4.1. Therapeutic indications

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.

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 summary of product characteristics (SmPC) 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 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.

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.

1If 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 1–3IRR

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 4IRR

Stop Polivy infusion immediately.

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).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active severe infections (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded.

Myelosuppression

Serious and severe neutropenia and febrile neutropenia have been reported in patients treated with Polivy as early as the first cycle of treatment. Prophylactic granulocyte colony stimulating factor (G‑CSF) administration was required in the clinical development and should be considered. Grade 3 or 4 thrombocytopenia or anaemia can also occur with Polivy. Complete blood counts should be monitored prior to each dose of Polivy. More frequent lab monitoring and/or Polivy delays or discontinuation should be considered for patients with Grade 3 or Grade 4 neutropenia and/or thrombocytopenia (see section 4.2).

Peripheral neuropathy (PN)

PN has been reported in patients treated with Polivy as early as the first cycle of treatment, and the risk increases with sequential doses. Patients with pre-existing PN may experience worsening of this condition. PN reported with treatment with Polivy is predominantly sensory PN. However, motor and sensorimotor PN have also been reported. Patients should be monitored for symptoms of PN such as hypoesthesia, hyperesthesia, paraesthesia, dysesthesia, neuropathic pain, burning sensation, muscle weakness, or gait disturbance. Patients experiencing new or worsening PN may require a delay, dose reduction, or discontinuation of Polivy (see section 4.2).

Infections

Serious, life threatening or fatal infections, including opportunistic infections, such as pneumonia (including pneumocystis jirovecii and other fungal pneumonia), bacteraemia, sepsis, herpes infection, and cytomegalovirus infection have been reported in patients treated with Polivy (see section 4.8). Reactivation of latent infections has been reported. Patients should be closely monitored during treatment for signs of bacterial, fungal, or viral infections and seek medical advice if signs and symptoms appear. Anti-infective prophylaxis should be considered throughout treatment with Polivy. Polivy should not be administered in the presence of an active severe infection. Polivy and any concomitant chemotherapy should be discontinued in patients who develop serious infections.

Human Immunodeficiency Virus (HIV)

Polivy has not been evaluated in patients with HIV. With regard to co-administration of CYP3A‑inhibitors see section 4.5.

Immunization

Live or live-attenuated vaccines should not be given concurrently with the treatment. Studies have not been conducted in patients who recently received live vaccines.

Progressive multifocal leukoencephalopathy (PML)

PML has been reported with Polivy treatment (see section 4.8). Patients should be monitored closely for new or worsening neurological, cognitive, or behavioural changes suggestive of PML. Polivy and any concomitant chemotherapy should be withheld if PML is suspected and permanently discontinued if the diagnosis is confirmed.

Tumour lysis syndrome (TLS)

Patients with high tumour burden and rapidly proliferative tumour may be at increased risk of TLS. Appropriate measures/prophylaxis in accordance with local guidelines should be taken prior to treatment with Polivy. Patients should be monitored closely for TLS during treatment with Polivy.

Infusion-related reactions

Polivy can cause IRRs, including severe cases. Delayed IRRs as late as 24 hours after receiving Polivy have occurred. An antihistamine and antipyretic should be administered prior to the administration of Polivy, and patients should be monitored closely throughout the infusion. If an IRR occurs, the infusion should be interrupted and appropriate medical management should be instituted (see section 4.2).

Embryo-foetal toxicity

Based on the mechanism of action and nonclinical studies, Polivy can be harmful to the foetus when administered to a pregnant woman (see section 5.3). Pregnant women should be advised regarding risk to the foetus.

Women of childbearing potential should be advised to use effective contraception during treatment with Polivy and for at least 9 months after the last dose (see section 4.6). Male patients with female partners of childbearing potential should be advised to use effective contraception during treatment with Polivy and for at least 6 months after the last dose (see section 4.6).

