POLIVY

Dosage and Administration ( 2.4 ) 8/2026 Warnings and Precautions ( 5.8 ) 3/2026

1 INDICATIONS AND USAGE POLIVY is a CD79b-directed antibody and microtubule inhibitor conjugate indicated: in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index score of 2 or greater. ( 1.1 ) in combination with bendamustine and a rituximab product for the treatment of adult patients with relapsed or refractory DLBCL, NOS, after at least two prior therapies. ( 1.2 ) 1.1 Previously Untreated DLBCL, NOS or HGBL POLIVY in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) is indicated for the treatment of adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index score of 2 or greater. 1.2 Relapsed or Refractory DLBCL, NOS POLIVY in combination with bendamustine and a rituximab product is indicated for the treatment of adult patients with relapsed or refractory DLBCL, NOS, after at least two prior therapies.

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 Grade 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 discont …

3 DOSAGE FORMS AND STRENGTHS For injection: 30 mg/vial or 140 mg/vial of polatuzumab vedotin-piiq as a white to grayish-white lyophilized powder in a single-dose vial for reconstitution and further dilution. For injection: 30 mg or 140 mg of polatuzumab vedotin-piiq as a lyophilized powder in a single-dose vial. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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) ] Infusion Site Extravasation Injury [see Warnings and Precautions (5.8) ] 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 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 neurop …

7 DRUG INTERACTIONS Concomitant use of strong CYP3A inhibitors or inducers has the potential to affect the exposure to unconjugated monomethyl auristatin E (MMAE). ( 7.1 ) 7.1 Effects of Other Drugs on POLIVY Strong CYP3A Inhibitors Concomitant use with a strong CYP3A4 inhibitor may increase unconjugated MMAE AUC [see Clinical Pharmacology (12.3) ] , which may increase POLIVY toxicities. Monitor patients for signs of toxicity. Strong CYP3A Inducers Concomitant use with a strong CYP3A4 inducer may decrease unconjugated MMAE AUC [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Hepatic impairment has the potential to increase exposure to MMAE. Monitor patients for adverse reactions. ( 8.6 ) Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , POLIVY can cause fetal harm. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of the small molecule component of POLIVY, MMAE, to pregnant rats during organogenesis at exposures below the clinical exposure at the recommended dose of 1.8 mg/kg POLIVY every 21 days resulted in embryo-fetal mortality and structural abnormalities (see Data ) . Advise a pregnant woman of the potential risks to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data No embryo-fetal development studies in animals have been performed with polatuzumab vedotin-piiq. In an embryo-fetal developmental study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of POLIVY, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose). 8.2 Lactation Risk Summary There is no information regarding the presence of polatuzumab vedotin-piiq in human milk, the effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with POLIVY and for 2 months after the last dose. 8.3 Females and Males of Reproductive Potential POLIVY can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating POLIVY [see Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] . Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for 5 months after the final dose [see Nonclinical Toxicity (13.1) ] . Infertility Females Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), POLIVY may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1) ] . Males Based on findings from animal studies, POLIVY may impair male fertility. The reversibility of this effect is unknown [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Safety and effectiveness of POLIVY have not been established in pediatric patients. 8.5 Geriatric Use Among 435 patients treated with POLIVY plus R-CHP in POLARIX, 227 (52%) were ≥65 years of age. No overall differences in safety or efficacy were observed between patients aged ≥65 years and younger patients. Among 173 patients treated with POLIVY plus BR in Study GO29365, 95 (55%) were ≥65 years of age. Patients aged ≥65 had a numerically higher incidence of serious adverse reactions (64%) than patients aged <65 (53%). This study did not include sufficient numbers of patients to determine whether efficacy differed in patients aged ≥65 and younger patients. 8.6 Hepatic Impairment Avoid the administration of POLIVY in patients with moderate or severe hepatic impairmen …

12.1 Mechanism of Action Polatuzumab vedotin-piiq is a CD79b-directed antibody-drug conjugate with activity against dividing B cells. The small molecule, MMAE, is an anti-mitotic agent covalently attached to the antibody via a cleavable linker. The monoclonal antibody binds to CD79b, a B-cell specific surface protein, which is a component of the B-cell receptor. Upon binding CD79b, polatuzumab vedotin-piiq is internalized, and the linker is cleaved by lysosomal proteases to enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.

11 DESCRIPTION Polatuzumab vedotin-piiq is a CD79b-directed antibody and microtubule inhibitor conjugate. It consists of three components: 1) the humanized immunoglobulin G1 (IgG1) monoclonal antibody specific for human CD79b; 2) the small molecule anti-mitotic agent MMAE; and 3) a protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB) that covalently attaches MMAE to the polatuzumab antibody. Polatuzumab vedotin-piiq has an approximate molecular weight of 150 kDa. An average of 3.5 molecules of MMAE are attached to each antibody molecule. Polatuzumab vedotin-piiq is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis. POLIVY (polatuzumab vedotin-piiq) for injection is supplied as a sterile, white to grayish-white, preservative-free, lyophilized powder, which has a cake-like appearance, for intravenous infusion after reconstitution and dilution. Each single-dose 30 mg POLIVY vial delivers 30 mg of polatuzumab vedotin-piiq, polysorbate-20 (1.8 mg), sodium hydroxide (0.82 mg), succinic acid (1.77 mg), and sucrose (62 mg). After reconstitution with 1.8 mL of any of the diluents listed in Table 5 , the final concentration is 20 mg/mL with a pH of approximately 5.3. Each single-dose 140 mg POLIVY vial delivers 140 mg of polatuzumab vedotin-piiq, polysorbate-20 (8.4 mg), sodium hydroxide (3.8 mg), succinic acid (8.27 mg), and sucrose (288 mg). After reconstitution with 7.2 mL of any of the diluents listed in Table 5 , the final concentration is 20 mg/mL with a pH of approximately 5.3. The POLIVY vial stoppers are not made with natural rubber latex. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied POLIVY (polatuzumab vedotin-piiq) for injection is a preservative-free, white to grayish-white lyophilized powder, which has a cake-like appearance. POLIVY is supplied as: Carton Contents NDC One 30 mg single-dose vial NDC 50242-103-01 One 140 mg single-dose vial NDC 50242-105-01 Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not use beyond the expiration date shown on the carton. Do not freeze. Do not shake. POLIVY is a hazardous drug. Follow applicable special handling and disposal procedures. 1