TRANSFORM HOW YOU USE DRUG INFORMATION

NOTE: Casirivimab and imdevimab are NOT authorized for treatment or post-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in geographic regions where infection or exposure is likely to have been caused by a non-susceptible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant. Omicron SARS-CoV-2 variant has become the dominant variant in the United States; and antiviral resistance data show that casirivimab and imdevimab are unlikely to retain activity against Omicron. The FDA will monitor conditions to determine whether use in a geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility, and CDC regional variant frequency data available at: covid.cdc.gov/covid-data-tracker/#variant-proportions.[65314][66127]

Individuals are deemed to be at high risk for progressing to severe COVID-19 if they meet at least 1 of the following criteria:

• Elderly (65 years or older)
• Obesity or overweight
  • Body mass index (BMI) greater than 25 kg/m²
  • If age 12 to 17 years, BMI greater than or equal to 85^th percentile for age and gender based on CDC growth charts
• Pregnancy
• Chronic kidney disease
• Diabetes
• Immunosuppressive disease or receiving immunosuppressive therapy
• Cardiovascular disease (including congential heart disease) or hypertension
• Chronic lung disease (e.g., chronic obstructive pulmonary disease, moderate-to-severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)
• Sickle cell disease
• Neurodevelopmental disorder (e.g., cerebral palsy) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes, severe congential anomalies)
• Medical-related technological dependency (e.g., tracheostomy, gastrostomy, positive pressure ventilation not related to COVID-19)

In addition, other medical conditions or factors (e.g., race, ethnicity) may also place individual patients at high risk, and authorization of casirivimab and imdevimab under the EUA is not limited to only those medical conditions or factors listed above. Health care providers are advised to consider the benefit-to-risk of an individual patient.[66127]

NOTE: There may be logistical or supply constraints that make it impossible to offer the available therapy to all eligible patients, making patient triage necessary. Health care providers should prioritize their use for patients at highest risk of clinical progression. Information on which individuals might receive the greatest benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention can be obtained from www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies. Health care providers are advised to consider the benefit-risk for each individual patient.[65314]

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

No dosage adjustments are needed.

NOTE: Casirivimab and imdevimab are NOT authorized for treatment or post-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in geographic regions where infection or exposure is likely to have been caused by a non-susceptible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant. Omicron SARS-CoV-2 variant has become the dominant variant in the United States; and antiviral resistance data show that casirivimab and imdevimab are unlikely to retain activity against Omicron. The FDA will monitor conditions to determine whether use in a geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility, and CDC regional variant frequency data available at: covid.cdc.gov/covid-data-tracker/#variant-proportions.[65314][66127]

Casirivimab and imdevimab are investigational neutralizing human immunoglobulin G-1 (IgG1) monoclonal antibodies with activity against SARS-CoV-2. They are not an FDA-approved treatment; however, they have been authorized for emergency use as a treatment for 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, including hospitalization or death. They are also authorized for use as post-exposure prophylaxis of COVID-19 in persons (12 years and older weighing at least 40 kg) exposed to SARS-CoV-2 who are at high risk for progressing to severe COVID-19 and are not fully vaccinated or are not expected to mount an adequate immune response to the complete COVID-19 vaccination. They are NOT authorized for treatment of 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 these drugs in hospitalized patients with COVID-19 who require high flow oxygen or mechanical ventilation may be associated with worsening clinical outcomes. Additionally, the combination is not authorized for pre-exposure prophylaxis, nor should it be used as a substitute for the COVID-19 vaccines.[66127]

The National Institutes of Health (NIH) COVID-19 guidelines recommend individuals who have recently been exposed to SARS-CoV-2 and have symptoms consistent with COVID-19 be evaluated for SARS-CoV-2 infection.

• If test results are positive for SARS-CoV-2, the NIH recommends against the use of casirivimab and imdevimab for treatment of high-risk, nonhospitalized patients with mild to moderate COVID-19. This recommendation is based on the Omicron SARS-CoV-2 variant becoming the dominant variant in the United States and real-time testing to identify rare, non-Omicron variants not being routinely available.
• If test results are negative for SARS-CoV-2, the NIH recommends against the use of casirivimab and imdevimab as post-exposure prophylaxis in adults who would be at high risk of clinical progression if infected (as defined by the EUA) and who are not fully vaccinated or are fully vaccinated but not expected to mount an adequate immune response. This recommendation is based on the Omicron SARS-CoV-2 variant becoming the dominant variant in the United States.

The use and timing of anti-SARS-CoV-2 antibodies should not be affected by prior exposure to the COVID-19 vaccine.[65314] Similarly, the Centers for Disease Control and Prevention (CDC) state that although some reduction in vaccine-induced antibody titers have been observed in persons who previously received antibody products, the benefits versus risks favor proceeding with vaccination; and thus, COVID-19 vaccination does not need to be delayed following receipt of anti-SARS-CoV-2 antibodies.[66175]

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 emergency use as a treatment for 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, including hospitalization or death. They are also authorized for use as post-exposure prophylaxis of COVID-19 in persons exposed to SARS-CoV-2 who are at high risk for progressing to severe COVID-19 and are not fully vaccinated or are not expected to mount an adequate immune response to the complete COVID-19 vaccination. Under the Emergency Use Authorization (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 handwashing) 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. Antiviral resistance data show that casirivimab and imdevimab are unlikely to retain activity against the Omicron SARS-CoV-2 variant (B.1.1.529/BA.1). Health care providers are advised to consider the prevalence of SARS-CoV-2 variants in their area when considering treatment options. Other anti-SARS-CoV-2 antibodies should be considered. 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 using VSV VLP pseudotyped with spike protein variants identified in circulating SARS-CoV-2, variants with reduced susceptibility to casirivimab alone included those with substitutions E406D (51-fold), V445T (107-fold), E484Q (19-fold), G485D (5-fold), G476S (5-fold), F486L (61-fold), F486S (more than 715-fold), Q493E (446-fold), Q493R (70-fold), and S494P (5-fold). Variants with reduced susceptibility to imdevimab alone included those with substitutions P337L (5-fold), N439K (463-fold), N439V (4-fold), N440K (28-fold), K444L (153-fold), K444M (1,577-fold), G446V (135-fold), N450D (9-fold), Q493R (5-fold), Q498H (17-fold), and P499S (206-fold). The G476D substitution has a 4-fold impact on casirivimab and imdevimab together. 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 (Alpha): All spike protein substitutions found in this variant, including key variant N501Y
• South Africa B1.1.529/BA.1 (Omicron)
• Key substitutions: G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H
• More than 1,013-fold reduced susceptibility; casirivimab and imdevimab are unlikely to be active against this variant
• South Africa B.1.351 variant (Beta): All spike protein substitutions found in this variant, including key variants K417N, E484K, and N501Y
• Brazil P.1 variant (Gamma): All spike protein substitutions found in this variant, including K417T, E484K, N501Y
• California B.1.427/B.1.429 variant (Epsilon): L452R
• New York B.1.526 variant (Iota): E484K
• NOTE: Not all New York B.1.526 isolates harbored the E484K substitution
• India B.1.617.1/B.1.617.3 variant (Kappa/no designation): L452R + E484Q
• India B.1.617.2 variant (Delta): L452R + T478K

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

Casirivimab and imdevimab are administered together via intravenous infusion or subcutaneous injection. 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