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Drug Forcast

Firvanq: The First Oral Solution For the Treatment of C. Difficile

Lillian Smith PharmD, MBA, CPh
LaToya Cuyler PharmD candidate
Aquaiel Troupe PharmD candidate

BACKGROUND

Clostridioides difficile infections have become an increasing burden on the health care system since the early 2000s.1Clostridioides difficile (formerly known as clostridium difficile) is a gram-positive bacterial infection transmitted through the fecal oral route, commonly presenting as diarrhea and pseudomembranous colitis.1 It was reclassified to the Clostridioides genus because of a gene-sequence analysis that found it to be phylogenetically distant, strictly speaking, from other members of Clostridium.2 Risk factors for infection include patients who are immunocompromised, elderly, have a history of C. difficile, and use proton pump inhibitors, as well as health care exposure. Studies have suggested that there are nearly a half-million C. difficile cases annually, thousands of deaths, and $4.8 billion in related costs in the United States.3 Use of antibiotics and exposure to the spore-forming organism are the strongest risk factors for development of C. difficile, which is typically diagnosed by a stool sample positive for C. difficile toxins. The use of antibiotics allows for an overgrowth of C. difficile bacteria by releasing toxins that cause the colitis seen in C. difficile infection.4 Transmission can be prevented by using contact precautions, assigning admitted patients to private rooms, and ensuring that health care personnel and visitors wash their hands with soap and water to remove spores. 

By way of the Hatch-Waxman Amendments of 1984, the 505(b)(2) pathway was created to avoid duplication of studies previously conducted on an approved drug product.7 Recently, CutisPharma received Food and Drug Administration (FDA) approval to release vancomycin hydrochloride (Firvanq), the only oral solution for the treatment of C. difficile. To expedite the approval of Firvanq, the safety and effectiveness clinical trials data for vancomycin capsules (Vancocin, ANI Pharmaceuticals) were used under the 505(b)(2) pathway to support its new drug application. Since oral vancomycin was previously available only as capsules and a compounded formulation, this article is intended to evaluate Firvanq and compare other agents currently available to treat C. difficile, more specifically fidaxomicin, metronidazole, and the capsule formulation of vancomycin. 

CLINICAL GUIDELINES

In February 2018, the Infectious Diseases Society of America (ISDA) and the Society for Healthcare Epidemiology of America (SHEA) updated the long-standing first-line treatment recommendations for C. difficile, which are outlined in Table 1. The most significant change noted in this update acknowledges that after 30 years of use, metronidazole is no longer among the recommended first-line treatments for an initial episode of C. difficile infection in adults. Instead, it is now listed as an alternative treatment option if vancomycin and fidaxomicin are unavailable. Additional parameters must also be considered based on the frequency of C. difficile occurrences. First recurrence of C. difficile infection is defined as a second episode occurring within eight weeks of a positive result during the initial episode.6 Subsequent recurrence is defined as a C. difficile infection occurring within eight weeks of a positive result from first or later recurrence. 

Table 1 C. Difficile Treatment Recommendations1
Initial episode, nonsevere Vancomycin HCl 125 mg QID for 10 days
-or-
Fidaxomicin 200 mg BID for 10 days

