Fidaxomicin

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# Overview
Fidaxomicin is a Macrolide that is FDA approved for the treatment of Clostridium difficile-Associated Diarrhea.   Common adverse reactions include Abdominal pain, nausea, vomiting, anemia, neutropenia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Clostridium difficile-Associated Diarrhea
- Dose is one 200 mg fidaxomicin tablet orally twice daily for 10 days with or without food.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fidaxomicin in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Fidaxomicin in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Fidaxomicin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fidaxomicin in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Fidaxomicin in pediatric patients.

# Contraindications
- Hypersensitivity to fidaxomicin.

# Warnings

### Not for Systemic Infections
- Since there is minimal systemic absorption of fidaxomicin, fidaxomicin 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, fidaxomicin 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 fidaxomicin to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.

### Development of Drug-Resistant Bacteria
- Prescribing fidaxomicin 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.

# Adverse Reactions

## Clinical Trials Experience
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 fidaxomicin 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 fidaxomicin (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 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

## Postmarketing 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
- Pruritus

# 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.

### Cyclosporine
- Cyclosporine is an inhibitor of multiple transporters, including P-gp.
- When cyclosporine was co-administered with fidaxomicin, 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fidaxomicin in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Fidaxomicin during labor and delivery.

### 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 fidaxomicin is administered to a nursing woman.

### Pediatric Use
- The safety and effectiveness of fidaxomicin in patients <18 years of age have not been established.

### Geriatic Use
- Of the total number of patients in controlled trials of fidaxomicin, 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.

### Gender
There is no FDA guidance on the use of Fidaxomicin with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Fidaxomicin with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Fidaxomicin in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Fidaxomicin in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fidaxomicin in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Fidaxomicin in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Fidaxomicin Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Fidaxomicin and IV administrations.

# 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.

# Pharmacology

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

## Structure
Fidaxomicin (fidaxomicin) is a macrolide antibacterial drug for oral administration. Its CAS chemical name is Oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-oxy]methyl]-12-oxy]-11-ethyl-8-hydroxy-18--9,13,15-trimethyl-, (3E,5E,8S,9E,11S,12R,13E,15E,18S)-. The structural formula of fidaxomicin is shown in Figure 1.

## 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.

## 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.

### 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 fidaxomicin 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 fidaxomicin 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, fidaxomicin 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 fidaxomicin 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 g/g and 213-1210 g/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.

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

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, and 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 Studies
In two randomized, double-blinded trials, a non-inferiority design was utilized to demonstrate the efficacy of fidaxomicin (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 fidaxomicin 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 fidaxomicin 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 patients.
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 did not demonstrate superiority in sustained clinical response when compared with vancomycin (Table 6).

# How Supplied
- Fidaxomicin 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.
- Fidaxomicin tablets are supplied as bottles of 20 tablets (NDC 52015-080-01).

## Storage
- Storage: 20 -25C (68 -77F); excursions permitted to 15 - 30C (59 - 86F).
- See USP controlled room temperature.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

### Administration with Food
- Patients should be informed that fidaxomicin tablets may be taken with or without food.

### Antibacterial Resistance
- Patients should be counseled that antibacterial drugs, including fidaxomicin, should only be used to treat bacterial infections. They do not treat viral infections. Patients should be counseled that fidaxomicin only treats Clostridium difficile-associated diarrhea and should not be used to treat any other infection.
- When fidaxomicin 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 fidaxomicin or other antibacterial drugs in the future.

# Precautions with Alcohol
Alcohol-Fidaxomicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Dificid

# Look-Alike Drug Names
There is limited information regarding Fidaxomicin Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price