polatuzumab vedotin (Rx)

Brand and Other Names:Polivy, polatuzumab vedotin-piiq
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 140mg/vial (single-dose vial)

Diffuse Large B-Cell Lymphoma

Indicated in combination with bendamustine and a rituximab product for treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after ≥2 prior therapies

Administer every 21-day cycle for 6 cycles

Day 1

  • Rituximab product 375 mg/m² IV PLUS
  • Bendamustine 90 mg/m² IV PLUS
  • Polatuzumab vedotin 1.8 mg/kg IV
  • May administer drugs in any sequence on Day 1

Day 2

  • Bendamustine 90 mg/m² IV

Dosage Modifications

Peripheral neuropathy

  • Grade 2-3
    • Hold dose until improvement to grade ≤1
    • If recovered to grade ≤1 on or before Day 14, permanently reduce dose to 1.4 mg/kg and restart with next cycle
    • Discontinue treatment if dose was previously reduced to 1.4 mg/kg or if not recovered to grade ≤1 or before Day 14
  • Grade 4: Discontinue treatment

Infusion-related reactions

  • Grade 1-3
    • Interrupt infusion and provide supportive care
    • Upon complete resolution of symptoms, resume infusion at 50% of the rate achieved prior to interruption; if no infusion-related reaction occurs, infusion rate may be titrated in increments of 50 mg/hr q30min
    • For the next cycle, infuse dose over 90 minutes; if no infusion-related reaction occurs, subsequent infusions may be administered over 30 minutes
    • Administer premedication for all cycles
    • Permanently discontinue if first grade 3 occurrence (eg, wheezing, bronchospasm, generalized urticaria), recurrent grade 2 wheezing or urticaria, or grade 3 symptoms
  • Grade 4
    • Stop infusion immediately; provide supportive care and permanently discontinue

Grade 3-4 neutropenia

  • Grade 3-4 severity on Day 1 of any cycle: Hold all treatment until ANC recovers to >1000/mcL
  • If primary cause is due to lymphoma, dose delay or reduction may not be needed
  • If ANC recovers to >1000/mcL on or before Day 7
    • Resume all treatment without any additional dose reductions
    • Consider granulocyte colony-stimulating factor (GCSF) prophylaxis for subsequent cycles, if not previously given
  • If ANC recovers to >1000/mcL after Day 7
    • Restart all treatment; consider GCSF 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 polatuzumab vedotin to 1.4 mg/kg

Grade 3-4 thrombocytopenia

  • Grade 3-4 severity on Day 1 of any cycle: Hold all treatment until platelets recover to >75,000/mcL
  • If primary cause is due to lymphoma, dose delay or reduction may not be needed
  • If platelets recover to >75,000/mcL on or before Day 7
    • Resume all treatment without any additional dose reductions
  • If platelets recover to >75,000/mcL after Day 7
    • Restart all treatment, with dose reduction of bendamustine
    • If dose reduction of bendamustine has already occurred, consider dose reduction of polatuzumab vedotin to 1.4 mg/kg

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No clinically significant differences in the pharmacokinetics of antibody-conjugated MMAE (acMMAE) or unconjugated monomethyl auristatin E (MMAE) were observed
  • Severe (CrCl 15-29 mL/min) or end-stage renal disease with or without dialysis: Pharmacokinetics are unknown

Hepatic impairment

  • Mild (bilirubin >ULN to ≤1.5x ULN or AST >ULN): No adjustment to starting dose
  • Moderate-to-severe (bilirubin >1.5x ULN): Avoid use; patients with moderate or severe hepatic impairment are likely to have increased exposure to MMAE, which may increase the risk of adverse reactions; use has not been studied in such patients

Safety and efficacy not established

Patients aged ≥65 had a higher incidence of serious adverse reactions than patients aged <65 years

Clinical studies did not include sufficient number of patients aged ≥65 years to determine whether they respond differently from younger patients

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Interactions

Interaction Checker

and polatuzumab vedotin

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    Contraindicated

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        Significant - Monitor Closely

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            Adverse Effects

            All grades of severity listed unless otherwise indicated

            >10%

            Lymphocyte count decreased (87%)

            Creatinine increased (87%)

            Neutrophil count decreased (78%)

            Neutrophil count decreased, grade ≥3 (61%)

            Hemoglobin decreased (78%)

            Platelet count decreased (76%)

            Neutropenia (49%)

            Thrombocytopenia (49%)

            Anemia (47%)

            Calcium decreased (44%)

            Neutropenia, grade ≥3 (42%)

            Thrombocytopenia, grade ≥3 (40%)

            Peripheral neuropathy (40%)

            Diarrhea (38%)

            SGPT/ALT increased (38%)

            SGOT/AST increased (36%)

            Lipase increased (36%)

