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Rifaximin - Indications, Contraindications, Dosage, Warnings, and Clinical Pharmacology

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Rifaximin is a medicine to treat traveler's diarrhea and irritable bowel syndrome. The below article explains Rifaximin in detail.

Medically reviewed by

Dr. Rajesh Jain

Published At July 26, 2022
Reviewed AtMarch 28, 2024

Overview:

Rifaximin is a semi-synthetic, non-systemic antibiotic that does not get absorbed into the bloodstream. Therefore, it acts directly on the bacteria affecting the gastrointestinal (GI) tract. Rifaximin treats traveler's diarrhea, irritable bowel syndrome (IBS), and hepatic encephalopathy.

In 2004, Rifaximin 200 mg got FDA (Food and Drug Administration) approval. In 2010, Rifaximin 550 mg received FDA approval, and in 2015, Rifaximin 550 mg received FDA approval for an additional indication.

Rifaximin works by arresting the growth of bacteria that lead to diarrhea in traveler's diarrhea and IBS. Severe liver damage can lead to the accumulation of toxins in the bloodstream, which in normal cases are cleared up by a healthy liver. These toxins reach the brain, thereby affecting brain functioning. The drug is also proved to be beneficial in treating hepatic encephalopathy. Rifaximin 200 mg is used to treat traveler's diarrhea in adults and children older than 12. Rifaximin 550 mg is used to treat IBS with diarrhea in adults and prevent episodes of hepatic encephalopathy in adults with liver dysfunction. It treats hepatic encephalopathy by stopping the growth of bacteria that release toxins into the bloodstream. However, Rifaximin is not effective in treating cases of traveler's diarrhea that are associated with bloody stools or fever. Also, the drug is ineffective in treating viral infections like cold and influenza.

How Does Rifaximin Work?

Rifaximin is a non-systemic antibiotic that works on small intestine bacteria. A study conducted in rats showed that Rifaximin reduces inflammation and pain sensitivity in the small intestine, increases the beneficial bacteria in the colon, and stabilizes the overall bacterial community. Rifaximin also prevents harmful bacteria from attaching to the cells of the small intestine. The outstanding feature of the drug is its ability to retain and promote the growth of good bacteria, unlike other antibiotics that have a negative impact on gut flora.

Indications and Uses of Rifaximin:

Rifaximin is commonly used in the treatment of:

  • Traveler's diarrhea in patients above 12 years of age in whom the condition is caused by non-invasive strains of Escherichia coli (E.coli).

  • Irritable bowel syndrome with diarrhea.

  • Hepatic encephalopathy.

Dosage and Administration:

Rifaximin tablets are recommended to be taken orally with or without food. For patients with traveler's diarrhea, the recommended dosage is one tablet of 200 mg thrice a day for three days.

Contraindications of Rifaximin:

The use of the drug is contraindicated in the following conditions:

  1. Diarrhea that is complicated with blood in stools or fever.

  2. Diarrhea is caused by pathogens other than E.coli.

  3. Patients who are hypersensitive to Rifaximin.

  4. Allergy to components of Rifaximin.

Warnings:

  • Rifaximin tablets should not be prescribed in patients in whom diarrhea is associated with blood in stools or fever.

  • Rifaximin tablets are ineffective in patients with traveler's diarrhea caused by Campylobacter jejuni.

  • There is no evidence regarding the drug's effectiveness in treating traveler's diarrhea caused by Shigella and Salmonella species.

  • The use of Rifaximin should be discontinued in patients whose diarrhea symptoms do not subside within 24 hours to 48 hours of starting the treatment with Rifaximin or in whom the symptoms worsen with time. An alternative antibiotic therapy must be considered.

  • Pseudomembranous colitis, a condition where there is an inflammation of the colon, leading to an increase in the frequency of bowel movements in a person, is a common side effect that occurs after the use of antibacterial agents. Patients with pseudomembranous colitis who experience traveler's diarrhea must be considered before starting the treatment with antibacterial medicines.

Antibacterial medications cause an overgrowth of Clostridium difficile, altering the normal gut flora. "Antibiotic-associated colitis" is primarily caused by the toxins released by Clostridium difficile. Many cases of pseudomembranous colitis have been reported in patients treated with antibacterial agents, with symptoms ranging from mild to severe. Therefore, therapeutic management has to be started in patients immediately after diagnosing pseudomembranous colitis. Mild cases respond by discontinuing the drug; however, moderate to severe cases require treatment with fluids and electrolytes, protein supplements, and antibacterial medicines that work against Clostridium difficile.

