FDA Label for Regen-cov

Authorized Use

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of the unapproved products casirivimab and imdevimab to be administered together for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults 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 progressing to severe COVID-19 and/or hospitalization.

Limitations Of Authorized Use

• Casirivimab and imdevimab are 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.
  • Benefit of treatment with casirivimab and imdevimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation with COVID-19.

  Casirivimab and imdevimab have been authorized by FDA for the emergency uses described above.

  Casirivimab and imdevimab are not FDA-approved for these uses.

  Casirivimab and imdevimab are authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of casirivimab and imdevimab under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

  Casirivimab and imdevimab carton and vial labels may instead be labeled REGN10933 and REGN10987 respectively.

  • Casirivimab and imdevimab are 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.
    • Benefit of treatment with casirivimab and imdevimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation with COVID-19 [see Warnings and Precautions (5.2)].
    
    

Boxed Warning

This EUA is for the use of the unapproved products, casirivimab and imdevimab, to be administered together for the treatment of mild to moderate COVID-19 in adults 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 progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use].

High risk is defined as patients who meet at least one of the following criteria:

• Have a body mass index (BMI) ≥35
• Have chronic kidney disease
• Have diabetes
• Have immunosuppressive disease
• Are currently receiving immunosuppressive treatment
• Are ≥65 years of age
• Are ≥55 years of age AND have
  • cardiovascular disease, OR
  • hypertension, OR
  • chronic obstructive pulmonary disease/other chronic respiratory disease.
  • Are 12 – 17 years of age AND have
    • BMI ≥85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm, OR
    • sickle cell disease, OR
    • congenital or acquired heart disease, OR
    • neurodevelopmental disorders, for example, cerebral palsy, OR
    • a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR
    • asthma, reactive airway or other chronic respiratory disease that requires daily medication for control.

    CASIRIVIMAB AND IMDEVIMAB MUST BE ADMINISTERED TOGETHER AFTER DILUTION BY INTRAVENOUS (IV) INFUSION ONLY.

    Casirivimab and imdevimab may only be administered in settings in which health care providers have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary.

    Health care providers must submit a report on all medication errors and ALL SERIOUS ADVERSE EVENTS potentially related to casirivimab and imdevimab. See Sections 8 and 9 of the Full EUA Prescribing Information for reporting instructions below.

    • The authorized dosage is 1,200 mg of casirivimab and 1,200 mg of imdevimab administered together as a single intravenous (IV) infusion as soon as possible after positive viral test for SARS-CoV-2 and within 10 days of symptom onset.
    • Casirivimab and imdevimab solutions must be diluted prior to administration.
    • Administer 1,200 mg of casirivimab and 1,200 mg of imdevimab together as a single IV infusion over at least 60 minutes via pump or gravity.
    • Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete.
    • Patients treated with casirivimab and imdevimab should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal items, 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 casirivimab and imdevimab in COVID-19, please see www.clinicaltrials.gov.

    
    

Contraindications

None.

Dosing

CASIRIVIMAB AND IMDEVIMAB MUST BE ADMINISTERED TOGETHER AFTER DILUTION BY INTRAVENOUS (IV) INFUSION ONLY.

Other

Patient Selection and Treatment Initiation

This section provides essential information on the unapproved products, casirivimab and imdevimab, for the treatment of mild to moderate COVID-19 in adults 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 progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use].

High risk is defined as patients who meet at least one of the following criteria:

• Have a body mass index (BMI) ≥35
• Have chronic kidney disease
• Have diabetes
• Have immunosuppressive disease
• Are currently receiving immunosuppressive treatment
• Are ≥65 years of age
• Are ≥55 years of age AND have
  • cardiovascular disease, OR
  • hypertension, OR
  • chronic obstructive pulmonary disease/other chronic respiratory disease.
  • Are 12 – 17 years of age AND have
    • BMI ≥85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm, OR
    • sickle cell disease, OR
    • congenital or acquired heart disease, OR
    • neurodevelopmental disorders, for example, cerebral palsy, OR
    • a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR
    • asthma, reactive airway or other chronic respiratory disease that requires daily medication for control.

    Dosage

    The dosage in adults and in pediatric patients (12 years of age and older weighing at least 40 kg) is 1,200 mg of casirivimab and 1,200 mg of imdevimab administered together as a single intravenous infusion over at least 60 minutes. Casirivimab and imdevimab solutions must be diluted prior to administration. Casirivimab and imdevimab should be given together as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset.

    Dosage Adjustment in Specific Populations

    No dosage adjustment is recommended in pregnant or lactating women and in patients with renal impairment [see Full EUA Prescribing Information, Use in Specific Populations (11)].

    Preparation and Administration

    Preparation

    Casirivimab and imdevimab are each supplied in individual single-dose vials. Casirivimab and imdevimab solutions must be diluted prior to administration.

    Casirivimab and imdevimab solution for infusion should be prepared by a 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 solution must be discarded, and fresh solution prepared.
      • The solution for each vial should be clear to slightly opalescent, colorless to pale yellow.
      • Obtain an IV infusion bag containing 250 mL of 0.9% Sodium Chloride Injection. Withdraw and discard 20 mL of 0.9% Sodium Chloride Injection from the infusion bag prior to adding casirivimab and imdevimab solutions according to Table 1.
      • Withdraw 10 mL of casirivimab and 10 mL of imdevimab from each respective vial using two separate syringes and dilute together in the infusion bag containing 0.9% Sodium Chloride Injection, see Table 1. Discard any product remaining in the vial.
      • 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. If immediate administration is not possible, store the diluted casirivimab and imdevimab infusion solution in the refrigerator between 2°C to 8°C (36°F to 46°F) for no more than 36 hours and at room temperature up to 25°C (77°F) for no more than 4 hours, including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.

      Casirivimab and imdevimab carton and vial labels may instead be labeled REGN10933 and REGN10987 respectively.

      Table 1: Recommended Dilution Instructions for Casirivimab and Imdevimab for IV Infusion

      NOTE: casirivimab = REGN10933; imdevimab = REGN10987
      Casirivimab and Imdevimab 2,400 mg Dose 1,200 mg of Casirivimab and 1,200 mg of Imdevimab are to be administered together as a single intravenous infusion for a combined 2,400 mg dose.	Antibody Dose	Volume to Withdraw from Vial	Number of Vials Needed One 11.1 mL vial of one antibody may be prepared with four 2.5 mL vials of the other antibody to create one treatment course.	Volume of 0.9% Sodium Chloride to Discard from a 250 mL Infusion Bag	Total Volume for Infusion	Maximum Infusion Rate	Minimum Infusion Time
      	Casirivimab REGN10933 1,200 mg	10 mL	1 vial of 11.1 mL OR 4 vials of 2.5 mL	20 mL	250 mL	250 mL/hr	60 minutes
      	Imdevimab REGN10987 1,200 mg	10 mL	1 vial of 11.1 mL OR 4 vials of 2.5 mL

      Administration

      Casirivimab and imdevimab infusion solution should be administered by a qualified healthcare professional using aseptic technique.

      • Gather the recommended materials for infusion:
        • 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 IV bag.
        • Prime the infusion set.
        • Administer as an IV infusion via pump or gravity over at least 60 minutes through an intravenous line containing a sterile, in-line or add-on 0.2-micron polyethersulfone (PES) filter (see Table 1).
        • The prepared infusion solution should not be administered simultaneously with any other medication. The compatibility of casirivimab and imdevimab injection with IV solutions and medications other than 0.9% Sodium Chloride Injection is not known.
        • After infusion is complete, flush with 0.9% Sodium Chloride Injection.
        • Discard unused product.
        • Clinically monitor patients during administration and observe patients for at least 1 hour after infusion is complete.

        Storage

        Refrigerate unopened vials at 2°C to 8°C (36°F to 46°F) in the individual original carton to protect from light. Do NOT freeze, shake, or expose to direct light.

        Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions

        There is a potential for serious hypersensitivity reaction, including anaphylaxis, with administration of casirivimab and imdevimab. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive therapy.

        Infusion-related reactions have been observed with administration of casirivimab and imdevimab.

        Signs and symptoms of infusion-related reactions may include:

        • fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness.

        If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care.

        Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19

        Benefit of treatment with casirivimab and imdevimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation with COVID-19. Therefore, casirivimab and imdevimab are not authorized for use in patients [see Limitations of Authorized Use]:

        • 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.

        Patient Selection and Treatment Initiation

        This section provides essential information on the unapproved products, casirivimab and imdevimab, to be administered together, for the treatment of mild to moderate COVID-19 in adults 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 progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use].

        High risk is defined as patients who meet at least one of the following criteria:

        • Have a body mass index (BMI) ≥35
        • Have chronic kidney disease
        • Have diabetes
        • Have immunosuppressive disease
        • Are currently receiving immunosuppressive treatment
        • Are ≥65 years of age
        • Are ≥55 years of age AND have
          • cardiovascular disease, OR
          • hypertension, OR
          • chronic obstructive pulmonary disease/other chronic respiratory disease.
          • Are 12 – 17 years of age AND have
            • BMI ≥85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm, OR
            • sickle cell disease, OR
            • congenital or acquired heart disease, OR
            • neurodevelopmental disorders, for example, cerebral palsy, OR
            • a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR
            • asthma, reactive airway or other chronic respiratory disease that requires daily medication for control.

            Pregnancy or Lactation

            No dosage adjustment is recommended in pregnant or lactating women [see Use in Specific Populations (11.1, 11.2)].

            Pediatric Use

            No dosage adjustment is recommended in pediatric patients who weigh at least 40 kg and are older than 12 years of age. Casirivimab and imdevimab are 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 Impairment

            No dosage adjustment is recommended in patients with renal impairment [see Use in Specific Populations (11.5)].

            Preparation

            Casirivimab and imdevimab are each supplied in individual single-dose vials. Casirivimab and imdevimab solutions must be diluted prior to administration.

            Casirivimab and imdevimab infusion solution should be prepared by a 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 solution must be discarded, and fresh solution prepared. The solution for each vial should be clear to slightly opalescent, colorless to pale yellow.
            • Obtain an IV infusion bag containing 250 mL of 0.9% Sodium Chloride Injection. Withdraw and discard 20 mL of 0.9% Sodium Chloride Injection from the infusion bag prior to adding casirivimab and imdevimab according to Table 2.
            • Withdraw 10 mL of casirivimab and 10 mL of imdevimab from each respective vial using two separate syringes and dilute together in the infusion bag containing 0.9% Sodium Chloride Injection, see Table 2. Discard any product remaining in the vial.
            • Gently invert infusion bag by hand approximately 10 times. Do not shake.
              This product is preservative-free and therefore, the diluted infusion solution should be administered immediately. If immediate administration is not possible, store the diluted casirivimab and imdevimab infusion solution in the refrigerator between 2°C to 8°C (36°F to 46°F) for no more than 36 hours and at room temperature up to 25°C (77°F) for no more than 4 hours, including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.

            Table 2: Recommended Dilution Instructions for Casirivimab and Imdevimab for IV Infusion

            NOTE: casirivimab = REGN10933; imdevimab = REGN10987
            Casirivimab and Imdevimab 2,400 mg Dose 1,200 mg of Casirivimab and 1,200 mg of Imdevimab are to be administered together as a single intravenous infusion for a combined 2,400 mg dose.	Antibody Dose	Volume to Withdraw from Vial	Number of Vials Needed One 11.1 mL vial of one antibody may be prepared with four 2.5 mL vials of the other antibody to create one treatment course.	Volume of 0.9% Sodium Chloride to Discard from a 250 mL Infusion Bag	Total Volume for Infusion	Maximum Infusion Rate	Minimum Infusion Time
            	Casirivimab REGN10933 1,200 mg	10 mL	1 vial of 11.1 mL OR 4 vials of 2.5 mL	20 mL	250 mL	250 mL/hr	60 minutes
            	Imdevimab REGN10987 1,200 mg	10 mL	1 vial of 11.1 mL OR 4 vials of 2.5 mL

            Administration

            Casirivimab and imdevimab infusion solution should be administered by a qualified healthcare professional using aseptic technique.

            • Gather the recommended materials for infusion:
              • 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 IV bag.
              • Prime the infusion set.
              • Administer as an IV infusion via pump or gravity over at least 60 minutes through an intravenous line containing a sterile, in-line or add-on 0.2-micron polyethersulfone (PES) filter (see Table 2).
              • The prepared infusion solution should not be administered simultaneously with any other medication. The compatibility of casirivimab and imdevimab injection with IV solutions and medications other than 0.9% Sodium Chloride Injection is not known.
              • After infusion is complete, flush with 0.9% Sodium Chloride Injection.
              • Discard unused product.
              • Clinically monitor patients during administration and observe patients for at least 1 hour after infusion is complete.

              Storage

              This product is preservative-free and therefore, the diluted infusion solution should be administered immediately. If immediate administration is not possible, store the diluted casirivimab and imdevimab infusion solution in the refrigerator between 2°C to 8°C (36°F to 46°F) for no more than 36 hours and at room temperature up to 25°C (77°F) for no more than 4 hours, including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.

              Hypersensitivity Including Anaphylaxis and Infusion-related Reactions

              One anaphylactic reaction was reported in the clinical program. The event began within 1 hour of completion of the infusion, and required treatment including epinephrine. The event resolved. Infusion-related reactions, of grade 2 or higher severity, were reported in 4 subjects (1.5%) in the 8,000 mg (4,000 mg casirivimab and 4,000 mg imdevimab) arm. These infusion-related reactions events were moderate in severity; and include pyrexia, chills, urticaria, pruritus, abdominal pain, and flushing. One infusion-related reaction (nausea) was reported in the placebo arm and none were reported in the 2,400 mg (1,200 mg casirivimab and 1,200 mg imdevimab) arm.

              In two subjects receiving the 8,000 mg dose of casirivimab and imdevimab, the infusion-related reactions (urticaria, pruritus, flushing, pyrexia, shortness of breath, chest tightness, nausea, vomiting) resulted in permanent discontinuation of the infusion. All events resolved [see Warnings and Precautions (5.1)].

              Risk Summary

              There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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 a 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.

              The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 2 to 4% and 15 to 20%, respectively.

              Risk Summary

              There 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 mother's clinical need for casirivimab and imdevimab and any potential adverse effects on the breastfed child from casirivimab and imdevimab 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.

              Specific Populations

              The 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 Interactions

              Casirivimab 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)].

              Antiviral Activity

              In a SARS-CoV-2 virus neutralization assay in Vero E6 cells, casirivimab, imdevimab, and the casirivimab + imdevimab combination neutralized SARS-CoV-2 (USA-WA1/2020 isolate) with EC₅₀ values of 37.4 pM (0.006 μg/mL), 42.1 pM (0.006 μg/mL), and 31.0 pM (0.005 μg/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 the casirivimab + imdevimab combination mediated ADCC with human natural killer (NK) effector cells. Casirivimab, imdevimab and the casirivimab + imdevimab combination mediated ADCP with human macrophages. Casirivimab, imdevimab and the casirivimab + imdevimab combination did not mediate complement-dependent cytotoxicity in cell-based assays.

              Antibody Dependent Enhancement (ADE) of Infection

              The potential of casirivimab and of imdevimab to mediate viral entry was assessed in immune cell lines co-incubated with recombinant vesicular stomatitis virus (VSV) pseudoparticles expressing SARS-CoV-2 spike protein at concentrations of mAb(s) down to approximately 10-fold below the respective neutralization EC₅₀ values. The casirivimab + imdevimab combination and imdevimab alone, but not casirivimab alone, mediated entry of pseudoparticles into FcγR2⁺ Raji and FcγR1⁺/FcγR2⁺ THP1 cells (maximum infection in total cells of 1.34% and 0.24%, respectively, for imdevimab; 0.69% and 0.06%, respectively for the casirivimab + imdevimab combination), but not any other cell lines tested (IM9, K562, Ramos and U937 cells).

              Antiviral Resistance

              There is a potential risk of treatment failure due to the development of viral variants that are resistant to the casirivimab + imdevimab combination.

              Escape variants were identified following passage in cell culture of recombinant VSV encoding SARS-CoV-2 spike protein in the presence of casirivimab or imdevimab individually, but not following passage in the presence of the casirivimab + imdevimab combination. Variants which showed reduced susceptibility to casirivimab included spike protein amino acid substitutions K417E, Y453F, L455F, F486V and Q493K, and variants which showed reduced susceptibility to imdevimab included K444Q and V445A substitutions. Each variant showing reduced susceptibility to one mAb retained susceptibility to the other, and all variants retained susceptibility to the casirivimab + imdevimab combination.

              In neutralization assays using VSV pseudotyped with 37 different receptor binding domain (RBD) variants identified as the most common RBD variations in circulation as of late March 2020, and D614G, D614N spike protein variants, casirivimab had reduced susceptibility (4.5-fold) to G476S and S494P variants, and imdevimab had reduced susceptibility (463-fold) to the N439K variant. The casirivimab + imdevimab combination retained activity against all variants tested.

              In clinical trial R10933-10987-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 a single time point (two at baseline in subjects from placebo and 2,400 mg casirivimab + imdevimab combination groups, and one at Day 25 in a subject from the 8,000 mg casirivimab + imdevimab combination group). The G446V variant had reduced susceptibility to imdevimab of 135-fold compared to wild-type in a VSV pseudoparticle neutralization assay but retained susceptibility to casirivimab and the casirivimab + imdevimab combination.

              It is possible that resistance-associated variants to the casirivimab + imdevimab combination could have cross-resistance to other mAbs targeting the receptor binding domain of SARS-CoV-2. The clinical impact is not known.

              Immune Response Attenuation

              There is a theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection.

              How Supplied

              Casirivimab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution supplied in a single-dose vial. Refer to Table 5.

              Imdevimab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution supplied in a single-dose vial. Refer to Table 5.

              CASIRIVIMAB AND IMDEVIMAB MUST BE ADMINISTERED TOGETHER.

              Table 5: How Casirivimab and Imdevimab are Supplied

              Antibody	Concentration	Package Size	NDC Number
              Casirivimab REGN 10933	1332 mg/11.1 mL (120 mg/mL)	1 vial per pack	61755-024-01
              	300 mg/2.5 mL (120 mg/mL)	1 vial per pack	61755-026-01
              Imdevimab REGN10987	1332 mg/11.1 mL (120 mg/mL)	1 vial per pack	61755-025-01
              	300 mg/2.5 mL (120 mg/mL)	1 vial per pack	61755-027-01

              
              

Warnings

There are limited clinical data available for casirivimab and imdevimab. Serious and unexpected adverse events may occur that have not been previously reported with casirivimab and imdevimab use.

Side Effects

Adverse events have been reported with casirivimab and imdevimab [see Full EUA Prescribing Information, Clinical Trials Experience (6.1)].

Additional adverse events associated with casirivimab and imdevimab, some of which may be serious, may become apparent with more widespread use.

Instructions For Health Care Providers

As the health care provider, you must communicate to your patient or parent/caregiver, as age appropriate, information consistent with the "Fact Sheet for Patients, Parents and Caregivers" (and provide a copy of the Fact Sheet) prior to the patient receiving casirivimab and imdevimab, including:

• FDA has authorized the emergency use of casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in adults 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 progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use].
• The patient or parent/caregiver has the option to accept or refuse casirivimab and imdevimab.
• The significant known and potential risks and benefits of casirivimab and imdevimab, and the extent to which such risks and benefits are unknown.
• Information on available alternative treatments and the risks and benefits of those alternatives, including clinical trials.
• Patients treated with casirivimab and imdevimab should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal items, clean and disinfect "high touch" surfaces, and frequent handwashing) according to CDC guidelines.

For information on clinical trials that are testing the use of casirivimab and imdevimab related to COVID-19, please see www.clinicaltrials.gov.

Mandatory Requirements For Casirivimab And Imdevimab Under Emergency Use Authorization:

In order to mitigate the risks of using this unapproved product under EUA and to optimize the potential benefit of casirivimab and imdevimab to be administered together, the following items are required. Use of casirivimab and imdevimab under this EUA is limited to the following (all requirements must be met):

• Treatment of mild to moderate COVID-19 in adults 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 progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use].
• As the health care provider, communicate to your patient or parent/caregiver, as age appropriate, information consistent with the "Fact Sheet for Patients, Parents and Caregivers" prior to the patient receiving casirivimab and imdevimab. Health care providers (to the extent practicable given the circumstances of the emergency) must document in the patient's medical record that the patient/caregiver has been:
  • a.Given the "Fact Sheet for Patients, Parents and Caregivers",
  • b.Informed of alternatives to receiving casirivimab and imdevimab, and
  • c.Informed that casirivimab and imdevimab are unapproved drugs that are authorized for use under this Emergency Use Authorization.
  • Patients with known hypersensitivity to any ingredient of casirivimab and imdevimab must not receive casirivimab and imdevimab.
  • The prescribing health care provider and/or the provider's designee are/is responsible for mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of casirivimab and imdevimab.
  • The prescribing health care provider and/or the provider's designee are/is responsible for mandatory reporting of all medication errors and serious adverse events* potentially related to casirivimab and imdevimab treatment within 7 calendar days from the onset of the event. The reports should include unique identifiers and the words "Casirivimab and imdevimab treatment under Emergency Use Authorization (EUA)" in the description section of the report.
    • Submit adverse event reports to FDA MedWatch using one of the following methods:
      • Complete and submit the report online:
        www.fda.gov/medwatch/report.htm, or
      • By using a postage-paid Form FDA 3500 (available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or
      • Call 1-800-FDA-1088 to request a reporting form
      • Submitted reports should include in the field name, "Describe Event, Problem, or Product Use/Medication Error" a statement "Casirivimab and imdevimab treatment under Emergency Use Authorization (EUA)."
      *Serious Adverse Events are defined as:
      • death;
      • a life-threatening adverse event;
      • inpatient hospitalization or prolongation of existing hospitalization;
      • a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions;
      • a congenital anomaly/birth defect;
      • a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.
      • OTHER REPORTING REQUIREMENTS
        In addition, please provide a copy of all FDA MedWatch forms to:
        Regeneron Pharmaceuticals, Inc
        Fax: 1-888-876-2736
        E-mail: [email protected]
        Or call Regeneron Pharmaceuticals at 1-844-734-6643 to report adverse events.
      
      

Approved Available Alternatives

There is no adequate, approved and available alternatives to casirivimab and imdevimab to be administered together for patients who have mild to moderate COVID-19 who are at high risk for progressing to severe COVID-19 and/or hospitalization. Additional information on COVID-19 treatments can be found at https://www.cdc.gov/coronavirus/2019-ncov/index.html. The health care provider should visit https://clinicaltrials.gov/ to determine whether the patient may be eligible for enrollment in a clinical trial.

Authority For Issuance Of The Eua

The Secretary of the Department of Health and Human Services (HHS) has declared a public health emergency that justifies the emergency use of drugs and biological products during the COVID-19 pandemic. FDA has issued this EUA, requested by Regeneron Pharmaceuticals, Inc. for the unapproved products, casirivimab and imdevimab, to be administered together, for the treatment of mild to moderate COVID-19 in adults 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 progressing to severe COVID-19 and/or hospitalization.

The health care provider should visit https://clinicaltrials.gov/ to determine whether there is an active clinical trial for the product in this disease/condition and whether enrollment of the patient(s) in a clinical trial is more appropriate than product use under this EUA.

Although limited scientific information is available, based on the totality of the scientific evidence available to date, it is reasonable to believe that casirivimab and imdevimab, administered together, may be effective for the treatment of COVID-19 in patients as specified in this Fact Sheet. You may be contacted and asked to provide information to help with the assessment of the use of the product during this emergency.

This EUA for casirivimab and imdevimab will end when the Secretary determines that the circumstances justifying the EUA no longer exist or when there is a change in the approval status of the product such that an EUA is no longer needed.

Contact Information

For additional information visit www.REGENCOV2.com

If you have questions, please contact Regeneron at 1-844-734-6643.

Full Eua Prescribing Information

1 Authorized Use

Casirivimab and imdevimab are authorized to be administered together for use under an EUA for the treatment of mild to moderate COVID-19 in adults 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 progressing to severe COVID-19 and/or hospitalization.

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.

CASIRIVIMAB AND IMDEVIMAB MUST BE ADMINISTERED TOGETHER AFTER DILUTION BY INTRAVENOUS (IV) INFUSION ONLY.

2.2 Dosage

The dosage in adults and pediatric patients (12 years of age and older weighing at least 40 kg) is 1,200 mg of casirivimab and 1,200 mg of imdevimab administered together as a single intravenous infusion. Casirivimab and imdevimab solutions must be diluted prior to administration.

Casirivimab and imdevimab should be given as soon as possible after a positive viral test for SARS-CoV-2 and within 10 days of symptom onset.

3 Dosage Forms And Strengths

Casirivimab is a 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) in a single-dose vial

Imdevimab is a 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) in a single-dose vial

Casirivimab and imdevimab carton and vial labels may instead be labeled REGN10933 and REGN10987 respectively.

4 Contraindications

None.

5 Warnings And Precautions

There are limited clinical data available for casirivimab and imdevimab. Serious and unexpected adverse events may occur that have not been previously reported with casirivimab and imdevimab use.

5.1 Hypersensitivity Including Anaphylaxis And Infusion-Related Reactions

There is a potential for serious hypersensitivity reactions, including anaphylaxis, with administration of casirivimab and imdevimab. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care.

Infusion-related reactions have been observed with administration of casirivimab and imdevimab.

Signs and symptoms of infusion related reactions may include:

• fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness.

If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care.

5.2 Limitations Of Benefit And Potential For Risk In Patients With Severe Covid-19

Benefit of treatment with casirivimab and imdevimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation with COVID-19. Therefore, casirivimab and imdevimab are not authorized for use in patients [see Limitations of Authorized Use]:

• 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.

6 Overall Safety Summary

Overall more than 2,100 subjects have been exposed to IV casirivimab and imdevimab in clinical trials in both hospitalized and non-hospitalized patients.

6.1 Clinical Trials Experience

The safety of casirivimab and imdevimab is based on analysis from one phase 1/2 trial of 799 ambulatory (non-hospitalized) subjects with COVID-19.

R10933-10987-COV-2067 is a randomized, double-blind, placebo-controlled clinical trial in ambulatory adults with mild to moderate COVID-19 symptoms who had a sample collected for the first positive SARS-CoV-2 viral infection determination within 3 days prior to the start of the infusion. Subjects were treated with a single infusion of 2,400 mg (1,200 mg casirivimab and 1,200 mg imdevimab) (N=258) or 8,000 mg (4,000 mg casirivimab and 4,000 mg imdevimab) (N=260), or placebo (n=262). The adverse events collected were infusion-related reactions and hypersensitivity reactions of moderate severity or higher through day 29, all serious adverse events (SAEs); and in phase 1 only, all grade 3 and 4 treatment-emergent adverse events.

Serious adverse events were reported in 4 subjects (1.6%) in the casirivimab and imdevimab 2,400 mg group, 2 subjects (0.8%) in the casirivimab and imdevimab 8,000 mg group, and 6 subjects (2.3%) in the placebo group. None of the SAEs were considered to be related to study drug. SAEs that were reported as Grade 3 or 4 adverse events were pneumonia, hyperglycemia, nausea and vomiting (2,400 mg casirivimab and imdevimab), intestinal obstruction and dyspnea (8,000 mg casirivimab and imdevimab) and COVID-19, pneumonia and hypoxia (placebo). Casirivimab and imdevimab are not authorized at the 8,000 mg dose (4,000 mg casirivimab and 4,000 mg imdevimab).

7 Patient Monitoring Recommendations

Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete [see Warnings and Precautions (5.1) and Clinical Trials Experience (6.1)].

8 Adverse Reactions And Medication Errors Reporting Requirements And Instructions

Clinical trials evaluating the safety of casirivimab and imdevimab are ongoing [see Overall Safety Summary (6)].

Completion of FDA MedWatch Form to report all medication errors and serious adverse events* occurring during casirivimab and imdevimab use and considered to be potentially related to casirivimab and imdevimab is mandatory and must be done by the prescribing healthcare provider and/or the provider's designee. These adverse events must be reported within 7 calendar days from the onset of the event:

*Serious Adverse Events are defined as:

• death;
• a life-threatening adverse event;
• inpatient hospitalization or prolongation of existing hospitalization;
• a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions;
• a congenital anomaly/birth defect;
• a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.

If a serious and unexpected adverse event occurs and appears to be associated with the use of casirivimab and imdevimab, the prescribing health care provider and/or the provider's designee should complete and submit a MedWatch form to FDA using one of the following methods:

• Complete and submit the report online: www.fda.gov/medwatch/report.htm, or
• Use a postage-paid Form FDA 3500 (available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or
• Call 1-800-FDA-1088 to request a reporting form

IMPORTANT: When reporting adverse events or medication errors to MedWatch, please complete the entire form with detailed information. It is important that the information reported to FDA be as detailed and complete as possible. Information to include:

• Patient demographics (e.g., patient initials, date of birth)
• Pertinent medical history
• Pertinent details regarding admission and course of illness
• Concomitant medications
• Timing of adverse event(s) in relationship to administration of casirivimab and imdevimab
• Pertinent laboratory and virology information
• Outcome of the event and any additional follow-up information if it is available at the time of the MedWatch report. Subsequent reporting of follow-up information should be completed if additional details become available.

The following steps are highlighted to provide the necessary information for safety tracking:

• In section A, box 1, provide the patient's initials in the Patient Identifier
• In section A, box 2, provide the patient's date of birth or age
• In section B, box 5, description of the event:
  • a.Write "Casirivimab and imdevimab treatment under Emergency Use Authorization (EUA)" as the first line
  • b.Provide a detailed report of medication error and/or adverse event. It is important to provide detailed information regarding the patient and adverse event/medication error for ongoing safety evaluation of this unapproved drug. Please see information to include listed above.
  • In section G, box 1, name and address:
    • a.Provide the name and contact information of the prescribing health care provider or institutional designee who is responsible for the report
    • b.Provide the address of the treating institution (NOT the health care provider's office address).
    
    

9 Other Reporting Requirements

In addition, please provide a copy of all FDA MedWatch forms to:

Regeneron Pharmaceuticals, Inc

Fax: 1-888-876-2736

E-mail: [email protected]

Or call Regeneron Pharmaceuticals at 1-844-734-6643 to report adverse events.

10 Drug Interactions

Casirivimab and imdevimab are 2 monoclonal antibodies (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.

11.3 Pediatric Use

The safety and effectiveness of casirivimab and imdevimab have not been assessed in pediatric patients. 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 Trial R10933-10987-COV-2067.

11.4 Geriatric Use

Of the 799 patients with SARS-CoV-2 infection randomized in Trial R10933-10987-COV-2067, 7% were 65 years or older, and 2% were 75 years of age or older. The difference in PK of casirivimab and imdevimab in geriatric patients compared to younger patients is unknown.

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.

12 Overdosage

Doses up to 8,000 mg (4,000 mg each of casirivimab and imdevimab, greater than 3 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 casirivimab and imdevimab.

13 Product Description

Casirivimab, a human immunoglobulin G-1 (IgG1) monoclonal antibody (mAb), is a covalent heterotetramer consisting of 2 heavy chains and 2 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 a sterile, preservative-free, clear to slightly opalescent and colorless to pale yellow solution in a single-dose vial for intravenous infusion after dilution available as a 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.

• 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, a human IgG1 mAb, is a covalent heterotetramer consisting of 2 heavy chains and 2 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 a sterile, preservative-free, clear to slightly opalescent and colorless to pale yellow solution in a single-dose vial for intravenous infusion after dilution available as a 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.

• 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.

14.1 Mechanism Of Action

Casirivimab (IgG1κ) and imdevimab (IgG1λ) 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 K_D = 45.8 pM and 46.7 pM, respectively. Casirivimab, imdevimab and the casirivimab + imdevimab combination blocked RBD binding to the human ACE2 receptor with IC₅₀ values of 56.4 pM, 165 pM and 81.8 pM, respectively [see Microbiology/Resistance Information (15)].

14.2 Pharmacodynamics

Trial R10933-10987-COV-2067 evaluated casirivimab and imdevimab with doses of 1 and 3.33 times the recommended doses (1,200 mg casirivimab and 1,200 mg imdevimab; 4,000 mg casirivimab and 4,000 mg imdevimab) in ambulatory patients with COVID-19. A flat dose-response relationship for efficacy was identified for casirivimab and imdevimab at those two doses, based on viral load and clinical outcomes.

14.3 Pharmacokinetics

Pharmacokinetic profiles of casirivimab and imdevimab are expected to be consistent with the profile of other IgG1 mAbs.

16 Nonclinical Toxicology

Carcinogenicity, genotoxicity, and reproductive toxicology studies have not been conducted with casirivimab and imdevimab.

In a toxicology study in cynomolgus monkeys, casirivimab and imdevimab had no adverse effects when administered intravenously. 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.

17 Animal Pharmacologic And Efficacy Data

The casirivimab + imdevimab combination has been assessed in rhesus macaque and Syrian golden hamster treatment models of SARS-CoV-2 infection. Therapeutic administration of the casirivimab + imdevimab combination 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 4 post-challenge in most animals, and reduced lung pathology relative to placebo-treated animals. Therapeutic administration of the casirivimab + imdevimab combination at 5 mg/kg and 50 mg/kg doses to hamsters 1-day post infection resulted in reduced weight loss relative to placebo treated animals, but had no clear effects on viral load in lung tissue. The applicability of these findings to a clinical setting is not known.

18.1 Mild To Moderate Covid-19 (R10933-10987-Cov-2067)

The data supporting this EUA are based on the analysis of Phase 1/2 from trial R10933-10987-COV-2067, that occurred after 799 enrolled subjects had completed at least 28 days of study duration. R10933-10987-COV-2067 is a randomized, double-blinded, placebo-controlled clinical trial studying casirivimab and imdevimab for the treatment of adult subjects with mild to moderate COVID-19 (subjects with COVID-19 symptoms who are not hospitalized). The trial enrolled adult subjects who were not hospitalized and had at least 1 or more COVID-19 symptoms that were at least mild in severity. Treatment was initiated within 3 days of obtaining a positive SARS-CoV-2 viral infection determination. Subjects were randomized in a 1:1:1 manner to receive a single intravenous (IV) infusion of 2,400 mg of casirivimab and imdevimab (1,200 mg of each) (n=266), or 8,000 mg of casirivimab and imdevimab (4,000 mg of each) (n=267), or placebo (n=266).

At baseline, the median age was 42 years (with 7% of subjects ages 65 years or older), 53% of the subjects were female, 85% were White, 50% were Hispanic or Latino, and 9% were Black; 34% were considered high risk (as defined in Section 2). Approximately 31% of subjects reported at least 1 severe symptom at baseline, 36% reported at least 1 moderate symptom and no severe symptoms, and 13% reported only mild symptoms. The median duration of symptoms was 3 days; mean viral load was 5.8 log₁₀ copies/mL at baseline. The baseline demographics and disease characteristics were well balanced across the casirivimab and imdevimab and placebo treatment groups.

The pre-specified primary endpoint in Phase 1/2 of trial R10933-10987-COV-2067 was the time weighted average (TWA) change from baseline in viral load (log₁₀ copies/mL), as measured by RT-qPCR in nasopharyngeal swab samples, in subjects with a positive baseline RT-qPCR value, i.e., the modified full analysis set (mFAS). In the mFAS for the Phase 1/2 analysis, the difference in TWA from Day 1 through Day 7 for the pooled doses of casirivimab and imdevimab compared with placebo (n=665) was -0.36 log₁₀ copies/mL (p<0.0001). The largest reductions in viral load relative to placebo occurred in patients with high viral load (-0.78 log₁₀ copies/mL) or who were seronegative (-0.69 log₁₀ copies/mL) at baseline. Reductions occurring from Day 1 through Day 11 were similar to those for Day 1 through Day 7. Figure 1 shows the mean change from baseline in SARS-COV-2 viral load over time.

Figure 1. Mean Change from Baseline in SARS-COV-2 Viral Load Over Time

Figure 1 - casirivimab imdevimab 01

While viral load was used to define the primary endpoint in the Phase 1/2 analysis, clinical evidence demonstrating that casirivimab and imdevimab may be effective came from the predefined secondary endpoint, medically attended visits (MAV) related to COVID-19. Medically attended visits comprised hospitalizations, emergency room visits, urgent care visits, or physician office/telemedicine visits for COVID-19. A lower proportion of subjects treated with casirivimab and imdevimab had COVID-19 related MAVs (2.8% for combined treatment arms vs 6.5% placebo). In post-hoc analyses, a lower proportion of subjects treated with casirivimab and imdevimab had COVID-19-related hospitalizations or emergency room visits compared to placebo, see Table 3. Results for this endpoint were suggestive of a relatively flat dose-response relationship. The absolute risk reduction for casirivimab and imdevimab compared to placebo was greater in subjects at high risk for progression to severe COVID-19 and/or hospitalization, according to the criteria outlined in section 2 (Table 4).

The median time to symptom improvement, as recorded in a trial-specific daily symptom diary, was 5 days for casirivimab and imdevimab-treated subjects, as compared with 6 days for placebo-treated subjects. Symptoms assessed were shortness of breath or difficulty breathing, chills, feverish, sore throat, cough, nausea, vomiting, diarrhea, headache, red or watery eyes, body and muscle aches, loss of taste or smell, fatigue, loss of appetite, confusion, dizziness, pressure or tight chest, chest pain, stomach ache, rash, sneezing, sputum/phlegm, runny nose. Symptom improvement was defined as symptoms scored as moderate or severe at baseline being scored as mild or absent, and symptoms scored as mild or absent at baseline being scored as absent.

Storage And Handling

Storage and Handling

Casirivimab is preservative-free. Discard any unused portion.

Imdevimab is preservative-free. Discard any unused portion.

Store unopened casirivimab and imdevimab vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

DO NOT FREEZE. DO NOT SHAKE. DO NOT EXPOSE TO DIRECT LIGHT.

Solution in vial requires dilution prior to administration. The prepared infusion solution is intended to be used immediately. If immediate administration is not possible, store diluted casirivimab and imdevimab solution in the refrigerator at 2°C to 8°C (36°F to 46°F) for no more than 36 hours and at room temperature up to 25°C (77°F) for no more than 4 hours, including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.

20 Patient Counseling Information

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

21 Contact Information

For additional information visit www.REGENCOV2.com

If you have questions, please contact Regeneron at 1-844-734-6643.

Manufactured by:
Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road
Tarrytown, NY 10591-6707
©2020 Regeneron Pharmaceuticals, Inc. All rights reserved.
Authorized: 11/2020

Spl Patient Package Insert

FACT SHEET FOR PATIENTS, PARENTS AND CAREGIVERS
EMERGENCY USE AUTHORIZATION (EUA) OF CASIRIVIMAB AND IMDEVIMAB FOR CORONAVIRUS DISEASE 2019
(COVID-19)

You are being given a medicine called casirivimab and imdevimab for the treatment of coronavirus disease 2019 (COVID-19). This Fact Sheet contains information to help you understand the potential risks and potential benefits of taking casirivimab and imdevimab, which you may receive.

Receiving casirivimab and imdevimab may benefit certain people with COVID-19.

Read this Fact Sheet for information about casirivimab and imdevimab. Talk to your healthcare provider if you have questions. It is your choice to receive casirivimab and imdevimab or stop at any time.

WHAT IS COVID-19?

COVID-19 is caused by a virus called a coronavirus. 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 occur 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, seem to be at higher risk of being hospitalized for COVID-19.

WHAT ARE THE SYMPTOMS OF COVID-19?

The symptoms of COVID-19 include fever, cough, and shortness of breath, which may appear 2 to 14 days after exposure. Serious illness including breathing problems can occur and may cause your other medical conditions to become worse.

WHAT IS CASIRIVIMAB AND IMDEVIMAB?

Casirivimab and imdevimab are investigational medicines used to treat mild to moderate symptoms of COVID-19 in non-hospitalized adults and adolescents (12 years of age and older who weigh at least 88 pounds (40 kg)), and who are at high risk for developing severe COVID-19 symptoms or the need for hospitalization. Casirivimab and imdevimab are investigational because they are still being studied. There is limited information known about the safety and effectiveness of using casirivimab and imdevimab to treat people with COVID-19.

The FDA has authorized the emergency use of casirivimab and imdevimab for the treatment 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.

WHAT SHOULD I TELL MY HEALTH CARE PROVIDER BEFORE I RECEIVE CASIRIVIMAB AND IMDEVIMAB?

Tell your healthcare provider about all of your medical conditions, including if you:

• Have any allergies
• Are pregnant or plan to become pregnant
• Are breastfeeding or plan to breastfeed
• Have any serious illnesses
• Are taking any medications (prescription, over-the-counter, vitamins, and herbal products)

HOW WILL I RECEIVE CASIRIVIMAB AND IMDEVIMAB?

• Casirivimab and imdevimab are two investigational medicines given together as a single intravenous infusion (through a vein) for at least 1 hour.
• You will receive one dose of casirivimab and imdevimab by intravenous infusion.

WHAT ARE THE IMPORTANT POSSIBLE SIDE EFFECTS OF CASIRIVIMAB AND IMDEVIMAB?

Possible side effects of casirivimab and imdevimab are:

• Allergic reactions. Allergic reactions can happen during and after infusion with casirivimab and imdevimab. Tell your healthcare provider or nurse, or get medical help right away if you get any of the following signs and symptoms of allergic reactions: fever, chills, low blood pressure, changes in your heartbeat, shortness of breath, wheezing, swelling of your lips, face, or throat, rash including hives, itching, headache, nausea, vomiting, sweating, muscle aches, dizziness and shivering.

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.

These are not all the possible side effects of casirivimab and imdevimab. Not a lot of people have been given casirivimab and imdevimab. Serious and unexpected side effects may happen. Casirivimab and imdevimab are still being studied so it is possible that all of the risks are not known at this time.

It is possible that casirivimab and imdevimab could interfere with your body's own ability to fight off a future infection of SARS-CoV-2. Similarly, casirivimab and imdevimab may reduce your body's immune response to a 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 THERE?

Like casirivimab and imdevimab, FDA may allow for the emergency use of other medicines to treat people with COVID-19. Go to https://www.covid19treatmentguidelines.nih.gov/ for information on other medicines used to treat people with COVID-19.

It is your choice to be treated or not to be treated with casirivimab and imdevimab. Should you decide not to receive casirivimab and imdevimab or stop it at any time, it will not change your standard medical care.

WHAT IF I AM PREGNANT OR BREASTFEEDING?

There is limited experience treating pregnant women or breastfeeding mothers with casirivimab and imdevimab. For a mother and unborn baby, the benefit of receiving casirivimab and imdevimab may be greater than the risk from the treatment. If you are pregnant or breastfeeding, discuss your options and specific situation with your healthcare provider.

HOW DO I REPORT SIDE EFFECTS WITH 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 I LEARN MORE?

• Ask your health care provider.
• Visit www.REGENCOV2.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 casirivimab and imdevimab available under an emergency access mechanism called an EUA. The EUA is supported by a 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.

Casirivimab and imdevimab have not undergone the same type of review as an FDA-approved or cleared product. The FDA may issue an EUA when certain criteria are met, which includes that there are no adequate, approved, available alternatives. In addition, the FDA decision is based on the totality of scientific evidence available showing that it is reasonable to believe that the product meets certain criteria for safety, performance, and labeling and may be effective in treatment of patients during the COVID-19 pandemic. All of these criteria must be met to allow for the product to be used in the treatment of patients during the COVID-19 pandemic.

The EUA for casirivimab and imdevimab 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 Road
Tarrytown, NY 10591-6707

©2020 Regeneron Pharmaceuticals, Inc. All rights reserved.
Authorized: 11/2020

Principal Display Panel - 300 Mg/2.5 Ml Vial Label - Casirivimab

701208

12345-00

Casirivimab
Injection

NDC 61755-026-00
Rx only

300 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 - casirivimab imdevimab 02

Principal Display Panel - 300 Mg/2.5 Ml Vial Carton - Casirivimab

NDC 61755-026-01

Rx only

Casirivimab
Injection

300 mg/2.5 mL (120 mg/mL)

For Intravenous Infusion after Dilution

For use under Emergency Use Authorization (EUA)

MUST ADMINISTER WITH IMDEVIMAB

Contains 1 Single-Dose Vial

Discard unused portion

PRINCIPAL DISPLAY PANEL - 300 mg/2.5 mL Vial Carton - Casirivimab - casirivimab imdevimab 03

Principal Display Panel - 300 Mg/2.5 Ml Modified Vial Label - Regn10933

701208

Subject Number

Solution for intravenous infusion or subcutaneous injection.
Administer in accordance with protocol instructions.
Store refrigerated at 2°C–8°C (36°F–46°F)
in original carton to protect from light.

Keep Out of Reach of Children. For Clinical Trial Use Only.

Caution: New Drug - Limited by Federal (or United States)
law to investigational use. Regeneron Pharmaceuticals, Inc.
Tarrytown, NY 10591 USA Tel: +1 914-847-7000

Lot

PRINCIPAL DISPLAY PANEL - 300 mg/2.5 mL Modified Vial Label - REGN10933 - casirivimab imdevimab 04

Principal Display Panel - 300 Mg/2.5 Ml Modified Vial Carton - Regn10933

Subject Number
Investigator
Date Dispensed

Contains:
1 vial Solution for intravenous infusion or subcutaneous injection

Administer in accordance with protocol instructions.

Store refrigerated at 2°C–8°C (36°F–46°F) in the original carton to
protect from light.

Keep Out of Reach of Children. For Clinical Trial Use Only.

Caution: New Drug - Limited by Federal (or United States) law to
investigational use.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 USA
Tel: +1 914-847-7000

PRINCIPAL DISPLAY PANEL - 300 mg/2.5 mL Modified Vial Carton - REGN10933 - casirivimab imdevimab 05

Principal Display Panel - 1332 Mg/11.1 Ml Vial Label - Casirivimab

701210

12345-00

Casirivimab
Injection

NDC 61755-024-00
Rx only

1332 mg/11.1 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.

PRINCIPAL DISPLAY PANEL - 1332 mg/11.1 mL Vial Label - Casirivimab - casirivimab imdevimab 06

Principal Display Panel - 1332 Mg/11.1 Ml Vial Carton - Casirivimab

NDC 61755-024-01

Rx only

Casirivimab
Injection

1332 mg/11.1 mL (120 mg/mL)

For Intravenous Infusion after Dilution

For use under Emergency Use Authorization (EUA)

MUST ADMINISTER WITH IMDEVIMAB

Contains 1 Single-Dose Vial

Discard unused portion

PRINCIPAL DISPLAY PANEL - 1332 mg/11.1 mL Vial Carton - Casirivimab - casirivimab imdevimab 07

Principal Display Panel - 1332 Mg/11.1 Ml Initial Clinical Vial Label - Regn10933

701210

Subject Number

Solution for intravenous administration.
Administer in accordance with protocol instructions.
Store refrigerated at 2°C – 8°C (36°F - 46°F)
in the original carton to protect from light.

Keep Out of Reach of Children. For Clinical Trial Use Only.

Caution: New Drug – Limited by Federal (or United States)
law to investigational use. Regeneron Pharmaceuticals, Inc.
Tarrytown, NY 10591 USA Tel: +1 914-847-7000

PRINCIPAL DISPLAY PANEL - 1332 mg/11.1 mL Initial Clinical Vial Label - REGN10933 - casirivimab imdevimab 08

Principal Display Panel - 1332 Mg/11.1 Ml Initial Clinical Vial Carton - Regn10933

Ref No. XXXXXXX

Lot XXXXXXXXXX

120 mg/mL 11.1 mL

REGN10933

PRINCIPAL DISPLAY PANEL - 1332 mg/11.1 mL Initial Clinical Vial Carton - REGN10933 - casirivimab imdevimab 09

Principal Display Panel - 300 Mg/2.5 Ml Vial Label - Imdevimab

701208

12345-00

Imdevimab
Injection

NDC 61755-027-00
Rx only

300 mg/2.5 mL (120 mg/mL)

For Intravenous Infusion after Dilution
For use under Emergency Use Authorization (EUA)
MUST ADMINISTER WITH CASIRIVIMAB
Mfd by: Regeneron Pharmaceuticals, Inc.

LOT/EXP

PRINCIPAL DISPLAY PANEL - 300 mg/2.5 mL Vial Label - Imdevimab - casirivimab imdevimab 10

Principal Display Panel - 300 Mg/2.5 Ml Vial Carton - Imdevimab

NDC 61755-027-01

Rx only

Imdevimab
Injection

300 mg/2.5 mL (120 mg/mL)

For Intravenous Infusion after Dilution

For use under Emergency Use Authorization (EUA)

MUST ADMINISTER WITH CASIRIVIMAB

Contains 1 Single-Dose Vial

Discard unused portion

PRINCIPAL DISPLAY PANEL - 300 mg/2.5 mL Vial Carton - Imdevimab - casirivimab imdevimab 11

Principal Display Panel - 300 Mg/2.5 Ml Modified Vial Label - Regn10987

701208

Subject Number

Solution for intravenous infusion or subcutaneous injection.
Administer in accordance with protocol instructions.
Store refrigerated at 2°C–8°C (36°F–46°F)
in original carton to protect from light.

Keep Out of Reach of Children. For Clinical Trial Use Only.

Caution: New Drug - Limited by Federal (or United States)
law to investigational use. Regeneron Pharmaceuticals, Inc.
Tarrytown, NY 10591 USA Tel: +1 914-847-7000

Lot

PRINCIPAL DISPLAY PANEL - 300 mg/2.5 mL Modified Vial Label - REGN10987 - casirivimab imdevimab 12

Principal Display Panel - 300 Mg/2.5 Ml Modified Vial Carton - Regn10987

Subject Number
Investigator
Date Dispensed

Contains:
1 vial Solution for intravenous infusion or subcutaneous injection

Administer in accordance with protocol instructions.

Store refrigerated at 2°C–8°C (36°F–46°F) in the original carton to
protect from light.

Keep Out of Reach of Children. For Clinical Trial Use Only.

Caution: New Drug - Limited by Federal (or United States) law to
investigational use.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 USA
Tel: +1 914-847-7000

PRINCIPAL DISPLAY PANEL - 300 mg/2.5 mL Modified Vial Carton - REGN10987 - casirivimab imdevimab 13

Principal Display Panel - 1332 Mg/11.1 Ml Vial Label - Imdevimab

701210

12345-00

Imdevimab
Injection

NDC 61755-025-00
Rx only

1332 mg/11.1 mL (120 mg/mL)

For Intravenous Infusion after Dilution
For use under Emergency Use Authorization (EUA)
MUST ADMINISTER WITH CASIRIVIMAB
Mfd by: Regeneron Pharmaceuticals, Inc.

PRINCIPAL DISPLAY PANEL - 1332 mg/11.1 mL Vial Label - Imdevimab - casirivimab imdevimab 14

Principal Display Panel - 1332 Mg/11.1 Ml Vial Carton - Imdevimab

NDC 61755-025-01

Rx only

Imdevimab
Injection

1332 mg/11.1 mL (120 mg/mL)

For Intravenous Infusion after Dilution

For use under Emergency Use Authorization (EUA)

MUST ADMINISTER WITH CASIRIVIMAB

Contains 1 Single-Dose Vial

Discard unused portion

PRINCIPAL DISPLAY PANEL - 1332 mg/11.1 mL Vial Carton - Imdevimab - casirivimab imdevimab 15

Principal Display Panel - 1332 Mg/11.1 Ml Initial Clinical Vial Label - Regn10987

701210

Subject Number

Solution for intravenous administration.
Administer in accordance with protocol instructions.
Store refrigerated at 2°C – 8°C (36°F - 46°F)
in original carton to protect from light.

Keep Out of Reach of Children. For Clinical Trial Use Only.

Caution: New Drug – Limited by Federal (or United States)
law to investigational use. Regeneron Pharmaceuticals, Inc.
Tarrytown, NY 10591 USA Tel: +1 914-847-7000

PRINCIPAL DISPLAY PANEL - 1332 mg/11.1 mL Initial Clinical Vial Label - REGN10987 - casirivimab imdevimab 16

Principal Display Panel - 1332 Mg/11.1 Ml Initial Clinical Vial Carton - Regn10987

Ref No. XXXXXXX

Lot XXXXXXXXXX

120 mg/mL 11.1 mL

REGN10987

PRINCIPAL DISPLAY PANEL - 1332 mg/11.1 mL Initial Clinical Vial Carton - REGN10987 - casirivimab imdevimab 17