Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Polivy in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) is indicated for the treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL).
Polivy in combination with bendamustine and rituximab is indicated for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are not candidates for haematopoietic stem cell transplant.
Polivy must only be administered under the supervision of a healthcare professional experienced in the diagnosis and treatment of cancer patients.
The recommended dose of Polivy is 1.8 mg/kg, given as an intravenous infusion every 21 days in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for 6 cycles. Polivy, rituximab, cyclophosphamide and doxorubicin can be administered in any order on Day 1 after the administration of prednisone. Prednisone is administered on Days 1-5 of each cycle. Cycles 7 and 8 consist of rituximab as monotherapy.
Refer to the summary of product characteristics (SmPC) of chemotherapy agents given in combination with Polivy for patients with previously untreated DLBCL.
The recommended dose of Polivy is 1.8 mg/kg, given as an intravenous infusion every 21 days in combination with bendamustine and rituximab for 6 cycles. Polivy, bendamustine and rituximab can be administered in any order on Day 1 of each cycle. When administered with Polivy, the recommended dose of bendamustine is 90 mg/m²/day on Day 1 and Day 2 of each cycle and the recommended dose of rituximab is 375 mg/m² on Day 1 of each cycle. Due to limited clinical experience in patients treated with 1.8 mg/kg Polivy at a total dose >240 mg, it is recommended not to exceed the dose 240 mg/cycle.
If not already premedicated, premedication with an antihistamine and anti-pyretic should be administered to patients prior to Polivy.
If a planned dose of Polivy is missed, it should be administered as soon as possible and the schedule of administration should be adjusted to maintain a 21-day interval between doses.
The infusion rate of Polivy should be slowed or interrupted if the patient develops an infusion-related reaction. Polivy should be discontinued immediately and permanently if the patient experiences a life-threatening reaction.
There are different potential dose modifications for Polivy in patients with previously untreated DLBCL and those who are relapsed or refractory.
For dose modifications to manage peripheral neuropathy (section 4.4) see Table 1 below.
Table 1. Polivy dose modifications for peripheral neuropathy (PN):
| Indication | Severity of PN on Day 1 of any cycle | Dose modification |
|---|---|---|
| Previously untreated DLBCL | Grade 2a | Sensory neuropathy: • Reduce Polivy to 1.4 mg/kg. • If Grade 2 persists or recurs at Day 1 of a future cycle, reduce Polivy to 1.0 mg/kg. • If already at 1.0 mg/kg and Grade 2 occurs at Day 1 of a future cycle, discontinue Polivy. Motor neuropathy: • Withhold Polivy dosing until improvement to Grade ≤1. • Restart Polivy at the next cycle at 1.4 mg/kg. • If already at 1.4 mg/kg and Grade 2 occurs at Day 1 of a future cycle, withhold Polivy dosing until improvement to Grade ≤ 1. Restart Polivy at 1.0 mg/kg. • If already at 1.0 mg/kg and Grade 2 occurs at Day 1 of a future cycle, discontinue Polivy. If concurrent sensory and motor neuropathy, follow the most severe restriction recommendation above. |
| Grade 3a | Sensory neuropathy: • Withhold Polivy dosing until improvement to Grade ≤ 2. • Reduce Polivy to 1.4 mg/kg. • If already at 1.4 mg/kg, reduce Polivy to 1.0 mg/kg. If already at 1.0 mg/kg, discontinue Polivy. Motor neuropathy: • Withhold Polivy dosing until improvement to Grade ≤ 1. • Restart Polivy at the next cycle at 1.4 mg/kg. • If already at 1.4 mg/kg and Grade 2–3 occurs, withhold Polivy dosing until improvement to Grade ≤ 1. Restart Polivy at 1.0 mg/kg. • If already at 1.0 mg/kg and Grade 2–3 occurs, discontinue Polivy. If concurrent sensory and motor neuropathy, follow the most severe restriction recommendation above. | |
| Grade 4 | Discontinue Polivy. | |
| R/R DLBCL | Grade 2–3 | Withhold Polivy dosing until improvement to ≤ Grade 1. If recovered to Grade ≤ 1 on or before Day 14, restart Polivy 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 on or before Day 14, discontinue Polivy. |
| Grade 4 | Discontinue Polivy. a R-CHP may continue to be administered. |
a R-CHP may continue to be administered.
For dose modifications to manage myelosuppression (section 4.4) see Table 2 below.