Precautions:

As an overgrowth of bacteria is familiar with antibiotics, any superinfection that occurs during treatment should be managed with appropriate measures. Patients are advised to stop using the drug when diarrhea persists even after treatment or if symptoms of diarrhea worsen.

For Patients:

What Is Traveler’s Diarrhea?

Traveler's diarrhea is a digestive system disorder that leads to abdominal cramps and severe diarrhea. It can occur due to an infection caused by bacteria, viruses, or parasites. The condition is not life-threatening and usually subsides on its own in a few days. However, the condition may be accompanied by dehydration, which must be managed by increasing the uptake of fluids and electrolytes.

What Are the Causes and Symptoms of Traveler’s Diarrhea?

Traveler's diarrhea occurs due to exposure to poor sanitary conditions.

The signs and symptoms of traveler's diarrhea include:

  • Nausea.

  • Vomiting.

  • Fever.

  • Excessive gas.

  • Bloating.

  • Appetite loss.

  • An urgency to defecate.

Those mentioned above are the usual symptoms. However, more serious symptoms that require immediate medical attention include:

  • Severe vomiting.

  • Bloody diarrhea.

  • Severe abdominal or rectal pain.

  • Fever when higher than 102 degrees Fahrenheit.

  • Severe dehydration symptoms.

Traveler's diarrhea that does not improve even after three days needs to be attended to by a doctor to prevent severe complications of dehydration.

How Is Traveler’s Diarrhea Treated?

The treatment of the condition depends on the cause. Mild cases can be managed by preventing dehydration and taking OTC (over-the-counter) medications. However, drinks like alcohol and caffeine must be avoided to enhance dehydration. Intake of mild and bland foods with little contamination risk must be preferred. Doctors may prescribe antibacterial agents based on the causative agent. Traveler's diarrhea caused by parasites is treated with antiparasitic drugs. In cases of severe dehydration, intravenous fluids containing glucose or electrolytes may be necessary.

For Doctors:

Description: Rifaximin is a semi-synthetic, non-systemic antibiotic. Rifaximin tablets are recommended for oral administration. They are film-coated tablets.

Active Ingredients: Each tablet contains 200 mg of Rifaximin.

Inactive Ingredients: Colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose, microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, titanium dioxide, and talc.

Chemical Name: 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-(epoxy pentadeca- [1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-á]-benzimidazole-1,15(2H)-dione,25-acetate.

Empirical Formula: C43H51N3O11.

Molecular Weight: 785.9

Clinical Pharmacology:

Pharmacokinetics:

Absorption:

Rifaximin can be administered with or without food. The systemic absorption of the drug was noted to be low when it was given in fasting conditions or 30 minutes after a high-fat diet. A single dose of 14C-Rifaximin was administered to four healthy male subjects to study the absorption of the drug. The mean overall radioactivity recovered in urine and feces of three subjects 168 hours after the drug administered was found to be 96.94 % plus or minus 5.64 % of the administered dose. Maximum radioactivity was found to be excreted in the feces alone, accounting for 96.62 % plus or minus 5.67 %, and only a small proportion of around 0.32 % was excreted in the urine. Analysis of the feces confirmed that Rifaximin was excreted unchanged. A low level of the drug in the urine points towards improper absorption through the gastrointestinal (GI) tract, thereby leading to a maximum amount of excretion through the feces. The pharmacokinetic parameters noted were Cmax 4.3 plus or minus 2.8 ng/mL (nanograms per milliliter), AUC (area under the curve) 19.5 plus or minus 16.5 ng*h/mL, and a median Tmax of 1.25 hours.

Systemic absorption of Rifaximin, 200 mg thrice daily, was evaluated in 13 patients with Shigellosis on days one and three during a three-day treatment course. There was no evidence regarding the accumulation of the drug on continuous administration for three days, including nine doses. As less than 0.4 % of the drug is absorbed through the intestines, Rifaximin treats systemic bacterial infections effectively.

Distribution:

Pharmacokinetic studies conducted in animals have shown that 80 % to 90 % of Rifaximin that was administered orally concentrated primarily in the gut, with less than 0.2 % in the kidney and liver and less than 0.1 % in the other tissues.

