ADVERSE REACTIONS SECTION.

6 OVERALL SAFETY SUMMARY. 6.1 Clinical Trials Experience. Overall, approximately 16,000 subjects have been exposed to REGEN-COV (casirivimab and imdevimab) in clinical trials in hospitalized and non-hospitalized subjects. Approximately 13,500 subjects received intravenous infusions and 2,500 subjects received subcutaneous injections.The safety of REGEN-COV (casirivimab and imdevimab) is based on analyses from COV-2067, Phase 1/2/3 trial of ambulatory (non-hospitalized) subjects with COVID-19; COV-2069, Phase post-exposure prophylaxis trial for prevention of COVID-19; and COV-2093, Phase trial evaluating the safety and pharmacokinetics of REGEN-COV repeat subcutaneous dosing every weeks for 24 weeks.. COV-2067This is randomized, double-blind, placebo-controlled clinical trial in subjects with mild to moderate COVID-19 who had sample collected for the first positive SARS-CoV-2 viral infection determination within days prior to the start of the infusion. In the phase portion of the trial, subjects were treated with single intravenous infusion of 600 mg of casirivimab and 600 mg of imdevimab (n=827), or 1,200 mg of casirivimab and 1,200 mg of imdevimab (n=1,849), or 4,000 mg of casirivimab and 4,000 mg of imdevimab (n=1,012), or placebo (n=1,843). REGEN-COV is not authorized at the 4,000 mg of casirivimab and 4,000 mg of imdevimab dose. The 1,200 mg of casirivimab and 1,200 mg of imdevimab is no longer authorized under this EUA [see Clinical Trial Results and Supporting Data for EUA (18)]. In pooled phase 1/2/3 analysis, infusion-related reactions (adverse event assessed as causally related by the investigator) of grade or higher severity have been observed in 10/4,206 (0.2%) of those who received REGEN-COV at the authorized dose or higher dose [see Warnings and Precautions (5.1)]. Overall, in Phase 1/2/3, three subjects receiving the 8,000 mg dose of REGEN-COV, and one subject receiving the 1,200 mg of casirivimab and 1,200 mg of imdevimab infusion-related reactions (urticaria, pruritus, flushing, pyrexia, shortness of breath, chest tightness, nausea, vomiting, rash) which resulted in permanent discontinuation of the infusion. All events resolved [see Warnings and Precautions (5.1) ].Anaphylactic reactions have been reported in the clinical program in subjects receiving REGEN-COV. The events began within hour of completion of the infusion, and in at least one case required treatment including epinephrine. The events resolved. COV-2069This is randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of REGEN-COV (casirivimab and imdevimab) for post-exposure prophylaxis of COVID-19 in household contacts of individuals infected with SARS-CoV-2. Subjects who were SARS-CoV-2 negative at baseline were enrolled in Cohort and received single dose of 600 mg of casirivimab and 600 mg of imdevimab subcutaneously (n=1,311) or placebo (n=1,306).Adverse events were reported in 265 subjects (20%) in the REGEN-COV group and 379 subjects (29%) in the placebo group. Injection site reactions (all grade and 2) occurred in 55 subjects (4%) in the REGEN-COV group and 19 subjects (2%) in the placebo group. The most common signs and symptoms of injection site reactions which occurred in at least 1% of subjects in the REGEN-COV group were erythema and pruritus. Hypersensitivity reactions occurred in subjects (0.2%) in the REGEN-COV group and all hypersensitivity reactions were grade in severity. There were no cases of anaphylaxis.Subjects who were SARS-CoV-2 positive at baseline were enrolled in Cohort and received single dose of 600 mg of casirivimab and 600 mg of imdevimab subcutaneously (n=155) or placebo (n=156).Adverse events were reported in 52 subjects (34%) in the REGEN-COV group and 75 subjects (48%) in the placebo group. Injection site reactions, all of which were grade or 2, occurred in subjects (4%) in the REGEN-COV group and subject (1%) in the placebo group. The most common signs and symptoms of injection site reactions which occurred in at least 1% of subjects in the REGN-COV group were ecchymosis and erythema. There were no cases of hypersensitivity reaction or anaphylaxis.. COV-2093This is randomized double-blind, placebo-controlled Phase trial evaluating the safety, pharmacokinetic and immunogenicity of repeated doses of 600 mg of casirivimab and 600 mg of imdevimab administered subcutaneously in healthy adult subjects. In COV-2093, subjects were randomized 3:1 to REGEN-COV (n=729) or placebo (n=240) administered every weeks for 24 weeks. Adverse events were reported in 380 subjects (52%) in the REGEN-COV group and 111 subjects (46%) in the placebo group. Injection site reactions occurred in 12% and 4% of subjects following single dose administration in the REGEN-COV and placebo groups, respectively; the remaining safety findings following subcutaneous administration in the REGEN-COV group were similar to the safety findings observed with intravenous administration of REGEN-COV in COV-2067.With repeat dosing, injection site reactions occurred in 252 subjects (35%) in the REGEN-COV group and 38 subjects (16%) in the placebo group; all injection site reactions were grade or in severity. Hypersensitivity reactions occurred in subjects (1%) in the REGEN-COV group; and all hypersensitivity reactions were grade or in severity. There were no cases of anaphylaxis. The authorized dosage for repeat dosing for post-exposure prophylaxis of COVID-19 for certain individuals who remain at high risk of exposure for longer than weeks is the initial dose of 600 mg casirivimab and 600 mg imdevimab followed by 300 mg of casirivimab and 300 mg of imdevimab administered every weeks [see Dosage and Administration (2.2)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

17 ANIMAL PHARMACOLOGIC AND EFFICACY DATA. Casirivimab and imdevimab administered together has been assessed in rhesus macaque and Syrian golden hamster treatment models of SARS-CoV-2 infection. Therapeutic administration of casirivimab and imdevimab together at 25 mg/kg or 150 mg/kg into rhesus macaques (n=4 for each dosing group) 1-day post infection resulted in approximately 1-2 log10 reductions in genomic and sub-genomic viral RNA in nasopharyngeal swabs and oral swabs at Day post-challenge in most animals, and reduced lung pathology relative to placebo-treated animals. Therapeutic administration of casirivimab and imdevimab together at mg/kg and 50 mg/kg doses to hamsters 1-day post infection resulted in reduced weight loss relative to placebo treated animals. In the prophylactic setting in rhesus macaques, administration of 50 mg/kg casirivimab and imdevimab together prior to challenge with SARS-CoV-2 demonstrated reduction in viral RNA via nasopharyngeal, oral swabs and bronchioalveolar lavage fluid, as well as reduction in lung inflammation. In the prophylactic setting in hamsters, administration of 0.5 mg/kg, mg/kg, or 50 mg/kg casirivimab and imdevimab together prior to challenge with SARS-CoV-2 protected against weight loss, and reduced percentage of lung area showing pneumonia pathology and severity of lung inflammation, indicative of reduced morbidity in this model. The applicability of these findings to clinical setting is not known.

BOXED WARNING SECTION.

TreatmentThis EUA is for the use of the unapproved product, REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, for the treatment of mild to moderate COVID-19 in adult and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death [see Limitations of Authorized Use (1.1)].. Post-Exposure ProphylaxisThis EUA is for the use of the unapproved product, REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, in adult and pediatric individuals (12 years of age and older weighing at least 40 kg) for post-exposure prophylaxis of COVID-19 in individuals who are at high risk for progression to severe COVID-19, including hospitalization or death, and are:not fully vaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications) and -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Center for Disease Control and Prevention (CDC) or -who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)].. not fully vaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications) and -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Center for Disease Control and Prevention (CDC) or -who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)].. -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Center for Disease Control and Prevention (CDC) or -who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)].. Criteria for Identifying High Risk IndividualsThe following medical conditions or other factors may place adults and pediatric patients (age 12-17 years and weighing at least 40 kg) at higher risk for progression to severe COVID-19:Older age (for example, age >=65 years of age)Obesity or being overweight (for example, BMI >25 kg/m2, or if age 12-17, have BMI >=85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinicalcharts.htm)PregnancyChronic kidney diseaseDiabetesImmunosuppressive disease or immunosuppressive treatmentCardiovascular disease (including congenital heart disease) or hypertensionChronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension)Sickle cell diseaseNeurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies)Having medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19))Other medical conditions or factors (for example, race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and authorization of REGEN-COV under the EUA is not limited to the medical conditions or factors listed above. For additional information on medical conditions and factors associated with increased risk for progression to severe COVID, see the CDC website: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Healthcare providers should consider the benefit-risk for an individual patient.. Older age (for example, age >=65 years of age). Obesity or being overweight (for example, BMI >25 kg/m2, or if age 12-17, have BMI >=85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinicalcharts.htm). Pregnancy. Chronic kidney disease. Diabetes. Immunosuppressive disease or immunosuppressive treatment. Cardiovascular disease (including congenital heart disease) or hypertension. Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension). Sickle cell disease. Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies). Having medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19)). Available Dosage Forms of REGEN-COV:REGEN-COV (casirivimab and imdevimab) is available as:1.A single vial which contains two antibodies co-formulated in 1:1 ratio of casirivimab and imdevimab or2.Individual antibody solutions in separate vials, which may be supplied in separate cartons or together in single carton (also referred to as co-packaged carton), or in dose pack.. 1.A single vial which contains two antibodies co-formulated in 1:1 ratio of casirivimab and imdevimab or. 2.Individual antibody solutions in separate vials, which may be supplied in separate cartons or together in single carton (also referred to as co-packaged carton), or in dose pack.. Routes of Administration for REGEN-COV:REGEN-COV may be administered by intravenous infusion or subcutaneous injection.FOR TREATMENT, INTRAVENOUS INFUSION IS STRONGLY RECOMMENDED. SUBCUTANEOUS INJECTION IS AN ALTERNATIVE ROUTE OF ADMINISTRATION WHEN INTRAVENOUS INFUSION IS NOT FEASIBLE AND WOULD LEAD TO DELAY IN TREATMENT.FOR POST-EXPOSURE PROPHYLAXIS, EITHER SUBCUTANEOUS INJECTION OR INTRAVENOUS INFUSION CAN BE USED.. Treatment DosageThe authorized dosage is 600 mg of casirivimab and 600 mg of imdevimab administered together as single intravenous infusion or by subcutaneous injection as soon as possible after positive SARS-CoV-2 viral testing and within 10 days of symptom onset [see Dosage and Administration (2.2) and Clinical Trial Results and Supporting Data for EUA (18.1)].The authorized dosage of 600 mg of casirivimab and 600 mg of imdevimab for subcutaneous administration for treatment is selected based on the totality of the scientific evidence, incorporating clinical data, viral load reduction data (pharmacodynamics) and pharmacokinetic data [see Clinical Pharmacology (14.2) and (14.3)]. The authorized dosage is 600 mg of casirivimab and 600 mg of imdevimab administered together as single intravenous infusion or by subcutaneous injection as soon as possible after positive SARS-CoV-2 viral testing and within 10 days of symptom onset [see Dosage and Administration (2.2) and Clinical Trial Results and Supporting Data for EUA (18.1)].. The authorized dosage of 600 mg of casirivimab and 600 mg of imdevimab for subcutaneous administration for treatment is selected based on the totality of the scientific evidence, incorporating clinical data, viral load reduction data (pharmacodynamics) and pharmacokinetic data [see Clinical Pharmacology (14.2) and (14.3)]. Post-exposure Prophylaxis Dosage The authorized dosage is 600 mg of casirivimab and 600 mg of imdevimab administered by subcutaneous injection or together as single intravenous infusion as soon as possible following exposure to SARS-CoV-2. For individuals in whom repeat dosing is determined to be appropriate for ongoing exposure to SARS-CoV-2 for longer than weeks and who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination, the initial dose is 600 mg of casirivimab and 600 mg of imdevimab by subcutaneous injection or intravenous infusion followed by subsequent repeat dosing of 300 mg of casirivimab and 300 mg of imdevimab by subcutaneous injection or intravenous infusion once every weeks for the duration of ongoing exposure. The authorized dosage including dosage for repeat dosing is based on the totality of the scientific evidence including clinical pharmacology data and clinical trial data [see Clinical Trial Results and Supporting Data for EUA (18.2) and Clinical Pharmacology (14.3)]. The authorized dosage is 600 mg of casirivimab and 600 mg of imdevimab administered by subcutaneous injection or together as single intravenous infusion as soon as possible following exposure to SARS-CoV-2.. For individuals in whom repeat dosing is determined to be appropriate for ongoing exposure to SARS-CoV-2 for longer than weeks and who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination, the initial dose is 600 mg of casirivimab and 600 mg of imdevimab by subcutaneous injection or intravenous infusion followed by subsequent repeat dosing of 300 mg of casirivimab and 300 mg of imdevimab by subcutaneous injection or intravenous infusion once every weeks for the duration of ongoing exposure.. The authorized dosage including dosage for repeat dosing is based on the totality of the scientific evidence including clinical pharmacology data and clinical trial data [see Clinical Trial Results and Supporting Data for EUA (18.2) and Clinical Pharmacology (14.3)]. For Intravenous Infusion:Co-formulated casirivimab and imdevimab solution in vial and casirivimab and imdevimab solutions in individual vials must be diluted prior to intravenous administration.Administer casirivimab and imdevimab together as single intravenous infusion via pump or gravity (see Table 1, Table 2, Table and Table 4).Clinically monitor patients during infusion and observe patients for at least hour after infusion is complete.. Co-formulated casirivimab and imdevimab solution in vial and casirivimab and imdevimab solutions in individual vials must be diluted prior to intravenous administration.. Administer casirivimab and imdevimab together as single intravenous infusion via pump or gravity (see Table 1, Table 2, Table and Table 4).. Clinically monitor patients during infusion and observe patients for at least hour after infusion is complete.. For Subcutaneous Injection:Administer casirivimab and imdevimab using the co-formulated solution in vial or using the individual vials (see Table and Table 6).Clinically monitor patients after injections and observe patients for at least hour after injections. For treatment, subcutaneous injection is an alternative route of administration when intravenous administration is not feasible and would lead to delay in treatment. For post-exposure prophylaxis, either subcutaneous injection or intravenous infusion can be administered.REGEN-COV may only be administered in settings in which health care providers have immediate access to medications to treat severe infusion or hypersensitivity reactions, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary.Health care providers must submit report on ALL MEDICATION ERRORS and ALL SERIOUS ADVERSE EVENTS potentially related to REGEN-COV. See Sections and of the Full EUA Prescribing Information for reporting instructions below.Patients treated with REGEN-COV should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal texts, clean and disinfect high touch surfaces, and frequent handwashing) according to CDC guidelines.The authorized dosage may be updated as additional data from clinical trials becomes available.For information on clinical trials that are testing the use of REGEN-COV in COVID-19, please see www.clinicaltrials.gov.. Administer casirivimab and imdevimab using the co-formulated solution in vial or using the individual vials (see Table and Table 6).. Clinically monitor patients after injections and observe patients for at least hour after injections. For treatment, subcutaneous injection is an alternative route of administration when intravenous administration is not feasible and would lead to delay in treatment. For post-exposure prophylaxis, either subcutaneous injection or intravenous infusion can be administered.. Patients treated with REGEN-COV should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal texts, clean and disinfect high touch surfaces, and frequent handwashing) according to CDC guidelines.

