HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedADAKVEO (crizanlizumab-tmca) injection is sterile, clear to opalescent, colorless to slightly brownish-yellow solution for intravenous infusion supplied as:Carton containing one 100 mg/10 mL (10 mg/mL) single-dose vial NDC 0078-0883-61The single-dose vial has rubber stopper and an aluminum cap with plastic flip-off disk. Each 10 mL vial is made of Type glass.Storage and HandlingStore and transport refrigerated at 2C to 8C (36F to 46F) in the original carton to protect from light.Do not shake. Do not freeze.. Store and transport refrigerated at 2C to 8C (36F to 46F) in the original carton to protect from light.. Do not shake. Do not freeze.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of ADAKVEO. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.General Disorders and Administration-site Conditions: Pain (in various locations) occurring during/within 24 hours of the infusion (e.g., potential infusion-related reaction) [see Warnings and Precautions (5.1)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Infusion-related reactions [see Warnings and Precautions (5.1)] Infusion-related reactions [see Warnings and Precautions (5.1)] Most common adverse reactions (incidence 10%) are nausea, arthralgia, back pain, abdominal pain, and pyrexia. (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 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 DiseaseThe safety of ADAKVEO was evaluated in the SUSTAIN trial [see Clinical Studies (14)]. Eligible patients were diagnosed with sickle cell disease (any genotype, including HbSS, HbSC, HbS beta0-thalassemia, HbSbeta+-thalassemia, and others). Patients received ADAKVEO 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 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of mg/kg.Among the 66 patients that received the recommended dose (5 mg/kg), 83% were exposed for 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 patients (3%) treated with ADAKVEO mg/kg; both reactions were pyrexia.Two deaths (3%) occurred in the ADAKVEO mg/kg treatment group. None of the deaths were considered to be related to ADAKVEO.The most common adverse reactions (>= 10%) were nausea, arthralgia, back pain, abdominal pain, and pyrexia. These adverse reactions, along with myalgia, musculoskeletal chest pain, and diarrhea may be signs and symptoms of an infusion-related reaction when observed during/within 24 hours of an infusion [see Warnings and Precautions (5.1)].Table summarizes the adverse reactions in the SUSTAIN trial.Table 2: Adverse Reactions (>= 10%) in Patients Receiving ADAKVEO With Difference Between Arms of 3% Compared to Placebo in SUSTAINaAbdominal pain: abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness.ADAKVEO mg/kgN 66n (%)PlaceboN 62n (%)Adverse ReactionsAll Grades(%)Grade >= 3(%)All Grades(%)Grade >= 3(%)Gastrointestinal Disorders Nausea12 (18)07 (11)1 (2) Abdominal paina (12)03 (5)0Musculoskeletal and Connective Tissue Disorders Arthralgia12 (18)1 (2)5 (8)1 (2) Back pain10 (15)07 (11)0General Disorders and Administration Site Conditions Pyrexia7 (11)1 (2)4 (7)0Clinically relevant adverse reactions (all Grades) that were reported in less than 10% of patients treated with ADAKVEO included: oropharyngeal pain, diarrhea, 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.. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other crizanlizumab-tmca products may be misleading.The immunogenicity of ADAKVEO was evaluated using validated bridging immunoassay for the detection of binding anti-crizanlizumab-tmca antibodies. In single arm, open label multiple dose study, of the 45 patients with sickle cell disease treated with ADAKVEO mg/kg tested positive for treatment-induced anti-crizanlizumab-tmca antibodies. In single-dose study of healthy subjects, of the 61 (1.6%) evaluable subjects tested positive for treatment-induced anti-crizanlizumab-tmca antibodies.. 6.3 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of ADAKVEO. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.General Disorders and Administration-site Conditions: Pain (in various locations) occurring during/within 24 hours of the infusion (e.g., potential infusion-related reaction) [see Warnings and Precautions (5.1)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. In the 26-week repeat-dose toxicity study, administration of crizanlizumab-tmca in cynomolgus monkeys at dose levels up to 50 mg/kg/dose once every weeks resulted in inflammation of the vessels in multiple tissues in out of 10 animals.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or genotoxicity studies have been conducted with crizanlizumab-tmca.In the 26-week repeat-dose toxicity study, cynomolgus monkeys were administered crizanlizumab-tmca once every weeks at doses up to 50 mg/kg (at least 13.5 times the human clinical exposure based on AUC in patients with sickle cell disease at mg/kg once every weeks). There were no adverse effects of crizanlizumab-tmca on male or female reproductive organs.