fidaxomicin 200 MG Oral Tablet [Dificid]

INDICATIONS AND USAGE Fidaxomicin tablets are a macrolide antibacterial indicated in adult patients for the treatment of C. difficile -associated diarrhea. ( 1.1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of fidaxomicin tablets and other antibacterial drugs, fidaxomicin tablets should be used only to treat infections that are proven or strongly suspected to be caused by C. difficile. ( 1.2 ) 1.1 Clostridioides difficile -Associated Diarrhea Fidaxomicin tablets are indicated in adult patients for the treatment of C. difficile-associated diarrhea (CDAD). 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of fidaxomicin tablets and other antibacterial drugs, fidaxomicin tablets should be used only to treat infections that are proven or strongly suspected to be caused by C. difficile. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Pediatric use information is approved for Cubist Pharmaceuticals LLC's DIFICID ® (fidaxomicin) tablets. However, due to Cubist Pharmaceuticals LLC's marketing exclusivity rights, this drug product is not labeled with that information.

DOSAGE AND ADMINISTRATION • Fidaxomicin tablets are administered orally with or without food. ( 2.1 ) • Adults o One 200 mg tablet orally twice daily for 10 days. ( 2.2 ) 2.1 Important Administration Instructions Fidaxomicin tablets are available for oral administration as 200 mg tablets. Fidaxomicin tablets are administered orally with or without food. 2.2 Adult Patients The recommended dosage for adults is one 200 mg fidaxomicin tablet orally twice daily for 10 days. Pediatric use information is approved for Cubist Pharmaceuticals LLC's DIFICID ® (fidaxomicin) tablets. However, due to Cubist Pharmaceuticals LLC's marketing exclusivity rights, this drug product is not labeled with that information.

WARNINGS AND PRECAUTIONS • Acute hypersensitivity reactions (angioedema, dyspnea, pruritus, and rash) have been reported. If a severe hypersensitivity reaction occurs, discontinue fidaxomicin tablets. ( 5.1 ) • Fidaxomicin tablets are not expected to be effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin. Fidaxomicin tablets should only be used for the treatment of C. difficile -associated diarrhea. ( 5.2 ) • Development of drug-resistant bacteria: Only use fidaxomicin tablets for infection proven or strongly suspected to be caused by C. difficile . ( 5.3 ) 5.1 Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash, pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin tablets. If a severe hypersensitivity reaction occurs, fidaxomicin tablets should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions to fidaxomicin tablets also reported a history of allergy to other macrolides. Physicians prescribing fidaxomicin tablets to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions. 5.2 Not for Use in Infections Other than C. difficile -Associated Diarrhea Fidaxomicin tablets are not expected to be effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin [see Clinical Pharmacology (12.3)] . Fidaxomicin tablets has not been studied for the treatment of infections other than CDAD. Fidaxomicin tablets should only be used for the treatment of CDAD. 5.3 Development of Drug-Resistant Bacteria Prescribing fidaxomicin tablets in the absence of 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.

CONTRAINDICATIONS Fidaxomicin tablets are contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in fidaxomicin tablets [see Warnings and Precautions ( 5.1 )]. Fidaxomicin tablets are contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in fidaxomicin tablets. ( 4 )

CLINICAL PHARMACOLOGY 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 50 mg, 100 mg, and 200 mg twice daily for 10 days, 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 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 Parameter Fidaxomicin OP- 1118 N Value N Value C max (ng/mL) 14 5.20 ± 2.81 14 12.0 ± 6.06 T max (h)* 14 2.00 (1.00 to 5.00) 14 1.02 (1.00 to 5.00) AUC 0 to t (ng-h/mL) 14 48.3 ± 18.4 14 103 ± 39.4 AUC 0 to ∞ (ng-h/mL) 9 62.9 ± 19.5 10 118 ± 43.3 t 1/2 (h) 9 11.7 ± 4.80 10 11.2 ± 3.01 * T max , reported as median (range). C max , maximum observed concentration; T max , time to maximum observed concentration; AUC 0 to t , area under the concentration-time curve from time 0 to the last measured concentration; AUC 0 to ∞ , 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 to 5 hours) were approximately 2- to 6-fold higher than C max values in healthy adults. Following administration of fidaxomicin tablets 200 mg twice daily for 10 days, OP-1118 plasma concentrations within the Tmax window were approximately 50% to 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 fidaxomicin tablets 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 to t remained unchanged. This decrease in C max is not considered clinically significant, and thus, fidaxomicin tablets 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 fidaxomicin tablets 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 to 2,710 mcg /g and 213 to 1,210 mcg /g, respectively. In contrast, plasma concentrations of fidaxomicin and OP-1118 within the T max window (1 to 5 hours) ranged 2 to 179 ng/mL and 10 to 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 fidaxomicin tablets 200 mg twice daily for 10 days, mean and median values of fidaxomicin and OP-1118 plasma concentrations within the Tmax window (1 to 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 Pediatric use information is approved for Cubist Pharmaceuticals LLC's DIFICID® (fidaxomicin) tablets. However, due to Cubist Pharmaceuticals LLC's marketing exclusivity rights, this drug product is not labeled with that information. Male and Female Patients Plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1 to 5 hours) did not vary by gender in patients treated with fidaxomicin tablets 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 fidaxomicin tablets 200 mg twice daily for 10 days, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1 to 5 hours) did not vary by severity of renal impairment (based on creatinine clearance) between mild (51 to 79 mL/min), moderate (31 to 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 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 C max (ng/mL) 14 19.4 14 4.67 4.15 (3.23 to 5.32) AUC 0 to ∞ (ng-h/mL) 8 114 9 59.5 1.92 (1.39 to 2.64) OP-1118 C max (ng/mL) 14 100 14 10.6 9.51 (6.93 to 13.05) AUC 0 to ∞ (ng-h/mL) 12 438 10 106 4.11 (3.06 to 5.53) * 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. 12.4 Microbiology 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 to 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 fidaxomicin tablets 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 mcg/mL to 16 mcg/mL at the time of CDAD recurrence. Interaction With Other Antimicro