Fidaxomicin

Class: Other Macrolides
VA Class: AM200
Chemical Name: (3E,5E,8S,9E,11S,12R,13E,15E,18S) - 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 - [(1R) - 1 - hydroxyethyl] - 9,13,15 - trimethyl - oxacyclooctadeca - 3,5,9,13,15 - pentaen - 2 - one
Molecular Formula: C52H74Cl2O18
CAS Number: 873857-62-6
Brands: Dificid

Introduction

Antibacterial; macrocycle antibiotic6 11 12 classified as a macrolide.1 26

Uses for Fidaxomicin

Clostridium difficile-associated Diarrhea

Treatment of Clostridium difficile-associated diarrhea (CDAD) in adults ≥18 years of age.1

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Designated an orphan drug by FDA for treatment of C. difficile infection (CDI) in pediatric patients.4

Fidaxomicin Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.1

Dosage

Adults

Clostridium difficile-associated Diarrhea
Oral

200 mg twice daily for 10 days.1

Special Populations

Renal Impairment

Dosage adjustment not recommended.1 (See Renal Impairment under Cautions.)

Hepatic Impairment

Manufacturer makes no specific dosage recommendations; pharmacokinetics not expected to be affected.1 (See Hepatic Impairment under Cautions.)

Geriatric Patients

Dosage adjustment not recommended.1 (See Geriatric Use under Cautions.)

Cautions for Fidaxomicin

Contraindications

  • Hypersensitivity to fidaxomicin.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Acute hypersensitivity reactions (e.g., dyspnea, rash, pruritus, angioedema of mouth, throat, face) reported.1 History of allergy to other macrolides reported in some of these patients.1

Consider possibility of hypersensitivity reactions if fidaxomicin prescribed for patient with known macrolide allergy.1

If severe hypersensitivity reaction occurs, discontinue fidaxomicin and administer appropriate therapy.1

Systemic Infections

Only minimal systemic absorption occurs following oral administration;1 20 not effective for treatment of systemic infections.1

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of fidaxomicin and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by C. difficile.1

Prescribing fidaxomicin in the absence of a proven or strongly suspected CDI is unlikely to provide benefit to the patient and increases risk of development of drug-resistant bacteria.1

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether distributed into milk;1 use with caution in nursing women.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1 Designated an orphan drug by FDA for treatment of CDI in pediatric patients.4

Geriatric Use

No overall differences in efficacy or safety observed in geriatric adults ≥65 years of age compared with younger adults.1

Plasma concentrations of fidaxomicin and its main metabolite (OP-1118) are higher in patients ≥65 years of age than in younger adults, but remain in the ng/mL range.1 Not considered clinically important; dosage adjustment not recommended.1

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics not formally studied, but elimination not expected to be substantially affected since fidaxomicin and its main metabolite (OP-1118) do not appear to undergo substantial hepatic metabolism.1

Renal Impairment

In clinical trials in patients with mild, moderate, or severe renal impairment (based on Clcr) receiving fidaxomicin (200 mg orally twice daily for 10 days), plasma concentrations of fidaxomicin and its main metabolite (OP-1118) did not vary by severity of renal impairment.1 Dosage adjustment not recommended.1

Common Adverse Effects

Nausea, vomiting, abdominal pain, GI hemorrhage, anemia, neutropenia.1

Interactions for Fidaxomicin

Metabolism of fidaxomicin and formation of its main metabolite (OP-1118) not dependent on CYP isoenzymes.1

Fidaxomicin and OP-1118 are substrates of P-glycoprotein (P-gp) transport system.1

Drugs Metabolized by Hepatic Microsomal Enzymes

No clinically important effect on pharmacokinetics of CYP3A4, CYP2C9, or CYP2C19 substrate.1 Manufacturer states dosage adjustments not needed if fidaxomicin used concomitantly with CYP isoenzyme substrates.1

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp inhibitors: Potential for substantial increase in plasma fidaxomicin and OP-1118 concentrations, but values still within the ng/mL range.1 Decrease in fidaxomicin and OP-1118 concentrations at the site of action (i.e., GI tract) is possible, but data from controlled clinical trials of fidaxomicin indicate that concomitant use of P-gp inhibitors had no attributable effect on safety or treatment outcome.1 Manufacturer states dosage adjustments not needed.1

P-gp substrates: Pharmacokinetics of P-gp substrate not substantially altered by fidaxomicin.1 Manufacturer states dosage adjustments not needed.1

Drugs that Increase Gastric pH

Interaction not formally studied; however, use of proton-pump inhibitors (PPIs) and histamine H2-receptor antagonists was common in 2 fidaxomicin phase 3 clinical trials; no observed differences in CDI recurrence rates among patients with or without exposure to PPIs and H2-receptor antagonists.9

Specific Drugs

Drug

Interaction

Comments

Cyclosporine

Substantially increased fidaxomicin and OP-1118 concentrations, but concentrations remain in the ng/mL range1

Dosage adjustment not needed1

Digoxin

No clinically important effect on digoxin pharmacokinetics1

Dosage adjustment not needed1

Metronidazole

Some in vitro evidence of synergistic antibacterial effects with fidaxomicin and OP-1118;26 27 no in vitro evidence of antagonism26 27

