POLIVY 30mg 20mg / ml powder for concentrate infusion solution medication leaflet

Polivy 30 mg powder for concentrate for solution for infusion.

Polivy 140 mg powder for concentrate for solution for infusion.

Polivy 30 mg powder for concentrate for solution for infusion

Each vial of powder for concentrate for solution for infusion contains 30 mg of polatuzumab vedotin.

After reconstitution, each mL contains 20 mg of polatuzumab vedotin.

Polivy 140 mg powder for concentrate for solution for infusion

Each vial of powder for concentrate for solution for infusion contains 140 mg of polatuzumab vedotin.

After reconstitution, each mL contains 20 mg of polatuzumab vedotin.

Polatuzumab vedotin is an antibody-drug conjugate composed of the anti-mitotic agent monomethylauristatin E (MMAE) covalently conjugated to a CD79b-directed monoclonal antibody (recombinanthumanized immunoglobulin G1 [IgG1], produced in Chinese Hamster Ovary cells by recombinant

DNA technology).

Each 30 mg vial of Polivy contains 1.8 mg of polysorbate 20.

Each 140 mg vial of Polivy contains 8.4 mg of polysorbate 20.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to greyish-white lyophilized cake.

Polivy in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) isindicated 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 patientswith relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are not candidates forhaematopoietic stem cell transplant.

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

Diffuse large B-cell lymphoma

The recommended dose of Polivy is 1.8 mg/kg, given as an intravenous infusion every 21 days incombination 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 afterthe administration of prednisone. Prednisone is administered on Days 1-5 of each cycle. Cycles 7 and8 consist of rituximab as monotherapy.

Refer to the summary of product characteristics (SmPC) of chemotherapy agents given in combinationwith 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 incombination with bendamustine and rituximab for 6 cycles. Polivy, bendamustine and rituximab canbe administered in any order on Day 1 of each cycle. When administered with Polivy, therecommended dose of bendamustine is 90 mg/m2/day on Day 1 and Day 2 of each cycle and therecommended dose of rituximab is 375 mg/m2 on Day 1 of each cycle. Due to limited clinicalexperience in patients treated with 1.8 mg/kg Polivy at a total dose >240 mg, it is recommended not toexceed the dose 240 mg/cycle.

Previously untreated and relapsed or refractory patients

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

If a planned dose of Polivy is missed, it should be administered as soon as possible and the schedule ofadministration 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-relatedreaction. Polivy should be discontinued immediately and permanently if the patient experiences alife-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 1of 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 afuture 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 afuture 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 afuture cycle, discontinue Polivy.

If concurrent sensory and motor neuropathy, follow the most severerestriction 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. Ifalready 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 at1.0 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 severerestriction 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 apermanently 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 managemyelosuppression

Indication Severity of Dose modificationmyelosuppressionon Day 1 of anycycle

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 ofcyclophosphamide and/or doxorubicin by 25-50%.

* if cyclophosphamide and/or doxorubicin are alreadyreduced by 25%, consider reducing one or both agents to50%.

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, resumeall treatment without any dose reductions.

If platelets recover to > 75,000/µL after Day 7:

* resume all treatment; consider a dose reduction ofcyclophosphamide and/or doxorubicin by 25-50%.

* if cyclophosphamide and/or doxorubicin are alreadyreduced by 25%, consider reducing one or both agents to50%.

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 alltreatment without any additional dose reductions.

If ANC recovers to > 1000/µL after Day 7:

* restart all treatment with a dose reduction ofbendamustine from 90 mg/m2 to 70 mg/m2 or 70 mg/m2 to50 mg/m2.

* if a bendamustine dose reduction to 50 mg/m2 hasalready 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, resumeall treatment without any dose reductions.

If platelets recover to > 75,000/µL after Day 7:

* restart all treatment with a dose reduction ofbendamustine from 90 mg/m2 to 70 mg/m2 or 70 mg/m2 to50 mg/m2.

* if a bendamustine dose reduction to 50 mg/m2 hasalready 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 Dose modificationon Day 1 of anycycle

Previously Grade 1-3 Interrupt Polivy infusion and give supportive treatment.untreated IRRand R/R For the first instance of Grade 3 wheezing, bronchospasm, or

DLBCL generalized urticaria, permanently discontinue Polivy.

For recurrent Grade 2 wheezing or urticaria, or for recurrenceof any Grade 3 symptoms, permanently discontinue Polivy.

Otherwise, upon complete resolution of symptoms, infusionmay be resumed at 50% of the rate achieved prior tointerruption. In the absence of infusion-related symptoms, therate of infusion may be escalated in increments of 50 mg/hourevery 30 minutes.