            Phosphorus decreased (33%)

            Pyrexia (33%)

            Platelet count decreased, grade ≥3 (31%)

            Decreased appetite (27%)

            Anemia, grade ≥3 (24%)

            Amylase increased (24%)

            Potassium decreased (24%)

            Pneumonia (22%)

            Dyspnea (19%)

            Vomiting (18%)

            Infusion-related reactions (18%)

            Hemoglobin decreased, grade ≥3 (18%)

            Pneumonia, grade ≥3 (16%)

            Hypokalemia (16%)

            Decreased weight (16%)

            Upper respiratory tract infection (16%)

            Lymphopenia (13%)

            Upper respiratory tract infection (13%)

            Hypoalbuminemia (13%)

            Dizziness (13%)

            Lower respiratory tract infection (10%)

            Herpes virus infection (12%)

            Hypocalcemia (11%)

            1-10%

            Hypokalemia, grade ≥3 (9%)

            Calcium decreased, grade ≥3 (9%)

            Hypophosphatemia (9%)

            Lipase increased, grade ≥3 (9%)

            Potassium decreased, grade ≥3 (7%)

            Phosphorus decreased, grade ≥3 (7%)

            Pancytopenia (7%)

            Elevated transaminase (7%)

            Lipase increase (7%)

            Arthralgia (7%)

            Diarrhea, grade ≥3 (4.4%)

            Pneumonitis (1.7-4.4%)

            Creatinine increased (4.4%)

            Vomiting, grade ≥3 (2.2%)

            Infusion-related reaction, grade ≥3 (2.2%)

            Pyrexia, grade ≥3 (2.2%)

            Decreased appetite, grade ≥3 (2.2%)

            Decreased weight, grade ≥3 (2.2%)

            Hypoalbuminemia, grade ≥3 (2.2%)

            Hypocalcemia, grade ≥3 (2.2%)

            Blurred vision (1.2%)

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            Warnings

            Contraindications

            None

            Cautions

            Infusion-related reactions reported; delayed infusion-related reactions may occur as late as 24 hr after receiving polatuzumab

            Serious or severe myelosuppression (eg, neutropenia, thrombocytopenia, anemia) may occur; monitor complete blood cell count during treatment

            Fatal and/or serious infections reported, including opportunistic infections such as sepsis, pneumonia (including Pneumocystis jiroveci and other fungal pneumonia), herpes virus infection, and cytomegalovirus infection; closely monitor for signs and symptoms of infection

            Progressive multifocal leukoencephalopathy (PML) reported after treatment; monitor for new or worsening neurological, cognitive, or behavioral changes; hold polatuzumab and any concomitant chemotherapy if PML is suspected, and permanently discontinue if diagnosis is confirmed

            Patients with high tumor burden and rapidly proliferative tumor may be at increased risk of tumor lysis syndrome; closely monitor and take appropriate measures, including tumor lysis syndrome prophylaxis

            Serious cases of hepatotoxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred; preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk of hepatotoxicity; monitor liver enzymes and bilirubin level

            Based on the mechanism of action and findings from animal studies, fetal harm may occur when administered to a pregnant woman (see Pregnancy)

            Peripheral neuropathy

            • Peripheral neuropathy, including severe cases, may occur as early as the first cycle of treatment and is a cumulative effect; may exacerbate preexisting peripheral neuropathy
            • Monitor for symptoms of peripheral neuropathy (eg, hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, gait disturbance)

            Drug interactions overview

            • MMAE is a CYP3A4 substrate
            • Strong CYP3A inhibitors
              • Concomitant use with a strong CYP3A4 inhibitor may increase unconjugated MMAE AUC, which may increase polatuzumab vedotin toxicities
              • Monitor for signs of toxicity
            • Strong CYP3A inducers
              • Concomitant use with a strong CYP3A4 inducer may decrease unconjugated MMAE AUC
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            Pregnancy

            Pregnancy

            Based on findings from animal studies and its mechanism of action, fetal harm may occur

            No data available for pregnant women to inform a drug-associated risk

            Verify pregnancy status in females of reproductive potential before initiating treatment

            Advise pregnant women of potential fetal risks

            Animal data

            • In animal reproduction studies, administration of the small molecule component of polatuzumab vedotin, MMAE, to pregnant rats during organogenesis at exposures below the clinical exposure at the recommended dose of 1.8 mg/kg every 21 days resulted in embryofetal mortality and structural abnormalities

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for 3 months after the final dose
            • Males with female partners of reproductive potential: Based on genotoxicity findings, use effective contraception during treatment and for at least 5 months after the final dose

            Infertility

            • Based on findings from animal studies, male fertility may be impaired; reversibility is unknown

