ADAKVEO

1 INDICATIONS AND USAGE ADAKVEO ® is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease. ADAKVEO is a selectin blocker indicated to reduce the frequency of vasoocclusive crises in adults and pediatric patients aged 16 years and older with sickle cell disease.

2 DOSAGE AND ADMINISTRATION Administer 5 mg/kg by intravenous infusion over a period of 30 minutes on Week 0, Week 2, and every 4 weeks thereafter. ( 2.1 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.2 ) 2.1 Recommended Dosage Administer ADAKVEO 5 mg/kg by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 weeks thereafter. If a dose is missed, administer ADAKVEO as soon as possible. If ADAKVEO is administered within 2 weeks after the missed dose, continue dosing according to the patient's original schedule. If ADAKVEO is administered more than 2 weeks after the missed dose, continue dosing every 4 weeks thereafter. Physicians should reevaluate the treatment at least yearly, to assess individual patient’s response to treatment and consider discontinuing therapy with ADAKVEO if no perceived benefit is achieved. ADAKVEO may be given with or without hydroxyurea. 2.2 Preparation and Administration ADAKVEO should be prepared and administered by a healthcare professional. Preparation Use aseptic technique to prepare the solution for infusion. Calculate the dose (mg) and the total volume (mL) of ADAKVEO solution required, and the number of ADAKVEO vials needed based on the patient’s actual body weight. Prepare 5 mg of ADAKVEO per kg of actual body weight. Calculate the volume of ADAKVEO to be used according to the following equation: Dilution Dilute ADAKVEO in 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a total volume of 100 mL for intravenous infusion as follows: Obtain the number of vials required. One vial is needed for every 10 mL of ADAKVEO. Bring vials to room temperature for a maximum of 4 hours prior to the start of preparation (piercing the first vial). Visually inspect the vials. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ADAKVEO is clear to opalescent, colorless or may have a slightly brownish-yellow tint. Do not use if particles are present in the solution. Obtain a 100 mL 0.9% Sodium Chloride Injection or 5% Dextrose Injection infusion bag/container. Infusion bags/containers must be made of either polyvinyl chloride (PVC), polyethylene (PE), or polypropylene (PP). Remove a volume of 0.9% Sodium Chloride Injection or 5% Dextrose Injection from the infusion bag/container that is equal to the required volume of ADAKVEO solution. Withdraw the necessary amount of ADAKVEO solution and dilute by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection. The volume of ADAKVEO added to the infusion bag/container should not exceed 96 mL. Gently invert the infusion bag to mix the diluted solution. DO NOT SHAKE. Single-dose vials. Discard unused portion. Storage Conditions of the Diluted Solution Administer ADAKVEO diluted solution as soon as possible. If not administered immediately, store the prepared solution either: At room temperature up to 25°C (77°F) for no more than 4.5 hours from the start of the preparation (piercing the first vial) to the completion of infusion. Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours, from the start of the time of the preparation (piercing the first vial) to the completion of infusion. This includes the storage of the diluted solution and the time to warm up to room temperature. Protect the diluted solution from light during storage under refrigeration. Administration Administer ADAKVEO diluted solution by intravenous infusion over a period of 30 minutes through an intravenous line, which must contain a sterile, nonpyrogenic 0.2-micron inline filter. No incompatibilities have been observed between ADAKVEO and infusion sets composed of PVC, polyethylene (PE-lined PVC), polyurethane (PU), and in-line filter membranes composed of polyethersulfone (PES, neutral and positively charged), positively charged polyamide (PA), and polysulphone (PSU). Do not mix or coadminister with other drugs through the same intravenous line. After administration of ADAKVEO, flush the line with at least 25 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Dispose of any unused product or waste material in accordance with local requirements. Preparation and Administration

4 CONTRAINDICATIONS None. None.

5 WARNINGS AND PRECAUTIONS Infusion-Related Reactions: Monitor for and advise patients of signs and symptoms. Discontinue ADAKVEO infusion for severe reactions and manage medically. Temporarily interrupt or slow the rate of infusion for mild or moderate infusion-related reactions and initiate symptomatic treatment. Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis). ( 5.1 ) Interference With Automated Platelet Counts (platelet clumping): Run test as soon as possible or use citrate tubes. ( 5.2 ) 5.1 Infusion-Related Reactions In the SUSTAIN clinical trial, infusion-related reactions (IRRs) (defined as occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. In the STAND clinical trial, IRRs were observed in 6 (7%) patients treated with ADAKVEO 5 mg/kg. IRRs presented most frequently as pain, nausea, vomiting, fatigue, dizziness, pruritis, diarrhea, and pyrexia. Some IRRs have required hospitalizations. The majority of these IRRs occurred during the first and second infusions. Monitor for and advise patients to report signs and symptoms of IRRs. Discontinue ADAKVEO infusion for severe IRRs and institute appropriate medical care. Consider permanent discontinuation of ADAKVEO treatment in case of severe IRRs. Manage mild to moderate infusion-related reactions with temporary interruption of infusion, slowing the rate of infusion, symptomatic treatment (e.g., acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), opioids, antihistamines, intravenous fluids, and/or oxygen therapy). For subsequent infusions, consider premedication and/or infusion rate reduction. Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis). Use of corticosteroids may increase the risk of complications such as acute chest syndrome and fat embolism. Infusion-Related Reactions and Vaso-occlusive Crises Infusion-related reactions are sometimes indistinguishable from vaso-occlusive crisis (VOC) events. IRRs and VOCs may occur concomitantly and/or VOCs may occur as a consequence of an IRR. 5.2 Laboratory Test Interference Interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO, in particular, when blood samples were collected in tubes containing ethylenediaminetetraacetic acid (EDTA). Mitigation strategies are recommended [see Drug Interactions (7.1)] .