Alternative if vancomycin HCl or fidaxomicin unavailable: metronidazole 500 mg PO TID for 10 days
Metronidazole 7.5 mg/kg/dose (max 500 mg) PO TID or QID for 10 days
-or-
Vancomycin HCl 10 mg/kg/dose (max 125 mg) PO QID for 10 days
Initial episode, severe Vancomycin HCl 125 mg PO QID for 10 days
-or-
Fidaxomicin 200 mg BID for 10 days
Vancomycin HCl 10 mg/kg/dose (max 500 mg) QID PO or by rectum for 10 days, with or without metronidazole 10 mg/kg/dose (max 500 mg) TID IV for 10 days
Initial episode, fulminant Vancomycin HCl 500 mg QID PO or NG for 10 days. If ileus present, consider adding rectal vancomycin and IV metronidazole 500 mg Q8h Vancomycin HCl 10 mg/kg/dose (max 500 mg) QID PO or by rectum for 10 days, with or without metronidazole 10 mg/kg/dose (max 500 mg) TID IV for 10 days
First
recurrence
Vancomycin HCl 125 mg QID for 10 days (if metronidazole was used for initial episode)
-or-
Vancomycin HCl 125 mg QID for 10–14 days, BID for a week, once daily for a week, and then every 2 or 3 days for 2–8 weeks (if vancomycin standard regimen was used for initial episode)
-or-
Fidaxomicin 200 mg BID for 10 days (if vancomycin was used for initial episode)
Metronidazole 7.5 mg/kg/dose (max 500 mg) TID or QID PO for 10 days
-or-
Vancomycin HCl 10 mg/kg/dose (max 125 mg) QID PO for 10 days
Second or
subsequent recurrence
Vancomycin HCl 125 mg QID for 10–14 days, BID for a week, once daily for a week, and then every 2 or 3 days for 2–8 weeks
-or-
Vancomycin HCl 125 mg QID for 10 days, followed by rifaximin 400 mg TID for 20 days
-or-
Fidaxomicin 200 mg BID for 10 days
-or-
Fecal microbiota transplantation
Vancomycin HCl 10 mg/kg/dose (max 125 mg) QID for 10–14 days, BID for a week, once daily for a week, and then every 2 or 3 days for 2–8 weeks
-or-
Vancomycin HCl 10 mg/kg/dose (max 500 mg) QID for 10 days followed by rifaximin (max 400 mg TID) for 20 days.
(Note: rifaximin has no pediatric dosing and is not approved for children under 12)
-or-
Fecal microbiota transplantation
BID = twice daily; IV = intravenous; NG = nasogastric tube; PO = by mouth; QID = four times daily; Q8h = every eight hours; TID = three times daily

The current first-line recommended treatment for an initial episode of nonsevere or severe C. difficile infection is oral vancomycin or fidaxomicin (Table 1).1 Therefore, vancomycin HCl, fidaxomicin, and metronidazole continue to be the leading agents for the treatment of C. difficile.

ISDA/SHEA guidelines also recommend that treatment determination for C. difficile infection should be based on the severity of the infection as outlined in Table 2. Initial nonsevere (mild-to-moderate) C. difficile infection is defined as a white blood cell (WBC) count less than 15,000 cells/mm3 and serum creatinine less than 1.5 times baseline.5 Initial severe C. difficile infection is defined as a WBC count of at least 15,000 cells/mm3 or serum creatinine of at least 1.5 times baseline.5 Fulminant (severe complicated) C. difficile infection is defined as a WBC count of at least 15,000 cells/mm3 or serum creatinine of at least 1.5 times baseline accompanied by hypotension, shock, ileus, or megacolon.5 

Table 2 Abbreviated C. Difficile Severity and Treatment Table
Severity of Infection Infection 2nd Infection
(1st Recurrence)
3rd Infection
(2nd Recurrence)
Mild-to-moderate disease: WBC count < 15,000 cells/mm3 and serum creatinine < 1.5 times baseline Vancomycin HCl 125 mg QID for 10 days Vancomycin HCl 125 mg QID for 10 days Vancomycin taper therapy: Vancomycin HCl 125 mg QID for 10–14 days, BID for a week, once daily for a week, and then every 2 or 3 days for 2–8 weeks
Severe disease: WBC count ≥ 15,000 cells/mm3 or serum creatinine ≥ 1.5 times baseline Vancomycin HCl 125 mg QID for 10 days Vancomycin HCl 125 mg QID for 10 days Fidaxomicin 200 mg BID for 10 days (if vancomycin was used for initial episode)
-or-
Fecal microbiota transplantation
Severe, complicated disease: hypotension, shock, ileus, or megacolon Vancomycin HCl 500 mg QID PO or NG for 10 days. If ileus present, consider adding rectal vancomycin and IV metronidazole 500 mg Q8h Vancomycin HCl 500 mg QID PO or NG for 10 days. If ileus present, consider adding rectal vancomycin and IV metronidazole 500 mg Q8h Vancomycin HCl 125 mg QID for 10 days, followed by rifaximin 400 mg TID for 20 days
-or-
Fidaxomicin 200 mg BID for 10 days (if vancomycin was used for initial episode)
-or-
Fecal microbiota transplantation
BID = twice daily; IV = intravenous; NG = nasogastric tube; PO = by mouth; QID = four times daily; Q8h = every eight hours; TID = three times daily; WBC = white blood count

