Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Polivy: Polatuzumab vedotin-piiq 140 mg (1 ea)
Pharmacology
Mechanism of Action
Polatuzumab vedotin is an antibody drug conjugate (ADC) directed at CD79b which consists of 3 components: 1) a CD79b-specific humanized IgG1 antibody; 2) a microtubule-disrupting agent, monomethylauristatin E (MMAE); and 3) a protease cleavable linker (which covalently conjugates MMAE to the polatuzumab antibody). The conjugate binds to CD79b (B-cell specific cell surface protein commonly expressed in mature B cell lymphomas [Tilly 2019]), and forms a complex which is internalized within the cell and releases MMAE. MMAE binds to the tubules and disrupts the cellular microtubule network, inducing cell cycle arrest (G2/M phase) and apoptosis.
Pharmacokinetics/Pharmacodynamics
Distribution
Vd: Antibody-conjugated MMAE: 3.15 L
Metabolism
Catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites; MMAE is a CYP3A4 substrate
Excretion
Clearance: Antibody-conjugated MMAE: ~0.9 L/day
Half-Life Elimination
Antibody-conjugated MMAE: ~12 days (at cycle 6); unconjugated MMAE: ~4 days (after first dose)
Protein Binding
MMAE: 71% to 77%
Use: Labeled Indications
Diffuse large B-cell lymphoma (relapsed or refractory): Treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (in combination with bendamustine and a rituximab product) not otherwise specified, after at least two prior therapies.
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Dosage and Administration
Dosing: Adult
Note: Administer Pneumocystis jiroveci pneumonia and herpes virus prophylaxis throughout polatuzumab vedotin treatment. If not already premedicated, administer an antihistamine and antipyretic at least 30 to 60 minutes prior to polatuzumab vedotin infusion. Consider prophylactic growth factor support, and administer tumor lysis syndrome prophylaxis as clinically necessary.
Diffuse large B-cell lymphoma, relapsed or refractory: IV: 1.8 mg/kg once every 21 days for 6 cycles (in combination with bendamustine and rituximab) (Sehn 2018).
Missed dose: If a polatuzumab vedotin dose is missed, administer as soon as possible. Adjust cycle schedule in order to maintain a 21-day interval between doses.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Hematologic toxicity: Note: If neutropenia or thrombocytopenia are due to lymphoma, dose delay or reduction may not be necessary.
Grade 3 or 4 neutropenia (on day 1 of any cycle): Interrupt all treatment until ANC recovers to >1,000/mm3. If ANC recovers to >1,000/mm3 on or before day 7, resume all treatment without any additional dose reductions. Consider growth factor support for subsequent cycles (if not previously administered).
If ANC recovers to >1,000/mm3 after day 7, resume all treatment; consider growth factor support for subsequent cycles (if not previously administered). If growth factor support was administered prophylactically, consider dose reduction of bendamustine. If bendamustine dose has already been reduced, consider dose reduction of polatuzumab vedotin to 1.4 mg/kg.
Grade 3 or 4 thrombocytopenia (on day 1 of any cycle): Interrupt all treatment until platelets recover to >75,000/mm3. If platelets recover to >75,000/mm3 on or before day 7, resume all treatment without any additional dose reductions.
If platelets recover to >75,000/mm3 after day 7, resume all treatment (with bendamustine dose reduction). If bendamustine dose has already been reduced, consider dose reduction of polatuzumab vedotin to 1.4 mg/kg.
Nonhematologic toxicities:
Infusion reaction:
Grade 1 to 3: Interrupt infusion and give supportive treatment. Permanently discontinue polatuzumab vedotin for the first instance of grade 3 wheezing, bronchospasm, or generalized urticaria, or for recurrent grade 2 wheezing or urticaria, or recurrence of any grade 3 symptoms.
Otherwise, when symptoms completely resolve, resume infusion at 50% of the prior rate. Infuse polatuzumab vedotin over 90 minutes in the subsequent cycle; if no infusion-related reaction occurs, may administer over 30 minutes with subsequent cycles (with appropriate premedications).
Grade 4: Discontinue polatuzumab vedotin infusion immediately (and permanently). Administer supportive treatment as clinically necessary.
Peripheral neuropathy:
Grade 2 or 3: Interrupt polatuzumab vedotin until improvement to ≤ grade 1. If recovery to ≤ grade 1 occurs on or before day 14, resume polatuzumab vedotin (with the next cycle) at a permanently reduced dose of 1.4 mg/kg. If grade 2 or 3 peripheral neuropathy occurs after the dose has already been reduced to 1.4 mg/kg, discontinue polatuzumab vedotin. If not recovered to ≤ grade 1 on or before day 14, discontinue polatuzumab vedotin.
Grade 4: Discontinue polatuzumab vedotin.
Progressive multifocal leukoencephalopathy: Withhold treatment (polatuzumab and concomitant chemotherapy) with new-onset symptoms suggestive of progressive multifocal leukoencephalopathy (PML); permanently discontinue if PML diagnosis confirmed.