CLINICAL PHARMACOLOGY SECTION.

14 CLINICAL PHARMACOLOGY. 14.1 Mechanism of Action. Casirivimab (IgG1) and imdevimab (IgG1) are two recombinant human mAbs which are unmodified in the Fc regions. Casirivimab and imdevimab bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2 with dissociation constants KD 45.8 pM and 46.7 pM, respectively. Casirivimab, imdevimab and casirivimab and imdevimab together blocked RBD binding to the human ACE2 receptor with IC50 values of 56.4 pM, 165 pM and 81.8 pM, respectively and prevents viral attachment to host cells [see Microbiology/Resistance Information (15) ].. 14.2 Pharmacodynamics. Trial COV-2067 evaluated REGEN-COV (casirivimab and imdevimab) with doses of up to 6.66 times the recommended dose (600 mg of casirivimab and 600 mg of imdevimab; 1,200 mg of casirivimab and 1,200 mg of imdevimab; 4,000 mg of casirivimab and 4,000 mg of imdevimab) in ambulatory patients with COVID-19. flat dose-response relationship for efficacy was identified for REGEN-COV at all doses, based on viral load and clinical outcomes. Similar reductions in viral load (log10 copies/mL) were observed in subjects for the (600 mg of casirivimab and 600 mg of imdevimab) intravenous and (600 mg of casirivimab and 600 mg of imdevimab) subcutaneous doses; however, only limited clinical outcome data are available for the subcutaneous route of administration for the treatment of symptomatic patients. 14.3 Pharmacokinetics. Both casirivimab and imdevimab exhibited linear and dose-proportional pharmacokinetics (PK) between (600 mg of casirivimab and 600 mg of imdevimab) to (4,000 mg of casirivimab and 4,000 mg of imdevimab) doses of REGEN-COV (casirivimab and imdevimab) following intravenous administration of single dose. summary of PK parameters after single (600 mg of casirivimab and 600 mg of imdevimab) intravenous dose, for each antibody is provided in Table 7.Table 7: Summary of PK Parameters for Casirivimab and Imdevimab After Single 600 mg of Casirivimab and 600 mg of Imdevimab Intravenous Dose of REGEN-COV in Study COV-2067PK ParameterMean (SD) CasirivimabImdevimabCeoi (mg/L)concentration at end of 1-hour infusion 192 (80.9)198 (84.8)C28 (mg/L)observed concentration 28 days after dosing, i.e., on day 29, as defined in the protocol 46.2 (22.3)38.5 (19.7)A summary of PK parameters after single 600 mg of casirivimab and 600 mg of imdevimab subcutaneous dose is shown in Table 8.Table 8: Summary of PK Parameters for Casirivimab and Imdevimab After Single 600 mg of Casirivimab and 600 mg of Imdevimab Subcutaneous Dose of REGEN-COV PK ParameterMean (SD) Mean (SD) concentration at 24 hours (C24) of casirivimab and imdevimab in serum with 1200 SC dosing, 22.5 (11.0) mg/L and 25.0 (16.4) mg/L, respectively CasirivimabImdevimabCmax (mg/L)55.6 (22.2)52.7 (22.5)tmax (day)Median (range) 8.00 (4.00, 87.0)7.00 (4.00, 15.0)AUC0-28 (mgday/L)1060 (363)950 (362)AUCinf (mgday/L)Value reported for subjects with %AUCinf extrapolated <20% 2580 (1349)1990 (1141)C28 (mg/L)Observed concentration 28 days after dosing, i.e., on day 29 30.7 (11.9)24.8 (9.58)Half-life (day)31.8 (8.35)26.9 (6.80)For the repeat dose prophylaxis intravenous and subcutaneous regimens, population pharmacokinetic simulations predicted that trough concentrations in serum at steady-state after an initial 600 mg casirivimab and 600 mg imdevimab intravenous or subcutaneous dose followed by monthly (every weeks) 300 mg casirivimab and 300 mg imdevimab intravenous or subcutaneous doses are similar to slightly higher than observed mean day 29 concentrations in serum for single 600 mg casirivimab and 600 mg imdevimab subcutaneous dose.. Specific PopulationsThe effect of different covariates (e.g., age, sex, race, body weight, disease severity, hepatic impairment) on the PK of casirivimab and imdevimab is unknown. Renal impairment is not expected to impact the PK of casirivimab and imdevimab, since mAbs with molecular weight >69 kDa are known not to undergo renal elimination. Similarly, dialysis is not expected to impact the PK of casirivimab and imdevimab.. Drug-Drug InteractionsCasirivimab and imdevimab are mAbs which are not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely [see Drug Interactions (10)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Overall, approximately 16,000 subjects have been exposed to REGEN-COV (casirivimab and imdevimab) in clinical trials in hospitalized and non-hospitalized subjects. Approximately 13,500 subjects received intravenous infusions and 2,500 subjects received subcutaneous injections.The safety of REGEN-COV (casirivimab and imdevimab) is based on analyses from COV-2067, Phase 1/2/3 trial of ambulatory (non-hospitalized) subjects with COVID-19; COV-2069, Phase post-exposure prophylaxis trial for prevention of COVID-19; and COV-2093, Phase trial evaluating the safety and pharmacokinetics of REGEN-COV repeat subcutaneous dosing every weeks for 24 weeks.. COV-2067This is randomized, double-blind, placebo-controlled clinical trial in subjects with mild to moderate COVID-19 who had sample collected for the first positive SARS-CoV-2 viral infection determination within days prior to the start of the infusion. In the phase portion of the trial, subjects were treated with single intravenous infusion of 600 mg of casirivimab and 600 mg of imdevimab (n=827), or 1,200 mg of casirivimab and 1,200 mg of imdevimab (n=1,849), or 4,000 mg of casirivimab and 4,000 mg of imdevimab (n=1,012), or placebo (n=1,843). REGEN-COV is not authorized at the 4,000 mg of casirivimab and 4,000 mg of imdevimab dose. The 1,200 mg of casirivimab and 1,200 mg of imdevimab is no longer authorized under this EUA [see Clinical Trial Results and Supporting Data for EUA (18)]. In pooled phase 1/2/3 analysis, infusion-related reactions (adverse event assessed as causally related by the investigator) of grade or higher severity have been observed in 10/4,206 (0.2%) of those who received REGEN-COV at the authorized dose or higher dose [see Warnings and Precautions (5.1)]. Overall, in Phase 1/2/3, three subjects receiving the 8,000 mg dose of REGEN-COV, and one subject receiving the 1,200 mg of casirivimab and 1,200 mg of imdevimab infusion-related reactions (urticaria, pruritus, flushing, pyrexia, shortness of breath, chest tightness, nausea, vomiting, rash) which resulted in permanent discontinuation of the infusion. All events resolved [see Warnings and Precautions (5.1) ].Anaphylactic reactions have been reported in the clinical program in subjects receiving REGEN-COV. The events began within hour of completion of the infusion, and in at least one case required treatment including epinephrine. The events resolved. COV-2069This is randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of REGEN-COV (casirivimab and imdevimab) for post-exposure prophylaxis of COVID-19 in household contacts of individuals infected with SARS-CoV-2. Subjects who were SARS-CoV-2 negative at baseline were enrolled in Cohort and received single dose of 600 mg of casirivimab and 600 mg of imdevimab subcutaneously (n=1,311) or placebo (n=1,306).Adverse events were reported in 265 subjects (20%) in the REGEN-COV group and 379 subjects (29%) in the placebo group. Injection site reactions (all grade and 2) occurred in 55 subjects (4%) in the REGEN-COV group and 19 subjects (2%) in the placebo group. The most common signs and symptoms of injection site reactions which occurred in at least 1% of subjects in the REGEN-COV group were erythema and pruritus. Hypersensitivity reactions occurred in subjects (0.2%) in the REGEN-COV group and all hypersensitivity reactions were grade in severity. There were no cases of anaphylaxis.Subjects who were SARS-CoV-2 positive at baseline were enrolled in Cohort and received single dose of 600 mg of casirivimab and 600 mg of imdevimab subcutaneously (n=155) or placebo (n=156).Adverse events were reported in 52 subjects (34%) in the REGEN-COV group and 75 subjects (48%) in the placebo group. Injection site reactions, all of which were grade or 2, occurred in subjects (4%) in the REGEN-COV group and subject (1%) in the placebo group. The most common signs and symptoms of injection site reactions which occurred in at least 1% of subjects in the REGN-COV group were ecchymosis and erythema. There were no cases of hypersensitivity reaction or anaphylaxis.. COV-2093This is randomized double-blind, placebo-controlled Phase trial evaluating the safety, pharmacokinetic and immunogenicity of repeated doses of 600 mg of casirivimab and 600 mg of imdevimab administered subcutaneously in healthy adult subjects. In COV-2093, subjects were randomized 3:1 to REGEN-COV (n=729) or placebo (n=240) administered every weeks for 24 weeks. Adverse events were reported in 380 subjects (52%) in the REGEN-COV group and 111 subjects (46%) in the placebo group. Injection site reactions occurred in 12% and 4% of subjects following single dose administration in the REGEN-COV and placebo groups, respectively; the remaining safety findings following subcutaneous administration in the REGEN-COV group were similar to the safety findings observed with intravenous administration of REGEN-COV in COV-2067.With repeat dosing, injection site reactions occurred in 252 subjects (35%) in the REGEN-COV group and 38 subjects (16%) in the placebo group; all injection site reactions were grade or in severity. Hypersensitivity reactions occurred in subjects (1%) in the REGEN-COV group; and all hypersensitivity reactions were grade or in severity. There were no cases of anaphylaxis. The authorized dosage for repeat dosing for post-exposure prophylaxis of COVID-19 for certain individuals who remain at high risk of exposure for longer than weeks is the initial dose of 600 mg casirivimab and 600 mg imdevimab followed by 300 mg of casirivimab and 300 mg of imdevimab administered every weeks [see Dosage and Administration (2.2)].

CONTRAINDICATIONS SECTION.

Contraindications. REGEN-COV is contraindicated in individuals with previous severe hypersensitivity reactions, including anaphylaxis, to REGEN-COV [see Warnings and Precautions (5.1)].

DESCRIPTION SECTION.

