Medical Policies - Prescription Drugs
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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.
Bezlotoxumab (Zinplava™) may be considered medically necessary to reduce recurrence risk of Clostridium difficile infection (CDI) when ALL the following criteria are met:
NOTE 1: High-risk CDI recurrence includes any of the following indications:
Bezlotoxumab (Zinplava™) is considered experimental, investigational and/or unproven when not meeting ALL criteria as outlined above.
Clostridium difficile (CD or C. diff) is a gram-positive, spore-forming bacterium or germ that colonizes in the human colon. CD is present in about 20% of the population. It can be found throughout the environment in soil, air, water, human and animal feces, and contained in food products. CD bacterium can lead to an infection within the colon called Clostridium difficile infection (CDI).
CD is the most common cause of infectious diarrhea in the healthcare setting and caused nearly 500,000 infections in one year, and 29,000 deaths. CDI accounts for significant rates of illness and death. In 2011, CDI was the 17th leading cause for people aged 65 years and older. The symptoms of CDI may include watery diarrhea, fever, nausea, abdominal cramping, dehydration, and loss of appetite. CDI is being increasingly recognized as a cause of diarrhea in the general community and in populations without the traditional risk factors for CDI. CDI recurs in about 1 in 5 patients. (1, 2)
The CDI risk factors include the following:
Recurrent CDI (rCDI) affects up to one quarter of all patients who respond to initial CDI therapy when given antibiotic therapies. (3) rCDI is the most common treatment management concern with current treatments, which has led to identifying clinical predictors of rCDI.
Bezlotoxumab (Zinplava™) is a human monoclonal antibody designed to reduce rCDI in adults who are receiving antibacterial drug treatment for the infection and are at high-risk for recurrence. Bezlotoxumab binds to CD toxin B and neutralizes its effects. The recommended dose is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes.
Bezlotoxumab (Zinplava™) (Merck Sharp & Dohme Corp., Whitehouse Station, NJ). was approved by the U.S. Food and Drug Administration (FDA) under a Biologics Licensing Application (BLA) on October 21, 2016 to reduce the risk of rCDI while undergoing antibiotic therapy for CDI. The label indicates that “Safety and efficacy of Zinplava™ in patients below 18 years of age have not been established.” (4)
The policy originated in 2017 and was based on the U.S. Food and Drug Administration (FDA) approved labeling for bezlotoxumab (Zinplava™). (4) A literature search of Medline was conducted through June 2018. The following is a summary of key literature to date.
The FDA approval of Zinplava™ was based on 2 randomized, double-blind, placebo-controlled, multicenter, phase 3 trials (Trial 1 [MODIFY I] and Trial 2 [MODIFY II]) in patients receiving standard of care (SoC) antibacterial drugs for treatment of Clostridium difficile infection (CDI) published by Wilcox et al. in 2017. (4, 5) Randomization was stratified by SoC (metronidazole, vancomycin, or fidaxomicin) and hospitalization status (inpatient versus outpatient) at the time of study entry.
Enrolled patients were 18 years of age or older and had a confirmed diagnosis of CDI, which was defined as diarrhea (passage of 3 or more loose bowel movements in 24 or fewer hours) and a positive stool test for toxigenic Clostridium difficile (CD) from a stool sample collected no more than 7 days before study entry. Patients were excluded if surgery for CDI was planned, or if they had uncontrolled chronic diarrheal illness. Patients received a 10- to 14-day course of oral SoC and a single infusion of Zinplava™ or placebo was administered during the course of SoC. Patients on oral vancomycin or oral fidaxomicin could have also received intravenous metronidazole. Choice of SoC was at the discretion of the health care provider. The day of the infusion of Zinplava™ or placebo in relation to the start of SoC ranged from the day prior to the start of SoC to 14 days after the start of SoC with the median being day 3 of SoC.