Table 2. Polivy, chemotherapy and rituximab dose modifications to manage myelosuppression:
| Indication | Severity of myelosuppression on Day 1 of any cycle | Dose modification |
|---|---|---|
| Previously untreated DLBCL | Grade 3–4 Neutropenia | Withhold all treatment until ANC* recovers to > 1000/µL. If ANC recovers to > 1000/µL on or before Day 7, resume all treatment without any dose reductions. If ANC recovers to > 1000/µL after Day 7: • resume all treatment; consider a dose reduction of cyclophosphamide and/or doxorubicin by 25-50%. • if cyclophosphamide and/or doxorubicin are already reduced by 25%, consider reducing one or both agents to 50%. |
| Grade 3–4 Thrombocytopenia | Withhold all treatment until platelets recover to > 75,000/µL. If platelets recover to > 75,000/µL on or before Day 7, resume all treatment without any dose reductions. If platelets recover to > 75,000/µL after Day 7: • resume all treatment; consider a dose reduction of cyclophosphamide and/or doxorubicin by 25-50%. • if cyclophosphamide and/or doxorubicin are already reduced by 25%, consider reducing one or both agents to 50%. | |
| R/R DLBCL | Grade 3–4 Neutropenia1 | Withhold all treatment until ANC recovers to > 1000/µL. If ANC recovers to > 1000/µL on or before Day 7, resume all treatment without any additional dose reductions. If ANC recovers to > 1000/µL after Day 7: • restart all treatment with a dose reduction of bendamustine from 90 mg/m² to 70 mg/m² or 70 mg/m² to 50 mg/m². • if a bendamustine dose reduction to 50 mg/m² has already occurred, discontinue all treatment. |
| Grade 3–4 Thrombocytopenia1 | Withhold all treatment until platelets recover to > 75,000/µL. If platelets recover to > 75,000/µL on or before Day 7, resume all treatment without any dose reductions. If platelets recover to > 75,000/µL after Day 7: • restart all treatment with a dose reduction of bendamustine from 90 mg/m² to 70 mg/m² or 70 mg/m² to 50 mg/m². • if a bendamustine dose reduction to 50 mg/m² has already occurred, discontinue all treatment. |
1 If primary cause is due to lymphoma, the dose of bendamustine may not need to be reduced.
* ANC: absolute neutrophil count
For dose modifications to manage Infusion-related reactions (section 4.4) see Table 3 below.
Table 3. Polivy dose modifications for Infusion-related reactions (IRRs):
| Indication | Severity of IRR on Day 1 of any cycle | Dose modification |
|---|---|---|
| Previously untreated and R/R DLBCL | Grade 1–3 IRR | 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. |
| Grade 4 IRR | Stop Polivy infusion immediately. Give supportive treatment. Permanently discontinue Polivy. |
No dose adjustment of Polivy is required in patients ≥65 years of age (see section 5.2).
No dose adjustment of Polivy is required in patients with creatinine clearance (CrCL) ≥30 mL/min. A recommended dose has not been determined for patients with CrCL <30mL/min due to limited data.
The administration of Polivy in patients with moderate or severe hepatic impairment (bilirubin greater than 1.5 × upper limit of normal [ULN]) should be avoided.
No adjustment in the starting dose is required when administering Polivy to patients with mild hepatic impairment (bilirubin greater than ULN to less than or equal to 1.5 × ULN or aspartate transaminase [AST] greater than ULN).
Per studied population in mild hepatic impairment (defined as AST or ALT >1.0 to 2.5 × ULN or total bilirubin >1.0 to 1.5 × ULN), there was a not more than 40% increase in unconjugated MMAE exposure, which was not deemed clinically significant.
The safety and efficacy in children and adolescents less than 18 years have not been established. No data are available.
Polivy is for intravenous use.
The initial dose of Polivy should be administered as a 90-minute intravenous infusion. Patients should be monitored for IRRs/hypersensitivity reactions during the infusion and for at least 90 minutes following completion of the initial dose.
If the prior 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 reconstituted and diluted using aseptic technique under the supervision of a healthcare professional. It should be administered as an intravenous infusion through a dedicated infusion line equipped with a sterile, non-pyrogenic, low-protein binding in-line or add-on filter (0.2 or 0.22 micrometer pore size) and catheter. Polivy must not be administered as intravenous push or bolus.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
Polivy contains a cytotoxic component which is covalently attached to the monoclonal antibody. Follow applicable proper handling and disposal procedure (see section 6.6).
