Evkeeza

1 INDICATIONS AND USAGE EVKEEZA is indicated as an adjunct to diet and exercise and other low-density lipoprotein-cholesterol (LDL-C) lowering therapies to reduce LDL-C in adults and pediatric patients, aged 1 year and older, with homozygous familial hypercholesterolemia (HoFH). EVKEEZA is an angiopoietin-like 3 (ANGPTL3) inhibitor indicated as an adjunct to diet and exercise and other low-density lipoprotein-cholesterol (LDL-C) lowering therapies to reduce LDL-C in adults and pediatric patients, aged 1 year and older, with homozygous familial hypercholesterolemia (HoFH). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of EVKEEZA is 15 mg/kg administered by intravenous (IV) infusion once monthly (every 4 weeks). ( 2.1 ) See the Full Prescribing Information for preparation instructions for the intravenous infusion. ( 2.2 ) Administer the diluted solution via IV infusion over 60 minutes through an IV line containing a sterile, in-line or add-on, 0.2-micron to 5-micron filter. ( 2.3 ) Do not mix other medications with EVKEEZA or administer other medications concomitantly via the same infusion line. ( 2.3 ) The rate of infusion may be slowed, interrupted or discontinued if the patient develops any signs of adverse reactions, including infusion or hypersensitivity reactions. ( 2.3 ) 2.1 Recommended Dosage The recommended dosage of EVKEEZA is 15 mg/kg administered by intravenous (IV) infusion over 60 minutes once monthly (every 4 weeks). If a dosage of EVKEEZA is missed, administer as soon as possible. Thereafter, EVKEEZA should be scheduled monthly from the date of the last dosage. Assess LDL-C when clinically appropriate. The LDL-lowering effect of EVKEEZA may be measured as early as 2 weeks after initiation. 2.2 Preparation Instructions for Intravenous Infusion Calculate the dosage (mg), total volume (mL) of EVKEEZA required, and the number of vials required based on the patient's current body weight. Visually inspect the solution for cloudiness, discoloration, and particulate matter prior to administration. EVKEEZA is a clear to slightly opalescent, colorless to pale-yellow solution. Do not administer if the solution is cloudy, discolored, or contains particulate matter. EVKEEZA is supplied as single-dose vials and does not contain a preservative. Prepare the diluted infusion using aseptic technique. Do not shake the vial. Withdraw the required volume from the vial(s) of EVKEEZA and transfer into an IV infusion bag of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Discard any unused portion left in the vials. Mix the diluted solution by gentle inversion; do not shake. Maximum diluent volume by patient weight is summarized in Table 1. Table 1: Maximum Diluent Volume by Patient Weight Patient Weight Maximum Diluent Volume 3 kg to less than 26 kg 5 mL/kg 26 kg to less than 45 kg 150 mL 45 kg and greater 250 mL The final concentration of the diluted solution should be between 0.5 mg/mL and 20 mg/mL depending on the patient's current body weight. Administer the diluted solution immediately after preparation and discard any unused portion left in the vial. If not administered immediately, store the diluted solution refrigerated at 2 °C to 8 °C (36 °F to 46 °F) for no more than 24 hours from the time of preparation OR at room temperature up to 25 °C (77 °F) for no more than 6 hours from the time of preparation to the end of the infusion. Do not freeze the diluted solution. 2.3 Administration Instructions for Intravenous Infusion If refrigerated, allow the diluted solution to come to room temperature prior to administration. Administer EVKEEZA diluted solution via IV infusion through an IV line containing a sterile, in-line or add-on, 0.2-micron to 5-micron filter over 60 minutes. Do not mix other medications with EVKEEZA or administer other medications concomitantly via the same infusion line. The rate of infusion may be slowed, interrupted or discontinued if the patient develops any signs of adverse reactions, including infusion or hypersensitivity reactions [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. EVKEEZA can be administered without regard to the timing of lipoprotein apheresis.

