Posology : מינונים

4.2    Posology and method of administration

Polivy must only be administered under the supervision of a healthcare professional experienced in the diagnosis and treatment of cancer patients.
Posology

Diffuse large B-cell lymphoma

Previously untreated 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 Prescribing Information of chemotherapy agents given in combination with Polivy for patients with previously untreated DLBCL.

Relapsed or refractory patients

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.

Previously untreated and relapsed or refractory patients

If not already premedicated, premedication with an antihistamine and anti-pyretic should be administered to patients prior to Polivy.

Delayed or missed doses

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.

Dose modifications

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     Dose modification
PN on Day 1 of any cycle
Previously    Grade 2a        Sensory neuropathy: untreated                       • Reduce Polivy to 1.4 mg/kg.
DLBCL                           • 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        Grade 2–3        Withhold Polivy dosing until improvement to ≤ Grade 1.
DLBCL                       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.


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            Dose modification myelosuppression on Day 1 of any cycle
Previously Grade 3–4              Withhold all treatment until ANC* recovers to > 1000/µL.
untreated  Neutropenia            If ANC recovers to > 1000/µL on or before Day 7, resume all DLBCL                             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              Withhold all treatment until platelets recover to > 75,000/µL.
Thrombocytopenia       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        Grade 3-4              Withhold all treatment until ANC recovers to > 1000/µL.
DLBCL      Neutropenia1           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              Withhold all treatment until platelets recover to > 75,000/µL.
Thrombocytopenia1      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        Dose modification on Day 1 of any cycle
Previously     Grade 1–3              Interrupt Polivy infusion and give supportive treatment.
untreated      IRR
For the first instance of Grade 3 wheezing, bronchospasm, or and R/R generalized urticaria, permanently discontinue Polivy.
DLBCL
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                Stop Polivy infusion immediately.
IRR                    Give supportive treatment.
Permanently discontinue Polivy.

Special populations
Elderly
No dose adjustment of Polivy is required in patients ≥ 65 years of age (see section 5.2).

Renal impairment
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.

Hepatic impairment
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.

Paediatric population
The safety and efficacy in children and adolescents less than 18 years have not been established. No data are available.


Method of administration

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.

Precaution to be taken before handling or administering the product

Polivy contains a cytotoxic component which is covalently attached to the monoclonal antibody.
Follow applicable proper handling and disposal procedure (see section 6.6).