Polatuzumab vedotin is a CD79b-directed antibody and microtubule inhibitor conjugate. It is indicated in combination with bendamustine and rituximab for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) following at least 2 prior therapies. Polatuzumab vedotin is also indicated for the treatment of adult patients with newly diagnosed DLBCL, NOS or high-grade B-cell lymphoma, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP regimen). Severe myelosuppression, infection, and hepatotoxicity have been reported with polatuzumab vedotin therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 1
-Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Minimal
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Polatuzumab vedotin is available as single-use 30-mg and 140-mg lyophilized powder vials.
-Premedicate with an antihistamine and antipyretic prior to the infusion.
-If a planned dose is missed, administer as soon as possible, and adjust the schedule of administration to maintain a 21-day interval between doses.
Reconstitution:
-Calculate the dose (mg) and the number of vials required.
-Reconstitute the 30-mg vial with 1.8 mL of sterile water for injection and the 140-mg vial with 7.2 mL of sterile water for injection to yield a final vial concentration of 20 mg/mL.
-Direct the stream of sterile water toward the wall of the vial and not directly at the cake or powder.
-Gently swirl the vial to aid in dissolution; do not shake.
-The vial solution should be colorless to slightly brown, clear to slightly opalescent, and free of visible particulates.
-Storage following reconstitution: store for up to 48 hours refrigerated (2 to 8 degrees C or 36 to 46 degrees F) or up to 8 hours at room temperature (9 to 25 degrees C or 47 to 77 degrees F) prior to dilution. Do not freeze or expose to direct sunlight.
Dilution:
-Dilute the calculated dose/volume in at least 50 mL of 0.45% sodium chloride injection, 0.9% sodium chloride injection, or 5% dextrose injection to achieve a final concentration of 0.72 mg/mL to 2.7 mg/mL.
-Discard any unused portion left in the vial.
-Gently mix by slowly inverting the infusion bag; do not shake.
-Do not transport diluted admixture through an automated system (e.g. pneumatic tube or automated cart). If the admixture will be transported to a separate facility, remove air from the infusion bag to prevent aggregation; an infusion set with a vented spike is required to ensure accurate dosing during the infusion if air is removed.
-Storage following dilution: For 0.45% sodium chloride injection diluent solutions, store up to 18 hours refrigerated or up to 4 hours at room temperature; for 0.9% sodium chloride injection diluent solutions, store up to 36 hours refrigerated or up to 4 hours at room temperature; or 5% dextrose injection diluent solutions, store up to 36 hours refrigerated or up to 6 hours at room temperature. Do not freeze or expose to direct sunlight.
-Limit transportation to 24 hours at 2 to 8 degrees C or 30 minutes at 9 to 25 degrees C; the total storage plus transportation times of the diluted product should not exceed the usual storage duration times.
Intravenous (IV) infusion:
-Use a dedicated infusion line containing a sterile, non-pyrogenic, low-protein binding in-line or add-on 0.2-or 0.22-micron filter and catheter for all infusions.
-Administer the first IV infusion over 90 minutes; monitor patients for infusion-related reactions during the infusion and for at least 90 minutes following completion of the initial dose.
-Administer subsequent infusions over 30 minutes if the previous infusion was well tolerated; monitor patients for infusion-related reactions during the infusion and for at least 30 minutes following the infusion.
-Do not mix or administer with other drugs.
Peripheral neuropathy has been reported as early as after the first cycle of polatuzumab vedotin therapy and is cumulative. Monitor patients for symptoms of motor or sensory neuropathy. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop new or worsening peripheral neuropathy. New or worsening peripheral neuropathy was reported following treatment with polatuzumab vedotin in combination with other anti-cancer agents in 53% (grade 3, 1.6%) of patients with newly diagnosed large B-cell lymphoma (n = 435) and 40% (grade 3, 2.3%) of patients with relapsed or refractory lymphoma (n = 173) in 2 clinical trials. The median onset of peripheral neuropathy was 2.3 and 2.1 months in these trials. The term peripheral neuropathy included neuralgia, dysesthesia, paresthesias, hypoesthesia, peroneal nerve palsy, hypotonia, hyporeflexia, neuromyopathy, and hyperesthesia.