For the next cycle, infuse Polivy over 90 minutes. If noinfusion-related reaction occurs, subsequent infusions may beadministered over 30 minutes. Administer premedication forall cycles.

Grade 4 Stop Polivy infusion immediately.

IRR 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. Arecommended 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 greaterthan 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 hepaticimpairment (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 ortotal bilirubin > 1.0 to 1.5 × ULN), there was a not more than 40% increase in unconjugated MMAEexposure, which was not deemed clinically significant.

The safety and efficacy in children and adolescents less than 18 years have not been established. Nodata are available.

Polivy is for intravenous use.

The initial dose of Polivy should be administered as a 90-minute intravenous infusion. Patients shouldbe monitored for IRRs/hypersensitivity reactions during the infusion and for at least 90 minutesfollowing completion of the initial dose.

If the prior infusion was well tolerated, the subsequent dose of Polivy may be administered as a30-minute infusion and patients should be monitored during the infusion and for at least 30 minutesafter completion of the infusion.

Polivy must be reconstituted and diluted using aseptic technique under the supervision of a healthcareprofessional. It should be administered as an intravenous infusion through a dedicated infusion lineequipped with a sterile, non-pyrogenic, low-protein binding in-line or add-on filter (0.2 or0.22 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, seesection 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).

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

Active severe infections (see section 4.4).

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

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 or4 thrombocytopenia or anaemia can also occur with Polivy. Complete blood counts should bemonitored prior to each dose of Polivy. More frequent lab monitoring and/or Polivy delays ordiscontinuation should be considered for patients with Grade 3 or Grade 4 neutropenia and/orthrombocytopenia (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 riskincreases with sequential doses. Patients with pre-existing PN may experience worsening of thiscondition. PN reported with treatment with Polivy is predominantly sensory PN. However, motor andsensorimotor PN have also been reported. Patients should be monitored for symptoms of PN such ashypoesthesia, hyperesthesia, paraesthesia, dysesthesia, neuropathic pain, burning sensation, muscleweakness, or gait disturbance. Patients experiencing new or worsening PN may require a delay, dosereduction, or discontinuation of Polivy (see section 4.2).

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 duringtreatment for signs of bacterial, fungal, or viral infections and seek medical advice if signs andsymptoms 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 anyconcomitant 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.

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

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

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 totreatment with Polivy. Patients should be monitored closely for TLS during treatment with Polivy.

Polivy can cause IRRs, including severe cases. Delayed IRRs as late as 24 hours after receiving Polivyhave 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, theinfusion should be interrupted and appropriate medical management should be instituted (seesection 4.2).

Embryo-foetal toxicity

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

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

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

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 seriousadverse reactions of 39.2% and 28.4% in patients aged < 65. A similar incidence of serious adversereactions was seen in elderly patients in the R-CHOP treatment arm.

Among 151 previously treated DLBCL patients treated with Polivy in combination with bendamustineand rituximab (BR) in Study GO29365, 103 (68%) were ≥ 65 years of age. Patients aged ≥ 65 had asimilar 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 responddifferently from younger patients.

Serious cases of hepatic toxicity that were consistent with hepatocellular injury, including elevationsof 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 mayincrease the risk. Liver enzymes and bilirubin level should be monitored (see section 4.2).

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

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

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

Based on physiological-based pharmacokinetic (PBPK) model simulations of MMAE released frompolatuzumab vedotin, strong CYP3A4 and P-gp inhibitors (e.g., ketoconazole) may increase the areaunder the concentration-time curve (AUC) of unconjugated MMAE by 48%. Caution is advised incase of concomitant treatment with CYP3A4 inhibitor. Patients receiving concomitant strong CYP3A4inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir,posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) should be monitored moreclosely for signs of toxicities.

Unconjugated MMAE is not predicted to alter the AUC of concomitant medicines that are CYP3A4substrates (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 combinationwith polatuzumab vedotin

The pharmacokinetics (PK) of rituximab, bendamustine, cyclophosphamide, and doxorubicin are notaffected by co-administration with polatuzumab vedotin. Concomitant rituximab is associated withincreased 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 andunconjugated MMAE for Polivy plus R-CHP are in line with other studies of Polivy. No doseadjustment is required.

Bendamustine does not affect acMMAE and unconjugated MMAE plasma AUC.

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

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

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

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

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

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

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

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

* during treatment and follow-up of previously untreated DLBCL patients from the pivotalclinical 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% ofpatients 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 febrileneutropenia (10.6%) and pneumonia (5.3%).

