非达霉素(Dificid)的中文说明书

Fidaxomicin (Dificid) was approved by the US FDA in May 2011 for the treatment of Clostridium difficile infection (CDI).

Indications for Fidaxomicin (Dificid)

For the treatment of diarrhea caused by Clostridioides difficile (formerly Clostridium difficile) infection (CDI; Clostridium difficile-associated diarrhea [CDAD]) in adults (≥18 years of age).

Designated by the FDA as an orphan drug for the treatment of pediatric patients with †CDI.

For the treatment of an initial episode of nonsevere CDI in adults, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) recommend oral vancomycin or oral fidaxomicin.

Dosage and usage of fidaxomicin (Dificid)

1. Dosage method

Oral administration, no need to consider the influence of food.

2. Dosage

(1) Adults: 200 mg twice a day for 10 days.

(2) Hepatic insufficiency: The manufacturer does not provide specific dosage recommendations; pharmacokinetics are not expected to be affected.

(3) Renal insufficiency: Dosage adjustment is not recommended.

(4) Elderly patients: Dosage adjustment is not recommended.

The pictures come from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

Contraindications of fidaxomicin (Dificid)

Allergy to fidaxomicin or any ingredient in the preparation.

Fidaxomicin (Dificid) Precautions

1. Hypersensitivity reaction

Acute hypersensitivity reactions (such as dyspnea, rash, itching, angioedema of the mouth, throat, and face) have been reported. Some of these patients had a history of hypersensitivity to other macrolides.

Consider the possibility of a hypersensitivity reaction if fidaxomicin is prescribed to a patient with a known macrolide allergy.

If a severe hypersensitivity reaction occurs, fidaxomicin should be discontinued and appropriate treatment instituted.

2. Systemic infection

Fidaxomicin is only used to treat diarrhea caused by Clostridium difficile. Since only minimal systemic absorption occurs after oral administration, it is not effective in treating other types of infections.

3. Selection and use of anti-infective drugs

In order to reduce the occurrence of drug-resistant bacteria and maintain the effectiveness of fidaxomicin and other antibacterial drugs, they should only be used to treat infections that are confirmed or strongly suspected to be caused by Clostridium difficile.

Prescribing fidaxomicin without proven or strongly suspected CDI is unlikely to benefit the patient and increases the risk of developing drug-resistant bacteria.

The results of culture and in vitro susceptibility testing should be used when selecting or adjusting anti-infective treatment regimens. In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infective agents for empiric therapy.

Use of fidaxomicin (Dificid) in special populations

1. Pregnancy period

Existing data are insufficient to provide information on whether there is a risk of major birth defects, miscarriage or adverse maternal and fetal outcomes when pregnant women use this drug.

No evidence of harm to the fetus was found when fidaxomicin was administered intravenously to rats and rabbits during organogenesis at doses that resulted in exposures to fidaxomicin and its major metabolite OP-1118 that were 65 times or more the exposure reported for humans at recommended doses.

2. Lactation

It is not known whether fidaxomicin or its major metabolite (OP-1118) is excreted into human milk, affects breastfed infants, or affects breast milk.

The developmental and health benefits of breastfeeding should be considered, as well as the mother's clinical need for fidaxomicin and the potential adverse effects of this drug or underlying maternal disease on the breastfed infant.

3. Pediatric medication

The safety and effectiveness in patients under 18 years of age have not been established. Designated as an orphan drug by the FDA for the treatment of pediatric patients with †CDI.

In a Phase 2a clinical trial of pediatric patients ≥6 months of age† with Clostridium difficile -associated diarrhea, the drug's safety profile was similar to that reported in adults.

4. Geriatric use

There is generally no difference in effectiveness or safety observed in older adults aged ≥65 years compared with younger adults.

Plasma concentrations of fidaxomicin and its major metabolite (OP-1118) were higher in patients ≥65 years of age than in younger adults, but remained within the nanograms per milliliter (ng/mL) range. Not considered clinically important; no dose adjustment recommended.

5. Hepatic insufficiency

The impact of hepatic insufficiency on pharmacokinetics has not been formally studied, but since fidaxomicin and its major metabolite (OP-1118) do not appear to undergo significant hepatic metabolism, their elimination is not expected to be substantially affected.

6. Renal insufficiency

In clinical trials in patients with mild, moderate, or severe renal insufficiency (based on creatinine clearance Clcr) who received fidaxomicin (200 mg orally twice daily for 10 days), plasma concentrations of fidaxomicin and its major metabolite (OP-1118) did not change with the severity of renal insufficiency. No dosage adjustment is recommended.

Common adverse reactions of fidaxomicin (Dificid)

Nausea, vomiting, abdominal pain, gastrointestinal bleeding, anemia, and neutropenia.