In the MODIFY I trial, 403 patients were randomized to receive Zinplava™ and 404 patients were randomized to receive placebo. In the MODIFY II trial, 407 subjects were randomized to receive Zinplava™ and 399 patients were randomized to receive placebo. The Full Analysis Set (FAS) was a subset of all randomized subjects with exclusions for: (i) not receiving infusion of study medication; (ii) not having a positive local stool test for toxigenic CD; (iii) not receiving protocol defined standard of care therapy within a 1 day window of the infusion. The baseline characteristics of the 1554 patients randomized to Zinplava™ or placebo in the FAS were similar across treatment arms and in MODIFY I and MODIFY II. The median age was 65 years, 85% were white, 57% were female, and 68% were inpatients. A similar proportion of patients received oral metronidazole (48%) or oral vancomycin (48%) and 4% of the patients received oral fidaxomicin as their SoC.
The following risk factors associated with a high-risk of CDI recurrence (rCDI) or CDI-related adverse outcomes were present in the study population: 51% were ≥65 years of age, 39% received one or more systemic antibacterial drugs (during the 12-week follow-up period), 28% had one or more episodes of CDI within the 6 months prior to the episode under treatment (15% had 2 or more episodes prior to the episode under treatment), 21% were immunocompromised and 16% presented at study entry with clinically severe CDI (as defined by a Zar score of ≥2  [Table 1 contains the different scoring methods to evaluate CDI]). A hypervirulent strain (ribotypes 027, 078 or 244) was isolated in 22% of patients who had a positive baseline culture, of which 87% (189 of 217 strains) were ribotype 027.
Table 1. Three Different Severity Criteria for Clostridium difficile Infection (CDI) (7)
≥3 diarrheal stools/day; may be accompanied by mild or moderate abdominal discomfort, elevated WBC count, and fever.
Mild-moderate criteria plus at least 1 of the following:
WBC count <15,000 cells/mm3 AND serum creatinine <1.5 × baseline.
CDI: Clostridium difficile Infection;
WBC: white blood cell;
ICU: intensive care unit;
IDSA: Infectious Diseases Society of America;
SHEA: Society for Healthcare Epidemiology of America;
a: Based on the clinical trial conducted by Zar et al. (6) One point is given for each of the following: age >60-65 years; temperature >38.3°C; albumin level <2.5 mg/dL; WBC count >15,000 cells/mm3. Two points are given for endoscopic evidence of pseudomembranous colitis and treatment in the ICU.
Patients were assessed for clinical cure of the presenting CDI episode, defined as no diarrhea for 2 consecutive days following the completion of a ≤14 day SoC regimen. Patients who achieved clinical cure were then assessed for recurrence of CDI through 12 weeks following administration of the infusion of Zinplava™ or placebo. CDI recurrence was defined as the development of a new episode of diarrhea associated with a positive stool test for toxigenic CD following clinical cure of the presenting CDI episode. Sustained clinical response was defined as clinical cure of the presenting CDI episode and no CDI recurrence through 12 weeks after infusion. Table 2 contains the results for MODIFY I and MODIFY II trials.
Table 2. Efficacy Results Through 12 Weeks After Infusion (MODIFY I Trial and MODIFY II Trial, Full Analysis Set*)
N = 386
N = 395
4.8 (-2.1, 11.7)
Reasons for failure to achieve sustained clinical response:
14.6 (7.7, 21.4)
Reasons for failure to achieve sustained clinical response:
Full Analysis Set*: A subset of all randomized subjects with exclusions for: (i) did not receive infusion of study medication; (ii) did not have a positive local stool test for toxigenic CD; (iii) did not receive protocol defined standard of care therapy within a 1 day window of the infusion;
SoC: Standard of Care antibacterial drugs (metronidazole or vancomycin or fidaxomicin) for CDI;
n (%): Number (percentage) of subjects in the analysis population meeting the criteria for endpoint;
N: Number of subjects included in the analysis population;
**: Adjusted difference of Zinplava™-placebo (95% confidence interval) based on Miettinen and Nurminen method stratified by SoC antibacterial drugs (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient).
In MODIFY I, the clinical cure rate of the presenting CDI episode was lower in the Zinplava™ arm as compared to the placebo arm and in MODIFY II, the clinical cure rate was lower in the placebo arm compared to the Zinplava™ arm. Patients in the Zinplava™ and placebo arms who did not achieve clinical cure of the presenting CDI episode (no diarrhea for 2 consecutive days following the completion of a ≤14 day SoC regimen) received a mean of 18 to 19 days of SoC and had a mean of 4 additional days of diarrhea following completion of SoC. Additional analyses showed that by 3 weeks’ post study drug infusion the clinical cure rates of the presenting CDI episode were similar between treatment arms.