Fever occurred in 16% to 33% (grade 3 or 4, 1.4% to 2.9%) of patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials.
Myelosuppression has been reported in patients who received polatuzumab vedotin-containing therapy. Monitor complete blood counts during treatment. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop severe myelosuppression. Neutropenia (44% to 60%; grade 3 and 4, 39% to 42%), thrombocytopenia (31% to 49%; grade 3 and 4, 8% to 40%), anemia (28% to 68%; grade 3 and 4, 14% to 24%), lymphopenia (80% or less; grade 3 and 4, 12% to 44%), leukopenia (13% or less; grade 3 or 4, 8% or less), febrile neutropenia (grade 3 and 4, 15% or less), and pancytopenia (7% or less) were reported following treatment with polatuzumab vedotin in combination with other anti-cancer agents. Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was given in 90% of patients with large B-cell lymphoma who received polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone and 42% of patients with diffuse large B-cell lymphoma who received polatuzumab vedotin plus bendamustine and rituximab in randomized trials.
Serious infectious events including Pneumocystis jiroveci pneumonia and fungal pneumonia have been reported in polatuzumab vedotin-treated patients in clinical trials. Closely monitor patients during treatment for signs and symptoms of infection. Grade 3 or higher infection was reported in 14% of patients with large B-cell lymphoma who received polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (n = 435) and 32% patients who received polatuzumab vedotin and chemoimmunotherapy with bendamustine and either rituximab or obinutuzumab (n = 173) in 2 randomized trials; infection-related death was reported in 1.1% and 2.9% of patients, respectively. Pneumonia (less than 10%; grade 3 or higher, 16% or less), respiratory tract infection (10% to 17%; grade 3 or 4, 0.5% or less), herpes virus infection (12% or less), sepsis (grade 3 or higher, less than 10%), and cytomegalovirus infection (less than 10%) occurred in patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials. The term respiratory tract infection included sinusitis, laryngitis, pharyngitis, nasopharyngitis, and rhinitis.
In a safety analysis of a multi-cohort study, progressive multifocal leukoencephalopathy (PML) was reported in 0.6% of patients with relapsed or refractory lymphoma who received polatuzumab vedotin and chemoimmunotherapy with bendamustine and either rituximab or obinutuzumab (n = 173). Evaluate patients who develop new neurological, cognitive, or behavioral signs and symptoms. Hold therapy if PML is suspected; permanently discontinue therapy in patients with confirmed PML.
Hepatotoxicity has been reported in polatuzumab vedotin-treated patients in clinical trials. Monitor liver function tests, including bilirubin, before and during therapy. Increased transaminase levels were reported in 7% (grade 3 or higher, 2.1%) of patients with large B-cell lymphoma who received polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (n = 435) and 8% (grade 3 or higher, 3.8%) of patients who received polatuzumab vedotin and chemoimmunotherapy with bendamustine and either rituximab or obinutuzumab (n = 173) in 2 randomized trials. Elevated hepatic enzymes that worsened from baseline including AST (36% or less; grade 3 or 4, 0.7% or less), ALT (38% or less; grade 3 or 4, 1.4% or less), and alkaline phosphatase (23% or less) levels that worsened from baseline occurred in patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials.
Gastrointestinal adverse events including diarrhea (31% to 45%; grade 3 and 4, 3.9% to 8%), vomiting (15% to 27%; grade 3 and 4, 1.1% to 2.9%), and anorexia/decreased appetite (17% to 29%; grade 3 and 4, 1.1% to 1.7%), nausea(42% or less; grade 3 and 4, 1.1% or less), constipation (29% or less; grade 3 and 4, 1.4% or less), mucositis (22% or less; grade 3 and 4, 1.4% or less), and abdominal pain (16% or less; grade 3 and 4, 1.1% or less) occurred in patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials. The term mucositis included stomatitis, oropharyngeal pain/discomfort, oral pain, mucosal inflammation, oral ulceration, aphthous ulcer, odynophagia, and tongue blistering.
Fatigue was reported in 40% or less (grade 3 or 4, 5% or less) of patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials.
Weight loss was reported in 16% or less (grade 3 or 4, 2.2% or less) of patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials.