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

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

* during treatment and follow-up of previously treated DLBCL patients (n=151) from the pivotalclinical 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 randomizedpatients (n=39) who received BR alone. Patients in the treatment arms received a median of5 cycles of treatment while randomized patients in the comparator arm received a median of3 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 BRin 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: febrileneutropenia (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 Polivyplus 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 frequencycategory 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), veryrare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness.

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

Very common pneumoniaa, upper respiratory tract infection

Common sepsisa, herpes virus infectiona, cytomegalovirus infection, urinary tractinfectionc

Very common febrile neutropenia, neutropenia, thrombocytopenia, anaemia, leukopenia

Common lymphopenia, pancytopenia

Very common hypokalaemia, decreased appetite

Common hypocalcaemia, hypoalbuminemia

Very common neuropathy peripheral

Common dizziness

Uncommon vision blurredb

Very common cough

Common pneumonitis, dyspnoeac

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

Very common alopeciac

Common pruritus, skin infectionsc, rashc, dry skinc

Musculoskeletal disorders

Common arthralgia, myalgiac

Very common pyrexia, fatigue, asthenia

Common peripheral edemac, chills

Very common weight decreased

Common transaminases increased, lipase increaseb, hypophosphataemia

Very Common infusion related reactiona ADR associated with fatal outcomeb 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 exceptwhere indicated with footnotes.

Rare and very rare ADRs: none

Description of selected adverse drug reactions

In a placebo-controlled study GO39942 (POLARIX), 0.5% of patients in the Polivy plus R-CHP armdiscontinued 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 in0.2% of patients in the Polivy plus R-CHP arm compared to no patients in the R-CHOP arm. Nopatients 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 dueto neutropenia compared to 2.6% of patients in the BR arm who discontinued treatment due toneutropenia. 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 toanaemia in either the Polivy plus BR arms or BR arm. In the Polivy plus BR arms, Grade 3 or higherneutropenia, 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, 2and 3 PN events were reported in 37.2%, 15.5% and 1.1% of patients, respectively. No Grade 4-5 PNevents were reported in either the Polivy plus R-CHP arm or R-CHOP arm. 0.7% of patientsdiscontinued 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 offirst event of PN was 2.27 months compared to 1.87 months in the R-CHOP arm. PN events resolvedin 57.8% of patients in the Polivy plus R-CHP arm as of the clinical cut off date compared to 66.9% inthe R-CHOP arm. The median time to peripheral neuropathy resolution was 4.04 months in the Polivyplus 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 werereported in 15.9% and 12.6% of patients, respectively. In the BR arm, Grade 1 and 2 PN events werereported in 2.6% and 5.1% of patients, respectively. One Grade 3 PN event was reported in the Polivyplus BR arms and no patients reported PN events in the BR arm. No Grade 4-5 PN events werereported in either the Polivy plus BR arms or BR arm. 2.6% of patients discontinued Polivy treatmentdue to PN and 2.0% of patients had Polivy dose reduction due to PN. No patients in the BR armdiscontinued treatment or had dose reductions due to PN. In the Polivy plus BR arms, the median timeto onset of first event of PN was 1.6 months, and 39.1% of patients with PN events reported eventresolution.

In a placebo-controlled study GO39942 (POLARIX), infections, including pneumonia and other typesof infections, were reported in 49.7% of patients in the Polivy plus R-CHP arm and 42.7% of patientsin the R-CHOP arm. Grade 3-4 infections occurred in 14.0% of patients in the Polivy plus R-CHP armand 11.2% of patients in the R-CHOP arm. In the Polivy plus R-CHP arm, serious infections werereported in 14.0% of patients and fatal infections were reported in 1.1% of patients. In the R-CHOParm, 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 infectioncompared to 10 patients (2.3%) in the R-CHOP arm.

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

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 treatedwith Polivy plus bendamustine and obinutuzumab. This patient had three prior lines of therapy thatincluded anti-CD20 antibodies.

In a placebo-controlled study GO39942 (POLARIX), hepatic toxicity was reported in 10.6% ofpatients 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 in76.1% 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 gastrointestinaltoxicity events were nausea and diarrhoea.

In an open-label study GO29365, gastrointestinal toxicity events were reported in 72.8% of patients inthe 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 to12.9% of patients in the BR arm. The most common gastrointestinal toxicity events were diarrhoeaand nausea.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience with overdose in human clinical trials. The highest dose tested to date is2.4 mg/kg administered as an intravenous infusion; it was associated with a higher frequency andseverity of PN events. Patients who experience overdose should have immediate interruption of theirinfusion and be closely monitored.

