Polivy
(polatuzumab vedotin-piiq)Dosage & Administration
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Polivy Prescribing Information
Previously Untreated DLBCL, NOS or HGBL
POLIVY in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) is indicated for the treatment of adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index score of 2 or greater.
Relapsed or Refractory DLBCL, NOS
POLIVY in combination with bendamustine and a rituximab product is indicated for the treatment of adult patients with relapsed or refractory DLBCL, NOS, after at least two prior therapies.
Recommended Dosage
Patients with Previously Untreated DLBCL, NOS or HGBL
The recommended dosage of POLIVY is 1.8 mg/kg administered as an intravenous infusion every 21 days for 6 cycles in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone [see Clinical Studies (14.1)]. Administer POLIVY, cyclophosphamide, doxorubicin, and a rituximab product in any order on Day 1 after the administration of prednisone. Prednisone is administered on Days 1–5 of each cycle.
Patients with Relapsed or Refractory DLBCL, NOS
The recommended dosage of POLIVY is 1.8 mg/kg administered as an intravenous infusion every 21 days for 6 cycles in combination with bendamustine and a rituximab product. Administer POLIVY, bendamustine, and a rituximab product in any order on Day 1 of each cycle. The recommended dose of bendamustine is 90 mg/m2/day on Days 1 and 2 when administered with POLIVY and a rituximab product. The recommended dose of rituximab product is 375 mg/m2 intravenously on Day 1 of each cycle.
For All Indicated Patients
If not already premedicated, administer an antihistamine and antipyretic at least 30 minutes prior to POLIVY.
If a planned dose of POLIVY is missed, administer as soon as possible. Adjust the schedule of administration to maintain a 21-day interval between doses.
Management of Adverse Reactions
Previously Untreated DLBCL, NOS or HGBL
Table 1 provides management guidelines for peripheral neuropathy in patients receiving POLIVY plus R-CHP [see Warnings and Precautions (5.1)].
| Adverse reaction | Grade | Dose modification * |
|---|---|---|
| R-CHP should be continued if POLIVY is withheld. If there is concurrent sensory and motor neuropathy, follow the guidance for the most severe neuropathy. If the grade of sensory and motor neuropathy are the same, follow the guidance for motor neuropathy. | ||
| ||
| Peripheral sensory neuropathy | Grade 1 | None |
| Grade 2 | If resolves to Grade 1 or lower before the next scheduled dose, resume at the same dose level. If Gr 2 persists at the next scheduled dose, reduce one dose level. | |
| Grade 3 | Withhold until Grade 2 or lower and reduce one dose level. | |
| Grade 4 | Permanently discontinue. | |
| Peripheral motor neuropathy | Grade 1 | None |
| Grade 2 or 3 | Withhold until Grade 1 or lower and reduce one dose level. | |
| Grade 4 | Permanently discontinue. | |
Table 2 provides management guidelines for infusion-related reaction and myelosuppression [see Warnings and Precautions (5.2 and 5.3)].
| Adverse Reaction | Dosage Modification * |
|---|---|
| Toxicity graded per National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 4.0. | |
| |
| Infusion-Related Reaction Grade 1–3 | Interrupt POLIVY infusion and give supportive treatment. For the first instance of Grade 3 wheezing, bronchospasm, or generalized urticaria, permanently discontinue POLIVY. For recurrent Grade 2 wheezing or urticaria, or for recurrence of any Grade 3 symptoms, permanently discontinue POLIVY. Otherwise, upon complete resolution of symptoms, infusion may be resumed at 50% of the rate achieved prior to interruption. In the absence of infusion related symptoms, the rate of infusion may be escalated in increments of 50 mg/hour every 30 minutes. For the next cycle, infuse POLIVY over 90 minutes. If no infusion-related reaction occurs, subsequent infusions may be administered over 30 minutes. Administer premedication for all cycles. |
| Infusion-Related Reaction Grade 4 | Stop POLIVY infusion immediately. Give supportive treatment. Discontinue POLIVY. |
| Neutropenia †, ‡ Grade 3–4 | Hold all treatment until ANC recovers to greater than or equal to 1,000/microliter. Consider therapeutic G-CSF if neutropenia occurs after prophylactic G-CSF. If ANC recovers to greater than or equal to 1,000/microliter on or before Day 7, resume all treatment without any dose reductions. If ANC recovers to greater than or equal to 1,000/microliter after Day 7:
|
| Thrombocytopenia †, ‡ Grade 3–4 | Hold all treatment until platelets recover to greater than or equal to 75,000/microliter. If platelets recover to greater than or equal to 75,000/microliter on or before Day 7, resume all treatment without any dose reductions. If platelets recover to greater than or equal to 75,000/microliter after Day 7:
|
Relapsed or Refractory DLBCL, NOS
Table 3 provides management guidelines for peripheral neuropathy, infusion-related reaction, and myelosuppression in patients receiving POLIVY in combination with bendamustine and a rituximab product [see Warnings and Precautions (5.1, 5.2, 5.3)].
