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Dificid

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Dificid

Dificid

CLINICAL PHARMACOLOGY

Mechanism of Action

Fidaxomicin is an antibacterial drug [see Microbiology].

Pharmacodynamics

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

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 2.

Table 2: Mean (± Standard Deviation) Pharmacokinetic Parameters of Fidaxomicin 200 mg in Healthy Adult Males

Parameter Fidaxomicin OP-1118
N Value N Value
Cmax (ng/mL) 14 5.20 ± 2.81 14 12.0 ± 6.06
Tmax (h)* 14 2.00 (1.00-5.00) 14 1.02 (1.00-5.00)
AUC0-t (ng•h/mL) 14 48.3 ± 18.4 14 103 ± 39.4
AUC0-∞ (ng•h/mL) 9 62.9 ± 19.5 10 118 ± 43.3
t½ (h) 9 11.7 ± 4.80 10 11.2 ± 3.01
*Tmax, reported as median (range)
Cmax, maximum observed concentration; Tmax, time to maximum observed concentration; AUC0-t, area under the concentration-time curve from time 0 to the last measured concentration; AUC0-∞, area under the concentration-time curve from time 0 to infinity; t½, 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 Tmax window (1-5 hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults. Following administration of DIFICID 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 DIFICID 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, 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 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 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

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 Tmax 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].

Gender

Plasma concentrations of fidaxomicin and OP-1118 within the Tmax 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.

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 Tmax 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.

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 Interactions

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 3 summarizes the impact of a co-administered drug (P-gp inhibitor) on the pharmacokinetics of fidaxomicin [see DRUG INTERACTIONS].

Table 3: Pharmacokinetic Parameters of Fidaxomicin and OP-1118 in the Presence of a Co-Administered Drug

Parameter Cyclosporine 200 mg + Fidaxomicin 200 mg* (N=14) Fidaxomicin 200 mg Alone (N=14) Mean Ratio of Parameters With/Without Co-Administered Drug (90% CI) No Effect = 1.00
N Mean N Mean
Fidaxomicin
  Cmax (ng/mL) 14 19.4 14 4.67 4.15
(3.23-5.32)
  AUC0-∞ (ng-h/mL) 8 114 9 59.5 1.92
(1.39-2.64)
OP-1118
  Cmax (ng/mL) 14 100 14 10.6 9.51
(6.93-13.05)
  AUC0-∞ (ng-h/mL) 12 438 10 106 4.11
(3.06-5.53)

* Cyclosporine was administered 1 hour before fidaxomicin CI, confidence interval

Fidaxomicin had no significant impact on the pharmacokinetics of the following coadministered 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.

Microbiology

Spectrum of Activity

Fidaxomicin is a fermentation product obtained from the Actinomycete Dactylosporangium aurantiacum. In vitro, fidaxomicin is active primarily against species of clostridia, including Clostridium difficile.

Mechanism of Action

Fidaxomicin is bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases.

Mechanism of Decreased Susceptibility to Fidaxomicin

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 a subject treated with DIFICID who had recurrence of CDAD. The C. difficile isolate from the treated subject went from a fidaxomicin baseline minimal inhibitory concentration (MIC) of 0.06 μg/mL to 16 μg/mL.

Cross-Resistance/Synergy/Post-Antibiotic Effect

Fidaxomicin demonstrates no in vitro cross-resistance with other classes of antibacterial drugs. Fidaxomicin and its main metabolite OP-1118 do not exhibit any antagonistic interaction with other classes of antibacterial drugs. In vitro synergistic interactions of fidaxomicin and OP-1118 have been observed in vitro with rifampin and rifaximin against C. difficile (FIC values ≤ 0.5). Fidaxomicin demonstrates a post-antibiotic effect vs. C. difficile of 6-10 hrs.

Susceptibility Testing

The clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community acquired pathogens. These reports should aid the physician in selecting appropriate antimicrobial drug therapy.

Dilution Techniques

Quantitative anaerobic in vitro methods can be used to determine the MIC of fidaxomicin needed to inhibit the growth of the C. difficile isolates. The MIC provides an estimate of the susceptibility of C. difficile isolate to fidaxomicin. The MIC should be determined using standardized procedures.1 Standardized methods are based on an agar dilution method or equivalent with standardized inoculum concentrations and standardized concentration of fidaxomicin powder.

Susceptibility Test Interpretive Criteria

In vitro susceptibility test interpretive criteria for fidaxomicin have not been determined. The relation of the in vitro fidaxomicin MIC to clinical efficacy of fidaxomicin against C. difficile isolates can be monitored using in vitro susceptibility results obtained from standardized anaerobe susceptibility testing methods.

Quality Control Parameters for Susceptibility Testing

In vitro susceptibility test quality control parameters were developed for fidaxomicin so that laboratories determining the susceptibility of C. difficile isolates to fidaxomicin can ascertain whether the susceptibility test is performing correctly. Standardized dilution techniques require the use of laboratory control microorganisms to monitor the technical aspects of the laboratory procedures. Standardized fidaxomicin powder should provide the MIC with the indicated quality control strain shown in Table 4.

Table 4: Acceptable Quality Control Ranges for Fidaxomicin

Microorganism MIC Range (μg/mL)
C. difficile (ATCC 700057) 0.03-0.25

Clinical Studies

In two randomized, double-blinded trials, a non-inferiority design was utilized to demonstrate the efficacy of DIFICID (200 mg twice daily for 10 days) compared to vancomycin (125 mg four times daily for 10 days) in adults with Clostridium difficileassociated diarrhea (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 therapy, 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 5, 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 5, 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 5: Clinical Response Rates at End-of-Therapy and Sustained Response at 25 days Post-Therapy

  Clinical Response at End of Treatment Sustained Response at Follow-Up
DIFICID % (N) Vancomycin % (N) Difference (95% CI) DIFICID % (N) Vancomycin % (N) Difference (95% CI)*
Trial 1 88%
(N=289)
86%
(N=307)
2.6%
(-2.9%, 8.0%)
70%
(N=289)
57%
(N=307)
12.7%
(4.4%, 20.9%)
Trial 2 88%
(N=253)
87%
(N=256)
1.0%
(-4.8%, 6.8%)
72%
(N=253)
57%
(N=256)
14.6%
(5.8%, 23.3%)
* Confidence interval 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 6).

Table 6: Sustained Clinical Response at 25 Days after Treatment by C. difficile REA Group at Baseline

Trial 1
Initial C. difficile Group DIFICID n/N (%) Vancomycin n/N (%) Difference (95% CI)
BI Isolates 44/76 (58%) 52/82 (63%) -5.5% (-20.3%, 9.5%)
Non-BI Isolates 105/126 (83%) 87/131 (66%) 16.9% (6.3%, 27.0%)
Trial 2
Initial C. difficile Group DIFICID n/N (%) Vancomycin n/N (%) Difference (95% CI)
BI Isolates 42/65 (65%) 31/60 (52%) 12.9% (-4.2%, 29.2%)
Non-BI Isolates 109/131 (83%) 77/121 (64%) 19.6% (8.7%, 30.0%)
* Interaction test between the effect on sustained response rate and BI versus non-BI isolates using logistic regression (p-values: trial 1: 0.009; trial 2: 0.29). Approximately 25% of the mITT population were missing data for REA group. Confidence intervals were derived using Wilson's score method.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – 7th edition. CLSI document M11-A7. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087-1898, 2007.

Last reviewed on RxList: 4/18/2013
This monograph has been modified to include the generic and brand name in many instances.

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