Pharmacotherapeutic group: antineoplastic agents; other antineoplastic agents; monoclonal antibodies

ATC code: L01FX14

Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potentanti-mitotic agent (monomethyl auristatin E, or MMAE) to B-cells, which results in the killing ofmalignant B-cells. The polatuzumab vedotin molecule consists of MMAE covalently attached to ahumanized immunoglobulin G1 monoclonal antibody via a cleavable linker. The monoclonal antibodybinds with high affinity and selectivity to CD79b, a cell surface component of the B-cell receptor.

CD79b expression is restricted to normal cells within the B-cell lineage (with the exception of plasmacells) and malignant B-cells; it is expressed in > 95% of diffuse large B-cell lymphoma. Upon binding

CD79b, polatuzumab vedotin is rapidly internalized and the linker is cleaved by lysosomal proteasesto enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells byinhibiting cell division and inducing apoptosis.

Polatuzumab vedotin did not prolong the mean QTc interval to any clinically relevant extent based on

ECG data from two open-label studies in patients with previously treated B-cell malignancies at therecommended dosage.

Previously untreated DLBCL

The efficacy of Polivy was evaluated in an international, multicenter, randomized double-blind,placebo-controlled study (POLARIX, GO39942) in 879 patients with previously untreated DLBCL.

Eligible patients were age 18-80, and had IPI score 2-5, and ECOG Performance Status 0-2.

Histologies included DLBCL (not otherwise specified (NOS), activated B-cell (ABC), germinal center

B-cell (GCB)), HGBL (NOS, double-hit, triple-hit), and other large B-cell lymphoma subtypes (EBVpositive, T-cell rich/histiocyte rich). Patients did not have known CNS lymphoma or peripheralneuropathy > Grade 1.

Patients were randomized 1:1 to receive Polivy plus R-CHP or R-CHOP for six 21-day cyclesfollowed by two additional cycles of rituximab alone in both arms. Patients were stratified by IPI score(2 vs 3-5), presence or absence of bulky disease (lesion ≥ 7.5 cm), and geographical region.

Polivy was administered intravenously at 1.8 mg/kg on Day 1 of Cycles 1-6. R-CHP or R-CHOP wereadministered starting on Day 1 of Cycles 1-6 followed by rituximab alone on Day 1 of Cycles 7-8.

Dosing in each treatment arm was administered according to the following:

* Polivy + R-CHP arm: Polivy 1.8 mg/kg, rituximab 375 mg/m², cyclophosphamide 750 mg/m²,doxorubicin 50 mg/m², and prednisone 100 mg/day, on Days 1-5 of every cycle, orally.

* R-CHOP arm: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m²,vincristine 1.4 mg/m², and prednisone 100 mg/day, on Days 1-5 of every cycle, orally.

The two treatment groups were generally balanced with respect to baseline demographics and diseasecharacteristics. The median age was 65 years (range 19 to 80 years), 53.6% of patients were white and53.8% were male, 43.8% had bulky disease, 38.0% had IPI score 2, 62.0% had IPI score 3-5, and88.7% had Stage 3 or 4 disease. The majority of patients (84.2%) had DLBCL (including NOS, ABC,and GCB).211 patients did not have a cell of origin (COO) result reported. Of the COO evaluable population(n=668), 33.1% of patients had ABC like DLBCL and 52.7% of patients had GCB like DLBCL, bygene expression profiling.

The primary endpoint of the study was investigator-assessed progression free survival. The medianduration of follow up was 28.2 months. Efficacy results are summarized in Table 5 and in Figure 1.

Table 5 Summary of efficacy in patients with previously untreated DLBCL from Study

GO39942 (POLARIX)

Polivy + R-CHP R-CHOP

N=440 N=439

Primary Endpoint

Progression free survival1,*

Number (%) of patients with events 107 (24.3%) 134 (30.5%)

HR (95% CI) 0.73 [0.57, 0.95]p-value3,** 0.01772-year PFS estimate (%) 76.7 70.2[95% CI] [72.65, 80.76] [65.80, 74.61]

Key secondary endpoints

Event-free survival (EFSeff)1

Number (%) of patients with event 112 (25.5%) 138 (31.4%)

HR [95% CI] 0.75 [0.58, 0.96]p-value3,** 0.0244

Objective Response Rate (ORR) at End of Treatment2

Responders (%) (CR, PR) 376 (85.5%) 368 (83.8%)

Difference in response rate (%) [95% CI] 1.63 [-3.32, 6.57]