| Adverse Reaction | Dosage Modification * |
|---|---|
| Toxicity graded per NCI CTCAE version 4.0. | |
| |
| Peripheral Neuropathy Grade 2–3 | Hold POLIVY dosing until improvement to Grade 1 or lower. If recovered to Grade 1 or lower on or before Day 14, restart POLIVY with the next cycle at a permanently reduced dose of 1.4 mg/kg. If a prior dose reduction to 1.4 mg/kg has occurred, discontinue POLIVY. If not recovered to Grade 1 or lower on or before Day 14, discontinue POLIVY. |
| Peripheral Neuropathy Grade 4 | Discontinue POLIVY. |
| Infusion-Related Reaction Grade 1–3 | Interrupt POLIVY infusion and give supportive treatment. For the first instance of Grade 3 wheezing, bronchospasm, or generalized urticaria, permanently discontinue POLIVY. For recurrent Grade 2 wheezing or urticaria, or for recurrence of any Grade 3 symptoms, permanently discontinue POLIVY. Otherwise, upon complete resolution of symptoms, infusion may be resumed at 50% of the rate achieved prior to interruption. In the absence of infusion related symptoms, the rate of infusion may be escalated in increments of 50 mg/hour every 30 minutes. For the next cycle, infuse POLIVY over 90 minutes. If no infusion-related reaction occurs, subsequent infusions may be administered over 30 minutes. Administer premedication for all cycles. |
| Infusion-Related Reaction Grade 4 | Stop POLIVY infusion immediately. Give supportive treatment. Permanently discontinue POLIVY. |
| Neutropenia †, ‡ Grade 3–4 | Hold all treatment until ANC recovers to greater than 1,000/microliter. If ANC recovers to greater than 1,000/microliter on or before Day 7, resume all treatment without any additional dose reductions. Consider granulocyte colony-stimulating factor prophylaxis for subsequent cycles, if not previously given. If ANC recovers to greater than 1,000/microliter after Day 7:
|
| Thrombocytopenia †, ‡ Grade 3–4 | Hold all treatment until platelets recover to greater than 75,000/microliter. If platelets recover to greater than 75,000/microliter on or before Day 7, resume all treatment without any additional dose reductions. If platelets recover to greater than 75,000/microliter after Day 7:
|
Recommended Prophylactic Medications
If not already premedicated for a rituximab product, administer an antihistamine and antipyretic at least 30 to 60 minutes prior to POLIVY for potential infusion-related reactions [see Warnings and Precautions (5.2)].
Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus throughout treatment with POLIVY.
Administer prophylactic granulocyte colony-stimulating factor (G-CSF) for neutropenia in patients receiving POLIVY plus R-CHP. Consider prophylactic G-CSF administration for neutropenia in patients receiving POLIVY plus bendamustine and a rituximab product [see Warnings and Precautions (5.3)].
Administer tumor lysis syndrome prophylaxis for patients at increased risk of tumor lysis syndrome [see Warnings and Precautions (5.6)].
Instructions for Preparation and Administration
Reconstitute and further dilute POLIVY prior to intravenous infusion.
POLIVY is a hazardous drug. Follow applicable special handling and disposal procedures.1
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Reconstitution
- Reconstitute immediately before dilution.
- More than one vial may be needed for a full dose. Calculate the dose, the total volume of reconstituted POLIVY solution required, and the number of POLIVY vials needed.