INDICATION AND USAGE8,9 

Vancomycin HCl (oral solution) has been approved by the FDA to treat C. difficile–associated diarrhea and enterocolitis caused by various bacteria (Staphylococcus aureus, methicillin-resistant strains). This indication is the same as that for the capsules.

MECHANISM OF ACTION8,9

Similar to its capsule counterpart, the primary mechanism of action of vancomycin HCl (oral solution) is inhibition of the biosynthesis of the cell wall. Vancomycin HCl also alters the permeability of the cell membrane.

PHARMACOKINETICS8,9

The bioavailability of vancomycin HCl is poor for all available oral formulations. Daily administration of vancomycin HCl oral formulations produces little to no measurable plasma concentrations. However, elevated fecal concentrations of the drug have been detected. Although vancomycin HCl has poor bioavailability, patients with renal impairment risk the increase of drug accumulation after multiple doses for all formulations. Therefore, no significant differences can be noted.

SAFETY CONSIDERATIONS

Adverse Effects8,9 

Clinical trials for both vancomycin formulations indicated that the most common adverse events were nausea (17%), abdominal pain (15%), and hypokalemia (13%). General warnings and precautions for vancomycin HCl include renal impairment, ototoxicity, increased risk of superinfection, development of drug-resistant bacteria, hemorrhagic occlusive retinal vasculitis, and potential systemic absorption in the presence of renal impairment/colitis. Additional labeling notes that in the event a patient has a hypersensitivity reaction to vancomycin (solution or capsules), further use is contraindicated.

Drug Interactions8,9

Drug interactions have not been studied in relationship to the oral formulations of vancomycin. 

Use in Special Populations

As stated previously, the clinical trials data on the safety and effectiveness of vancomycin capsules (Vancocin) were used under the 505(b)(2) pathway to support the new drug application approval of the oral solution (Firvanq). The following section outlines the data for both the capsule and solution formulations.

Pregnancy8,9

No data are available for oral vancomycin use in pregnancy. However, human studies have been conducted on pregnant women by administering intravenous (IV) vancomycin. The results of the controlled clinical study concluded that there was no abnormal sensorineural hearing loss.10 Animal studies have also demonstrated no evidence of fetal defects when the mother was given IV vancomycin HCl.

Lactation8,9

There are no adequate data to assess vancomycin concentrations in breast milk for either the capsule or solution formulations. However, systemic absorption of oral vancomycin is minimal due to its low bioavailability.

Pediatric Use8,9

Both vancomycin formulations are approved by the FDA for use in patients younger than 18 years of age.

Geriatric Use8,9

Clinical trials found that use of oral vancomycin (capsules or solution) for the treatment of C. difficile–associated diarrhea increases the risk of nephrotoxicity in patients older than 65 years of age. Nephrotoxicity can occur during or after treatment. It is recommended that renal function be monitored throughout the duration of therapy, as well as following the completion of treatment.

DOSAGE AND ADMINISTRATION8,9

Vancomycin oral solution is available as a 25-mg/mL kit and 50-mg/mL kit, which are reconstituted with sterile water and then diluted with Ora-Sweet and distilled water to improve taste. Vancomycin capsules are available as 125-mg and 250-mg capsules. The recommended dosage regimen for both formulations is 125 mg orally four times daily for 10 days. The pediatric dosage regimen is 40 mg/kg in three or four divided doses for seven to 10 days. 