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Crizanlizumab-tmca is humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands, including P-selectin glycoprotein ligand (PSGL-1). Crizanlizumab-tmca can also dissociate preformed P-selectin/PSGL-1 complex. Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.. 12.2 Pharmacodynamics. ADAKVEO resulted in dose-dependent P-selectin inhibition (measured ex vivo) in patients with sickle cell disease and healthy volunteers.. 12.3 Pharmacokinetics. The pharmacokinetics of crizanlizumab-tmca were evaluated in healthy volunteers and patients with sickle cell disease. The mean crizanlizumab-tmca Cmax, AUClast, or AUCinf increased disproportionally over the dose range of 0.2 to mg/kg (0.04 to 1.6 times the approved recommended dosage) in healthy volunteers. In healthy volunteers administered the mg/kg dose, the mean [coefficient of variation (CV%)] crizanlizumab-tmca Cmax, AUClast, or AUCinf were 0.16 (15.3%) mg/mL, 33.6 (12.6%) mghr/mL and 34.6 (13.1%) mghr/mL, respectively.DistributionThe mean (% CV) volume of distribution was 4.26 (25.1%) after single crizanlizumab-tmca mg/kg intravenous infusion in healthy volunteers.EliminationThe mean (% CV) terminal elimination half-life (t1/2) of crizanlizumab-tmca was 10.6 (20.5%) days and the mean clearance was 11.7 (16.2%) mL/hr at mg/kg doses in healthy volunteers. The mean (% CV) elimination t1/2 of crizanlizumab-tmca was 7.6 (28.5%) days during dosing interval in patients with sickle cell disease.MetabolismCrizanlizumab-tmca is expected to be metabolized into small peptides by catabolic pathways.Specific PopulationsThe effect of renal or hepatic impairment on the pharmacokinetics of crizanlizumab-tmca is unknown.Drug Interaction StudiesHydroxyurea had no clinically meaningful effect on crizanlizumab-tmca pharmacokinetics in patients in clinical studies.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of ADAKVEO was evaluated in patients with sickle cell disease in SUSTAIN [NCT01895361], 52-week, randomized, multicenter, placebo-controlled, double-blind study. total of 198 patients with sickle cell disease, any genotype (HbSS, HbSC, HbS/beta0-thalassemia, HbS/beta+-thalassemia, and others), and history of 2-10 VOCs in the previous 12 months were eligible for inclusion. Patients were randomized 1:1:1 to ADAKVEO mg/kg (N 67), ADAKVEO 2.5 mg/kg (N 66), or placebo (N 65) administered over period of 30 minutes by intravenous infusion on Week 0, Week 2, and every weeks thereafter for treatment duration of 52 weeks. Randomization was stratified by patients already receiving hydroxyurea (Y/N) and by the number of VOCs in the previous 12 months (2 to 4, to 10).Patients received ADAKVEO (with or without hydroxyurea) and were allowed to receive occasional transfusions and pain medications [i.e., acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids] on an as needed basis.Patients recruited in the study had complications associated with sickle cell disease and other comorbidities, including history of acute chest syndrome (18%); pulmonary hypertension (8%); priapism (7%); psychiatric manifestations (25%), including depression and anxiety; hypertension (17%); cholelithiasis (17%). Demographic and other baseline characteristics were similar among the treatment groups (see Table 3).Table 3: Demographics and Baseline Characteristics in SUSTAIN StudyAbbreviation: VOCs, vasoocclusive crises.ADAKVEO mg/kg(N 67)Placebo(N 65)Age (years) Median2926 Range16, 6316, 56Gender, (%) Male32 (48%)27 (42%) Female35 (52%)38 (59%)Ethnicity, (%) Hispanic or Latino20 (30%)11 (17%) Not Hispanic or Latino45 (67%)53 (82%) Unknown2 (3%)1 (2%)Race black or African American60 (90%)60 (92%) white4 (6%)3 (5%) Other3 (5%)2 (3%)Sickle cell disease genotype, (%) HbSS47 (70%)47 (72%) HbSC9 (13%)8 (12%) HbS/beta0 thalassemia3 (5%)7 (11%) HbS/beta+ thalassemia7 (10%)1 (2%) Other1 (2%)2 (3%)Hydroxyurea use, (%) Yes42 (63%)40 (62%) No25 (37%)25 (39%)Number of VOCs in previous 12 months, (%) to 442 (63%)41 (63%) to 1025 (37%)24 (37%)Efficacy was evaluated in the SUSTAIN study by the annual rate of VOCs leading to healthcare visit. VOC leading to healthcare visit was defined as an acute episode of pain with no cause other than vasoocclusive event that required medical facility visit and treatment with oral or parenteral opioids, or parenteral NSAIDs. Acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism (requiring visit to medical facility) were also considered VOCs.Patients with sickle cell disease who received ADAKVEO mg/kg had lower median annual rate of VOC compared to patients who received placebo (1.63 vs. 2.98) which was statistically significant (p 0.010). Reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype and/or hydroxyurea use.Thirty-six percent (36%) of patients treated with ADAKVEO mg/kg did not experience VOC compared to 17% of placebo-treated patients. The median time to first VOC from randomization was 4.1 months in the ADAKVEO mg/kg arm compared to 1.4 months in the placebo.The main efficacy results of the pivotal study, SUSTAIN, are summarized in Table 4.Table 4: Efficacy Results from SUSTAIN Trial in Sickle Cell Diseasea Abbreviations: HL, hodges-lehmann; VOCs, vasoocclusive crises. aVOCs were as assessed by an independent review committee. bStandard median. cHL median difference [95% confidence interval (CI)].EventADAKVEO, mg/kgb (n 67)Placebob (n 65)Treatment Difference Estimatec Annual rate of VOCa 1.632.98HL -1.01, (-2.00, 0.00)Annual rate of days hospitalized46.87.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 DiseaseThe safety of ADAKVEO was evaluated in the SUSTAIN trial [see Clinical Studies (14)]. Eligible patients were diagnosed with sickle cell disease (any genotype, including HbSS, HbSC, HbS beta0-thalassemia, HbSbeta+-thalassemia, and others). Patients received ADAKVEO 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 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of mg/kg.Among the 66 patients that received the recommended dose (5 mg/kg), 83% were exposed for 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 patients (3%) treated with ADAKVEO mg/kg; both reactions were pyrexia.Two deaths (3%) occurred in the ADAKVEO mg/kg treatment group. None of the deaths were considered to be related to ADAKVEO.The most common adverse reactions (>= 10%) were nausea, arthralgia, back pain, abdominal pain, and pyrexia. These adverse reactions, along with myalgia, musculoskeletal chest pain, and diarrhea may be signs and symptoms of an infusion-related reaction when observed during/within 24 hours of an infusion [see Warnings and Precautions (5.1)].Table summarizes the adverse reactions in the SUSTAIN trial.Table 2: Adverse Reactions (>= 10%) in Patients Receiving ADAKVEO With Difference Between Arms of 3% Compared to Placebo in SUSTAINaAbdominal pain: abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness.ADAKVEO mg/kgN 66n (%)PlaceboN 62n (%)Adverse ReactionsAll Grades(%)Grade >= 3(%)All Grades(%)Grade >= 3(%)Gastrointestinal Disorders Nausea12 (18)07 (11)1 (2) Abdominal paina (12)03 (5)0Musculoskeletal and Connective Tissue Disorders Arthralgia12 (18)1 (2)5 (8)1 (2) Back pain10 (15)07 (11)0General Disorders and Administration Site Conditions Pyrexia7 (11)1 (2)4 (7)0Clinically relevant adverse reactions (all Grades) that were reported in less than 10% of patients treated with ADAKVEO included: oropharyngeal pain, diarrhea, 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11 DESCRIPTION. Crizanlizumab-tmca is P-selectin blocker humanized IgG2 kappa monoclonal antibody that binds to P-selectin. Crizanlizumab-tmca is produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells. It is composed of heavy chains, each containing 448 amino acids, and light chains each containing 218 amino acids, with theoretical molecular weight of approximately 146 kDa.ADAKVEO (crizanlizumab-tmca) injection is supplied as sterile, preservative-free, clear to opalescent, colorless to slightly brownish-yellow solution for dilution and subsequent administration by intravenous infusion. Each 10 mL vial contains 100 mg crizanlizumab-tmca, citric acid (5.4 mg), polysorbate 80 (2 mg), sodium citrate (50.5 mg), sucrose (753.3 mg) and water for injection with pH of 6.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer mg/kg by intravenous infusion over period of 30 minutes on Week 0, Week 2, and every weeks thereafter. (2.1)See Full Prescribing Information for instructions on preparation and administration. (2.2). 2.1 Recommended Dosage. Administer ADAKVEO mg/kg by intravenous infusion over period of 30 minutes at Week 0, Week 2, and every weeks thereafter.If dose is missed, administer ADAKVEO as soon as possible.If ADAKVEO is administered within weeks after the missed dose, continue dosing according to the patients original schedule.If ADAKVEO is administered more than weeks after the missed dose, continue dosing every weeks thereafter.ADAKVEO may be given with or without hydroxyurea.. 2.2 Preparation and Administration. ADAKVEO should be prepared and administered by healthcare professional.PreparationUse 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 patients actual body weight.Prepare mg of ADAKVEO per kg of actual body weight. Calculate the volume of ADAKVEO to be used according to the following equation:DilutionDilute ADAKVEO in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to 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 maximum of 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 slightly brownish-yellow tint.Do not use if particles are present in the solution. Obtain 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 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 SolutionAdminister ADAKVEO diluted solution as soon as possible. If not administered immediately, store the prepared solution either:At room temperature up to 25C (77F) 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 2C to 8C (36F to 46F) 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.AdministrationAdminister ADAKVEO diluted solution by intravenous infusion over period of 30 minutes through an intravenous line, which must contain 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 or 5% Dextrose Injection.Dispose of any unused product or waste material in accordance with local requirements.. 