Pivekimab Sunirine-pvzy for Lymphoma

1. INDICATIONS AND USAGE DECNUPAZ is indicated for the treatment of adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). DECNUPAZ is a CD123-directed antibody and alkylating agent conjugate indicated for the treatment of adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). ( 1 )

2. DOSAGE AND ADMINISTRATION For intravenous infusion only. ( 2.6 ) The recommended dose of DECNUPAZ is 0.045 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. ( 2.2 ) Premedicate with a corticosteroid on the day prior to infusion and premedicate with a corticosteroid, antihistamine, and an antipyretic at least 30 to 60 minutes prior to DECNUPAZ infusion. ( 2.3 ) DECNUPAZ requires reconstitution followed by two dilutions prior to administration. See full Prescribing Information for instructions on preparation and administration. ( 2.5 , 2.6 ) 2.1 Important Administration Instructions DECNUPAZ requires reconstitution followed by two dilutions prior to administration. Read the entire preparation instructions carefully before preparing and administering DECNUPAZ. 2.2 Recommended Dosage The recommended dose of DECNUPAZ in adult patients with BPDCN is 0.045 mg/kg intravenously over approximately 15-30 minutes once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Calculate the dose based on the patient’s actual body weight [see Dosage and Administration ( 2.5 ) ] . 2.3 Premedications Administer the premedications in Table 1 the day prior to and the day of the infusion of DECNUPAZ to reduce the risk of infusion-related reactions (IRRs) [see Warnings and Precautions ( 5.2 )] . Table 1. Recommended Premedications Prior to Each DECNUPAZ Infusion Administration Time P rior to DECNUPAZ Infusion Premedication Route of Administration Dose ( or equivalent) Day before DECNUPAZ infusion Corticosteroid Oral or intravenous Dexamethasone 8 mg twice daily 30 to 60 minutes prior to infusion Corticosteroid Intravenous Dexamethasone 8 mg Antihistamine Intravenous Diphenhydramine 25 mg to 50 mg Antipyretic Oral Acetaminophen 325 mg to 650 mg 2.4 Dosage Modifications for Adverse Reactions Table 2 provides recommended dosage modifications for DECNUPAZ due to adverse reactions. Table 2. Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity of Adverse Reaction a Dose Modification Guidelines Veno-occlusive disease (VOD) [see Warnings and Precautions ( 5.1 )] Any Grade Permanently discontinue DECNUPAZ Increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT) [see Warnings and Precautions ( 5.1 )] Either AST or ALT is >2.5 x ULN Delay further DECNUPAZ dosing until AST or ALT have returned to ≤2.5 × ULN Increased bilirubin [see Warnings and Precautions ( 5.1 )] Total bilirubin > 1.5 × ULN Delay further DECNUPAZ dosing until total bilirubin has returned to ≤1.5 × ULN Infusion-related reactions [see Warnings and Precautions ( 5.2 )] Grade 2 Interrupt DECNUPAZ infusion and institute appropriate medical management After full resolution of symptoms, resume DECNUPAZ infusion at 50% of the previous rate and if no further symptoms appear, increase rate as appropriate until infusion is completed Grade 3 Stop DECNUPAZ infusion and institute appropriate medical management After full resolution of symptoms, resume the infusion at 50% of the previous rate If symptoms recur, permanently discontinue Grade 4 Permanently discontinue DECNUPAZ Edema [see Warnings and Precautions ( 5.3 )] Grade 1 (5-10% inter-limb discrepancy in volume or circumference, 4 kg weight gain, or 1+ pitting edema (2 mm)) Follow weekly weights Consider administering diuretic therapy Grade 2 (10-30% inter-limb discrepancy in volume or circumference, >4 kg weight gain, or 2+ pitting edema (4 mm)) Administer diuretic therapy Manage hypoalbuminemia as needed Delay further DECNUPAZ dosing until edema has returned to Grade 0-1 or baseline If delayed more than 2 weeks, consider dose reduction before resuming Grade 3 (> 30% inter-limb discrepancy in volume, or 3+/4+ pitting edema (>6 mm)) Consider combination diuretic therapy Manage hypoalbuminemia as needed Delay further DECNUPAZ dosing until edema has returned to Grade 0-1 or baseline Consider resuming DECNUPAZ infusion at 0.015 mg/kg intravenously once every 3 weeks Grade 4 (life threatening) Permanently discontinue DECNUPAZ Other Non-hematologic Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 Delay further DECNUPAZ dosing until resolved to ≤ Grade 2 or baseline Grade 4 Permanently discontinue DECNUPAZ ULN=upper limit of normal a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03; Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening. 