DIFICID Film-coated tablet Ref.[10868] Active ingredients: Fidaxomicin

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.

The pharmacokinetic parameters of fidaxomicin and its main metabolite OP-1118 following a single dose of 200 mg in healthy adult males (N=14) are summarized in Table 4.

Table 4. Mean (± Standard Deviation) Pharmacokinetic Parameters of Fidaxomicin 200 mg in Healthy Adult Males:

^* T_max, reported as median (range).
C_max, maximum observed concentration; T_max, time to maximum observed concentration; AUC_0-t, area under the concentration-time curve from time 0 to the last measured concentration; AUC_0-∞, area under the concentration-time curve from time 0 to infinity; t_1/2, elimination half-life

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 T_max window (1-5 hours) were approximately 2- to 6-fold higher than C_max values in healthy adults. Following administration of DIFICID 200 mg twice daily for 10 days, OP-1118 plasma concentrations within the T_max 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 DIFICID to healthy adults (N=28) with a high-fat meal versus under fasting conditions, C_max of fidaxomicin and OP-1118 decreased by 21.5% and 33.4%, respectively, while AUC_0-t remained unchanged. This decrease in C_max is not considered clinically significant, and thus, DIFICID 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 DIFICID 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 T_max window (1-5 hours) ranged 2-179 ng/mL and 10-829 ng/mL, respectively.

Elimination

Metabolism

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.

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.

Specific Populations

Geriatric Patients

In controlled trials of patients treated with DIFICID 200 mg twice daily for 10 days, mean and median values of fidaxomicin and OP-1118 plasma concentrations within the T_max window (1-5 hours) were approximately 2- to 4-fold higher in elderly patients (≥65 years of age) versus non-elderly patients (<65 years of age). Despite greater exposures in elderly patients, fidaxomicin and OP-1118 plasma concentrations remained in the ng/mL range [see Use in Specific Populations (8.5)].

Pediatric Patients

Similar to adults, fidaxomicin has minimal systemic absorption following oral administration across all age groups in pediatric patients. Plasma concentrations remained in the ng/mL range at the therapeutic dose in pediatric patients with mean (± standard deviation) plasma concentrations of 39.41 (±62.15) ng/mL of fidaxomicin and 116.64 (±259.10) ng/mL of OP-1118 at 1 to 5 hours post-dose.

Male and Female Patients

Plasma concentrations of fidaxomicin and OP-1118 within the T_max window (1-5 hours) did not vary by gender in patients treated with DIFICID 200 mg twice daily for 10 days from controlled trials. No dose adjustment is recommended based on gender.

Patients with Renal Impairment

In controlled trials of patients treated with DIFICID 200 mg twice daily for 10 days, plasma concentrations of fidaxomicin and OP-1118 within the T_max window (1-5 hours) did not vary by severity of renal impairment (based on creatinine clearance) between mild (51-79 mL/min), moderate (31-50 mL/min), and severe (≤30 mL/min) categories. No dose adjustment is recommended based on renal function.

Patients with Hepatic Impairment

The impact of hepatic impairment on the pharmacokinetics of fidaxomicin has not been evaluated. Because fidaxomicin and OP-1118 do not appear to undergo significant hepatic metabolism, elimination of fidaxomicin and OP-1118 is not expected to be significantly affected by hepatic impairment.

Drug Interaction Studies

In vivo studies were conducted to evaluate intestinal drug-drug interactions of fidaxomicin as a P-gp substrate, P-gp inhibitor, and inhibitor of major CYP enzymes expressed in the gastrointestinal tract (CYP3A4, CYP2C9, and CYP2C19).

Table 5 summarizes the impact of a co-administered drug (P-gp inhibitor) on the pharmacokinetics of fidaxomicin [see Drug Interactions (7.1)].

Table 5. Pharmacokinetic Parameters of Fidaxomicin and OP-1118 in the Presence of a Co-Administered Drug:

^* Cyclosporine was administered 1 hour before fidaxomicin.
^† CI – confidence interval

Fidaxomicin had no significant impact on the pharmacokinetics of the following co-administered drugs: digoxin (P-gp substrate), midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). No dose adjustment is warranted when fidaxomicin is co-administered with substrates of P-gp or CYP enzymes.

Mechanism of Action

Fidaxomicin is a fermentation product obtained from the Actinomycete Dactylosporangium aurantiacum. Fidaxomicin is a macrolide antibacterial drug that inhibits RNA synthesis by binding to RNA polymerases. Fidaxomicin is bactericidal against C. difficile in vitro, and demonstrates a post-antibiotic effect vs. C. difficile of 6-10 hrs.

Resistance

Fidaxomicin demonstrates no in vitro cross-resistance with other classes of antibacterial drugs. In vitro studies indicate a low frequency of spontaneous resistance to fidaxomicin in C. difficile (ranging from <1.4 × 10^-9 to 12.8 × 10^-9). A specific mutation (Val-ll43-Gly) in the beta subunit of RNA polymerase is associated with reduced susceptibility to fidaxomicin. This mutation was created in the laboratory and seen during clinical trials in a C. difficile isolate obtained from an adult subject treated with DIFICID who had recurrence of CDAD. The fidaxomicin minimum inhibitory concentration (MIC) of the C. difficile isolate from this subject increased from a baseline of 0.06 µg/mL to 16 µg/mL at the time of CDAD recurrence.