- Using a sterile syringe, slowly inject Sterile Water for Injection, USP, using the volume provided in Table 4, into the POLIVY vial, with the stream directed toward the inside wall of the vial to obtain a concentration of 20 mg/mL of polatuzumab vedotin-piiq.
| Strength | Volume of Sterile Water for Injection, USP required for reconstitution |
|---|---|
| 30 mg vial | 1.8 mL |
| 140 mg vial | 7.2 mL |
- Swirl the vial gently until completely dissolved. Do not shake.
- Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution should appear colorless to slightly brown, clear to slightly opalescent, and free of visible particulates. Do not use if the reconstituted solution is discolored, is cloudy, or contains visible particulates. Do not freeze or expose to direct sunlight.
- If needed, store unused reconstituted POLIVY solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours or at room temperature (9°C to 25°C, 47°F to 77°F) up to a maximum of 8 hours prior to dilution. Discard vial when cumulative storage time prior to dilution exceeds 48 hours.
Dilution
- Dilute polatuzumab vedotin-piiq to a final concentration of 0.72–2.7 mg/mL in an intravenous infusion bag with a minimum volume of 50 mL containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
- Determine the volume of 20 mg/mL reconstituted solution needed based on the required dose.
- Withdraw the required volume of reconstituted solution from the POLIVY vial using a sterile syringe and dilute into the intravenous infusion bag. Discard any unused portion left in the vial.
- Gently mix the intravenous bag by slowly inverting the bag. Do not shake.
- Inspect the intravenous bag for particulates and discard if present.
- If not used immediately, store the diluted POLIVY solution as specified in Table 5. Discard if storage time exceeds these limits. Do not freeze or expose to direct sunlight.
| Diluent Used to Prepare Solution for Infusion | Diluted POLIVY Solution Storage Conditions * |
|---|---|
| |
| 0.9% Sodium Chloride Injection, USP | Up to 36 hours at 2°C to 8°C (36°F to 46°F) or up to 4 hours at room temperature (9 to 25°C, 47 to 77°F) |
| 0.45% Sodium Chloride Injection, USP | Up to 18 hours at 2°C to 8°C (36°F to 46°F) or up to 4 hours at room temperature (9 to 25°C, 47 to 77°F) |
| 5% Dextrose Injection, USP | Up to 36 hours at 2°C to 8°C (36°F to 46°F) or up to 6 hours at room temperature (9 to 25°C, 47 to 77°F) |
- Limit transportation to 30 minutes at 9°C to 25°C or 24 hours at 2°C to 8°C (refer to instructions below). The total storage plus transportation times of the diluted product should not exceed the storage duration specified in Table 5.
- Agitation stress can result in aggregation. Limit agitation of diluted product during preparation and transportation to administration site. Do not transport diluted product through an automated system (e.g., pneumatic tube or automated cart). If the prepared solution will be transported to a separate facility, remove air from the infusion bag to prevent aggregation. If air is removed, an infusion set with a vented spike is required to ensure accurate dosing during the infusion.
- No incompatibilities have been observed between POLIVY and intravenous infusion bags with product-contacting materials of polyvinyl chloride (PVC) or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP). No incompatibilities have been observed with infusion sets or infusion aids with product-contacting materials of PVC, PE, polyurethane (PU), polybutadiene (PBD), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyetherurethane (PEU), fluorinated ethylene propylene (FEP), or polytetrafluorethylene (PTFE), or with filter membranes composed of polyether sulfone (PES) or polysulfone (PSU).
Administration
- Administer POLIVY as an intravenous infusion only.
- Administer the initial dose of POLIVY over 90 minutes. Monitor patients for infusion-related reactions during the infusion and for a minimum of 90 minutes following completion of the initial dose. If the previous infusion was well tolerated, the subsequent dose of POLIVY may be administered as a 30-minute infusion and patients should be monitored during the infusion and for at least 30 minutes after completion of the infusion.
- POLIVY must be administered using a dedicated infusion line equipped with a sterile, non-pyrogenic, low-protein-binding in-line or add-on filter (0.2- or 0.22-micron pore size) and a catheter.