Electrolyte or other laboratory abnormalities including hypokalemia (16%; grade 3 and 4, 9%), hypoalbuminemia (13%; grade 3 and 4, 2.2%), hypocalcemia (11%; grade 3 and 4, 2.2%), and hypophosphatemia (9%) occurred in patients with relapsed or refractory DLBCL who received polatuzumab vedotin plus bendamustine and rituximab (n= 45) in a randomized trial. Hypokalemia was reported in 18% of patients with relapsed or refractory lymphoma who received polatuzumab vedotin and chemoimmunotherapy with bendamustine and either rituximab or obinutuzumab (n = 173) in a safety analysis of a multi-cohort study; grade 3 and 4 hypokalemia occurred in 6% of patients.
Arthralgia (7% or less) and musculoskeletal pain (19% or less; grade 3 or 4, 0.5% or less) were reported in patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials. The term musculoskeletal pain included back pain, musculoskeletal chest pain, neck pain, myalgia, and bone pain.
Increased lipase level occurred in 7% of patients with relapsed or refractory DLBCL who received polatuzumab vedotin plus bendamustine and rituximab (n= 45) in a randomized trial; worsening lipase (35%; grade 3 and 4, 9%) and amylase/hyperamylasemia (24%) levels (increased from baseline) were also reported. Increased lipase level was reported in 3.5% of patients with relapsed or refractory lymphoma who received polatuzumab vedotin and chemoimmunotherapy with bendamustine and either rituximab or obinutuzumab (n = 173) in a safety analysis of a multi-cohort study.
Nephrotoxicity, specifically increased serum creatinine level (87% or less; grade 3 or 4, 4.4% or less) and renal insufficiency (less than 10%) were reported in patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials.
Cough (15%), dyspnea (19% or less; grade 3 or 4, 0.9% or less), and pneumonitis (less than 10%) were reported in patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials.
Blurred vision was reported in 1.2% of patients with relapsed or refractory lymphoma who received polatuzumab vedotin and chemoimmunotherapy with bendamustine and either rituximab or obinutuzumab (n = 173) in a safety analysis of a multi-cohort study.
Despite premedication, infusion-related reactions were reported in 7% to 18% (grade 3 or 4, 2.2% or less) of patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials. Reaction symptoms that occurred in 1% or more of patients included chills, dyspnea, fever, pruritus, rash, and chest discomfort; urticaria may also occur. Delayed reactions occurring up to 24 hours after the infusion have occurred. Monitor patients closely for symptoms of a reaction during and for at least 90 minutes after the first polatuzumab vedotin infusion and for at least 30 minutes after subsequent infusions. Stop the infusion and institute appropriate supportive management in patients who develop an infusion-related reaction. Immediately and permanently discontinue therapy if a grade 4 reaction occurs.
Antibody formation occurred in 1.4% and 6% of polatuzumab vedotin-treated patients in 2 clinical trials. No patients who developed antibodies to polatuzumab tested positive for neutralizing antibodies.
Altered taste/dysgeusia (14% or less), headache (13% or less; grade 3 or 4, 0.2% or less), and dizziness (13% or less) were reported in patients with lymphoma who received polatuzumab vedotin in combination with other anti-cancer agents in clinical trials.
Alopecia (24%) and rash including dermatitis (13%; grade 3 or 4, 0.7%) were reported in patients with large B-cell lymphoma who received polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (n = 435) in a randomized trial.
Tumor lysis syndrome (TLS) (less than 10%) and increased uric acid level/hyperuricemia (19%; grade 3 or 4, 18%) were reported in patients with large B-cell lymphoma who received polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (n = 435) in a randomized trial. Institute appropriate prophylactic measures (e.g., hydration, uric acid lowering therapy) and monitor patients for signs of TLS (e.g., serum electrolytes, uric acid, serum creatinine) prior to and during therapy.
Edema was reported in 14% (grade 3 or 4, 0.5%) of patients with large B-cell lymphoma who received polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (n = 435) in a randomized trial. The term edema included face edema/swelling, peripheral edema, fluid retention/overload, and pulmonary edema.
Peripheral neuropathy, primarily sensory neuropathy, has been reported with polatuzumab vedotin therapy; the incidence of peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesias, burning sensation, neuropathic pain, weakness, or gait disturbance). Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop new or worsening peripheral neuropathy.