7 DRUG INTERACTIONS 7.1 Laboratory Test Interference Platelet Tests ADAKVEO interferes with automated platelet counts (platelet clumping) in particular when blood samples are collected in tubes containing EDTA, which may lead to unevaluable or falsely decreased platelet counts. Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion-related reactions [see Warnings and Precautions (5.1)] The most common adverse reactions (incidence ≥ 10%) were headache, arthralgia, nausea, back pain, fatigue, abdominal pain, pyrexia, diarrhea, vomiting, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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. Sickle Cell Disease SUSTAIN Trial The safety of ADAKVEO was evaluated in the SUSTAIN trial [see Clinical Studies (14.1)] . Eligible patients were diagnosed with sickle cell disease (any genotype, including HbSS, HbSC, HbS beta 0 -thalassemia, HbS beta + -thalassemia, and others). Patients received ADAKVEO 5 mg/kg (N = 66) or 2.5 mg/kg (N = 64) or placebo (N = 62) administered by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of 5 mg/kg. Among the 66 patients that received the recommended dose (5 mg/kg), 83% were exposed for 6 months or longer and 61% were exposed for approximately one year; forty-two (64%) patients were treated with ADAKVEO in combination with hydroxyurea. Serious adverse reactions were reported in 2 patients (3%) treated with ADAKVEO 5 mg/kg; both reactions were pyrexia. Two deaths (3%) occurred in the ADAKVEO 5 mg/kg treatment group. None of the deaths were considered to be related to ADAKVEO. The most common adverse reactions (≥ 10%) were arthralgia, nausea, back pain, abdominal pain, pyrexia, and diarrhea. Table 1 summarizes the adverse reactions in the SUSTAIN trial. Table 1: Adverse Reactions (≥ 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of > 3% Compared to Placebo in SUSTAIN a Abdominal pain: abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness. ADAKVEO 5 mg/kg N = 66 % Placebo N = 62 % Adverse Reactions All Grades % Grade ≥ 3 % All Grades % Grade ≥ 3 % Arthralgia 18 2 8 2 Nausea 18 0 11 2 Back pain 15 0 11 0 Abdominal pain a 12 0 5 0 Pyrexia 11 12 7 0 Diarrhea 11 0 3 2 Clinically relevant adverse reactions (all Grades) that were reported in less than 10% of patients treated with ADAKVEO included: oropharyngeal pain, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction. STAND Trial The safety of ADAKVEO was also evaluated in the STAND trial [see Clinical Studies (14.1)] . Eligible patients were diagnosed with sickle cell disease (any genotype, including HbSS, HbSC, HbS beta 0 -thalassemia, HbS beta + -thalassemia, and others). Patients received ADAKVEO 5 mg/kg (N = 84) or 7.5 mg/kg (N = 83) or placebo (N = 85) administered by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of 5 mg/kg. Among the 84 patients that received the recommended dose (5 mg/kg), 93% were exposed for approximately 6 months or longer and 88% were exposed for approximately one year; sixty-two (74%) patients were treated with ADAKVEO in combination with hydroxyurea. Serious adverse reactions were reported in 2 patients (2%) treated with ADAKVEO 5 mg/kg and this reaction was pain. The most common adverse reactions (≥ 10%) were headache, nausea, fatigue, vomiting, and oropharyngeal pain. Table 2: Adverse Reactions (≥ 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of > 3% Compared to Placebo in STAND a Fatigue includes asthenia and malaise. ADAKVEO 5 mg/kg N = 84 % Placebo N = 85 % Adverse Reactions All Grades % Grade ≥ 3 % All Grades % Grade ≥ 3 % Headache 25 1 19 0 Nausea 17 0 9 0 Fatigue a 13 0 8 0 Vomiting 10 0 5 0 Oropharyngeal pain 10 0 4 0 Clinically relevant adverse reactions (all Grades) that were reported in less than 10% of patients treated with ADAKVEO or events having a difference of less than 3% between ADAKVEO treatment arms and placebo included: diarrhea, pruritus, dizziness, infusion-related reaction, infusion-site reaction.

8.1 Pregnancy Risk Summary Based on data from animal studies, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. In an animal reproduction study, intravenous administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at 5 mg/kg/dose once every 4 weeks (see Data) . There are insufficient human data on ADAKVEO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for VOCs, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality. Data Animal Data In an enhanced pre- and postnatal development study in cynomolgus monkeys, pregnant animals received intravenous doses of crizanlizumab-tmca at 10 and 50 mg/kg once every 2 weeks during the period of onset of organogenesis through delivery. No maternal toxicity was observed. Maternal exposures at doses of 10 and 50 mg/kg were between 2.8 and 16 times, respectively, the human clinical exposure based on area under the curve (AUC) in patients with sickle cell disease at 5 mg/kg/dose once every 4 weeks. There was an increase in fetal loss (abortions or still births) at both crizanlizumab-tmca doses which was higher in the third trimester. There were no effects on infant growth and development through 6-months postpartum that were attributable to crizanlizumab-tmca. Measurable crizanlizumab-tmca serum concentrations were observed in the infant monkeys at postnatal Day 28, confirming that crizanlizumab crosses the placental barrier.