Normix

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Normix and other antibacterial drugs, Normix 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.

Travelers’ Diarrhea

Normix is indicated for the treatment of travelers' diarrhea (TD) caused by noninvasive strains of Escherichia coli in adults and pediatric patients 12 years of age and older.

Limitations Of Use

Normix 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.

Hepatic Encephalopathy

Normix is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults.

In the trials of Normix 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.

Normix 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.

Irritable Bowel Syndrome With Diarrhea

Normix is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

Dosage For Travelers ’ Diarrhea

The recommended dose of Normix is one 200 mg tablet taken orally three times a day for 3 days.

Dosage For Hepatic Encephalopathy

The recommended dose of Normix is one 550 mg tablet taken orally two times a day.

Dosage For Irritable Bowel Syndrome With Diarrhea

Sections or subsections omitted from the full prescribing information are not listed.

The recommended dose of Normix is one 550 mg tablet taken orally three times a day for 14 days.

Patients who experience a recurrence of symptoms can be retreated up to two times with the same dosage regimen.

Administration

Normix can be taken with or without food.

Normix is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in Normix. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Travelers’ Diarrhea Not Caused By Escherichia Coli

Normix 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 Normix if diarrhea symptoms get worse or persist more than 24 to 48 hours and alternative antibiotic therapy should be considered.

Normix is not effective in cases of travelers' diarrhea due to Campylobacter jejuni. The effectiveness of Normix in travelers' diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. Normix should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

Clostridium Difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Normix, 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.

Development Of Drug-Resistant Bacteria

Prescribing Normix 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.

Severe (Child-Pugh Class C) Hepatic Impairment

There is increased systemic exposure in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering Normix to patients with severe hepatic impairment (Child-Pugh Class C).

Concomitant Use With P-glycoprotein Inhibitors

Concomitant administration of drugs that are P-glycoprotein inhibitors with Normix can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of Normix and a P-glycoprotein inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-glycoprotein inhibitors may further increase the systemic exposure to rifaximin.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Malignant schwannomas in the heart were significantly increased in male Crl:CD® (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg per day (doses equivalent to 2.4 to 4 times the recommended dose of 200 mg three times daily for TD, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for HE, based on relative body surface area comparisons). There was no increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for 26 weeks at 150 to 2000 mg/kg per day (doses equivalent to 1.2 to 16 times the recommended daily dose for TD and equivalent to 0.7 to 9 times the recommended daily dose for HE, based on relative body surface area comparisons).

Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay. There was no effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately 5 times the clinical dose of 600 mg per day for TD, and approximately 2.6 times the clinical dose of 1100 mg per day for HE, adjusted for body surface area).

Use In Specific Populations

Pregnancy

Risk Summary

There are no available data on Normix use in pregnant women to inform any drug associated risks. Teratogenic effects were observed in animal reproduction studies following administration of rifaximin to pregnant rats and rabbits during organogenesis at doses approximately 0.9 to 5 times and 0.7 to 33 times, respectively of the recommended human doses of 600 mg to 1650 mg per day. In rabbits, ocular, oral and maxillofacial, cardiac, and lumbar spine malformations were observed. Ocular malformations were observed in both rats and rabbits at doses that caused reduced maternal body weight gain. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise pregnant women of the potential risk to a fetus.

Data

Animal Data

Rifaximin was teratogenic in rats at doses of 150 to 300 mg/kg (approximately 2.5 to 5 times the recommended dose for TD [600 mg per day], and approximately 1.3 to 2.6 times the recommended dose  for HE [1100 mg per day], and approximately 0.9 to 1.8 times the recommended dose for IBS-D [1650 mg per day] adjusted for body surface area). Rifaximin was teratogenic in rabbits at doses of 62.5 to 1000 mg/kg (approximately 2 to 33 times the recommended dose for TD [600 mg per day], and approximately 1.1 to 18 times the recommended dose for HE [1100 mg per day], and approximately 0.7 to 12 times the recommended dose for IBS-D [1650 mg per day] adjusted for body surface area). These effects include cleft palate, agnathia, jaw shortening, hemorrhage, eye partially open, small eyes, brachygnathia, incomplete ossification, and increased thoracolumbar vertebrae.

A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses of rifaximin up to 300 mg/kg per day (approximately 5 times the recommended dose for TD [600 mg per day], and approximately 2.6 times the recommended dose for HE [1100 mg per day], and approximately 1.8 times the recommended dose for IBS-D [1650 mg per day] adjusted for body surface area).

Lactation

Risk Summary

There is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breastfed infant, or the effects of rifaximin on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Normix and any potential adverse effects on the breastfed infant from Normix or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of Normix has not been established in pediatric patients less than 12 years of age with TD or in patients less than 18 years of age for HE and IBS-D.

Geriatric Use

Of the total number of patients in the clinical study of Normix for HE, 19% of patients were 65 and over, while 2% were 75 and over. In the clinical studies of IBS-D, 11% of patients were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either indication. Clinical studies with Normix for TD did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. 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.

