Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
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 number of 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 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).
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).
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.
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 not been conducted in patients who recently received live vaccines.
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.
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.
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).
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).
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).
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.
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).
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
No dedicated clinical drug-drug interaction studies with polatuzumab vedotin in humans have been conducted.
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.
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.
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.
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.
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.
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.
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.
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).
The safety of Polivy has been evaluated in 435 patients in Study GO39942 (POLARIX). The ADRs described in section 4.8 were identified:
In previously untreated DLBCL patients treated with Polivy plus R-CHP:
The safety of Polivy has been evaluated in 151 patients in Study GO29365. The ADRs described in section 4.8 were identified:
In previously treated DLBCL patients treated with Polivy plus BR:
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 |
| Investigations | |
| Very common | weight decreased |
| Common | transaminases increased, lipase increaseb, hypophosphataemia |
| 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
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 RCHOP 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.
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 RCHOP 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.
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.
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.
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 RCHP 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.
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 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 via the national reporting system listed in Appendix V.
This medicinal product must not be mixed or diluted with other medicinal products except those mentioned in section 6.6.
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