Xifaxan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XIFAXAN

Composition:

Active substance: rifaximin;

One film-coated tablet contains 550 mg of rifaximin;

Excipients: sodium starch glycolate (type A), glycerol distearate, colloidal anhydrous silicon dioxide, talc, microcrystalline cellulose, hypromellose, titanium dioxide (E 171), disodium edetate, propylene glycol, iron oxide red (E 172).

Dosage form. Film-coated tablets.

Main physicochemical properties: pink, oval, biconvex, film-coated tablets, embossed with "RX" on one side.

Pharmacotherapeutic group. Agents used in intestinal infections. Antibiotics. ATC code A07A A11.

Pharmacological Properties

Pharmacodynamics

The active substance of the medicinal product XIFAXAN is rifaximin – an antimicrobial agent of the rifamycin class that irreversibly binds to the beta subunit of bacterial DNA-dependent RNA polymerase, thereby inhibiting bacterial RNA and protein synthesis.

Rifaximin has a broad spectrum of antimicrobial activity against most Gram-positive and Gram-negative aerobic and anaerobic bacteria, including strains that produce ammonia. Rifaximin may inhibit the division of urea-deaminating bacteria, thereby reducing the production of ammonia and other compounds believed to be important in the pathogenesis of hepatic encephalopathy.

Mechanism of Resistance

Resistance to rifaximin is primarily due to a reversible chromosomal single-step rearrangement of the rpoB gene encoding bacterial RNA polymerase.

Clinical studies investigating changes in intestinal flora sensitivity in patients with traveler's diarrhea failed to detect the emergence of rifaximin-resistant Gram-positive (e.g., enterococci) or Gram-negative (E. coli) microorganisms during a 3-day course of treatment with rifaximin.

The development of resistance in normal intestinal bacterial flora was studied following repeated high-dose administration of rifaximin in healthy volunteers and patients with inflammatory bowel disease. Resistant strains emerged during the study, but they were unstable, did not colonize the gastrointestinal tract, and did not displace rifaximin-sensitive strains. After discontinuation of treatment, resistant strains rapidly disappeared.

Preclinical and clinical data suggest that treatment with rifaximin in patients carrying strains of Mycobacterium tuberculosis and Neisseria meningitidis will not lead to the development of resistance to rifampicin.

Susceptibility

Rifaximin is a non-absorbable antibacterial agent. In vitro susceptibility testing results cannot reliably predict bacterial susceptibility or resistance to rifaximin. Currently, there are insufficient data to establish a clinical breakpoint for rifaximin susceptibility.

In vitro studies have evaluated the activity of rifaximin against several pathogens, including ammonia-producing bacteria such as strains of Escherichia coli, Clostridium, Enterobacteriaceae, and Bacteroides. Due to its very low gastrointestinal absorption, rifaximin is clinically ineffective against invasive pathogens, even when these bacteria appear susceptible in vitro.

Clinical Efficacy

Hepatic Encephalopathy

The efficacy and safety of rifaximin administered at a dose of 550 mg twice daily in adult patients with hepatic encephalopathy (HE) in remission were evaluated in a 6-month randomized, double-blind, placebo-controlled phase 3 study.

A total of 299 subjects were randomized to receive either rifaximin 550 mg twice daily (n = 140) or placebo (n = 159) for 6 months. In the main study, 91% of subjects in both groups concurrently received lactulose. Patients with a MELD (Model for End-Stage Liver Disease) score > 25 were excluded from the study.

The primary endpoint was time to the first breakthrough episode of overt HE, after which the patient was withdrawn from the study. A breakthrough episode of overt HE was defined as a clear worsening of neurological function and an increase in the Conn score to grade ≥ 2. In patients with a baseline Conn score of 0, a breakthrough episode of overt HE was defined as an increase in the Conn score to 1 and asterixis grade to 1.

During the 6-month period, a breakthrough episode of overt HE occurred in 31 of 140 patients in the rifaximin group (22%) and in 73 of 159 patients in the placebo group (46%). Rifaximin reduced the risk of HE exacerbation by 58% (p < 0.0001) and the risk of HE-related hospitalization by 50% (p < 0.013) compared to placebo.

