CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. AdultsThe safety of DIFICID 200 mg tablets taken twice day for 10 days was evaluated in 564 adult patients with CDAD in two active-controlled trials with 86.7% of patients receiving full course of treatment.Thirty-three adult patients receiving DIFICID (5.9%) withdrew from trials as 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 DIFICID and vancomycin patients in Phase trials. The most common selected adverse reactions occurring in >=2% of adult patients treated with DIFICID are listed in Table 2.Table 2: Selected Adverse Reactions with an Incidence of >=2% Reported in DIFICID-Treated Adult Patients in Controlled TrialsSystem Organ ClassDIFICID(N=564)Vancomycin(N=583) Adverse Reactionn (%)n (%)Blood and Lymphatic System Disorders Anemia14 (2%)12 (2%) Neutropenia14 (2%)6 (1%)Gastrointestinal Disorders Nausea62 (11%)66 (11%) Vomiting41 (7%)37 (6%) Abdominal Pain33 (6%)23 (4%) Gastrointestinal Hemorrhage20 (4%)12 (2%)The following adverse reactions were reported in <2% of adult patients taking DIFICID tablets in controlled trials:Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolonInvestigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet countMetabolism and Nutrition Disorders: hyperglycemia, metabolic acidosisSkin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash. PediatricsThe safety of DIFICID in pediatric patients months to less than 18 years of age was evaluated in Phase single-arm trial in 38 patients and Phase randomized, active-controlled trial in 98 patients treated with DIFICID and 44 patients treated with vancomycin [see Clinical Studies (14.2)]. In both studies, patients received DIFICID orally twice daily for 10 days. Patients <2 years of age, or weighing <12.5 kg, or unable to swallow tablets received weight-based doses of DIFICID oral suspension. Patients weighing at least 12.5 kg and able to swallow tablets received the 200 mg DIFICID tablet. The age range in the Phase trial was 11 months to 17 years and in the Phase trial was month to 17 years (one patient was less than months of age).One death occurred in the Phase single-arm trial. In the Phase trial, there were deaths in DIFICID-treated patients and no deaths in vancomycin-treated patients during the study period (40 days). All deaths occurred in patients less than years of age and appeared to be related to underlying comorbidities [see Clinical Studies (14.2)]. Treatment discontinuation due to adverse reactions occurred in 7.9% (3/38) of patients in the Phase trial, and in 1% (1/98) and 2.3% (1/44) of DIFICID- and vancomycin-treated patients, respectively, in the Phase trial. The most common selected adverse reactions occurring in >=5% of pediatric patients treated with DIFICID in the Phase trial are listed in Table 3.Table 3: Selected Adverse Reactions with an Incidence of >=5% Reported in DIFICID-Treated Pediatric Patients in the Controlled TrialSystem Organ ClassDIFICID(N=98)Vancomycin(N=44) Adverse Reactionn (%)n (%)Gastrointestinal Disorders Abdominal painIncludes abdominal pain, abdominal pain lower, and abdominal pain upper (8.2)9 (20.5) Vomiting7 (7.1)6 (13.6) Diarrhea7 (7.1)5 (11.4) Constipation5 (5.1)1 (2.3)General Disorders and Administration Site Conditions Pyrexia13 (13.3)10 (22.7)Investigations Aminotransferases increasedIncludes alanine aminotransferase increased, aspartate aminotransferase increased, and hepatic enzyme increased (5.1)1 (2.3)Skin and Subcutaneous Tissue Disorders RashIncludes rash, rash follicular, rash maculo-papular, and exfoliative rash (5.1)1 (2.3)The following adverse reactions were reported in <5% of pediatric patients taking DIFICID in clinical trials:Skin and Subcutaneous Tissue Disorders: urticaria, pruritus.

CONTRAINDICATIONS SECTION.

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

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic parameters of fidaxomicin and its main metabolite OP-1118 following 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 MalesParameterFidaxomicinOP-1118NValueNValueCmax (ng/mL)145.20 +- 2.811412.0 +- 6.06Tmax (h)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 to the last measured concentration; AUC0-, area under the concentration-time curve from time to infinity; t1/2, elimination half-life 142.00 (1.00-5.00)141.02 (1.00-5.00)AUC0-t (ng-h/mL)1448.3 +- 18.414103 +- 39.4AUC0- (ng-h/mL)962.9 +- 19.510118 +- 43.3t1/2 (h)911.7 +- 4.801011.2 +- 3.01. AbsorptionFidaxomicin 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 and 10.In food-effect study involving administration of DIFICID to healthy adults (N=28) with 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.. DistributionFidaxomicin 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 ug/g and 213-1210 ug/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.. Elimination. MetabolismFidaxomicin 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.. ExcretionFidaxomicin 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 single dose of 200 mg.. Specific Populations. Geriatric PatientsIn 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 (8.5)].. Pediatric PatientsSimilar 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 to hours post-dose.. Male and Female PatientsPlasma 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.. Patients with Renal ImpairmentIn 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.. Patients with Hepatic ImpairmentThe 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 StudiesIn vivo studies were conducted to evaluate intestinal drug-drug interactions of fidaxomicin as P-gp substrate, P-gp inhibitor, and inhibitor of major CYP enzymes expressed in the gastrointestinal tract (CYP3A4, CYP2C9, and CYP2C19).Table summarizes the impact of 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 Co-Administered DrugParameterCyclosporine 200 mg Fidaxomicin 200 mgCyclosporine was administered hour before fidaxomicin. (N=14)Fidaxomicin 200 mg Alone(N=14)Mean Ratio of Parameters With/Without Co-Administered Drug (90% CI CI confidence interval)No Effect 1.00NMeanNMeanFidaxomicin Cmax (ng/mL)1419.4144.674.15 (3.23-5.32) AUC0- (ng-h/mL)8114959.51.92 (1.39-2.64)OP-1118 Cmax (ng/mL)141001410.69.51 (6.93-13.05) AUC0- (ng-h/mL)12438101064.11 (3.06-5.53)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.

