الجرعة وطريقة الإعطاء
2 DOSAGE AND ADMINISTRATION The recommended dose of POLIVY is 1.8 mg/kg as an intravenous infusion every 21 days for 6 cycles. ( 2 ) Administer the initial POLIVY dose over 90 minutes. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated. ( 2 ) Premedicate with an antihistamine and antipyretic before POLIVY. ( 2 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.4 ) 2.1 Recommended Dosage Patients with Previously Untreated DLBCL, NOS or HGBL The recommended dosage of POLIVY is 1.8 mg/kg administered as an intravenous infusion every 21 days for 6 cycles in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone [see Clinical Studies (14.1) ] . Administer POLIVY, cyclophosphamide, doxorubicin, and a rituximab product in any order on Day 1 after the administration of prednisone. Prednisone is administered on Days 1–5 of each cycle. Patients with Relapsed or Refractory DLBCL, NOS The recommended dosage of POLIVY is 1.8 mg/kg administered as an intravenous infusion every 21 days for 6 cycles in combination with bendamustine and a rituximab product. Administer POLIVY, bendamustine, and a rituximab product in any order on Day 1 of each cycle. The recommended dose of bendamustine is 90 mg/m 2 /day on Days 1 and 2 when administered with POLIVY and a rituximab product. The recommended dose of rituximab product is 375 mg/m 2 intravenously on Day 1 of each cycle. For All Indicated Patients If not already premedicated, administer an antihistamine and antipyretic at least 30 minutes prior to POLIVY. If a planned dose of POLIVY is missed, administer as soon as possible. Adjust the schedule of administration to maintain a 21-day interval between doses. 2.2 Management of Adverse Reactions Previously Untreated DLBCL, NOS or HGBL Table 1 provides management guidelines for peripheral neuropathy in patients receiving POLIVY plus R-CHP [see Warnings and Precautions (5.1) ] . Table 1 Management of Peripheral Neuropathy in Patients Receiving POLIVY Plus R-CHP Adverse reaction Grade Dose modification Starting dose for POLIVY is 1.8 mg/kg. First dose reduction level is 1.4 mg/kg. Second dose reduction level is 1 mg/kg. No further dose reduction is recommended beyond 1 mg/kg. If further reduction needed discontinue POLIVY. R-CHP should be continued if POLIVY is withheld. If there is concurrent sensory and motor neuropathy, follow the guidance for the most severe neuropathy. If the grade of sensory and motor neuropathy are the same, follow the guidance for motor neuropathy. Peripheral sensory neuropathy Grade 1 None Grade 2 If resolves to Grade 1 or lower before the next scheduled dose, resume at the same dose level. If Gr 2 persists at the next scheduled dose, reduce one dose level. Grade 3 Withhold until Grade 2 or lower and reduce one dose level. Grade 4 Permanently discontinue. Peripheral motor neuropathy Grade 1 None Grade 2 or 3 Withhold until Grade 1 or lower and reduce one dose level. Grade 4 Permanently discontinue. Table 2 provides management guidelines for infusion-related reaction and myelosuppression [see Warnings and Precautions (5.2 and 5.3) ] . Table 2 Management of Infusion-Related Reaction and Myelosuppression in Patients Receiving POLIVY Plus R-CHP Adverse Reaction Dosage Modification Starting dose for POLIVY is 1.8 mg/kg. First dose reduction level is 1.4 mg/kg. Second dose reduction level is 1 mg/kg. No further dose reduction is recommended beyond 1 mg/kg. If further reduction needed discontinue POLIVY. Toxicity graded per National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 4.0. Infusion-Related Reaction Grade 1–3 Interrupt POLIVY infusion and give supportive treatment. For the first instance of Grade 3 wheezing, bronchospasm, or generalized urticaria, permanently discontinue POLIVY. For recurrent Grade 2 wheezing or urticaria, or for recurrence of any Grade 3 symptoms, permanently discontinue POLIVY. Otherwise, upon complete resolution of symptoms, infusion may be resumed at 50% of the rate achieved prior to interruption. In the absence of infusion related symptoms, the rate of infusion may be escalated in increments of 50 mg/hour every 30 minutes. For the next cycle, infuse POLIVY over 90 minutes. If no infusion-related reaction occurs, subsequent infusions may be administered over 30 minutes. Administer premedication for all cycles. Infusion-Related Reaction Grade 4 Stop POLIVY infusion immediately. Give supportive treatment. Discontinue POLIVY. Neutropenia Severity on Day 1 of any cycle. , If primary cause is lymphoma, dosage delay or reduction