Infusion-related reactions have been reported with polatuzumab vedotin therapy; therefore, premedicate patients with an antihistamine and antipyretic prior to each infusion. Delayed reactions occurring up to 24 hours after the infusion have been reported. Monitor patients closely for symptoms of a reaction (e.g., fever, chills, flushing, dyspnea, hypotension, and urticaria) during and for at least 90 minutes after the first polatuzumab vedotin infusion and for at least 30 minutes after subsequent infusions. Immediately and permanently discontinue therapy if a grade 4 reaction occurs. Stop the infusion and institute appropriate supportive management in patients who develop an infusion-related reaction.
Severe hematologic toxicities (e.g., anemia, thrombocytopenia, neutropenia) have been reported with polatuzumab vedotin therapy. Obtain complete blood counts prior to and during polatuzumab vedotin therapy. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 neutropenia or thrombocytopenia. Prophylactic granulocyte colony stimulating factor (G-CSF) use is recommended in patients who receive polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone; consider prophylactic G-CSF use in patients who receive polatuzumab vedotin plus bendamustine and rituximab.
Serious infection (e.g., pneumonia and sepsis) including opportunistic infections (e.g., cytomegalovirus) have been reported with polatuzumab vedotin therapy; some cases were fatal. Administer Pneumocystis jiroveci pneumonia and herpes infection prophylaxis during polatuzumab vedotin therapy. Closely monitor patients during treatment for signs and symptoms of bacterial infection, fungal infection, and viral infection.
Progressive multifocal leukoencephalopathy (PML) has been reported in patients who received polatuzumab vedotin plus bendamustine and rituximab therapy. Evaluate patients who develop new neurological, cognitive, or behavioral signs and symptoms such as confusion; changes in vision, speech, or walking; or loss of balance. Hold therapy if PML is suspected; permanently discontinue therapy in patients with confirmed PML.
Tumor lysis syndrome (TLS) may occur with polatuzumab vedotin. Patients with rapidly proliferating tumors and/or a high tumor burden may have an increased risk of developing TLS. Institute appropriate prophylactic measures (e.g., hydration, uric acid lowering therapy) and monitor patients for signs of TLS (e.g., serum electrolytes, uric acid, serum creatinine) prior to and during therapy.
Avoid the use of polatuzumab vedotin in patients with moderate or severe hepatic impairment (total bilirubin level more than 1.5 times the ULN and any AST level); no initial dosage adjustment is recommended in patients with mild hepatic impairment. Obtain liver function tests (LFTs), including bilirubin, before and during therapy. Patients with pre-existing hepatic disease or elevated LFTs at baseline and patients who are receiving concomitant medications may be at increased risk for developing hepatotoxicity.
Polatuzumab vedotin may cause fetal harm if administered during pregnancy based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid becoming pregnant while receiving polatuzumab vedotin. If a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus. In a study in pregnant rats, embryo-fetal toxicities including death and structural abnormalities (e.g., protruding tongue, malrotated limbs, gastroschisis, and agnathia) were observed at polatuzumab vedotin doses that resulted in maternal exposure that was about 0.5-fold the human exposure at the recommended dose.
Counsel patients about the reproductive risk and contraception requirements during polatuzumab vedotin treatment. Pregnancy testing should be performed prior to starting polatuzumab vedotin in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 3 months after polatuzumab vedotin therapy. Women who become pregnant while receiving polatuzumab vedotin should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during therapy and for 5 months after therapy due to the risk of male-mediated teratogenicity. Polatuzumab vedotin may cause reversible infertility in females based on findings in animal studies with other MMAE-containing antibody-drug conjugates. It may also impair male fertility based on data from animal studies.
No information is available regarding the presence of polatuzumab vedotin in human milk, the effects on the breastfed infant, or the effects on milk production. Due to the potential for serious adverse reactions in the nursing child, breast-feeding is not recommended during or for2 months after the last polatuzumab vedotin dose.
For the treatment of non-Hodgkin's lymphoma (NHL):
NOTE: The FDA has designated polatuzumab vedotin as an orphan drug for the treatment of diffuse large B-cell lymphoma (DLBCL).