            Lactation

            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 potential for serious adverse reactions in a breastfed children, advise women not to breastfeed during treatment and for at least 2 months after last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            CD79b-directed antibody-drug conjugate (ADC) consisting of three components: the humanized immunoglobulin G1 (IgG1) monoclonal antibody specific for human CD79b, the small molecule antimitotic agent MMAE, and a protease cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB)

            MMAE is an antimitotic agent covalently attached to the antibody via a cleavable linker

            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 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

            Absorption

            Peak plasma concentration: 803 ng/mL (acMMAE); 6.82 ng/mL (unconjugated MMAE)

            AUC: 1860 ng·day/mL (acMMAE); 52.3 ng·day/mL (unconjugated MMAE)

            Cycle 3 acMMAE AUC were predicted to increase by ~30% over Cycle 1 AUC, and achieved >90% of the Cycle 6 AUC

            Distribution

            Vd (based on population PK analysis): 3.15 L (acMMAE)

            Protein bound (human): 71-77% (MMAE)

            Metabolism

            Has not been studied in humans

            Expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites

            MMAE is a CYP3A4 substrate

            Elimination

            Half-life: ~12 days (acMMAE at Cycle 6); ~4 days (unconjugated MMAE ~ 4 days after the first infusion)

            Clearance: 0.9 L/day

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            Administration

            IV Compatibilities

            0.9% NaCl

            0.45% NaCl

            Dextrose 5%

            IV Preparation

            Polatuzumab vedotin is a cytotoxic drug; follow applicable special handling and disposal procedures

            Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit

            Reconstitution

            • Reconstitute immediately before dilution
            • Calculate dose, total volume of reconstituted solution required, and number of vials needed
            • Reconstitute each 140-mg vial by slowly injecting 7.2 mL of sterile water for injection with the stream directed toward the inside wall of the vial to obtain a concentration of 20 mg/mL of polatuzumab vedotin
            • Gently swirl vial until completely dissolved; do not shake
            • Inspect reconstituted solution for discoloration and particulate matter; should appear colorless to slightly brown, clear to slightly opalescent, and free of visible particulates
            • Do not use if the reconstituted solution is discolored, cloudy, or contains visible particulates; do not freeze or expose to direct sunlight

            Dilution

            • Dilute polatuzumab vedotin to a final concentration of 0.72-2.7 mg/mL in at least a 50-mL IV infusion bag containing 0.9% NaCl, 0.45% NaCl, or D5W
            • Withdraw the required volume of reconstituted solution and dilute into IV infusion bag
            • Discard any unused portion left in the vial
            • Gently mix IV bag by slowly inverting the bag; do not shake
            • Visually inspect IV bag for particulates and discard if present
            • Limit agitation of diluted product during preparation and transportation to administration site
            • Do not transport diluted product
            • If 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 infusion through an automated system (eg, pneumatic tube, automated cart)

            IV Administration

            IV infusion only

            Administer via dedicated infusion line equipped with sterile, nonpyrogenic, low-protein-binding in-line or add-on filter (0.2- or 0.22-micron pore size) and catheter

            Initial dose: Infuse over 90 minutes; monitor patients for infusion-related reactions during infusion and for at least 90 minutes following completion of initial dose

            Subsequent doses (if previous infusion was well tolerated): Infuse over 30 minutes; monitor during infusion and for at least 30 minutes after completion of infusion

            Premedication

            • If not already premedicated for rituximab product, administer an antihistamine and antipyretic at least 30-60 minutes before polatuzumab vedotin for potential infusion-related reactions
            • Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpes virus during treatment
            • Consider prophylactic GCSF administration for neutropenia
            • Administer tumor lysis syndrome prophylaxis for patients at increased risk of tumor lysis syndrome

            Missed dose

            • If a planned dose is missed, administer as soon as possible
            • Adjust dosing schedule to maintain a 21-day interval between doses

            Storage

            Unused vial: Store refrigerated at 2-8°C (36-46°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

            Reconstituted vial: Refrigerate at 2-8°C (36-46°F) for up to 48 hr or at room temperature (9-25°C [47-77°F]) up to a maximum of 8 hr prior to dilution; discard vial when cumulative storage time prior to dilution exceeds 48 hr

            Diluted solution

            • 0.9% NaCl: Store for up to 24 hr at 2-8°C (36-46°F) or up to 4 hr at room temperature (9-25°C [47-77°F])
            • 0.45% NaCl: Store for up to 18 hr at 2-8°C (36-46°F) or up to 4 hr at room temperature (9-25°C [47-77°F])
            • Dextrose 5%: Store up to 36 hr at 2-8°C (36-46°F) or up to 6 hr at room temperature (9-25°C [47-77°F])
            • Limit transportation to 30 minutes at 9-25°C (47-77°F) or 12 hr at 2-8°C (36-46°F)
            • Protect from light; do not freeze; do not shake
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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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