Combination therapy with rifaximin and lactulose demonstrated a statistically significant reduction in mortality in patients with HE compared to lactulose alone, as shown in a systematic review and meta-analysis of four randomized and three observational studies involving 1822 patients (risk difference [RD] -0.11, 95% CI from -0.19 to -0.03, P = 0.009). Additional sensitivity analyses confirmed these results. In particular, a pooled analysis of two randomized studies including 320 patients treated for up to 10 days and followed during hospitalization showed a statistically significant reduction in mortality (RD -0.22, 95% CI from -0.33 to -0.12, P < 0.0001).

Irritable Bowel Syndrome with Diarrhea

The efficacy and safety of rifaximin administered at a dose of 550 mg three times daily for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) were evaluated in three randomized, multicenter, double-blind, placebo-controlled studies involving adult patients.

In studies RFIB3007 and RFIB3008, which had identical designs, a total of 1258 patients meeting Rome II criteria for IBS were randomized to receive either rifaximin 550 mg three times daily (n = 624) or placebo (n = 634) for 14 days, followed by a 10-week observation period without treatment. Patients with constipation-predominant IBS were excluded from the studies.

The primary endpoint in both studies was the proportion of patients who adequately responded to treatment—defined as adequate relief of IBS symptoms for at least two weeks during the month following the 14-day treatment period.

Adequate symptom relief during the month following the 2-week treatment period was observed more frequently in patients receiving rifaximin compared to those receiving placebo (126 of 309 patients [41%] vs. 98 of 314 patients [31%], p = 0.0125 in study RFIB3007; 128 of 315 patients [41%] vs. 103 of 320 patients [32%], p = 0.0263 in study RFIB3008).

The studies also evaluated a composite endpoint defined as the number of patients meeting treatment response criteria based on abdominal pain and stool consistency related to IBS.

During the month following treatment, a greater proportion of patients receiving rifaximin responded based on abdominal pain and stool consistency compared to those receiving placebo (144 of 309 patients [47%] vs. 121 of 314 patients [39%], p < 0.05 in study RFIB3007; 147 of 315 patients [47%] vs. 116 of 320 patients [36%], p < 0.01 in study RFIB3008).

Study RFIB3053, a 46-week trial, evaluated repeat treatment in adult patients with IBS-D meeting Rome III criteria. A total of 2579 patients received an initial 14-day open-label course of rifaximin, followed by a 4-week observation period without treatment. At the end of the observation period, patients were assessed for treatment response defined by the following criteria:

• Improvement in weekly average abdominal pain score by ≥ 30% compared to baseline as assessed by daily diary;
• Reduction in the number of days per week with daily stool consistency type 6 or 7 on the Bristol Stool Scale by at least 50% compared to baseline.

Patients who responded to treatment were then monitored for up to 20 weeks without treatment to assess for recurrence of IBS-D symptoms such as abdominal pain or soft/watery stools.

Upon recurrence of these symptoms, patients were randomized to a double-blind, placebo-controlled re-treatment phase.

A total of 1074 (44%) of 2438 patients who responded to initial treatment with improvement in abdominal pain and stool consistency were evaluated over 22 weeks for sustained response or recurrence of IBS symptoms. The response rates for each IBS symptom during the open-label phase were similar to those observed in studies RFIB3007 and RFIB3008.

Subsequently, a total of 636 patients experiencing symptom recurrence were randomized to the double-blind re-treatment phase. The median time to recurrence in patients who initially responded during the open-label rifaximin treatment phase was 10 weeks (range: 6 to 24 weeks).

These patients received either rifaximin 550 mg three times daily (n = 328) or placebo (n = 308) for two additional 14-day re-treatment courses separated by a 10-week interval. The patient groups receiving rifaximin and placebo had similar baseline IBS symptom scores at the time of recurrence and randomization to the double-blind phase, although symptom scores were less severe than at entry into the open-label phase.

In the double-blind, placebo-controlled part of the study, the proportion of patients responding to re-treatment based on IBS-related abdominal pain and stool consistency (as defined above) was assessed during the 4 weeks following the first course of re-treatment with rifaximin.

During the month following treatment, a greater proportion of patients receiving rifaximin responded based on abdominal pain and stool consistency compared to those receiving placebo (125 of 328 patients [38%] vs. 97 of 308 patients [31%], p < 0.05). The difference in treatment response rate was 7% with a 95% confidence interval (from 0.9% to 16.9%).

