TRANSFORM HOW YOU USE DRUG INFORMATION

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

No dosage adjustments are needed.

Casirivimab and imdevimab are investigational neutralizing human immunoglobulin G-1 (IgG1) monoclonal antibodies with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They are not an FDA-approved treatment; however, they have been authorized for use under an Emergency Use Authorization (EUA) to treat mild to moderate COVID-19 in patients (12 years and older weighing at least 40 kg) with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19 or hospitalization. The drug is NOT authorized for use in patients who are hospitalized due to COVID-19, who require oxygen therapy for COVID-19, or who require an increase in baseline oxygen flow rate due to COVID-19 if already on chronic oxygen therapy for an underlying condition. Use of the drug in hospitalized patients with COVID-19 who require high flow oxygen or mechanism ventilation may be associated with worsening clinical outcomes.[66127] The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend using combination anti-SARS-CoV-2 monoclonal antibodies (including casirivimab and imdevimab) to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression as defined by the EUA criteria. The NIH emphasizes that anti-SARS-CoV-2 antibodies should NOT be used to treat patients hospitalized due to COVID-19, except in a clinical trial; however, their use should be considered for high risk persons with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19. Anti-SARS-CoV-2 antibodies should be started as soon as possible after positive test results for SARS-CoV-2 and within 10 days of symptom onset. For patients who receive anti-SARS-CoV-2 antibodies, defer administration of the COVID-19 vaccination for at least 90 days as a precaution to avoid interference with vaccine-induced immune responses. Conversely, the use and timing of treatment with anti-SARS-CoV-2 antibodies should not be affected by prior vaccinations in patients who develop COVID-19 after receiving the vaccine.[65314]

For storage information, see the specific product information within the How Supplied section.

NOTE: Casirivimab and imdevimab are not FDA-approved medications; however, they have been authorized for use under an Emergency Use Authorization (EUA) to treat mild to moderate COVID-19 in patients with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19 or hospitalization. Under the EUA, health care providers are required to communicate to the patient, parent, or caregiver information consistent with the "Fact Sheet for Patients, Parents and Caregivers" prior to the patient receiving treatment; such information includes the following:

• The option to accept or refuse casirivimab and imdevimab
• The significant known and potential risks and benefits of treatment, and the extent to which such potential risks and benefits are unknown
• Available alternative treatments and the risk and benefits of those alternatives
• The need to continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal items, clean and disinfect, frequent hand washing) according to CDC guidelines

NOTE: Under the EUA, health care providers are required to report all medication errors and serious adverse events potentially related to casirivimab and imdevimab therapy within 7 calendar days from the onset of the event.[66127]

Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worsening clinical outcomes when administered to hospitalized patients with COVID-19 who require high flow oxygen or mechanical ventilation. Therefore, the drug is not authorized for use in patients who are hospitalized due to COVID-19, who require oxygen therapy for COVID-19, or who require an increase in baseline oxygen flow rate due to COVID-19 if already on chronic oxygen therapy for an underlying condition.[66127]

Casirivimab and imdevimab are recombinant human immunoglobulin G-1 (IgG1) monoclonal antibodies used in combination as an antiviral medication to target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The antibodies bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2, which prevents the virus from interacting with the human ACE2 receptor. In Jurkat target cells expressing SARS-CoV-2 spike proteins, the combination of casirivimab plus imdevimab elicited antibody-dependent cell-mediated cytotoxicity (ADCC) with human natural killer (NK) effector cells and antibody-dependent cellular phagocytosis (ADCP) with human macrophages. However, the combination did not mediate complement-dependent cytotoxicity in cell-based assays. The estimated 50% effective concentration (EC₅₀) of casirivimab plus imdevimab in neutralizing SARS-CoV-2 in Vero cells is 0.005 mcg/mL.[66127][66130]

There is a potential for treatment failure due to the development of viral variants that are resistant to the combination of casirivimab and imdevimab. Health care providers are advised to consider the prevalence of SARS-CoV-2 variants in their area when considering treatment options. In cell culture studies, spike protein amino acid substitutions in variants showing reduced susceptibility to casirivimab alone include K417E (182-fold), K417N (7-fold), K417R (61-fold), Y453F (more than 438-fold), L455F (80-fold), E484K (25-fold), F486V (more than 438-fold), and Q493K (more than 438-fold). Variants showing reduced susceptibility to imdevimab alone include substitutions K444N (more than 755-fold), K444Q (more than 548-fold), K444T (more than 1,033-fold), and V445A (548-fold). Casirivimab and imdevimab together show reduced susceptibility to variants with substitutions K444T (6-fold) and V445A (5-fold). In neutralization assays of 39 different spike protein variants identified in circulating SARS-CoV-2, variants with reduced susceptibility to casirivimab alone included those with substitutions Q409E (4-fold), G476S (5-fold), S494P (5-fold), E484Q (9-fold), and Q493E (446-fold). Variants with reduced susceptibility to imdevimab alone included 1 with N439K (463-fold) substitution. Casirivimab and imdevimab together retained activity against all variants tested. Neutralization data for SARS-CoV-2 variant substitutions identified through global surveillance have found no change in susceptibility (i.e., less than 2-fold reduction) to casirivimab and imdevimab together. The variants and key substitutions are as follows:

• United Kingdom B.1.1.7 variant: All spike protein substitutions found in this variant, including key variant N501Y
• South Africa B.1.351 variant: All spike protein substitutions found in this variant, including key variants K417N, E484K, and N501Y
• Brazil P.1 variant: K417T + E484K
• California B.1.427/B.1.429 variant: L452R
• New York B.1.526 variant: E484K
  
  • NOTE: Not all New York B.1.526 isolates harbored the E484K substitution

It is unknown how these data correlate with clinical outcomes.[66127]

Casirivimab and imdevimab are administered via intravenous infusion. Data regarding the pharmacokinetics of casirivimab and imdevimab are limited; however, the pharmacokinetic profiles are expected to be consistent with the profile of other IgG1 monoclonal antibodies. Casirivimab and imdevimab are not metabolized by cytochrome P450 enzymes, nor are they renally excreted.[66127]

Affected cytochrome P450 isoenzymes: none