CLINICAL STUDIES 

Phase 3 Trials8,9

The efficacy of oral vancomycin was demonstrated in two phase 3 trials among patients 18 years of age and older with active C. difficile–associated diarrhea who had received less than 48 hours of treatment with oral vancomycin or metronidazole in the five days prior to enrollment. Patients received vancomycin 125 mg orally four times a day for 10 days. The full analysis set was used to assess efficacy among randomized patients who previously received at least one dose of vancomycin HCl. 

The requirement for clinical success included the absence of diarrhea and abdominal pain after completion of therapy on day 10. The clinical success rate was 81.3% (n = 134) and 80.8% (n = 125) in clinical trials 1 and 2, respectively. Symptoms of diarrhea resolved within an average time of five days and four days in trials 1 and 2, respectively. Patients older than 65 years of age with symptoms of diarrhea experienced recovery in six days and four days in trials 1 and 2, respectively. The recurrence of C. difficile was 23% (trial 1) and 18% (trial 2).

Fidaxomicin Versus Vancomycin10,17 

In a prospective, multicenter, double-blind, randomized, parallel-group trial, Louie et al. compared the efficacy and safety of fidaxomicin with vancomycin for the treatment of C. difficile. Patients were randomized to receive either fidaxomicin 200 mg twice daily (n = 287) or vancomycin 125 mg four times daily (n = 309) for 10 days. The study included patients 16 years of age and older diagnosed with C. difficile. Patients were eligible for enrollment if they received four doses of metronidazole or vancomycin. Patients were excluded if other antibiotics were in use. 

The study defined clinical cure as the absence of three or more unformed stools for two days. Treatment with fidaxomicin 200 mg twice daily was noninferior (88.2%) to treatment with vancomycin 125 mg four times daily (85.8%) using the intent-to-treat analysis. Per-protocol analysis found that fidaxomicin treatment was noninferior (92.1%) compared to vancomycin treatment (89.8%). However, recurrence rates were significantly lower for fidaxomicin than vancomycin in both the modified intent-to-treat analysis and per-protocol analysis (15.4% versus 25.3%). There was no significant difference in the adverse event profile between the two treatments.

Vancomycin Versus Metronidazole11

Zar et al. conducted a large, prospective, randomized, double-blind, placebo- controlled trial to compare vancomycin to metronidazole for the treatment of C. difficile stratified by disease severity. The study included patients (mean age, 57 years) who presented with C. difficile. Patients were stratified into severity groups using an assessment score created solely for the purpose of the study. A score greater than 2 was categorized as severe C. difficile. Initially, 172 patients were randomized into severity groups: mild disease (n = 90) and severe disease (n = 82). However, only 150 patients completed the trial due to withdrawals from the study. Of the 150 patients, 81 were stratified to the mild-disease group and 69 patients to the severe group. Within the mild-disease group, 41 patients received metronidazole 250-mg tablets four times daily and liquid placebo for 10 days; 40 received vancomycin HCl oral compounded suspension 125 mg four times daily and placebo tablets. In the severe-disease group, 38 received metronidazole 250-mg tablets four times daily and liquid placebo; 31 received vancomycin liquid 125 mg four times daily.

Clinical cure for mild disease with metronidazole and vancomycin was 90% and 98%, respectively. Clinical cure for severe disease with metronidazole and vancomycin was 76% and 97%, respectively. The overall cure rate was 84% for metronidazole and 97% for vancomycin. Recurrence of C. difficile in patients who were cured with either metronidazole or vancomycin was 14% and 7%, respectively. 

P&T COMMITTEE CONSIDERATIONS

According to IDSA guidelines, vancomycin HCl, fidaxomicin, and metronidazole are the treatment options for C. difficile. Recent updates to the guidelines recommend initial treatment with vancomycin or fidaxomicin due to the decreased risk of recurrence of C. difficile one month after the completion of therapy compared to metronidazole.1 The adverse events and pharmacokinetic profiles for vancomycin HCl and fidaxomicin are similar, including nausea and abdominal pain, with the exception of an increased risk of hypokalemia associated with all vancomycin HCl formulations. However, the side effect and pharmacokinetic profile for metronidazole is more extensive.
Metronidazole is absorbed systemically to the cerebrospinal fluid, breast milk, and saliva. It has adverse effects that include psychotic reactions with disulfiram use, encephalopathy, peripheral neuropathy, carcinogenic effect, convulsive seizures, metallic taste, and nausea. 

