非达霉素(Dificid)的详细说明书：作用与功效,用法用量,副作用,注意事项等

Fidaxomicin (Dificid) is a macrolide antibacterial drug that exerts a bactericidal effect by inhibiting bacterial RNA polymerase.

Indications of fidaxomicin (Dificid)

Clostridium difficile-associated diarrhea

It is suitable for the treatment of Clostridium difficile-associated diarrhea (CDAD) in adult and pediatric patients 6 months and older.

Dosage of fidaxomicin (Dificid)

1. Adult patients

The recommended dose for adult patients is to take a 200 mg fidaxomicin tablet orally once, twice daily for 10 days.

2. Pediatric patients (6 months to less than 18 years old)

For pediatric patients weighing at least 12.5 kg and able to swallow tablets, the recommended dose is one 200 mg fidaxomicin tablet taken orally twice daily for 10 days.

3. Dosage forms and specifications

200 mg white to off-white film-coated oblong tablets; each tablet is engraved with "FDX" on one side and "200" on the other side.

4. Overdose

There are no case reports of acute overdose in humans. Dogs were given fidaxomicin tablets of 9600 mg/day (more than 100 times the human dose based on body weight) for 3 months, and no drug-related adverse effects were observed.

Contraindications of fidaxomicin (Dificid)

Fidaxomicin is contraindicated in patients with known allergy to fidaxomicin or any component of fidaxomicin.

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.

Fidaxomicin (Dificid) Precautions

1. Hypersensitivity reaction

Fidaxomicin has been reported to cause acute hypersensitivity reactions, including dyspnea, rash, itching, and angioedema of the mouth, throat and face. If a serious hypersensitivity reaction occurs, fidaxomicin should be discontinued and appropriate therapy initiated.

Some patients who develop hypersensitivity reactions to fidaxomicin also report a history of allergies to other macrolides. Physicians who prescribe fidaxomicin to patients with known macrolide allergy should be aware of the possibility of hypersensitivity reactions.

2. Not suitable for infections other than Clostridium difficile-associated diarrhea

Due to the minimal systemic absorption of fidaxomicin, fidaxomicin is not expected to be effective in treating other types of infections [see Clinical Pharmacology (12.3)]. Fidaxomicin has not been studied for the treatment of infections other than CDAD. Fidaxomicin should be used only to treat CDAD.

3. The development of drug-resistant bacteria

Prescribing fidaxomicin without confirmed or strongly suspected Clostridium difficile infection is unlikely to bring benefit to the patient and will increase the risk of developing drug-resistant bacteria.

Adverse reactions of fidaxomicin (Dificid)

1. Adults

(1), gastrointestinal diseases: abdominal distension, abdominal tenderness, indigestion, dysphagia, flatulence, intestinal obstruction, megacolon.

(2) Examination: increased blood alkaline phosphatase, decreased blood bicarbonate, increased liver enzymes, and decreased platelet count.

(3) Metabolic and nutritional disorders: hyperglycemia, metabolic acidosis.

(4) Skin and subcutaneous tissue diseases: drug eruption, itching, rash.

2. Pediatrics

(1), skin and subcutaneous tissue diseases: urticaria, itching

(2), hypersensitivity reaction: dyspnea, angioedema, rash, itching.

Fidaxomicin (Dificid) drug interactions

Ciclosporine

Cyclosporine is an inhibitor of multiple transporters, including P-gp. When cyclosporine was coadministered with fidaxomicin, plasma concentrations of fidaxomicin and OP-1118 increased significantly but remained within the nanograms per milliliter (ng/mL) range.

Concentrations of fidaxomicin and OP-1118 at the site of action (i.e., the gastrointestinal tract) may also be reduced by P-gp inhibition; however, in controlled clinical trials, concomitant use of P-gp inhibitors had no attributable effect on safety or treatment outcomes in adult patients treated with fidaxomicin. Based on these results, fidaxomicin can be coadministered with P-gp inhibitors and no dose adjustment is recommended.

