Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Tillotts Pharma GmbH, Warmbacher Strasse 80, 79618 Rheinfelden, Germany
Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents, antibiotics
ATC code: A07AA12
Fidaxomicin is an antibiotic belonging to the macrocyclic class of antibacterials. Fidaxomicin is bactericidal and inhibits RNA synthesis by bacterial RNA polymerase. It interferes with RNA polymerase at a distinct site from that of rifamycins. Inhibition of the Clostridial RNA polymerase occurs at a concentration 20-fold lower than that for the E. coli enzyme (1 μM vs. 20 μM), partly explaining the significant specificity of fidaxomicin activity. Fidaxomicin has been shown to inhibit C. difficile sporulation in vitro.
Fidaxomicin is a locally acting drug. As a topical agent, systemic PK/PD relationships cannot be established, however in vitro data show fidaxomicin to have time-dependent bactericidal activity and suggest time over MIC may be the parameter most predicative of clinical efficacy.
Fidaxomicin is a topically acting drug that cannot be used to treat systemic infections; therefore the establishment of a clinical breakpoint is not relevant. The epidemiological cut-off value for fidaxomicin and C. difficile, distinguishing the wild-type population from isolates with acquired resistance traits, is ≥1.0 mg/L.
Fidaxomicin is a narrow spectrum antimicrobial drug with bactericidal activity against C. difficile. Fidaxomicin has an MIC90 of 0.25 mg/L versus C. difficile, and its main metabolite, OP-1118, has an MIC90 of 8 mg/L. Gram negative organisms are intrinsically not susceptible to fidaxomicin.
Studies have demonstrated that fidaxomicin treatment did not affect Bacteroides concentrations or other major components of the microbiota in the faeces of CDI patients.
There are no known transferable elements that confer resistance to fidaxomicin. Also no cross-resistance has been discovered with any other antibiotic class including β-lactams, macrolides, metronidazole, quinolones, rifampin, and vancomycin. Specific mutations of RNA polymerase are associated with reduced susceptibility to fidaxomicin.
The efficacy of fidaxomicin was evaluated in two pivotal, randomised, double-blind Phase 3 studies (Study 003 and 004). Fidaxomicin was compared with orally administered vancomycin. The primary endpoint was clinical cure assessed after 12 days.
Non-inferiority of fidaxomicin compared with vancomycin was demonstrated in both studies (see Table 2).
Table 2. Combined results of studies 003 and 004:
| Per Protocol (PP) | Fidaxomicin (200mg bid for 10 days) | Vancomycin (125mg qid for 10 days) | 95% Confidence Interval* |
| Clinical Cure | 91.9% (442/481 patients) | 90.2% (467/518 patients) | (-1.8, 5.3) |
| modified Intent-to- Treat (mITT) | Fidaxomicin (200mg bid) | Vancomycin (125mg qid) | 95% Confidence Interval* |
| Clinical Cure | 87.9% (474/539 patients) | 86.2% (488/566 patients) | (-2.3, 5.7) |
* for treatment difference
The rate of recurrence in the 30 days following treatment was assessed as a secondary endpoint. The rate of recurrence (including relapses) was significantly lower with fidaxomicin (14.1% versus 26.0% with a 95% CI of [-16.8%, -6.8%]), however these trials were not prospectively designed to prove prevention of reinfection with a new strain.
In the two pivotal clinical trials of patients with CDI, 47.9% (479/999) of patients (per protocol population) were ≥65 years of age and 27.5% (275/999) of patients were treated with concomitant antibiotics during the study period. Twenty-four percent of patients met at least one of the following three criteria at baseline for scoring severity: body temperature >38.5°C, leukocyte count >15,000, or creatinine value ≥1.5 mg/dl. Patients with fulminant colitis and patients with multiple episodes (defined as more than one prior episode within the previous 3 months) of CDI were excluded from the studies.
EXTEND was a randomised, open-label study that compared extended-pulse fidaxomicin dosing with orally administered vancomycin. The primary endpoint was sustained clinical cure 30 days after end of treatment (Day 55 for fidaxomicin, day 40 for vancomycin). The sustained clinical cure 30 days after end of treatment was significantly higher for fidaxomicin vs. vancomycin (see Table 3).
Table 3. Results of EXTEND study:
| modified Intent-to- Treat (mITT) | Fidaxomicin (200mg bid for 5 days then 200mg every other day) | Vancomycin (125mg qid for 10 days) | 95% Confidence Interval* |
| Clinical cure 30 days after end of treatment | 70.1% (124/177 patients) | 59.2% (106/179 patients) | (1.0, 20.7) |
* for treatment difference
The trial was conducted with adults aged 60 years and older. The median age of the patients was 75. 72% (257/356) received other antibiotics within the last 90 days. 36.5% had a severe infection.