2.5 Instructions for Preparation Preparation Use aseptic technique to prepare DECNUPAZ. DECNUPAZ is a hazardous drug. Follow applicable special handling and disposal procedures in accordance with local requirements. 1 Determine the dose and the number of DECNUPAZ vials needed. More than one vial may be needed to achieve a full dose. Remove the DECNUPAZ vial(s) from the refrigerator and allow the vial(s) to reach room temperature 15°C to 30°C (59℉ to 86°F) before use. Reconstitution Using a sterile syringe, reconstitute DECNUPAZ by slowly injecting 1.1 mL of Sterile Water for Injection into each vial to obtain a concentration of 2 mg/mL. Each single-dose vial contains 1 mL (2 mg) of withdrawable DECNUPAZ. Gently swirl the vial in a circular motion. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution in each vial should appear clear to slightly opalescent, colorless to slightly yellow and free of visible contaminants, particles and/or particulates. Do not use if discoloration or particulate matter is present. DECNUPAZ contains no preservative. Use reconstituted solution immediately. If not used immediately, store the reconstituted DECNUPAZ vials in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 4 hours from the time of reconstitution. Do not freeze. First Dilution DECNUPAZ must be diluted with 5% Dextrose Injection. Add 4.8 mL of 5% Dextrose Injection to the reconstituted solution in the vial. Mix the diluted solution by gentle inversion. Do not shake. The resulting diluted solution concentration is 0.4 mg/mL. Calculate the required administration volume needed from the first dilution of vial(s). Volume needed from vial(s) after first dilution (mL) = Dose (mg) / 0.4 mg/mL DECNUPAZ requires a second dilution prior to administration. Second Dilution Withdraw the calculated volume from the first dilution of vial(s) using an appropriately sized syringe. Withdraw an equal volume of 5% Dextrose Injection in an appropriately sized second syringe. Attach a connector to the two syringes and transfer DECNUPAZ into the syringe containing 5% Dextrose Injection. Disconnect the syringes. Draw air into the syringe containing the DECNUPAZ diluted solution and close. Gently invert the syringe to mix the solution. Do not shake. Remove air bubbles from the syringe before administration. The final concentration is 0.2 mg/mL. Discard any unused drug remaining in the vial(s). Do not use an in-line filter due to increased drug loss. If an in-line filter is required, a 1.2 micron polyethersulfone (PES) filter can be used. Storage of Diluted Solution Immediately use diluted DECNUPAZ solution. The total storage time from the start of dose preparation to completion of administration should not exceed 24 hours. Store the diluted solution of DECNUPAZ under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours, including up to 8 hours at room temperature at 9°C to 25°C (48°F to 77°F), from the time of reconstitution to completion of the intravenous infusion. Discard diluted infusion solution if storage time exceeds these limits. If refrigerated, allow approximately 30 minutes for the diluted solution to come to room temperature prior to administration. Do not shake. Do not freeze the diluted infusion solution. Protect from light during storage. Do not shake. 2.6 Administration After preparing the dose for infusion, vis

5. WARNINGS AND PRECAUTIONS I nfusion -related reactions (IRR) : DECNUPAZ can cause serious, life-threatening IRR. Premedicate with a corticosteroid the day before infusion, and premedicate with a corticosteroid, antihistamine, and an antipyretic prior to DECNUPAZ infusion. Monitor patients for IRR. Interrupt, reduce the rate of infusion, or permanently discontinue DECNUPAZ based on the severity. ( 5.2 ) Edema : Monitor for the development of edema and fluid retention. Depending on severity, delay, consider resuming at a lower dose, or permanently discontinue DECNUPAZ. ( 5.3 ) Sulfite Allergic Reactions : DECNUPAZ contains sodium metabisulfite, which may cause allergic type reactions, including anaphylactic symptoms and asthmatic episodes in certain susceptible