Pharmacokinetics

Absorption

Pharmacokinetic studies have demonstrated minimal (less than 1%) absorption of rifaximin in its polymorphic α form following oral administration. After repeated administration of therapeutic doses to both healthy volunteers and patients with impaired intestinal mucosa (inflammatory bowel disease), plasma levels of rifaximin were very low (less than 10 ng/mL). In patients with HE, following administration of rifaximin 550 mg twice daily, mean rifaximin exposure was approximately 12 times higher than that observed in healthy volunteers receiving the same doses.

Clinically insignificant increases in systemic absorption of rifaximin were observed when rifaximin was administered within 30 minutes after a high-fat breakfast.

In patients with IBS-D receiving rifaximin 550 mg twice daily, mean exposure was comparable to that observed in healthy individuals.

Distribution

Rifaximin is moderately bound to human plasma proteins. In vivo, the mean degree of protein binding of rifaximin was 67.5% in healthy volunteers and 62% in patients with liver impairment.

Metabolism

Studies have shown that rifaximin is not metabolized during passage through the gastrointestinal tract.

In a study using radiolabeled rifaximin, 0.025% of the administered dose was excreted in urine, and less than 0.01% of the dose was metabolized to 25-desacetylrifaximin—the only metabolite of rifaximin identified in humans.

Excretion

Data from the study with radiolabeled rifaximin suggest that the drug is almost exclusively and completely eliminated in feces (96.9% of the administered dose). Urinary excretion of labeled rifaximin does not exceed 0.4% of the administered dose.

Linearity/Non-linearity

Rifaximin systemic exposure in humans is considered to exhibit non-linear, dose-dependent pharmacokinetics, consistent with absorption limited by the dissolution rate of rifaximin.

Clinical characteristics.

Indications.

• Reduction in recurrence of overt episodes of hepatic encephalopathy in patients aged 18 years and older;
• treatment of irritable bowel syndrome with diarrhea in patients aged 18 years and older.

Contraindications.

• Hypersensitivity to rifaximin, rifamycin derivatives, or any of the excipients of the drug;
• intestinal obstruction.

Interaction with other medicinal products and other types of interactions.

There is no experience with concomitant use of rifaximin and other antibacterial agents of the rifamycin class for the treatment of systemic bacterial infections.

In vitro study data indicate that rifaximin does not inhibit the major enzymes of the cytochrome P450 system (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) responsible for drug metabolism. In in vitro induction studies, rifaximin did not induce CYP1A2 and CYP2B6, but acted as a weak inducer of the CYP3A4 isoenzyme of cytochrome P450.

In clinical drug interaction studies involving healthy volunteers, rifaximin was shown not to significantly affect the pharmacokinetics of substrates of the CYP3A4 enzyme. However, in patients with impaired liver function, the possibility cannot be excluded that rifaximin may reduce the efficacy of concomitantly administered CYP3A4 enzyme substrates (e.g., warfarin, antiepileptic and antiarrhythmic agents, and oral contraceptives), due to increased systemic exposure to rifaximin in such patients compared to healthy individuals.

In patients receiving warfarin, both decreases and increases in international normalized ratio (INR) values have been reported when rifaximin was coadministered. If such concomitant administration is necessary, careful monitoring of the INR is recommended when initiating or discontinuing rifaximin. Dose adjustments of oral anticoagulants may be required.

In vitro study results suggest that rifaximin is a substrate with moderate affinity for P-glycoprotein (P-gp) and is metabolized by the CYP3A4 isoenzyme. It is unknown whether concomitant administration with drugs that inhibit CYP3A4 may increase systemic exposure to rifaximin.

In healthy subjects, concomitant administration of a single 600 mg dose of cyclosporine, a potent P-glycoprotein inhibitor, and a single 550 mg dose of rifaximin resulted in 83-fold and 124-fold increases in mean Cmax and AUC∞ values for rifaximin, respectively. The clinical significance of this increase in systemic exposure is unknown.

In vitro studies have investigated the potential for drug interactions at the level of transport systems. Results of these studies suggest that clinical interactions between rifaximin and other compounds excreted via P-gp and other transport proteins (MRP2, MRP4, BCRP, and BSEP) are unlikely.

Special precautions for use

Cases of diarrhea caused by Clostridium difficile (CDAD) have been reported for nearly all antibiotics, including rifaximin. A potential association between rifaximin treatment and CDAD or pseudomembranous colitis cannot be excluded.

Concomitant use of rifaximin with other rifamycins is not recommended due to lack of data and the potential risk of severe intestinal flora imbalance with unpredictable consequences.