Renal Impairment

The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.

Hepatic Impairment

Following administration of Normix 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC τ) of rifaximin was about 10-, 14-, and 21-fold higher in those patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) and severe (Child- Pugh Class 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 Normix is administered to patients with severe hepatic impairment.

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 Normix 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 Normix. 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.

The adverse reaction that occurred at a frequency ≥2% in Normix-treated patients (n=320) at a higher rate than placebo (n=228) in the two placebo-controlled trials of TD was:

• headache (10% Normix, 9% placebo)

Hepatic Encephalopathy

The data described below reflect exposure to Normix 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 Normix 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 followup study (n=280). The population studied had a mean age of 56 (range: 21 to 82) years; approximately 20% of the patients were ≥65 years old, 61% were male, 86% were White, and 4% were Black. Ninetyone percent of patients in the trial were taking lactulose concomitantly. The most common adverse reactions that occurred at an incidence ≥5% and at a higher incidence in Normix-treated subjects than in the placebo group in the 6-month trial are provided in Table 1.

Table 1: Most Common Adverse Reactions in HE Trial

Irritable Bowel Syndrome With Diarrhea

The safety of Normix for the treatment of IBS-D was evaluated in 3 placebo-controlled studies in which 952 patients were randomized to Normix 550 mg three times a day for 14 days. Across the 3 studies, 96% of patients received at least 14 days of treatment with Normix. In Trials 1 and 2, 624 patients received only one 14-day treatment. Trial 3 evaluated the safety of Normix in 328 patients who received 1 open-label treatment and 2 double-blind repeat treatments of 14 days each over a period of up to 46 weeks. The combined population studied had a mean age of 47 (range: 18 to 88) years of whom approximately 11% of the patients were ≥65 years old, 72% were female, 88% were White, 9% were Black and 12% were Hispanic.

The adverse reaction that occurred at a frequency ≥2% in Normix-treated patients at a higher rate than placebo in Trials 1 and 2 for IBS-D was:

• nausea (3% Normix, 2% placebo)

The adverse reactions that occurred at a frequency >2% in Normix-treated patients (n=328) at a higher rate than placebo (n=308) in Trial 3 for IBS-D during the double-blind treatment phase were:

ALT increased (Normix 2%, placebo 1%)

• nausea (Normix 2%, placebo 1%)

Less Common Adverse Reactions

The following adverse reactions, presented by body system, were reported in less than 2% of patients in clinical trials of TD and IBS-D and in less than 5% of patients in clinical trials of HE:

Hepatobiliary disorders: Clostridium colitis

Investigations: Increased blood creatine phosphokinase

Musculoskeletal and connective tissue disorders: myalgia

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Normix. 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, reported in ≥5% of Patients Receiving Normix and at a higher incidence than placebo frequency of reporting or causal connection to Normix.

Infections And Infestations

Cases of C. difficile-associated colitis have been reported.

General

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 Normix. In clinical studies at doses higher than the recommended dose (greater than 600 mg per day for TD, greater than 1100 mg per day for HE or greater than 1650 mg per day for IBS-D), adverse reactions were similar in subjects who received doses higher than the recommended dose and placebo. In the case of overdosage, discontinue Normix, treat symptomatically, and institute supportive measures as required.

Absorption

In healthy subjects, the mean time to reach peak rifaximin plasma concentrations was about an hour and the mean Cmax ranged 2.4 to 4 ng/mL after a single dose and multiple doses of Normix 550 mg.

Travelers Diarrhea

Systemic absorption of Normix (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. Normix is not suitable for treating systemic bacterial infections because of limited systemic exposure after oral administration.

Hepatic Encephalopathy

Mean rifaximin exposure (AUC τ) in patients with a history of HE was approximately 12-fold higher than that observed in healthy subjects. Among patients with a history of HE, 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.

Irritable Bowel Syndrome With Diarrhea

In patients with irritable bowel syndrome with diarrhea (IBS-D) treated with Normix 550 mg three times a day for 14 days, the median Tmax was 1 hour and mean Cmax and AUCtau were generally comparable with those in healthy subjects. After multiple doses, AUC was 1.65-fold higher than that on Day 1 in IBS-D patients (Table 2).

Table 2: Mean (± SD) Pharmacokinetic Parameters of Rifaximin Following Normix 550 mg Three Times a Day in IBS-D Patients and Healthy Subjects

Food Effect In Healthy Subjects

A high-fat meal consumed 30 minutes prior to Normix 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 but did not significantly affect Cmax.

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 Normix was administered.

Elimination

The mean half-life of rifaximin in healthy subjects at steady-state was 5.6 hours and was 6 hours in IBSD patients.

Metabolism

In an in vitro study rifaximin was metabolized mainly by CYP3A4. Rifaximin accounted for 18% of radioactivity in plasma suggesting that the absorbed rifaximin undergoes extensive metabolism.

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 mostly as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug.

Biliary excretion of rifaximin was suggested by a separate study in which rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa.