Coverage Policy Manual
Policy #: 2017023
Category: Pharmacy
Initiated: June 2017
Last Review: February 2026
Bezlotoxumab (e.g., Zinplava)
Description:
Effective February 13, 2027 this policy will be archived.
 
 
Bezlotoxumab is a human monoclonal antibody that binds to C. difficile toxin B and neutralizes its effect. (Clinical Pharmacology, 2017).
 
Regulatory
 
Bezlotoxumab (e.g., Zinplava) was FDA approved in October 2016 to reduce recurrence of Clostridium difficile infection (CDI) in individuals 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at a high risk for CDI recurrence (U.S. FDA, 2016). In May of 2023, this indication was expanded to include pediatric individuals 1 year of age and older.
 
Coding
 
See CPC/HCPCS Code section below.
 
Policy/
Coverage:
Effective February 13, 2027 this policy will be archived.
 
 
Effective November 01, 2026
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Bezlotoxumab (e.g., Zinplava) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered when member receives a “recommended” determination from criteria review in InterQual® for Bezlotoxumab (e.g., Zinplava) based on diagnosis and requested product.
 
Click the following link to view the specific criteria in InterQual®: https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
 
See Criteria below.
 
Bezlotoxumab (e.g., Zinplava) meets Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is covered or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:
 
1. Individual has a current diagnosis of Clostridium difficile Infection (Zinplava, 2023); AND
2. Individual is 1 year of age or older (Zinplava, 2023) confirmed by a positive stool test for Clostridium difficile; AND
3. Individual is at high risk of recurrence, defined as meeting one of the following criteria (Wilcox, 2017):
a. Individual is 65 years old or older; OR
b. Individual has severe Clostridium difficile infection at presentation; OR
c. Individual has history of Clostridium difficile infection in the previous 6 months; OR
d. Individual is Immunocompromised; OR
e. Individual has presence of Clostridium difficile ribotype 027 (Alfonso, 2018); AND
4. Individual has received less than or equal to 14 days of antibiotic treatment (e.g., fidaxomicin, metronidazole, or vancomycin) for Clostridium difficile infection (Wilcox, 2017); AND
5. Individual has no previous use of a monoclonal antibody against Clostridium difficile infection (including any previous use of bezlotoxumab) (Zinplava, 2023); AND
6. Limited to a single course of treatment and must be dosed in accordance with the FDA label.
 
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Bezlotoxumab (e.g., Zinplava) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.
 
For contracts without Primary Coverage Criteria, Bezlotoxumab (e.g., Zinplava) is considered not Medically Necessary and is not covered or is investigational for any indication or circumstance not described above. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Click the following link to view the specific criteria in InterQual®: https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Please refer to a separate policy on Maximum Dosage and Frequency (policy #2025031) for pharmacologic/biologic medications.
 
Effective February 2026 to October 31, 2026
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Bezlotoxumab (e.g., Zinplava) meets Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is covered or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:
 
1. Individual has a current diagnosis of Clostridium difficile Infection (Zinplava, 2023); AND
2. Individual is 1 year of age or older (Zinplava, 2023) confirmed by a positive stool test for Clostridium difficile; AND
3. Individual is at high risk of recurrence, defined as meeting one of the following criteria (Wilcox, 2017):
a. Individual is 65 years old or older; OR
b. Individual has severe Clostridium difficile infection at presentation; OR
c. Individual has history of Clostridium difficile infection in the previous 6 months; OR
d. Individual is Immunocompromised; OR
e. Individual has presence of Clostridium difficile ribotype 027 (Alfonso, 2018); AND
4. Individual has received less than or equal to 14 days of antibiotic treatment (e.g., fidaxomicin, metronidazole, or vancomycin) for Clostridium difficile infection (Wilcox, 2017); AND
5. Individual has no previous use of a monoclonal antibody against Clostridium difficile infection (including any previous use of bezlotoxumab) (Zinplava, 2023); AND
6. Limited to a single course of treatment and must be dosed in accordance with the FDA label.
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Bezlotoxumab (e.g., Zinplava), for any indication or circumstance not described above, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
 
For members with contracts without Primary Coverage Criteria, Bezlotoxumab (e.g., Zinplava), for any indication or circumstance not described above, is considered not Medically Necessary and is not covered or is investigational. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
DOSAGE AND ADMINISTRATION
 
For FDA labeled indications, Bezlotoxumab (e.g., Zinplava) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.
 