may not be needed. Grade 3–4 Hold all treatment until ANC recovers to greater than or equal to 1,000/microliter. Consider therapeutic G-CSF if neutropenia occurs after prophylactic G-CSF. If ANC recovers to greater than or equal to 1,000/microliter on or before Day 7, resume all treatment without any dose reductions. If ANC recovers to greater than or equal to 1,000/microliter after Day 7: resume all treatment administer prophylactic G-CSF in next cycle. If G-CSF was already given, consider a dose reduction of POLIVY. Thrombocytopenia , Grade 3–4 Hold all treatment until platelets recover to greater than or equal to 75,000/microliter. If platelets recover to greater than or equal to 75,000/microliter on or before Day 7, resume all treatment without any dose reductions. If platelets recover to greater than or equal to 75,000/microliter after Day 7: resume all treatment and consider a dose reduction of POLIVY. Relapsed or Refractory DLBCL, NOS Table 3 provides management guidelines for peripheral neuropathy, infusion-related reaction, and myelosuppression in patients receiving POLIVY in combination with bendamustine and a rituximab product [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Table 3 Management of Peripheral Neuropathy, Infusion-Related Reaction, and Myelosuppression in Patients Receiving POLIVY Plus Bendamustine and a Rituximab Product Adverse Reaction Dosage Modification Starting dose for POLIVY is 1.8 mg/kg. First dose reduction level is 1.4 mg/kg. Second dose reduction level is 1 mg/kg. No further dose reduction is recommended beyond 1 mg/kg. If further reduction needed discontinue POLIVY. Toxicity graded per NCI CTCAE version 4.0. Peripheral Neuropathy Grade 2–3 Hold POLIVY dosing until improvement to Grade 1 or lower. If recovered to Grade 1 or lower on or before Day 14, restart POLIVY with the next cycle at a permanently reduced dose of 1.4 mg/kg. If a prior dose reduction to 1.4 mg/kg has occurred, discontinue POLIVY. If not recovered to Grade 1 or lower on or before Day 14, discontinue POLIVY. Peripheral Neuropathy Grade 4 Discontinue POLIVY. Infusion-Related Reaction Grade 1–3 Interrupt POLIVY infusion and give supportive treatment. For the first instance of Grade 3 wheezing, bronchospasm, or generalized urticaria, permanently discontinue POLIVY. For recurrent Grade 2 wheezing or urticaria, or for recurrence of any Grade 3 symptoms, permanently discontinue POLIVY. Otherwise, upon complete resolution of symptoms, infusion may be resumed at 50% of the rate achieved prior to interruption. In the absence of infusion related symptoms, the rate of infusion may be escalated in increments of 50 mg/hour every 30 minutes. For the next cycle, infuse POLIVY over 90 minutes. If no infusion-related reaction occurs, subsequent infusions may be administered over 30 minutes. Administer premedication for all cycles. Infusion-Related Reaction Grade 4 Stop POLIVY infusion immediately. Give supportive treatment. Permanently discontinue POLIVY. Neutropenia Severity on Day 1 of any cycle. , If primary cause is lymphoma, dosage delay or reduction may not be needed. Grade 3–4 Hold all treatment until ANC recovers to greater than 1,000/microliter. If ANC recovers to greater than 1,000/microliter on or before Day 7, resume all treatment without any additional dose reductions. Consider granulocyte colony-stimulating factor prophylaxis for subsequent cycles, if not previously given. If ANC recovers to greater than 1,000/microliter after Day 7: restart all treatment. Consider granulocyte colony-stimulating factor prophylaxis for subsequent cycles, if not previously given. If prophylaxis was given, consider dose reduction of bendamustine. if dose reduction of bendamustine has already occurred, consider dose reduction of POLIVY to 1.4 mg/kg. Thrombocytopenia , Grade 3–4 Hold all treatment until platelets recover to greater than 75,000/microliter. If platelets recover to greater than 75,000/microliter on or before Day 7, resume all treatment without any additional dose reductions. If platelets recover to greater than 75,000/microliter after Day 7: restart all treatment, with dose reduction of bendamustine. if dose reduction of bendamustine has already occurred, consider dose reduction of POLIVY to 1.4 mg/kg. 2.3 Recommended Prophylactic Medications If not already premedicated for a rituximab product, administer an antihistamine and antipyretic at least 30 to 60 minutes prior to POLIVY for potential infusion-related reactions [see Warnings and Precautions (5.2) ] . Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus throughout treatment with POLIVY. Administer prophylactic granulocyte colony-stimulating factor (G-CSF) for neutropenia in patients receiving POLIVY plus R-CHP. Consider prophylactic G-CSF administration for neutropenia in patients receiving POLIVY plus bendamustine and a rituximab product [see Warnings and Precautions (5.3) ] . Administer tumor lysis syndrome prophylaxis for patients at increased risk of tumor lysis syndrome [see Warnings and Precautions (5.6) ] . 2.4 Instructions for Preparation and Administration Reconstitute and further dilute POLIVY prior to intravenous infusion. POLIVY is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitution Reconstitute immediately before dilution. More than one vial may be needed for a full dose. Calculate the dose, the total volume of reconstituted POLIVY solution required, and the number of POLIVY vials needed. Using a sterile syringe, slowly inject Sterile Water for Injection, USP, using the volume provided in Table 4 , into the POLIVY vial, with the stream directed toward the inside wall of the vial to obtain a concentration of 20 mg/mL of polatuzumab vedotin-piiq. Table 4 Reconstitution Volumes Strength Volume of Sterile Water for Injection, USP required for reconstitution 30 mg vial 1.8 mL 140 mg vial 7.2 mL Swirl the vial gently until completely dissolved. Do not shake . Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution should appear colorless to slightly brown, clear to slightly opalescent, and free of visible particulates. Do not use if the reconstituted solution is discolored, is cloudy, or contains visible particulates. Do not freeze or expose to direct sunlight . If needed, store unused reconstituted POLIVY solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours or at room temperature (9°C to 25°C, 47°F to 77°F) up to a maximum of 8 hours prior to dilution. Discard vial when cumulative storage time prior to dilution exceeds 48 hours. Dilution Dilute polatuzumab vedotin-piiq to a final concentration of 0.72–2.7 mg/mL in an intravenous infusion bag with a minimum volume of 50 mL containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Determine the volume of 20 mg/mL reconstituted solution needed based on the required dose. Withdraw the required volume of reconstituted solution from the POLIVY vial using a sterile syringe and dilute into the intravenous infusion bag. Discard any unused portion left in the vial. Gently mix the intravenous bag by slowly inverting the bag. Do not shake . Inspect the intravenous bag for particulates and discard if present. If not used immediately, store the diluted POLIVY solution as specified in Table 5 . Discard if storage time exceeds these limits. Do not freeze or expose to direct sunlight . Table 5 Diluted POLIVY Solution Storage Conditions Diluent Used to Prepare Solution for Infusion Diluted POLIVY Solution Storage Conditions To ensure product stability, do not exceed specified storage durations. 0.9% Sodium Chloride Injection, USP Up to 36 hours at 2°C to 8°C (36°F to 46°F) or up to 4 hours at room temperature (9 to 25°C, 47 to 77°F) 0.45% Sodium Chloride Injection, USP Up to 18 hours at 2°C to 8°C (36°F to 46°F) or up to 4 hours at room temperature (9 to 25°C, 47 to 77°F) 5% Dextrose Injection, USP Up to 36 hours at 2°C to 8°C (36°F to 46°F) or up to 6 hours at room temperature (9 to 25°C, 47 to 77°F) Limit transportation to 30 minutes at 9°C to 25°C or 24 hours at 2°C to 8°C (refer to instructions below). The total storage plus transportation times of the diluted product should not exceed the storage duration specified in Table 5 . Agitation stress can result in aggregation. Limit agitation of diluted product during preparation and transportation to administration site. Do not transport diluted product through an automated system (e.g., pneumatic tube or automated cart). If the prepared solution will be transported to a separate facility, remove air from the infusion bag to prevent aggregation. If air is removed, an infusion set with a vented spike is required to ensure accurate dosing during the infusion. No incompatibilities have been observed between POLIVY and intravenous infusion bags with product-contacting materials of polyvinyl chloride (PVC) or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP). No incompatibilities have been observed with infusion sets or infusion aids with product-contacting materials of PVC, PE, polyurethane (PU), polybutadiene (PBD), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyetherurethane (PEU), fluorinated ethylene propylene (FEP), or polytetrafluorethylene (PTFE), or with filter membranes composed of polyether sulfone (PES) or polysulfone (PSU). Administration Administer POLIVY as an intravenous infusion only. Administer the initial dose of POLIVY over 90 minutes. Monitor patients for infusion-related reactions during the infusion and for a minimum of 90 minutes following completion of the initial dose. If the previous infusion was well tolerated, the subsequent dose of POLIVY may be administered as a 30-minute infusion and patients should be monitored during the infusion and for at least 30 minutes after completion of the infusion. POLIVY must be administered using a dedicated infusion line equipped with a sterile, non-pyrogenic, low-protein-binding in-line or add-on filter (0.2- or 0.22-micron pore size) and a catheter. Do not mix POLIVY with or administer as an infusion with other drugs.
Side Effects Overview
6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Peripheral Neuropathy [see Warnings and Precautions (5.1) ] Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Myelosuppression [see Warnings and Precautions (5.3) ] Serious and Opportunistic Infections [see Warnings and Precautions (5.4) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.5) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] The most common adverse reactions (≥20%) in patients with large B-cell lymphoma treated with POLIVY in combination with R-CHP, excluding laboratory abnormalities, are peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. Grade 3 to 4 laboratory abnormalities (≥10%) are lymphopenia, neutropenia, hyperuricemia, and anemia. ( 6.1 ) The most common adverse reaction (≥20%) in patients with relapsed or refractory DLBCL treated with POLIVY in combination with BR are neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect exposure to POLIVY 1.8 mg/kg in 480 patients with large B-cell lymphoma (LBCL), including those with previously untreated LBCL (POLARIX) and relapsed or refractory DLBCL (GO29365). Previously Untreated DLBCL, NOS or HGBL GO39942 (POLARIX) The safety of POLIVY in combination with R-CHP chemoimmunotherapy was evaluated in POLARIX, a randomized double-blind, placebo-controlled, multicenter study of 873 patients with previously untreated large B-cell lymphoma, 435 of whom received POLIVY plus R-CHP [see Clinical Studies (14.1) ] . Patients were randomized 1:1 to receive POLIVY plus R-CHP or to receive R-CHOP for six 21-day cycles followed by two additional cycles of rituximab alone in both arms. Granulocyte colony-stimulating factor (G-CSF) primary prophylaxis was required and administered to 90% of patients in the POLIVY plus R-CHP arm and 93% of patients in the R-CHOP arm. Following premedication with an antihistamine and antipyretic, POLIVY was administered intravenously at 1.8 mg/kg on Day 1 of Cycles 1–6. R-CHP was administered starting on Day 1 of Cycles 1–6. Rituximab monotherapy was administered on Day 1 of Cycles 7–8 [see Clinical Studies (14.1) ] . The trial required an absolute neutrophil count ≥1,000/µL, platelet count ≥75,000/µL, creatinine clearance (CLcr) ≥40 mL/min, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease. The trial excluded patients having age >80, ECOG performance status above 2, known central nervous system (CNS) lymphoma, and Grade 2 or higher peripheral neuropathy. The median age was 65 years overall (range: 19 to 80 years); 54% of patients were male; 53% were White, 19% were Asian, 2%, Black or African American, and 5% were Hispanic or Latino. In the POLIVY plus R-CHP group, 92% of patients received 6 cycles of POLIVY, and 94% completed 6 cycles of combination therapy. Serious adverse reactions occurred in 34% of patients who received POLIVY plus R-CHP, including febrile neutropenia and pneumonia in ≥5% of recipients. Fatal adverse reactions occurred in 3% of recipients of POLIVY plus R-CHP within 90 days of last treatment, primarily from infection including pneumonia (0.9%) and sepsis (0.2%). Adverse reactions led to dose reduction of POLIVY in 6% of patients, mainly from peripheral neuropathy. Adverse reactions lead to dose interruption of POLIVY in 18% of patients, most commonly from pneumonia and neutropenia, and permanent discontinuation of POLIVY in 4.4% of patients. Table 6 summarizes adverse reactions in POLARIX. In recipients of POLIVY plus R-CHP, adverse reactions in ≥20% of patients, excluding laboratory abnormalities, were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. New or worsening