4 CONTRAINDICATIONS EVKEEZA is contraindicated in patients with a history of serious hypersensitivity reaction to evinacumab-dgnb or to any of the excipients in EVKEEZA. Serious hypersensitivity reactions, including anaphylaxis, have occurred [see Warnings and Precautions (5.1) ]. History of serious hypersensitivity reactions to evinacumab-dgnb or to any of the excipients in EVKEEZA. ( 4 )

5 WARNINGS AND PRECAUTIONS Serious Hypersensitivity Reactions : Have occurred with EVKEEZA in clinical trials. If a serious hypersensitivity reaction occurs, discontinue EVKEEZA, treat according to standard-of-care and monitor until signs and symptoms resolve. ( 5.1 ) Embryo-Fetal Toxicity : EVKEEZA may cause fetal harm based on animal studies. Advise patients who may become pregnant of the risk to a fetus. Consider obtaining a pregnancy test prior to initiating treatment with EVKEEZA. Advise patients who may become pregnant to use contraception during treatment and for at least 5 months following the last dosage. ( 5.2 , 8.1 , 8.3 ) 5.1 Serious Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have occurred with EVKEEZA [see Adverse Reactions (6.1) ] . If signs or symptoms of serious hypersensitivity reactions occur, discontinue EVKEEZA infusion, treat according to the standard-of-care, and monitor until signs and symptoms resolve. EVKEEZA is contraindicated in patients with a history of serious hypersensitivity reaction to evinacumab-dgnb. 5.2 Embryo-Fetal Toxicity Based on the findings in animal reproduction studies, EVKEEZA may cause fetal harm when administered to pregnant patients. Administration of evinacumab-dgnb to rabbits during organogenesis caused increases in fetal malformations at doses below the human exposure. Advise patients who may become pregnant of the risk to a fetus. Consider obtaining a pregnancy test prior to initiating treatment with EVKEEZA. Advise patients who may become pregnant to use effective contraception during treatment with EVKEEZA and for at least 5 months following the last dosage of EVKEEZA [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Common adverse reactions (≥5%) were nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-833-385-3392 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. Adverse Reactions in Adult and Pediatric Patients (aged 12 to 17 years) with HoFH Safety data are based on pooled results from two randomized, double-blind, placebo-controlled trials that included 81 patients treated with EVKEEZA. The mean age of EVKEEZA-treated patients was 48 years (range: 15 to 75 years); 52% were females; 5% were Hispanic; 82% were White, 7% Asian, 3% Black or African American, and 9% other races. Forty-four (54%) EVKEEZA-treated patients had HoFH. Patients received EVKEEZA as add-on therapy to other lipid-lowering therapies, including maximally tolerated statin, ezetimibe, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, lomitapide, and apheresis. Adverse reactions led to discontinuation of treatment in 1 (2%) patient who received placebo, and 2 (2%) patients treated with EVKEEZA, including 1 case of anaphylaxis. The most common adverse reactions (reported in greater than 3% of EVKEEZA-treated patients and more frequently than in placebo) are shown in Table 2. Table 2: Adverse Reactions Occurring in >3% of Adult and Pediatric Patients Aged 12 to 17 Years Treated with EVKEEZA and Greater than Placebo in 24-Week, Pooled, Placebo-Controlled Trials Adverse Reactions Placebo (N = 54) % EVKEEZA (N = 81) % Nasopharyngitis 13 16 Influenza like illness 6 7 Dizziness 0 6 Rhinorrhea 0 5 Nausea 2 5 Pain in extremity 0 4 Asthenia 0 4 Other adverse reactions occurring in less than 3% of patients treated with EVKEEZA and greater than placebo included constipation, upper respiratory tract infection, nasal congestion, and abdominal pain. Transient, mild to moderate decreases in diastolic blood pressure and increases in heart rate occurred in clinical trials of EVKEEZA infusion but did not require intervention and resolved post-infusion. Serious Hypersensitivity Reactions Anaphylaxis was reported in 0% patients who received placebo and 1 (1%) patient treated with EVKEEZA. Infusion Reactions Infusion reactions were reported in 2 (4%) patients who received placebo and 6 (7%) patients treated with EVKEEZA. The following infusion reactions occurred in EVKEEZA-treated patients: infusion site pruritus, pyrexia, muscular weakness, nausea, and nasal congestion. Adverse Reactions in Pediatric Patients (aged 5 to 11 years) with HoFH Safety data are based on pooled results from a three-part, open-label trial in 20 pediatric patients with HoFH (aged 5 to 11 years) with a median treatment duration of 50 weeks. Part A was a trial of 6 patients who received a single intravenous dose of EVKEEZA 15 mg/kg to determine the dosage for the rest of the trial. Part B was a single-arm, 24-week trial of EVKEEZA 15 mg/kg given intravenously every 4 weeks in 14 unique patients [see Clinical Studies (14) ]. Part C was a 48-week extension trial of EVKEEZA 15 mg/kg given intravenously every 4 weeks that consisted of 20 patients who entered directly from Parts A or B. The mean age was 9 years (range: 5 to 11 years); 60% females; 70% White, 10% Asian, 5% Black or African American, 5% American Indian or Alaska Native, and 10% other races. The safety profile of EVKEEZA observed in these patients was consistent with the safety profile observed in adults and pediatric patients aged 12 years and older, with the additional adverse reaction of fatigue. Fatigue was reported in 3 (15%) patients.