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 patients actual body weight.Prepare mg of ADAKVEO per kg of actual body weight. Prepare mg of ADAKVEO per kg of actual body weight.. Calculate the volume of ADAKVEO to be used according to the following equation:. Obtain the number of vials required. One vial is needed for every 10 mL of ADAKVEO.. Bring vials to room temperature for maximum of 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 slightly brownish-yellow tint.Do not use if particles are present in the solution. 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 slightly brownish-yellow tint.. Do not use if particles are present in the solution.. Obtain 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). Infusion bags/containers must be made of either polyvinyl chloride (PVC), polyethylene (PE), or polypropylene (PP).. Remove 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. 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.. At room temperature up to 25C (77F) 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 2C to 8C (36F to 46F) 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.. Administer ADAKVEO diluted solution by intravenous infusion over period of 30 minutes through an intravenous line, which must contain 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 or 5% Dextrose Injection.. Dispose of any unused product or waste material in accordance with local requirements.. Preparation and Administration. 2.3 Management of Infusion-Related Reactions. No dose reductions are recommended. Management for infusion-related reactions for ADAKVEO is described in Table 1.Table 1. Recommended Management for Infusion-Related ReactionsaExercise caution with the use of corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis).Severity of Adverse ReactionRecommendationMild to moderate infusion-related reactionsTemporarily interrupt the infusion or slow the rate of infusion Initiate symptomatic treatmenta (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antihistamines, intravenous fluids, and/or oxygen therapy)For subsequent infusions, consider premedication and/or reduce the infusion rateSevere infusion-related reactions Discontinue infusionInstitute appropriate medical carea Consider permanent discontinuation of ADAKVEO. Temporarily interrupt the infusion or slow the rate of infusion Initiate symptomatic treatmenta (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antihistamines, intravenous fluids, and/or oxygen therapy). For subsequent infusions, consider premedication and/or reduce the infusion rate. Discontinue infusion. Institute appropriate medical carea Consider permanent discontinuation of ADAKVEO.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 100 mg/10 mL (10 mg/mL) as clear to opalescent, colorless to slightly brownish-yellow solution in single-dose vial.. Injection: 100 mg/10 mL (10 mg/mL) solution in single-dose vial.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Laboratory Test Interference. Platelet TestsADAKVEO 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 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of ADAKVEO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other crizanlizumab-tmca products may be misleading.The immunogenicity of ADAKVEO was evaluated using validated bridging immunoassay for the detection of binding anti-crizanlizumab-tmca antibodies. In single arm, open label multiple dose study, of the 45 patients with sickle cell disease treated with ADAKVEO mg/kg tested positive for treatment-induced anti-crizanlizumab-tmca antibodies. In single-dose study of healthy subjects, of the 61 (1.6%) evaluable subjects tested positive for treatment-induced anti-crizanlizumab-tmca antibodies.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Infusion-Related ReactionsAdvise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.1)].Interference With Automated Platelet CountsAdvise patients to inform their healthcare provider that they are receiving ADAKVEO prior to any blood tests due to the potential interference with laboratory tests used to measure platelet counts [see Warnings and Precautions (5.2)].Manufactured by:Novartis Pharmaceuticals CorporationOne Health PlazaEast Hanover, New Jersey 07936US License No. 1244(C) NovartisT2021-102.