all antibiotics, can alter the mix of bacteria in the intestine. This can lead to an overgrowth of a bacteria called Clostridium Difficile (C. difficile). If you take Rifaximin, there is a small risk that you could experience diarrhea caused by C. difficile.

Consult your doctor immediately or go to the Accident & Emergency department of your nearest hospital if you notice any of the following:

• Swelling of the face, lips or tongue which may make swallowing or breathing difficult.
• Asthma, wheezing, shortness of breath.
• Sudden or severe itching, skin rash, hives.

WARNING AND PRECAUTIONS

• Use with P-glycoprotein Inhibitors: Caution should be exercised when concomitant use of Rifaximin and a P Glycoprotein inhibitor such as Ciclosporin is needed.
• Use with Warfarin: Both decreases and increases in international normalized ratio (in some cases with bleeding events) have been reported in patients maintained on warfarin and prescribed Rifaximin. If co-administration is necessary, the international normalized ratio should be carefully monitored with the addition or withdrawal of Rifaximin. Adjustments in the dose of oral anticoagulants may be necessary.
• Effects on Fertility: There were no effects on fertility in rats treated with Rifaximin at oral doses up to 300 mg/kg/day (about 2.5 times the MRHD based on body surface area).
• Use in Pregnancy: Pregnancy Category B1: Non clinical studies of placental transfer of Rifaximin/metabolites have not been conducted. There was no evidence of Teratogenicity in pregnant rats or rabbits treated with Rifaximin during the period of Organogenesis at respective oral doses up to 300 and 1000 mg/kg/day. The dose in rats was about 2.5 times the MRHD based on body surface area. Compared with clinical exposure (plasma AUC) at the MRHD, the exposure in rabbits was slightly greater than that in Healthy volunteers but less than that in hepatically impaired patients.
• Use in Lactation: It is unknown whether Rifaximin/metabolites are excreted in human milk. A risk to the child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Rifaximin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
• Oral administration of Rifaximin to rats from early gestation to weaning at doses up to 300 mg/kg/day (about 2.5 times the MRHD based on body surface area) did not elicit any adverse effects on gestation or parturition, or on offspring viability, development and reproductive performance.
• Pediatric Use: The safety and effectiveness of Rifaximin for the prevention of recurrence of Hepatic encephalopathy have not been established in patients under 18 years of age.
• Use in the Elderly: In the controlled trial with Rifaximin 550 mg for Hepatic Encephalopathy, 19.4% were aged 65 years 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.
• Genotoxicity: Rifaximin was not Genotoxic in the bacterial reverse mutation assay, chromosomal aberratio n assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay.
• Carcinogenicity: The carcinogenic potential of Rifaximin was examined in a 2 year study with CD rats. Oral administration at doses up to 250 mg/kg/day (about twice the MRHD based on body surface area) produced no evidence of a carcinogenic effect except for an increased trend in malignant schwannomas in the heart in males but not females, at an incidence (5%) exceeding the maximum historical control incidence (1.7%). Despite lack of statistical significance of pairwise testing and absence of this finding in females, a possible relationship to treatment cannot be dismissed.
• There was no increase in Tumors in Tg.rasH2 mice treated orally with Rifaximin for 26 weeks at doses up to 2000 mg/kg/day (mean plasma concentrations 2-5 times the clinical Cmax in healthy volunteers, less than clinical exposure in HepaticaIIy impaired patients).
• 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. Hyper toxin 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.
• Renal Impairment: No clinical data are available on the use of Rifaximin in patients with impaired renal function.
• Severe (Child-Pugh C) Hepatic Impairment: There is increased systemic exposure in patients with hepatic impairment. The clinical trials were limited to patients with MELD scores < 25. Therefore, caution should be exercised when administering Rifaximin to patients with severe Hepatic Impairment (Child-Pugh C).
• Development of drug resistant bacteria: Resistant strains of bacteria including Staphylococcus aureus are more likely to develop if patients are exposed to Rifaximin long term. It is likely that strains resistant to Rifaximin will also be resistant to Rifampicin. Therefore Rifaximin is not recommended for use in patients at low risk for development of further episodes of HE or who have a satisfactory response to alternative treatments.

CONTRAINDICATIONS

• Rifaximin is contraindicated in patients with a Hypersensitivity to Rifaximin, any of the Rifamycin antimicrobial agents, or any of the components in Rifaximin.
• Hypersensitivity reactions have included Exfoliative Dermatitis, Angioneurotic Oedema, and Anaphylaxis.
• Cases of intestinal obstruction.