POSTMARKETING EXPERIENCE SECTION.

6.2Post Marketing Experience. The following adverse reactions have been identified during post-approval use of DIFICID. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity reactions (dyspnea, angioedema, rash, pruritus).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions in adults (incidence >=2%) are nausea, vomiting, abdominal pain, gastrointestinal hemorrhage, anemia, and neutropenia. (6)The most common adverse reactions in pediatric patients (incidence >=5%) treated with DIFICID are pyrexia, abdominal pain, vomiting, diarrhea, constipation, increased aminotransferases, and rash. (6)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. AdultsThe safety of DIFICID 200 mg tablets taken twice day for 10 days was evaluated in 564 adult patients with CDAD in two active-controlled trials with 86.7% of patients receiving full course of treatment.Thirty-three adult patients receiving DIFICID (5.9%) withdrew from trials as 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 DIFICID and vancomycin patients in Phase trials. The most common selected adverse reactions occurring in >=2% of adult patients treated with DIFICID are listed in Table 2.Table 2: Selected Adverse Reactions with an Incidence of >=2% Reported in DIFICID-Treated Adult Patients in Controlled TrialsSystem Organ ClassDIFICID(N=564)Vancomycin(N=583) Adverse Reactionn (%)n (%)Blood and Lymphatic System Disorders Anemia14 (2%)12 (2%) Neutropenia14 (2%)6 (1%)Gastrointestinal Disorders Nausea62 (11%)66 (11%) Vomiting41 (7%)37 (6%) Abdominal Pain33 (6%)23 (4%) Gastrointestinal Hemorrhage20 (4%)12 (2%)The following adverse reactions were reported in <2% of adult patients taking DIFICID tablets in controlled trials:Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolonInvestigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet countMetabolism and Nutrition Disorders: hyperglycemia, metabolic acidosisSkin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash. PediatricsThe safety of DIFICID in pediatric patients months to less than 18 years of age was evaluated in Phase single-arm trial in 38 patients and Phase randomized, active-controlled trial in 98 patients treated with DIFICID and 44 patients treated with vancomycin [see Clinical Studies (14.2)]. In both studies, patients received DIFICID orally twice daily for 10 days. Patients <2 years of age, or weighing <12.5 kg, or unable to swallow tablets received weight-based doses of DIFICID oral suspension. Patients weighing at least 12.5 kg and able to swallow tablets received the 200 mg DIFICID tablet. The age range in the Phase trial was 11 months to 17 years and in the Phase trial was month to 17 years (one patient was less than months of age).One death occurred in the Phase single-arm trial. In the Phase trial, there were deaths in DIFICID-treated patients and no deaths in vancomycin-treated patients during the study period (40 days). All deaths occurred in patients less than years of age and appeared to be related to underlying comorbidities [see Clinical Studies (14.2)]. Treatment discontinuation due to adverse reactions occurred in 7.9% (3/38) of patients in the Phase trial, and in 1% (1/98) and 2.3% (1/44) of DIFICID- and vancomycin-treated patients, respectively, in the Phase trial. The most common selected adverse reactions occurring in >=5% of pediatric patients treated with DIFICID in the Phase trial are listed in Table 3.Table 3: Selected Adverse Reactions with an Incidence of >=5% Reported in DIFICID-Treated Pediatric Patients in the Controlled TrialSystem Organ ClassDIFICID(N=98)Vancomycin(N=44) Adverse Reactionn (%)n (%)Gastrointestinal Disorders Abdominal painIncludes abdominal pain, abdominal pain lower, and abdominal pain upper (8.2)9 (20.5) Vomiting7 (7.1)6 (13.6) Diarrhea7 (7.1)5 (11.4) Constipation5 (5.1)1 (2.3)General Disorders and Administration Site Conditions Pyrexia13 (13.3)10 (22.7)Investigations Aminotransferases increasedIncludes alanine aminotransferase increased, aspartate aminotransferase increased, and hepatic enzyme increased (5.1)1 (2.3)Skin and Subcutaneous Tissue Disorders RashIncludes rash, rash follicular, rash maculo-papular, and exfoliative rash (5.1)1 (2.3)The following adverse reactions were reported in <5% of pediatric patients taking DIFICID in clinical trials:Skin and Subcutaneous Tissue Disorders: urticaria, pruritus. 6.2Post Marketing Experience. The following adverse reactions have been identified during post-approval use of DIFICID. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity reactions (dyspnea, angioedema, rash, pruritus).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 (AUC0-t) was approximately 100 times that in humans.

CLINICAL PHARMACOLOGY SECTION.