- Do not mix POLIVY with or administer as an infusion with other drugs.
For injection: 30 mg/vial or 140 mg/vial of polatuzumab vedotin-piiq as a white to grayish-white lyophilized powder in a single-dose vial for reconstitution and further dilution.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], POLIVY can cause fetal harm. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of the small molecule component of POLIVY, MMAE, to pregnant rats during organogenesis at exposures below the clinical exposure at the recommended dose of 1.8 mg/kg POLIVY every 21 days resulted in embryo-fetal mortality and structural abnormalities (see Data). Advise a pregnant woman of the potential risks to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data
Animal Data
No embryo-fetal development studies in animals have been performed with polatuzumab vedotin-piiq. In an embryo-fetal developmental study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of POLIVY, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose).
Lactation
Risk Summary
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 the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with POLIVY and for 2 months after the last dose.
Females and Males of Reproductive Potential
POLIVY can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating POLIVY [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for 5 months after the final dose [see Nonclinical Toxicity (13.1)].
Infertility
Females
Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), POLIVY may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].
Males
Based on findings from animal studies, POLIVY may impair male fertility. The reversibility of this effect is unknown [see Nonclinical Toxicology (13.1)].
Pediatric Use
Safety and effectiveness of POLIVY have not been established in pediatric patients.
Geriatric Use
Among 435 patients treated with POLIVY plus R-CHP in POLARIX, 227 (52%) were ≥65 years of age. No overall differences in safety or efficacy were observed between patients aged ≥65 years and younger patients.
Among 173 patients treated with POLIVY plus BR in Study GO29365, 95 (55%) were ≥65 years of age. Patients aged ≥65 had a numerically higher incidence of serious adverse reactions (64%) than patients aged <65 (53%). This study did not include sufficient numbers of patients to determine whether efficacy differed in patients aged ≥65 and younger patients.
Hepatic Impairment
Avoid the administration of POLIVY in patients with moderate or severe hepatic impairment (total bilirubin greater than 1.5 × ULN and any AST). Patients with moderate or severe hepatic impairment are likely to have increased exposure to MMAE, which may increase the risk of adverse reactions. POLIVY has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) and Warnings and Precautions (5.7)].
No adjustment in the starting dose is required when administering POLIVY to patients with mild hepatic impairment (total bilirubin 1 to 1.5 × ULN or AST greater than ULN).
None.
Peripheral Neuropathy
POLIVY can cause peripheral neuropathy, including severe cases. Peripheral neuropathy occurs as early as the first cycle of treatment and is a cumulative effect [see Adverse Reactions (6.1)]. POLIVY may exacerbate pre-existing peripheral neuropathy.
In POLARIX, of 435 patients treated with POLIVY plus R-CHP, 53% reported new or worsening peripheral neuropathy, with a median time to onset of 2.3 months. Peripheral neuropathy was Grade 1 in 39% of patients, Grade 2 in 12%, and Grade 3 in 1.6%. Peripheral neuropathy resulted in dose reduction in 4% of treated patients and treatment discontinuation in 0.7%. Among patients with peripheral neuropathy after POLIVY, 58% reported resolution after a median of 4 months.
In Study GO29365, of 173 patients treated with POLIVY, 40% reported new or worsening peripheral neuropathy, with a median time to onset of 2.1 months. Peripheral neuropathy was Grade 1 in 26% of patients, Grade 2 in 12%, and Grade 3 in 2.3%. Peripheral neuropathy resulted in POLIVY dose reduction in 2.9% of treated patients, dose delay in 1.2%, and permanent discontinuation in 2.9%. Sixty-five percent of patients reported improvement or resolution of peripheral neuropathy after a median of 1 month, and 48% reported complete resolution.
The peripheral neuropathy is predominantly sensory; however, motor and sensorimotor peripheral neuropathy also occur. Monitor for symptoms of peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, or gait disturbance. Patients experiencing new or worsening peripheral neuropathy may require a delay, dose reduction, or discontinuation of POLIVY [see Dosage and Administration (2.2)].
Infusion-Related Reactions
POLIVY can cause infusion-related reactions, including severe cases. Delayed infusion-related reactions as late as 24 hours after receiving POLIVY have occurred.
