1.1 Clostridium difficile-Associated Diarrhea

DIFICID is a macrolide antibacterial drug indicated in adults (≥18years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD).

5.1 Not for Systemic Infections

Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections.

5.2 Development of Drug Resistant Bacteria

Prescribing DIFICID in the absence of a proven or strongly suspected C.difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice.

The safety of DIFICID 200mg tablets taken twice a day for 10days was eva luated in 564patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment.

Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase3 studies.

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials:

Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon

Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count

Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis

Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash

7.1 Cyclosporine

Cyclosporine is an inhibitor of multiple transporters, including P-gp. When cyclosporine was co-administered with DIFICID, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range [see Clinical Pharmacology (12.3)]. Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e.,gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials. Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended.

8.1 Pregnancy

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7mg/kg, respectively. The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether fidaxomicin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of DIFICID in patients <18years of age have not been established.

8.5 Geriatric Use

Of the total number of patients in controlled trials of DIFICID, 50% were 65years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects.

In controlled trials, elderly patients (≥65years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65years of age) [see Clinical Pharmacology (12.3)]. However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

12.1 Mechanism of Action

Fidaxomicin is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Fidaxomicin acts locally in the gastrointestinal tract on C.difficile. In a dose-ranging trial (N=48) of fidaxomicin using 50mg, 100mg, and 200mg twice daily for 10days, a dose-response relationship was observed for efficacy.

12.3 Pharmacokinetics

The pharmacokinetic parameters of fidaxomicin and its main metabolite OP-1118 following a single dose of 200mg in healthy adult males (N=14) are summarized in Table2.

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 (1-5hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults. Following administration of DIFICID 200mg twice daily for 10days, OP-1118 plasma concentrations within the Tmax window were approximately 50-80% higher than on Day1, while concentrations of fidaxomicin were similar on Days1 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 200mg twice daily for 10days from controlled trials, fecal concentrations of fidaxomicin and OP-1118 obtained within 24hours of the last dose ranged from 639-2710mcg/g and 213-1210mcg/g, respectively. In contrast, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5hours) ranged 2-179ng/mL and 10-829ng/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 200mg and 300mg. 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 200mg.

Specific Populations

Geriatric

In controlled trials of patients treated with DIFICID 200mg twice daily for 10days, mean and median values of fidaxomicin and OP-1118 plasma concentrations within the Tmax window (1-5hours) were approximately 2-4fold higher in elderly patients (≥65years of age) versus non-elderly patients (<65years 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)].

Gender

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

Renal Impairment

In controlled trials of patients treated with DIFICID 200mg twice daily for 10days, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5hours) did not vary by severity of renal impairment (based on creatinine clearance) between mild (51-79mL/min), moderate (31-50mL/min), and severe (≤30mL/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 eva luated. 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

Invivo studies were conducted to eva luate 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 (7.1)].

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.

12.4 Microbiology

Spectrum of Activity

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

Mechanism of Action

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

Mechanism of Decreased Susceptibility to Fidaxomicin

Invitro 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 0.06mcg/mL to 16mcg/mL.

Cross-Resistance/Synergy/Post-Antibiotic Effect

Fidaxomicin demonstrates no invitro 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. Invitro 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- 10hrs.

Susceptibility Testing

The clinical microbiology laboratory should provide cumulative results of the invitro 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 procedures1. 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

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

Quality Control Parameters for Susceptibility Testing

Invitro 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 Table4.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term carcinogenicity studies have not been conducted to eva luate 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 6.3mg/kg. The exposure (AUC0-t) was approximately 100times that in humans.

16.1 How Supplied

DIFICID tablets are white to off-white film-coated, oblong tablets containing 200mg of fidaxomicin; each tablet is debossed with "FDX" on one side and "200" on the other side.

DIFICID tablets are supplied as:

• Bottles of 20tablets, (NDC 52015-080-01)
• Bottles of 60tablets, (NDC 52015-080-02)
• 10tablet aluminum blister cards, with 10cards per carton, (NDC 52015-080-12)

16.2 Storage

Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

See USP Controlled Room Temperature.

17.1 Administration with Food

Patients should be informed that DIFICID tablets may be taken with or without food.

17.2 Antibacterial Resistance

Patients should be counseled that antibacterial drugs, including DIFICID, should only be used to treat bacterial infections. They do not treat viral infections. Patients should be counseled that DIFICID only treats Clostridium difficile-associated diarrhea and should not be used to treat any other infection. When DIFICID tablets are prescribed, patients should be told that, although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)decrease the effectiveness of the immediate treatment and (2)increase the likelihood that bacteria will develop resistance and will not be treatable by DIFICID or other antibacterial drugs in the future.

Manufactured for Optimer Pharmaceuticals, Inc., San Diego CA 92121 by Patheon, Inc.

DIFICID™ is a trademark of Optimer Pharmaceuticals, Inc.

Product protected by US Patent Nos. 7,378,508; 7,507,564; 7,863,249; and 7,906,489

Optimer Pharmaceuticals, Inc.
10110 Sorrento Valley Road, SuiteC
San Diego, CA 92121
(858) 909-0736

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