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Zinplava

Generic Name: Bezlotoxumab
Class: Antitoxins and Immune Globulins
Molecular Formula: C6464H9974N1726O2014S46
CAS Number: 1246264-45-8

Introduction

Antitoxin; fully human IgG1 monoclonal antibody that binds to and neutralizes Clostridium difficile toxin B.1 2 8 11 14

Uses for Zinplava

Clostridium difficile Infection

Reduction of recurrence of Clostridium difficile infection (CDI) in adults ≥18 years of age who are receiving anti-infective treatment for CDI and are at high risk for CDI recurrence.1 2

Not indicated for treatment of CDI.1 Does not have any antibacterial activity;1 use only in patients receiving an anti-infective regimen usually recommended for treatment of CDI (e.g., 10-day regimen of metronidazole, vancomycin, or fidaxomicin).1

Approximately 10–30% of patients have CDI recurrence within 1–8 weeks after appropriate anti-infective treatment for initial CDI episode;6 7 10 11 13 14 rate of recurrence may be as high as 40–65% in those with previous CDI recurrence.7 10

Risk factors for recurrent CDI include advanced age (≥65 years of age), impaired immune response as a result of disease or medical therapy, recent treatment with anti-infectives or continued use of anti-infectives not directed against C. difficile after CDI is diagnosed, recent hospitalization, comorbidity (severe underlying disease, especially chronic kidney disease), history of CDI within past 6 months, severe CDI, hypervirulent strains of C. difficile (e.g., polymerase chain reaction [PCR] ribotypes 027, 078, or 244), alterations in normal gut microbiota, and use of drugs that decrease gastric acid (e.g., proton-pump inhibitors, histamine H2-receptor antagonists).1 7 10 12 16

Pathogenic strains of C. difficile produce 2 exotoxins, toxin A (TcdA) and toxin B (TcdB), that induce cytotoxicity and inflammation in the colon resulting in symptomatic intestinal CDI.8 11 13 14 15 Bezlotoxumab binds to and neutralizes C. difficile toxin B;2 8 11 13 provides a form of passive immunity against C. difficile2 13 and, when used in addition to anti-infective regimen usually recommended for treatment of CDI, may reduce risk of CDI recurrence.1 2

Zinplava Dosage and Administration

General

  • Administer only while patient is receiving an anti-infective regimen for treatment of CDI.1

Administration

Administer by IV infusion;1 do not administer by IV injection.1

IV Infusion

For solution compatibility information, see Compatibility under Stability.

Must be diluted prior to IV infusion.1

After dilution, administer through a separate IV line using an in-line or add-on, low-protein-binding filter with a pore size of 0.2–5 µm.1

May be infused via a central line or peripheral catheter.1

Vials contain no preservatives;1 for single use only.1

Dilution

Withdraw appropriate dose from vial(s) containing 25 mg/mL of bezlotoxumab and transfer into IV infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection to provide a final concentration of 1–10 mg/mL.1 Gently invert IV bag to mix solution.1

Do not shake vials or final infusion solution.1

Discard any unused portion remaining in vial.1

Complete the infusion within 16 hours following dilution if stored at room temperature or within 24 hours if stored in refrigerator.1

If IV bag containing diluted solution is refrigerated, allow it to come to room temperature prior to IV infusion.1

Rate of Administration

Administer by IV infusion over 60 minutes.1

Dosage

Adults

Clostridium difficile Infection (CDI)
Reduction of CDI Recurrence
IV

10 mg/kg as a single dose.1

Safety and efficacy of >1 dose of bezlotoxumab not evaluated.1

Special Populations

Geriatric Patients

Dosage adjustments not needed in patients ≥65 years of age.1

Cautions for Zinplava

Contraindications

  • Manufacturer states none.1

Warnings/Precautions

Heart Failure

Heart failure, including fatalities, reported in some patients who received bezlotoxumab, primarily in those with history of CHF.1 In clinical trials, heart failure reported in 12.7 or 4.8% of patients with history of CHF who received bezlotoxumab or placebo, respectively.1