Fidaxomicin (Dificid) drug interactions

1. Drugs metabolized by liver microsomal enzymes

Have no clinically important impact on the pharmacokinetics of CYP3A4, CYP2C9 or CYP2C19 substrates. The manufacturer states that no dose adjustment is necessary if fidaxomicin is used concomitantly with CYP isoenzyme substrates.

2. Drugs that affect or are affected by P-glycoprotein transport

(1) P-gp inhibitors: may significantly increase the concentration of fidaxomicin and OP-1118 in plasma, but their values ​​are still within the ng/mL range. Concentrations of fidaxomicin and OP-1118 at the site of action (i.e., the gastrointestinal tract) may be reduced, but data from controlled clinical trials of fidaxomicin indicate that coadministration of P-gp inhibitors has no attributable effect on safety or treatment outcome. The manufacturer states that no dose adjustment is necessary.

(2) P-gp substrate: Fidaxomicin will not significantly change the pharmacokinetics of P-gp substrate. The manufacturer states that no dose adjustment is necessary.

Fidaxomicin (Dificid) Pharmacokinetics

1. Absorption

Bioavailability: Only minimal systemic absorption occurs after oral administration.

After a single oral dose of 200 mg in healthy adults, the mean peak plasma concentrations of fidaxomicin and its major metabolite (OP-1118) were 5.2 ng/mL and 12 ng/mL, respectively, and were reached within 1-2 hours.

Although the plasma concentrations of fidaxomicin and OP-1118 in CDI patients 1-5 hours after dosing were approximately 2-6 times that of healthy adults, their plasma concentrations remained in the ng/mL range. There was no evidence of fidaxomicin accumulation in plasma after 10 days of treatment.

Food: In healthy adults, administration with a high-fat meal reduced the peak plasma concentrations of fidaxomicin and OP-1118 by approximately 22% and 33%, respectively, but did not affect the AUC (area under the drug-time curve); not considered clinically important.

2. Distribution

After oral administration, it is mainly limited to the gastrointestinal tract and acts locally.

3. Metabolism

Mainly converted into OP-1118 through the hydrolysis of isobutyrate. Although OP-1118 also has antibacterial activity against C. difficile, its activity is lower than fidaxomicin.

The metabolism of fidaxomicin and the formation of OP-1118 are independent of CYP isoenzymes.

4. Elimination pathways

Fidaxomicin is primarily excreted in the feces. In healthy adults, >92% of the oral dose is recovered in the feces as fidaxomicin and OP-1118; <1% of the dose is recovered in the urine as OP-1118.

In some patients receiving fidaxomicin (200 mg orally twice daily for 10 days), fecal concentrations of fidaxomicin and OP-1118 obtained within 24 hours after the last dose ranged from 639–2710 mcg/g and 213–1210 mcg/g, respectively.

Half-life: The elimination half-life of fidaxomicin in adults is approximately 12 hours; the elimination half-life of OP-1118 is approximately 11 hours.

Fidaxomicin (Dificid) Pharmacokinetics in Special Populations

In elderly patients ≥65 years old, the plasma concentrations of fidaxomicin and OP-1118 1-5 hours after taking the drug are approximately 2-4 times that of adults under 65 years old; it is not considered to be clinically important.

In controlled trials in patients receiving fidaxomicin (200 mg twice daily for 10 days), plasma concentrations of fidaxomicin and OP-1118 were not affected by the severity of patients with mild, moderate, or severe (based on Clcr) renal insufficiency.

The effect of hepatic insufficiency on the pharmacokinetics of fidaxomicin has not been formally studied. Hepatic insufficiency is not expected to materially affect fidaxomicin and OP-1118 concentrations as no significant hepatic metabolism appears to occur.

Fidaxomicin (Dificid) Storage

Tablets should be stored at 20°C–25°C (with exposure to 15°C–30°C).

Mechanism of action of fidaxomicin (Dificid)

Fidaxomicin is a macrocyclic antibiotic classified as a macrolide. Other commercially available macrolides have a 14- or 15-membered lactone ring structure; fidaxomicin has an 18-membered macrolide structure.

After oral administration, only minimal systemic absorption occurs; primarily limited to the gastrointestinal tract and acts locally.

Has a narrow spectrum of antibacterial activity. Active against some Gram-positive bacteria; limited or inactive against Gram-negative bacteria, and inactive against Candida albicans.

Warm Tips

1. Inform patients that skipping doses or not completing the full course of treatment may reduce effectiveness and increase the possibility that bacteria will become resistant and cannot be treated with fidaxomicin or other antibacterial drugs in the future.

2. Inform the patient that fidaxomicin can be taken with food or on an empty stomach.