Dificid (fidaxomicin)

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

• nausea (11%),
• vomiting (7%),
• abdominal pain (6%),
• gastrointestinal hemorrhage (4%),
• anemia (2%), and
• neutropenia (2%).

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

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

Gastrointestinal Disorders:

• abdominal distension,
• abdominal tenderness,
• dyspepsia,
• dysphagia,
• flatulence,
• intestinal obstruction,
• megacolon

Investigations:

• increased blood alkaline phosphatase,
• decreased blood bicarbonate,
• increased hepatic enzymes,
• decreased platelet count

Metabolism and Nutrition Disorders:

• hyperglycemia,
• metabolic acidosis

Skin and Subcutaneous Tissue Disorders:

• drug eruption,
• pruritus,
• rash

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

Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract.

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. 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.

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.

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.

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.