Grade 3 to 4 laboratory abnormalities in ≥10% of patients were lymphopenia, neutropenia, hyperuricemia, and anemia. Table 6 Select Adverse Reactions Occurring in ≥10% of Patients Treated with POLIVY Plus R-CHP in POLARIX Adverse Reactions by Body System POLIVY + R-CHP n = 435 R-CHOP n = 438 All Grades, % Grade 3–4, % All Grades, % Grade 3–4, % The table includes a combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.0. Blood and Lymphatic System Disorders Laboratory values are based on integrated analysis of laboratory and adverse reaction data. Reported investigations exclude electrolytes. Lymphopenia 80 44 77 44 Anemia 68 14 67 11 Neutropenia 60 39 60 42 Thrombocytopenia 32 8 33 6 Febrile neutropenia Febrile neutropenia includes febrile neutropenia, febrile bone marrow aplasia, and neutropenic sepsis. 15 15 9 9 Investigations Creatinine increased 66 0.7 64 0.9 Aspartate aminotransferase increased 26 0.7 23 1.1 Alanine aminotransferase increased 25 1.4 27 0.5 Alkaline phosphatase increased 23 0 22 0.5 Uric acid increased 19 18 17 16 Weight decreased 13 0.9 12 0.2 Nervous System Disorders Peripheral neuropathy At last assessment, peripheral neuropathy was unresolved in 42% in the POLIVY + R-CHP arm and in 33% in the R-CHOP arm. , Peripheral neuropathy includes all terms containing "neuropathy", neuralgia, dysesthesia, paresthesia, hypoesthesia, peroneal nerve palsy, hypotonia, hyporeflexia, neuromyopathy, and hyperesthesia. 53 1.6 54 1.1 Altered taste 14 0 16 0 Headache 13 0.2 14 0.9 Gastrointestinal Disorders Nausea 42 1.1 37 0.5 Diarrhea 31 3.9 20 1.8 Constipation 29 1.1 29 0.2 Mucositis Mucositis includes stomatitis, oropharyngeal pain, mucosal inflammation, mouth ulceration, oral pain, oropharyngeal discomfort, aphthous ulcer, odynophagia, oral discomfort, tongue blistering, and tongue ulceration. 22 1.4 19 0.5 Abdominal pain Abdominal pain includes abdominal pain, abdominal discomfort, gastrointestinal pain, epigastric discomfort, and related terms. 16 1.1 14 1.6 Vomiting 15 1.1 14 0.7 General Disorders Fatigue 37 2.5 38 3.0 Pyrexia 16 1.4 13 0 Edema Edema includes edema, face edema, swelling face, edema peripheral, fluid overload, fluid retention, pulmonary edema, peripheral swelling, and swelling. 14 0.5 11 0.2 Infusion-related reaction Infusion related reaction is reflective of the combination regimen due to same-day administration. 13 1.1 16 1.6 Skin and Subcutaneous Tissue Disorders Alopecia 24 0 24 0.2 Rash Rash includes rash, dermatitis, and related terms. 13 0.7 11 0 Musculoskeletal Disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, myalgia, and bone pain. 19 0.5 21 1.8 Infections Upper respiratory tract infection Upper respiratory tract infection incudes sinusitis, laryngitis, pharyngitis, nasopharyngitis, rhinitis, and specific infections. 17 0.5 16 0.5 Metabolism and Nutrition Disorders Decreased appetite 17 1.1 14 0.7 Respiratory Disorders Cough 15 0 14 0 Dyspnea 13 0.9 10 0.9 Other clinically relevant adverse reactions in <10% of recipients of POLIVY plus R-CHP included: Infections: pneumonia, herpesvirus infection, sepsis, cytomegalovirus infection Metabolic disorders: tumor lysis syndrome Renal disorders: renal insufficiency Respiratory disorders: pneumonitis Relapsed or Refractory DLBCL, NOS GO29365 The data described in this section reflect exposure to POLIVY in Study GO29365, a multicenter clinical trial for adult patients with relapsed or refractory B-cell lymphomas [see Clinical Studies (14.2) ] . In patients with relapsed or refractory DLBCL, the trial included a single-arm safety evaluation of POLIVY in combination with bendamustine and a rituximab product (BR) (n = 6), followed by an open-label randomization to POLIVY in combination with BR versus BR alone (n = 39 treated per arm). Following premedication with an antihistamine and antipyretic, POLIVY 1.8 mg/kg was administered by intravenous infusion on Day 2 of Cycle 1 and on Day 1 of Cycles 2–6, with a cycle length of 21 days. Bendamustine 90 mg/m 2 daily was administered intravenously on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2–6. A rituximab product dosed at 375 mg/m 2 was administered intravenously on Day 1 of each cycle. Granulocyte colony-stimulating factor primary prophylaxis was optional and administered to 42% of recipients of POLIVY plus BR. In POLIVY-treated patients (n = 45), the median age was 67 years (range 33 – 86) with 58% being ≥age 65, 69% were male, 69% were White, and 87% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial required an absolute neutrophil