Fertility

In non-clinical studies, polatuzumab vedotin has resulted in testicular toxicity, and may impair male reproductive function and fertility (see section 5.3). Therefore, men being treated with Polivy are advised to have sperm samples preserved and stored before treatment (see section 4.6).

Elderly

Among 435 previously untreated DLBCL patients treated with Polivy in combination with R-CHP in Study GO39942, 227 (52.2%) were ≥ 65 years of age. Patients aged ≥ 65 had an incidence of serious adverse reactions of 39.2% and 28.4% in patients aged < 65. A similar incidence of serious adverse reactions was seen in elderly patients in the R-CHOP treatment arm.

Among 151 previously treated DLBCL patients treated with Polivy in combination with bendamustine and rituximab (BR) in Study GO29365, 103 (68%) were ≥ 65 years of age. Patients aged ≥ 65 had a similar incidence of serious adverse reactions (55%) to patients aged < 65 (56%). Clinical studies of Polivy did not include sufficient numbers of patients aged ≥ 65 to determine whether they respond differently from younger patients.

Hepatic toxicity

Serious cases of hepatic toxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with Polivy (see section 4.8). Pre‑existing liver disease, elevated baseline liver enzymes, and concomitant medicinal products may increase the risk. Liver enzymes and bilirubin level should be monitored (see section 4.2).

Infusion site extravasation injury

Skin and soft tissue injury following polatuzumab vedotin administration has been observed within hours to weeks after occurrence of extravasation (see section 4.8). Ensure good venous access prior to starting Polivy and monitor for possible infusion site extravasation during administration. If extravasation occurs, stop the infusion, monitor for tissue damage, and manage in accordance with local clinical guidelines.

Based on clinical decision the remaining dose may be administered in an alternate limb.

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

This medicinal product contains polysorbate 20. Each vial of Polivy 30 mg powder for concentrate for solution for infusion contains 1.8 mg of polysorbate 20. Each vial of Polivy 140 mg powder for concentrate for solution for infusion contains 8.4 mg of polysorbate 20, which is equivalent to 1.2 mg/ml. Polysorbate 20 may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No dedicated clinical drug-drug interaction studies with polatuzumab vedotin in humans have been conducted.

Drug interactions with concomitant medicines that are CYP3A4 inhibitors, substrates or inducers and co-medications that are P-gp inhibitors

Based on physiological-based pharmacokinetic (PBPK) model simulations of MMAE released from polatuzumab vedotin, strong CYP3A4 and P-gp inhibitors (e.g., ketoconazole) may increase the area under the concentration-time curve (AUC) of unconjugated MMAE by 48%. Caution is advised in case of concomitant treatment with CYP3A4 inhibitor. Patients receiving concomitant strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) should be monitored more closely for signs of toxicities.

Unconjugated MMAE is not predicted to alter the AUC of concomitant medicines that are CYP3A4 substrates (e.g., midazolam).

Strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, St John's wort [Hypericum perforatum]) may decrease the exposure of unconjugated MMAE.

Drug interactions of rituximab, bendamustine, cyclophosphamide, and doxorubicin in combination with polatuzumab vedotin

The pharmacokinetics (PK) of rituximab, bendamustine, cyclophosphamide, and doxorubicin are not affected by co-administration with polatuzumab vedotin. Concomitant rituximab is associated with increased antibody conjugated MMAE (acMMAE) plasma AUC by 24% and decreased unconjugated MMAE plasma AUC by 37%, based on population PK analysis. The plasma AUC of acMMAE and unconjugated MMAE for Polivy plus R-CHP are in line with other studies of Polivy. No dose adjustment is required.

Bendamustine does not affect acMMAE and unconjugated MMAE plasma AUC.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women

Women of childbearing potential should be advised to use effective contraception during treatment with polatuzumab vedotin and for at least 9 months after the last dose.

Men

Male patients with female partners of childbearing potential should be advised to use effective contraception during treatment with polatuzumab vedotin and for at least 6 months after the last dose.