-for the treatment of relapsed or refractory DLBCL (not otherwise specified) following at least 2 prior therapies, in combination with bendamustine and rituximab:
Intravenous dosage:
Adults: 1.8 mg/kg IV on day 1 repeated every 21 days for 6 cycles; administer in combination with bendamustine (90 mg/m2 IV on days 1 and 2) and rituximab (375 mg/m2 IV on day 1). Premedicate with an antihistamine and antipyretic 30 to 60 minutes prior to polatuzumab vedotin. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer Pneumocystis jiroveci pneumonia and herpes virus prophylaxis during polatuzumab vedotin therapy. Consider prophylactic granulocyte colony stimulating factor use. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who severe develop toxicity. The primary endpoint of complete response (CR) rate at the end of treatment, assessed by an independent review committee (IRC), was significantly improved in a randomly assigned cohort of transplant ineligible patients with relapsed or refractory DLBCL who received polatuzumab vedotin plus bendamustine and rituximab (BR) compared with BR alone (40% v 17.5%; p = 0.026) in a randomized phase 2 trial (n = 80; GO29365 trial). At a median follow-up time of 22.3 months, the median progression-free survival (PFS; 9.5 months vs. 3.7 months; hazard ratio (HR) = 0.36; 95% CI, 0.21 to 0.63) and overall survival (OS; 12.4 months vs. 4.7 months; HR = 0.42; 95% CI, 0.24 to 0.75) times were also significantly improved in the polatuzumab vedotin-containing arm. In 106 additional patients who received polatuzumab vedotin plus BR in a single-arm extension cohort (median follow-up, 15.2 months), the IRC-assessed CR rate was 38.7%, the median PFS time was 6.6 months, and the median OS time was 12.5 months. In a pooled analysis of 152 patients (median age, 69 years; range, 24 to 94 years) who received polatuzumab vedotin plus BR, the median number of prior therapies was 2 (range, 1 to 7 therapies).
-for the treatment of previously untreated DLBCL (not otherwise specified) or high-grade B-cell lymphoma in patients who have an International Prognostic Index score of 2 or greater, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP regimen):
Intravenous dosage:
Adults: 1.8 mg/kg IV on day 1 repeated every 21 days for 6 cycles. In a randomized clinical trial, polatuzumab vedotin was administered in combination with rituximab (375 mg/m2 IV on day 1 for 8 cycles), cyclophosphamide (750 mg/m2 IV on day 1), doxorubicin (50 mg/m2 IV on day 1) plus prednisone (100 mg PO daily) on days 1, 2, 3, 4, and 5. Premedicate with an antihistamine and antipyretic 30 to 60 minutes prior to polatuzumab vedotin. Hold therapy if an infusion-related reaction occurs; an infusion rate reduction or therapy discontinuation may be necessary depending on the severity of the reaction. Administer Pneumocystis jiroveci pneumonia and herpes virus prophylaxis during polatuzumab vedotin therapy. Prophylactic granulocyte colony stimulating factor use is recommended. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop severe toxicity.
Therapeutic Drug Monitoring:
Dosage Guidelines for Treatment-Related Toxicity:
Recommended Dosage Reductions:
First reduction: 1.4 mg/kg IV every 21 days.
Second reduction: 1 mg/kg IV every 21 days.*
*Permanently discontinue therapy if further reduction is needed.
Infusion-Related Reactions
Grade 1, 2, or 3 toxicity: Hold the polatuzumab vedotin infusion and administer appropriate supportive therapy. Resume the infusion at 50% of the previous rate when symptoms completely resolve; the infusion rate may be escalated in increments of 50 mg/hour every 30 minutes in the absence of infusion-related symptoms. Infuse polatuzumab vedotin over 90 minutes for the next cycle of therapy; subsequent infusions may be given over 30 minutes if no infusion-related symptoms occur.
Recurrent grade 2 wheezing or urticaria; grade 3 wheezing, bronchospasm, or generalized urticaria; or recurrent grade 3 toxicity: Permanently discontinue polatuzumab vedotin.
Grade 4 toxicity: Stop the polatuzumab vedotin infusion and administer appropriate supportive therapy. Do not resume polatuzumab vedotin.