There is no experience with overdose in human clinical trials. The highest dose tested to date is 2.4 mg/kg administered as an intravenous infusion; it was associated with a higher frequency and severity of PN events. Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.
Unopened vial:
30 months.
Reconstituted solution:
From a microbiological point of view, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours refrigerated (2°C-8°C), unless reconstitution has taken place in controlled and validated aseptic conditions. Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to 72 hours refrigerated (2°C-8°C) and up to 24 hours at room temperature (9°C-25°C).
Diluted solution:
From a microbiological point of view, the prepared solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours refrigerated (2°C-8°C), unless dilution has taken place in controlled and validated aseptic conditions. Chemical and physical stability of the prepared solution for infusion has been demonstrated for the durations listed in Table 7. The diluted solution must be discarded if storage time exceeds the limits specified in Table 7.
Table 7. Durations for which chemical and physical stability of the prepared solution for infusion have been demonstrated:
| Diluent used to prepare solution for infusion | Solution for infusion storage conditions1 |
|---|---|
| Sodium chloride 9 mg/mL (0.9%) | Up to 72 hours refrigerated (2°C−8°C) or up to 4 hours at room temperature (9°C−25°C) |
| Sodium chloride 4.5 mg/mL (0.45%) | Up to 72 hours refrigerated (2°C−8°C) or up to 8 hours at room temperature (9°C−25°C) |
| 5% glucose | Up to 72 hours refrigerated (2°C−8°C) or up to 8 hours at room temperature (9°C−25°C) |
1 To ensure product stability, do not exceed specified storage durations.
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
Polivy 30 mg powder for concentrate for solution for infusion: 6 mL vial (colourless Type 1 glass) closed with a stopper (fluororesin laminate), with an aluminium seal with plastic flip-off cap containing 30 mg polatuzumab vedotin. Pack size of one vial.
Polivy 140 mg powder for concentrate for solution for infusion: 20 mL vial (colourless Type 1 glass) closed with a stopper (fluororesin laminate), with an aluminium seal with plastic flip-off cap containing 140 mg polatuzumab vedotin. Pack size of one vial.
Polivy contains a cytotoxic component. To be administered under the supervision of a physician experienced in the use of cytotoxic agents. Procedures for proper handling and disposal of antineoplastic and cytotoxic medicines should be used.
The reconstituted product contains no preservative and is intended for single-dose only. Proper aseptic technique throughout the handling of this medicinal product should be followed.
Polivy must be reconstituted using sterile water for injection and diluted into an intravenous infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection, or sodium chloride 4.5 mg/ml (0.45%) solution for injection, or 5% glucose prior to administration.
The reconstituted solution and solution for infusion should not be frozen or exposed to direct sunlight.
1. Polivy must be diluted to a final concentration of 0.72-2.7 mg/mL in an intravenous infusion bag, with a minimum volume of 50 mL, containing 9 mg/mL sodium chloride solution for injection, or 4.5 mg/mL sodium chloride solution for injection, or 5% glucose.
2. Determine the volume of 20 mg/mL reconstituted solution needed based on the required dose (see below):
Total Polivy dose (mL) to be further diluted = Polivy dose (mg/kg) X patient’s weight (kg) / Reconstituted vial concentration (20 mg/mL)
3. 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.
4. Gently mix the intravenous bag by slowly inverting the bag. Do not shake.
5. Inspect the intravenous bag for particulates and discard if present.
Avoid transportation of the prepared solution for infusion as agitation stress can result in aggregation. If the prepared infusion will be transported, remove air from the infusion bag and limit transportation to 30 minutes room temperature (9°C−25°C) or 24 hours refrigerated (2°C−8°C). If air is removed, an infusion set with a vented spike is required to ensure accurate dosing during the infusion. The total storage plus transportation times of the diluted product should not exceed the storage duration specified in Table 7 (see section 6.3).
Polivy must be administered using a dedicated infusion line equipped with sterile, non-pyrogenic, low-protein binding in-line or add-on filter (0.2 or 0.22 micrometer pore size) and catheter.
Polivy is compatible with intravenous infusion bags with product contacting materials of polyvinyl chloride (PVC) or polyolefins such as polyethylene (PE) and polypropylene. In addition, no incompatibilities have been observed with infusion sets or infusion aids with product contacting materials of PVC, PE, polyurethane, polybutadiene, acrylonitrile butadiene styrene, polycarbonate, polyetherurethane, fluorinated ethylene propylene, or polytetrafluorethylene and with filter membranes composed of polyether sulfone or polysulfone.
Polivy is for single-use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
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