The recommended dose of Bezlotoxumab (e.g., Zinplava) is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes.
 
Bezlotoxumab (e.g., Zinplava) is available as 1,000 mg/40 mL (25 mg/mL) solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Effective March 20, 2024 to January 2026
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Bezlotoxumab meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is covered when ALL the following criteria are met:
 
1. Individual has a current diagnosis of Clostridium difficile Infection (Zinplava, 2023); AND
2. Individual is 1 year of age or older (Zinplava, 2023) confirmed by a positive stool test for Clostridium difficile; AND
3. Individual is at high risk of recurrence, defined as meeting one of the following criteria (Wilcox, 2017):
a. Individual is age 65 years of age or older; OR
b. Individual has severe Clostridium difficile infection at presentation; OR
c. Individual has history of Clostridium difficile infection in the previous 6 months; OR
d. Individual is Immunocompromised; OR
e. Individual has presence of Clostridium difficile ribotype 027 (Alfonso, 2018); AND
4. Individual has received less than or equal to 14 days of antibiotic treatment (e.g., fidaxomicin, metronidazole, or vancomycin) for Clostridium difficile infection (Wilcox, 2017); AND
5. Individual has no previous use of a monoclonal antibody against Clostridium difficile infection (including any previous use of bezlotoxumab) (Zinplava, 2023); AND
6. Limited to a single course of treatment and must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of Bezlotoxumab is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes.
 
Bezlotoxumab is available as 1,000 mg/40 mL (25 mg/mL) solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Bezlotoxumab (e.g., Zinplava) for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Bezlotoxumab for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective March 2023 to March 19, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Bezlotoxumab meets primary coverage criteria that there be scientific evidence of effectivess in improving health outcomes and is covered when ALL of the following criteria are met:
 
    1. Current diagnosis of Clostridium difficile Infection (FDA, 2017)
    2. Individual is ≥18 years of age (FDA, 2017)
    3. Individual  is at high risk of recurrence, defined as meeting one of the following criteria (Wilcox, 2017):
a.  Age ≥ 65 years old or
b.  Severe  C. difficile infection at presentation or
c.  History of C. difficile infection in the previous 6 months or
d.  Immunocompromised
4. Individual has received ≤14 days of antibiotic treatment for C. difficile infection (Wilcox, 2017).
5. No previous use of a monoclonal antibody against C. difficile infection (FDA, 2017).
6.  Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of Bezlotoxumab is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes.
 
Bezlotoxumab is available as 1,000 mg/40 mL (25 mg/mL) solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of bezlotoxumab does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication or circumstance other than those outlined above and is considered investigational for the following:
 
    1. All indications and individual populations not meeting the above criteria
    2. Individual with a previous use of a monoclonal antibody against C. difficile infection (including any previous use of bezlotoxumab).
3.  C difficile infection for greater than 14 days prior to receiving bezlotoxumab.
 
For members with contracts without primary coverage criteria, Bezlotoxumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective March 2023 to March 19, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Bezlotoxumab meets primary coverage criteria that there be scientific evidence of effectivess in improving health outcomes and is covered when ALL of the following criteria are met:
 
    1. Current diagnosis of Clostridium difficile Infection (FDA, 2017)
    2. Individual is ≥18 years of age (FDA, 2017)
    3. Individual  is at high risk of recurrence, defined as meeting one of the following criteria (Wilcox, 2017):
a.  Age ≥ 65 years old or
b.  Severe  C. difficile infection at presentation or
c.  History of C. difficile infection in the previous 6 months or
d.  Immunocompromised
4. Individual has received ≤14 days of antibiotic treatment for C. difficile infection (Wilcox, 2017).
5. No previous use of a monoclonal antibody against C. difficile infection (FDA, 2017).
6.  Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of Bezlotoxumab is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes.
 