Polatuzumab plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP)
Peripheral Neuropathy
NOTE: Continue R-CHP if polatuzumab is held due to peripheral neuropathy. Follow the guidance for the most severe neuropathy if there is concurrent sensory and motor neuropathy. If the grade of sensory and motor neuropathy are the same, follow the guidance for motor neuropathy.
Sensory Neuropathy
Grade 2 toxicity: If the toxicity resolves to grade 1 or lower prior to the next dose, resume therapy at the same dose level. If grade 2 toxicity persists with the next dose, reduce subsequent doses by 1 dose level.
Grade 3 toxicity: Hold therapy until the toxicity resolves to grade 2 or lower. Reduce subsequent doses by 1 dose level.
Grade 4 toxicity: Discontinue polatuzumab vedotin therapy.
Motor Neuropathy
Grade 2 or 3 toxicity: Hold therapy until the toxicity resolves to grade 1 or lower. Reduce subsequent doses by 1 dose level.
Grade 4 toxicity: Discontinue polatuzumab vedotin therapy.
Hematologic Toxicity
NOTE: If the primary cause of hematologic toxicity is lymphoma, a dosage delay or reduction may not be needed.
Grade 3 or 4 neutropenia: Hold all treatment until the absolute neutrophil count (ANC) recovers to at least 1,000 cells/microL. Consider therapeutic use of a granulocyte colony stimulating factor (G-CSF) if neutropenia occurs after prophylactic G-CSF. Resume all treatment at the previous dosages if the ANC recovers on or before day 7. If the ANC recovers after day 7, resume therapy and administer prophylactic G-CSF in the next cycle. If G-CSF was already given, consider a polatuzumab vedotin dose reduction.
Grade 3 or 4 thrombocytopenia: Hold all treatment until the platelet count recovers to at least 75,000 cells/microL. Resume all treatment at the previous dosages if the platelet count recovers on or before day 7. If the platelet count recovers after day 7, resume therapy but reduce the dose of bendamustine. If bendamustine has already been dose reduced, consider a polatuzumab vedotin dose reduction
Polatuzumab plus Bendamustine and Rituximab
Peripheral Neuropathy
Grade 2 or 3 toxicity: Hold polatuzumab vedotin until the toxicity resolves to grade 1 or lower. Resume therapy with the next cycle at a reduced polatuzumab vedotin dose of 1.4 mg/kg if the toxicity recovers by day 14. If the toxicity does not resolve by day 14 or if the toxicity recurs after a polatuzumab vedotin dose reduction, discontinue polatuzumab vedotin therapy.
Grade 4 toxicity: Discontinue polatuzumab vedotin therapy.
Hematologic Toxicity
NOTE: If the primary cause of hematologic toxicity is lymphoma, a dosage delay or reduction may not be needed.
Grade 3 or 4 neutropenia: Hold all treatment until the absolute neutrophil count (ANC) recovers to more than 1,000 cells/microL.; consider the prophylactic use of a granulocyte colony stimulating factor for subsequent cycles of therapy. Resume all treatment at the previous dosages if the ANC recovers on or before day 7. If the ANC recovers after day 7, resume therapy but consider a bendamustine dose reduction. If bendamustine has already been dose reduced, consider reducing the polatuzumab vedotin dose to 1.4 mg/kg. Consider the prophylactic use of a G-CSF for subsequent cycles of therapy.
Grade 3 or 4 thrombocytopenia: Hold all treatment until the platelet count recovers to more than 75,000 cells/microL. Resume all treatment at the previous dosages if the platelet count recovers on or before day 7. If the platelet count recovers after day 7, resume therapy but reduce the dose of bendamustine. If bendamustine has already been dose reduced, consider reducing the polatuzumab vedotin dose to 1.4 mg/kg.
Maximum Dosage Limits:
-Adults
1.8 mg/kg IV every 21 days.
-Adolescents
1.8 mg/kg IV every 21 days.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (total bilirubin level of 1 to 1.5 times the ULN or AST level more than the ULN): No initial dosage adjustment.