Despite minimal absorption (less than 1%), rifaximin, similar to other rifamycin derivatives, may turn urine reddish in color; patients should be informed about this possibility.

The drug should be used with caution in patients with severe hepatic impairment (Child-Pugh class C) and in patients with a MELD score > 25.

Rifaximin should be administered with caution when used concomitantly with P-glycoprotein inhibitors such as cyclosporine.

When rifaximin is administered to patients taking warfarin, both decreases and increases in international normalized ratio (INR) have been reported, with bleeding events observed in some cases. If concomitant use is necessary, close monitoring of INR is required when initiating or discontinuing rifaximin. Dose adjustments of oral anticoagulants may be needed to maintain the desired level of anticoagulation.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Data on the use of rifaximin in pregnant women are lacking or limited. In animal studies, transient effects on ossification and skeletal changes in the fetus were observed. As a precautionary measure, the use of rifaximin during pregnancy is not recommended.

It is unknown whether rifaximin or its metabolites pass into human breast milk; therefore, a risk to breastfed infants cannot be excluded. Hence, during breastfeeding, a decision should be made whether to discontinue breastfeeding or to discontinue/abstain from the drug, taking into account the benefits of breastfeeding for the child and the necessity of treatment for the mother.

Animal studies have not shown any direct or indirect harmful effects of rifaximin on male or female fertility.

Ability to affect reaction speed when driving vehicles or operating machinery.

If dizziness occurs during treatment with this medicinal product, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

Overt Hepatic Encephalopathy

The recommended dose is 550 mg twice daily as long-term treatment to reduce recurrences of overt hepatic encephalopathy.

In the main clinical studies, 91% of patients were concurrently receiving lactulose.

The duration of treatment should be determined by the physician.

Irritable Bowel Syndrome with Diarrhea (IBS-D)

The recommended dose is 550 mg three times daily for 14 days. For patients with recurrent symptoms, up to two treatment courses using this regimen may be administered.

Method of Administration

Administer orally, swallowing with a glass of water. The drug may be taken independently of food intake.

Special Patient Groups

Geriatric Patients

Since there are no differences in safety and efficacy of rifaximin between younger patients and elderly patients, dosage adjustment in elderly patients is not required.

Patients with Hepatic Impairment

Available clinical data indicate increased systemic exposure to rifaximin in patients with hepatic impairment compared to healthy individuals. Systemic exposure to rifaximin was approximately 10, 13, and 20 times higher in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively, compared to healthy volunteers. Nevertheless, the increased systemic exposure in patients with hepatic impairment should be considered in light of the local gastrointestinal action of rifaximin, its low systemic bioavailability, and the available safety data from use in patients with liver cirrhosis. Therefore, due to its primarily local action, dosage adjustment of rifaximin in these patients is not recommended.

Patients with Renal Impairment

Clinical data on the use of rifaximin in patients with renal impairment are limited. Although dosage adjustment is not recommended for such patients, XIFAXAN should be administered with caution in patients with renal impairment.

Pediatric Population

The safety and efficacy of XIFAXAN in children (under 18 years of age) have not been established.

Overdose

No cases of overdose have been reported.

In clinical trials treating travelers' diarrhea, doses of rifaximin up to 1800 mg per day were well tolerated without the development of serious clinical manifestations. Administration of doses up to 2400 mg per day for 7 days in patients and healthy volunteers did not result in any clinically significant adverse effects related to high-dose exposure.

In the event of accidental overdose, symptomatic and supportive treatment is recommended.

Adverse Reactions

Hepatic Encephalopathy

The safety of rifaximin in patients with hepatic encephalopathy (HE) in remission was evaluated in two studies – RFHE3001 and RFHE3002.

In study RFHE3001, treatment with rifaximin 550 mg twice daily for 6 months (140 patients) was compared to placebo (159 patients), while in study RFHE3002, 322 patients were treated, of whom 152 patients were from study RFHE3001. Patients received 550 mg of rifaximin twice daily for 12 months (66% of patients) and for 24 months (39% of patients).

Additionally, in three further studies, 152 patients with HE received various doses of rifaximin ranging from 600 mg to 2400 mg per day for up to 14 days.

The adverse reactions observed in the placebo-controlled study RFHE3001, the long-term study RFHE3002, and during post-marketing surveillance are listed below. Adverse reactions are classified by system organ class and frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000).

Infections and infestations

Uncommon: Clostridial infection, urinary tract infection, candidiasis.