8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, EVKEEZA may cause fetal harm when administered to pregnant patients. Available human data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Evinacumab-dgnb is a human IgG4 monoclonal antibody [see Description (11) ], and human IgG is known to cross the placental barrier; therefore, evinacumab-dgnb has the potential to be transmitted from the mother to the developing fetus. Subcutaneous administration of evinacumab-dgnb to pregnant rabbits during the period of organogenesis resulted in fetal malformations (domed head, hydrocephalus, and flexed limbs) at doses below the maximum recommended human dose (MRHD). No adverse embryofetal effects were observed with subcutaneous administration of evinacumab-dgnb to pregnant rats during the period of organogenesis at doses below the MRHD. Measurable evinacumab-dgnb serum concentrations were observed in fetal rabbit and rat sera at birth, indicating that evinacumab-dgnb, like other IgG antibodies, crosses the placental barrier (see Data ). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. If a patient becomes pregnant while receiving EVKEEZA, healthcare providers should report EVKEEZA exposure by calling 1-833-385-3392. Data Animal Data In an embryo-fetal development study in pregnant rabbits, evinacumab-dgnb was administered subcutaneously at doses of 1, 5, 10 and 30 mg/kg every 3 days (Q3D) during the period of organogenesis from gestation day 7 to day 19. Evinacumab-dgnb was teratogenic in rabbits, causing domed head, dilation of the lateral and third ventricles of the brain, and flexed fore/hind paws at maternal evinacumab-dgnb exposures below human exposure at the MRHD of 15 mg/kg every 4 weeks, based on AUC. Other fetal malformations, consisting of irregular and abnormal ossification in the skull, palate, and metacarpal, and enlarged anterior and/or posterior fontanelles occurred and were consistent with significant maternal toxicity (including early deaths due to abortion and premature delivery at all doses, reduction in maternal body weight gains, and reduced maternal food consumption). Increased incidences of post-implantation losses, resorptions (total, early, and late), and decreased fetal body weight were also consistent with maternal toxicity. Evinacumab-dgnb was present in the sera of fetuses born from mothers at 10 and 30 mg/kg/Q3D at levels higher than in maternal serum. In an embryo-fetal development study in pregnant rats, evinacumab-dgnb was administered subcutaneously at doses of 5, 10, 30 and 100 mg/kg/Q3D during the period of organogenesis from gestation day 6 to day 18. Maternal exposures to evinacumab-dgnb were below the human exposure measured at the MRHD. Evinacumab-dgnb resulted in unexplained maternal deaths at 100 mg/kg/Q3D. Evinacumab-dgnb crossed the placenta and was present at ratios (C Fetal /C Maternal ) ranging from 0.42 to 0.65. No adverse effects on embryofetal development were observed at any dose. In a combined fertility, embryofetal, and pre- and postnatal development study, female rats were administered evinacumab-dgnb via subcutaneous injection at doses of 30 and 100 mg/kg/Q3D beginning 2 weeks prior to mating and continuing to gestation day 21 or lactation day 21. Mean maternal systemic exposures were below the human exposure at the MRHD throughout the study. No maternal or developmental toxicity was observed.