count ≥1500/µL, platelet count ≥75/µL, creatinine clearance (CLcr) ≥40 mL/min, hepatic transaminases ≤2.5 times ULN, and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease. Patients with Grade 2 or higher peripheral neuropathy or prior allogeneic hematopoietic stem cell transplantation (HSCT) were excluded. Patients treated with POLIVY plus BR received a median of 5 cycles, with 49% receiving 6 cycles. Patients treated with BR alone received a median of 3 cycles, with 23% receiving 6 cycles. Fatal adverse reactions occurred in 7% of recipients of POLIVY plus BR within 90 days of last treatment. Serious adverse reactions occurred in 64%, most often from infection. Serious adverse reactions in ≥5% of recipients of POLIVY plus BR included pneumonia (16%), febrile neutropenia (11%), pyrexia (9%), and sepsis (7%). In recipients of POLIVY plus BR, adverse reactions led to dose reduction in 18%, dose interruption in 51%, and permanent discontinuation of all treatment in 31%. The most common adverse reactions leading to treatment discontinuation were thrombocytopenia and/or neutropenia. Table 7 summarizes commonly reported adverse reactions. In recipients of POLIVY plus BR, adverse reactions in ≥20% of patients included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Table 7 Adverse Reactions Occurring in >10% of Patients with Relapsed or Refractory DLBCL and ≥5% More in the POLIVY Plus Bendamustine and Rituximab Product Group in Study GO29365 Adverse Reactions by Body System POLIVY + BR n = 45 BR n = 39 All Grades, % Grade 3 or Higher, % All Grades, % Grade 3 or Higher, % The table includes a combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4. Blood and Lymphatic System Disorders Neutropenia 49 42 44 36 Thrombocytopenia 49 40 33 26 Anemia 47 24 28 18 Lymphopenia 13 13 8 8 Nervous System Disorders Peripheral neuropathy 40 0 8 0 Dizziness 13 0 8 0 Gastrointestinal Disorders Diarrhea 38 4.4 28 5 Vomiting 18 2.2 13 0 General Disorders Infusion-related reaction 18 2.2 8 0 Pyrexia 33 2.2 23 0 Decreased appetite 27 2.2 21 0 Infections Pneumonia 22 16 Includes 2 fatalities. 15 2.6 Includes 1 fatality. Upper respiratory tract infection 13 0 8 0 Investigations Weight decreased 16 2.2 8 2.6 Metabolism and Nutrition Disorders Hypokalemia 16 9 10 2.6 Hypoalbuminemia 13 2.2 8 0 Hypocalcemia 11 2.2 5 0 Other clinically relevant adverse reactions (<10% or with a <5% difference) in recipients of POLIVY plus BR included: Blood and lymphatic system disorders: pancytopenia (7%) Musculoskeletal disorders: arthralgia (7%) Investigations: hypophosphatemia (9%), transaminase elevation (7%), lipase increased (7%) Respiratory disorders: pneumonitis (4.4%) Selected treatment-emergent laboratory abnormalities are summarized in Table 8 . In recipients of POLIVY plus BR, >20% of patients developed Grade 3 or 4 neutropenia, leukopenia, or thrombocytopenia, and >10% developed Grade 4 neutropenia (13%) or Grade 4 thrombocytopenia (11%). Table 8 Select Laboratory Abnormalities Worsening from Baseline in Patients with Relapsed or Refractory DLBCL and ≥5% More in the POLIVY Plus Bendamustine and Rituximab Product Group Laboratory Parameter Includes laboratory abnormalities that are new or worsening in grade or with worsening from baseline unknown. POLIVY + BR n = 45 BR n = 39 All Grades, (%) Grade 3–4, (%) All Grades, (%) Grade 3–4, (%) Hematologic Lymphocyte count decreased 87 87 90 82 Neutrophil count decreased 78 61 56 33 Hemoglobin decreased 78 18 62 10 Platelet count decreased 76 31 64 26 Chemistry Creatinine increased 87 4.4 77 5 Calcium decreased 44 9 26 0 SGPT/ALT increased 38 0 8 2.6 SGOT/AST increased 36 0 26 2.6 Lipase increased 36 9 13 5 Phosphorus decreased 33 7 28 8 Amylase increased 24 0 18 2.6 Potassium decreased 24 11 28 5 Safety was also evaluated in 173 adult patients with relapsed or refractory lymphoma who received POLIVY, bendamustine, and either a rituximab product or obinutuzumab in Study GO29365, including the 45 patients with DLBCL described above. In the expanded safety population, the median age was 66 years (range 27 – 86), 57% were male, 91% had an ECOG performance status of 0-1, and 32% had a history of peripheral neuropathy at baseline. Fatal adverse reactions occurred in 4.6% of recipients of POLIVY within 90 days of last treatment, with infection as a leading cause. Serious adverse reactions occurred in 60%, most often from infection. Table 9 summarizes the most common adverse reactions in the expanded safety population. The overall safety profile was similar to that