Reconstitution
Reconstitute each 140 mg vial with 7.2 mL SWFI, resulting in a concentration of 20 mg/mL. Add SWFI slowly, directing it toward the vial wall. Swirl gently to dissolve, do not shake. Reconstituted solution should appear colorless to slightly brown, clear to slightly opalescent, without visible particles. Further dilute in at least 50 mL of either NS, ½NS, or D5W to a final concentration of 0.72 to 2.7 mg/mL. Gently invert bag to mix; do not shake. Do not mix with other medications. Limit agitation of solution diluted for infusion during preparation (agitation may cause aggregation). Do not transport through an automated system (eg, pneumatic tube or automated cart); if transported to a separate facility, remove air from the infusion bag to prevent agitation. If air is removed, an infusion set with a vented spike is required during infusion.
Administration
IV: Infuse the initial dose over 90 minutes. Infuse using a dedicated infusion line with a sterile, nonpyrogenic, low-protein binding in-line or add-on 0.2- or 0.22-micron filter. Monitor for infusion-related reactions for a minimum of 90 minutes after the initial infusion is completed. If the initial infusion rate is tolerated, subsequent doses may be infused over 30 minutes (monitor for a minimum of 30 minutes after completion of infusion).
If not already premedicated, administer an antihistamine and antipyretic 30 to 60 minutes prior to each infusion. If an infusion-related reaction occurs, interrupt polatuzumab vedotin infusion and administer supportive treatment as necessary. Upon resolution, resume infusion at 50% of the prior rate. If tolerated (no infusion-related reactions), may escalate infusion rate in increments of 50 mg/hour every 30 minutes. See also Dosing: Adjustment for Toxicity.
Polatuzumab vedotin, bendamustine, and rituximab may be administered in any order (on day 1 of each cycle). Do not administer as IV push or bolus; do not mix or infuse with other medications.
Storage
Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Store in original carton to protect from light. Do not shake. Reconstituted solution should be diluted immediately; however, unused reconstituted solution may be stored at 2°C to 8°C (36°F to 46°F) for up to 48 hours, or at 9°C to 25°C (47°F to 77°F) for up to 8 hours prior to dilution; discard vial when cumulative storage time (prior to dilution) exceeds 48 hours. Solutions diluted for infusion in NS, ½NS, or D5W are stable for up to 24 hours, 18 hours, or 36 hours (respectively) at 2°C to 8°C (36°F to 46°F), or up to 4 hours, 4 hours, or 6 hours (respectively) at 9°C to 25°C (47°F to 77°F). Limit transportation time to 30 minutes at 9°C to 25°C (47°F to 77°F) or 12 hours at 2°C to 8°C (36°F to 46°F). Do not exceed storage duration (total storage plus transportation times of the diluted solution). Limit agitation of solution diluted for infusion during transportation (agitation may cause aggregation). For reconstituted solution and solutions diluted for infusion, do not freeze or expose to direct sunlight.
Drug Interactions
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be increased. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification
Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination
Adverse Reactions
>10%:
Central nervous system: Peripheral neuropathy (40%; grade 3: 2%), dizziness (13%)
Endocrine & metabolic: Decreased serum calcium (44%), hypokalemia (16%), weight loss (16%), hypoalbuminemia (13%), hypocalcemia (11%)
Gastrointestinal: Diarrhea (38%), increased serum lipase (7% to 36%), decreased appetite (27%), increased serum amylase (24%), vomiting (18%)
Hematologic & oncologic: Neutropenia (49%; grade ≥3: 42%; grade 4: 13% to 24%), thrombocytopenia (49%; grade ≥3: 40%; grade 4: 11% to 16%), anemia (47%; grade ≥3: 24%), lymphocytopenia (13%, grade ≥3: 13%; grade 4: 9%), febrile neutropenia (11%; grade ≥3: 11%; grade 4: 4%)
Hepatic: Increased serum alanine aminotransferase (38%), increased serum aspartate transaminase (36%)
Renal: Increased serum creatinine (87%)
Respiratory: Pneumonia (16% to 22%; including fungal pneumonia), upper respiratory tract infection (13%)
Miscellaneous: Fever (9% to 33%), infusion related reaction (18%)
1% to 10%:
Endocrine & metabolic: Hypophosphatemia (9%)
Hematologic & oncologic: Pancytopenia (7%)
Hepatic: Increased serum transaminases (7%), hepatotoxicity (2%)
Immunologic: Antibody development (3% to 6%)
Infection: Sepsis (7%)
Neuromuscular & skeletal: Arthralgia (7%)
Respiratory: Pneumonitis (4%)
<1%: Progressive multifocal leukoencephalopathy
Frequency not defined:
Hepatic: Increased serum bilirubin
Infection: Cytomegalovirus disease, herpes virus infection
Respiratory: Pneumonia due to Pneumocystis jirovecii
Warnings/Precautions
Concerns related to adverse effects:
- Bone marrow suppression: Serious or severe myelosuppression may occur with polatuzumab vedotin treatment. Grade 3 or higher neutropenia, thrombocytopenia, anemia, lymphopenia, and neutropenic fever have been reported. Over 40% of patients received primary prophylaxis with granulocyte colony stimulating factor. Monitor blood counts throughout therapy; myelosuppression may require treatment interruption, dose reduction, and/or discontinuation. Consider prophylaxis with granulocyte colony stimulating factor.