Bezlotoxumab is available as 1,000 mg/40 mL (25 mg/mL) solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of bezlotoxumab does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication or circumstance other than those outlined above and is considered investigational for the following:
 
    1. All indications and individual populations not meeting the above criteria
    2. Individual with a previous use of a monoclonal antibody against C. difficile infection (including any previous use of bezlotoxumab).
3.  C difficile infection for greater than 14 days prior to receiving bezlotoxumab.
 
For members with contracts without primary coverage criteria, Bezlotoxumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective March 2019 to February 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
Bezlotoxumab meets primary coverage criteria and is covered when ALL of the following criteria are met:
 
  1. Current diagnosis of Clostridium difficile Infection (FDA, 2017)
  2. Patient is ≥18 years of age (FDA, 2017)
  3. Patient is at high risk of recurrence, defined as meeting one of the following criteria (Wilcox, 2017):
    • Age ≥ 65 years old or
    • Severe  C. difficile infection at presentation or
    • History of C. difficile infection in the previous 6 months or
    • Immunocompromised
4. Patient has received ≤14 days of antibiotic treatment for C. difficile infection (Wilcox, 2017).
5. No previous use of a monoclonal antibody against C. difficile infection (FDA, 2017).
 
Dosage and Administration
 
The recommended dose of Bezlotoxumab is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of bezlotoxumab does not meet primary coverage criteria and is considered investigational for the following:
 
  1. All indications and patient populations not meeting the above criteria
  2. Patients with a previous use of a monoclonal antibody against C. difficile infection (including any previous use of bezlotoxumab).
  3. C difficile infection for greater than 14 days prior to receiving bezlotoxumab.
 
Effective June 2017 - February 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
Bezlotoxumab meets primary coverage criteria and is covered when ALL of the following criteria are met:
 
    1. Current diagnosis of Clostridium difficile Infection
    2. Patient is ≥18 years of age
    3. Patient is at high risk of recurrence, defined as meeting one of the following criteria:
        • Age ≥ 65 years old or
        • Severe  C. difficile infection at presentation or
        • History of C. difficile infection in the previous 6 months or
        • Immunocompromised
 
4. Patient has received ≤14 days of antibiotic treatment for C. difficile infection.
5. No previous use of a monoclonal antibody against C. difficile infection.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of bezlotoxumab does not meet primary coverage criteria and is considered investigational for the following:
 
    1. All indications and patient populations not meeting the above criteria
    2. Patients with a previous use of a monoclonal antibody against C. difficile infection (including any previous use of bezlotoxumab).
    3. C difficile infection for greater than 14 days prior to receiving bezlotoxumab.
 