In patients with history of CHF, fatalities occurred in 19.5 or 12.5% of patients who received bezlotoxumab or placebo, respectively.1 Causes of death varied and included heart failure, infections, and respiratory failure.1

Use in patients with history of CHF only if potential benefits outweigh risks.1

Infusion Reactions

Infusion-related reactions reported in 10 or 8% of patients who received bezlotoxumab or placebo, respectively, in clinical trials.1 2

Infusion-related adverse effects reported in bezlotoxumab-treated patients and at frequency greater than with placebo were nausea, fatigue, pyrexia, dizziness, headache, dyspnea, and hypertension.1 Usually occurred on day of or day after IV infusion of bezlotoxumab, generally considered mild to moderate in severity, and resolved within 24 hours after onset.1

In clinical trials, infusion-related reactions that may have been signs of acute hypersensitivity reaction included nausea, vomiting, chills, fatigue, infusion-site conditions, pyrexia, arthralgia, myalgia, dizziness, headache, dyspnea, nasal congestion, pruritus, rash, urticaria, flushing, hot flush, hypotension, and hypertension.2

Immunogenicity and Antibody Formation

Treatment-emergent anti-bezlotoxumab antibodies not detected in clinical trials in patients with CDI who received bezlotoxumab.1 However, as with all therapeutic proteins, potential for immunogenicity exists.1

Specific Populations

Pregnancy

Data not available regarding use of bezlotoxumab in pregnant women.1 Animal reproductive and developmental studies not conducted.1

Lactation

Not known whether bezlotoxumab distributes into human milk, affects human milk production, or affects breast-fed infant.1

Consider benefits of breast-feeding and importance of the drug to the woman;1 also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

In clinical trials, 50% of patients treated with bezlotoxumab were ≥65 years of age and 27% were ≥75 years of age.1 No substantial differences in safety or efficacy relative to younger adults.1

Hepatic Impairment

Evaluated in patients with mild, moderate, or severe hepatic impairment;1 no evidence of clinically important effects on bezlotoxumab pharmacokinetics.1

Renal Impairment

Evaluated in patients with mild, moderate, or severe renal impairment or with end-stage renal disease;1 no evidence of clinically important effects on bezlotoxumab pharmacokinetics.1

Common Adverse Effects

Infusion reactions,1 2 nausea,1 2 diarrhea,2 abdominal pain,2 pyrexia,1 2 headache.1 2

Interactions for Zinplava

Specific drug interaction studies not performed.4

Drug interactions not expected because bezlotoxumab is eliminated by catabolism (see Elimination under Pharmacokinetics).1

Not a substrate for and does not inhibit or induce CYP isoenzymes.4

Zinplava Pharmacokinetics

Distribution

Extent

Mean volume of distribution is 7.33 L following IV infusion.1

Systemically administered bezlotoxumab may be translocated to gut lumen via nonspecific paracellular transport facilitated by C. difficile toxin-induced disruption of intestinal epithelium integrity.13

Not known whether distributed into milk.1

Plasma Protein Binding

Not expected.1

Elimination

Metabolism

Undergoes protein catabolism;1 degraded into small peptides and individual amino acids.4

Elimination Route

Not excreted by renal elimination.4

Has been detected in feces.4

Half-life

Approximately 19 days.1

Special Populations

Clearance increases with increasing body weight.1

Pharmacokinetics not substantially affected by renal or hepatic impairment, age ≥65 years, gender, ethnicity, or comorbid conditions.1

Stability

Storage

Parenteral

For Injection, for IV Infusion

2–8°C;1 keep in original container to protect from light.1

Prior to dilution, may be stored for up to 24 hours at room temperature protected from light.1

Diluted solutions may be stored at room temperature for up to 16 hours or at 2–8°C for up to 24 hours;1 these storage times include the duration of IV infusion.1

Do not freeze vials or diluted solutions.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Actions