12 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 dose-ranging trial (N=48) of fidaxomicin using 50 mg, 100 mg, and 200 mg twice daily for 10 days, dose-response relationship was observed for efficacy.. 12.3 Pharmacokinetics. The pharmacokinetic parameters of fidaxomicin and its main metabolite OP-1118 following 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 MalesParameterFidaxomicinOP-1118NValueNValueCmax (ng/mL)145.20 +- 2.811412.0 +- 6.06Tmax (h)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 to the last measured concentration; AUC0-, area under the concentration-time curve from time to infinity; t1/2, elimination half-life 142.00 (1.00-5.00)141.02 (1.00-5.00)AUC0-t (ng-h/mL)1448.3 +- 18.414103 +- 39.4AUC0- (ng-h/mL)962.9 +- 19.510118 +- 43.3t1/2 (h)911.7 +- 4.801011.2 +- 3.01. AbsorptionFidaxomicin 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 and 10.In food-effect study involving administration of DIFICID to healthy adults (N=28) with 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.. DistributionFidaxomicin 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 ug/g and 213-1210 ug/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.. Elimination. MetabolismFidaxomicin 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.. ExcretionFidaxomicin 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 single dose of 200 mg.. Specific Populations. Geriatric PatientsIn 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 (8.5)].. Pediatric PatientsSimilar 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 to hours post-dose.. Male and Female PatientsPlasma 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.. Patients with Renal ImpairmentIn 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.. Patients with Hepatic ImpairmentThe 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 StudiesIn vivo studies were conducted to evaluate intestinal drug-drug interactions of fidaxomicin as P-gp substrate, P-gp inhibitor, and inhibitor of major CYP enzymes expressed in the gastrointestinal tract (CYP3A4, CYP2C9, and CYP2C19).Table summarizes the impact of 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 Co-Administered DrugParameterCyclosporine 200 mg Fidaxomicin 200 mgCyclosporine was administered hour before fidaxomicin. (N=14)Fidaxomicin 200 mg Alone(N=14)Mean Ratio of Parameters With/Without Co-Administered Drug (90% CI CI confidence interval)No Effect 1.00NMeanNMeanFidaxomicin Cmax (ng/mL)1419.4144.674.15 (3.23-5.32) AUC0- (ng-h/mL)8114959.51.92 (1.39-2.64)OP-1118 Cmax (ng/mL)141001410.69.51 (6.93-13.05) AUC0- (ng-h/mL)12438101064.11 (3.06-5.53)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 ActionFidaxomicin is fermentation product obtained from the Actinomycete Dactylosporangium aurantiacum. Fidaxomicin is macrolide antibacterial drug that inhibits RNA synthesis by binding to RNA polymerases. Fidaxomicin is bactericidal against C. difficile in vitro, and demonstrates post-antibiotic effect vs. C. difficile of 6-10 hrs.. ResistanceFidaxomicin demonstrates no in vitro cross-resistance with other classes of antibacterial drugs. In vitro studies indicate low frequency of spontaneous resistance to fidaxomicin in C. difficile (ranging from <1.4 10-9 to 12.8 10-9). 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 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 baseline of 0.06 ug/mL to 16 ug/mL at the time of CDAD recurrence.. Interaction With Other AntimicrobialsFidaxomicin 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 ActivityFidaxomicin 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 TestingFor 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Clinical Studies of DIFICID in Adult Patients with CDAD. In two randomized, double-blinded trials, 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 or 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 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 investigators 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 PatientsClinical Response at End of TreatmentSustained Response at 25 days Post-TreatmentDIFICID (N)Vancomycin (N)Difference (95% CI)Confidence interval (CI) was derived using Wilsons 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. DIFICID (N)Vancomycin (N)Difference (95% CI) Trial 188% (N=289)86% (N=307)2.6% (-2.9%, 8.0%)70% (N=289)57% (N=307)12.7% (4.4%, 20.9%)Trial 288% (N=253)87% (N=256)1.0% (-4.8%, 6.8%)72% (N=253)57% (N=256)14.6% (5.8%, 23.3%)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 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 PatientsTrial 1Initial C. difficile GroupDIFICID n/N (%)Vancomycin n/N (%)Difference (95% CI)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 (CI) were derived using Wilsons score method. BI Isolates44/76 (58%)52/82 (63%)-5.5% (-20.3%, 9.5%)Non-BI Isolates105/126 (83%)87/131 (66%)16.9% (6.3%, 27.0%)Trial 2Initial C. difficile GroupDIFICID n/N (%)Vancomycin n/N (%)Difference (95% CI) BI Isolates42/65 (65%)31/60 (52%)12.9% (-4.2%, 29.2%)Non-BI Isolates109/131 (83%)77/121 (64%)19.6% (8.7%, 30.0%). 14.2Clinical Studies of DIFICID in Pediatric Patients with CDAD. The safety and efficacy of DIFICID in pediatric patients months to less than 18 years of age was investigated in 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 2:1 ratio. Randomized patients were stratified by age group as follows: 30 aged months to <2 years, 49 aged to <6 years, 40 aged 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 consecutive days while on treatment and the patient remained well with no requirement for further CDAD therapy through 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 consecutive days while on treatment and the patient remained well with no requirement for further CDAD therapy through 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 PatientsClinical ResponseSustained Response at 30 days Post-TreatmentDIFICIDn/N (%)Vancomycinn/N (%)Difference(95% CI)DIFICIDn/N (%)Vancomycinn/N (%)Difference(95% CI)Overall76/98 (77.6)31/44 (70.5)7.5(-7.4, 23.9)67/98 (68.4)22/44 (50.0)18.4(1.5, 35.3)<2 years13/20 (65.0)9/10 (90.0)11/20 (55.0)7/10 (70.0)>=2 to <6 years25/32 (78.1)12/16 (75.0)21/32 (65.6)8/16 (50.0)>=6 to <12 years23/26 (88.5)5/10 (50.0)22/26 (84.6)4/10 (40.0)>=12 to <18 years15/20 (75.0)5/8 (62.5)13/20 (65.0)3/8 (37.5).