Rare: Pneumonia, cellulitis, upper respiratory tract infections, rhinitis.

Blood and lymphatic system disorders

Uncommon: Anaemia.

Metabolism and nutrition disorders

Uncommon: Anorexia, hyperkalaemia.

Rare: Dehydration.

Psychiatric disorders

Common: Depression.

Uncommon: Confusional state, anxiety, somnolence, insomnia.

Nervous system disorders

Common: Dizziness, headache.

Uncommon: Balance disorder, amnesia, convulsions, attention disorders, hypaesthesia, memory disorders.

Vascular disorders

Uncommon: Flushing.

Rare: Arterial hypertension, arterial hypotension.

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea.

Uncommon: Pleural effusion.

Rare: Chronic obstructive pulmonary disease.

Gastrointestinal disorders

Common: Upper abdominal pain, sensation of abdominal distension, diarrhoea, nausea, vomiting, ascites.

Uncommon: Abdominal pain, oesophageal varices haemorrhage, dry mouth, stomach discomfort.

Rare: Constipation.

Skin and subcutaneous tissue disorders

Common: Rash, pruritus.

Musculoskeletal and connective tissue disorders

Common: Muscle spasm, arthralgia.

Uncommon: Myalgia.

Rare: Back pain.

Renal and urinary disorders

Uncommon: Dysuria, pollakiuria.

Rare: Proteinuria.

General disorders and administration site conditions

Common: Peripheral oedema.

Uncommon: Oedema, pyrexia.

Rare: Asthenia.

Injury, poisoning and procedural complications

Uncommon: Fall.

Rare: Contusion, procedural pain.

Irritable bowel syndrome with diarrhoea

The safety of rifaximin for the treatment of irritable bowel syndrome with diarrhoea (IBS-D) was evaluated in three placebo-controlled studies, in which 952 patients were randomized to receive 550 mg of rifaximin three times daily for 14 days. In these three studies, 96% of patients completed at least the 14-day treatment with rifaximin.

In two studies, 624 patients received only one 14-day course of treatment. In the third study, the safety of rifaximin was evaluated in 328 patients who underwent one open-label course and two double-blind repeat treatment courses of 14 days each over a period of up to 46 weeks. The combined patient population in the studies had a mean age of 47 years (range 18 to 88 years).

In patients receiving rifaximin in the first two studies, adverse reactions observed at a frequency ≥ 2% and more frequently than in the placebo group included:

• Gastrointestinal disorders: nausea (3% – rifaximin, 2% – placebo).

In the third study, during the double-blind treatment phase for IBS-D in patients receiving rifaximin (n = 328), adverse reactions observed at a frequency ≥ 2% and more frequently than in the placebo group (n = 308) included:

• Investigations: increased ALT levels (rifaximin – 2%, placebo – 1%);
• Gastrointestinal disorders: nausea (rifaximin – 2%, placebo – 1%).

Adverse reactions observed in less than 2% of patients treated for IBS-D in clinical studies included:

• Infections and infestations: Clostridium difficile colitis,
• Investigations: increased blood creatine phosphokinase levels,
• Musculoskeletal and connective tissue disorders: myalgia.

Post-marketing surveillance

Additional adverse reactions have been reported during post-marketing use of XIFAXAN. The frequency of these adverse reactions cannot be estimated reliably because the information is derived from spontaneous reports. Therefore, the frequency of such adverse events is listed as unknown (cannot be estimated based on available data).

System organ class by MedDRA	Frequency unknown
Blood and lymphatic system disorders	Thrombocytopenia
Immune system disorders	Anaphylactic reactions, angioneurotic edema, hypersensitivity
Vascular disorders	Pre-syncope, syncope
Hepatobiliary disorders	Abnormal liver function test results
Skin and subcutaneous tissue disorders	Dermatitis, eczema
Investigations	Abnormal international normalized ratio values

Reporting of adverse reactions following marketing authorization of the medicinal product is of significant importance. This enables continuous monitoring of the benefit-risk balance of the use of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of the reach of children.

Packaging. 14 tablets in a blister made of PVC-PE-PVDC/aluminum; 2, 3 or 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Alfasigma S.p.A./Alfasigma S.p.A.

Manufacturer's address and address of the place of business activity.

Via Enrico Fermi 1, 65020 Alanno (Pescara), Italy /
Via Enrico Fermi 1, 65020 Alanno (Pescara), Italy.