13 PRODUCT DESCRIPTION. Casirivimab, human immunoglobulin G-1 (IgG1) monoclonal antibody (mAb), is covalent heterotetramer consisting of heavy chains and light chains produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture and has an approximate molecular weight of 145.23 kDa.Casirivimab injection is sterile, preservative-free, clear to slightly opalescent and colorless to pale yellow solution in vial for subcutaneous use or intravenous infusion after dilution available as 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) solution and must be administered with imdevimab. The vial stoppers are not made with natural rubber latex.Casirivimab: Each 2.5 mL of solution contains 300 mg of casirivimab, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and Water for Injection, USP. The pH is 6.0.Casirivimab: Each 11.1 mL of solution contains 1,332 mg of casirivimab, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose (888 mg), and Water for Injection, USP. The pH is 6.0.Imdevimab, human IgG1 mAb, is covalent heterotetramer consisting of heavy chains and light chains produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture and has an approximate molecular weight of 144.14 kDa.Imdevimab injection is sterile, preservative-free, clear to slightly opalescent and colorless to pale yellow solution in vial for subcutaneous use or intravenous infusion after dilution available as 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) solution and must be administered with casirivimab. The vial stoppers are not made with natural rubber latex.Imdevimab: Each 2.5 mL of solution contains 300 mg of imdevimab, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and Water for Injection, USP. The pH is 6.0.Imdevimab: Each 11.1 mL of solution contains 1,332 mg of imdevimab, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose (888 mg), and Water for Injection, USP. The pH is 6.0.REGEN-COV (casirivimab and imdevimab solution) injection is sterile, preservative-free, clear to slightly opalescent, and colorless to pale yellow 10 mL solution in vial for intravenous infusion after dilution. The vial stoppers are not made with natural rubber latex.Each 10 mL of solution contains 600 mg of casirivimab, 600 mg of imdevimab, L-histidine (7.4 mg), L-histidine monohydrochloride monohydrate (10.9 mg), polysorbate 80 (10.0 mg), sucrose (800 mg), and Water for Injection, USP. The pH is 6.0.. Casirivimab: Each 2.5 mL of solution contains 300 mg of casirivimab, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and Water for Injection, USP. The pH is 6.0.. Casirivimab: Each 11.1 mL of solution contains 1,332 mg of casirivimab, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose (888 mg), and Water for Injection, USP. The pH is 6.0.. Imdevimab: Each 2.5 mL of solution contains 300 mg of imdevimab, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and Water for Injection, USP. The pH is 6.0.. Imdevimab: Each 11.1 mL of solution contains 1,332 mg of imdevimab, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose (888 mg), and Water for Injection, USP. The pH is 6.0.. Each 10 mL of solution contains 600 mg of casirivimab, 600 mg of imdevimab, L-histidine (7.4 mg), L-histidine monohydrochloride monohydrate (10.9 mg), polysorbate 80 (10.0 mg), sucrose (800 mg), and Water for Injection, USP. The pH is 6.0.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 2.1 Patient Selection. The optimal dosing regimen for treatment of COVID-19 has not yet been established.The recommended dosing regimen may be updated as data from clinical trials become available.. Patient Selection for Treatment and Post-Exposure Prophylaxis. Treatment:This section provides essential information on the unapproved product, REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, for the treatment of adult and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death [see Limitations of Authorized Use (1.1)].. Post-Exposure Prophylaxis:This section provides essential information on the unapproved product, REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied in individual vials to be administered together, in adult and pediatric individuals (12 years of age and older weighing at least 40 kg) for the post-exposure prophylaxis of COVID-19 in individuals who are at high risk for progression to severe COVID-19, including hospitalization or death, and are:not fully vaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications) and -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC) or-who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)]. The following medical conditions or other factors may place adults and pediatric patients (age 12-17 years and weighing at least 40 kg) at higher risk for progression to severe COVID-19:Older age (for example, age >=65 years of age)Obesity or being overweight (for example, BMI >25 kg/m2, or if age 12-17, have BMI >=85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinicalcharts.htm)PregnancyChronic kidney diseaseDiabetesImmunosuppressive disease or immunosuppressive treatmentCardiovascular disease (including congenital heart disease) or hypertensionChronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension)Sickle cell diseaseNeurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies)Having medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19))Other medical conditions or factors (for example, race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and authorization of REGEN-COV under the EUA is not limited to the medical conditions or factors listed above.For additional information on medical conditions and factors associated with increased risk for progression to severe COVID-19, see the CDC website: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Healthcare providers should consider the benefit-risk for an individual patient.. not fully vaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications) and -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC) or-who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)]. -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC) or. -who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)].. Older age (for example, age >=65 years of age). Obesity or being overweight (for example, BMI >25 kg/m2, or if age 12-17, have BMI >=85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinicalcharts.htm). Pregnancy. Chronic kidney disease. Diabetes. Immunosuppressive disease or immunosuppressive treatment. Cardiovascular disease (including congenital heart disease) or hypertension. Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension). Sickle cell disease. Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies). Having medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19)). 2.2 Dosage. Treatment:The dosage in adult and pediatric patients (12 years of age and older weighing at least 40 kg) is 600 mg of casirivimab and 600 mg of imdevimab administered together as single intravenous infusion or by subcutaneous injection. Casirivimab and imdevimab should be given together as soon as possible after positive viral test for SARS-CoV-2 and within 10 days of symptom onset.. Post-Exposure Prophylaxis:The dosage in adult and pediatric individuals (12 years of age and older weighing at least 40 kg) is 600 mg of casirivimab and 600 mg of imdevimab administered by subcutaneous injection or together as single intravenous infusion. Casirivimab and imdevimab should be given together as soon as possible following exposure to SARS-CoV-2.For individuals whom repeat dosing is determined to be appropriate for ongoing exposure to SARS-CoV-2 for longer than weeks and who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination, the initial dose is 600 mg of casirivimab and 600 mg of imdevimab by subcutaneous injection or intravenous infusion followed by subsequent repeat dosing of 300 mg of casirivimab and 300 mg of imdevimab by subcutaneous injection or intravenous infusion once every weeks for the duration of ongoing exposure.. For Intravenous Infusion:Casirivimab and imdevimab solution co-formulated in vial and in individual vials, including co-packaged carton and dose pack, must be diluted prior to intravenous administration.Administer casirivimab and imdevimab together as single intravenous infusion via pump or gravity (see Table 1, Table 2, Table and Table 4).Clinically monitor patients during infusion and observe patients for at least hour after infusion is complete.. Casirivimab and imdevimab solution co-formulated in vial and in individual vials, including co-packaged carton and dose pack, must be diluted prior to intravenous administration.. Administer casirivimab and imdevimab together as single intravenous infusion via pump or gravity (see Table 1, Table 2, Table and Table 4).. Clinically monitor patients during infusion and observe patients for at least hour after infusion is complete.. For Subcutaneous Injection:Administer casirivimab and imdevimab using the co-formulated vial or using the individual vials by subcutaneous injection (see Table and Table 6).Clinically monitor patients after injections and observe patients for at least 1hour.. Administer casirivimab and imdevimab using the co-formulated vial or using the individual vials by subcutaneous injection (see Table and Table 6).. Clinically monitor patients after injections and observe patients for at least 1hour.. 2.3 Dose Adjustment in Specific Populations. Pregnancy or LactationNo dosage adjustment is recommended in pregnant or lactating women [see Use in Specific Populations (11.1, 11.2)].. Pediatric UseNo dosage adjustment is recommended in pediatric patients who weigh at least 40 kg and are older than 12 years of age. REGEN-COV (casirivimab and imdevimab) is not recommended for pediatric patients weighing less than 40 kg or those less than 12 years of age [see Use in Specific Populations (11.3)].. Renal ImpairmentNo dosage adjustment is recommended in patients with renal impairment [see Use in Specific Populations (11.5)]. 2.4 Dose Preparation and Administration. There are TWO different formulations of REGEN-COV:Casirivimab and imdevimab co-formulated solution containing two antibodies in 1:1 ratio in vial.Casirivimab and imdevimab available as individual antibody solutions in separate vials supplied as follows:Individual vials in individual cartons, ortogether in single carton (also referred to as co-packaged carton), orin dose pack. The dose pack contains individual vials of casirivimab and imdevimab, configurations that may vary in vial size, strength and appearance and are available in dose pack configurations that include 2, 5, and cartons [see Full EUA Prescribing Information, How Supplied/Storage and Handling (19)]. For treatment, intravenous infusion is strongly recommended. Subcutaneous injection is an alternative route of administration when intravenous infusion is not feasible and would lead to delay in treatment. For post-exposure prophylaxis, either subcutaneous injection or intravenous infusion can be used.There are differences in the way the two formulations are prepared. Carefully follow the preparation procedures below.Casirivimab and imdevimab co-formulated solution in vial and casirivimab or imdevimab as individual antibody solutions in separate 11.1 mL vials may be used to prepare more than one dose simultaneously as appropriate, either in intravenous bags or in syringes for subcutaneous injection. Discard any product remaining in the vial.Store unopened casirivimab and imdevimab vials in refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light. Unopened vials may be stored in the original carton at room temperature [up to 25C (77F)] and must be used within 30 days. If not used in the 30 days, discard vials.Under the EUA, single-dose vial may be used to prepare more than one dose.. Casirivimab and imdevimab co-formulated solution containing two antibodies in 1:1 ratio in vial.. Casirivimab and imdevimab available as individual antibody solutions in separate vials supplied as follows:Individual vials in individual cartons, ortogether in single carton (also referred to as co-packaged carton), orin dose pack. The dose pack contains individual vials of casirivimab and imdevimab, configurations that may vary in vial size, strength and appearance and are available in dose pack configurations that include 2, 5, and cartons [see Full EUA Prescribing Information, How Supplied/Storage and Handling (19)]. Individual vials in individual cartons, or. together in single carton (also referred to as co-packaged carton), or. in dose pack. The dose pack contains individual vials of casirivimab and imdevimab, configurations that may vary in vial size, strength and appearance and are available in dose pack configurations that include 2, 5, and cartons [see Full EUA Prescribing Information, How Supplied/Storage and Handling (19)]. Casirivimab and imdevimab co-formulated solution in vial and casirivimab or imdevimab as individual antibody solutions in separate 11.1 mL vials may be used to prepare more than one dose simultaneously as appropriate, either in intravenous bags or in syringes for subcutaneous injection. Discard any product remaining in the vial.. Store unopened casirivimab and imdevimab vials in refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light. Unopened vials may be stored in the original carton at room temperature [up to 25C (77F)] and must be used within 30 days. If not used in the 30 days, discard vials.. Preparation for Intravenous InfusionFor treatment, the preferred route of administration for casirivimab and imdevimab is by intravenous infusion after dilution.Casirivimab and imdevimab solution for intravenous infusion should be prepared by qualified healthcare professional using aseptic technique:Remove the casirivimab and imdevimab vials from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes before preparation. Do not expose to direct heat. Do not shake the vials.Inspect casirivimab and imdevimab vials visually for particulate matter and discoloration prior to administration. Should either be observed, the vial must be discarded and replaced with new vial.The solution for each vial should be clear to slightly opalescent, colorless to pale yellow. Obtain prefilled intravenous infusion bag containing either 50 mL, 100 mL, 150 mL, or 250 mL of either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.Withdraw the appropriate amount of casirivimab and imdevimab from each respective vial(s) and inject into prefilled infusion bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, (see Table and Table 2). If using one vial to prepare more than one infusion bag, then prepare all infusion bags at the same time. The product is preservative-free, therefore do not store unused solution in vial(s).Gently invert infusion bag by hand approximately 10 times to mix. Do not shake.This product is preservative-free and therefore, the diluted infusion solution should be administered immediately (see Table and Table 4).If immediate administration is not possible, store the diluted casirivimab and imdevimab infusion solution in the refrigerator between 2C to 8C (36F to 46F) for no more than 36 hours or at room temperature up to 25C (77F) for no more than hours. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration. Table 1: Recommended Dilution Instructions for 600 mg of Casirivimab and 600 mg of Imdevimab for Intravenous InfusionSize of Prefilled 0.9% Sodium Chloride or 5% Dextrose Infusion BagPreparing Using Co-Formulated Casirivimab and Imdevimab VialPreparing Casirivimab and Imdevimab Using Individual Vials600 mg of casirivimab and 600 mg of imdevimab are added to the same infusion bag and administered together as single intravenous infusion. 