While there are no known drug interactions with the administration of vancomycin, metronidazole has significant drug interactions with warfarin, lithium, busulfan, and drugs that induce or inhibit cytochrome P450. Fidaxomicin has drug interactions with cyclosporine and is not FDA-approved for treatment in patients younger than 18 years of age. Table 3 provides a comparison of current treatment options to include differentiation of pharmacokinetic profiles, dosing, dosage forms, recommended use, safety considerations, and the advantages and disadvantages of each drug. 

Table 3 C. Difficile Treatment Comparison
Drug Vancomycin HCl8,9 Fidaxomicin12 Metronidazole13,14
Dosage form Oral solution Oral capsule Oral compounded suspension Oral tablet Oral tablet Intravenous solution
Strengths   • 125 mg
• 250 mg
25 mg/mL
(reconstituted with sterile water, then diluted [1:1] Ora-Sweet and distilled water)
200 mg tablet •250 mg •500 mg 500 mg/100 mL
Recommended dose for initial nonsevere episode in adults 125 mg orally QID for 10 days 200 mg orally BID for 10 days 500 mg orally TID for 10 days; alternative if vancomycin or fidaxomicin unavailable Not applicable
Pharmacokinetics • Minimal systemic absorption
• Elimination: feces
• Systemic absorption in cerebrospinal fluid, breast milk, and salvia
• Precaution in severe hepatic disease
• Elimination: renal, 60%–80%, fecal 6%–15%
Safety considerations (most common side effects) • Nausea (17%)
• Abdominal pain (15%)
• Hypokalemia (13%)
• Pregnancy Category B
• Nausea (11%)
• Abdominal pain (6%)
• DDI with cyclosporine
• Psychotic reaction with disulfiram use
• Encephalopathy
• Peripheral neuropathy
• Carcinogenic
• Convulsive seizures
• Nausea
• Metallic taste (tablet only)
• Interaction with warfarin, lithium, busulfan, drugs that induce or inhibit CYP450
• Pregnancy Category B
Advantages • Pre-measured powder and diluent
• Grape flavored
• No preparation required
• Generic available
Oral dosage form • Efficacy
• Decreased risk of reoccurrence one month post treatment
Inexpensive
Disadvantages No generics available Expensive • Bitter tasteM
• Prep and cleaning
• Time spent compounding
• Expensive
• Not used in patients < 18 years of age
Increased risk of reoccurrence one month post treatment
BID = twice daily; DDI = drug–drug interactions; QID = four times daily; TID = three times daily

Treating patients infected with C. difficile is expensive, and economic barriers remain an issue in the outpatient setting.16Table 4 provides a list of average wholesale prices for recommended therapies. Although metronidazole is the most reasonably priced option, it is not as efficacious as vancomycin and fidaxomicin. Fidaxomicin is administered twice daily, compared to four times daily with vancomycin HCl. Although fidaxomicin is given less frequently, no generic formulation is available, and consequently it is more expensive. The increased cost of therapy could result in cost-related nonadherence, with continued treatment in the outpatient setting resulting in higher health care costs associated with readmission.16 However, the recent FDA approval of the oral solution formulation of vancomycin has provided an alternative cost-effective option for patients. Other potential benefits of Firvanq include:

  • Ready-to-use formulation
  • Grape flavor 
  • Improved outpatient adherence 
  • No need for prior authorization 
  • Not being considered a specialty drug in contrast to the compounded oral suspension
Table 4 Selected Average Wholesale Prices for Full-Course Treatment of Initial Nonsevere Episode of C. Difficile in Adults15
Drug/Strength Brand Generic
Vancomycin HCl oral solution
25 mg/mL $150 N/A
50 mg/mL $100 N/A
Vancomycin HCl capsules
125 mg $3,775 $1,252
Vancomycin HCl powder (for compounded oral suspension)
5 g N/A $24–107
Ora-Sweet 16 oz N/A $24 (bottle)
Fidaxomicin tablets
200 mg $4,639 N/A
Metronidazole tablets
250 mg $619 $15–$35
500 mg $552 $7–$21