Metabolism:

In vitro studies have demonstrated that Rifaximin in concentrations of 2 ng/mL to 200 ng/mL has not inhibited the cytochrome P450 isoenzymes like 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. Also, the drug was found to induce cytochrome P450 3A4, an isoenzyme induced by Rifampicin. In addition, drug interaction studies that have used Midazolam and an oral contraceptive containing Ethinyl estradiol and Norgestimate have shown that Rifaximin did not alter the pharmacokinetics of either of them.

Excretion:

Rifaximin is predominantly excreted through the feces in an unchanged form. When 14 healthy volunteers were administered 400 mg of 14C-Rifximin, about 97 % of the administered dose was recovered in the feces, with about 0.32 % being recovered in urine.

Pharmacokinetics in Special Populations:

Geriatric Patients: The drug's pharmacokinetics in populations over 65 years are yet to be studied.

Pediatric Patients: The pharmacokinetics and safe use of the drug have not been studied in pediatric populations of any age.

Gender: There is no available evidence on the effect of gender on the drug's pharmacokinetics.

Renal Insufficiency Patients: There is no evidence of the pharmacokinetics of the drug in patients with impaired renal function.

Hepatic Insufficiency Patients: Patients with hepatic encephalopathy who were administered Rifaximin 800 mg thrice daily for seven days showed a mean peak plasma concentration of 13.5 micrograms per milliliter. It was demonstrated that less than 0.1 % of the administered dose was recovered at the end of seven days. Due to minimal systemic absorption being an advantage of Rifaximin, dosage adjustments are not recommended in patients with hepatic impairment.

Drug Interactions:

In vitro studies have shown Rifaximin to induce cytochrome P450 3A4. Also, two clinical drug interaction studies were conducted between Rifaximin and Midazolam, and Rifaximin and an oral contraceptive drug containing Ethinyl estradiol and Norgestimate to assess the effects of the pharmacokinetics of Rifaximin on these drugs.

An open-label, randomized, cross-over drug interaction trial was designed to study the drug interaction between Midazolam 2 mg intravenous (IV) or 6 mg oral dose and 200 mg Rifaximin that was administered orally every eight hours for three days and every eight hours for seven days. Rifaximin did not significantly impact Midazolam's systemic distribution, and metabolism or its major metabolite 1’-hydroxymidazolam were unaffected. Therefore, Rifaximin did not affect the hepatic or intestinal CYP3A4 activity.

Studies conducted on 28 healthy females to determine the effects of Rifaximin on an oral contraceptive containing Ethinyl estradiol and Norgestimate showed that Rifaximin unaltered the pharmacokinetics of the oral contraceptive.

Microbiology:

Rifaximin works by inhibiting bacterial RNA (ribonucleic acid) synthesis. It acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase. E.coli developing resistance to Rifaximin has been demonstrated in in-vitro studies; however, a similar effect has not been noted clinically. Rifaximin has been proved to work effectively against enterotoxigenic and enteroaggregative strains of E.coli.

Susceptibility Tests:

Based on the National Committee for Clinical Laboratory Standards (NCCLS), in-vitro susceptibility testing was done using an agar dilution method M7-A61. However, the relation between clinical outcome and susceptibility testing has not been determined.

Carcinogenesis:

The carcinogenicity effects of Rifaximin have not yet been studied. However, the drug did not exhibit any genotoxic effects in the bacterial reverse mutation assay, chromosomal aberration assay, CHO/HGPRT mutation assay, and rat bone marrow micronucleus assay.

Impairment of Fertility:

Studies have shown that no fertility impairment in male or female rats was administered up to 300 mg/kg.

Effects on Pregnancy:

The teratogenic effects of Rifaximin were studied in rats and rabbits. Rats were administered a dosage of 150 mg/kg to 300 mg/kg, and rabbits were administered 62.5 mg/kg to 1000 mg/kg. Effects like cleft palate, jaw shortening, agnathia, hemorrhage, small eyes, brachygnathia, incomplete ossification, and an increase in the number of thoracolumbar vertebrae were observed. However, there are no significant studies to determine the teratogenic effects on a human fetus. Therefore, using Rifaximin tablets during pregnancy is suggested only when the benefits outweigh the risks.

Effects on Lactation:

It is unclear whether Rifaximin is excreted in human milk. However, as many drugs are expressed in breast milk that can have a negative impact on nursing infants, a decision has to be taken whether to discontinue breastfeeding during intake of the medicine or avoid recommending the medicine after assessing the need for Rifaximin for the mother.

