Polivy Drug Information

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.

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.

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. 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.

Administer POLIVY, bendamustine, and a rituximab product in any order on Day 1 of each cycle. 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.

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. Table 1 Management of Peripheral Neuropathy in Patients Receiving POLIVY Plus R-CHP Table 2 provides management guidelines for infusion-related reaction and myelosuppression. Table 3 Management of Peripheral Neuropathy, Infusion-Related Reaction, and Myelosuppression in Patients Receiving POLIVY Plus Bendamustine and a Rituximab Product

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. 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. Administer tumor lysis syndrome prophylaxis for patients at increased risk of tumor lysis syndrome.

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 one of the following diluents into the POLIVY vial using the volume provided in Table 4: Sterile Water for Injection, USP Bacteriostatic Water for Injection, USP 0.9% Sodium Chloride Injection, USP 0.45% Sodium Chloride Injection, USP Direct the stream toward the inside wall of the vial to obtain a concentration of 20 mg/mL of polatuzumab vedotin-piiq. 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 prior to dilution according to the storage conditions and maximum durations specified in Table 5 based on the diluent used for reconstitution. Discard vial when cumulative storage time prior to dilution exceeds 168 hours. 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 according to the storage conditions and maximum durations specified in Table 6 based on the diluents used for reconstitution and infusion.

Discard if storage time exceeds these limits. Table 6 Storage of Diluted POLIVY Solution Limit transportation to 30 minutes at room temperature (9°C to 25°C) or 24 hours refrigerated 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 6.

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. Confirm patency of the intravenous line prior to infusion.

Monitor for extravasation; if extravasation occurs, stop the infusion and manage medically. 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.

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.

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. 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. Serious adverse reactions occurred in 34% of patients who received POLIVY plus R-CHP, including febrile neutropenia and pneumonia in ≥5% of recipients. 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 7 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 7 Select Adverse Reactions Occurring in ≥10% of Patients Treated with POLIVY Plus R-CHP in POLARIX 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. 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).

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. 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. 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 8 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 9 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 3 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.

Fatal adverse reactions occurred in 4.6% of recipients of POLIVY within 90 days of last treatment, with infection as a leading cause. Table 10 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.

Effects of Other Drugs on POLIVY Strong CYP3A Inhibitors

Concomitant use with a strong CYP3A4 inhibitor may increase unconjugated MMAE AUC, 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.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, 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 at the recommended dose).

Pediatric Use Safety and effectiveness of POLIVY have not been established in pediatric patients.