Interaction With Other Antimicrobials

Fidaxomicin and its main metabolite OP-1118 do not exhibit any antagonistic interaction with other classes of antibacterial drugs. Synergistic interactions of fidaxomicin and OP-1118 have been observed in vitro with rifampin and rifaximin against C. difficile.

Antimicrobial Activity

Fidaxomicin has been shown to be active against most isolates of Clostridioides (formerly Clostridium) difficile, both in vitro and in clinical infections [see Indications and Usage (1)].

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Long-term carcinogenicity studies have not been conducted to evaluate the carcinogenic potential of fidaxomicin.

Neither fidaxomicin nor OP-1118 was mutagenic in the Ames assay. Fidaxomicin was also negative in the rat micronucleus assay. However, fidaxomicin was clastogenic in Chinese hamster ovary cells.

Fidaxomicin did not affect the fertility of male and female rats at intravenous doses of 6.3 mg/kg. The exposure (AUC_0-t) was approximately 100 times that in humans.

14.1 Clinical Studies of DIFICID in Adult Patients with CDAD

In two randomized, double-blinded trials, a non-inferiority design was utilized to demonstrate the efficacy of DIFICID (200 mg tablets twice daily for 10 days) compared to vancomycin (125 mg four times daily for 10 days) in adults with CDAD.

Enrolled patients were 18 years of age or older and received no more than 24 hours of pretreatment with vancomycin or metronidazole. CDAD was defined by >3 unformed bowel movements (or >200 mL of unformed stool for subjects having rectal collection devices) in the 24 hours before randomization, and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization. Enrolled patients had either no prior CDAD history or only one prior CDAD episode in the past three months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.

The demographic profile and baseline CDAD characteristics of enrolled subjects were similar in the two trials. Patients had a median age of 64 years, were mainly white (90%), female (58%), and inpatients (63%). The median number of bowel movements per day was 6, and 37% of subjects had severe CDAD (defined as 10 or more unformed bowel movements per day or WBC ≥15000/mm³). Diarrhea alone was reported in 45% of patients and 84% of subjects had no prior CDAD episode.

The primary efficacy endpoint was the clinical response rate at the end of treatment, based upon improvement in diarrhea or other symptoms such that, in the investigator’s judgment, further CDAD treatment was not needed. An additional efficacy endpoint was sustained clinical response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment. Sustained response was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment.

The results for clinical response at the end of treatment in both trials, shown in Table 6, indicate that DIFICID is non-inferior to vancomycin based on the 95% confidence interval (CI) lower limit being greater than the non-inferiority margin of -10%.

The results for sustained clinical response at the end of the follow-up period, also shown in Table 6, indicate that DIFICID is superior to vancomycin on this endpoint. Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in DIFICID patients.

Table 6. Clinical Response Rates at End-of-Treatment and Sustained Response at 25 days Post-Treatment in Adult Patients:

^* Confidence interval (CI) was derived using Wilson’s score method. Approximately 5%-9% of the data in each trial and treatment arm were missing sustained response information and were imputed using multiple imputation method.

Restriction Endonuclease Analysis (REA) was used to identify C. difficile baseline isolates in the BI group, isolates associated with increasing rates and severity of CDAD in the US in the years prior to the clinical trials. Similar rates of clinical response at the end of treatment and proven or suspected CDAD during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients infected with a BI isolate. However, DIFICID did not demonstrate superiority in sustained clinical response when compared with vancomycin (Table 7).

Table 7. Sustained Clinical Response at 25 Days after Treatment by C. difficile REA Group at Baseline in Adult Patients:

14.2 Clinical Studies of DIFICID in Pediatric Patients with CDAD

The safety and efficacy of DIFICID in pediatric patients 6 months to less than 18 years of age was investigated in a Phase 3, multicenter, investigator-blinded, randomized, comparative trial (NCT02218372). In this trial, 148 patients were randomized, of whom 142 received either DIFICID or vancomycin in a 2:1 ratio. Randomized patients were stratified by age group as follows: 30 aged 6 months to <2 years, 49 aged 2 to <6 years, 40 aged 6 to <12 years, and 29 aged 12 to <18 years (one patient <6 months of age was enrolled in the trial). Treatment arms were balanced regarding demographics and other baseline characteristics.

Clinical response for patients <2 years of age was defined as the absence of watery stools for at least 2 consecutive days while on treatment and the patient remained well with no requirement for further CDAD therapy through 2 days after completing treatment as assessed by the Investigator. Clinical response for patients ≥2 to <18 years of age was defined as <3 unformed bowel movements for at least 2 consecutive days while on treatment and the patient remained well with no requirement for further CDAD therapy through 2 days after completing treatment as assessed by the Investigator. Sustained clinical response was defined as the proportion of treated patients with confirmed clinical response and no CDAD recurrence through 30 days after end of treatment. The clinical response and sustained clinical response overall and by age groups are presented in Table 8.

Table 8. Clinical Response and Sustained Response Overall and by Age Group in Pediatric Patients: