VEOPOZ

1 INDICATIONS AND USAGE VEOPOZ is indicated for the treatment of adult and pediatric patients 1 year of age and older with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease. VEOPOZ is a complement inhibitor indicated for the treatment of adult and pediatric patients 1 year of age and older with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease. ( 1 )

2 DOSAGE AND ADMINISTRATION See the full prescribing information for meningococcal vaccine and prophylaxis recommendations prior to the first dose of VEOPOZ. ( 2.1 ) Recommended Dosage: Day 1 (loading dose): Administer a single 30 mg/kg dose by intravenous infusion after dilution. ( 2.2 ) Day 8 and thereafter (maintenance dosage): Inject 10 mg/kg as a subcutaneous injection once weekly starting on Day 8. The maintenance dosage may be increased to 12 mg/kg once weekly if there is inadequate clinical response after at least 3 weekly doses (i.e., starting from Week 4). The maximum maintenance dosage is 800 mg once weekly. ( 2.2 ) See full prescribing information for instructions on preparation and administration. ( 2.2 , 2.3 , 2.4 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Prior to First Dose of VEOPOZ Vaccinate patients for meningococcal infection (serogroups A, C, W, and Y [MenACWY] and serogroup B [MenB]) according to current ACIP recommendations for patients receiving a complement inhibitor at least 2 weeks prior to administering the first dose of VEOPOZ [see Warnings and Precautions (5.1) ] . If urgent VEOPOZ therapy is indicated in a patient who is not up-to-date with vaccines for both MenACWY and MenB according to ACIP recommendations, administer meningococcal vaccine(s) as soon as possible and provide the patient with antibacterial drug prophylaxis. The efficacy, duration, and drug regimens for antibacterial drug prophylaxis have not been studied in patients receiving complement inhibitors, including VEOPOZ. 2.2 Recommended Dosage and Administration The recommended dosage of VEOPOZ is as follows: Day 1 (Loading Dose) : Administer a single 30 mg/kg dose by intravenous infusion after dilution [see Dosage and Administration (2.3) ] . Day 8 and Thereafter (Maintenance Dosage) : Inject 10 mg/kg as a subcutaneous injection once weekly starting on Day 8 [see Dosage and Administration (2.4) ] . The maintenance dosage may be increased to 12 mg/kg once weekly if there is inadequate clinical response after at least 3 weekly doses (i.e., starting from Week 4). The maximum maintenance dosage is 800 mg once weekly. Doses greater than 400 mg require 2 injections. 2.3 Intravenous Infusion Loading Dose: Preparation and Administration Instructions VEOPOZ for intravenous use must be prepared and administered by a healthcare provider. Preparation Instructions for Intravenous Infusion Loading Dose Remove VEOPOZ vial(s) from refrigeration and allow the vial(s) to sit for at least 45 minutes at room temperature 20ºC to 25ºC (68ºF to 77ºF) before use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. VEOPOZ should be a clear to slightly opalescent, colorless to pale yellow solution that is free from visible particulates. Discard the vial(s) if the solution is cloudy, discolored or contains particulate matter. Gently swirl the vial(s) in an upright position. Do not shake the vial(s) as this may result in foaming. Use a 21G stainless steel needle with Luer-Lok to withdraw the calculated volume of VEOPOZ from the vial(s). Discard any unused VEOPOZ remaining in the vial(s). Dilute VEOPOZ in an intravenous infusion bag of 25 mL to 250 mL of either 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 6.7 mg/mL to 20 mg/mL. Mix the diluted solution by gentle inversion. Do not shake. Administration Instructions for Intravenous Infusion Loading Dose Infuse through an intravenous line containing a sterile, in-line or add-on 0.2-micron to 5-micron filter. Infusion rate: infuse over a minimum of 1 hour; do not exceed maximum rate of 1000 mg/hour Do not co-administer other medications through the same intravenous line Observe the patient for 30 minutes following completion of the infusion [see Warnings and Precautions (5.3) ]. Storage of Diluted Intravenous Solution Administer the diluted VEOPOZ solution immediately after preparation. If not used immediately, store at room temperature up to 25°C (77°F) for no more than 8 hours from the time of preparation to the end of the infusion or refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of preparation to the end of infusion. If stored in the refrigerator, allow the diluted solution to come to room temperature prior to administration. Discard the unused VEOPOZ diluted solution after 8 hours if stored at room temperature or after 24 hours if refrigerated. Do not freeze the diluted solution. 2.4 Subcutaneous Maintenance Dose: Preparation and Administration Instructions VEOPOZ for subcutaneous use must be prepared and administered by a healthcare provider. Preparation Instructions for Subcutaneous Maintenance Dose Remove VEOPOZ vial(s) from refrigeration and allow the vial(s) to sit for at least 45 minutes at room temperature 20ºC to 25ºC (68ºF to 77ºF) before use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. VEOPOZ should be a clear to slightly opalescent, colorless to pale yellow solution that is free from visible particulates. Discard the vial(s) if the solution is cloudy, discolored or contains particulate matter. Gently swirl the vial(s) in an upright position. Do not shake the vial(s) as this may result in foaming. Use a withdrawal needle (21G needle with Luer-Lok) to withdraw the calculated dose volume of VEOPOZ from the appropriate number of vial(s). Discard any unused VEOPOZ remaining in the vial(s). For patients receiving a dose greater than 400 mg, preparation of 2 separate injections will be required for subcutaneous administration of the total dose volume. Change the needle on the syringe to an injection needle fulfilling the following criteria: 25G to 27G and 1/2 or 5/8-inch stainless steel needle with Luer-Lok. Administration Instructions for Subcutaneous Maintenance Dose Inject VEOPOZ into the abdomen, thigh, or upper arm. Rotate sites. Do not inject VEOPOZ into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. When administering more than one injection, administer consecutively, each at different injection sites. Observe the patient for 30 minutes following completion of the first subcutaneous injection [see Warnings and Precautions (5.3) ] . Storage of Subcutaneous Injection Administer the subcutaneous injection within 4 hours of preparation. 2.5 Recommendations Regarding Missed Maintenance Subcutaneous Dose(s) If a subcutaneous maintenance dose of VEOPOZ is missed, administer as soon as possible within 3 days after the missed dose. Do not administer 2 doses on the same day to make up for a missed dose. If more than 3 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule. The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 4 days (96 hours).

4 CONTRAINDICATIONS VEOPOZ is contraindicated in: Patients with unresolved Neisseria meningitidis infection [see Warnings and Precautions (5.1) ] . VEOPOZ is contraindicated in patients with unresolved Neisseria meningitidis infection. ( 4 )

5 WARNINGS AND PRECAUTIONS Other Bacterial Infections : Interrupt treatment with VEOPOZ in patients who are undergoing treatment for a serious encapsulated bacterial infection until the infection is resolved. ( 5.2 ) Systemic Hypersensitivity Reactions : Interrupt infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. ( 5.3 ) Immune Complex Formation : Transition between other complement inhibitors has resulted in decreased drug concentrations and possible hypersensitivity reactions. Consider this potential if switching complement inhibitors to VEOPOZ. ( 5.4 ) 5.1 Serious Meningococcal Infections Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The use of VEOPOZ increases a patient's susceptibility to serious and life-threatening meningococcal infections (septicemia and/or meningitis) caused by any serogroup, including nongroupable strains. Complete or update meningococcal vaccination (for serogroups A, C, W, and Y [MenACWY] and serogroup B [MenB]) at least 2 weeks prior to administering the first dose of VEOPOZ, according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of VEOPOZ therapy. If urgent VEOPOZ therapy is indicated in a patient who is not up-to-date with both MenACWY and MenB vaccines according to ACIP recommendations, administer meningococcal vaccine(s) as soon as possible and provide the patient with antibacterial drug prophylaxis. The efficacy, duration, and drug regimens for antibacterial drug prophylaxis have not been studied in patients receiving complement inhibitors. Because of inhibition of complement activity by VEOPOZ, as well as risk of infection caused by nongroupable strains of N. meningitidis , vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients and caregivers of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Interrupt treatment with VEOPOZ in patients who are undergoing treatment for serious meningococcal infection until the infection is resolved [see Contraindications (4) ] . 5.2 Other Bacterial Infections VEOPOZ blocks terminal complement activation; therefore, patients may have increased susceptibility to encapsulated bacterial infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Patients treated with VEOPOZ may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. Patients receiving VEOPOZ are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. Interrupt treatment with VEOPOZ in patients who are undergoing treatment for a serious encapsulated bacterial infection until the infection is resolved. Counsel patients about gonorrhea prevention and advise regular testing for patients at risk. 5.3 Systemic Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported with administration of complement inhibitors. Interrupt VEOPOZ and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. 5.4 Immune Complex Formation Immune complex formation has been reported during the transition of therapy between complement inhibitors, resulting in transient decrease in drug concentrations as well as symptoms suggestive of hypersensitivity reactions. However, this has not been studied in patients with CD55-deficient PLE switching from other complement inhibitors to pozelimab. The potential for immune complex formation should be considered if switching complement inhibitors.

7 DRUG INTERACTIONS Intravenous Immunoglobulin : May decrease pozelimab concentrations; avoid concomitant use. If concomitant use cannot be avoided, monitor patients for worsening of clinical signs and symptoms of disease. ( 7.1 ) 7.1 Intravenous Immunoglobulin VEOPOZ has not been studied in combination with intravenous immunoglobulin. Intravenous immunoglobulin may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as pozelimab thereby decreasing serum pozelimab concentrations. Avoid concomitant use of intravenous immunoglobulin with VEOPOZ. If concomitant use cannot be avoided, monitor patients for worsening of clinical signs and symptoms of CD55-deficient PLE [see Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Meningococcal Infections [see Warnings and Precautions (5.1) ] Other Bacterial Infections [see Warnings and Precautions (5.2) ] Systemic Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Immune Complex Formation [see Warnings and Precautions (5.4) ] Most common adverse reactions (in two or more patients) are: upper respiratory tract infection, fracture, urticaria, and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-855-583-6769 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VEOPOZ was evaluated in 10 patients with CD55-deficient PLE (ranging from 3 to 19 years of age) in a single-arm study [see Clinical Studies (14) ] . The median duration of exposure was 104 weeks (range: 75 to 140 weeks). Adverse reactions reported in two or more patients are summarized in Table 1. Table 1: Adverse Reactions Reported in Two or More VEOPOZ-Treated Patients with CD55-deficient PLE in a Clinical Trial Adverse Reactions VEOPOZ N=10 n (%) Upper respiratory tract infection Composed of similar terms 3 (30) Fracture 3 (30) Urticaria 2 (20) Alopecia 2 (20) Additionally, injection site reactions (including dermatitis and erythema), metabolic acidosis, gingival bleeding, increased blood uric acid, increased liver enzymes, hematuria and proteinuria were reported in one patient each. Vital Signs: Four patients reported elevated systolic and/or diastolic blood pressure readings above the normal range for age at multiple study visits.

8.1 Pregnancy Risk Summary Although there are no data on VEOPOZ use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, monoclonal antibodies can be actively transported across the placenta . In an animal reproduction study in monkeys, pozelimab-bbfg did not adversely affect embryofetal or postnatal development when administered from pregnancy confirmation through parturition at doses that produced exposure up to 3.3 to 3.8 times the predicted clinical exposures (on an AUC basis; see Data ). 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 outcome. 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. Data Animal Data In an enhanced pre- and postnatal development study, pregnant female monkeys were subcutaneously administered pozelimab-bbfg at doses of 5 or 50 mg/kg once weekly from confirmation of pregnancy (gestation day 20) through parturition (approximately gestation day 160). No adverse effects were observed on maintenance of pregnancy, pregnancy outcome, or on the development of offspring through postnatal day 90 at doses up to 3.3-3.8 times the predicted clinical exposures.