Fidaxomicin (Dificid) Use in Special Populations

1. Pregnancy

The limited available data on the use of fidaxomicin in pregnant women are insufficient to elucidate its drug risks associated with major birth defects, miscarriage, or adverse maternal and infant outcomes. Embryo-fetal reproduction studies with intravenous administration of fidaxomicin and rabbits during organogenesis showed no evidence of fetal harm at exposures of fidaxomicin and OP-1118 (its major metabolite), respectively, that were 65 times or higher the clinical exposure at recommended doses of fidaxomicin.

2. Lactation period

There is no information on the presence of fidaxomicin or its major metabolite OP-1118 in human milk, its effects on breastfed infants, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered, taking into account the mother's clinical need for fidaxomicin and any potential adverse effects of fidaxomicin or the underlying maternal condition on the breastfed infant.

3. Pediatric use

The safety and effectiveness of fidaxomicin for the treatment of CDAD have been established in pediatric patients aged 6 months to less than 18 years old. Supporting evidence for the use of fidaxomicin in these age groups comes from adequate and well-controlled trials of fidaxomicin in adult patients with CDAD, as well as pharmacokinetic, safety, and efficacy data from pediatric trials.

No new safety signals related to the use of fidaxomicin in pediatric patients were identified in pediatric trials. The safety and effectiveness of fidaxomicin have not been established in pediatric patients younger than 6 months of age.

4. Drug use in the elderly

Among the total number of patients in controlled trials of fidaxomicin, 50% were patients aged 65 and above, and 31% were patients aged 75 and above. No overall differences in the safety or effectiveness of fidaxomicin were observed between these subjects and younger subjects compared with vancomycin.

In controlled trials, plasma concentrations of fidaxomicin and its major metabolite OP-1118 were higher in elderly patients (≥65 years) than in non-elderly patients (<65 years). However, the higher exposures in elderly patients were not considered clinically significant. No dose adjustment is recommended in elderly patients.

Mechanism of action of fidaxomicin (Dificid)

Fidaxomicin is an antibacterial drug that acts locally on Clostridium difficile in the gastrointestinal tract. 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 for efficacy was observed.

Fidaxomicin (Dificid) Pharmacokinetics

1. Absorption

After oral administration, the systemic absorption of fidaxomicin is minimal. At therapeutic doses, the plasma concentrations of fidaxomicin and OP-1118 are in the ng/mL range. In patients treated with fidaxomicin in controlled trials, fidaxomicin and OP-1118 plasma concentrations obtained during the Tmax window (1-5 hours) were approximately 2 to 6 times higher than Cmax values ​​in healthy adults.

After taking fidaxomicin 200 mg twice daily for 10 days, OP-1118 plasma concentrations during the Tmax window were approximately 50%-80% higher than on day 1, while fidaxomicin concentrations were similar on days 1 and 10.

Food: In a food effect study of fidaxomicin administered to healthy adults (N=28) under high-fat meals and fasting conditions, the Cmax of fidaxomicin and OP-1118 were reduced by 21.5% and 33.4%, respectively, while the AUC0-t remained unchanged. This decrease in Cmax is not considered clinically significant and, therefore, fidaxomicin may be administered with or without food.

2. Distribution

After oral administration, fidaxomicin is primarily localized to the gastrointestinal tract. In patients selected from controlled trials who received fidaxomicin 200 mg twice daily for 10 days (N=8), fecal concentrations of fidaxomicin and OP-1118 obtained within 24 hours after the last dose ranged from 639 to 2710 µg/g and 213 to 1210 µg/g, respectively. In comparison, the plasma concentration ranges of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) were 2-179ng/mL and 10-829ng/mL, respectively.

3. Metabolism

Fidaxomicin is mainly converted through the hydrolysis of isobutyrate to form its main and microbiologically active metabolite OP-1118. The metabolism of fidaxomicin and the formation of OP-1118 are independent of cytochrome P450 (CYP) enzymes.