people. ( 5.4 ) Embryo-fetal toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.5 ) 5.1 Hepatotoxicity , Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome) DECNUPAZ can cause hepatotoxicity, including VOD, a severe form of hepatotoxicity. In CADENZA, VOD occurred in 6% (7/116) of adult patients during treatment or following a subsequent hematopoietic stem cell transplantation (HSCT). Of the 7 total patients who developed VOD, 3 patients had treatment-naïve BPDCN and 4 patients had relapsed/refractory BPDCN. Among all 116 patients treated with DECNUPAZ at 0.045 mg/kg, VOD occurred in 2/116 (2%) during treatment, with onset up to 30 days after the last dose. Among 19 patients with BPDCN who proceeded to HSCT, VOD occurred in 5/19 patients (26%), including two fatal cases. The median time from subsequent HSCT to onset of VOD was 11 days (range: 7 – 25 days). After receiving DECNUPAZ, patients should be closely monitored for signs and symptoms of VOD including elevations in ALT, AST, total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitor liver tests, including ALT, AST, and total bilirubin, prior to each dose of DECNUPAZ. Based on elevations of liver tests, delay DECNUPAZ. In patients who experience VOD, discontinue DECNUPAZ and treat according to standard medical practice [see Dosage and Administration ( 2.4 )] . 5.2 Infusion-Related Reactions DECNUPAZ can cause serious, life-threatening infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. In CADENZA, IRRs occurred in 26% (30/116) of patients during treatment with DECNUPAZ at 0.045 mg/kg once every three weeks, including Grade 1 in 4.3% (5/116), Grade 2 in 16% (19/116), and Grade 3 in 5% (6/116) of patients. IRR occurred in Cycle 1 in 25% (29/116) of patients with decreasing frequency in subsequent cycles. IRR led to discontinuation in one patient. Premedicate with a corticosteroid the day before infusion, and premedicate with a corticosteroid, antihistamine, and antipyretic prior to dosing [ see Dosage and Administration ( 2.3 )] . Premedication the day before infusion and prior to dosing led to reduced frequency and severity of IRRs. Monitor patients closely for potential IRR during the infusion and for at least four hours, or longer as clinically indicated, after the first infusion and for at least 1 hour after subsequent infusions. Interrupt infusion of DECNUPAZ and institute appropriate medical management if an infusion-related reaction occurs. Depending on the severity of the infusion-related reaction, reduce infusion rate or permanently discontinue [see Dosage and Administration ( 2.4 )]. 5.3 Edema DECNUPAZ can cause edema and fluid retention, including serious events. In CADENZA, Grade 3-4 edema occurred in 16% (18/116) of patients treated with DECNUPAZ, including Grade 3-4 generalized edema in 2.6% (3/116) of patients [see Adverse Reactions ( 6.1 )]. Monitor patients for new or worsening edema. For Grade 2 or Grade 3 edema, delay further dosing of DECNUPAZ until edema has returned to Grade 0-1 or baseline. For Grade 3 edema or Grade 2 edema with dose delay for more than 2 weeks, consider resuming at a lower dose. For Grade 4 edema, permanently discontinue. Institute appropriate medical management for edema [see Dosage and Administration ( 2.4 )] . 5.4 Sulfite Allergic Reactions DECNUPAZ contains sodium metabisulfite, a sulfite that may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, DECNUPAZ can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (FGN849) and affects actively dividing cells [see Clinical Pharmacology ( 12.1 ), Nonclinical Toxicology ( 13.1 )] . Advise patients of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with DECNUPAZ and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with DECNUPAZ, and for 4 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

7. DRUG INTERACTIONS Strong and M oderate CYP3A Inhibitors : Closely monitor for DECNUPAZ adverse reactions ( 7.1 ) 7.1 Effect of Other Drugs on DECNUPAZ Strong and moderate CYP3A inhibitors Closely monitor patients for adverse reactions with DECNUPAZ when used concomitantly with strong and moderate CYP3A inhibitors. FGN849 is a substrate of CYP3A [see Clinical Pharmacology ( 12.3 )] . Concomitant use of DECNUPAZ with strong and moderate CYP3A inhibitors may increase unconjugated FGN849 exposure, which may increase the risk of DECNUPAZ adverse reactions.

6. ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Hepatotoxicity, Including Hepatic VOD (also known as Sinusoidal Obstruction Syndrome) [see Warnings and Precautions ( 5.1 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.2 )] Edema [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (≥20%) were edema, fatigue, musculoskeletal pain, hemorrhage, infusion-related reactions, nausea, and diarrhea. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥10%) were neutrophils decreased, platelets decreased, lymphocyte count decreased, white blood cells decreased, hemoglobin decreased, and glucose increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical T rials 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 DECNUPAZ was evaluated in CADENZA, a single-arm, open-label study that included 116 adults with newly diagnosed or relapsed/refractory myeloid malignancies, including 84 with BPDCN, treated with DECNUPAZ 0.045 mg/kg once every three weeks. The median number of cycles administered was 3 (range: 1 to 34) in the overall population, and 3.5 (range: 1 to 34) in patients with BPDCN. Serious adverse reactions occurred in 55% of patients treated with DECNUPAZ. The most common (≥2%) serious adverse reactions were febrile neutropenia, pneumonia, edema, sepsis, hemorrhage, thrombosis, infusion-related reactions, viral infection, pneumonitis, infections without specified pathogens, pyrexia, and musculoskeletal pain. Fatal adverse reactions occurred in 4.3% of patients who received DECNUPAZ, including cardiac arrest (0.9%), clostridium difficile infection (0.9%), failure to thrive (0.9%), depressed level of consciousness (0.9%), and respiratory failure (0.9%). Permanent discontinuation due to adverse reactions occurred in 10% of patients who received DECNUPAZ. Adverse reactions which resulted in permanent discontinuation of DECNUPAZ in ≥1% of patients included veno-occlusive disease and pneumonitis. Dosage interruptions of DECNUPAZ due to adverse reactions occurred in 37% of patients. Adverse reactions which resulted in dosage interruptions in ≥2% of patients included edema, pneumonia, infusion-related reaction, bacterial infections, fatigue, hemorrhage, neutropenia, pneumonitis, and pyrexia. Dose reductions of DECNUPAZ due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dose reductions in ≥2% of patients included edema. The most common adverse reactions (≥20%) were edema, fatigue, musculoskeletal pain, hemorrhage, infusion-related reactions, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥10%) were neutrophils decreased, platelets decreased, lymphocyte count decreased, white blood cells decreased, hemoglobin decreased, and glucose increased. Table 3 summarizes the common adverse reactions (≥10%) in patients treated with DECNUPAZ in CADENZA. Table 3. Adverse Reactions (≥10%) in Patients Who Received DECNUPAZ in CADENZA DECNUPAZ (N=116) Adverse Reaction § All Grades (%) Grade 3 or 4 (%) General disorders and administration site conditions Edema a 52 16 Fatigue b 34 5 Pyrexia b 16 0.9 Chills 11 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain b 34 8 Vascular disorders Hemorrhage b 28 6 Thrombosis b 13 5 Injury, poisoning and procedural complications Infusion-related reactions 26 5 Fall 13 1.7 Gastrointestinal disorders Nausea b 24 0.9 Diarrhea b 21 0.9 Constipation 19 0 Abdominal pain b 14 0.9 Respiratory , thoracic and mediastinal disorders Dyspnea b 19 1.7 Cough b 15 0 Skin and subcutaneous tissue disorders Rash c 19 0 Nervous system