50 mLAdd 10 mL of co-formulated casirivimab and imdevimab (1 vial) into prefilled 0.9% Sodium Chloride or 5% Dextrose infusion bag and administer as instructed belowAdd:5 mL of casirivimab (may use vials of 2.5 mL OR vial of 11.1 mL) and5 mL of imdevimab (may use vials of 2.5 mL OR vial of 11.1 mL)and inject into prefilled 0.9% Sodium Chloride or 5% Dextrose infusion bag and administer as instructed below100 mL150 mL250 mLTable 2: Recommended Dilution Instructions for 300 mg of Casirivimab and 300 mg of Imdevimab for Intravenous Infusion for Repeat DosingSubsequent repeat dosing every weeks after initial 600 mg casirivimab and 600 mg imdevimab dosing for the duration of ongoing exposure. Size of Prefilled 0.9% Sodium Chloride or 5% Dextrose Infusion BagPreparing Using Co-Formulated Casirivimab and Imdevimab VialPreparing Casirivimab and Imdevimab Using Individual Vials300 mg of casirivimab and 300 mg of imdevimab are added to the same infusion bag and administered together as single intravenous infusion. 50 mLAdd mL of co-formulated casirivimab and imdevimab into prefilled 0.9% Sodium Chloride or 5% Dextrose infusion bag and administer as instructed belowAdd: 2.5 mL of casirivimab (may use vial of 2.5 mL OR vial of 11.1 mL) and2.5 mL of imdevimab (may use vial of 2.5 mL OR vial of 11.1 mL)and inject into prefilled 0.9% Sodium Chloride or 5% Dextrose infusion bag and administer as instructed below 100 mL150 mL250 mL. Remove the casirivimab and imdevimab vials from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes before preparation. Do not expose to direct heat. Do not shake the vials.. Inspect casirivimab and imdevimab vials visually for particulate matter and discoloration prior to administration. Should either be observed, the vial must be discarded and replaced with new vial.The solution for each vial should be clear to slightly opalescent, colorless to pale yellow. The solution for each vial should be clear to slightly opalescent, colorless to pale yellow.. Obtain prefilled intravenous infusion bag containing either 50 mL, 100 mL, 150 mL, or 250 mL of either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.. Withdraw the appropriate amount of casirivimab and imdevimab from each respective vial(s) and inject into prefilled infusion bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, (see Table and Table 2). If using one vial to prepare more than one infusion bag, then prepare all infusion bags at the same time. The product is preservative-free, therefore do not store unused solution in vial(s).. Gently invert infusion bag by hand approximately 10 times to mix. Do not shake.. This product is preservative-free and therefore, the diluted infusion solution should be administered immediately (see Table and Table 4).If immediate administration is not possible, store the diluted casirivimab and imdevimab infusion solution in the refrigerator between 2C to 8C (36F to 46F) for no more than 36 hours or at room temperature up to 25C (77F) for no more than hours. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration. If immediate administration is not possible, store the diluted casirivimab and imdevimab infusion solution in the refrigerator between 2C to 8C (36F to 46F) for no more than 36 hours or at room temperature up to 25C (77F) for no more than hours. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.. mL of casirivimab (may use vials of 2.5 mL OR vial of 11.1 mL) and. mL of imdevimab (may use vials of 2.5 mL OR vial of 11.1 mL). 2.5 mL of casirivimab (may use vial of 2.5 mL OR vial of 11.1 mL) and. 2.5 mL of imdevimab (may use vial of 2.5 mL OR vial of 11.1 mL). Administration by Intravenous InfusionCasirivimab and imdevimab infusion solution should be administered by qualified healthcare professional using aseptic technique.Gather the recommended materials for infusion:Polyvinyl chloride (PVC), polyethylene (PE)-lined PVC, or polyurethane (PU) infusion setIn-line or add-on 0.2 micron polyethersulfone (PES) filter Attach the infusion set to the intravenous bag.Prime the infusion set.Administer the entire infusion solution in the bag via pump or gravity through an intravenous line containing sterile, in-line or add-on 0.2-micron polyethersulfone (PES) filter (see Table and Table 4). Due to potential overfill of prefilled saline bags, the entire infusion solution in the bag should be administered to avoid underdosage.The prepared infusion solution should not be administered simultaneously with any other medication. The compatibility of casirivimab and imdevimab injection with intravenous solutions and medications other than 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is not known.After infusion is complete, flush the tubing with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to ensure delivery of the required dose.Discard unused product.Clinically monitor patients during administration and observe patients for at least hour after infusion is complete.Table 3: Recommended Administration Rate for 600 mg of Casirivimab and 600 mg of Imdevimab for Intravenous InfusionSize of Prefilled 0.9% Sodium Chloride or 5% Dextrose Infusion Bag usedMaximum Infusion RateMinimum Infusion Time50 mLThe minimum infusion time for patients administered casirivimab and imdevimab together using the 50 mL prefilled 0.9% Sodium Chloride or 5% Dextrose infusion bag must be at least 20 minutes to ensure safe use. 180 mL/hr20 minutes100 mL310 mL/hr21 minutes150 mL310 mL/hr31 minutes250 mL310 mL/hr50 minutesTable 4: Recommended Administration Rate for 300 mg of Casirivimab and 300 mg of Imdevimab for Intravenous Infusion for Repeat DosingSubsequent repeat dosing every weeks after initial 600 mg casirivimab and 600 mg imdevimab dosing for the duration of ongoing exposure. Size of Prefilled 0.9% Sodium Chloride or 5% Dextrose Infusion Bag usedMaximum Infusion RateMinimum Infusion Time50 mLThe minimum infusion time for patients administered casirivimab and imdevimab together using the 50 mL prefilled 0.9% Sodium Chloride or 5% Dextrose infusion bag must be at least 20 minutes to ensure safe use. 165 mL/hr20 minutes100 mL310 mL/hr20 minutes150 mL310 mL/hr30 minutes250 mL310 mL/hr49 minutes. Gather the recommended materials for infusion:Polyvinyl chloride (PVC), polyethylene (PE)-lined PVC, or polyurethane (PU) infusion setIn-line or add-on 0.2 micron polyethersulfone (PES) filter Polyvinyl chloride (PVC), polyethylene (PE)-lined PVC, or polyurethane (PU) infusion set. In-line or add-on 0.2 micron polyethersulfone (PES) filter. Attach the infusion set to the intravenous bag.. Prime the infusion set.. Administer the entire infusion solution in the bag via pump or gravity through an intravenous line containing sterile, in-line or add-on 0.2-micron polyethersulfone (PES) filter (see Table and Table 4). Due to potential overfill of prefilled saline bags, the entire infusion solution in the bag should be administered to avoid underdosage.. The prepared infusion solution should not be administered simultaneously with any other medication. The compatibility of casirivimab and imdevimab injection with intravenous solutions and medications other than 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is not known.. After infusion is complete, flush the tubing with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to ensure delivery of the required dose.. Discard unused product.. Clinically monitor patients during administration and observe patients for at least hour after infusion is complete.. Preparation for Subcutaneous Injection Remove the casirivimab and imdevimab vial(s) from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes before preparation. Do not expose to direct heat. Do not shake the vials. Inspect casirivimab and imdevimab vial(s) visually for particulate matter and discoloration prior to administration. Should either be observed, the vial must be discarded and replaced with new vial. The solution for each vial should be clear to slightly opalescent, colorless to pale yellow.Casirivimab and imdevimab should be prepared using the appropriate number of syringes (see Table and Table 6). Obtain mL or mL polypropylene Luer Lock syringes with luer connection and 21-gauge 1/2 inch transfer needles.Withdraw the appropriate amount of solution into each syringe (see Table and Table 6). Prepare all syringes at the same time.Replace the 21-gauge transfer needle with 25-gauge or 27-gauge needle for subcutaneous injection.This product is preservative-free and therefore, the prepared syringes should be administered immediately. If immediate administration is not possible, store the prepared casirivimab and imdevimab syringes in the refrigerator between 2oC to 8oC (36oF to 46oF) for no more than 24 hours, or at room temperature up to 25oC (77oF) for no more than hours. If refrigerated, allow the syringes to equilibrate to room temperature for approximately 20 minutes prior to administration.Table 5: Preparation of 600 mg of Casirivimab and 600 mg of Imdevimab for Subcutaneous InjectionsPrepare 600 mg of Casirivimab and 600 mg of ImdevimabPreparation of SyringesUsing Casirivimab and Imdevimab Co-formulated VialWithdraw 2.5 mL solution per syringe into FOUR separate syringes.Using Casirivimab and Imdevimab Individual VialsCasirivimab: Withdraw 2.5 mL solution per syringe into TWO separate syringes.Imdevimab: Withdraw 2.5 mL solution per syringe into TWO separate syringes.For total of syringes.Table 6: Preparation of 300 mg of Casirivimab and 300 mg of Imdevimab for Subcutaneous Injections for Repeat DosingSubsequent repeat dosing every weeks after initial 600 mg casirivimab and 600 mg imdevimab dosing for the duration of ongoing exposure. Prepare 300 mg of Casirivimab and 300 mg of ImdevimabPreparation of SyringesUsing Casirivimab and Imdevimab Co-formulated VialWithdraw 2.5 mL solution per syringe into TWO separate syringes.Using Casirivimab and Imdevimab Individual VialsCasirivimab: Withdraw 2.5 mL solution into ONE syringe.Imdevimab: Withdraw 2.5 mL solution into ONE syringe.For total of syringes.. Casirivimab and imdevimab should be prepared using the appropriate number of syringes (see Table and Table 6). Obtain mL or mL polypropylene Luer Lock syringes with luer connection and 21-gauge 1/2 inch transfer needles.. Withdraw the appropriate amount of solution into each syringe (see Table and Table 6). Prepare all syringes at the same time.. Replace the 21-gauge transfer needle with 25-gauge or 27-gauge needle for subcutaneous injection.. This product is preservative-free and therefore, the prepared syringes should be administered immediately. If immediate administration is not possible, store the prepared casirivimab and imdevimab syringes in the refrigerator between 2oC to 8oC (36oF to 46oF) for no more than 24 hours, or at room temperature up to 25oC (77oF) for no more than hours. If refrigerated, allow the syringes to equilibrate to room temperature for approximately 20 minutes prior to administration.. Casirivimab: Withdraw 2.5 mL solution per syringe into TWO separate syringes.. Imdevimab: Withdraw 2.5 mL solution per syringe into TWO separate syringes.. Casirivimab: Withdraw 2.5 mL solution into ONE syringe.. Imdevimab: Withdraw 2.5 mL solution into ONE syringe.. Administration for Subcutaneous InjectionFor the administration of 600 mg of casirivimab and 600 mg of imdevimab, gather syringes (see Table 5) and prepare for subcutaneous injections.For the administration of 300 mg of casirivimab and 300 mg of imdevimab, gather syringes (see Table 6) and prepare for subcutaneous injections.Administer the subcutaneous injections consecutively, each at different injection site, into the thigh, back of the upper arm, or abdomen, except for inches (5 cm) around the navel. The waistline should be avoided.When administering the subcutaneous injections, it is recommended that providers use different quadrants of the abdomen or upper thighs or back of the upper arms to space apart each 2.5 mL subcutaneous injection of casirivimab and imdevimab. DO NOT inject into skin that is tender, damaged, bruised, or scarred.Clinically monitor patients after injections and observe patients for at least hour.. For the administration of 600 mg of casirivimab and 600 mg of imdevimab, gather syringes (see Table 5) and prepare for subcutaneous injections.. For the administration of 300 mg of casirivimab and 300 mg of imdevimab, gather syringes (see Table 6) and prepare for subcutaneous injections.. Administer the subcutaneous injections consecutively, each at different injection site, into the thigh, back of the upper arm, or abdomen, except for inches (5 cm) around the navel. The waistline should be avoided.. When administering the subcutaneous injections, it is recommended that providers use different quadrants of the abdomen or upper thighs or back of the upper arms to space apart each 2.5 mL subcutaneous injection of casirivimab and imdevimab. DO NOT inject into skin that is tender, damaged, bruised, or scarred.. Clinically monitor patients after injections and observe patients for at least hour.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. REGEN-COV (casirivimab and imdevimab) is available as:A single vial which contains two antibodies co-formulated in 1:1 ratio of casirivimab and imdevimab. Co-formulated casirivimab and imdevimab is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution available as:Injection: 600 mg of casirivimab and 600 mg of imdevimab per 10 mL (60 mg/60 mg per mL) in single-doseUnder the EUA, single-dose vial may be used to prepare more than one dose. vial Individual antibody solutions in separate single-dose vials, which may be supplied in separate cartons or together in single carton (also referred to as co-packaged carton), or as dose pack.Casirivimab is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution available as:Injection: 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) Imdevimab is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution available as:Injection: 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) Each REGEN-COV dose pack contains 1,200 mg of casirivimab [REGN10933] and 1,200 mg of imdevimab [REGN10987] [see How Supplied/Storage and Handling (19)]. Casirivimab and imdevimab vial labels and carton labeling may instead be labeled REGN10933 and REGN10987, respectively. A single vial which contains two antibodies co-formulated in 1:1 ratio of casirivimab and imdevimab. Co-formulated casirivimab and imdevimab is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution available as:Injection: 600 mg of casirivimab and 600 mg of imdevimab per 10 mL (60 mg/60 mg per mL) in single-doseUnder the EUA, single-dose vial may be used to prepare more than one dose. vial Injection: 600 mg of casirivimab and 600 mg of imdevimab per 10 mL (60 mg/60 mg per mL) in single-doseUnder the EUA, single-dose vial may be used to prepare more than one dose. vial. Individual antibody solutions in separate single-dose vials, which may be supplied in separate cartons or together in single carton (also referred to as co-packaged carton), or as dose pack.Casirivimab is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution available as:Injection: 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) Imdevimab is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution available as:Injection: 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) Each REGEN-COV dose pack contains 1,200 mg of casirivimab [REGN10933] and 1,200 mg of imdevimab [REGN10987] [see How Supplied/Storage and Handling (19)]. Casirivimab and imdevimab vial labels and carton labeling may instead be labeled REGN10933 and REGN10987, respectively. Casirivimab is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution available as:Injection: 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) Injection: 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL). Imdevimab is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution available as:Injection: 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) Injection: 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL). Each REGEN-COV dose pack contains 1,200 mg of casirivimab [REGN10933] and 1,200 mg of imdevimab [REGN10987] [see How Supplied/Storage and Handling (19)]. Casirivimab and imdevimab vial labels and carton labeling may instead be labeled REGN10933 and REGN10987, respectively.

DRUG INTERACTIONS SECTION.

10 DRUG INTERACTIONS. REGEN-COV consists of monoclonal antibodies (mAbs), casirivimab and imdevimab, which are not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

GERIATRIC USE SECTION.

11.4 Geriatric Use. Of the 4,567 subjects with SARS-CoV-2 infection randomized in Trial COV-2067, 14% were 65 years or older, and 4% were 75 years of age or older. Of the 3,029 subjects randomized in Trial COV-2069, 9% were 65 years or older and 2% were 75 years of age or older. Of the 974 subjects randomized in Trial COV-2093, 13% were 65 years or older and 2% were 75 years of age or older. The difference in pharmacokinetics (PK) of casirivimab and imdevimab in geriatric patients compared to younger patients is unknown [see Clinical Trial Results and Supporting Data for EUA (18.1)].

HEPATIC IMPAIRMENT SUBSECTION.

11.6 Hepatic Impairment. The effect of hepatic impairment on PK of casirivimab and imdevimab is unknown.

HOW SUPPLIED SECTION.

19 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedCo-formulated casirivimab and imdevimab injection is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution supplied in vial. Refer to Table 12.Casirivimab injection is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution supplied in vial. Refer to Table 13.Imdevimab injection is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution supplied in vial. Refer to Table 13.REGEN-COV (casirivimab and imdevimab) injection is available as:1.A single vial which contains two antibodies co-formulated in 1:1 ratio of casirivimab and imdevimab (Table 12). 2.Individual antibody solutions in separate vials, which may be supplied in separate cartons (Table 13) or together in single carton (also referred to as co-packaged carton) (Table 14), or in dose pack (Table 15).Table 12: Co-Formulated Casirivimab and ImdevimabAntibodyConcentrationPackage SizeNDC NumberREGEN-COV (casirivimab and imdevimab)600 mg/600 mg per 10 mL (60 mg/60 mg per mL)1 vial per carton61755-039-01INDIVIDUAL CASIRIVIMAB AND IMDEVIMAB SOLUTIONS MUST BE ADMINISTERED TOGETHER.Table 13: Individual Package SizeAntibodyConcentrationPackage SizeNDC NumberCasirivimab REGN109331,332 mg/11.1 mL (120 mg/mL)1 vial per carton61755-024-01300 mg/2.5 mL (120 mg/mL)1 vial per carton61755-026-01Imdevimab REGN109871,332 mg/11.1 mL (120 mg/mL)1 vial per carton61755-025-01300 mg/2.5 mL (120 mg/mL)1 vial per carton61755-027-01Each co-packaged carton contains vial of casirivimab and vial of imdevimab. Refer to Table 14.Table 14: Casirivimab and Imdevimab Co-Packaged CartonCo-Packaged Carton ContentsCo-Packaged ComponentsConcentrationCo-Packaged Carton NDC Number2 Vials1 vial of casirivimab(NDC 61755-024-00)1,332 mg/11.1 mL(120 mg/mL)61755-042-021 vial of imdevimab(NDC 61755-025-00)1,332 mg/11.1 mL(120 mg/mL)2 Vials1 vial of casirivimab(NDC 61755-026-00)300 mg/2.5 mL(120 mg/mL)61755-045-021 vial of imdevimab (NDC 61755-027-00)300 mg/2.5 mL(120 mg/mL)Each REGEN-COV dose pack contains sufficient number of vials of casirivimab [REGN10933] and imdevimab [REGN10987] to prepare up to two treatment doses (600 mg of casirivimab and 600 mg of imdevimab). Refer to Table 15.Table 15: Dose Pack Providing 1,200 mg Casirivimab and 1,200 mg ImdevimabREGEN-COVDose Pack SizeREGEN-COVDose Pack ComponentsConcentrationREGEN-COVDose Pack NDC Number2 Cartons1 vial of casirivimabREGN10933 (NDC 61755-024-01)1,332 mg/11.1 mL(120 mg/mL)61755-035-021 vial of imdevimabREGN10987(NDC 61755-025-01)1,332 mg/11.1 mL(120 mg/mL)8 Cartons4 vials of casirivimabREGN10933(NDC 61755-026-01)300 mg/2.5 mL(120 mg/mL)61755-036-084 vials of imdevimabREGN10987(NDC 61755-027-01)300 mg/2.5 mL(120 mg/mL)5 Cartons1 vial of casirivimabREGN10933(NDC 61755-024-01)1,332 mg/11.1 mL(120 mg/mL)61755-037-054 vials of imdevimabREGN10987(NDC 61755-027-01)300 mg/2.5 mL(120 mg/mL)5 Cartons4 vials of casirivimabREGN10933(NDC 61755-026-01)300 mg/2.5 mL(120 mg/mL)61755-038-051 vial of imdevimabREGN10987(NDC 61755-025-01)1,332 mg/11.1 mL(120 mg/mL). 1.A single vial which contains two antibodies co-formulated in 1:1 ratio of casirivimab and imdevimab (Table 12). 2.Individual antibody solutions in separate vials, which may be supplied in separate cartons (Table 13) or together in single carton (also referred to as co-packaged carton) (Table 14), or in dose pack (Table 15).. Storage and HandlingCasirivimab is preservative-free. Discard any unused portion.Imdevimab is preservative-free. Discard any unused portion.Store unopened casirivimab and imdevimab vials in refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light. Unopened vials may be stored in the original carton at room temperature [up to 25C (77F)] and must be used within 30 days. If not used in the 30 days, discard vials.DO NOT FREEZE. DO NOT SHAKE. DO NOT EXPOSE TO DIRECT LIGHT.Solution in vial requires dilution prior to intravenous administration. The prepared infusion solution is intended to be used immediately. If immediate administration is not possible, store diluted casirivimab and imdevimab infusion solution in the refrigerator at 2C to 8C (36F to 46F) for no more than 36 hours or at room temperature up to 25C (77F) for no more than hours. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.The prepared syringes should be administered immediately. If immediate administration is not possible, store the prepared casirivimab and imdevimab syringes in the refrigerator between 2oC to 8oC (36oF to 46oF) for no more than 24 hours, or at room temperature up to 25oC (77oF) for no more than hours. If refrigerated, allow the syringes to equilibrate to room temperature for approximately 20 minutes prior to administration.

INDICATIONS & USAGE SECTION.

1 AUTHORIZED USE. 1.1 TREATMENT. REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, is authorized for use under an EUA for the treatment of mild to moderate COVID-19 in adult and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.. Limitations of Authorized UseREGEN-COV is not authorized for treatment of mild to moderate COVID-19 in geographic regions where infection is likely to have been caused by non-susceptible SARS-CoV-2 variant based on available information such as variant susceptibility to this drug and regional variant frequency. -FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs. REGEN-COV (casirivimab and imdevimab) is not authorized for use in patients:-who are hospitalized due to COVID-19, OR-who require oxygen therapy due to COVID-19, OR-who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation [see Warnings and Precautions (5.2)].. REGEN-COV is not authorized for treatment of mild to moderate COVID-19 in geographic regions where infection is likely to have been caused by non-susceptible SARS-CoV-2 variant based on available information such as variant susceptibility to this drug and regional variant frequency. -FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs. -FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs.. REGEN-COV (casirivimab and imdevimab) is not authorized for use in patients:-who are hospitalized due to COVID-19, OR-who require oxygen therapy due to COVID-19, OR-who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity. -who are hospitalized due to COVID-19, OR. -who require oxygen therapy due to COVID-19, OR. -who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation [see Warnings and Precautions (5.2)].. 1.2 POST-EXPOSURE PROPHYLAXIS. REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, is authorized for use under an EUA for the post-exposure prophylaxis of COVID-19 in adult and pediatric individuals (12 years of age and older weighing at least 40 kg) who are at high risk for progression to severe COVID-19, including hospitalization or death, and are:not fully vaccinatedIndividuals are considered to be fully vaccinated weeks after their second vaccine dose in 2-dose series (such as the Pfizer or Moderna vaccines), or weeks after single-dose vaccine (such as Johnson Johnsons Janssen vaccine). See this website for more details: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.htmlvaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medicationsSee this website for more details: https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/fully-vaccinated-people.html) and -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC)Close contact with an infected individual is defined as: being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). See this website for additional details: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html or-who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons). not fully vaccinatedIndividuals are considered to be fully vaccinated weeks after their second vaccine dose in 2-dose series (such as the Pfizer or Moderna vaccines), or weeks after single-dose vaccine (such as Johnson Johnsons Janssen vaccine). See this website for more details: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.htmlvaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medicationsSee this website for more details: https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/fully-vaccinated-people.html) and -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC)Close contact with an infected individual is defined as: being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). See this website for additional details: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html or-who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons). -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC)Close contact with an infected individual is defined as: being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). See this website for additional details: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html or. -who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons).. Limitations of Authorized UseREGEN-COV is not authorized for post-exposure prophylaxis of COVID-19 in geographic regions where exposure is likely to have been to non-susceptible SARS-CoV-2 variant, based on available information including variant susceptibility to this drug and regional variant frequency.-FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs. Post-exposure prophylaxis with REGEN-COV (casirivimab and imdevimab) is not substitute for vaccination against COVID-19. REGEN-COV (casirivimab and imdevimab) is not authorized for pre-exposure prophylaxis for prevention of COVID-19.. REGEN-COV is not authorized for post-exposure prophylaxis of COVID-19 in geographic regions where exposure is likely to have been to non-susceptible SARS-CoV-2 variant, based on available information including variant susceptibility to this drug and regional variant frequency.-FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs. -FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs. Post-exposure prophylaxis with REGEN-COV (casirivimab and imdevimab) is not substitute for vaccination against COVID-19. REGEN-COV (casirivimab and imdevimab) is not authorized for pre-exposure prophylaxis for prevention of COVID-19.

INFORMATION FOR PATIENTS SECTION.