Complete Response (%) (CR) Rate2,*

Responders (%) 343 (78.0%) 325 (74.0%)

Difference in response rate (%) [95% CI] 3.92 [-1.89, 9.70]

Partial response (%) (PR) 33 (7.5%) 43 (9.8%)95% CI Clopper-Pearson [5.22, 10.37] [7.18, 12.97]

INV: Investigator; BICR: Blinded independent central review; CI: Confidence interval; HR: Hazard ratio;

PFS: Progression free survival; EFSeff: Event free survival efficacy: used to reflect EFS events that are due toefficacy and defined as time from date of randomization to the earliest occurrence of any of the following:disease progression/relapse, death due to any cause, the primary efficacy reason determined by the investigator,other than disease progression/relapse, that led to initiation of any non-protocol specified anti-lymphomatreatment (NALT), if biopsy was obtained after treatment completion and was positive for residual diseaseregardless of whether NALT was initiated or not; CMH: Cochran-Mantel-Haenszel1) INV-assessed2) BICR-assessed3) Log-rank test, stratified

*Per Lugano 2014 Response Criteria

**Stratified by IPI (2 vs 3-5), presence or absence of bulky disease, geography

At the interim analysis, the key secondary endpoint of OS was immature and was not statisticallydifferent [stratified hazard ratio of 0.94 (95% CI, 0.65, 1.37); p=0.7524].

Figure 1 Kaplan Meier curve of INV-assessed progression-free survival (PFS) in Study

GO39942 (POLARIX)

Relapsed or refractory DLBCL

The efficacy of Polivy was evaluated in an international, multicentre, open-label study (GO29365)which included a randomized cohort of 80 patients with previously treated DLBCL. Patients wererandomized 1:1 to receive Polivy plus BR or BR alone for six 21-day cycles. Patients were stratifiedby duration of response to last prior treatment of ≤ 12 months or > 12 months.

Eligible patients were not candidates for autologous haematopoietic stem cell transplant (HSCT) andhad relapsed or refractory disease after receiving at least one prior systemic chemotherapy regimen.

The study excluded patients with prior allogeneic HSCT, central nervous system lymphoma,transformed indolent lymphoma, grade 3b FL, significant cardiovascular or pulmonary disease, activeinfections, AST or alanine transaminase (ALT) > 2.5 × ULN or total bilirubin ≥ 1.5 × ULN, creatinine> 1.5 × ULN (or CrCl < 40 mL/min) unless due to underlying lymphoma.

Polivy was given intravenously at 1.8 mg/kg administered on Day 2 of Cycle 1 and on Day 1 of

Cycles 2-6. Bendamustine was administered at 90 mg/m2 intravenously daily on Days 2 and 3 of

Cycle 1 and on Days 1 and 2 of Cycles 2-6. Rituximab was administered at 375 mg/m2 on Day 1 of

Cycles 1-6.

Among the 80 patients who were randomized to receive Polivy plus BR (n=40) or BR alone (n=40)the majority were white (71%) and male (66%). The median age was 69 years (range: 30-86 years).

Sixty-four out of 80 patients (80%) had ECOG performance status (PS) of 0-1 and 14 out of80 patients (18%) had ECOG PS of 2. The majority of patients (98%) had DLBCL not otherwisespecified (NOS). Overall, 48% of patients had activated B-cell (ABC) DLBCL and 40% had germinalcenter B-cell like (GCB) DLBCL. Primary reasons patients were not candidates for HSCT includedage (40%), insufficient response to salvage therapy (26%) and prior transplant failure (20%). Themedian number of prior therapies was 2 (range: 1-7), with 29% (n=23) receiving one prior therapy,25% (n=20) receiving 2 prior therapies, and 46% (n=37) receiving 3 or more prior therapies. Allexcept one patient in the pola+BR arm of the randomized Phase II were naïve to bendamustinetreatment. 80% of patients had refractory disease. For patients who received polatuzumab vedotin plus

BR and had CD3+ lymphocyte count evaluated, the absolute CD3+ lymphocyte count was> 200 cells/μL in 95%, 79% and 83% of patients analyzed at prior to therapy (n=134), end oftreatment (n=72) and 6 months after end of treatment (n=18), respectively.

The primary endpoint of the study was complete response (CR) rate at end of treatment (6-8 weeksafter Day 1 of Cycle 6 or last study treatment) as assessed by PET-CT by an Independent Review

Committee (IRC).