At therapeutic doses, OP-1118 is the predominant circulating compound in healthy adults, followed by fidaxomicin.

4. Excretion

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

Population-specific pharmacokinetics of fidaxomicin (Dificid)

1. Elderly patients

In controlled trials of patients receiving fidaxomicin 200 mg twice daily for 10 days, the mean and median plasma concentrations of fidaxomicin and OP-1118 during the Tmax window period (1-5 hours) were approximately 2 to 4 times higher in elderly patients (≥65 years) than in non-elderly patients (<65 years).

Despite higher exposure in elderly patients, plasma concentrations of fidaxomicin and OP-1118 remained in the ng/mL range [see Use in Specific Populations (8.5)].

2. Pediatric patients

Similar to adults, fidaxomicin is rarely absorbed systemically after oral administration. At therapeutic doses, plasma concentrations in pediatric patients remained within the ng/mL range, with mean (± standard deviation) plasma concentrations of fidaxomicin and OP-1118 at 116.64 (±259.10) ng/mL from 1 to 5 hours postdose.

3. Male and female patients

In patients who received fidaxomicin 200 mg twice daily for 10 days in a controlled trial, fidaxomicin and OP-1118 plasma concentrations during the Tmax window period (1-5 hours) did not differ by gender. No dosage adjustments based on gender are recommended.

4. Patients with renal insufficiency

In a controlled trial of patients receiving fidaxomicin 200 mg twice daily for 10 days, fidaxomicin and OP-1 within the Tmax window period (1-5 hours) 118 Plasma concentrations did not vary with severity of renal insufficiency (based on creatinine clearance) between mild (51-79 mL/min), moderate (31-50 mL/min), and severe (≤30 mL/min) categories. Dosage adjustments based on renal function are not recommended.

5. Patients with hepatic insufficiency

The impact of hepatic insufficiency on the pharmacokinetics of fidaxomicin has not been evaluated. As fidaxomicin and OP-1118 do not appear to undergo significant hepatic metabolism, hepatic insufficiency is not expected to significantly affect the elimination of fidaxomicin and OP-1118.

Fidaxomicin (Dificid) drug interactions

1. Fidaxomicin has no significant effect on the pharmacokinetics of the following co-administered drugs: digoxin (P-gp substrate), midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 substrate).

2. When fidaxomicin is co-administered with P-gp or CYP enzyme substrates, no dose adjustment is required.

3. Fidaxomicin and its main metabolite OP-1118 do not show any antagonistic effects with other classes of antibacterial drugs. Synergistic interactions of fidaxomicin and OP-1118 with rifampicin and rifaximin have been observed in vitro against Clostridium difficile.

Mechanism of action of fidaxomicin (Dificid)

Fidaxomicin is a fermentation product obtained from the actinomycete Dactylosporangiumaurantiacum. Fidaxomicin is a macrolide antibacterial drug that inhibits RNA synthesis by binding to RNA polymerase. Fidaxomicin is bactericidal against C. difficile in vitro and shows a 6-10 hour post-antibiotic effect against C. difficile.

Fidaxomicin (Dificid) Storage

Store fidaxomicin tablets at 20°C-25°C (68°F-77°F); allow excursions between 15°C-30°C (59°F-86°F). See USP Controlled Room Temperature. Store in original bottle.

Warm Tips

1. Inform patients and caregivers that fidaxomicin tablets and oral suspension can be taken with or without food.

2. Patients should be informed that fidaxomicin is only used to treat bacterial infections and cannot treat viral infections (such as the common cold).

3. When fidaxomicin is prescribed to treat Clostridium difficile infection, patients should be informed that although it is common to feel better early in the course of treatment, the medication should be taken strictly as directed. Skipping doses or not completing the full course of treatment may reduce the effectiveness of immediate treatment and increase the likelihood that the bacteria will become resistant and cannot be treated with fidaxomicin or other antibacterial drugs in the future.