FACT SHEET FOR PATIENTS, PARENTS AND CAREGIVERSEMERGENCY USE AUTHORIZATION (EUA) OF REGEN-COV(TM) (casirivimab and imdevimab) FOR CORONAVIRUS DISEASE 2019 (COVID-19)You are being given medicine called REGEN-COV (casirivimab and imdevimab) for the treatment or post-exposure prevention of coronavirus disease 2019 (COVID-19). SARS-CoV-2 is the virus that causes COVID-19. This Fact Sheet contains information to help you understand the potential risks and potential benefits of taking REGEN-COV.Receiving REGEN-COV may benefit certain people with COVID-19 and may help prevent certain people who have been exposed to someone who is infected with SARS-CoV-2 from getting SARS-CoV-2 infection, or may prevent certain people who are at high risk of exposure to someone who is infected with SARS-CoV-2 from getting SARS-CoV-2 infection.Read this Fact Sheet for information about REGEN-COV. Talk to your healthcare provider if you have questions. It is your choice to receive REGEN-COV or stop at any time.WHAT IS COVID-19COVID-19 is caused by virus called coronavirus, SARS-CoV-2. People can get COVID-19 through contact with another person who has the virus.COVID-19 illnesses have ranged from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause some of your other medical conditions to become worse. People of all ages with severe, long-lasting (chronic) medical conditions like heart disease, lung disease, and diabetes, for example, and other conditions including obesity, seem to be at higher risk of being hospitalized for COVID-19. Older age, with or without other conditions, also places people at higher risk of being hospitalized for COVID-19.WHAT ARE THE SYMPTOMS OF COVID-19The symptoms of COVID-19 include fever, cough, and shortness of breath, which may appear to 14 days after exposure. Serious illness including breathing problems can occur and may cause your other medical conditions to become worse.WHAT IS REGEN-COV (casirivimab and imdevimab)REGEN-COV is an investigational medicine used in adults and adolescents (12 years of age and older who weigh at least 88 pounds (40 kg)) who are at high risk for severe COVID-19, including hospitalization or death for:treatment of mild to moderate symptoms of COVID-19post-exposure prevention of COVID-19 in persons who are:not fully vaccinated against COVID-19 (Individuals are considered to be fully vaccinated weeks after their second vaccine dose in 2-dose series [such as the Pfizer or Moderna vaccines], or weeks after single-dose vaccine [such as Johnson Johnsons Janssen vaccine]), or,are not expected to build up enough of an immune response to the complete COVID-19 vaccination (for example, someone with immunocompromising conditions, including someone who is taking immunosuppressive medications), and have been exposed to someone who is infected with SARS-CoV-2. Close contact with someone who is infected with SARS-CoV-2 is defined as being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). For additional details, go to https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html, or someone who is at high risk of being exposed to someone who is infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons). REGEN-COV is investigational because it is still being studied. There is limited information known about the safety and effectiveness of using REGEN-COV to treat people with COVID-19 or to prevent COVID-19 in people who are at high risk of being exposed to someone who is infected with SARS-CoV-2. REGEN-COV is not authorized for pre-exposure prophylaxis for prevention of COVID-19.The FDA has authorized the emergency use of REGEN-COV for the treatment of COVID-19 and the post-exposure prevention of COVID-19 under an Emergency Use Authorization (EUA). For more information on EUA, see the What is an Emergency Use Authorization (EUA) section at the end of this Fact Sheet.WHO SHOULD NOT TAKE REGEN-COVDo not take REGEN-COV if you have had severe allergic reaction to REGEN-COV.WHAT SHOULD TELL MY HEALTH CARE PROVIDER BEFORE RECEIVE REGEN-COVTell your healthcare provider about all of your medical conditions, including if you:Have any allergiesHave had severe allergic reaction including anaphylaxis to REGEN-COV previouslyHave received COVID-19 vaccineHave any serious illnessesAre pregnant or plan to become pregnantAre breastfeeding or plan to breastfeedAre taking any medications (prescription, over-the-counter, vitamins, and herbal products)HOW WILL RECEIVE REGEN-COV (casirivimab and imdevimab)REGEN-COV consists of two investigational medicines, casirivimab and imdevimab, given together at the same time through vein (intravenous or IV) or injected in the tissue just under the skin (subcutaneous injections). Your healthcare provider will determine the most appropriate way for you to be given REGEN-COV. Treatment: If you are receiving an intravenous infusion, the infusion will take 20 to 50 minutes or longer. Your healthcare provider will determine the duration of your infusion.If your healthcare provider determines that you are unable to receive REGEN-COV as an intravenous infusion which would lead to delay in treatment, then as an alternative, REGEN-COV can be given in the form of subcutaneous injections. If you are receiving subcutaneous injections, your dose will be provided as multiple injections given in separate locations around the same time. Post-exposure prevention: If you are receiving subcutaneous injections, your dose will be provided as multiple injections given in separate locations around the same time. If you are receiving an intravenous infusion, the infusion will take 20 to 50 minutes or longer.After the initial dose, if your healthcare provider determines that you need to receive additional doses of REGEN-COV for ongoing protection, the additional intravenous or subcutaneous doses would be administered monthly. WHAT ARE THE IMPORTANT POSSIBLE SIDE EFFECTS OF REGEN-COV (casirivimab and imdevimab)Possible side effects of REGEN-COV are: Allergic reactions. Allergic reactions can happen during and after infusion or injection of REGEN-COV. Tell your healthcare provider right away or seek immediate medical attention if you get any of the following signs and symptoms of allergic reactions: fever, chills, nausea, headache, shortness of breath, low or high blood pressure, rapid or slow heart rate, chest discomfort or pain, weakness, confusion, feeling tired, wheezing, swelling of your lips, face, or throat, rash including hives, itching, muscle aches, feeling faint, dizziness and sweating. These reactions may be severe or life threatening.Worsening symptoms after treatment: You may experience new or worsening symptoms after infusion or injection, including fever, difficulty breathing, rapid or slow heart rate, tiredness, weakness or confusion. If these symptoms occur, contact your healthcare provider or seek immediate medical attention as some of these symptoms have required hospitalization. It is unknown if these symptoms are related to treatment or are due to the progression of COVID-19.The side effects of getting any medicine by vein may include brief pain, bleeding, bruising of the skin, soreness, swelling, and possible infection at the infusion site. The side effects of getting any medicine by subcutaneous injection may include pain, bruising of the skin, soreness, swelling, and possible infection at the injection site.These are not all the possible side effects of REGEN-COV. Not lot of people have been given REGEN-COV. Serious and unexpected side effects may happen. REGEN-COV is still being studied so it is possible that all of the risks are not known at this time.It is possible that REGEN-COV could interfere with your bodys own ability to fight off future infection of SARS-CoV-2. Similarly, REGEN-COV may reduce your bodys immune response to vaccine for SARS-CoV-2. Specific studies have not been conducted to address these possible risks. Talk to your healthcare provider if you have any questions.WHAT OTHER TREATMENT CHOICES ARE THERELike REGEN-COV (casirivimab and imdevimab), FDA may allow for the emergency use of other medicines to treat people with COVID-19. Go to https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization for information on the emergency use of other medicines that are not approved by FDA that are used to treat people with COVID-19. Your healthcare provider may talk with you about clinical trials you may be eligible for.It is your choice to be treated or not to be treated with REGEN-COV. Should you decide not to receive REGEN-COV or stop it at any time, it will not change your standard medical care.WHAT OTHER PREVENTION CHOICES ARE THEREVaccines to prevent COVID-19 are also available under Emergency Use Authorization. Use of REGEN-COV does not replace vaccination against COVID-19. REGEN-COV is not authorized for pre-exposure prophylaxis for prevention of COVID-19.WHAT IF AM PREGNANT OR BREASTFEEDINGThere is limited experience using REGEN-COV (casirivimab and imdevimab) in pregnant women or breastfeeding mothers. For mother and unborn baby, the benefit of receiving REGEN-COV may be greater than the risk of using the product. If you are pregnant or breastfeeding, discuss your options and specific situation with your healthcare provider.HOW DO REPORT SIDE EFFECTS WITH REGEN-COV (casirivimab and imdevimab)Tell your healthcare provider right away if you have any side effect that bothers you or does not go away.Report side effects to FDA MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088 or call 1-844-734-6643.HOW CAN LEARN MOREAsk your health care provider.Visit www.REGENCOV.com Visit https://www.covid19treatmentguidelines.nih.gov/Contact your local or state public health department.WHAT IS AN EMERGENCY USE AUTHORIZATION (EUA)The United States FDA has made REGEN-COV (casirivimab and imdevimab) available under an emergency access mechanism called an EUA. The EUA is supported by Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic.REGEN-COV has not undergone the same type of review as an FDA-approved product. In issuing an EUA under the COVID-19 public health emergency, the FDA must determine, among other things, that based on the totality of scientific evidence available, it is reasonable to believe that the product may be effective for diagnosing, treating, or preventing COVID-19, or serious or life-threatening disease or condition caused by COVID-19; that the known and potential benefits of the product, when used to diagnose, treat, or prevent such disease or condition, outweigh the known and potential risks of such product; and that there are no adequate, approved and available alternatives. All of these criteria must be met to allow for the medicine to be used in the treatment of COVID-19 or prevention of COVID-19 during the COVID-19 pandemic.The EUA for REGEN-COV is in effect for the duration of the COVID-19 declaration justifying emergency use of these products, unless terminated or revoked (after which the products may no longer be used).Manufactured by:Regeneron Pharmaceuticals, Inc.777 Old Saw Mill River RoadTarrytown, NY 10591-6707(C)2022 Regeneron Pharmaceuticals, Inc. All rights reserved.Revised: 01/2022. treatment of mild to moderate symptoms of COVID-19. post-exposure prevention of COVID-19 in persons who are:not fully vaccinated against COVID-19 (Individuals are considered to be fully vaccinated weeks after their second vaccine dose in 2-dose series [such as the Pfizer or Moderna vaccines], or weeks after single-dose vaccine [such as Johnson Johnsons Janssen vaccine]), or,are not expected to build up enough of an immune response to the complete COVID-19 vaccination (for example, someone with immunocompromising conditions, including someone who is taking immunosuppressive medications), and have been exposed to someone who is infected with SARS-CoV-2. Close contact with someone who is infected with SARS-CoV-2 is defined as being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). For additional details, go to https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html, or someone who is at high risk of being exposed to someone who is infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons). not fully vaccinated against COVID-19 (Individuals are considered to be fully vaccinated weeks after their second vaccine dose in 2-dose series [such as the Pfizer or Moderna vaccines], or weeks after single-dose vaccine [such as Johnson Johnsons Janssen vaccine]), or,. are not expected to build up enough of an immune response to the complete COVID-19 vaccination (for example, someone with immunocompromising conditions, including someone who is taking immunosuppressive medications), and have been exposed to someone who is infected with SARS-CoV-2. Close contact with someone who is infected with SARS-CoV-2 is defined as being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). For additional details, go to https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html, or someone who is at high risk of being exposed to someone who is infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons). have been exposed to someone who is infected with SARS-CoV-2. Close contact with someone who is infected with SARS-CoV-2 is defined as being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). For additional details, go to https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html, or someone who is at high risk of being exposed to someone who is infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons).. Have any allergies. Have had severe allergic reaction including anaphylaxis to REGEN-COV previously. Have received COVID-19 vaccine. Have any serious illnesses. Are pregnant or plan to become pregnant. Are breastfeeding or plan to breastfeed. Are taking any medications (prescription, over-the-counter, vitamins, and herbal products). REGEN-COV consists of two investigational medicines, casirivimab and imdevimab, given together at the same time through vein (intravenous or IV) or injected in the tissue just under the skin (subcutaneous injections). Your healthcare provider will determine the most appropriate way for you to be given REGEN-COV. Treatment: If you are receiving an intravenous infusion, the infusion will take 20 to 50 minutes or longer. Your healthcare provider will determine the duration of your infusion.If your healthcare provider determines that you are unable to receive REGEN-COV as an intravenous infusion which would lead to delay in treatment, then as an alternative, REGEN-COV can be given in the form of subcutaneous injections. If you are receiving subcutaneous injections, your dose will be provided as multiple injections given in separate locations around the same time. If your healthcare provider determines that you are unable to receive REGEN-COV as an intravenous infusion which would lead to delay in treatment, then as an alternative, REGEN-COV can be given in the form of subcutaneous injections. If you are receiving subcutaneous injections, your dose will be provided as multiple injections given in separate locations around the same time.. Post-exposure prevention: If you are receiving subcutaneous injections, your dose will be provided as multiple injections given in separate locations around the same time. If you are receiving an intravenous infusion, the infusion will take 20 to 50 minutes or longer.After the initial dose, if your healthcare provider determines that you need to receive additional doses of REGEN-COV for ongoing protection, the additional intravenous or subcutaneous doses would be administered monthly. After the initial dose, if your healthcare provider determines that you need to receive additional doses of REGEN-COV for ongoing protection, the additional intravenous or subcutaneous doses would be administered monthly. Allergic reactions. Allergic reactions can happen during and after infusion or injection of REGEN-COV. Tell your healthcare provider right away or seek immediate medical attention if you get any of the following signs and symptoms of allergic reactions: fever, chills, nausea, headache, shortness of breath, low or high blood pressure, rapid or slow heart rate, chest discomfort or pain, weakness, confusion, feeling tired, wheezing, swelling of your lips, face, or throat, rash including hives, itching, muscle aches, feeling faint, dizziness and sweating. These reactions may be severe or life threatening.. Worsening symptoms after treatment: You may experience new or worsening symptoms after infusion or injection, including fever, difficulty breathing, rapid or slow heart rate, tiredness, weakness or confusion. If these symptoms occur, contact your healthcare provider or seek immediate medical attention as some of these symptoms have required hospitalization. It is unknown if these symptoms are related to treatment or are due to the progression of COVID-19.. Ask your health care provider.. Visit www.REGENCOV.com Visit https://www.covid19treatmentguidelines.nih.gov/. Contact your local or state public health department.

LACTATION SECTION.

11.2 Lactation. Risk SummaryThere are no available data on the presence of casirivimab and/or imdevimab in human milk or animal milk, the effects on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for REGEN-COV (casirivimab and imdevimab) and any potential adverse effects on the breastfed child from REGEN-COV or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

MECHANISM OF ACTION SECTION.

14.1 Mechanism of Action. Casirivimab (IgG1) and imdevimab (IgG1) are two recombinant human mAbs which are unmodified in the Fc regions. Casirivimab and imdevimab bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2 with dissociation constants KD 45.8 pM and 46.7 pM, respectively. Casirivimab, imdevimab and casirivimab and imdevimab together blocked RBD binding to the human ACE2 receptor with IC50 values of 56.4 pM, 165 pM and 81.8 pM, respectively and prevents viral attachment to host cells [see Microbiology/Resistance Information (15) ].

MICROBIOLOGY SECTION.