Table 6 Summary of efficacy in patients with previously treated DLBCL from study

GO29365

Polivy + bendamustine Bendamustine ++ rituximab rituximab

N=40 N=40

Median observation time 22 months

Primary endpoint

Complete Response Rate* (IRC-assessed) at

End of treatment**

Responders (%) 16 (40.0) 7 (17.5)

Difference in response rate (%) [95% CI] 22.5 [2.6, 40.2]p-value (CMH chi-squared test***) 0.0261

Key secondary and exploratory endpoints

Duration of response (INV-assessed)

Number of patients included in analysis 28 13

Number (%) of patients with event 17 (60.7) 11 (84.6)

Median DOR (95% CI), months 10.3 (5.6, NE) 4.1 (2.6, 12.7)

HR [95% CI] 0.44 [0.20, 0.95]p-value (Log-Rank test, stratified***) 0.0321

Overall Response Rate* (INV-assessed) at Endof Treatment**

Responders (%) (CR, PR) 19 (47.5) 7 (17.5)

Difference in response rate (%) 30.0 [9.5, 47.4][95% CI]p-value (CMH chi-squared test***) 0.0036

Complete Response (%) (CR) 17 (42.5) 6 (15.0)

Difference in response rate (%) 27.5 [7.7, 44.7][95% CI]p-value (CMH chi-squared test***) 0.0061

Partial Response (%) (PR) 2 (5.0) 1 (2.5)95% CI Clopper-Pearson [0.6, 16.9] [0.06, 13.2]

Best Overall Response Rate* (INV-assessed)

Responders (%) (CR, PR) 28 (70.0) 13 (32.5)

Difference in response rate (%) 37.5 [15.6, 54.7][95% CI]

Complete Response (%) (CR) 23 (57.5) 8 (20.0)95% CI Clopper-Pearson [40.9, 73.0] [9.1, 35.7]

Partial Response (%) (PR) 5 (12.5) 5 (12.5)95% CI Clopper-Pearson [4.2, 26.8] [4.2, 26.8]

CI: Confidence Interval; CMH: Cochran-Mantel-Haenszel; CR: Complete Response; DOR: Duration of

Response; HR: Hazard Ratio; INV: Investigator; IRC: Independent Review Committee; NE: Not evaluable; PR:

Partial Response

*Per modified Lugano 2014 criteria: Bone marrow confirmation of PET-CT CR required. PET-CT PR requiredmeeting both PET-CT criteria and CT criteria.

**6-8 weeks after Day 1 of Cycle 6 or last study treatment

*** Stratification by duration of response to prior therapy (≤ 12 months vs > 12 months)

Overall survival (OS) was an exploratory endpoint which was not type 1 error controlled. The median

OS in the Polivy plus BR arm was 12.4 months (95% CI: 9.0, NE) vs 4.7 months (95% CI: 3.7, 8.3) inthe control arm. The unadjusted estimate for OS HR was 0.42. When accounting for the influence ofbaseline covariates the OS HR was adjusted to 0.59. Covariates included primary refractory status,number of prior lines of therapy, IPI, and prior stem cell transplant.

Investigator-assessed progression free survival (PFS) was an exploratory endpoint which was nottype 1 error controlled. The median PFS in the Polivy plus BR arm was 7.6 months (95% CI: 6.0,17.0) vs 2.0 months (95% CI: 1.5, 3.7) in the control arm. The unadjusted estimate for PFS HR was0.34.

As with all therapeutic proteins, there is the potential for an immune response in patients treated withpolatuzumab vedotin. In Studies GO39442 (POLARIX) and GO29365, 1.4% (6/427) and 5.2%(12/233) of patients tested positive for antibodies against polatuzumab vedotin, respectively, of whichnone were positive for neutralizing antibodies. Due to the limited number of anti-polatuzumab vedotinantibody positive patients, no conclusions can be drawn concerning a potential effect ofimmunogenicity on efficacy or safety.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity andspecificity, assay methodology, sample handling, timing of sample collection, concomitantmedications and underlying disease. For these reasons, comparison of incidence of antibodies topolatuzumab vedotin with the incidence of antibodies to other products may be misleading.

The European Medicines Agency has waived the obligation to submit results of studies with Polivy inall subsets of the paediatric population for the treatment of mature B-cell neoplasms (see section 4.2for information on paediatric use).