described above. Adverse reactions in ≥20% of patients were diarrhea, neutropenia, peripheral neuropathy, fatigue, thrombocytopenia, pyrexia, decreased appetite, anemia, and vomiting. Infection-related adverse reactions in >10% of patients included upper respiratory tract infection, febrile neutropenia, pneumonia, and herpesvirus infection. Table 9 Most Common Adverse Reactions (≥20% Any Grade or ≥5% Grade 3 or Higher) in Recipients of POLIVY and Chemoimmunotherapy for Relapsed or Refractory Lymphoma Adverse Reaction by Body System POLIVY + Bendamustine + Rituximab Product or Obinutuzumab n = 173 All Grades, % Grade 3 or Higher, % The table includes a combination of grouped and ungrouped terms. Blood and Lymphatic System Disorders Neutropenia 44 39 Thrombocytopenia 31 23 Anemia 28 14 Febrile neutropenia Primary prophylaxis with granulocyte colony-stimulating factor was given to 46% of all patients. 13 13 Leukopenia 13 8 Lymphopenia 12 12 Nervous System Disorders Peripheral neuropathy 40 2.3 Gastrointestinal Disorders Diarrhea 45 8 Vomiting 27 2.9 General Disorders Fatigue 40 5 Pyrexia 30 2.9 Decreased appetite 29 1.7 Infections Pneumonia 13 10 Includes 5 fatalities. Sepsis 6 6 Includes 4 fatalities. Metabolism and Nutrition Disorders Hypokalemia 18 6 Other clinically relevant adverse reactions (<20% any grade) included: General disorders: infusion-related reaction (7%) Infection: upper respiratory tract infection (16%), lower respiratory tract infection (10%), herpesvirus infection (12%), cytomegalovirus infection (1.2%) Respiratory: dyspnea (19%), pneumonitis (1.7%) Nervous system disorders: dizziness (10%) Investigations: weight decrease (10%), transaminase elevation (8%), lipase increase (3.5%) Musculoskeletal disorders: arthralgia (7%) Eye disorders: blurred vision (1.2%)
التحذيرات والاحتياطات
5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Monitor patients for peripheral neuropathy and modify or discontinue dose accordingly. ( 5.1 ) Infusion-Related Reactions: Premedicate with an antihistamine and antipyretic. Monitor patients closely during infusions. Interrupt or discontinue infusion for reactions. ( 5.2 ) Myelosuppression: Monitor complete blood counts. Manage using dose delays or reductions and growth factor support. Monitor for signs of infection. ( 5.3 ) Serious and Opportunistic Infections: Closely monitor patients for signs of bacterial, fungal, or viral infections. ( 5.4 ) Progressive Multifocal Leukoencephalopathy (PML): Monitor patients for new or worsening neurological, cognitive, or behavioral changes suggestive of PML. ( 5.5 ) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden or rapidly proliferative tumors. ( 5.6 ) Hepatotoxicity: Monitor liver enzymes and bilirubin. ( 5.7 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 3 months after the last dose. ( 5.8 ) 5.1 Peripheral Neuropathy POLIVY can cause peripheral neuropathy, including severe cases. Peripheral neuropathy occurs as early as the first cycle of treatment and is a cumulative effect [see Adverse Reactions (6.1) ] . POLIVY may exacerbate pre-existing peripheral neuropathy. In POLARIX, of 435 patients treated with POLIVY plus R-CHP, 53% reported new or worsening peripheral neuropathy, with a median time to onset of 2.3 months. Peripheral neuropathy was Grade 1 in 39% of patients, Grade 2 in 12%, and Grade 3 in 1.6%. Peripheral neuropathy resulted in dose reduction in 4% of treated patients and treatment discontinuation in 0.7%. Among patients with peripheral neuropathy after POLIVY, 58% reported resolution after a median of 4 months. In Study GO29365, of 173 patients treated with POLIVY, 40% reported new or worsening peripheral neuropathy, with a median time to onset of 2.1 months. Peripheral neuropathy was Grade 1 in 26% of patients, Grade 2 in 12%, and Grade 3 in 2.3%. Peripheral neuropathy resulted in POLIVY dose reduction in 2.9% of treated patients, dose delay in 1.2%, and permanent discontinuation in 2.9%. Sixty-five percent of patients reported improvement or resolution of peripheral neuropathy after a median of 1 month, and 48% reported complete resolution. The peripheral neuropathy is predominantly sensory; however, motor and sensorimotor peripheral neuropathy also occur. Monitor for symptoms of peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, or gait disturbance. Patients experiencing new or worsening peripheral neuropathy may require a delay, dose reduction, or discontinuation of POLIVY [see Dosage and Administration (2.2) ] . 