DESCRIPTION SECTION.

11 DESCRIPTION. DIFICID (fidaxomicin) is macrolide antibacterial drug for oral administration. Its CAS chemical name is Oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl--D-mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)--D-lyxo-hexopyranosyl]oxy]-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-, (3E,5E,8S,9E,11S,12R,13E,15E,18S)-. The structural formula of fidaxomicin is shown in Figure 1.Figure 1: Structural Formula of FidaxomicinDIFICID tablets are film-coated and contain 200 mg of fidaxomicin per tablet and the following inactive ingredients: butylated hydroxytoluene, hydroxypropyl cellulose, lecithin (soy), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, sodium starch glycolate, talc, and titanium dioxide.DIFICID for oral suspension is supplied as granules in bottles containing 5.45 of fidaxomicin (40 mg of fidaxomicin per mL after reconstitution) and the following inactive ingredients: citric acid, microcrystalline cellulose, mixed berry flavor, sodium benzoate, sodium citrate, sodium starch glycolate, sucralose, and xanthan gum.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. DIFICID is administered orally with or without food. (2.1)AdultsOne 200 mg tablet orally twice daily for 10 days. (2.2)Pediatrics (6 Months to Less than 18 Years of Age)TabletsPediatric patients weighing at least 12.5 kg and able to swallow tablets: One 200 mg tablet orally twice daily for 10 days. (2.3)Oral SuspensionPediatric patients weighing at least kg: Weight-based dosing of the oral suspension twice daily for 10 days using an oral dosing syringe, as specified in Table in the full prescribing information. (2.3)For instructions on preparation and administration of DIFICID oral suspension, see full prescribing information. (2.4). DIFICID is administered orally with or without food. (2.1). AdultsOne 200 mg tablet orally twice daily for 10 days. (2.2). One 200 mg tablet orally twice daily for 10 days. (2.2). Pediatrics (6 Months to Less than 18 Years of Age). TabletsPediatric patients weighing at least 12.5 kg and able to swallow tablets: One 200 mg tablet orally twice daily for 10 days. (2.3). Pediatric patients weighing at least 12.5 kg and able to swallow tablets: One 200 mg tablet orally twice daily for 10 days. (2.3). Oral SuspensionPediatric patients weighing at least kg: Weight-based dosing of the oral suspension twice daily for 10 days using an oral dosing syringe, as specified in Table in the full prescribing information. (2.3)For instructions on preparation and administration of DIFICID oral suspension, see full prescribing information. (2.4). Pediatric patients weighing at least kg: Weight-based dosing of the oral suspension twice daily for 10 days using an oral dosing syringe, as specified in Table in the full prescribing information. (2.3). For instructions on preparation and administration of DIFICID oral suspension, see full prescribing information. (2.4). 2.1Important Administration Instructions. DIFICID is available for oral administration as 200 mg tablets and as granules for oral suspension (40 mg/mL (200 mg/5 mL) when reconstituted). DIFICID is administered orally with or without food.. 2.2Adult Patients. The recommended dosage for adults is one 200 mg DIFICID tablet orally twice daily for 10 days.. 2.3Pediatric Patients (6 Months to Less than 18 Years of Age). TabletsThe recommended dosage for pediatric patients weighing at least 12.5 kg and able to swallow tablets is one 200 mg DIFICID tablet administered orally twice daily for 10 days. If unable to swallow tablets, pediatric patients may be dosed with DIFICID oral suspension as recommended in Table below.. Oral SuspensionThe recommended dosage for pediatric patients based on weight are shown in Table 1. Administer DIFICID oral suspension orally twice daily for 10 days using an oral dosing syringe [see Dosage and Administration (2.4)].Table 1: Recommended Dosage of DIFICID Oral Suspension in Pediatric Patients, Based on WeightBody WeightDose Administered Twice DailyVolume of 40 mg/mL Suspension to be Administered Orally Twice Daily4 kg to less than kg80 mg2 mL7 kg to less than kg120 mg3 mL9 kg to less than 12.5 kg160 mg4 mL12.5 kg and above200 mg5 mL. 2.4Preparation and Administration of DIFICID Oral Suspension. PreparationShake the glass bottle to ensure the granules move around freely and no caking has occurred.Measure 130 mL of purified water, add to the glass bottle, and cap tightly.Hold bottle in horizontal position and shake bottle vigorously in that position for at least minutes.Verify that homogeneous suspension is obtained. If not, repeat the shaking step.Once homogeneous suspension is visually confirmed, shake an additional 30 seconds.Let bottle stand for minute.Verify that the suspension is still homogeneous. If not, repeat steps through 6.Once reconstituted, DIFICID oral suspension is white to yellowish white in color.Write discard date (current date plus 12 days) on the bottle [see How Supplied/Storage and Handling (16.1, 16.2)].. Shake the glass bottle to ensure the granules move around freely and no caking has occurred.. Measure 130 mL of purified water, add to the glass bottle, and cap tightly.. Hold bottle in horizontal position and shake bottle vigorously in that position for at least minutes.. Verify that homogeneous suspension is obtained. If not, repeat the shaking step.. Once homogeneous suspension is visually confirmed, shake an additional 30 seconds.. Let bottle stand for minute.. Verify that the suspension is still homogeneous. If not, repeat steps through 6.. Once reconstituted, DIFICID oral suspension is white to yellowish white in color.. Write discard date (current date plus 12 days) on the bottle [see How Supplied/Storage and Handling (16.1, 16.2)].. Storage of Reconstituted Oral SuspensionStore the reconstituted oral suspension in refrigerator [between 36F-46F (2C-8C)] for up to 12 days. Discard after 12 days.. Store the reconstituted oral suspension in refrigerator [between 36F-46F (2C-8C)] for up to 12 days. Discard after 12 days.. AdministrationRemove bottle from refrigerator 15 minutes prior to each administration.Shake vigorously until suspension has an even consistency.Remove cap, then administer orally with or without food using an oral dosing syringe.Between doses, replace cap and store in refrigerator.. Remove bottle from refrigerator 15 minutes prior to each administration.. Shake vigorously until suspension has an even consistency.. Remove cap, then administer orally with or without food using an oral dosing syringe.. Between doses, replace cap and store in refrigerator.