NDC 52015-700 Dificid

Fidaxomicin

NDC Product Code 52015-700

NDC CODE: 52015-700

Proprietary Name: Dificid What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Fidaxomicin What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat a severe intestinal condition (Clostridium difficile-associated diarrhea) due to a type of resistant bacteria. This condition may rarely occur after taking antibiotics. Symptoms include persistent diarrhea, stomach/abdominal pain or cramping, and blood/mucus in your stool. Fidaxomicin is known as a macrolide antibiotic. It works by stopping the growth of this resistant bacteria. This antibiotic works in the intestines and is not absorbed by your body. It should only be used to treat this type of intestinal bacterial infection. It will not work for other types of infections, including viral infections (such as common cold, flu). Unnecessary use or misuse of any antibiotic can lead to its decreased effectiveness.

NDC Code Structure

  • 52015 - Merck Sharp & Dohme Corp.

NDC 52015-700-22

Package Description: 1 POUCH in 1 CARTON > 1 BOTTLE, GLASS in 1 POUCH (52015-700-23) > 150 mL in 1 BOTTLE, GLASS (52015-700-21)

NDC Product Information

Dificid with NDC 52015-700 is a a human prescription drug product labeled by Merck Sharp & Dohme Corp.. The generic name of Dificid is fidaxomicin. The product's dosage form is granule, for suspension and is administered via oral form.

Labeler Name: Merck Sharp & Dohme Corp.

Dosage Form: Granule, For Suspension - A small medicinal particle or grain made available in its more stable dry form, to be reconstituted with solvent just before dispensing to form a suspension; the granules are so prepared to contain not only the medicinal agent, but the colorants, flavorants, and any other desired pharmaceutic ingredient.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Dificid Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • FIDAXOMICIN 200 mg/5mL

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Macrolides - [CS]
  • Macrolide Antibacterial - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Merck Sharp & Dohme Corp.
Labeler Code: 52015
FDA Application Number: NDA213138 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 02-18-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Dificid Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And 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 Clostridium difficile.

1.1 Clostridium Difficile-Associated Diarrhea

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

2 Dosage And Administration

The recommended dose is one 200 mg DIFICID tablet orally twice daily for 10 days with or without food.

3 Dosage Forms And Strengths

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

4 Contraindications

Hypersensitivity to fidaxomicin.

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 Hypersensitivity Reactions

Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID® should be discontinued and appropriate therapy should be instituted.Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.

5.3 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 reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients 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 Phase 3 studies.Table 1: Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled TrialsSystem Organ ClassDIFICID(N=564)Vancomycin(N=583)  Preferred Termn (%)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 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

6.2 Post Marketing Experience

Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible.Hypersensitivity reactions (dyspnea, angioedema, rash, and pruritus) have been reported.

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.

7.1 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.

Teratogenic Effects

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/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 <18 years of age have not been established.

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 fidaxomicin 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.

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 3 months.

11 Description

DIFICID (fidaxomicin) is a 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-β-D- mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-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 (200 mg) are film-coated and contain the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, hydroxypropyl cellulose, butylated hydroxytoluene, sodium starch glycolate, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, and lecithin (soy).

12.1 Mechanism Of Action

Fidaxomicin is an antibacterial drug [see Clinical Pharmacology (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 2.Table 2: 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 0 to the last measured concentration; AUC0-∞, area under the concentration-time curve from time 0 to infinity; t1/2, elimination half-life142.00 (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

Other

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 1 and 10.In a food-effect study involving administration of DIFICID to healthy adults (N=28) with a high-fat meal versus under fasting conditions, Cmax of fidaxomicin and OP-1118 decreased by 21.5% and 33.4%, respectively, while AUC0-t remained unchanged. This decrease in Cmax is not considered clinically significant, and thus, DIFICID may be administered with or without food.

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 µg/g and 213-1210 µg/g, respectively. In contrast, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) ranged 2-179 ng/mL and 10-829 ng/mL, respectively.

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 a single dose of 200 mg.

Specific Populations

GeriatricIn 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)].

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

Renal 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.

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 InteractionsIn vivo studies were conducted to evaluate intestinal drug-drug interactions of fidaxomicin as a P-gp substrate, P-gp inhibitor, and inhibitor of major CYP enzymes expressed in the gastrointestinal tract (CYP3A4, CYP2C9, and CYP2C19).Table 3 summarizes the impact of a co-administered drug (P-gp inhibitor) on the pharmacokinetics of fidaxomicin [see Drug Interactions (7.1)].Table 3: Pharmacokinetic Parameters of Fidaxomicin and OP-1118 in the Presence of a Co-Administered DrugParameterCyclosporine 200 mg + Fidaxomicin 200 mgCyclosporine was administered 1 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.