Midazolam

No clinically important effect on midazolam pharmacokinetics1

Dosage adjustment not needed1

Omeprazole

No clinically important effect on omeprazole pharmacokinetics1

Dosage adjustment not needed1

Rifamycins (rifampin, rifaximin)

In vitro evidence of synergistic antibacterial effects with fidaxomicin and OP-1118 against C. difficile;1 26 27 no in vitro evidence of antagonism26 27

Warfarin

No clinically important effect on warfarin pharmacokinetics1

Dosage adjustment not needed1

Fidaxomicin Pharmacokinetics

Absorption

Bioavailability

Only minimal systemic absorption occurs following oral administration.1 20

Following a single 200-mg oral dose in healthy adults, mean peak plasma concentrations of fidaxomicin and its main metabolite (OP-1118) average 5.2 and 12 ng/mL, respectively, and are attained within 1– 2 hours.1

Although plasma concentrations of fidaxomicin and OP-1118 at 1–5 hours after a dose are approximately 2–6 times higher in patients with CDI than in healthy adults, plasma concentrations remain in the ng/mL range.1 No evidence of accumulation of fidaxomicin in plasma after 10 days of treatment.1

Food

Administration with a high-fat meal in healthy adults decreased peak plasma concentrations of fidaxomicin and OP-1118 by approximately 22 and 33%, respectively, but did not affect AUC;1 not considered clinically important.1

Special Populations

Plasma concentrations of fidaxomicin and OP-1118 at 1–5 hours after a dose are approximately 2–4 times higher in geriatric patients ≥65 years of age than in adults <65 years of age;1 not considered clinically important.1

In controlled trials in patients receiving fidaxomicin (200 mg twice daily for 10 days), plasma concentrations of fidaxomicin and OP-1118 were not affected by severity of renal impairment in those with mild, moderate, or severe impairment (based on Clcr).1

Effect of hepatic impairment on pharmacokinetics of fidaxomicin not formally studied.1 Because significant hepatic metabolism does not appear to occur, concentrations of fidaxomicin and OP-1118 are not expected to be substantially affected by hepatic impairment.1

Distribution

Extent

Following oral administration, remains mainly confined to and acts locally in the GI tract.1

Elimination

Metabolism

Mainly transformed by hydrolysis at the isobutyryl ester to form OP-1118.1 Although OP-1118 also has antibacterial activity against C. difficile,1 5 13 27 it is less active than fidaxomicin.5 13 27

Metabolism of fidaxomicin and formation of OP-1118 not dependent on CYP isoenzymes.1

Elimination Route

Excreted principally in feces.1 In healthy adults, >92% of an oral dose is recovered in feces as fidaxomicin and OP-1118;1 <1% of dose recovered in urine as OP-1118.1

In some patients treated with fidaxomicin (200 mg orally twice daily for 10 days), fecal concentrations of fidaxomicin and OP-1118 obtained within 24 hours of the last dose ranged from 639–2710 and 213–1210 mcg/g, respectively.1

Half-life

Adults: Fidaxomicin elimination half-life is approximately 12 hours; OP-1118 elimination half-life is approximately 11 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Macrocycle antibiotic6 11 12 that has been classified as a macrolide.1 26 Other commercially available macrolides have 14- or 15-member lactone ring structures; fidaxomicin has an 18-member macrocyclic ester structure.6 11

  • Following oral administration, only minimal systemic absorption occurs;1 20 remains mainly confined to and acts locally in the GI tract.1

  • Has a narrow spectrum of antibacterial activity.6 11 13 15 22 23 24 25 Active against certain gram-positive bacteria;6 11 13 15 23 25 26 27 has limited or no activity against gram-negative bacteria and Candida albicans.6 11 13 15 23 25 26 27

  • Active in vitro and in vivo against Clostridium difficile, a spore-forming, gram-positive anaerobe.6 11 13 21 23 25 MIC90 of fidaxomicin for C. difficile generally ranges from 0.125–0.5 mcg/mL.6 11 21 23 24 Appears to have greater in vitro activity against C. difficile and may have a more minimal impact in vivo on normal intestinal flora than some other anti-infectives used for treatment of CDI.3 6 15

  • Both fidaxomicin and its main metabolite (OP-1118) are bactericidal against C. difficile in vitro,1 6 13 and exert a postantibiotic effect against the organism.5 6 Although exact mechanism of action not fully determined, the drug acts as an RNA polymerase inhibitor1 6 27 and appears to inhibit RNA synthesis in susceptible bacteria by binding to DNA-RNA polymerase complex prior to formation of open DNA-RNA polymerase complex needed for initiation of transcription.6 27 This is distinct from mechanism of action of other commercially available macrolides, which interfere with translation in susceptible bacteria by acting at the ribosomal level of protein synthesis.27