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Film-coated tablets: 200 mg (3)For oral suspension: 40 mg/mL (200 mg/5 mL) when reconstituted (3). Film-coated tablets: 200 mg (3). For oral suspension: 40 mg/mL (200 mg/5 mL) when reconstituted (3). DIFICID tablets200 mg white to off-white film-coated, oblong tablets; each tablet is debossed with FDX on one side and 200 on the other side.. DIFICID for oral suspensionWhite to yellowish white granules; following reconstitution, each mL of white to yellowish white oral suspension contains 40 mg of fidaxomicin (200 mg of fidaxomicin per mL).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract.. 7.1Cyclosporine. 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 adult patients in controlled clinical trials. Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of DIFICID compared to vancomycin were observed between these subjects and younger subjects.In controlled trials, elderly patients (>=65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. TabletsDIFICID tablets are white to off-white film-coated, oblong tablets containing 200 mg of fidaxomicin per tablet; each tablet is debossed with FDX on one side and 200 on the other side.DIFICID tablets are supplied as bottles of 20 tablets (NDC 52015-080-01).. Granules for Oral SuspensionDIFICID granules for oral suspension are white to yellowish white.DIFICID granules for oral suspension (NDC 52015-700-22) is supplied as 150 mL amber glass bottles of 9.53 of granules that contain 5.45 of fidaxomicin. Each glass bottle has child-resistant cap and is sealed in laminated aluminum foil pouch. After reconstitution, the total oral suspension volume is 136 mL. Discard unused suspension after 12 days. The concentration of fidaxomicin is 40 mg/mL (200 mg per mL) in the reconstituted oral suspension.. 16.2 Storage. TabletsStore DIFICID tablets at 20C-25C (68F-77F); excursions permitted to 15C-30C (59F-86F). See USP controlled room temperature. Store in the original bottle.. Granules for oral suspensionStore DIFICID granules for oral suspension at 20C-25C (68F-77F); excursions permitted to 15C-30C (59F-86F). Store in the original package. Do not open pouch until time of use.Once reconstituted, store DIFICID oral suspension refrigerated at 2C-8C (36F-46F) for up to 12 days. Store capped in the original bottle.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DIFICID is macrolide antibacterial indicated in adult and pediatric patients months of age and older for the treatment of C. difficile-associated diarrhea. (1.1)To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID 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. DIFICID(R) is indicated in adult and pediatric patients aged months and older 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 DIFICID and other antibacterial drugs, DIFICID 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Oral SuspensionRemove the bottle from the refrigerator 15 minutes prior to each administration.Instruct patients or caregivers to use an oral dosing syringe to correctly measure the prescribed amount of medication. Inform patients or caregivers that oral dosing syringes may be obtained from their pharmacy.Inform the patients or caregivers that DIFICID oral suspension should be prepared by healthcare professional. Advise them to contact healthcare professional for any questions regarding administration of DIFICID oral suspension.. Administration with FoodInform patients and caregivers that DIFICID tablets and oral suspension may be taken with or without food.. Antibacterial ResistancePatients should be counseled that antibacterial drugs, including DIFICID, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When DIFICID is prescribed to treat C. difficile infection, 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.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information on the presence of fidaxomicin or its main metabolite, OP-1118, in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DIFICID and any potential adverse effects on the breastfed infant from DIFICID or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Fidaxomicin is an antibacterial drug [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionFidaxomicin is fermentation product obtained from the Actinomycete Dactylosporangium aurantiacum. Fidaxomicin is macrolide antibacterial drug that inhibits RNA synthesis by binding to RNA polymerases. Fidaxomicin is bactericidal against C. difficile in vitro, and demonstrates post-antibiotic effect vs. C. difficile of 6-10 hrs.. ResistanceFidaxomicin demonstrates no in vitro cross-resistance with other classes of antibacterial drugs. In vitro studies indicate low frequency of spontaneous resistance to fidaxomicin in C. difficile (ranging from <1.4 10-9 to 12.8 10-9). 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 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 baseline of 0.06 ug/mL to 16 ug/mL at the time of CDAD recurrence.. Interaction With Other AntimicrobialsFidaxomicin 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 ActivityFidaxomicin 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 TestingFor 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 (AUC0-t) was approximately 100 times that in humans.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for months.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 200 mg Tablet Bottle Carton. NDC 52015-080-01 20 tabletsDIFICID(R) (fidaxomicin) tablets200 mg per tabletRx onlyManuf. for:Merck Sharp Dohme Corp.,a subsidiary of MERCK CO.,INC. Whitehouse Station, NJ 08889, USAManuf. by: Patheon Inc.Mississauga, Ontario,L5N 7k9, CanadaFidaxomicin (active ingred.)Made In India.Formulated In Canada.. PRINCIPAL DISPLAY PANEL 200 mg Tablet Bottle Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of DIFICID for the treatment of CDAD have been established in pediatric patients months to less than 18 years of age. Use of DIFICID in these age groups is supported by evidence from adequate and well-controlled trials of DIFICID in adults with CDAD and pharmacokinetic, safety and efficacy data from pediatric trials [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. No new safety signals associated with the use of DIFICID in pediatric patients were identified in the pediatric trials [see Adverse Reactions (6.1)].The safety and effectiveness of DIFICID have not been established in pediatric patients younger than months of age.