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  • CLASSES

    Miscellaneous Monoclonal Antibodies that Target Cell Surface Receptors

    DEA CLASS

    Rx

    DESCRIPTION

    CD79b-directed antibody-drug conjugate
    Used for relapsed or refractory diffuse large B-cell lymphoma, in combination with bendamustine and rituximab
    Severe myelosuppression has been reported

    COMMON BRAND NAMES

    Polivy

    HOW SUPPLIED

    POLIVY Intravenous Inj Pwd: 140mg

    DOSAGE & INDICATIONS

    For the treatment of non-Hodgkin's lymphoma (NHL).
    For the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) following at least 2 prior therapies, in combination with bendamustine and rituximab.
    NOTE: The FDA has designated polatuzumab vedotin as an orphan drug for the treatment of DLBCL.
    Intravenous dosage
    Adults

    1.8 mg/kg IV on day 1 in combination with bendamustine 90 mg/m2 IV on days 1 and 2 and rituximab 375 mg/m2 IV on day 1 repeated every 21 days for 6 cycles. Premedicate with an antihistamine and antipyretic 30 to 60 minutes prior to polatuzumab vedotin. Therapy interruption, a dose reduction, or discontinuation may be necessary in patients who develop toxicity. Administer Pneumocystis jiroveci pneumonia and herpes prophylaxis during polatuzumab vedotin therapy. Consider prophylactic granulocyte colony-stimulating factor use. The complete response rate was 45% and 18% in a cohort of patients with relapsed or refractory DLBCL who received polatuzumab vedotinin plus bendamustine and rituximab (BR) (n = 40) and BR alone (n = 40), respectively, in a multicenter, randomized trial (study GO29365). Patients (median age, 69 years; range, 30 to 86 years) in this trial were not eligible for an autologous hematopoietic stem-cell transplantation and had received a median of 2 prior therapies (range, 1 to 7 therapies).

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (bilirubin level greater than the upper limit of normal (ULN) to 1.5-times the ULN or a AST level greater than the ULN): No initial dosage adjustment.Moderate or severe hepatic impairment (bilirubin level greater than 1.5-times the ULN): Avoid use.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    CAUTION: Observe and exercise usual cautions for preparing, handling, and administering cytotoxic drugs.

    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.

    STORAGE

    Polivy:
    - Diluted product must be used within 8 hours if stored at room temperature or within 48 hours if stored under refrigeration (36 to 46 degrees F)
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container
    - Store reconstituted product in accordance with package insert instructions

    CONTRAINDICATIONS / PRECAUTIONS

    Peripheral neuropathy

    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

    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.

    Anemia, neutropenia, thrombocytopenia

    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; consider the addition of prophylactic granulocyte-colony stimulating factor with subsequent cycles of therapy.

    Fungal infection, herpes infection, infection, viral infection

    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

    Progressive multifocal leukoencephalopathy (PML) has been reported with polatuzumab vedotin 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)

    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.

    Hepatic disease

    Avoid the use of polatuzumab vedotin in patients with moderate or severe hepatic impairment (bilirubin level greater than 1.5-times the upper limit of normal); 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.

    Pregnancy

    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.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    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 at least 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 at least 5 months after therapy due to the risk of male-mediated teratogenicity. Based on animal studies, polatuzumab vedotin may cause infertility in males.

    Breast-feeding

    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 for at least 2 months after the last polatuzumab vedotin dose.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 39.0-42.0
    thrombocytopenia / Delayed / 23.0-40.0
    anemia / Delayed / 24.0-28.0
    infection / Delayed / 0-16.0
    lymphopenia / Delayed / 12.0-13.0
    hypokalemia / Delayed / 6.0-9.0
    leukopenia / Delayed / 0-8.0
    diarrhea / Early / 4.4-8.0
    pancytopenia / Delayed / 0-7.0
    fatigue / Early / 0-5.0
    elevated hepatic enzymes / Delayed / 0-3.8
    fever / Early / 2.2-2.9
    vomiting / Early / 2.2-2.9
    peripheral neuropathy / Delayed / 0-2.3
    anorexia / Delayed / 1.7-2.2
    weight loss / Delayed / 0-2.2
    hypoalbuminemia / Delayed / 0-2.2
    hypocalcemia / Delayed / 0-2.2
    infusion-related reactions / Rapid / 0-2.2
    progressive multifocal leukoencephalopathy / Delayed / 0-0.6
    nephrotoxicity / Delayed / Incidence not known

    Moderate

    hyperamylasemia / Delayed / 0-24.0
    dyspnea / Early / 0-19.0
    hypophosphatemia / Delayed / 0-9.0
    pneumonitis / Delayed / 1.7-4.4
    antibody formation / Delayed / 2.6-2.6
    blurred vision / Early / 0-1.2
    hypotension / Rapid / Incidence not known

    Mild

    dizziness / Early / 10.0-13.0
    arthralgia / Delayed / 7.0-7.0
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    Amoxicillin; Clarithromycin; Lansoprazole: (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%.
    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%.
    Atropine; Hyoscyamine; Phenobarbital; 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%.
    Belladonna Alkaloids; Ergotamine; 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%.
    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%.
    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%.
    Conivaptan: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of conivaptan due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; conivaptan 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%.
    Dasabuvir; Ombitasvir; Paritaprevir; 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%.
    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%.
    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%.
    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%.
    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%.
    Ombitasvir; Paritaprevir; 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%.
    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%.
    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%.
    Telithromycin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of telithromycin due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; telithromycin is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
    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%.
    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%.

    PREGNANCY AND LACTATION

    Pregnancy

    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 at least 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 at least 5 months after therapy due to the risk of male-mediated teratogenicity. Based on animal studies, polatuzumab vedotin may cause infertility in males.

    MECHANISM OF ACTION

    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.[64290]

    PHARMACOKINETICS

    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 approximately 12 days (95% CI, 8.1 to 19.5 days) at the last treatment cycle, and the predicted clearance is 0.9 L/day. The terminal half-life of unconjugated MMAE is approximately 4 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.

    Intravenous Route

    Following the first dose of polatuzumab vedotin 1.8 mg/kg IV, the mean Cmax and AUC values for the antibody-conjugated MMAE (acMMAE) were 803 (+/- 233) ng/mL and 1,860 (+/- 966) ng X day/mL, respectively; the Cmax and AUC values for the unconjugated MMAE were 6.82 (+/- 4.73) ng/mL and 52.3 (+/- 18) 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.[64290]