  • In vitro studies indicate a low frequency of spontaneous resistance to fidaxomicin in C. difficile.1 6 Fidaxomicin-resistant strains of C. difficile have been generated in vitro1 6 and reduced susceptibility has been reported rarely in clinical specimens.1 21 A single mutation (Val-1143-Gly) in the β subunit of RNA polymerase was identified in C. difficile obtained from a patient who had recurrence of CDAD after fidaxomicin treatment.1 Cross-resistance with other anti-infectives not reported to date.1 6 11

Advice to Patients

  • Advise patients that antibacterials (including fidaxomicin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 Importance of advising patients that fidaxomicin is used only to treat CDAD and should not be used to treat any other infection.1

  • Importance of completing full course of therapy, even if feeling better after a few days.1

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with fidaxomicin or other antibacterials in the future.1

  • Advise patients that fidaxomicin may be taken with or without food.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Fidaxomicin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg

Dificid

Optimer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Optimer Pharmaceuticals, Inc. Dificid (fidaxomicin) tablets prescribing information. San Diego, CA; 2013 Mar.

2. Louie TJ, Miller MA, Me KM et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011; 364:422-30. [PubMed 21288078]

3. DuPont HL. The search for effective treatment of Clostridium difficile infection. N Engl J Med. 2011; 364:473-5. [PubMed 21288079]

4. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website. Accessed 2011 Dec 19.

5. Babakhani F, Gomez A, Robert N et al. Postantibiotic effect of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile. Antimicrob Agents Chemother. 2011; 55:4427-9. [PubMed 21709084]

6. Venugopal AA, Johnson S. Fidaxomicin: A Novel Macrocyclic Antibiotic Approved for Treatment of Clostridium difficile Infection. Clin Infect Dis. 2011; :.

7. O’Donoghue C, Kyne L. Update on Clostridium difficile infection. Curr Opin Gastroenterol. 2011; 27:38-47. [PubMed 21099432]

8. Linsky A, Gupta K, Hermos JA. Fidaxomicin for Clostridium difficile. N Engl J Med. 2011; 364:1875.

9. Louie TJ, Gorbach S, Sears P. Fidaxomicin for Clostridium difficile infection. N Engl J Med. 2011; 364:1875-6.

10. Gerding DN, Johnson S. Management of Clostridium difficile infection: thinking inside and outside the box. Clin Infect Dis. 2010; 51:1306-13. [PubMed 20979491]

11. Hardesty JS, Juang P. Fidaxomicin: a macrocyclic antibiotic for the treatment of Clostridium difficile infection. Pharmacotherapy. 2011; 31:877-86. [PubMed 21923589]

12. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 201699Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

13. Babakhani F, Gomez A, Robert N et al. Killing kinetics of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile. J Med Microbiol.. 2011; 60:1213–7.

14. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31:431-55. [PubMed 20307191]

15. Pannerden CMF, Verbon A, Kuipers EJ. Recurrent Clostridium difficile. Drugs. 2011; 71:853-68. [PubMed 21568363]

16. Bauer MP, Kuijper EJ, van Dissel JT et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI). Clin Microbiol Infect. 2009; 15:1067-79. [PubMed 19929973]

17. Jaber MR, Olafsson S, Fung WL et al. Clinical review of the management of fulminant Clostridium difficile infection. Am J Gastroenterol. 2008; 103:3195-203; quiz 3204. [PubMed 18853982]

18. Linsky A, Gupta K, Lawler EV et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010; 170:772-8. [PubMed 20458084]

19. Drekonja DM, Butler M, Macdonald R et al. Comparative Effectiveness of Clostridium difficile Treatments: A Systematic Review. Ann Intern Med. 2011; 155:839-47. [PubMed 22184691]

20. Shue YK, Sears PS, Shangle S et al. Safety, tolerance, and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses. Antimicrob Agents Chemother. 2008; 52:1391-5. [PubMed 18268081]

21. Goldstein EJ, Citron DM, Sears P et al. Comparative susceptibilities to fidaxomicin (OPT-80) of isolates collected at baseline, recurrence, and failure from patients in two phase III trials of fidaxomicin against Clostridium difficile infection. Antimicrob Agents Chemother. 2011; 55:5194-9. [PubMed 21844318]

22. Biedenbach DJ, Ross JE, Putnam SD et al. In vitro activity of fidaxomicin (OPT-80) tested against contemporary clinical isolates of Staphylococcus spp. and Enterococcus spp. Antimicrob Agents Chemother. 2010; 54:2273-5. [PubMed 20308391]

23. Credito KL, Appelbaum PC. Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species. Antimicrob Agents Chemother. 2004; 48:4430-4. [PubMed 15504874]

24. Karlowsky JA, Laing NM, Zhanel GG. In vitro activity of OPT-80 tested against clinical isolates of toxin-producing Clostridium difficile. Antimicrob Agents Chemother. 2008; 52:4163-5. [PubMed 18725442]

25. Ackermann G, Löffler B, Adler D et al. In vitro activity of OPT-80 against Clostridium difficile. Antimicrob Agents Chemother. 2004; 48:2280-2. [PubMed 15155234]

26. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 201699Orig1s000: Summary Review. From FDA website.

27. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 201699Orig1s000: Microbiology review(s). From FDA website.

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