Efficacy results in patients at high-risk for CDI recurrence (i.e., patients aged 65 years and older, with a history of CDI in the past 6 months, immunocompromised state, severe CDI at presentation, or CD ribotype 027) were consistent with the efficacy results in the overall trial population in MODIFY I and II.
In May 2017, Chapin et al. published a literature review of clinical efficacy, safety, and pharmacokinetics in humans and animals from 1946 through April 2017. (8) Included in the data review were the 2 phase 3 MODIFY trials. Results demonstrated a 40% relative reduction of rCDI with Zinplava™ compared with placebo (16.5% versus 26.6%, P < 0.0001). The most common adverse drug events associated with Zinplava™ were mild to moderate infusion-related reactions (10.3%). The authors concluded that in patients treated with SoC antibiotics, Zinplava™ is effective in decreasing rCDI. Zinplava™ has no apparent effect on treatment of an initial CDI episode. Considering increasing rates of CDI, Zinplava™ is a promising option for preventing recurrent episodes. The greatest benefit has been demonstrated in high-risk patients, though the targeted patient population is yet to be defined.
Prior to the MODIFY trials, in 2014, Zilberberg et al. completed a retrospective cohort study of 4200 patients recently hospitalized for initial CDI treatment. (9) Four hundred twenty-five patients developed rCDI. Eight risk factors for rCDI were identified, which include: advanced age, high Charlson score (prediction of 1 year mortality based on range of comorbid conditions), prior exposure to healthcare system (i.e., clinics), at least 1 inpatient admission within 60 days prior to rCDI, receiving one antimicrobial agent, receiving gastric suppressors and non-CDI antimicrobials, discharge to a healthcare facility following inpatient treatment, or readmission as an inpatient both before and/or after the end of the initial CDI treatment.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov did not identify any ongoing or unpublished trials that would likely influence this review.
Professional Guidelines and Position Statements
There are no professional guidelines and position statements that would likely influence this review.
Summary of Evidence
The evidence is sufficient to support the use of Zinplava™ for the U.S. Food and Drug Administration (FDA) approved indication for patients at high-risk of recurrent Clostridium difficile infection (CDI), which is based on clinical trials outcomes documented in the published labeling. Efficacy results were document in the 2 phase 3 MODIFY trials in patients aged 65 years and older, with a history of CDI in the past 6 months, immunocompromised state, severe CDI at presentation, or CD ribotype 027.
The evidence is insufficient to support the use of Zinplava™ beyond the FDA approved indications, i.e., patients under the age of 18 years, without concurrent use of antibiotics, and treatment of initial CDI, as Zinplava™ has no apparent effect on outcomes. In those instances, treatment using Zinplava™ is considered experimental, investigational and/or unproven.
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Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
The following codes may be applicable to this Medical policy and may not be all inclusive.
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
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The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
|8/15/2018||Document updated with literature review. Coverage unchanged.|
|7/1/2017||New medical document. Bezlotoxumab (Zinplava™) may be considered medically necessary to reduce recurrence risk of Clostridium difficile infection (CDI) when ALL the following criteria are met: Patient is 18 years of age and older; AND Patient is receiving antibacterial drug treatment of confirmed diagnosis of CDI; AND Patient is at a high-risk for CDI recurrence (rCDI) (see NOTE below). NOTE: High-risk CDI recurrence includes any of the following indications: Age ≥ 65 years of age; or Long-term use of systemic antibiotics; or One or more prior episodes of CDI within last 6 months; or Immunocompromised (i.e., prior solid organ transplant recipient, hematological malignancy, receiving antineoplastic/immunomodulating/corticosteroid agent, being asplenic or current neutropenic/pancytopenic, or having AIDS/immunodeficiency); or Confirmed hypervirulent strain of CD defined as ribotypes 027, 078, or 244. Bezlotoxumab (Zinplava™) is considered experimental, investigational and/or unproven when not meeting ALL criteria as outlined above.|
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