Use in Pediatric Patients:

The safety and effectiveness of Rifaximin in pediatric patients younger than 12 years of age are yet to be studied.

Use in Geriatric Patients:

Sufficient clinical evidence is not available to assess the safety of Rifaximin in elderly patients aged 65 years and above, to assess whether they respond differently when compared to younger patients.

Adverse Reactions:

The safe use of Rifaximin tablets was evaluated in a clinical study of 320 patients in two placebo-controlled clinical trials. About 95 % of the patients received three days of treatment with Rifaximin tablets.

The following adverse reactions to the use of the drug were noted, that included:

  • Headache.

  • Abdominal pain.

  • Flatulence.

  • An urgency to defecate.

  • Nausea.

  • Vomiting.

  • Pyrexia.

  • Constipation.

  • Rectal tenesmus.

The above adverse effects were noted in less than 2 % of patients who were given Rifaximin. The adverse effects that were noted involving various systems, irrespective of the casual exposure to the drug, included:

  • Blood and lymphatic system effects included lymphocytosis, monocytosis, or neutropenia.

  • Ear and labyrinth effects included ear pain, tinnitus, or motion sickness.

  • GI (gastrointestinal) effects included diarrhea, abdominal distension, dryness of the throat, inguinal hernia, gingival disorder, dry lips, discomfort of the stomach, and fecal abnormality.

  • General health effects included fatigue or chest pain.

  • Infections included upper respiratory tract infections, respiratory tract infections, or dysentery.

  • Metabolic or nutritional effects included anorexia or dehydration.

  • Nervous system disorders included dizziness, syncope, migraine, or loss of taste sensation.

  • Musculoskeletal and bone disorders included myalgia, arthralgia, back pain, and muscle spasms.

  • Psychiatric disorders included insomnia.

  • Renal and urinary disorders included dysuria, hematuria, choluria, proteinuria, and increased urinary frequency.

  • Respiratory disorders included pharyngitis, nasopharyngitis, pharyngolaryngeal pain, rhinitis, rhinorrhea, or dyspnea.

  • Skin disorders included rashes, clamminess, or increased sweating.

  • Vascular disorders included hot flashes.

Post-approval Experience:

Hypersensitivity reactions that included rash, exfoliative dermatitis, urticaria, flushing, pruritus, and angioneurotic edema were noted in a few patients who were administered Rifaximin post-approval. The reactions were noted to occur within less than 15 minutes of drug administration.

Drug Abuse:

There are no reported cases of drug abuse.

Drug Dependency:

There are no reported cases of drug dependency.

Overdosage:

There is no documented treatment for overdosage of Rifaximin tablets, where the daily dose extended the recommended dose of greater than 600 mg/day. However, discontinuation of the medication, symptomatic treatment, and initiation of supportive measures is recommended in cases of overdosage.

How Is Rifaximin Supplied?

Rifaximin tablets are supplied as pink-colored, circular, biconvex tablets that are debossed with "Sx" on one side. The tablets are supplied in a dosage of 200 mg.

What Are the Storage Recommendations for Rifaximin?

It is recommended to store Rifaximin tablets at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit). Excursion permitted to 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit).

Clinical Studies:

Two randomized, multi-center, double-blind, placebo-controlled clinical studies were conducted in adult patients diagnosed with traveler's diarrhea, in whom stool samples were collected before the start of the treatment and one to three days following the end of treatment to identify the enteric pathogens. Escherichia coli was the predominant pathogenic organism identified in both studies. Studies have shown a significant reduction in the duration of diarrhea and a higher clinical cure rate with the administration of Rifaximin. In addition, invasive pathogens like Campylobacter jejuni were isolated from the stools of patients with fever and bloody stools. Adult subjects affected with Shigella flexneri 2a were treated with Rifaximin. Patients who did not have the effectiveness of Rifaximin treatment were identified and treated with the antibacterial Ciprofloxacin.

Frequently Asked Questions

1.

What Is Rifaximin?

Rifaximin is an antibiotic drug used in the following:
- In the treatment of irritable bowel syndrome (IBS), with diarrhea.
- Treatment of travelers’ diarrhea caused by the microorganism Escherichia coli.
- Hepatic encephalopathy.

2.

Can Rifaximin Be Used for Gastritis?

Rifaximin has demonstrated in vitro activity against Helicobacter pylori-associated gastritis, peptic ulcer disease, and non-ulcer dyspepsia. Additional research is being undertaken to assess the effects of Rifaximin in H.pylori-associated conditions.

