Fidaxomicin

Fidaxomicin is a Macrolide Antibiotic belonging to antidiarrheal/antimicrobial agent.

Fidaxomicin is a macrolide antibiotic used to treat diarrhea associated with Clostridium difficile infection.

Fidaxomicin has minimal systemic absorption following oral administration, with plasma concentrations of fidaxomicin and OP-1118 in the ng/mL range at the therapeutic dose. In fidaxomicin-treated patients from controlled trials, plasma concentrations of fidaxomicin and OP-1118 obtained within the Tmax window (1-5 hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults. Fidaxomicin is mainly confined to the gastrointestinal tract following oral administration. Fidaxomicin is primarily transformed by hydrolysis at the isobutyryl ester to form its main and microbiologically active metabolite, OP-1118. Metabolism of fidaxomicin and formation of OP-1118 are not dependent on cytochrome P450 (CYP) enzymes. Fidaxomicin is mainly excreted in feces.

Fidaxomicin shows common side effects like Nausea, vomiting, stomach pain, constipation.

Fidaxomicin is available in the form of Oral Tablet and Oral suspension.

Fidaxomicin is available in India, US, China, Japan, Singapore, France, Spain, Italy, Russia, and Australia.

Fidaxomicin belongs to the antimicrobial agent acts as a Macrolide Antibiotic.

Fidaxomicin inhibits RNA polymerase sigma subunit resulting in inhibition of protein synthesis and cell death in susceptible organisms including C. difficile; bactericidal.

The Data of onset and duration of action of Fidaxomicin is not clinically established.

The Tmax of Fidaxomicin is approximately 1.75 hours.

Fidaxomicin is available in the form of Oral Tablet and Oral suspension.

Fidaxomicin Tablet is taken orally, usually once daily for 10 days.

Fidaxomicin is a macrolide antibiotic used to treat diarrhea associated with Clostridium difficile infection.

Fidaxomicin is a Macrolide Antibiotic belonging to antidiarrheal/antimicrobial agent.

Fidaxomicin is a macrocyclic antibiotic. It inhibits Clostridium difficile through inhibition of RNA synthesis by binding to RNA polymerase sigma subunit.

Fidaxomicin is approved for use in the following clinical indications

• Clostridioides difficile infection

Fidaxomicin is a macrolide antibiotic used to treat diarrhea associated with Clostridium difficile infection.

• Clostridioides difficile infection

Initial infection

Oral: 200 mg twice daily for 10 days. If delayed response to treatment, a longer duration (eg, up to 14 days) may be considered.

Recurrent infection

Oral: 200 mg twice daily for 10 days or 200 mg twice daily for 5 days, followed by 200 mg once every other day for 20 days.

Fidaxomicin is available in various strengths as 200 mg and 40 mg/mL.

Fidaxomicin is available in the form of Oral Tablet and Oral suspension.

Avoid consumption of High-fat meal, it may decrease the Cmax of Fidaxomicin and its metabolite in a clinically insignificant way.

Fidaxomicin is contraindicated in patients with

• Patients who have known hypersensitivity to fidaxomicin or any other ingredient in Fidaxomicin.

• Lack of Effectiveness for Infections Other Than C. Difficile-Associated Diarrhea

Fidaxomicin should only be used for the treatment of C. difficile-associated diarrhea. Fidaxomicin is not effective for treatment of other types of infections due to minimal systemic absorption of fidaxomicin.

• Hypersensitivity Reactions

Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, Fidaxomicin should be discontinued, and appropriate therapy should be instituted. Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing Fidaxomicin to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.

• Development Of Drug-Resistant Bacteria

Prescribing Fidaxomicin in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

There is no information on the presence of fidaxomicin or its main metabolite, OP-1118, in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fidaxomicin and any potential adverse effects on the breastfed infant from Fidaxomicin or from the underlying maternal condition.

The limited available data on use of Fidaxomicin in pregnant women are insufficient to inform any drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Embryo-fetal reproduction studies in rats and rabbits dosed intravenously during organogenesis revealed no evidence of harm to the fetus at fidaxomicin and OP-1118 (its main metabolite) exposures 65-fold or higher than the clinical exposure at the Fidaxomicin recommended dose [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Avoid consumption of High-fat meal, it may decrease the Cmax of Fidaxomicin and its metabolite in a clinically insignificant way.

Common

● Nausea, Fever, Pruritus, skin rash, urticaria, decreased serum bicarbonate, hyperglycemia, metabolic acidosis, Abdominal distention, abdominal pain, abdominal tenderness, constipation, diarrhea, dyspepsia, dysphagia, flatulence, gastrointestinal hemorrhage, intestinal obstruction, non-Hirschsprung megacolon, vomiting, Anemia, decreased platelet count, neutropenia, Increased liver enzymes, increased serum alkaline phosphatase, increased serum transaminases, Fixed drug eruption.

Rare

● Hepatotoxicity (idiosyncratic), Angioedema, hypersensitivity reaction.

• Cyclosporine

Cyclosporine is an inhibitor of multiple transporters, including P-gp. When cyclosporine was co-administered with Fidaxomicin, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range. Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials. Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended.

● Bacillus clausii

Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy.

