Dificlir

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Dificlir and other antibacterial drugs, Dificlir should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile.

Clostridium difficile-Associated Diarrhea

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

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

Hypersensitivity to fidaxomicin.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Not For Systemic Infections

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

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, Dificlir® 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 Dificlir to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.

Development Of Drug-Resistant Bacteria

Prescribing Dificlir 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.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

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.

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 Dificlir is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Of the total number of patients in controlled trials of Dificlir®, 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). However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

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 Dificlir 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 Dificlir (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 Dificlir Patients in Controlled Trials

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

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

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

Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis

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

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.

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.

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.

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 Males

Absorption

Fidaxomicin has minimal systemic absorption following oral administration, with plasma concentrations of fidaxomicin and OP-1118 in the ng/mL range at the therapeutic dose. In fidaxomicin-treated patients from controlled trials, plasma concentrations of fidaxomicin and OP-1118 obtained within the Tmax window (1-5 hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults. Following administration of Dificlir 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 Dificlir 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, Dificlir may be administered with or without food.

Distribution

Fidaxomicin is mainly confined to the gastrointestinal tract following oral administration. In selected patients (N=8) treated with Dificlir 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.

Metabolism

Fidaxomicin is primarily transformed by hydrolysis at the isobutyryl ester to form its main and microbiologically active metabolite, OP-1118. Metabolism of fidaxomicin and formation of OP-1118 are not dependent on cytochrome P450 (CYP) enzymes.

At the therapeutic dose, OP-1118 was the predominant circulating compound in healthy adults, followed by fidaxomicin.

Excretion

Fidaxomicin is mainly excreted in feces. In one trial of healthy adults (N=11), more than 92% of the dose was recovered in the stool as fidaxomicin and OP-1118 following single doses of 200 mg and 300 mg. In another trial of healthy adults (N=6), 0.59% of the dose was recovered in urine as OP-1118 only following a single dose of 200 mg.