  • Bezlotoxumab, a fully human IgG1 monoclonal antibody, binds to and neutralizes C. difficile toxin B.1 2 Antitoxin antibody2 13 used to provide a form of passive immunity to reduce risk of CDI recurrence.1 2

  • Pathogenic C. difficile produce 2 exotoxins, toxin A (TcdA) and toxin B (TcdB), that cause symptomatic intestinal CDI.8 11 13 14 15 Bezlotoxumab has high affinity for and binds to C. difficile toxin B1 , thereby preventing the toxin from binding to target epithelial cells in the colon.1 8 11 13 14 In vitro studies in cell-based assays indicate that, by neutralizing C. difficile toxin B, bezlotoxumab reduces toxin B-mediated damage to intestinal wall and decreases release of toxin B-mediated proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-α], interleukin-1β [IL-1β]).8 11 13 14

  • In vitro studies indicate bezlotoxumab binds to and directly neutralizes toxin B produced by various C. difficile ribotypes.3 There is some evidence that bezlotoxumab has reduced binding affinity for and reduced neutralization activity against toxin B produced by some hypervirulent C. difficile (e.g., ribotypes 027 and 078) compared with toxin B produced by some other ribotypes.3

  • Does not bind to and cannot neutralize C. difficile toxin A.1 3

  • Has no direct antibacterial effect on C. difficile;1 is not an antibacterial agent.1

Advice to Patients

  • Importance of reading patient information provided by the manufacturer.1

  • Advise patients that bezlotoxumab is used to help reduce the risk of recurrence of CDI and does not replace anti-infectives used for treatment of CDI.1 Importance of patients continuing to take anti-infective treatment for CDI as directed, even after they receive bezlotoxumab.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 (e.g., CHF).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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Bezlotoxumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Concentrate, for injection, for IV infusion

25 mg/mL

Zinplava

Merck

AHFS DI Essentials. © Copyright 2017, Selected Revisions June 5, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Merck & Co. Zinplava (bezlotoxumab) injection for intravenous use prescribing information. Whitehouse Station, NJ. 2016 Oct.

2. Wilcox MH, Gerding DN, Poxton IR et al. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017; 376:305-317. [PubMed 28121498]

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761046Orig1s000: Microbiology/virology reviews: From FDA website.

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761046Orig1s000: Clinical pharmacology and biopharmaceutics review(s): From FDA website.

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761046Orig1s000: Summary Review: From FDA website.

6. Lessa FC, Mu Y, Bamberg WM et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015; 372:825-34. [PubMed 25714160]

7. Abdelfatah M, Nayfe R, Nijim A et al. Factors Predicting Recurrence of Clostridium difficile Infection (CDI) in Hospitalized Patients: Retrospective Study of More Than 2000 Patients. J Investig Med. 2015; 63:747-51. [PubMed 25871748]

8. Koon HW, Shih DQ, Hing TC et al. Human monoclonal antibodies against Clostridium difficile toxins A and B inhibit inflammatory and histologic responses to the toxins in human colon and peripheral blood monocytes. Antimicrob Agents Chemother. 2013; 57:3214-23. [PubMed 23629713]

9. Lowy I, Molrine DC, Leav BA et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010; 362:197-205. [PubMed 20089970]

10. Surawicz CM, Brandt LJ, Binion DG et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013; 108:478-98; quiz 499. [PubMed 23439232]

11. 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; 83:822-31. [PubMed 25486992]

12. 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]

13. Zhang Z, Chen X, Hernandez LD et al. Toxin-mediated paracellular transport of antitoxin antibodies facilitates protection against Clostridium difficile infection. Infect Immun. 2015; 83:405-16. [PubMed 25385797]

14. Orth P, Xiao L, Hernandez LD et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014; 289:18008-21. [PubMed 24821719]

15. Humphreys DP, Wilcox MH. Antibodies for treatment of Clostridium difficile infection. Clin Vaccine Immunol. 2014; 21:913-23. [PubMed 24789799]

16. Debast SB, Bauer MP, Kuijper EJ et al. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014; 20 Suppl 2:1-26. [PubMed 24118601]

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