Polatuzumab vedotin interacts in the following cases:
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.
Strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, St John’s wort [Hypericum perforatum]) may decrease the exposure of unconjugated MMAE.
A recommended dose has not been determined for patients with CrCL <30mL/min due to limited data.
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 polatuzumab vedotin. Patients should be monitored closely for TLS during treatment with polatuzumab vedotin.
There are no data in pregnant women using polatuzumab vedotin. Studies in animals have shown reproductive toxicity. 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. Polatuzumab vedotin 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 polatuzumab vedotin and for at least 3 months after the last dose.
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.
In nonclinical studies, polatuzumab vedotin has resulted in testicular toxicity, and may impair male reproductive function and fertility.
Therefore, men being treated with this medicine are advised to have sperm samples preserved and stored before treatment. Men being treated with polatuzumab vedotin are advised not to father a child during treatment and for up to 6 months following the last dose.
Polatuzumab vedotin has minor influence on the ability to drive and use machines. IRRs, PN, fatigue, and dizziness may occur during treatment with polatuzumab vedotin.
The safety of polatuzumab vedotin has been evaluated in 435 patients in Study GO39942 (POLARIX). The ADRs described were identified:
In previously untreated DLBCL patients treated with polatuzumab vedotin plus R-CHP:
The safety of polatuzumab vedotin has been evaluated in 151 patients in Study GO29365. The ADRs described were identified:
In previously treated DLBCL patients treated with polatuzumab vedotin plus BR:
The ADRs in 586 patients treated with polatuzumab vedotin are presented in the table below. 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.
Tabulated list of ADRs in patients treated with polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin plus R-CHP arm compared to no patients in the R-CHOP arm. No patients discontinued treatment due to anaemia in either the polatuzumab vedotin plus R-CHP arm or R-CHOP arm.
In an open-label study GO29365, 4% of patients in the polatuzumab vedotin plus BR arms discontinued polatuzumab vedotin 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 polatuzumab vedotin plus BR arms and 5.1% of patients in the BR arm. No patients discontinued treatment due to anaemia in either the polatuzumab vedotin plus BR arms or BR arm. In the polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin plus R-CHP arm or R-CHOP arm. 0.7% of patients discontinued study treatment in the polatuzumab vedotin plus R-CHP arm due to PN compared to 2.3% in the RCHOP arm. 4.6% of patients in the polatuzumab vedotin plus R-CHP arm had study treatment dose reduction due to PN compared to 8.2% in the R-CHOP arm. In the polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin plus R-CHP arm compared to 4.6 months in the R-CHOP arm.
In an open-label study GO29365, in the polatuzumab vedotin 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 polatuzumab vedotin plus BR arms and no patients reported PN events in the BR arm. No Grade 4-5 PN events were reported in either the polatuzumab vedotin plus BR arms or BR arm. 2.6% of patients discontinued polatuzumab vedotin treatment due to PN and 2.0% of patients had polatuzumab vedotin dose reduction due to PN. No patients in the BR arm discontinued treatment or had dose reductions due to PN. In the polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin plus R-CHP arm and 11.2% of patients in the R-CHOP arm. In the polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin plus BR arms and 51.3% of patients in the BR arm. In the polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin plus R-CHP arm and 7.3% of patients in the R-CHOP arm. In the polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin 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 polatuzumab vedotin plus BR arms compared to 12.9% of patients in the BR arm. The most common gastrointestinal toxicity events were diarrhoea and nausea.
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