Antibody-conjugated MMAE (acMMAE) plasma exposure increased dose-proportionally over the 0.1to 2.4 mg/kg polatuzumab vedotin dose range. After the first 1.8 mg/kg polatuzumab vedotin dose, theacMMAE mean maximum concentration (Cmax) was 803 (±233) ng/mL and the area under theconcentration-time curve from time zero to infinity (AUCinf) was 1860 (±966) day*ng/mL. Based onthe population PK analysis, Cycle 3 acMMAE AUC increased by approximately 30% over Cycle 1

AUC, and achieved more than 90% of the Cycle 6 AUC. The terminal half-life at Cycle 6 wasapproximately 12 days (95% CI of 8.1-19.5 days) for acMMAE. Based on population PK analysis, thepredicted acMMAE concentration at the end of Cycle 6 is approximately 80% of the theoreticalsteady-state value. Exposures of unconjugated MMAE, the cytotoxic component of polatuzumabvedotin, increased dose proportionally over the 0.1 to 2.4 mg/kg polatuzumab vedotin dose range.

MMAE plasma concentrations followed formation rate limited kinetics. After the first 1.8 mg/kgpolatuzumab vedotin dose, the Cmax was 6.82 (±4.73) ng/mL, the time to maximum plasmaconcentration is approximately 2.5 days, and the terminal half-life is approximately 4 days. Plasmaexposures of unconjugated MMAE are < 3% of acMMAE exposures. Based on the population PKanalysis there is a decrease of plasma unconjugated MMAE exposure (AUC) after repeated every-three-week dosing.

Based on population pharmacokinetics simulations, a post-hoc analysis predicted exposure tounconjugated MMAE for patients with bodyweight over 100 kg to be increased by not more than 55%.

Polivy is administered as an intravenous infusion. There have been no studies performed with otherroutes of administration.

The population estimate of central volume of distribution for acMMAE was 3.15 L, whichapproximated plasma volume. In vitro, MMAE is moderately bound (71%-77%) to human plasmaproteins. MMAE does not significantly partition into human red blood cells in vitro; the blood toplasma ratio is 0.79 to 0.98.

In vitro data indicate that MMAE is a P-gp substrate but does not inhibit P-gp at clinically relevantconcentrations.

Polatuzumab vedotin is expected to undergo catabolism in patients, resulting in the production ofsmall peptides, amino acids, unconjugated MMAE, and unconjugated MMAE related catabolites. Thelevels of MMAE metabolites have not been measured in human plasma.

In vitro studies indicate that MMAE is a substrate for CYP3A4/5 but does not induce major CYPenzymes. MMAE is a weak time-dependent inhibitor of CYP3A4/5 but does not competitively inhibit

CYP3A4/5 at clinically relevant concentrations.

MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

Based on a population PK analysis, the conjugate (acMMAE) is primarily eliminated by non-specificlinear clearance pathway with a value of 0.9 L/day. In vivo studies in rats dosed with polatuzumabvedotin (radiolabel on MMAE) demonstrate that the majority of radioactivity is excreted in faeces andthe minority of radioactivity is excreted in urine.

No studies have been conducted to investigate the pharmacokinetics of polatuzumab vedotin in thepaediatric population (<18 years old).

Age did not have an effect on the pharmacokinetics of acMMAE and unconjugated MMAE based onpopulation PK analyses with patients aged 19-89 years. No significant difference was observed in thepharmacokinetics of acMMAE and unconjugated MMAE among patients < 65 years of age (n=394)and patients ≥ 65 years of age (n=495) based on population PK analyses.

In patients with mild (CrCL 60-89 mL/min, n=361) or moderate (CrCL 30-59 mL/min, n=163) renalimpairment, acMMAE and unconjugated MMAE exposures are similar to patients with normal renalfunction (CrCL ≥ 90 mL/min, n=356), based on population PK analyses. There are insufficient data toassess the impact of severe renal impairment (CrCL 15-29 mL/min, n=4) on PK. No data are availablein patients with end-stage renal disease and/or who are on dialysis.

In patients with mild hepatic impairment [AST or ALT > 1.0 to 2.5 × ULN or total bilirubin > 1.0 to1.5 × ULN, n=133], acMMAE exposures are similar whereas unconjugated MMAE AUC are not morethan 40% higher compared to patients with normal hepatic function (n=737), based on population PKanalyses.

There are insufficient data to assess the impact of moderate hepatic impairment (total bilirubin> 1.5-3 × ULN, n=11) on PK. Limited data are available in patients with severe hepatic impairment orliver transplantation.

In both rats and cynomolgus monkeys, the predominant systemic toxicities associated withadministration of MMAE and polatuzumab vedotin included reversible bone marrow toxicity andassociated peripheral blood cell effects.

No dedicated mutagenicity studies have been performed with polatuzumab vedotin. MMAE was notmutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphomaforward mutation assay.