Moderate or severe hepatic impairment (total bilirubin level greater than 1.5 times the ULN and any AST level): Avoid use.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Adagrasib: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of adagrasib due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A and adagrasib is a strong CYP3A inhibitor. Strong CYP3A inhibitors are predicted to increase the exposure of MMAE by 45%.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of clarithromycin due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Apalutamide: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of apalutamide due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; apalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Atazanavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of atazanavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; atazanavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Atazanavir; Cobicistat: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of atazanavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; atazanavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%. (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of cobicistat due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Carbamazepine: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of carbamazepine due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; carbamazepine is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Ceritinib: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ceritinib due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ceritinib is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Chloramphenicol: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of chloramphenicol due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; chloramphenicol is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of clarithromycin due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Cobicistat: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of cobicistat due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Darunavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of darunavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Darunavir; Cobicistat: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of cobicistat due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%. (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of darunavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of cobicistat due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%. (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of darunavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Delavirdine: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of delavirdine due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; delavirdine is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of cobicistat due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of cobicistat due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Encorafenib: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of encorafenib due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A and encorafenib is a strong CYP3A inducer. Strong CYP3A inducers are predicted to decrease the exposure of MMAE by 63%.
Enzalutamide: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of enzalutamide due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Fosamprenavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of fosamprenavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; fosamprenavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Fosphenytoin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of fosphenytoin due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; fosphenytoin is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Grapefruit juice: (Moderate) Advise patients to avoid grapefruit juice while taking polatuzumab vedotin due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; grapefruit juice is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Idelalisib: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of idelalisib due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; idelalisib is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Indinavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of indinavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; indinavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of rifampin due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; rifampin is a strong CYP3A4 inducer. Rifampin is predicted to decrease the exposure of MMAE by 63%.
Isoniazid, INH; Rifampin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of rifampin due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; rifampin is a strong CYP3A4 inducer. Rifampin is predicted to decrease the exposure of MMAE by 63%.
Itraconazole: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of itraconazole due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; itraconazole is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Ketoconazole: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ketoconazole due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Ketoconazole is predicted to increase the exposure of MMAE by 45%.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of clarithromycin due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Levoketoconazole: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ketoconazole due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Ketoconazole is predicted to increase the exposure of MMAE by 45%.
Lopinavir; Ritonavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ritonavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Lumacaftor; Ivacaftor: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of lumacaftor; ivacaftor due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Lumacaftor; Ivacaftor: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of lumacaftor; ivacaftor due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Mifepristone: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of mifepristone due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; mifepristone is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of mitotane due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; mitotane is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Nefazodone: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of nefazodone due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; nefazodone is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Nelfinavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of nelfinavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; nelfinavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ritonavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Phenobarbital: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of phenobarbital due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; phenobarbital is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of phenobarbital due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; phenobarbital is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Phenytoin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of phenytoin due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; phenytoin is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Posaconazole: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of posaconazole due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; posaconazole is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Primidone: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of primidone due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; primidone is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Ribociclib: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ribociclib due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ribociclib is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Ribociclib; Letrozole: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ribociclib due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ribociclib is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Rifampin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of rifampin due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; rifampin is a strong CYP3A4 inducer. Rifampin is predicted to decrease the exposure of MMAE by 63%.
Ritonavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ritonavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Saquinavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of saquinavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; saquinavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
St. John's Wort, Hypericum perforatum: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of St. John's Wort due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; St. John's Wort is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Tipranavir: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of tipranavir/ritonavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; tipranavir boosted with ritonavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of clarithromycin due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Voriconazole: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of voriconazole due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; voriconazole is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate (ADC) consisting of 3 components including the humanized IgG1 monoclonal antibody specific for human CD79b; the small molecule anti-mitotic agent monomethyl auristatin E (MMAE); and a protease-cleavable linker, maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB), that covalently attaches MMAE to the polatuzumab antibody. The anticancer activity of polatuzumab vedotin is due to the binding of the ADC to CD79b expressing B-cells followed by the internalization of the ADC-CD79b complex, and the release of MMAE via selective proteolytic cleavage. MMAE inhibits cell division and induces apoptosis in rapidly dividing cells by binding to microtubules.