Pregnancy

There are no data in pregnant women using Polivy. Studies in animals have shown reproductive toxicity (see section 5.3). Based on the mechanism of action and nonclinical studies, polatuzumab vedotin can be harmful to the foetus when administered to a pregnant woman. In women of childbearing potential, the pregnancy status shall be checked prior to treatment. Polivy is not recommended during pregnancy and in women of childbearing potential not using contraception unless the potential benefit for the mother outweighs the potential risk to the foetus.

Breast‑feeding

It is not known whether polatuzumab vedotin or its metabolites are excreted in human breast milk. A risk for breast-feeding children cannot be excluded. Women should discontinue breast-feeding during treatment with Polivy and for at least 3 months after the last dose.

Fertility

In nonclinical studies, polatuzumab vedotin has resulted in testicular toxicity, and may impair male reproductive function and fertility (see section 5.3).

Therefore, men being treated with this medicine are advised to have sperm samples preserved and stored before treatment. Men being treated with Polivy are advised not to father a child during treatment and for up to 6 months following the last dose.

4.7. Effects on ability to drive and use machines

Polivy has minor influence on the ability to drive and use machines. IRRs, PN, fatigue, and dizziness may occur during treatment with Polivy (see sections 4.4 and 4.8).

4.8. Undesirable effects

Summary of the safety profile

The safety of Polivy has been evaluated in 435 patients in Study GO39942 (POLARIX). The ADRs described in section 4.8 were identified:

• during treatment and follow-up of previously untreated DLBCL patients from the pivotal clinical trial GO39942 (POLARIX), who received Polivy plus R-CHP (n=435) or R-CHOP (n=438). In the Polivy plus R-CHP group, 91.7% received 6 cycles of Polivy versus 88.5% of patients who received 6 cycles of vincristine in the R-CHOP group.

In previously untreated DLBCL patients treated with Polivy plus R-CHP:

• The most frequently-reported (≥ 30%) adverse drug reactions (ADRs) in patients treated with Polivy plus R-CHP for previously untreated DLBCL were neuropathy peripheral (52.9%), nausea (41.6%), neutropenia (38.4%), and diarrhoea (30.8%).

• Serious adverse reactions were reported in 24.1% of Polivy plus R-CHP treated patients.

• The most common serious adverse reactions reported in ≥ 5% of patients were febrile neutropenia (10.6%) and pneumonia (5.3%).

• The ADRs leading to treatment regimen discontinuation in > 1% of patients treated with Polivy plus R-CHP was pneumonia (1.1%).

The safety of Polivy has been evaluated in 151 patients in Study GO29365. The ADRs described in section 4.8 were identified:

• during treatment and follow-up of previously treated DLBCL patients (n=151) from the pivotal clinical trial GO29365. This includes run-in phase patients (n=6), randomized patients (n=39), and extension cohort patients (n=106) who received Polivy plus BR compared to randomized patients (n=39) who received BR alone. Patients in the treatment arms received a median of 5 cycles of treatment while randomized patients in the comparator arm received a median of 3 cycles of treatment.

In previously treated DLBCL patients treated with Polivy plus BR:

• The most frequently reported (≥ 30%) ADRs (all grades) in patients treated with Polivy plus BR in previously treated DLBCL were neutropenia (45.7%), diarrhoea (35.8%), nausea (33.1%), thrombocytopenia (32.5%), anaemia (31.8%) and neuropathy peripheral (30.5%).

• Serious adverse reactions were reported in 41.7% of Polivy plus BR treated patients.

• The most common serious adverse reactions reported in ≥ 5% of patients were: febrile neutropenia (10.6%), sepsis (9.9%), pneumonia (8.6%) and pyrexia (7.9%).

• The ADR leading to treatment regimen discontinuation in > 5% of patients treated with Polivy plus BR was thrombocytopenia (7.9%).