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe limited available data on use of DIFICID in pregnant women are insufficient to inform any drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Embryo-fetal reproduction studies in rats and rabbits dosed intravenously during organogenesis revealed no evidence of harm to the fetus at fidaxomicin and OP-1118 (its main metabolite) exposures 65-fold or higher than the clinical exposure at the DIFICID recommended dose [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataIn pregnant rats, fidaxomicin was administered intravenously at doses of 4, 8, and 15 mg/kg/day from gestation day through 17 (during the period of organogenesis). No embryo/fetal effects were noted in this study at exposures (AUC) 193-fold higher for fidaxomicin, and 65-fold higher for OP-1118 than the clinical exposure at the DIFICID recommended dose.In pregnant rabbits, fidaxomicin was administered intravenously at doses of 2, 4, and 7.5 mg/kg/day from gestation day through 18 (during the period of organogenesis). No embryo/fetal effects were noted in this study at exposures 66-fold higher for fidaxomicin, and 245-fold higher for OP-1118 than the clinical exposure at the DIFICID recommended dose.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information DIFICID(R) (dih-fih-sid)(fidaxomicin) tablets, for oral use DIFICID(R) (dih-fih-sid)(fidaxomicin) for oral suspension What You Need to Know About Your MedicineBefore you take DIFICID, be sure you understand what it is for and how to take it.If you have questions about DIFICID, ask your doctor or pharmacist.Remember that your doctor has prescribed DIFICID only for you. Never give this medicine to anyone else.Keep this Patient Information for DIFICID so you can read it again.What is DIFICIDDIFICID is an antibiotic medicine used to treat an infection called Clostridioides difficile-associated diarrhea (CDAD) in adults and children months of age and older. Clostridioides difficile (C-diff) is bacterium that can cause an infection that can damage your colon and cause stomach pain and severe diarrhea. DIFICID is not to be used to treat other types of infections in the body.Sometimes infections are caused by viruses rather than bacteria. Antibiotic medicines, including DIFICID, do not kill viruses.It is not known if DIFICID is safe and effective in children under months old.Who should not take DIFICIDDo not take DIFICID if you are allergic to fidaxomicin, or any other ingredient in DIFICID. See the end of this Patient Information for complete list of ingredients in DIFICID.What should tell my doctor before taking DIFICIDPregnancyIf you are pregnant or plan to become pregnant, tell your doctor before you take DIFICID.It is not known if DIFICID will harm your baby while you are pregnant.If you are pregnant, you and your doctor should decide together if you will take DIFICID.BreastfeedingIf you are breastfeeding or plan to breastfeed, tell your doctor before you take DIFICID.It is not known if DIFICID passes into breast milk.If you are breastfeeding, you and your doctor should decide together if you will take DIFICID.Other MedicinesTell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal and dietary supplements.Know the medicines you take. Keep list of your medicines to show your doctor and pharmacist when you get new medicine.Allergic ReactionsSee Who should not take DIFICIDIf you are allergic to other kinds of antibiotics called macrolides (for example: azithromycin (Zithromax) or clarithromycin (Biaxin)) or any other ingredient in DIFICID, tell your doctor. See the end of this Patient Information for complete list of ingredients in DIFICID.How do take DIFICIDTake DIFICID tablets or oral suspension exactly as prescribed by your doctor.Take DIFICID twice day (approximately every 12 hours). For example, if you take your first dose at 8:00 a.m. you should take your second dose at 8:00 p.m.You can take DIFICID with or without food.If DIFICID oral suspension is prescribed for your child:DIFICID oral suspension is liquid that your pharmacist will mix before it is given to you.Store DIFICID oral suspension in the refrigerator (see How should store DIFICID).Take the bottle out of the refrigerator 15 minutes before giving the dose to your child.Shake the bottle well before each dose. DIFICID oral suspension should be white to yellowish white.Remove the cap and measure the dose with the oral dosing syringe provided by your pharmacist.Give the dose by mouth to your child using the oral dosing syringe.Put the cap back on the bottle and store in the refrigerator after each dose. Do not skip any doses or stop taking DIFICID until you finish your prescribed treatment, even if you begin to feel better, unless you have serious allergic reaction (see What are the possible side effects of DIFICID).This will lower the chance that the bacteria will become resistant to DIFICID. If this happens, DIFICID and other antibiotic medicines may not work in the future.What are the possible side effects of DIFICIDDIFICID can cause serious side effects, including:Allergic reaction. If you get severe allergic reaction while taking DIFICID, including problems breathing or shortness of breath, rash, itching or hives, or swelling of the mouth, throat, or face, stop taking DIFICID and get emergency medical help right away.Common side effects of DIFICID include:The most common side effects of DIFICID in adults include:nauseavomitingstomach painbleeding in the stomach or intestineslow red blood cell count (anemia)low white blood cell count (neutropenia)The most common side effects of DIFICID in children include:fevervomitingdiarrheastomach painconstipationrashhigh levels of enzymes called aminotransferases in the blood, which may indicate liver damageOther less common side effects of DIFICID may include:swelling of any body part (such as your face, lips, tongue or around your eyes)itchinghivesbloatingstomach tendernessheartburnproblems swallowinghigh blood sugar (hyperglycemia)abnormal liver testslow levels of blood bicarbonatepassing gasintestinal blockageserious bowel inflammation (toxic megacolon)low platelet count (important for clotting and to control bleeding)high levels of acid in your blood (metabolic acidosis)If you have any side effect that bothers you or does not go away, tell your doctor.There may be other side effects to DIFICID that are not listed. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store DIFICIDDIFICID tabletsStore DIFICID tablets at room temperature between 68F to 77F (20C to 25C).Keep DIFICID in its original bottle until you are ready to take it.DIFICID for oral suspensionStore DIFICID oral suspension in the refrigerator between 36F to 46F (2C to 8C) for up to 12 days. Throw away (discard) any unused DIFICID oral suspension by the date written on the bottle.Keep DIFICID in its original child-resistant bottle with the cap on until you are ready to give it to your child.Keep DIFICID and all medicines out of the reach of children.General information about the safe and effective use of DIFICID.Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do not take DIFICID for condition for which it was not prescribed. Do not give DIFICID to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about DIFICID that is written for health professionals.What if have questions Call your doctor.Call Merck, the company that makes DIFICID, at 1-800-444-2080.Go to the website www.DIFICID.com.You can also find the full prescribing information written for doctors at www.DIFICID.com What are the ingredients in DIFICIDDIFICID tabletsActive ingredient: fidaxomicin.Inactive ingredients: butylated hydroxytoluene, hydroxypropyl cellulose, lecithin (soy), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, sodium starch glycolate, talc, and titanium dioxide.DIFICID for oral suspensionActive ingredient: fidaxomicin.Inactive ingredients: citric acid, microcrystalline cellulose, mixed berry flavor, sodium benzoate, sodium citrate, sodium starch glycolate, sucralose, and xanthan gum.. Before you take DIFICID, be sure you understand what it is for and how to take it.. If you have questions about DIFICID, ask your doctor or pharmacist.. Remember that your doctor has prescribed DIFICID only for you. Never give this medicine to anyone else.. Keep this Patient Information for DIFICID so you can read it again.. DIFICID is not to be used to treat other types of infections in the body.. Sometimes infections are caused by viruses rather than bacteria. Antibiotic medicines, including DIFICID, do not kill viruses.. If you are pregnant or plan to become pregnant, tell your doctor before you take DIFICID.. It is not known if DIFICID will harm your baby while you are pregnant.. If you are pregnant, you and your doctor should decide together if you will take DIFICID.. If you are breastfeeding or plan to breastfeed, tell your doctor before you take DIFICID.. It is not known if DIFICID passes into breast milk.. If you are breastfeeding, you and your doctor should decide together if you will take DIFICID.. Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal and dietary supplements.. Know the medicines you take. Keep list of your medicines to show your doctor and pharmacist when you get new medicine.. See Who should not take DIFICID. If you are allergic to other kinds of antibiotics called macrolides (for example: azithromycin (Zithromax) or clarithromycin (Biaxin)) or any other ingredient in DIFICID, tell your doctor. See the end of this Patient Information for complete list of ingredients in DIFICID.. Take DIFICID tablets or oral suspension exactly as prescribed by your doctor.. Take DIFICID twice day (approximately every 12 hours). For example, if you take your first dose at 8:00 a.m. you should take your second dose at 8:00 p.m.. You can take DIFICID with or without food.. If DIFICID oral suspension is prescribed for your child:DIFICID oral suspension is liquid that your pharmacist will mix before it is given to you.Store DIFICID oral suspension in the refrigerator (see How should store DIFICID).Take the bottle out of the refrigerator 15 minutes before giving the dose to your child.Shake the bottle well before each dose. DIFICID oral suspension should be white to yellowish white.Remove the cap and measure the dose with the oral dosing syringe provided by your pharmacist.Give the dose by mouth to your child using the oral dosing syringe.Put the cap back on the bottle and store in the refrigerator after each dose. DIFICID oral suspension is liquid that your pharmacist will mix before it is given to you.. Store DIFICID oral suspension in the refrigerator (see How should store DIFICID).. Take the bottle out of the refrigerator 15 minutes before giving the dose to your child.. Shake the bottle well before each dose. DIFICID oral suspension should be white to yellowish white.. Remove the cap and measure the dose with the oral dosing syringe provided by your pharmacist.. Give the dose by mouth to your child using the oral dosing syringe.. Put the cap back on the bottle and store in the refrigerator after each dose.. Do not skip any doses or stop taking DIFICID until you finish your prescribed treatment, even if you begin to feel better, unless you have serious allergic reaction (see What are the possible side effects of DIFICID).This will lower the chance that the bacteria will become resistant to DIFICID. If this happens, DIFICID and other antibiotic medicines may not work in the future.. Allergic reaction. If you get severe allergic reaction while taking DIFICID, including problems breathing or shortness of breath, rash, itching or hives, or swelling of the mouth, throat, or face, stop taking DIFICID and get emergency medical help right away.. nausea. vomiting. stomach pain. bleeding in the stomach or intestines. low red blood cell count (anemia). low white blood cell count (neutropenia). fever. vomiting. diarrhea. stomach pain. constipation. rash. high levels of enzymes called aminotransferases in the blood, which may indicate liver damage. swelling of any body part (such as your face, lips, tongue or around your eyes). itching. hives. bloating. stomach tenderness. heartburn. problems swallowing. high blood sugar (hyperglycemia). abnormal liver tests. low levels of blood bicarbonate. passing gas. intestinal blockage. serious bowel inflammation (toxic megacolon). low platelet count (important for clotting and to control bleeding). high levels of acid in your blood (metabolic acidosis). Store DIFICID tablets at room temperature between 68F to 77F (20C to 25C).. Keep DIFICID in its original bottle until you are ready to take it.. Store DIFICID oral suspension in the refrigerator between 36F to 46F (2C to 8C) for up to 12 days. Throw away (discard) any unused DIFICID oral suspension by the date written on the bottle.. Keep DIFICID in its original child-resistant bottle with the cap on until you are ready to give it to your child.. Call your doctor.. Call Merck, the company that makes DIFICID, at 1-800-444-2080.. Go to the website www.DIFICID.com.. You can also find the full prescribing information written for doctors at www.DIFICID.com Active ingredient: fidaxomicin.. Inactive ingredients: butylated hydroxytoluene, hydroxypropyl cellulose, lecithin (soy), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, sodium starch glycolate, talc, and titanium dioxide.. Active ingredient: fidaxomicin.. Inactive ingredients: citric acid, microcrystalline cellulose, mixed berry flavor, sodium benzoate, sodium citrate, sodium starch glycolate, sucralose, and xanthan gum.

