Fidaxomicin Drug Information
Generic name: FIDAXOMICIN
Macrolide Antibacterial [EPC]
Uses of Fidaxomicin
Clostridioides difficile -Associated Diarrhea Fidaxomicin tablets are indicated in adult patients for
the treatment of C. difficile-associated diarrhea (CDAD).
Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness
of fidaxomicin tablets and other antibacterial drugs, fidaxomicin tablets should be used only to treat infections that are proven or strongly suspected to be caused by C. difficile. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Pediatric use information is approved for Cubist Pharmaceuticals LLC's DIFICID ® (fidaxomicin) tablets. However, due to Cubist Pharmaceuticals LLC's marketing exclusivity rights, this drug product is not labeled with that information.
Dosage & Administration of Fidaxomicin
Important
Administration Instructions Fidaxomicin tablets are available for oral administration as 200 mg tablets. Fidaxomicin tablets are administered orally with or without food.
Adult Patients
The recommended dosage for adults is one 200 mg fidaxomicin tablet orally twice daily for 10 days. Pediatric use information is approved for Cubist Pharmaceuticals LLC's DIFICID ® (fidaxomicin) tablets. However, due to Cubist Pharmaceuticals LLC's marketing exclusivity rights, this drug product is not labeled with that information.
Side Effects of Fidaxomicin
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. Adults The safety of fidaxomicin 200 mg tablets taken twice a day for 10 days was evaluated in 564 adult patients with CDAD in two active-controlled trials with 86.7% of patients receiving a full course of treatment. Thirty-three adult patients receiving fidaxomicin tablets (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 tablets and vancomycin patients in Phase 3 trials. The most common selected adverse reactions occurring in ≥2% of adult patients treated with fidaxomicin tablets are listed in Table 2. Table 2: Selected Adverse Reactions with an Incidence of ≥2% Reported in Fidaxomicin-Treated Adult Patients in Controlled Trials System Organ Class Adverse Reaction Fidaxomicin (N=564) Vancomycin (N=583) n (%) n (%) Blood and Lymphatic System Disorders Anemia 14 (2%) 12 (2%) Neutropenia 14 (2%) 6 (1%) Gastrointestinal Disorders Nausea 62 (11%) 66 (11%) Vomiting 41 (7%) 37 (6%) Abdominal Pain 33 (6%) 23 (4%) Gastrointestinal Hemorrhage 20 (4%) 12 (2%) The following adverse reactions were reported in <2% of adult patients taking fidaxomicin 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
The following adverse reactions have been identified during post-approval use of fidaxomicin tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions (dyspnea, angioedema, rash, pruritus) Pediatric use information is approved for Cubist Pharmaceuticals LLC's DIFICID ® (fidaxomicin) tablets.
However, due to Cubist Pharmaceuticals LLC's marketing exclusivity rights, this drug product is not labeled with that information.
Warnings & Cautions for Fidaxomicin
Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash, pruritus, and angioedema of
the mouth, throat, and face have been reported with fidaxomicin tablets. If a severe hypersensitivity reaction occurs, fidaxomicin tablets should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions to fidaxomicin tablets also reported a history of allergy to other macrolides.
Physicians prescribing fidaxomicin tablets to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.
Not for Use in Infections Other than C. difficile -Associated Diarrhea Fidaxomicin
tablets are not expected to be effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin. Fidaxomicin tablets have not been studied for the treatment of infections other than CDAD. Fidaxomicin tablets should only be used for the treatment of CDAD.
Development of Drug-Resistant Bacteria Prescribing fidaxomicin tablets in the absence of proven
or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Drug Interactions with Fidaxomicin
Cyclosporine Cyclosporine is an inhibitor of multiple transporters, including P-gp.
When cyclosporine was co-administered with fidaxomicin tablets, 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 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.
Pregnancy Safety for Fidaxomicin
Pregnancy Risk Summary The limited available data on use of fidaxomicin tablets 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 fidaxomicin tablets recommended dose. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.
All pregnancies have a 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 2 to 4% and 15 to 20%, respectively. Data Animal Data In pregnant rats, fidaxomicin was administered intravenously at doses of 4, 8, and 15 mg/kg/day from gestation day 6 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 fidaxomicin tablets recommended dose.
In pregnant rabbits, fidaxomicin was administered intravenously at doses of 2, 4, and 7.5 mg/kg/day from gestation day 6 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 fidaxomicin tablets recommended dose.
Pediatric Use of Fidaxomicin
Pediatric Use The safety and effectiveness of fidaxomicin tablets have not been established in pediatric patients younger than 6 months of age. Pediatric use information is approved for Cubist Pharmaceuticals LLC's DIFICID ® (fidaxomicin) tablets. However, due to Cubist Pharmaceuticals LLC's marketing exclusivity rights, this drug product is not labeled with that information.
Contraindications for Fidaxomicin
Fidaxomicin tablets are contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in fidaxomicin tablets. Fidaxomicin tablets are contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in fidaxomicin tablets.
Overdosage Information for Fidaxomicin
No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9,600 mg/day (over 100 times the human dose, scaled by weight) for 3 months.
Clinical Studies of Fidaxomicin
Clinical Studies of Fidaxomicin Tablets in Adult Patients with
CDAD In two randomized, double-blinded trials, a non-inferiority design was utilized to demonstrate the efficacy of fidaxomicin tablets (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 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 ≥15,000/mm 3 ). 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 6, indicate that fidaxomicin tablets 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 fidaxomicin tablets 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 fidaxomicin tablets patients.
Table 6: Clinical Response Rates at End-of-Treatment and Sustained Response at 25 days Post-Treatment in Adult Patients Clinical Response at End of Treatment Sustained Response at 25 days Post- Treatment Fidaxomicin % (N) Vancomycin % (N) Difference (95% CI)* Fidaxomicin % (N) Vancomycin % (N) Difference (95% CI)* Trial 1 88% (N=289) 86% (N=307) 2.6% (-2.9%, 8.0%) 70% (N=289) 57% (N=307) 12.7% (4.4%, 20.9%) Trial 2 88% (N=253) 87% (N=256) 1.0% (-4.8%, 6.8%) 72% (N=253) 57% (N=256) 14.6% (5.8%, 23.3%) * 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. 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, fidaxomicin tablets 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 Patients Trial 1 Initial C. difficile Group Fidaxomicin n/N (%) Vancomycin n/N (%) Difference (95% CI)* BI Isolates 44/76 (58%) 52/82 (63%) -5.5% (-20.3%, 9.5%) Non-BI Isolates 105/126 (83%) 87/131 (66%) 16.9% (6.3%, 27.0%) Trial 2 Initial C. difficile Group Fidaxomicin n/N (%) Vancomycin n/N (%) Difference (95% CI)* BI Isolates 42/65 (65%) 31/60 (52%) 12.9% (-4.2%, 29.2%) Non-BI Isolates 109/131 (83%) 77/121 (64%) 19.6% (8.7%, 30.0%) * 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.
Pediatric use information is approved for Cubist Pharmaceuticals LLC's DIFICID ® (fidaxomicin) tablets. However, due to Cubist Pharmaceuticals LLC's marketing exclusivity rights, this drug product is not labeled with that information.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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