5.2 Infusion-Related Reactions POLIVY can cause infusion-related reactions, including severe cases. Delayed infusion-related reactions as late as 24 hours after receiving POLIVY have occurred. With premedication, 13% of patients (58/435) in POLARIX reported infusion-related reactions after the administration of POLIVY plus R-CHP. The reactions were Grade 1 in 4.4% of patients, Grade 2 in 8%, and Grade 3 in 1.1%. With premedication, 7% of patients (12/173) in Study GO29365 reported infusion-related reactions after the administration of POLIVY. The reactions were Grade 1 in 4.6% of patients, Grade 2 in 1.7%, and Grade 3 in 0.6%. Symptoms occurring in ≥1% of patients included chills, dyspnea, pyrexia, pruritus, rash, and chest discomfort. Administer an antihistamine and antipyretic prior to the administration of POLIVY, and monitor patients closely throughout the infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management [see Dosage and Administration (2.2) ] . 5.3 Myelosuppression Treatment with POLIVY can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia. In POLARIX, 90% of patients treated with POLIVY plus R-CHP had primary prophylaxis with G-CSF. Grade 3–4 hematologic adverse reactions included lymphopenia (44%), neutropenia (39%), febrile neutropenia (15%), anemia (14%), and thrombocytopenia (8%) [see Adverse Reactions (6.1) ] . In Study GO29365, in patients treated with POLIVY plus BR (n = 45), 42% received primary prophylaxis with G-CSF. Grade 3 or higher hematologic adverse reactions included neutropenia (42%), thrombocytopenia (40%), anemia (24%), lymphopenia (13%), and febrile neutropenia (11%) [see Adverse Reactions (6.1) ] . Grade 4 hematologic adverse reactions included neutropenia (24%), thrombocytopenia (16%), lymphopenia (9%), and febrile neutropenia (4.4%). Cytopenias were the most common reason for treatment discontinuation (18% of all patients). Monitor complete blood counts throughout treatment. Cytopenias may require a delay, dose reduction, or discontinuation of POLIVY [see Dosage and Administration (2.2) ] . Administer prophylactic G-CSF for neutropenia in patients receiving POLIVY plus R-CHP. Consider prophylactic G-CSF administration in patients receiving POLIVY plus bendamustine and a rituximab product. 5.4 Serious and Opportunistic Infections Fatal and/or serious infections, including opportunistic infections such as sepsis, pneumonia (including Pneumocystis jiroveci and other fungal pneumonia), herpesvirus infection, and cytomegalovirus infection have occurred in patients treated with POLIVY [see Adverse Reactions (6.1) ] . In POLARIX, Grade 3–4 infections occurred in 14% (61/435) of patients treated with POLIVY plus R-CHP and infection-related deaths were reported in 1.1% of patients. In Study GO29365, Grade 3 or higher infections occurred in 32% (55/173) of patients treated with POLIVYand infection-related deaths were reported in 2.9% of patients within 90 days of last treatment. Closely monitor patients during treatment for signs of infection. Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus. Administer prophylactic G-CSF for neutropenia as recommended [see Dosage and Administration (2.3) ] . 5.5 Progressive Multifocal Leukoencephalopathy (PML) PML has been reported after treatment with POLIVY plus bendamustine and obinutuzumab in study GO29365 (0.6%, 1/173). Monitor for new or worsening neurological, cognitive, or behavioral changes. Hold POLIVY and any concomitant chemotherapy if PML is suspected, and permanently discontinue if the diagnosis is confirmed. 5.6 Tumor Lysis Syndrome POLIVY may cause tumor lysis syndrome. Patients with high tumor burden and rapidly proliferative tumor may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures, including tumor lysis syndrome prophylaxis. 5.7 Hepatotoxicity Serious cases of hepatotoxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with POLIVY. In recipients of POLIVY plus R-CHP, Grade 3–4 elevation of ALT and AST developed in 1.4% and 0.7% of patients, respectively. In Study GO29365, Grade 3 and Grade 4 transaminase elevations each developed in 1.9% of patients. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk of hepatotoxicity. Monitor liver enzymes and bilirubin level. 5.8 Embryo-Fetal Toxicity Based on the mechanism of action and findings from animal studies, POLIVY can cause fetal harm when administered to a pregnant woman. The small molecule component of POLIVY, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for 5 months after the last dose [see Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.1) ] .