disorder s Neuropathy peripheral d 18 1.7 Headache b 16 2.6 Dizziness b 10 0.9 Metabolism and nutrition disorders Decreased appetite b 16 0.9 Infections and i nfestations Infections without specified pathogens b 16 6 Viral infections e 13 6 Bacterial infections f 12 5 Pneumonia g 11 9 Psychiatric disorders Insomnia 15 0 Blood and lymphatic system disorders Febrile neutropenia 11 11 § Adverse reactions were graded based on CTCAE Version 4.03 a. Edema includes acute pulmonary edema, face edema, generalized edema, hypervolemia, edema, edema genital, edema peripheral, pericardial effusion, peripheral swelling, pleural effusion, pulmonary edema, swelling face, weight increased, ascites. b. Consists of multiple related terms. c. Rash includes erythema, erythema nodosum, guttate psoriasis, photosensitivity reaction, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, skin lesion, skin lesion inflammation, stasis dermatitis. d. Neuropathy peripheral includes burning sensation, dysesthesia, facial nerve disorder, hypoesthesia, IIIrd nerve disorder, neuralgia, neuropathy peripheral, paresthesia, sciatica. e. Viral infections includes COVID-19, cytomegalovirus infection, HCoV-229E infection, herpes simplex, herpes zoster, herpes zoster disseminated, influenza, ophthalmic herpes simplex, oral herpes. f. Bacterial infections includes cellulitis, clostridium difficile infection, erysipelas, folliculitis, vulval abscess. g. Pneumonia includes pneumocystis jirovecii pneumonia, pneumonia, pneumonia viral. Clinically relevant adverse reactions occurring in <10% of patients who received DECNUPAZ in CADENZA included: Vascular disorders : capillary leak syndrome (9%) a , hypotension b (7%) Gastrointestinal disorders: stomatitis b (6%) Infections and infestations: sepsis c (7%), fungal infections d (5%) Respiratory, thoracic and mediastinal disorders: pneumonitis (5%) Cardiac disorders : arrhythmia e (6%) Renal and urinary disorders : acute kidney injury b (6%) Hepatobiliary disorders: veno-occlusive disease (1.7%) a. At least 2 of the following new onset signs and symptoms within 7 days of each other: hypoalbuminemia (including albumin <3.0 g/dL), edema (including weight increase >5 kg), hypotension (including systolic blood pressure <90 mmHg). b. Consists of multiple related terms. c. Includes bacteremia, klebsiella bacteremia, pulmonary sepsis, sepsis, and streptococcal bacteremia. d. Includes candida infection, fungal balanitis, fungal foot infection, fungal skin infection. e. Includes arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, tachyarrhythmia. Table 4 summarizes laboratory abnormalities in CADENZA. Table 4. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received DECNUPAZ in CADENZA Laboratory Abnormality* DECNUPAZ a All Grades (%) Grade 3 or 4 (%) Chemistry Creatinine increased 76 0 Glucose increased 53 10 Albumin decreased 50 1.8 Phosphate decreased 39 8 Calcium decreased 34 1.8 Alanine aminotransferase increased 32 4.4 Aspartate aminotransferase increased 29 0.9 Sodium decreased 28 1.8 Potassium decreased 26 3.5 Alkaline phosphatase increased 20 0.9 Magnesium decreased 18 0 Bilirubin increased 16 0.9 Hematology Platelets decreased 64 40 Neutrophils decreased 63 45 Lymphocyte count decreased 62 39 White blood cells decreased 55 34 Hemoglobin decreased 40 20 * Laboratory abnormalities were graded based on CTCAE Version 4.03. a The denominator used to calculate the rate varied from 78 to 114 based on the number of patients with at least one post-baseline value.