Fidaxomicin
FDA Drug Information • Also known as: Dificid, Fidaxomicin
- Brand Names
- Dificid, Fidaxomicin
- Dosage Form
- POWDER
- Product Type
- BULK INGREDIENT
Description
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-[(1 R )-1-hydroxyethyl]-9,13,15-trimethyl-, (3 E ,5 E ,8 S ,9 E ,11 S ,12 R ,13 E ,15 E ,18 S )-. The structural formula of fidaxomicin is shown in Figure 1. Figure 1: Structural Formula of Fidaxomicin DIFICID tablets are film-coated and contain 200 mg of fidaxomicin per tablet and the following inactive ingredients: butylated hydroxytoluene, hydroxypropyl cellulose, lecithin (soy), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, sodium starch glycolate, talc, and titanium dioxide. DIFICID for oral suspension is supplied as granules in bottles containing 5.45 g of fidaxomicin (40 mg of fidaxomicin per mL after reconstitution) and the following inactive ingredients: citric acid, microcrystalline cellulose, mixed berry flavor, sodium benzoate, sodium citrate, sodium starch glycolate, sucralose, and xanthan gum. Chemical Structure
What Is Fidaxomicin Used For?
1 INDICATIONS AND USAGE DIFICID is a macrolide antibacterial indicated in adult and pediatric patients 6 months of age and older for the treatment of C. difficile -associated diarrhea. ( 1.1 ) 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 C. difficile . ( 1.2 ) 1.1 Clostridioides difficile -Associated Diarrhea DIFICID ® is indicated in adult and pediatric patients aged 6 months and older for the treatment of C. difficile -associated diarrhea (CDAD). 1.2 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 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.
Dosage and Administration
2 DOSAGE AND ADMINISTRATION DIFICID is administered orally with or without food. ( 2.1 ) Adults One 200 mg tablet orally twice daily for 10 days. ( 2.2 ) Pediatrics (6 Months to Less than 18 Years of Age) Tablets Pediatric patients weighing at least 12.5 kg and able to swallow tablets: One 200 mg tablet orally twice daily for 10 days. ( 2.3 ) Oral Suspension Pediatric patients weighing at least 4 kg: Weight-based dosing of the oral suspension twice daily for 10 days using an oral dosing syringe, as specified in Table 1 in the full prescribing information. ( 2.3 ) For instructions on preparation and administration of DIFICID oral suspension, see full prescribing information. ( 2.4 ) 2.1 Important Administration Instructions DIFICID is available for oral administration as 200 mg tablets and as granules for oral suspension (40 mg/mL (200 mg/5 mL) when reconstituted). DIFICID is administered orally with or without food. 2.2 Adult Patients The recommended dosage for adults is one 200 mg DIFICID tablet orally twice daily for 10 days. 2.3 Pediatric Patients (6 Months to Less than 18 Years of Age) Tablets The recommended dosage for pediatric patients weighing at least 12.5 kg and able to swallow tablets is one 200 mg DIFICID tablet administered orally twice daily for 10 days. If unable to swallow tablets, pediatric patients may be dosed with DIFICID oral suspension as recommended in Table 1 below. Oral Suspension The recommended dosage for pediatric patients based on weight are shown in Table 1. Administer DIFICID oral suspension orally twice daily for 10 days using an oral dosing syringe [see Dosage and Administration (2.4) ] . Table 1: Recommended Dosage of DIFICID Oral Suspension in Pediatric Patients, Based on Weight Body Weight Dose Administered Twice Daily Volume of 40 mg/mL Suspension to be Administered Orally Twice Daily 4 kg to less than 7 kg 80 mg 2 mL 7 kg to less than 9 kg 120 mg 3 mL 9 kg to less than 12.5 kg 160 mg 4 mL 12.5 kg and above 200 mg 5 mL 2.4 Preparation and Administration of DIFICID Oral Suspension Preparation Shake the glass bottle to ensure the granules move around freely and no caking has occurred. Measure 130 mL of purified water, add to the glass bottle, and cap tightly. Hold bottle in a horizontal position and shake bottle vigorously in that position for at least 2 minutes. Verify that a homogeneous suspension is obtained. If not, repeat the shaking step. Once a homogeneous suspension is visually confirmed, shake an additional 30 seconds. Let bottle stand for 1 minute. Verify that the suspension is still homogeneous. If not, repeat steps 3 through 6. Once reconstituted, DIFICID oral suspension is white to yellowish white in color. Write discard date (current date plus 12 days) on the bottle [see How Supplied/Storage and Handling (16.1 , 16.2) ] . Storage of Reconstituted Oral Suspension Store the reconstituted oral suspension in a refrigerator [between 36°F-46°F (2°C-8°C)] for up to 12 days. Discard after 12 days....