3.

How Is Rifaximin Unique From Other Antibiotics?

Rifaximin is a broad-spectrum antibiotic effective against both gram-positive and gram-negative anaerobic and aerobic bacteria. It is primarily used in diseases of the gastrointestinal tract and liver due to its non-absorbable profile. It has also demonstrated an effect of enteric protozoa in HIV patients with Cryptosporidium parvum and Blastocystitis hominis infections.

4.

How Should Rifaximin Be Taken?

Rifaximin is available in tablet form and can be taken with or without food. To treat travelers’ diarrhea, it is recommended three times daily for three days; for hepatic encephalopathy, it is taken twice daily; and for IBS, it is advised three times daily for 14 days. It must be taken approximately at the same time every day. As exactly as directed by the doctor.

5.

Does Rifaximin Reduce Gastric Problems?

Studies suggest that Rifaximin reduces the amount of abdominal gas production by decreasing abnormal bacterial fermentation. It is also reported to have an eradication rate for bacterial overgrowth of around 70 percent. It is also effective against conditions such as bloating and flatulence.

6.

Which Is the Best Antibiotic for Intestinal Infection?

The drug used to treat gastrointestinal infection depends on the type of microorganism. Penicillins, cephalosporins, antifolate or sulfa combinations, Nitroimidazole groups of drugs, etc, are some of the most effective and common antibiotics used in the treatment of gastrointestinal infection.

7.

Is Rifaximin Effective Than Metronidazole?

According to research, Rifaximin treatment is found significantly effective in the reduction of symptoms of Clostridium difficile infection (CDI) which were unresponsive to the treatment with Metronidazole. It was also observed that a combination of drugs, such as Rifaximin, Vancomycin, and probiotics for a duration of seven weeks, would resolve the recurrence of CDI-associated diarrhea.

8.

Can Rifaximin Be Used for Fatty Liver?

Non-alcoholic fatty liver disease (NAFLD) can be caused by increased insulin resistance, increased BMI, upregulation of proinflammatory cytokines, and lipopolysaccharide. Rifaximin, which is a minimally absorbable antibiotic, can be effective against a broad spectrum of gut bacteria, and it was also reported that administration of Rifaximin for around six months reduced NAFLD liver fat scores and also improved insulin resistance.

9.

Which Is the Best Medicine for Gastritis?

The treatment of gastritis depends on the symptoms, cause, and severity of the condition. Antibiotics can be effective in treating gastritis caused by H.pylori organisms in the digestive tract. The doctor may advise a combination of medications such as Clarithromycin, Amoxicillin, or Metronidazole to destroy the microorganisms causing gastritis.

10.

Does Rifaximin Cause Liver Damage?

Despite its widespread use, little evidence is available that Rifaximin, when administered orally, may cause injury to the liver in the form of elevations in the serum enzymes or manifestation of any clinically apparent liver disease. However, it has minimal systemic absorption. Hence it is less likely to cause any significant changes in liver function.

11.

What Are the Contraindications of Rifaximin?

Rifaximin is contraindicated in the following conditions;
- Complicated cases of diarrhea with blood in stools or fever.
- Diarrhea caused due to microorganisms other than E.coli.
- Patients who are allergic or hypersensitive to Rifaximin or its components.

12.

How Long Does It Take for Rifaximin to Work?

Rifaximin acts by destroying the bacteria and preventing its growth; when Rifaximin is used to treat travelers’ diarrhea, it may take around 24 to 48 hours to notice any improvements in the symptoms. In cases of IBS, the symptoms are sustained for around ten weeks following the treatment with Rifaximin.

13.

What Are the Foods to Be Avoided While Taking Rifaximin?

While there are no specific foods to be avoided while taking Rifaximin, however, people with IBS are advised not to consume caffeinated drinks, dairy products, alcohol, processed and sugary foods, and insoluble fiber. Patients with travelers’ diarrhea are advised not to consume raw leafy vegetables, raw meat, uncooked or undercooked fish, and unwashed fruits and vegetables.

14.

Can Rifaximin Treat Constipation?

Studies have suggested that Rifaximin may improve symptoms of chronic constipation by altering gut-microbe-derived methane production and slowing colon transit. However, it is known to offer symptomatic relief for patients suffering from irritable bowel syndrome without constipation.
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Dr. Rajesh Jain

General Practitioner

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