Tabulated list of ADRs from clinical trials

The ADRs in 586 patients treated with Polivy are presented in Table 4. The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 4 Tabulated list of ADRs in patients treated with Polivy in clinical trials

Infections and infestations

Very common

pneumoniaa, upper respiratory tract infection

Common

sepsisa, herpes virus infectiona, cytomegalovirus infection, urinary tract infectionc

Blood and lymphatic system disorders

Very common

febrile neutropenia, neutropenia, thrombocytopenia, anaemia, leukopenia

Common

lymphopenia, pancytopenia

Metabolism and nutrition disorders

Very common

hypokalaemia, decreased appetite

Common

hypocalcaemia, hypoalbuminemia

Nervous system disorders

Very common

neuropathy peripheral

Common

dizziness

Eye disorders

Uncommon

vision blurredb

Respiratory, thoracic and mediastinal disorders

Very common

cough

Common

pneumonitis, dyspnoeac

Gastrointestinal disorders

Very common

diarrhoea, nausea, constipation, vomiting, mucositisc, abdominal pain

Skin and subcutaneous tissue disorders

Very common

alopeciac

Common

pruritus, skin infectionsc, rashc, dry skinc

Musculoskeletal disorders

Common

arthralgia, myalgiac

General disorders and administration site conditions

Very common

pyrexia, fatigue, asthenia

Common

peripheral edemac, chills

Uncommon

infusion site reactions

Investigations

Very common

weight decreased

Common

lipase increaseb, hypophosphataemia

Hepatobiliary disorders

Common

transaminases increased

Injury, poisoning and procedural complications

Very Common

infusion related reaction

a ADR associated with fatal outcome

b ADRs observed in relapsed or refractory DLBCL only.

c ADRs observed in previously untreated DLBCL only.

The listed ADRs were observed in both previously untreated DLBCL and relapsed or refractory DLBCL except where indicated with footnotes.

Rare and very rare ADRs: none

Description of selected adverse drug reactions

Myelosuppression

In a placebo-controlled study GO39942 (POLARIX), 0.5% of patients in the Polivy plus R-CHP arm discontinued study treatment due to neutropenia. No patients discontinued study treatment in the R-CHOP arm due to neutropenia. Thrombocytopenia events led to discontinuation of study treatment in 0.2% of patients in the Polivy plus R-CHP arm compared to no patients in the R-CHOP arm. No patients discontinued treatment due to anaemia in either the Polivy plus R-CHP arm or R-CHOP arm.

In an open-label study GO29365, 4% of patients in the Polivy plus BR arms discontinued Polivy due to neutropenia compared to 2.6% of patients in the BR arm who discontinued treatment due to neutropenia. Thrombocytopenia events led to discontinuation of treatment in 7.9% of patients in the Polivy plus BR arms and 5.1% of patients in the BR arm. No patients discontinued treatment due to anaemia in either the Polivy plus BR arms or BR arm. In the Polivy plus BR arms, Grade 3 or higher neutropenia, thrombocytopenia, and anaemia were reported in 40.4%, 25.8%, and 12.6% of patients, respectively.

Peripheral neuropathy (PN)

In a placebo-controlled study GO39942 (POLARIX), in the Polivy plus R-CHP arm, Grade 1, 2, and 3 PN were reported in 39.1%, 12.2% and 1.6% of patients, respectively. In the R-CHOP arm, Grade 1, 2 and 3 PN events were reported in 37.2%, 15.5% and 1.1% of patients, respectively. No Grade 4-5 PN events were reported in either the Polivy plus R-CHP arm or R-CHOP arm. 0.7% of patients discontinued study treatment in the Polivy plus R-CHP arm due to PN compared to 2.3% in the R-CHOP arm. 4.6% of patients in the Polivy plus R-CHP arm had study treatment dose reduction due to PN compared to 8.2% in the R-CHOP arm. In the Polivy plus R-CHP arm, the median time to onset of first event of PN was 2.27 months compared to 1.87 months in the R-CHOP arm. PN events resolved in 57.8% of patients in the Polivy plus R-CHP arm as of the clinical cut off date compared to 66.9% in the R-CHOP arm. The median time to peripheral neuropathy resolution was 4.04 months in the Polivy plus R-CHP arm compared to 4.6 months in the R-CHOP arm.