Polatuzumab vedotin is administered intravenously. It is a CD79b-directed antibody-drug conjugate (ADC) consisting of 3 components including the humanized IgG1 monoclonal antibody specific for human CD79b; the small molecule anti-mitotic agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to the polatuzumab antibody. The pharmacokinetics of the antibody-conjugated MMAE (acMMAE) and unconjugated MMAE (the cytotoxic component of polatuzumab vedotin) were evaluated. In vitro, the protein binding of MMAE ranges from 71% to 77% and the blood to plasma ratio is 0.79 to 0.98. For acMMAE, the estimated central volume of distribution is 3.15 L, the terminal half-life is 12 (range, 4.5 to 36.7) days at the end of cycle 6, and the predicted clearance is 0.9 L/day. The terminal half-life of unconjugated MMAE is 3.74 (range, 1.58 to 10.1) days after the first polatuzumab vedotin dose. Polatuzumab vedotin likely undergoes catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp
MMAE is a substrate of CYP3A4. Potent inhibitors or inducers of CYP3A4 may alter MMAE exposure; therefore, close monitoring is recommended if polatuzumab vedotin is coadministered with a strong CYP3A4 inhibitor or inducer. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, MMAE is not expected to affect exposure to midazolam, a sensitive CYP3A4 substrate. MMAE is a P-glycoprotein (P-gp) substrate in vitro.
-Route-Specific Pharmacokinetics
Intravenous Route
Following the first dose of polatuzumab vedotin 1.8 mg/kg IV in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), the geometric mean Cmax and AUC values for the antibody-conjugated MMAE (acMMAE) were 688 (coefficient of variation (CV), 15%) ng/mL and 2,040 (CV, 35%) ng X day/mL, respectively; the geometric mean Cmax and AUC values for the unconjugated MMAE were 3.19 (CV, 57%) ng/mL and 31 (CV, 56%) ng X day/mL, respectively. Following the first dose of polatuzumab vedotin 1.8 mg/kg IV in patients with newly diagnosed DLBCL, the geometric mean Cmax and AUC values for the acMMAE were 587 (CV, 15%) ng/mL and 1,690 (CV, 22%) ng X day/mL, respectively; the geometric mean Cmax and AUC values for the unconjugated MMAE were 2.45 (CV, 46%) ng/mL and 20.8 (CV, 50%) ng X day/mL, respectively. Plasma exposures of acMMAE and unconjugated MMAE were dose proportional over a range of 0.1 to 2.4 mg/kg. Compared with cycle 1 values, acMMAE AUC values were predicted to increase by about 30% at cycle 3 and greater than 90% at cycle 6. Unconjugated MMAE AUC values were less than 3% of the acMMAE AUC values and unconjugated MMAE Cmax and AUC values were predicted to decrease after repeated every-3-week dosing.
-Special Populations
Hepatic Impairment
MMAE AUC values were increased by 40% and 11% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and previously untreated DLBCL, respectively, who had mild hepatic impairment (total bilirubin level of 1 to 1.5 times the ULN and any AST level more than the ULN). Mild hepatic impairment was not associated with a significant difference in antibody-conjugated MMAE (acMMAE) exposure. It is not known if moderate or severe hepatic impairment (total bilirubin level more than 1.5 times the ULN and any AST Level) or liver transplantation has a clinically significant impact on the pharmacokinetic parameters of acMMAE or unconjugated MMAE. Polatuzumab vedotin has not been evaluated in patients with moderate or severe hepatic impairment; however, these patients are likely to have increased MMAE exposure.
Renal Impairment
Mild to moderate renal impairment (creatinine clearance (CrCl) of 30 to 89 mL/min) had no clinically significant impact on the pharmacokinetic parameters of antibody-conjugated MMAE (acMMAE) or unconjugated MMAE. It is not known if severe renal impairment (CrCl of 15 to 29 mL/min) or end-stage renal disease with or without dialysis has a clinically significant impact on the pharmacokinetic parameters of acMMAE or unconjugated MMAE.
Geriatric
Age (range, 19 to 89 years) had no clinically significant impact on the pharmacokinetic parameters of polatuzumab vedotin.
Gender Differences
Gender had no clinically significant impact on the pharmacokinetic parameters of polatuzumab vedotin.
Ethnic Differences
Race/ethnicity (White patients, 69%; Asian patients, 11%) had no clinically significant impact on the pharmacokinetic parameters of polatuzumab vedotin.