Medical Policy

 

Subject: Bezlotoxumab (ZINPLAVA™)
Document #: DRUG.00090 Publish Date:    12/27/2017
Status: Revised Last Review Date:    02/02/2017

Description/Scope

This document addresses the use of bezlotoxumab (ZINPLAVA; Merck, Kenilworth, NJ), a fully human monoclonal (mAb) IgG1/kappa antibody that binds to Clostridium difficile (C. difficile) toxin B, used to reduce recurrence of Clostridium difficile infection (CDI).

Position Statement

Medically Necessary:

A single injection of bezlotoxumab is considered medically necessary to reduce recurrence of Clostridium difficile infection in individuals 18 years of age or older when all the following criteria are met:

  1. Confirmed Clostridium difficile infection when both of the criteria below are met:
    1. Passage of three or more loose stools within 24 hours or less; and
    2. Positive stool test for toxigenic Clostridium difficile from a stool sample collected not more than 7 days prior to scheduled infusion; and
  2. Currently receiving antibacterial therapy for Clostridium difficile infection; and
  3. Individual is at high risk of Clostridium difficile infection recurrence meeting any one of the following:
    1. Individual 65 years of age or older, with a history of Clostridium difficile infection in the past 6 months; or
    2. Immunocompromised state; or
    3. Severe Clostridium difficile infection at presentation (meeting any one of the three definitions of severe Clostridium difficile in the definitions section), or
    4. Clostridium difficile ribotype 027.

Investigational and Not Medically Necessary:

The use of bezlotoxumab is considered investigational and not medically necessary when the above criteria are not met, and for all other conditions, including but not limited to first-line therapy.

Rationale

C. difficile infection is usually caused by the use of antibiotics, which alters the normal flora of the intestinal tract and results in a pseudomembranous colitis due to the opportunistic colonization by C. difficile.

On October 21, 2016 intravenously (IV)-administered bezlotoxumab was the first human mAb to achieve accelerated approval and breakthrough therapy status by the U.S. Food and Drug Administration (FDA), because it is the first therapeutic option indicated to reduce recurrence of CDI in individuals 18 years of age or older currently receiving standard-of-care (SOC) antibiotics for CDI and who are at a high risk for CDI recurrence.

The FDA approval of bezlotoxumab was based on safety and efficacy demonstrated in two Phase III randomized, multicenter, double-blind, placebo-controlled trials. Notable enrollment criteria for both trials included individuals with confirmed diagnosis of CDI (≥ 3 loose stools in ≤ 24 hours and + stool test for toxigenic C. difficile collected within the previous 7 days) who were 18 years of age or older and receiving or planning to receive SOC therapy for CDI (antibiotics). Subjects recorded stools in a daily log and study personnel determined if a recurrence had occurred. The primary outcome in both studies was the proportion of participants who had a CDI recurrence in the treatment arms compared to the placebo. A notable secondary outcome was global cure rate.

The first Phase III study, P001, was an adaptive, factorial trial which enrolled participants into one of the following four study arms: actoxumab (anti-toxin A antibody), bezlotoxumab (anti-toxin B antibody), actoxumab + bezlotoxumab, or placebo (0.9% sodium chloride). Study treatment was for the prevention of CDI recurrence in subjects who were receiving antibacterial treatment for CDI. Enrollment in the actoxoumab-only arm was halted early due to an interim analysis based on safety concerns relative to the placebo arm and inferior efficacy relative to the actoxumab + bezlotoxumab arm. The remaining three arms continued enrollment through trial end. In total, 1452 individuals were randomized into the trial. In the actoxumab + bezlotoxumab and bezlotoxumab only arms, a significantly lower proportion of individuals had a CDI recurrence; 15.9% (p<0.0001) and 17.4% (p=0.0006), respectively, as compared to 27.6% in the placebo arm. The difference between the proportion in the actoxumab + bezlotoxumab and bezlotoxumab only arms was not statistically different (p=0.594). The difference in the secondary endpoint of global cure did not reach statistical significance in the actoxumab + bezlotoxumab arm (58.7%) or bezlotoxumab (60.1%) in comparison to placebo (55.2%).

In the second Phase III study, P002, 1203 participants were randomized similarly to Study P001 into one of four study arms, although the actoxumab arm alone was not included. There was a significantly lower proportion of subjects with CDI recurrence in the actoxumab + bezlotoxumab (14.9%; p=0.0002) and bezlotoxumab (15.7%; p=0.0006) arms as compared to the placebo arm (25.7%); there was no significant difference between the actoxumab + bezlotoxumab and bezlotoxumab only arms (p=0.748). The proportion of study participants who achieved a global cure was significantly higher in the bezlotoxumab arm compared to the placebo (p<0.001), but not in the actoxumab + bezlotoxumab arm compared to placebo (p=0.137).

Overall, the combination of actoxumab + bezlotoxumab was not found to enhance efficacy in the prevention of recurrence of CDI over bezlotoxumab alone. Bezlotoxumab, given as a single IV infusion, had an overall favorable safety profile with rates of adverse events and deaths similar to placebo. There was no increase in adverse events related to potential immune-mediated reactions in the bezlotoxumab arm compared to the placebo arm. Numerically, there was a higher number of serious adverse events and deaths in the bezlotoxumab arm compared to the placebo arm amongst subjects who reportedly had congestive heart failure at baseline.

Background/Overview

According to the Centers for Disease Control and Prevention (CDC), C. difficile infected nearly 500,000 individuals in 2011. Nearly 83,000 of those that contracted the infection experienced at least one recurrence, and approximately 29,000 deaths were reported within 30 days of the initial diagnosis. The infection is preventable using infection control recommendations and appropriate use of antibiotics (CDC, 2015).

Bezlotoxumab (ZINPLAVA) 2016 FDA Product Information (PI) label includes the following warnings, precautions and adverse events:

Warning and precautions:

Heart failure: Was reported more commonly in ZINPLAVA-treated patients with a history of congestive heart failure (CHF) in the two Phase 3 clinical trials. In patients with a history of CHF, ZINPLAVA should be reserved for use when the benefit outweighs the risk.

Adverse reactions:

Definitions

Clinical cure: Cure of the baseline episode of Clostridium difficile infection after a standard-of-care (SOC) regimen of ≤ 14 days (up to 16 calendar days) with no reported diarrhea (≤ 2 loose stools per 24 hours) on the 2 days immediately following the last day of SOC treatment.

Clinically severe Clostridium difficile infection (CDI): As defined by one of the following:

Clostridium difficile infection (CDI): A bacterium causing symptoms ranging from diarrhea to more serious intestinal conditions such as colitis.

CDI recurrence: The development of a new episode of diarrhea associated with a positive stool test for C. difficile toxin following clinical cure of the initial CDI episode.

Global cure: clinical cure of the initial CDI episode and no CDI recurrence through Week 12 (with this endpoint, those who are not clinical cures are more appropriately considered failures in study analyses).

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

J0565

Injection, bezlotoxumab, 10 mg [ZINPLAVA]

 

 

ICD-10 Procedure

 

XW033A3

Introduction of bezlotoxumab monoclonal antibody into peripheral vein, percutaneous approach, new technology group 3 [ZINPLAVA]

XW043A3

Introduction of bezlotoxumab monoclonal antibody into central vein, percutaneous approach, new technology group 3 [ZINPLAVA]

 

 

ICD-10 Diagnosis

 

 

A04.71-A04.72

Enterocolitis due to Clostridium difficile

 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for the prevention of recurrent Clostridium difficile infection. N Eng J Med. 2017; 376(4):305-317.
  2. Yang Z, Ramsey J, Hamza T, et al. Mechanisms of protection against clostridium difficile infection by the monoclonal antitoxin antibodies Actoxumab and Bezlotoxumab. Infect Immun. 2015; 83(2):822-831.
  3. Zar FA, Bakkanagari SR at al. 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.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Bezlotoxumab Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised November 4 2016. Accessed on January 5, 2017.
  2. Bezlotoxumab (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated October 2016. Available at: http://www.micromedexsolutions.com. Accessed on January 5, 2017.
  3. Christina M, Surawicz MD, Lawrence J, et al. Guidelines for diagnosis, treatment, and prevention of clostridium difficile infections. Am J Gastroenterol. 2013; 108:478-498.
  4. 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 Disease Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31(5):431-455.
  5. Merck Sharp & Dohme Corp. A study of MK-3415, MK-6072, and MK-3415A in participants receiving antibiotic therapy for clostridium difficile infection (MK-3415A-001) (MODIFY I). NLM Identifier: NCT01241552. Last updated October 24, 2016. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01241552?term=NCT01241552&rank=1 . Accessed on January 5, 2017.
  6. Merck Sharp & Dohme Corp. A study of MK-6072 and MK-3415A in participants receiving antibiotic therapy for clostridium difficile infection (MK-3415A-002) (MODIFY 11). NLM Identifier: NCT01513239. Last updated October 29, 2015. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01513239?term=NCT01513239&rank=1 . Accessed on January 5, 2017.
  7. 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.
  8. ZINPLAVA [Product Information]. Whitehouse Station, NJ. Merck Sharp & Dohme Corp.; October 21, 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761046s000lbl.pdf. Accessed on January 5, 2017.
Websites for Additional Information
  1. Centers for Disease Control and Prevention. Healthcare-associated infections (HAIs). Updated September 23, 2015. Available at: https://www.cdc.gov/HAI/organisms/cdiff/Cdiff_clinicians.html . Accessed on January 5, 2017.
Index

Bezlotoxumab
ZINPLAVA

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
  01/01/2018 The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 HCPCS changes; added J0565, removed C9490 deleted 12/31/2017 and NOC codes; also added ICD-10-PCS codes XW033A3 and XW043A3.
  10/01/2017 Updated Coding section with 10/01/2017 ICD-10-CM diagnosis code changes.
  07/01/2017 Updated Coding section with 07/01/2017 HCPCS changes.
Revised 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Clarified MN criteria. Updated Definitions, References and Websites sections.
New 11/03/2016 MPTAC review. Initial document development.