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

Mechanism of Decreased Susceptibility to FidaxomicinIn vitro studies indicate a low frequency of spontaneous resistance to fidaxomicin in C. difficile (ranging from <1.4 × 10-9 to 12.8 × 10-9). A specific mutation (Val-ll43-Gly) in the beta subunit of RNA polymerase is associated with reduced susceptibility to fidaxomicin. This mutation was created in the laboratory and seen during clinical trials in a C. difficile isolate obtained from a subject treated with DIFICID who had recurrence of CDAD. The C. difficile isolate from the treated subject went from a fidaxomicin baseline minimal inhibitory concentration (MIC) of 0.06 µg/mL to 16 µg/mL.

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

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

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

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

Quality Control Parameters for Susceptibility TestingIn vitro susceptibility test quality control parameters were developed for fidaxomicin so that laboratories determining the susceptibility of C. difficile isolates to fidaxomicin can ascertain whether the susceptibility test is performing correctly. Standardized dilution techniques require the use of laboratory control microorganisms to monitor the technical aspects of the laboratory procedures. Standardized fidaxomicin powder should provide the MIC with the indicated quality control strain shown in Table 4.Table 4: Acceptable Quality Control Ranges for FidaxomicinMicroorganismMIC Range (µg/mL)C. difficile (ATCC 700057)0.03-0.25

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC., Whitehouse Station, NJ 08889, USAManufactured by: Patheon Inc.Mississauga, Ontario, L5N 7K9, CanadaFor patent information: www.merck.com/product/patent/home.htmlCopyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved.uspi-mk5119-t-1512r000

Mechanism Of Action

Mechanism of ActionFidaxomicin is bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases.

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.

14 Clinical Studies

In two randomized, double-blinded trials, a non-inferiority design was utilized to demonstrate the efficacy of DIFICID® (200 mg twice daily for 10 days) compared to vancomycin (125 mg four times daily for 10 days) in adults with Clostridium difficile-associated diarrhea (CDAD).Enrolled patients were 18 years of age or older, and received no more than 24 hours of pretreatment with vancomycin or metronidazole. CDAD was defined by >3 unformed bowel movements (or >200 mL of unformed stool for subjects having rectal collection devices) in the 24 hours before randomization, and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization. Enrolled patients had either no prior CDAD history or only one prior CDAD episode in the past three months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.The demographic profile and baseline CDAD characteristics of enrolled subjects were similar in the two trials. Patients had a median age of 64 years, were mainly white (90%), female (58%), and inpatients (63%). The median number of bowel movements per day was 6, and 37% of subjects had severe CDAD (defined as 10 or more unformed bowel movements per day or WBC ≥15000/mm3). Diarrhea alone was reported in 45% of patients and 84% of subjects had no prior CDAD episode.The primary efficacy endpoint was the clinical response rate at the end of treatment, based upon improvement in diarrhea or other symptoms such that, in the investigator's judgment, further CDAD treatment was not needed. An additional efficacy endpoint was sustained clinical response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment. Sustained response was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment.The results for clinical response at the end of treatment in both trials, shown in Table 5, indicate that DIFICID is non-inferior to vancomycin based on the 95% confidence interval (CI) lower limit being greater than the non-inferiority margin of -10%.The results for sustained clinical response at the end of the follow-up period, also shown in Table 5, indicate that DIFICID is superior to vancomycin on this endpoint. Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in DIFICID patients.Table 5: Clinical Response Rates at End-of-Treatment and Sustained Response at 25 days Post-TreatmentClinical Response at End of TreatmentSustained Response at 25 days Post TreatmentDIFICID% (N)Vancomycin% (N)Difference(95% CI)Confidence interval (CI) was derived using Wilson's score method. Approximately 5%-9% of the data in each trial and treatment arm were missing sustained response information and were imputed using multiple imputation method.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 a BI isolate. However, DIFICID did not demonstrate superiority in sustained clinical response when compared with vancomycin (Table 6).Table 6: Sustained Clinical Response at 25 Days after Treatment by C. difficile REA Group at BaselineTrial 1Initial C. difficile GroupDIFICIDn/N (%)Vancomycinn/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 Wilson's 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 GroupDIFICIDn/N (%)Vancomycinn/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%)

15 References

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

16.1 How Supplied

DIFICID® tablets are white to off-white film-coated, oblong tablets containing 200 mg of fidaxomicin; 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).

16.2 Storage

Storage: 20°-25°C (68°-77°F); excursions permitted to 15° - 30°C (59° - 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.

* Please review the disclaimer below.