Polivy · 4.1 Therapeutic indications · 1

HOS-098853 · has-adverse-reaction-information · PDF-Seite 11

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), randomised patients (n=39), and extension cohort patients (n=106) who received Polivy plus BR compared to randomised patients (n=39) who received BR alone. Patients in the treatment arms received a median of 5 cycles of treatment while randomised 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 treatmen

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HOS-098849 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active severe infections (see section 4.4).

HOS-098848 · has-indication-information · PDF-Seite 2

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.

HOS-098851 · has-interaction-information · PDF-Seite 9

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). 9 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.

HOS-098852 · has-pregnancy-information · PDF-Seite 10

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.

HOS-098850 · has-warning-information · PDF-Seite 7

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, 7 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

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