With premedication, 13% of patients (58/435) in POLARIX reported infusion-related reactions after the administration of POLIVY plus R-CHP. The reactions were Grade 1 in 4.4% of patients, Grade 2 in 8%, and Grade 3 in 1.1%.
With premedication, 7% of patients (12/173) in Study GO29365 reported infusion-related reactions after the administration of POLIVY. The reactions were Grade 1 in 4.6% of patients, Grade 2 in 1.7%, and Grade 3 in 0.6%.
Symptoms occurring in ≥1% of patients included chills, dyspnea, pyrexia, pruritus, rash, and chest discomfort. Administer an antihistamine and antipyretic prior to the administration of POLIVY, and monitor patients closely throughout the infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management [see Dosage and Administration (2.2)].
Myelosuppression
Treatment with POLIVY can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia.
In POLARIX, 90% of patients treated with POLIVY plus R-CHP had primary prophylaxis with G-CSF. Grade 3–4 hematologic adverse reactions included lymphopenia (44%), neutropenia (39%), febrile neutropenia (15%), anemia (14%), and thrombocytopenia (8%) [see Adverse Reactions (6.1)].
In Study GO29365, in patients treated with POLIVY plus BR (n = 45), 42% received primary prophylaxis with G-CSF. Grade 3 or higher hematologic adverse reactions included neutropenia (42%), thrombocytopenia (40%), anemia (24%), lymphopenia (13%), and febrile neutropenia (11%) [see Adverse Reactions (6.1)]. Grade 4 hematologic adverse reactions included neutropenia (24%), thrombocytopenia (16%), lymphopenia (9%), and febrile neutropenia (4.4%). Cytopenias were the most common reason for treatment discontinuation (18% of all patients).
Monitor complete blood counts throughout treatment. Cytopenias may require a delay, dose reduction, or discontinuation of POLIVY [see Dosage and Administration (2.2)]. Administer prophylactic G-CSF for neutropenia in patients receiving POLIVY plus R-CHP. Consider prophylactic G-CSF administration in patients receiving POLIVY plus bendamustine and a rituximab product.
Serious and Opportunistic Infections
Fatal and/or serious infections, including opportunistic infections such as sepsis, pneumonia (including Pneumocystis jiroveci and other fungal pneumonia), herpesvirus infection, and cytomegalovirus infection have occurred in patients treated with POLIVY [see Adverse Reactions (6.1)].
In POLARIX, Grade 3–4 infections occurred in 14% (61/435) of patients treated with POLIVY plus R-CHP and infection-related deaths were reported in 1.1% of patients.
In Study GO29365, Grade 3 or higher infections occurred in 32% (55/173) of patients treated with POLIVYand infection-related deaths were reported in 2.9% of patients within 90 days of last treatment.
Closely monitor patients during treatment for signs of infection. Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus. Administer prophylactic G-CSF for neutropenia as recommended [see Dosage and Administration (2.3)].
Progressive Multifocal Leukoencephalopathy (PML)
PML has been reported after treatment with POLIVY plus bendamustine and obinutuzumab in study GO29365 (0.6%, 1/173). Monitor for new or worsening neurological, cognitive, or behavioral changes. Hold POLIVY and any concomitant chemotherapy if PML is suspected, and permanently discontinue if the diagnosis is confirmed.
Tumor Lysis Syndrome
POLIVY may cause tumor lysis syndrome. Patients with high tumor burden and rapidly proliferative tumor may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures, including tumor lysis syndrome prophylaxis.
Hepatotoxicity
Serious cases of hepatotoxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with POLIVY.
In recipients of POLIVY plus R-CHP, Grade 3–4 elevation of ALT and AST developed in 1.4% and 0.7% of patients, respectively.
In Study GO29365, Grade 3 and Grade 4 transaminase elevations each developed in 1.9% of patients.
Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk of hepatotoxicity. Monitor liver enzymes and bilirubin level.
Embryo-Fetal Toxicity
Based on the mechanism of action and findings from animal studies, POLIVY can cause fetal harm when administered to a pregnant woman. The small molecule component of POLIVY, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for 5 months after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].