● Cholera Vaccine

Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics.

● Immune Checkpoint Inhibitors

Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors.

● Mizolastine

Macrolide Antibiotics may increase the serum concentration of Mizolastine.

● Sodium Picosulfate

Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic.

● Typhoid Vaccine

Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose.

The common side effects of Fidaxomicin include the following

Common side effects

• Nausea, vomiting, stomach pain, constipation.

Rare side effects

• Rash, itching, swelling of the face, throat, tongue, lips, and eyes, shortness of breath, difficulty breathing or swallowing, weakness, Fatigue, dizziness, Headache, chest pain, fast, pounding heartbeat, pale skin, cold hands and feet, stomach cramps, bright red blood in vomit, vomit that looks like coffee-grounds, black, tarry stools, bright red blood in stools, fever, sore throat, chills, or other signs of infection.

• Pregnancy

Pregnancy Category B

The limited available data on use of Fidaxomicin in pregnant women are insufficient to inform any drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Embryo-fetal reproduction studies in rats and rabbits dosed intravenously during organogenesis revealed no evidence of harm to the fetus at fidaxomicin and OP-1118 (its main metabolite) exposures 65-fold or higher than the clinical exposure at the Fidaxomicin recommended dose. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

• Nursing Mothers

There is no information on the presence of fidaxomicin or its main metabolite, OP-1118, in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fidaxomicin and any potential adverse effects on the breastfed infant from Fidaxomicin or from the underlying maternal condition.

• Pediatric Use

The safety and effectiveness of Fidaxomicin for the treatment of CDAD have been established in pediatric patients 6 months to less than 18 years of age. Use of Fidaxomicin in these age groups is supported by evidence from adequate and well-controlled trials of Fidaxomicin in adults with CDAD and pharmacokinetic, safety and efficacy data from pediatric trials. No new safety signals associated with the use of Fidaxomicin in pediatric patients were identified in the pediatric trials. The safety and effectiveness of Fidaxomicin have not been established in pediatric patients younger than 6 months of age.

• Geriatric Use

Of the total number of patients in controlled trials of Fidaxomicin, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of Fidaxomicin compared to vancomycin were observed between these subjects and younger subjects. In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age). However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months.

Pharmacodynamic

Fidaxomicin acts locally in the gastrointestinal tract on C. difficile. In a dose-ranging trial (N=48) of fidaxomicin using 50 mg, 100 mg, and 200 mg twice daily for 10 days, a dose-response relationship was observed for efficacy.

Pharmacokinetics

• Absorption

Fidaxomicin has minimal systemic absorption following oral administration, with plasma concentrations of fidaxomicin and OP-1118 in the ng/mL range at the therapeutic dose. In fidaxomicin-treated patients from controlled trials, plasma concentrations of fidaxomicin and OP-1118 obtained within the Tmax window (1-5 hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults. Following administration of Fidaxomicin 200 mg twice daily for 10 days, OP-1118 plasma concentrations within the Tmax window were approximately 50%-80% higher than on Day 1, while concentrations of fidaxomicin were similar on Days 1 and 10. In a food-effect study involving administration of FIDAXOMICIN to healthy adults (N=28) with a high-fat meal versus under fasting conditions, Cmax of fidaxomicin and OP-1118 decreased by 21.5% and 33.4%, respectively, while AUC0-t remained unchanged. This decrease in Cmax is not considered clinically significant, and thus, Fidaxomicin may be administered with or without food.

• Distribution

Fidaxomicin is mainly confined to the gastrointestinal tract following oral administration. In selected patients (N=8) treated with Fidaxomicin 200 mg twice daily for 10 days from controlled trials, fecal concentrations of fidaxomicin and OP-1118 obtained within 24 hours of the last dose ranged from 639-2710 µg /g and 213-1210 µg /g, respectively. In contrast, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) ranged 2-179 ng/mL and 10-829 ng/mL, respectively.

• Metabolism

Fidaxomicin is primarily transformed by hydrolysis at the isobutyl ester to form its main and microbiologically active metabolite, OP-1118. Metabolism of fidaxomicin and formation of OP-1118 are not dependent on cytochrome P450 (CYP) enzymes. At the therapeutic dose, OP-1118 was the predominant circulating compound in healthy adults, followed by fidaxomicin.

• Excretion

Fidaxomicin is mainly excreted in feces. In one trial of healthy adults (N=11), more than 92% of the dose was recovered in the stool as fidaxomicin and OP-1118 following single doses of 200 mg and 300 mg. In another trial of healthy adults (N=6), 0.59% of the dose was recovered in urine as OP-1118 only following a single dose of 200 mg.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213138lbl.pdf
• https://www.rxlist.com/Fidaxomicin-drug.htm#warnings
• https://reference.medscape.com/drug/Fidaxomicin-fidaxomicin-999663
• https://medlineplus.gov/druginfo/meds/a611040.html#precautions
• https://www.drugs.com/dosage/fidaxomicin.html
• https://www.mims.com/philippines/drug/info/fidaxomicin?mtype=generic
• https://go.drugbank.com/drugs/DB08874
• https://www.uptodate.com/contents/fidaxomicin-drug-information#F12923777