15 MICROBIOLOGY/RESISTANCE INFORMATION. Antiviral ActivityIn SARS-CoV-2 virus neutralization assay in Vero E6 cells, casirivimab, imdevimab, and casirivimab and imdevimab together neutralized SARS-CoV-2 (USA-WA1/2020 isolate) with EC50 values of 37.4 pM (0.006 ug/mL), 42.1 pM (0.006 ug/mL), and 31.0 pM (0.005 ug/mL), respectively.Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) were assessed using Jurkat target cells expressing SARS-CoV-2 spike protein. Casirivimab, imdevimab and casirivimab and imdevimab together mediated ADCC with human natural killer (NK) effector cells. Casirivimab, imdevimab and casirivimab and imdevimab together mediated ADCP with human macrophages. Casirivimab, imdevimab and casirivimab and imdevimab together did not mediate complement-dependent cytotoxicity in cell-based assays.. Antibody Dependent Enhancement (ADE) of InfectionThe potential of casirivimab and of imdevimab to mediate viral entry was assessed in immune cell lines co-incubated with recombinant vesicular stomatitis virus (VSV) virus-like particles (VLP) pseudotyped with SARS-CoV-2 spike protein at concentrations of mAb(s) down to approximately 10-fold below the respective neutralization EC50 values. Casirivimab and imdevimab together and imdevimab alone, but not casirivimab alone, mediated entry of pseudotyped VLP into FcR2+ Raji and FcR1+/FcR2+ THP1 cells (maximum infection in total cells of 1.34% and 0.24%, respectively, for imdevimab; 0.69% and 0.06%, respectively for casirivimab and imdevimab together), but not any other cell lines tested (IM9, K562, Ramos and U937 cells).. Antiviral ResistanceThere is potential risk of treatment failure due to the development of viral variants that are resistant to casirivimab and imdevimab administered together. Prescribing healthcare providers should consider the prevalence of SARS-CoV-2 variants in their area, where data are available, when considering treatment options.Escape variants were identified following two passages in cell culture of recombinant VSV encoding SARS-CoV-2 spike protein in the presence of casirivimab or imdevimab individually, but not following two passages in the presence of casirivimab and imdevimab together. Variants which showed reduced susceptibility to casirivimab alone included those with spike protein amino acid substitutions K417E (182-fold), K417N (7-fold), K417R (61-fold), Y453F (>438-fold), L455F (80-fold), E484K (25-fold), F486V (>438-fold) and Q493K (>438-fold). Variants which showed reduced susceptibility to imdevimab alone included substitutions K444N (>755-fold), K444Q (>548-fold), K444T (>1,033-fold), and V445A (>548-fold). Casirivimab and imdevimab together showed reduced susceptibility to variants with K444T (6-fold) and V445A (5-fold) substitutions.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 E406D (51-fold), G476S (5-fold), E484Q (19-fold), G485D (5-fold), F486L (61-fold), F486S (>715-fold), Q493E (446-fold), Q493R (77-fold), and S494P (5-fold) substitutions, and variants with reduced susceptibility to imdevimab alone included those with 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), Q498H (17-fold), P499S (206-fold) substitutions. The G476D substitution had an impact (4-fold) on casirivimab and imdevimab together. Substitutions tested concurrently which had reduced susceptibility to casirivimab and imdevimab together included N440K+E484K (21-fold), found in the B.1.619/B.1.625 lineages, and N439K+E484K (23-fold), found in the AV.1 lineage; variants harboring these concurrent substitutions have been detected rarely in the US.Casirivimab and imdevimab individually and together retained neutralization activity against pseudotyped VLP expressing all spike protein substitutions found in the B.1.1.7 lineage (Alpha; UK origin) and against pseudotyped VLP expressing only N501Y found in B.1.1.7 and other circulating lineages (Table 9). Casirivimab and imdevimab together retained neutralization activity against pseudotyped VLP expressing all spike protein substitutions, or individual substitutions K417N, E484K or N501Y, found in the B.1.351 lineage (Beta; South Africa origin), and all spike protein substitutions or key substitutions K417T, E484K, or N501Y, found in the P.1 lineage (Gamma; Brazil origin), although casirivimab alone, but not imdevimab, had reduced activity against pseudotyped VLP expressing K417N (7-fold) or E484K (25-fold). The E484K substitution is also found in the B.1.526 lineage (Iota; USA [New York] origin). Casirivimab and imdevimab, individually and together, retained neutralization activity against the L452R substitution found in the B.1.427/B.1.429 lineages (Epsilon; USA [California] origin).Casirivimab and imdevimab, individually and together, retained neutralization activity against pseudotyped VLP expressing L452R+T478K substitutions found in the B.1.617.2 and AY.3 lineages (Delta; India origin). Casirivimab and imdevimab together retained neutralization activity against pseudotyped VLP expressing L452R+E484Q substitutions, found in the B.1.617.1/B.1.617.3 lineages (Kappa/no designation; India origin), although casirivimab alone, but not imdevimab, had reduced activity against pseudotyped VLP expressing L452R+E484Q (7-fold). Casirivimab and imdevimab together retained activity against pseudotyped VLP expressing R346K+E484K+N501Y found in the B.1.621/B.1.621.1 (Mu; Colombia origin) lineage although casirivimab alone, but not imdevimab, had reduced activity against pseudotyped VLP expressing R346K+E484K+N501Y (23-fold).Casirivimab and imdevimab, individually (>1732-fold and >754-fold, respectively) and together (>1013-fold), demonstrated reduced neutralization activity against VLP pseudotyped with the full spike protein sequence of the B.1.1.529/BA.1 (Omicron; South Africa origin) lineage.Table 9: Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions with Casirivimab and Imdevimab TogetherLineage with Spike Protein SubstitutionCountry First IdentifiedWHO NomenclatureKey SubstitutionsFold Reduction in SusceptibilityAbbreviations: del, deletion; ins, insertionB.1.1.7UKAlphaN501YPseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: del69-70, del145, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. no changeNo change: <=2-fold reduction in susceptibility. B.1.351South AfricaBetaK417N+E484K+N501YPseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: D80Y, D215Y, del241-243, K417N, E484K, N501Y, D614G, A701V. no change P.1BrazilGammaK417T+E484K+N501YPseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I, V1176F. no change B.1.617.2/AY.3IndiaDeltaL452R+T478Kno change B.1.427/B.1.429USA (California)EpsilonL452Rno change B.1.526Not all isolates of the New York lineage harbor the E484K substitution (as of February 2021). USA(New York)IotaE484Kno change B.1.617.1/B.1.617.3IndiaKappa/no designationL452R+E484Qno change B.1.621/B.1.621.1ColombiaMuR346K+E484K+N501Yno change B.1.1.529/BA.1South AfricaOmicronG339D+S371L+S373P+S375F+K417N+N440K, G446S+S477N+T478K+E484A+Q493R+G496S+Q498R+N501Y+Y505HPseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: A67V, del69-70, T95I, G142D/del143-145, del211/L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F >1013-foldCasirivimab and imdevimab together are unlikely to be active against variants from this lineage Due to the large reduction of pseudotyped VLP neutralization activity against spike protein from the B.1.1.529/BA.1 (Omicron;South Africa origin) variant, it is unlikely that casirivimab and imdevimab together will be active against this variant.Casirivimab and imdevimab together retained activity against authentic SARS-CoV-2 variants of B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.1 (Kappa) lineages (Table 10), although casirivimab alone, but not imdevimab, had reduced activity against B.1.351 (5-fold), P.1 (>371-fold) and B.1.617.1 (6-fold) variants. It is not known how pseudotyped VLP or authentic SARS-CoV-2 data correlate with clinical outcomes. Table 10: Authentic SARS-CoV-2 Neutralization Data for Casirivimab and Imdevimab TogetherSARS-CoV-2 LineageCountry First IdentifiedWHO NomenclatureKey SubstitutionsKey substitutions occurring in receptor binding domain of spike protein which are associated with each lineage Fold Reduction in SusceptibilityB.1.1.7UKAlphaN501Yno changeNo change: <=2-fold reduction in susceptibility. B.1.351South AfricaBetaK417N+E484K+N501Yno change P.1BrazilGammaK417T+E484K+N501Yno change B.1.617.2IndiaDeltaL452R+T478Kno change B.1.617.1IndiaKappaL452R+E484Qno change In clinical trial COV-2067, interim data indicated only one variant (G446V) occurring at an allele fraction >=15%, which was detected in 3/66 subjects who had nucleotide sequencing data, each at single time point (two at baseline in subjects from placebo and 2,400 mg casirivimab and imdevimab groups, and one at Day 25 in subject from the 8,000 mg casirivimab and imdevimab group). The G446V variant had reduced susceptibility to imdevimab of 135-fold compared to wild-type in pseudotyped VSV VLP neutralization assay but retained susceptibility to casirivimab alone and casirivimab and imdevimab together.It is possible that resistance-associated variants to casirivimab and imdevimab together could have cross-resistance to other mAbs targeting the receptor binding domain of SARS-CoV-2. The clinical impact is not known.. Immune Response AttenuationThere is theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection.

NONCLINICAL TOXICOLOGY SECTION.

16 NONCLINICAL TOXICOLOGY. Carcinogenicity, genotoxicity, and reproductive toxicology studies have not been conducted with casirivimab and imdevimab. In toxicology study in cynomolgus monkeys, casirivimab and imdevimab had no adverse effects when administered intravenously or subcutaneously. Non-adverse liver findings (minor transient increases in AST and ALT) were observed.In tissue cross-reactivity studies with casirivimab and imdevimab using human adult and fetal tissues, no binding of clinical concern was detected.

OVERDOSAGE SECTION.

12 OVERDOSAGE. Doses up to 8,000 mg (4,000 mg each of casirivimab and imdevimab, greater than times the recommended dose) have been administered in clinical trials without dose-limiting toxicity. Treatment of overdose should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with REGEN-COV (casirivimab and imdevimab).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 300 mg/2.5 mL Vial Label Casirivimab. 70120812345-00Casirivimab InjectionNDC 61755-026-00 Rx only300 mg/2.5 mL (120 mg/mL)For Intravenous Infusion after Dilution For use under Emergency Use Authorization (EUA) MUST ADMINISTER WITH IMDEVIMAB Mfd by: Regeneron Pharmaceuticals, Inc.LOT/EXP. PRINCIPAL DISPLAY PANEL 300 mg/2.5 mL Vial Label Casirivimab.

PATIENT COUNSELING INFORMATION.

20 PATIENT COUNSELING INFORMATION. Patients treated with REGEN-COV (casirivimab and imdevimab) should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal texts, clean and disinfect high touch surfaces, and frequent handwashing) according to CDC guidelines. Also see Fact Sheet for Patients, Parents and Caregivers.

PEDIATRIC USE SECTION.

11.3 Pediatric Use. REGEN-COV is not authorized for use in pediatric patients under 12 years of age or weighing less than 40 kg. The safety and effectiveness of casirivimab and imdevimab are being assessed in pediatric and adolescent patients in an ongoing clinical trial. The recommended dosing regimen is expected to result in comparable serum exposures of casirivimab and imdevimab in patients 12 years of age and older and weighing at least 40 kg as observed in adults, since adults with similar body weight have been included in Trials COV-2067, COV-2069, and COV-2093.

PHARMACODYNAMICS SECTION.

14.2 Pharmacodynamics. Trial COV-2067 evaluated REGEN-COV (casirivimab and imdevimab) with doses of up to 6.66 times the recommended dose (600 mg of casirivimab and 600 mg of imdevimab; 1,200 mg of casirivimab and 1,200 mg of imdevimab; 4,000 mg of casirivimab and 4,000 mg of imdevimab) in ambulatory patients with COVID-19. flat dose-response relationship for efficacy was identified for REGEN-COV at all doses, based on viral load and clinical outcomes. Similar reductions in viral load (log10 copies/mL) were observed in subjects for the (600 mg of casirivimab and 600 mg of imdevimab) intravenous and (600 mg of casirivimab and 600 mg of imdevimab) subcutaneous doses; however, only limited clinical outcome data are available for the subcutaneous route of administration for the treatment of symptomatic patients.

PHARMACOKINETICS SECTION.

14.3 Pharmacokinetics. Both casirivimab and imdevimab exhibited linear and dose-proportional pharmacokinetics (PK) between (600 mg of casirivimab and 600 mg of imdevimab) to (4,000 mg of casirivimab and 4,000 mg of imdevimab) doses of REGEN-COV (casirivimab and imdevimab) following intravenous administration of single dose. summary of PK parameters after single (600 mg of casirivimab and 600 mg of imdevimab) intravenous dose, for each antibody is provided in Table 7.Table 7: Summary of PK Parameters for Casirivimab and Imdevimab After Single 600 mg of Casirivimab and 600 mg of Imdevimab Intravenous Dose of REGEN-COV in Study COV-2067PK ParameterMean (SD) CasirivimabImdevimabCeoi (mg/L)concentration at end of 1-hour infusion 192 (80.9)198 (84.8)C28 (mg/L)observed concentration 28 days after dosing, i.e., on day 29, as defined in the protocol 46.2 (22.3)38.5 (19.7)A summary of PK parameters after single 600 mg of casirivimab and 600 mg of imdevimab subcutaneous dose is shown in Table 8.Table 8: Summary of PK Parameters for Casirivimab and Imdevimab After Single 600 mg of Casirivimab and 600 mg of Imdevimab Subcutaneous Dose of REGEN-COV PK ParameterMean (SD) Mean (SD) concentration at 24 hours (C24) of casirivimab and imdevimab in serum with 1200 SC dosing, 22.5 (11.0) mg/L and 25.0 (16.4) mg/L, respectively CasirivimabImdevimabCmax (mg/L)55.6 (22.2)52.7 (22.5)tmax (day)Median (range) 8.00 (4.00, 87.0)7.00 (4.00, 15.0)AUC0-28 (mgday/L)1060 (363)950 (362)AUCinf (mgday/L)Value reported for subjects with %AUCinf extrapolated <20% 2580 (1349)1990 (1141)C28 (mg/L)Observed concentration 28 days after dosing, i.e., on day 29 30.7 (11.9)24.8 (9.58)Half-life (day)31.8 (8.35)26.9 (6.80)For the repeat dose prophylaxis intravenous and subcutaneous regimens, population pharmacokinetic simulations predicted that trough concentrations in serum at steady-state after an initial 600 mg casirivimab and 600 mg imdevimab intravenous or subcutaneous dose followed by monthly (every weeks) 300 mg casirivimab and 300 mg imdevimab intravenous or subcutaneous doses are similar to slightly higher than observed mean day 29 concentrations in serum for single 600 mg casirivimab and 600 mg imdevimab subcutaneous dose.. Specific PopulationsThe effect of different covariates (e.g., age, sex, race, body weight, disease severity, hepatic impairment) on the PK of casirivimab and imdevimab is unknown. Renal impairment is not expected to impact the PK of casirivimab and imdevimab, since mAbs with molecular weight >69 kDa are known not to undergo renal elimination. Similarly, dialysis is not expected to impact the PK of casirivimab and imdevimab.. Drug-Drug InteractionsCasirivimab and imdevimab are mAbs which are not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely [see Drug Interactions (10)].