SPL UNCLASSIFIED SECTION.

1.1 Clostridioides difficile-Associated Diarrhea. DIFICID(R) is indicated in adult and pediatric patients aged months and older for the treatment of C. difficile-associated diarrhea (CDAD).

STORAGE AND HANDLING SECTION.

16.2 Storage. TabletsStore DIFICID tablets at 20C-25C (68F-77F); excursions permitted to 15C-30C (59F-86F). See USP controlled room temperature. Store in the original bottle.. Granules for oral suspensionStore DIFICID granules for oral suspension at 20C-25C (68F-77F); excursions permitted to 15C-30C (59F-86F). Store in the original package. Do not open pouch until time of use.Once reconstituted, store DIFICID oral suspension refrigerated at 2C-8C (36F-46F) for up to 12 days. Store capped in the original bottle.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatrics: The safety and effectiveness of DIFICID have not been established in pediatric patients younger than months of age. (8.4). 8.1 Pregnancy. Risk SummaryThe limited available data on use of DIFICID in pregnant women are insufficient to inform any drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Embryo-fetal reproduction studies in rats and rabbits dosed intravenously during organogenesis revealed no evidence of harm to the fetus at fidaxomicin and OP-1118 (its main metabolite) exposures 65-fold or higher than the clinical exposure at the DIFICID recommended dose [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataIn pregnant rats, fidaxomicin was administered intravenously at doses of 4, 8, and 15 mg/kg/day from gestation day through 17 (during the period of organogenesis). No embryo/fetal effects were noted in this study at exposures (AUC) 193-fold higher for fidaxomicin, and 65-fold higher for OP-1118 than the clinical exposure at the DIFICID recommended dose.In pregnant rabbits, fidaxomicin was administered intravenously at doses of 2, 4, and 7.5 mg/kg/day from gestation day through 18 (during the period of organogenesis). No embryo/fetal effects were noted in this study at exposures 66-fold higher for fidaxomicin, and 245-fold higher for OP-1118 than the clinical exposure at the DIFICID recommended dose.. 8.2 Lactation. Risk SummaryThere is no information on the presence of fidaxomicin or its main metabolite, OP-1118, in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DIFICID and any potential adverse effects on the breastfed infant from DIFICID or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of DIFICID for the treatment of CDAD have been established in pediatric patients months to less than 18 years of age. Use of DIFICID in these age groups is supported by evidence from adequate and well-controlled trials of DIFICID in adults with CDAD and pharmacokinetic, safety and efficacy data from pediatric trials [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. No new safety signals associated with the use of DIFICID in pediatric patients were identified in the pediatric trials [see Adverse Reactions (6.1)].The safety and effectiveness of DIFICID have not been established in pediatric patients younger than months of age.. 8.5 Geriatric Use. Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of DIFICID compared to vancomycin were observed between these subjects and younger subjects.In controlled trials, elderly patients (>=65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years 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.

WARNINGS AND PRECAUTIONS SECTION.

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