MMAE was genotoxic in the rat bone marrow micronucleus study probably through an aneugenicmechanism. This mechanism is consistent with the pharmacological effect of MMAE as a microtubuledisrupting agent.

No dedicated carcinogenicity studies have been performed with polatuzumab vedotin and/or MMAE.

No dedicated fertility studies in animals have been performed with polatuzumab vedotin. However,results of the 4-week rat toxicity study indicate the potential for polatuzumab vedotin to impair malereproductive function and fertility. Testicular seminiferous tubule degeneration did not reversefollowing a 6-week treatment-free period and correlated with decreased testes weight and grossfindings at recovery necropsy of small and/or soft testes in males given ≥ 2 mg/kg.

No dedicated teratogenicity studies in animals have been performed with polatuzumab vedotin.

However, treatment of pregnant rats with MMAE at 0.2 mg/kg caused embryolethality and foetalmalformations (including protruding tongue, malrotated limbs, gastroschisis, and agnathia). Systemicexposure (AUC) in rats at a dose of 0.2 mg/kg MMAE is approximately 50% of the AUC in patientswho received the recommended dose of 1.8 mg/kg Polivy every 21 days.

Succinic acid

Sodium hydroxide (for pH-adjustment)

Sucrose

Polysorbate 20 (E 432)

This medicinal product must not be mixed or diluted with other medicinal products except thosementioned in section 6.6.

Unopened vial30 months

From a microbiological point of view, the reconstituted solution should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours refrigerated (2 °C-8 °C), unless reconstitution hastaken place in controlled and validated aseptic conditions. Chemical and physical in-use stability ofthe reconstituted solution has been demonstrated for up to 72 hours refrigerated (2 °C-8 °C) and up to24 hours at room temperature (9 °C-25 °C).

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 theuser and would normally not be longer than 24 hours refrigerated (2 °C-8 °C), unless dilution hastaken place in controlled and validated aseptic conditions. Chemical and physical stability of theprepared solution for infusion has been demonstrated for the durations listed in Table 7. The dilutedsolution 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 forinfusion have been demonstrated

Diluent used to prepare solution Solution for infusionfor infusion storage conditions1

Sodium chloride 9 mg/mL (0.9%) Up to 72 hours refrigerated (2 °C − 8 °C) orup 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) orup to 8 hours at room temperature (9 °C − 25 °C)5% glucose Up to 72 hours refrigerated (2 °C − 8 °C) orup 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 aluminiumseal 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 aluminiumseal 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 physicianexperienced in the use of cytotoxic agents. Procedures for proper handling and disposal ofantineoplastic and cytotoxic medicines should be used.

The reconstituted product contains no preservative and is intended for single-dose only. Proper aseptictechnique throughout the handling of this medicinal product should be followed.

Polivy must be reconstituted using sterile water for injection and diluted into an intravenous infusionbag 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.

* Polivy 30 mg: Using a sterile syringe, slowly inject 1.8 mL of sterile water for injection into the30 mg Polivy vial to yield a single-dose solution containing 20 mg/mL polatuzumab vedotin.

Direct the stream toward the wall of the vial and not directly on the lyophilized cake.

* Polivy 140 mg: Using a sterile syringe, slowly inject 7.2 mL of sterile water for injection intothe 140 mg Polivy vial to yield a single-dose solution containing 20 mg/mL polatuzumabvedotin. Direct the stream toward the wall of the vial and not directly on the lyophilized cake.

* Swirl the vial gently until completely dissolved. Do not shake.

* Inspect the reconstituted solution for discoloration and particulate matter. The reconstitutedsolution should appear colourless to slightly brown, clear to slightly opalescent, and free ofvisible particulates. Do not use if the reconstituted solution is discoloured, is cloudy, or containsvisible particulates.

Instructions for dilution1. Polivy must be diluted to a final concentration of 0.72-2.7 mg/mL in an intravenous infusionbag, with a minimum volume of 50 mL, containing 9 mg/mL sodium chloride solution forinjection, 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 sterilesyringe 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 transportationto 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 totalstorage plus transportation times of the diluted product should not exceed the storage durationspecified 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 polyvinylchloride (PVC) or polyolefins such as polyethylene (PE) and polypropylene. In addition, noincompatibilities have been observed with infusion sets or infusion aids with product contactingmaterials of PVC, PE, polyurethane, polybutadiene, acrylonitrile butadiene styrene, polycarbonate,polyetherurethane, fluorinated ethylene propylene, or polytetrafluorethylene and with filtermembranes 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.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/19/1388/001

EU/1/19/1388/002

Date of first authorisation: 16 January 2020

Date of latest renewal: 03 December 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.