PREGNANCY SECTION.

11.1 Pregnancy. Risk SummaryThere are insufficient data to evaluate drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. REGEN-COV (casirivimab and imdevimab) should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus.Nonclinical reproductive toxicity studies have not been conducted with casirivimab and imdevimab. In tissue cross-reactivity study with casirivimab and imdevimab using human fetal tissues, no binding of clinical concern was detected. Human immunoglobulin G1 (IgG1) antibodies are known to cross the placental barrier; therefore, casirivimab and imdevimab have the potential to be transferred from the mother to the developing fetus. It is unknown whether the potential transfer of casirivimab and imdevimab provides any treatment benefit or risk to the developing fetus. There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-Associated Maternal and/or Embryo-Fetal RiskCOVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.

RENAL IMPAIRMENT SUBSECTION.

11.5 Renal Impairment. Casirivimab and imdevimab are not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of casirivimab and imdevimab.

SPL UNCLASSIFIED SECTION.

AUTHORIZED USE. TREATMENTThe U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of the unapproved product, REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adult and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.. Limitations of Authorized UseREGEN-COV is not authorized for treatment of mild to moderate COVID-19 in geographic regions where infection is likely to have been caused by non-susceptible SARS-CoV-2 variant based on available information such as variant susceptibility to this drug and regional variant frequency. -FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs.FDA will monitor conditions to determine whether use in geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility [see Microbiology/Resistance Information (15)], and CDC regional variant frequency data available at: https://covid.cdc.gov/covid-data-tracker/variant-proportions. REGEN-COV (casirivimab and imdevimab) is not authorized for use in patients:-who are hospitalized due to COVID-19, OR-who require oxygen therapy due to COVID-19, OR-who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.. REGEN-COV is not authorized for treatment of mild to moderate COVID-19 in geographic regions where infection is likely to have been caused by non-susceptible SARS-CoV-2 variant based on available information such as variant susceptibility to this drug and regional variant frequency. -FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs.FDA will monitor conditions to determine whether use in geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility [see Microbiology/Resistance Information (15)], and CDC regional variant frequency data available at: https://covid.cdc.gov/covid-data-tracker/variant-proportions. -FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs.FDA will monitor conditions to determine whether use in geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility [see Microbiology/Resistance Information (15)], and CDC regional variant frequency data available at: https://covid.cdc.gov/covid-data-tracker/variant-proportions.. REGEN-COV (casirivimab and imdevimab) is not authorized for use in patients:-who are hospitalized due to COVID-19, OR-who require oxygen therapy due to COVID-19, OR-who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity. -who are hospitalized due to COVID-19, OR. -who require oxygen therapy due to COVID-19, OR. -who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.. POST-EXPOSURE PROPHYLAXISThe U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of the unapproved product, REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, in adult and pediatric individuals (12 years of age and older weighing at least 40 kg) for post-exposure prophylaxis of COVID-19 in individuals who are at high risk for progression to severe COVID-19, including hospitalization or death, and are:not fully vaccinatedIndividuals are considered to be fully vaccinated weeks after their second vaccine dose in 2-dose series (such as the Pfizer or Moderna vaccines), or weeks after single-dose vaccine (such as Johnson Johnsons Janssen vaccine). See this website for more details: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.htmlvaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medicationsSee this website for more details: https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/fully-vaccinated-people.html) and -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC)Close contact with an infected individual is defined as: being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). See this website for additional details: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html or-who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)]. not fully vaccinatedIndividuals are considered to be fully vaccinated weeks after their second vaccine dose in 2-dose series (such as the Pfizer or Moderna vaccines), or weeks after single-dose vaccine (such as Johnson Johnsons Janssen vaccine). See this website for more details: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.htmlvaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medicationsSee this website for more details: https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/fully-vaccinated-people.html) and -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC)Close contact with an infected individual is defined as: being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). See this website for additional details: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html or-who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)]. -have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC)Close contact with an infected individual is defined as: being within feet for total of 15 minutes or more, providing care at home to someone who is sick, having direct physical contact with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being exposed to respiratory droplets from an infected person (sneezing or coughing, for example). See this website for additional details: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html or. -who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [see Limitations of Authorized Use (1.2)].. Limitations of Authorized UseREGEN-COV is not authorized for post-exposure prophylaxis of COVID-19 in geographic regions where exposure is likely to have been to non-susceptible SARS-CoV-2 variant, based on available information including variant susceptibility to this drug and regional variant frequency.FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs. FDA will monitor conditions to determine whether use in geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility [see Microbiology/Resistance Information (15)], and CDC regional variant frequency data available at: https://covid.cdc.gov/covid-data-tracker/variant-proportions. Post-exposure prophylaxis with REGEN-COV (casirivimab and imdevimab) is not substitute for vaccination against COVID-19.REGEN-COV (casirivimab and imdevimab) is not authorized for pre-exposure prophylaxis for prevention of COVID-19.. REGEN-COV is not authorized for post-exposure prophylaxis of COVID-19 in geographic regions where exposure is likely to have been to non-susceptible SARS-CoV-2 variant, based on available information including variant susceptibility to this drug and regional variant frequency.FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs. FDA will monitor conditions to determine whether use in geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility [see Microbiology/Resistance Information (15)], and CDC regional variant frequency data available at: https://covid.cdc.gov/covid-data-tracker/variant-proportions. FDAs determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorizationcoviddrugs. FDA will monitor conditions to determine whether use in geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility [see Microbiology/Resistance Information (15)], and CDC regional variant frequency data available at: https://covid.cdc.gov/covid-data-tracker/variant-proportions. Post-exposure prophylaxis with REGEN-COV (casirivimab and imdevimab) is not substitute for vaccination against COVID-19.. REGEN-COV (casirivimab and imdevimab) is not authorized for pre-exposure prophylaxis for prevention of COVID-19.

STORAGE AND HANDLING SECTION.

Storage. Store unopened casirivimab and imdevimab vials in refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light. Unopened vials may be stored in the original carton at room temperature [up to 25C (77F)] and must be used within 30 days. If not used in the 30 days, discard vials.

USE IN SPECIFIC POPULATIONS SECTION.

11 USE IN SPECIFIC POPULATIONS. 11.1 Pregnancy. Risk SummaryThere are insufficient data to evaluate drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. REGEN-COV (casirivimab and imdevimab) should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus.Nonclinical reproductive toxicity studies have not been conducted with casirivimab and imdevimab. In tissue cross-reactivity study with casirivimab and imdevimab using human fetal tissues, no binding of clinical concern was detected. Human immunoglobulin G1 (IgG1) antibodies are known to cross the placental barrier; therefore, casirivimab and imdevimab have the potential to be transferred from the mother to the developing fetus. It is unknown whether the potential transfer of casirivimab and imdevimab provides any treatment benefit or risk to the developing fetus. There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-Associated Maternal and/or Embryo-Fetal RiskCOVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.. 11.2 Lactation. Risk SummaryThere are no available data on the presence of casirivimab and/or imdevimab in human milk or animal milk, the effects on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for REGEN-COV (casirivimab and imdevimab) and any potential adverse effects on the breastfed child from REGEN-COV or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.. 11.3 Pediatric Use. REGEN-COV is not authorized for use in pediatric patients under 12 years of age or weighing less than 40 kg. The safety and effectiveness of casirivimab and imdevimab are being assessed in pediatric and adolescent patients in an ongoing clinical trial. The recommended dosing regimen is expected to result in comparable serum exposures of casirivimab and imdevimab in patients 12 years of age and older and weighing at least 40 kg as observed in adults, since adults with similar body weight have been included in Trials COV-2067, COV-2069, and COV-2093.. 11.4 Geriatric Use. Of the 4,567 subjects with SARS-CoV-2 infection randomized in Trial COV-2067, 14% were 65 years or older, and 4% were 75 years of age or older. Of the 3,029 subjects randomized in Trial COV-2069, 9% were 65 years or older and 2% were 75 years of age or older. Of the 974 subjects randomized in Trial COV-2093, 13% were 65 years or older and 2% were 75 years of age or older. The difference in pharmacokinetics (PK) of casirivimab and imdevimab in geriatric patients compared to younger patients is unknown [see Clinical Trial Results and Supporting Data for EUA (18.1)].. 11.5 Renal Impairment. Casirivimab and imdevimab are not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of casirivimab and imdevimab.. 11.6 Hepatic Impairment. The effect of hepatic impairment on PK of casirivimab and imdevimab is unknown.. 11.7 Other Specific Populations. The effect of other covariates (e.g., sex, race, body weight, disease severity) on PK of casirivimab and imdevimab is unknown.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. There are limited clinical data available for REGEN-COV (casirivimab and imdevimab). Serious and unexpected adverse events may occur that have not been previously reported with REGEN-COV use.. 5.1 Hypersensitivity including Anaphylaxis and Infusion-Related Reactions. Serious hypersensitivity reactions, including anaphylaxis, have been reported with administration of REGEN-COV (casirivimab and imdevimab). If signs or symptoms of clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care.Infusion-related reactions, occurring during the infusion and up to 24 hours after the infusion, have been observed with administration of REGEN-COV. These reactions may be severe or life threatening.Signs and symptoms of infusion related reactions may include:fever, difficulty breathing, reduced oxygen saturation, chills, nausea, arrhythmia (e.g., atrial fibrillation, tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vasovagal reactions (e.g., pre-syncope, syncope), dizziness, fatigue, and diaphoresis [see Overall Safety Summary (6.1)].If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care.Hypersensitivity reactions occurring more than 24 hours after the infusion have also been reported with the use of REGEN-COV under Emergency Use Authorization.. fever, difficulty breathing, reduced oxygen saturation, chills, nausea, arrhythmia (e.g., atrial fibrillation, tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vasovagal reactions (e.g., pre-syncope, syncope), dizziness, fatigue, and diaphoresis [see Overall Safety Summary (6.1)].. 5.2 Clinical Worsening After REGEN-COV Administration. Clinical worsening of COVID-19 after administration of REGEN-COV has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrhythmia (e.g., atrial fibrillation, tachycardia, bradycardia), fatigue, and altered mental status. Some of these events required hospitalization. It is not known if these events were related to REGEN-COV use or were due to progression of COVID-19.. 5.3 Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, REGEN-COV is not authorized for use in patients [see Limitations of Authorized Use (1.1)]:who are hospitalized due to COVID-19, ORwho require oxygen therapy due to COVID-19, ORwho require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.. who are hospitalized due to COVID-19, OR. who require oxygen therapy due to COVID-19, OR. who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.

WARNINGS SECTION.

Warnings. There are limited clinical data available for REGEN-COV (casirivimab and imdevimab). Serious and unexpected adverse events may occur that have not been previously reported with REGEN-COV use.. Hypersensitivity Including Anaphylaxis and Infusion-Related ReactionsSerious hypersensitivity reactions, including anaphylaxis, have been observed with administration of REGEN-COV (casirivimab and imdevimab). If signs or symptoms of clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive therapy.Infusion-related reactions, occurring during the infusion and up to 24 hours after the infusion, have been observed with administration of REGEN-COV. These reactions may be severe or life-threatening.Signs and symptoms of infusion-related reactions may include:fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vasovagal reactions (e.g., pre-syncope, syncope), dizziness, and diaphoresis.Consider slowing or stopping the infusion and administer appropriate medications and/or supportive care if an infusion-related reaction occurs.Hypersensitivity reactions occurring more than 24 hours after the infusion have also been reported with the use of REGEN-COV under Emergency Use Authorization.. fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vasovagal reactions (e.g., pre-syncope, syncope), dizziness, and diaphoresis.. Clinical Worsening After REGEN-COV AdministrationClinical worsening of COVID-19 after administration of REGEN-COV has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrhythmia (e.g., atrial fibrillation, tachycardia, bradycardia), fatigue, and altered mental status. Some of these events required hospitalization. It is not known if these events were related to REGEN-COV use or were due to progression of COVID-19.. Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, REGEN-COV is not authorized for use in patients [see Limitations of Authorized Use (1.1)]:who are hospitalized due to COVID-19, ORwho require oxygen therapy due to COVID-19, ORwho require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.. who are hospitalized due to COVID-19, OR. who require oxygen therapy due to COVID-19, OR. who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.