CONCLUSION

The approval of vancomycin HCl oral solution (Firvanq, CutisPharma) using the 505(b)(2) pathway allowed the company to rely on the safety and effectiveness clinical trials used for the capsule formulation (Vancocin, ANI Pharmaceuticals). Vancomycin HCl oral solution offers a noteworthy first-line treatment option for patients suffering C. difficile infection. This option is not only effective at every level of severity in C. difficile, it is also useful in both the pediatric and adult populations, unlike fidaxomicin. 

With all factors considered, the use of vancomycin HCl oral solution should be preferred in comparison with other treatment options for initial episodes and first recurrences of C. difficile infection. In the case of a second or subsequent recurrence of C. difficile, using vancomycin taper therapy, fecal microbiota transplantation, or fidaxomicin oral tablets (except in pediatric patients) should be considered. While the new oral solution is more cost-effective, additional studies would be beneficial to further investigate the pharmacokinetics, safety, efficacy, and drug interactions associated with vancomycin HCl oral solution given the alternative method of absorption.

Author bio: 

Dr. Smith is an Associate Professor of Pharmacy Practice at Lake Erie College of Osteopathic Medicine (LECOM), School of Pharmacy, in Bradenton, Florida. Latoya Cuyler and Aquaiel Troupe are currently Doctors of Pharmacy Candidates at that institution.

REFERENCES

  1. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66(7):e1–e48.
  2. Lawson PA, Citron DM, Tyrrell KL, Finegold SM. Reclassification of Clostridium difficile as Clostridioides difficile (Hall and O’Toole 1935) Prévot 1938. Anaerobe 2016;40:95–99.
  3. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372(9):825–834.
  4. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108(4):478–498.
  5. Gomez-Simmonds A, Kubin CJ, Furuya EY. Comparison of 3 severity criteria for Clostridium difficile infection. Infect Control Hosp Epidemiol 2014;35(2),196–199.
  6. Kamboj M, Khosa P, Kaltsas A, et al. Relapse versus reinfection: surveillance of Clostridium difficile infection. Clin Infect Dis 2011;53(10):1003–1006.
  7. Freije I, Lamouche S, Tanguay M. Review of drugs approved via the 505 (b)(2) pathway: uncovering drug development trends and regulatory requirements. Ther Innov Regul Sci 2019 Jan 7:2168479018811889. doi: 10.1177/2168479018811889. 
  8. Firvanq (vancomycin hydrochloride for oral solution) prescribing information. Wilmington, Massachusetts: CutisPharma; January 2018.
  9. Vancocin (vancomycin hydrochloride capsules) prescribing information. Exton, Pennsylvania: Viro Pharma, Inc.; December 2011.
  10. Reyes MP, Ostrea EM Jr, Rintelmann W. Vancomycin during pregnancy: Does it cause hearing loss or nephrotoxicity in infants? Am J Obstet Gynecol 1989;161(4):977–981. 
  11. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile–associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45(3):302–307.
  12. Dificid (fidaxomicin) prescribing information. Whitehouse Station, New Jersey: Merck & Co., Inc., 2019.
  13. Flagyl (metronidazole tablet) prescribing information. New York, New York: Pfizer, 2018.
  14. Flagyl (metronidazole intravenous) prescribing information. New York, New York: Pfizer, 2013.
  15. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, Illinois. Available at: http://online.lexi.com. Accessed April 24, 2019.
  16. Bunnell KL, Danziger LH, Johnson, S. Economic Barriers in the treatment of Clostridium difficile infection with oral vancomycin. Open Forum Infect Dis 2017;4(2). doi: 10.1093/ofid/ofx078.
  17. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364 (5):422–431.