 
Rationale:
The efficacy of bezlotoxumab was assessed in two unpublished, randomized, double-blind, placebo-controlled phase III studies (Modify I and Modify II)(Wilcox et al, 2017). To be included, patients had to be 18 years of age or older with a positive diagnosis of C. difficile infection and receiving antibacterial therapy.  Exclusion criteria included any uncontrolled chronic diarrheal illness, any previous exposure to monoclonal antibodies against C. difficile toxins or C. difficile vaccines, planned surgery within 24 hours, C. difficile antibiotic therapy longer than 14 days, or have received drugs that decrease gastrointestinal peristalsis.  Patients were assessed for global cure, defined as clinical cure of the primary infection (no diarrhea for 2 consecutive days and no recurrence within 12 weeks after infusion) or CDI recurrence, defined as new diarrhea episode and positive stool test for C. difficile toxin within 12 weeks after infusion.  In the Modify I trial (n=781), 17.4% of bezlotoxumab patients had a recurrence, as compared to 27.6% of the placebo group (p=0.0003).  In that same trial, 60.1% had a global cure, as compared to 55.2% of the placebo group, which was not statistically significant (p=0.09).  In Modify II trial (n=773),  15.7% of patients treated with bezlotoxumab had recurrence, as compared to 25.7% in the placebo group (p=0.0003).  Of those patients, 66.8% of the bezlotoxumab patients had global cure, as compared to 52.1% in the placebo group, which was statistically significant (p<0.001).  A subgroup analysis using data from both Modify I and Modify II of high risk patients, defined as age ≥65, severe C. difficile infection at presentation, history of C. difficile infection in the previous 6 months, or immunocompromised state, was conducted.  The absolute difference in recurrence and global cure was higher in this subgroup than in the overall population.  Bezlotoxumab was generally well tolerated in these studies, although heart failure patients reported more heart failure adverse events in the bezlotoxumab group than in the placebo group.
 
2019 Update
A literature search conducted through February 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
In June 2023, Sferra et al has published results of MODIFY III study, a multicenter, double-blind, placebo-controlled study of bezlotoxumab in children (1 to <18 years) receiving antibacterial treatment for CDI. Participants were randomized 3:1 to receive a single infusion of bezlotoxumab (10 mg/kg) or placebo and were stratified by age at randomization (cohort 1: 12 to <18 years, cohort 2: 1 to <12 years). The primary objective was to characterize bezlotoxumab pharmacokinetics to support dose selection for pediatric patients; the primary endpoint was the area under the bezlotoxumab serum concentration–time curve (AUC0-inf). Safety, tolerability, and efficacy were monitored for 12 weeks post-infusion. A total of 148 participants were randomized and 143 were treated: 107 with bezlotoxumab and 36 with placebo (cohort 1 n = 60, cohort 2 n = 83; median age 9.0 years); 52.4% of participants were male and 80.4% were white. Geometric mean ratios (90% CI) for bezlotoxumab AUC0-inf were 1.06 (0.95, 1.18) and 0.82 (0.75, 0.89) h * μg/mL for cohorts 1 and 2, respectively. Bezlotoxumab 10 mg/kg was generally well-tolerated with an adverse event profile similar to placebo, including no treatment discontinuations due to adverse events. CDI recurrence was low and comparable for bezlotoxumab (11.2%) and placebo (14.7%).
 
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2025. No new literature was identified that would prompt a change in the coverage statement.
 
2026 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2026. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
J0565Injection, bezlotoxumab, 10 mg
J3490Unclassified drugs
J3590Unclassified biologics
References:
Alonso CD, Mahoney MV.(2018) Bezlotoxumab for the prevention of Clostridium difficile infection: a review of current evidence and satety profile. Infection and drug resistance. 2018 Dec 17:1-9

Elsevier.(2017) Bezlotoxumab. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2017- [cited 2017 May 24]. Available from: http://www.clinicalpharmacology.com

Merck & Co., Inc..;(2016) Zinplava® [package insert]. Whitehouse Station, NJ: Merck & Co., Inc..; 2016

Sferra TJ, Merta T, Neely M, Murta de Oliveira C, Lassaletta A, Fortuny Guasch C, Dorr MB, Winchell G, Su FH, Perko S, Fernsler D, Waskin H, Holden SR.(2023) Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III). J Pediatric Infect Dis Soc. 2023 Jun 30;12(6):334-341. doi: 10.1093/jpids/piad031. PMID: 37389891; PMCID: PMC10312293.

U.S. Food & Drug Administration.(2017) Zinplava FDA approval https://www.fda.gov/search.

Wilcox MH, Gerding DN, Poxton IR, et al.(2017) Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017;376(4):305-317.

Zinplava [package insert]. Whitehouse Station, NJ: Merck & Co., Inc;
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.
CPT Codes Copyright © 2026 American Medical Association.