- Hepatotoxicity: Serious hepatotoxicity has occurred; cases were consistent with hepatocellular injury, with elevations of transaminases and/or bilirubin. Grade 3 and 4 transaminase elevations occurred in a small percentage of patients; suspected drug-induced liver injury (AST or ALT >3 times ULN and total bilirubin >2 times ULN) also occurred. The risk for hepatotoxicity may be increased with preexisting liver disease, elevated baseline liver enzymes, and concurrent hepatotoxic medications. Monitor liver enzymes and bilirubin.
- Infection: Serious and/or fatal infection, including opportunistic infections such as sepsis, pneumonia (including Pneumocystis jiroveci and other fungal pneumonia), herpesvirus, and cytomegalovirus have occurred; closely monitor for signs or symptoms of bacterial, fungal, or viral infections. Prophylaxis for P. jiroveci pneumonia and herpes virus is required throughout polatuzumab vedotin treatment. Grade 3 or higher infection occurred in almost one-third of patients; infection-related mortality was reported in a small percentage of patients within 90 days of the last treatment.
- Infusion-related reactions: Infusion-related reactions, including severe cases, have been reported. Symptoms included fever, chills, flushing, dyspnea, hypotension, and urticaria; most reactions were grade 1 or 2 in nature. Infusion reactions may occur as late as 24 hours after administration. Monitor during and following infusion. Premedicate prior to polatuzumab vedotin administration with an antihistamine and antipyretic. If an infusion-related reaction occurs, interrupt infusion and administer appropriate medical intervention.
- Peripheral neuropathy: Peripheral neuropathy is common and cumulative, and may worsen preexisting peripheral neuropathy. Neuropathy may occur as early as the first cycle of therapy. Neuropathy is usually sensory, although motor and sensorimotor peripheral neuropathy has also been observed; the majority of cases were grade 1 or 2 (grade 3 toxicity has also been reported). The median time to onset was 2.1 months; neuropathy completely resolved in approximately one-half of patients, and close to two-thirds of patients saw improvement or resolution of neuropathy after a median of one month. Monitor for signs/symptoms of neuropathy (hypoesthesia, hyperesthesia, paresthesia, dysesthesia, burning sensation, neuropathic pain, weakness, or gait disturbance). Treatment interruption, dose reduction, and/or discontinuation may be recommended for new or worsening neuropathy.
- Progressive multifocal leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) has been reported with polatuzumab vedotin. Monitor for new or worsening neurological, cognitive, and/or behavioral changes. Withhold polatuzumab vedotin and concomitant chemotherapy with new-onset symptoms suggestive of PML; permanently discontinue if diagnosis of PML is confirmed.
- Tumor lysis syndrome: Tumor lysis syndrome (TLS) may occur; risk of TLS is higher in patients with a high tumor burden and/or with rapid tumor proliferation. Monitor closely and administer TLS prophylaxis/management as clinically necessary.
Disease-related concerns:
- Hepatic impairment: Avoid use in patients with moderate to severe hepatic impairment. Exposure to the microtubule-disrupting agent monomethylauristatin E (MMAE; a component of polatuzumab vedotin) may be increased in patients with moderate to severe impairment and lead to an increased incidence of adverse events.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Monitoring Parameters
CBC throughout treatment; liver function tests. Pregnancy test (in females of reproductive potential) prior to treatment initiation. Monitor for at least 90 minutes after the first infusion and at least 30 minutes after subsequent infusions for signs/symptoms of infusion-related reactions. Monitor for signs of neuropathy (hypoesthesia, hyperesthesia, paresthesia, dysesthesia, burning sensation, or neuropathic pain or weakness, or gait disturbance), tumor lysis syndrome, signs/symptoms of progressive multifocal leukoencephalopathy and infection.
Pregnancy
Pregnancy Considerations
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to polatuzumab vedotin may cause fetal harm.
Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment and for at least 3 months after the last polatuzumab vedotin dose. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 5 months after the last polatuzumab vedotin dose.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience diarrhea, vomiting, lack of appetite, dizziness, common cold symptoms, weight loss, or joint pain. Have patient report immediately to prescriber signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), signs of infusion reactions, signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), severe loss of strength and energy, flushing, shortness of breath, severe dizziness, passing out, burning or numbness feeling, muscle weakness, abnormal gait, or signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
