Rifaximax Tablet 400 mg

Rifaximin Tablets IP 200 mg

Rifaximax 200

Each film coated tablet contains :

Rifaximin IP 200 mg

Excipients q.s.

Colours : Sunset Yellow FCF & Titanium Dioxide I.P.

Film-coated tablet.

200 mg

4.1 Therapeutic indication

Rifaximax 200 mg is indicated for For infectious diarrhoea in adults. Rifaximax 400 mg is indicated for For the treatment of hepatic encephalopathy. Rifaximax 550 mg is indicated for Reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients > 18 years of age.

4.2 Posology and method of administration

Posology

Rifaximax 200 mg

200 mg every 8 hours for three days (total 9 doses). Rifaximin must not be used for more than 3 days even if symptoms continue and a second course of treatment must not be taken.

Rifaximax 400 mg

400 mg tablet taken every 8 hours as per the need assessed by treating physician.

Rifaximax 550 mg

Recommended dose : 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. Rifaximin can be administered with or without food

Paediatric population

The safety and efficacy of Rifaximin tablets in children (aged less than 18 years) have not been established.

Elderly

No dosage adjustment is necessary as the safety and efficacy data of Rifaximin tablets showed no differences between the elderly and the younger patients.

Hepatic impairment

A dosage adjustment for patients with hepatic insufficiency is not necessary.

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

4.3 Contraindications

Rifaximax must not be used in the following conditions :

• Hypersensitivity to rifaximin, rifamycin-derivatives or to any of the excipients.
• Cases of intestinal obstruction.

4.4 Special warnings and precautions for use

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including rifaximin. The potential association of rifaximin treatment with CDAD and pseudomembranous colitis (PMC) cannot be ruled out.

Due to the lack of data and the potential for severe disruption of gut flora with unknown consequences, concomitant administration of rifaximin with other rifamycins is not recommended.

Patients should be informed that despite the negligible absorption of the drug (less than 1%), like all rifamycin derivatives, rifaximin may cause a reddish discolouration of the urine. Hepatic Impairment : use with caution in patients with severe (Child-Pugh C) hepatic impairment and in patients with MELD (Model for End-Stage Liver Disease) score > 25. Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein such as ciclosporin is needed.

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 treatment with rifaximin. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

4.5 Interaction with other medicinal products and other forms of interaction

There is no experience regarding administration of rifaximin to subjects who are taking another rifamycin antibacterial agent to treat a systemic bacterial infection. In vitro data show that rifaximin did not inhibit the major cytochrome P-450 (CYP) drug metabolizing enzymes (CYPs1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4). In in vitro induction studies, rifaximin did not induce CYP1A2 and CYP 2B6 but was a weak inducer of CYP3A4.

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, antiepileptics, antiarrhythmics, oral contraceptives), due to the higher systemic exposure with respect to healthy subjects.

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. 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 P-gp and/or CYP3A4 can increase the systemic exposure of rifaximin.

In healthy subjects, co-administration of a single dose of ciclosporin (600 mg), a potent Pglycoprotein inhibitor, with a single dose of rifaximin (550 mg) resulted in 83-fold and 124- fold increases in rifaximin mean Cmax and AUC∞. 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).

4.6 Special Populations

Pregnancy

There is no or limited data from the use of rifaximin in pregnant women. Animal studies showed transient effects on ossification and skeletal variations in the foetus. As a precautionary measure, use of rifaximin during pregnancy is not recommended.

Breastfeeding

It is unknown whether rifaximin/metabolites are excreted in human milk. A risk to the breast-fed 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.

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to male and female fertility.

4.7 Effects on ability to drive and use machines

Dizziness has been reported in clinical controlled trials. However, rifaximin has negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

Website : https://www.zuventus.co.in/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine

4.9 Overdose

No case of overdose has been reported.

In clinical trials with patients suffering from traveller's diarrhoea doses of up to 1800 mg/day have been tolerated without any severe clinical sign. Even in patients/subjects with normal bacterial flora rifaximin in dosages of up to 2400 mg/day for 7 days did not result in any relevant clinical symptoms related to the high dosage.

In case of accidental overdose, symptomatic treatment and supportive care are suggested.

5.1 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-deaminating bacteria, thereby reducing the production of ammonia and other compounds that are believed to be important to the pathogenesis of hepatic encephalopathy.

5.2 Pharmacodynamic properties

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 traveller's diarrhoea 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 colonise 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 meningitidiswill 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, Bacteroides 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

5.3 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 metabolised 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 14C-rifaximin is almost exclusively and completely excreted in faeces (96.9 % of the administered dose). The urinary recovery of 14Crifaximin does not exceed 0.4% of the administered dose.

6.1 Animal toxicology or pharmacology

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In a rat embryofetal development study, a slight and transient delay in ossification that did not affect the normal development of the offspring, was observed at 300 mg /kg /day (2.7 times the proposed clinical dose for hepatic encephalopathy, adjusted for body surface area). In the rabbit, following oral administration of rifaximin during gestation, an increase in the incidence of skeletal variations was observed (at doses similar to those proposed clinically for hepatic encephalopathy). The clinical relevance of these findings is unknown.

Rifaximax tablets contain rifaximin, a non-aminoglycoside semi-synthetic, non-systemic antibiotic derived from rifamycin SV. It is an antibacterial drug Each film-coated tablet of Rifaximax contains Rifaximin 220 / 400 / 550 mg.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Rifaximax 200 : A strip of 10 tablets.

Rifaximax 400 : A strip of 10 tablets.

Rifaximax 550 : A strip of 10 tablets.

8.4 Storage and handling instructions

Store in a dry place at a temperature not exceeding 25°C. Protect from light.

Keep out of reach of children.

Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including RIFAXIMAX, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibiotics alters the normal flora of the colon which may lead to C. difficile. Patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If diarrhea occurs after therapy or does not improve or worsens during therapy, advise patients to contact a physician as soon as possible.

Administration with food

Inform patients that Rifaximax may be taken with or without food.

Antibacterial resistance

Counsel patients that antibacterial drugs including RIFAXIMAX should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Rifaximax is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by RIFAXIMAX or other antibacterial drugs in the future.

12 July 2024

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