The safety and efficacy of fidaxomicin in paediatric patients from birth to less than 18 years of age was investigated in a multicentre, investigator-blind, randomised, parallel group study where 148 patients were randomised to either fidaxomicin or vancomycin in a 2:1 ratio. A total of 30, 49, 40 and 29 patients were randomised in the age groups of birth to <2 years, 2 to <6 years, 6 to <12 years and 12 to <18 years, respectively. Confirmed clinical response 2 days after end of treatment was similar between the fidaxomicin and vancomycin group (77.6% vs 70.5% with a point difference of 7.5% and 95% CI for the difference of [-7.4%, 23.9%]). The rate of recurrence 30 days after end of treatment was numerically lower with fidaxomicin (11.8% vs 29.0%), but the rate difference is not statistically significant (point difference of -15.8% and 95% CI for the difference of [-34.5%, 0.5%]). Both treatments had a similar safety profile.
The bioavailability in humans is unknown. In healthy adults, Cmax is approximately 9.88 ng/ml and AUC0-t is 69.5 ng•hr/ml following administration of 200 mg fidaxomicin, with a Tmax of 1.75 hours. In CDI patients, average peak plasma levels of fidaxomicin and its main metabolite OP-1118 tend to be 2- to 6-fold higher than in healthy adults. There was very limited accumulation of fidaxomicin or OP-1118 in plasma following administration of 200 mg fidaxomicin every 12 hours for 10 days.
Cmax for fidaxomicin and OP-1118 in plasma were 22% and 33% lower following a high fat meal vs fasting, but the extent of exposure (AUC0-t) was equivalent.
Fidaxomicin and the metabolite OP-1118 are substrates of P-gp. In vitro studies showed that fidaxomicin and the metabolite OP-1118 are inhibitors of the transporters BCRP, MRP2 and OATP2B1, but were not found to be substrates. Under conditions of clinical use, fidaxomicin has no clinically relevant effect on the exposure of rosuvastatin, a substrate for OATP2B1 and BCRP (see section 4.5). The clinical relevance of MRP2 inhibition is not yet known.
The volume of distribution in humans is unknown, due to very limited absorption of fidaxomicin.
No extensive analysis of metabolites in plasma has been performed, due to low levels of systemic absorption of fidaxomicin. A main metabolite, OP-1118, is formed through hydrolysis of the isobutyryl ester. In vitro metabolism studies showed that the formation of OP-1118 is not dependent on CYP450 enzymes. This metabolite also shows antimicrobial activity (see section 5.1).
Fidaxomicin does not induce or inhibit CYP450 enzymes in vitro.
Following a single dose of 200 mg fidaxomicin, the majority of the administered dose (over 92%) was recovered in the stool as fidaxomicin or its metabolite OP-1118 (66%). The main elimination pathways of systemically available fidaxomicin have not been characterized. Elimination through urine is negligible (<1%). Only very low levels of OP-1118 and no fidaxomicin was detectable in human urine. The half life of fidaxomicin is approximately 8-10 h.
Plasma levels appear to be elevated in the elderly (age ≥65 years). Fidaxomicin and OP-1118 levels were approximately 2 times higher in patients ≥65 years compared to patients <65 years. This difference is not considered clinically relevant.
After administration of film-coated tablets, the mean (SD) plasma levels in the paediatric patients from 6 to less than 18 years was 48.53 (69.85) ng/ml and 143.63 (286.31) ng/ml for fidaxomicin and its main metabolite OP-1118, respectively, at 1 to 5 hours postdose.
Data from an open label, single arm study in adult CDI patients with concomitant inflammatory bowel disease (IBD) indicated no major difference in plasma concentrations of fidaxomicin or its main metabolite OP-1118 in patients with IBD as compared with patients without IBD in other studies. The maximum fidaxomicin and OP-1118 plasma levels in CDI patients with concomitant IBD were within the range of levels found in CDI patients without IBD.
Limited data from adult patients with an active history of chronic hepatic cirrhosis in the Phase 3 studies showed that median plasma levels of fidaxomicin and OP-1118 may be approximately 2- and 3-fold higher, respectively, than in non-cirrhotic patients.
Limited data from adult patients suggest that there is no major difference in plasma concentration of fidaxomicin or OP-1118 between patients with reduced renal function (creatinine clearance <50 ml/min) and patients with normal renal function (creatinine clearance ≥50 ml/min).
Limited data suggest that gender, weight and race do not have any major influence on the plasma concentration of fidaxomicin or OP-1118.
Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, and reproductive toxicity.
Reproductive and fertility parameters showed no statistically significant differences in rats treated with fidaxomicin at doses up to 6.3 mg/kg/day (intravenous).
No target organs for toxicity were observed in juvenile animals, and no important potential risks have been observed in the nonclinical studies that might be relevant for paediatric patients.
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