In an open-label study GO29365, in the Polivy plus BR arms, Grade 1 PN and Grade 2 PN were reported in 15.9% and 12.6% of patients, respectively. In the BR arm, Grade 1 and 2 PN events were reported in 2.6% and 5.1% of patients, respectively. One Grade 3 PN event was reported in the Polivy plus BR arms and no patients reported PN events in the BR arm. No Grade 4-5 PN events were reported in either the Polivy plus BR arms or BR arm. 2.6% of patients discontinued Polivy treatment due to PN and 2.0% of patients had Polivy dose reduction due to PN. No patients in the BR arm discontinued treatment or had dose reductions due to PN. In the Polivy plus BR arms, the median time to onset of first event of PN was 1.6 months, and 39.1% of patients with PN events reported event resolution.

Infections

In a placebo-controlled study GO39942 (POLARIX), infections, including pneumonia and other types of infections, were reported in 49.7% of patients in the Polivy plus R-CHP arm and 42.7% of patients in the R-CHOP arm. Grade 3-4 infections occurred in 14.0% of patients in the Polivy plus R-CHP arm and 11.2% of patients in the R-CHOP arm. In the Polivy plus R-CHP arm, serious infections were reported in 14.0% of patients and fatal infections were reported in 1.1% of patients. In the R-CHOP arm, serious infections were reported in 10.3% of patients and fatal infections were reported in 1.4% of patients. 7 patients (1.6%) in the Polivy plus R-CHP arm discontinued treatment due to infection compared to 10 patients (2.3%) in the R-CHOP arm.

In an open-label study GO29365, infections, including pneumonia and other types of infections, were reported in 48.3% of patients in the Polivy plus BR arms and 51.3% of patients in the BR arm. In the Polivy plus BR arms, serious infections were reported in 27.2% of patients and fatal infections were reported in 6.6% of patients. In the BR arm, serious infections were reported in 30.8% of patients and fatal infections were reported in 10.3% of patients. Four patients (2.6%) in the Polivy plus BR arms discontinued treatment due to infection compared to 2 patients (5.1%) in the BR arm.

Progressive multifocal leukoencephalopathy (PML)

In a placebo-controlled study GO39942 (POLARIX), no cases of PML were reported.

In an open-label study GO29365, one case of PML, which was fatal, occurred in one patient treated with Polivy plus bendamustine and obinutuzumab. This patient had three prior lines of therapy that included anti-CD20 antibodies.

Hepatic toxicity

In a placebo-controlled study GO39942 (POLARIX), hepatic toxicity was reported in 10.6% of patients in the Polivy plus R-CHP arm and 7.3% of patients in the R-CHOP arm. In the Polivy plus R-CHP arm, most events were Grade 1-2 (8.7%); Grade 3 events were reported in 1.8% of patients. There were no Grade 4 or 5 events. Serious hepatic toxicity events were reported in 1 patient (0.2%) and were reversible.

In another study, two cases of serious hepatic toxicity (hepatocellular injury and hepatic steatosis) were reported and were reversible.

Gastrointestinal toxicity

In a placebo-controlled study GO39942 (POLARIX), gastrointestinal toxicity events were reported in 76.1% of patients in the Polivy plus R-CHP arm compared to 71.9% of patients in the R-CHOP arm. Most events were Grade 1–2, and Grade ≥3 events were reported in 9.7% of patients in the Polivy plus R-CHP arm compared to 8.2% of patients in the R-CHOP arm. The most common gastrointestinal toxicity events were nausea and diarrhoea.

In an open-label study GO29365, gastrointestinal toxicity events were reported in 72.8% of patients in the Polivy plus BR arms compared to 66.7% of patients in the BR arm. Most events were Grade 1-2, and Grade 3-4 events were reported in 16.5% of patients in the Polivy plus BR arms compared to 12.9% of patients in the BR arm. The most common gastrointestinal toxicity events were diarrhoea and nausea.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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.