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The most common adverse reactions in adults (incidence ≥2%) are nausea, vomiting, abdominal pain, gastrointestinal hemorrhage, anemia, and neutropenia. ( 6 ) The most common adverse reactions in pediatric patients (incidence ≥5%) treated with DIFICID are pyrexia, abdominal pain, vomiting, diarrhea, constipation, increased aminotransferases, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Adults The safety of DIFICID 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 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 DIFICID and vancomycin patients in Phase 3 trials. The most common selected adverse reactions occurring in ≥2% of adult patients treated with DIFICID are listed in Table 2. Table 2: Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID-Treated Adult Patients in Controlled Trials System Organ Class DIFICID (N=564) Vancomycin (N=583) Adverse Reaction 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 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 Pediatrics The safety of DIFICID in pediatric patients 6 months to less than 18 years of age was evaluated in a Phase 2 single-arm trial in 38 patients and a Phase 3 randomized, active-controlled trial in 98 patients treated with DIFICID and 44 patients treated with vancomycin [see Clinical Studies (14.2) ] . In both studies, patients received DIFICID orally twice daily for 10 days. Patients <2 years of age, or weighing <12.5 kg, or unable to swallow tablets received weight-based doses of DIFICID oral suspension. Patients weighing at least 12.5 kg and able to swallow tablets received the 200 mg DIFICID tablet. The age range in the Phase 2 trial was 11 months to 17 years and in the Phase 3 trial was 1 month to 17 years (one patient was less than 6 months of age). One death occurred in the Phase 2 single-arm trial. In the Phase 3 trial, there were 3 deaths in DIFICID-treated patients and no deaths in vancomycin-treated patients during the study period (40 days). All deaths occurred in patients less than 2 years of age and appeared to be related to underlying comorbidities [see Clinical Studies (14.2) ]. Treatment discontinuation due to adverse reactions occurred in 7.9% (3/38) of patients in the Phase 2 trial, and in 1% (1/98) and 2.3% (1/44) of DIFICID- and vancomycin-treated patients, respectively, in the Phase 3 trial. The most common selected adverse reactions occurring in ≥5% of pediatric patients treated with DIFICID in the Phase 3 trial are listed in Table 3. Table 3:...
Drug Interactions
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 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.
Contraindications
4 CONTRAINDICATIONS DIFICID is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in DIFICID [see Warnings and Precautions (5.1) ] . DIFICID is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in DIFICID. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary The limited available data on use of DIFICID 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 DIFICID recommended dose [see Data ]. 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 DIFICID 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 DIFICID recommended dose.
Overdosage
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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tablets DIFICID tablets are white to off-white film-coated, oblong tablets containing 200 mg of fidaxomicin per tablet; 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). Granules for Oral Suspension DIFICID granules for oral suspension are white to yellowish white. DIFICID granules for oral suspension (NDC 52015-700-22) is supplied as 150 mL amber glass bottles of 9.53 g of granules that contain 5.45 g of fidaxomicin. Each glass bottle has a child-resistant cap and is sealed in a laminated aluminum foil pouch. After reconstitution, the total oral suspension volume is 136 mL. Discard unused suspension after 12 days. The concentration of fidaxomicin is 40 mg/mL (200 mg per 5 mL) in the reconstituted oral suspension. 16.2 Storage Tablets Store DIFICID tablets at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F). See USP controlled room temperature. Store in the original bottle. Granules for oral suspension Store DIFICID granules for oral suspension at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F). Store in the original package. Do not open pouch until time of use. Once reconstituted, store DIFICID oral suspension refrigerated at 2°C-8°C (36°F-46°F) for up to 12 days. Store capped in the original bottle.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.