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no data on the presence of crizanlizumab-tmca in human or animal milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to crizanlizumab-tmca are unknown.The developmental and health benefits of breast-feeding should be considered along with the mothers clinical need for ADAKVEO and any potential adverse effects on the breastfed child from ADAKVEO or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Crizanlizumab-tmca is humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands, including P-selectin glycoprotein ligand (PSGL-1). Crizanlizumab-tmca can also dissociate preformed P-selectin/PSGL-1 complex. Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or genotoxicity studies have been conducted with crizanlizumab-tmca.In the 26-week repeat-dose toxicity study, cynomolgus monkeys were administered crizanlizumab-tmca once every weeks at doses up to 50 mg/kg (at least 13.5 times the human clinical exposure based on AUC in patients with sickle cell disease at mg/kg once every weeks). There were no adverse effects of crizanlizumab-tmca on male or female reproductive organs.. 13.2 Animal Toxicology and/or Pharmacology. In the 26-week repeat-dose toxicity study, administration of crizanlizumab-tmca in cynomolgus monkeys at dose levels up to 50 mg/kg/dose once every weeks resulted in inflammation of the vessels in multiple tissues in out of 10 animals.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 0078-0883-61Rx OnlyADAKVEO(R) (crizanlizumab-tmca)Injection100 mg/10 mL(10 mg/mL)For intravenous infusion after dilution.1 Single-Dose Vial.Discard Unused Portion.NOVARTIS. PRINCIPAL DISPLAY PANELNDC 0078-0883-61 Rx OnlyADAKVEO(R)(crizanlizumab-tmca)Injection100 mg/10 mL(10 mg/mL)For intravenous infusion after dilution.1 Single-Dose Vial.Discard Unused Portion.NOVARTIS.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of ADAKVEO for sickle cell disease have been established in pediatric patients aged 16 years and older. Use of ADAKVEO for sickle cell disease is supported by evidence from adequate and well-controlled studies in adults and pediatric patients (SUSTAIN Trial). The SUSTAIN trial enrolled one pediatric patient treated with ADAKVEO mg/kg aged 16 years old [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)].The safety and efficacy of ADAKVEO in pediatric patients below the age of 16 years have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. ADAKVEO resulted in dose-dependent P-selectin inhibition (measured ex vivo) in patients with sickle cell disease and healthy volunteers.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of crizanlizumab-tmca were evaluated in healthy volunteers and patients with sickle cell disease. The mean crizanlizumab-tmca Cmax, AUClast, or AUCinf increased disproportionally over the dose range of 0.2 to mg/kg (0.04 to 1.6 times the approved recommended dosage) in healthy volunteers. In healthy volunteers administered the mg/kg dose, the mean [coefficient of variation (CV%)] crizanlizumab-tmca Cmax, AUClast, or AUCinf were 0.16 (15.3%) mg/mL, 33.6 (12.6%) mghr/mL and 34.6 (13.1%) mghr/mL, respectively.DistributionThe mean (% CV) volume of distribution was 4.26 (25.1%) after single crizanlizumab-tmca mg/kg intravenous infusion in healthy volunteers.EliminationThe mean (% CV) terminal elimination half-life (t1/2) of crizanlizumab-tmca was 10.6 (20.5%) days and the mean clearance was 11.7 (16.2%) mL/hr at mg/kg doses in healthy volunteers. The mean (% CV) elimination t1/2 of crizanlizumab-tmca was 7.6 (28.5%) days during dosing interval in patients with sickle cell disease.MetabolismCrizanlizumab-tmca is expected to be metabolized into small peptides by catabolic pathways.Specific PopulationsThe effect of renal or hepatic impairment on the pharmacokinetics of crizanlizumab-tmca is unknown.Drug Interaction StudiesHydroxyurea had no clinically meaningful effect on crizanlizumab-tmca pharmacokinetics in patients in clinical studies.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on data from animal studies, ADAKVEO has the potential to cause fetal harm when administered to 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 non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at mg/kg/dose once every weeks (see Data).There are insufficient human data on ADAKVEO use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to 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 background risk of birth defect, loss, or other adverse outcomes.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskWomen 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.DataAnimal DataIn 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 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 mg/kg/dose once every 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-tmca crosses the placental barrier.

RECENT MAJOR CHANGES SECTION.

Dosing and Administration, Management of Infusion-Related Reactions (2.3)7/2021Warnings and Precautions, Infusion-Related Reactions (5.1)7/2021.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: July 2021PATIENT INFORMATIONADAKVEO(R) (ah dak vee oh)(crizanlizumab-tmca)injection, for intravenous useWhat is the most important information should know about ADAKVEOADAKVEO may cause serious side effects, including:Infusion-related reactions. Infusion-related reactions may happen during or within 24 hours of receiving an infusion of ADAKVEO. Your healthcare provider may slow down, temporarily stop, or completely stop your infusion with ADAKVEO if you have an infusion-related reaction. You may continue to receive ADAKVEO at slower infusion rate and your healthcare provider may give you certain medicines before your infusion to lower your risk of getting an infusion-related reaction. Your healthcare provider should monitor you for signs and symptoms of infusion-related reactions and treat your symptoms as needed. Tell your healthcare provider right away if you get any of the following signs or symptoms of an infusion-related reaction:pain in various locationsheadachefeverchills or shiveringnauseavomitingdiarrheatirednessdizzinesssweatinghivesitchingshortness of breath or wheezingADAKVEO may interfere with certain blood test. Tell your healthcare providers that you are receiving ADAKVEO before having any blood tests. ADAKVEO may interfere with laboratory test to measure your platelet counts.See What are possible side effects of ADAKVEO for more information about side effects.What is ADAKVEOADAKVEO is prescription medicine used in people 16 years of age and older who have sickle cell disease to help reduce how often painful crises happen.It is not known if ADAKVEO is safe and effective in children under 16 years of age.Before receiving ADAKVEO, tell your healthcare provider about all of your medical conditions, including if you:are pregnant or plan to become pregnant. ADAKVEO may harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if ADAKVEO passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby during treatment with ADAKVEO.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive ADAKVEOYour healthcare provider will give you ADAKVEO as an infusion into your vein through an intravenous (IV) line over 30 minutes.You will receive your first infusion, and then second infusion weeks later. After that, you will receive an infusion every weeks.Your healthcare provider may also prescribe other treatments for you to take during treatment with ADAKVEO.Do not stop receiving ADAKVEO unless your healthcare provider tells you to.If you miss an appointment for infusion, call your healthcare provider as soon as possible to reschedule. What are the possible side effects of ADAKVEOADAKVEO may cause serious side effects. See What is the most important information should know about ADAKVEOThe most common side effects of ADAKVEO include:nauseajoint painback painstomach-area (abdominal) pain or tendernessfeverThese are not all of the possible side effects of ADAKVEO. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ADAKVEO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your healthcare provider or pharmacist for more information about ADAKVEO.What are the ingredients in ADAKVEOActive ingredient: crizanlizumab-tmca Inactive ingredients: citric acid, polysorbate 80, sodium citrate, sucrose, and water for injectionManufactured by: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936U.S. License No. 1244(C) NovartisFor more information, go to www.adakveo.com or call 1-877-ADAKVE-0 (1-877-232-5830).T2021-103. Infusion-related reactions. Infusion-related reactions may happen during or within 24 hours of receiving an infusion of ADAKVEO. Your healthcare provider may slow down, temporarily stop, or completely stop your infusion with ADAKVEO if you have an infusion-related reaction. You may continue to receive ADAKVEO at slower infusion rate and your healthcare provider may give you certain medicines before your infusion to lower your risk of getting an infusion-related reaction. Your healthcare provider should monitor you for signs and symptoms of infusion-related reactions and treat your symptoms as needed. Tell your healthcare provider right away if you get any of the following signs or symptoms of an infusion-related reaction:. pain in various locations. headache. fever. chills or shivering. nausea. vomiting. diarrhea. tiredness. dizziness. sweating. hives. itching. shortness of breath or wheezing. ADAKVEO may interfere with certain blood test. Tell your healthcare providers that you are receiving ADAKVEO before having any blood tests. ADAKVEO may interfere with laboratory test to measure your platelet counts.. are pregnant or plan to become pregnant. ADAKVEO may harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if ADAKVEO passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby during treatment with ADAKVEO.. Your healthcare provider will give you ADAKVEO as an infusion into your vein through an intravenous (IV) line over 30 minutes.. You will receive your first infusion, and then second infusion weeks later. After that, you will receive an infusion every weeks.. Your healthcare provider may also prescribe other treatments for you to take during treatment with ADAKVEO.. Do not stop receiving ADAKVEO unless your healthcare provider tells you to.. If you miss an appointment for infusion, call your healthcare provider as soon as possible to reschedule. nausea. joint pain. back pain. stomach-area (abdominal) pain or tenderness. fever.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. Administer ADAKVEO mg/kg by intravenous infusion over period of 30 minutes at Week 0, Week 2, and every weeks thereafter.If dose is missed, administer ADAKVEO as soon as possible.If ADAKVEO is administered within weeks after the missed dose, continue dosing according to the patients original schedule.If ADAKVEO is administered more than weeks after the missed dose, continue dosing every weeks thereafter.ADAKVEO may be given with or without hydroxyurea.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May cause fetal harm. (8.1). 8.1 Pregnancy. Risk SummaryBased on data from animal studies, ADAKVEO has the potential to cause fetal harm when administered to 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 non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at mg/kg/dose once every weeks (see Data).There are insufficient human data on ADAKVEO use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to 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 background risk of birth defect, loss, or other adverse outcomes.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskWomen 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.DataAnimal DataIn 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 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 mg/kg/dose once every 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-tmca crosses the placental barrier.. 8.2 Lactation. Risk SummaryThere is no data on the presence of crizanlizumab-tmca in human or animal milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to crizanlizumab-tmca are unknown.The developmental and health benefits of breast-feeding should be considered along with the mothers clinical need for ADAKVEO and any potential adverse effects on the breastfed child from ADAKVEO or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of ADAKVEO for sickle cell disease have been established in pediatric patients aged 16 years and older. Use of ADAKVEO for sickle cell disease is supported by evidence from adequate and well-controlled studies in adults and pediatric patients (SUSTAIN Trial). The SUSTAIN trial enrolled one pediatric patient treated with ADAKVEO mg/kg aged 16 years old [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)].The safety and efficacy of ADAKVEO in pediatric patients below the age of 16 years have not been established.. 8.5 Geriatric Use. Clinical studies of ADAKVEO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

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). (2.3, 5.1)Interference With Automated Platelet Counts (platelet clumping): Run test as soon as possible or use citrate tubes. (5.2). 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). (2.3, 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 (defined as occurring during/within 24 hours of infusion) were observed in (3%) patients treated with ADAKVEO mg/kg [see Adverse Reactions (6.1)].In the postmarketing setting, cases of infusion-related reactions, including severe pain events, have been reported, which required hospitalizations. The majority of these infusion-related reactions occurred during the first and second infusions. The management of pain events has included acetaminophen, NSAIDs, opioids, antihistamines, intravenous fluids, and/or oxygen therapy. Some patients have also experienced subsequent complications, such as acute chest syndrome and fat embolism, particularly those treated with steroids.Monitor for and advise patients of signs and symptoms of infusion-related reactions, which may include pain in various locations, headache, fever, chills, nausea, vomiting, diarrhea, fatigue, dizziness, pruritus, urticaria, sweating, and shortness of breath or wheezing.Discontinue ADAKVEO infusion for severe infusion-related reactions and institute appropriate medical care [see Dosage and Administration (2.3)].For management recommendations of mild or moderate infusion-related reaction [see Dosage and Administration (2.3)].Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis).. 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)].