Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

The safety of Polivy has been evaluated in 435 patients in Study GO39942 (POLARIX). The ADRs described in section 4.8 were identified:
•     during treatment and follow-up of previously untreated DLBCL patients from the pivotal clinical trial GO39942 (POLARIX), who received Polivy plus R-CHP (n=435) or R-CHOP (n=438). In the Polivy plus R-CHP group, 91.7% received 6 cycles of Polivy versus 88.5% of patients who received 6 cycles of vincristine in the R-CHOP group.

In previously untreated DLBCL patients treated with Polivy plus R-CHP:
•     The most frequently-reported (≥ 30%) adverse drug reactions (ADRs) in patients treated with Polivy plus R-CHP for previously untreated DLBCL were neuropathy peripheral (52.9%), nausea (41.6%), neutropenia (38.4%), and diarrhoea (30.8%).
•     Serious adverse reactions were reported in 24.1% of Polivy plus R-CHP treated patients.
•     The most common serious adverse reactions reported in ≥ 5% of patients were febrile neutropenia (10.6%) and pneumonia (5.3%).
•     The ADRs leading to treatment regimen discontinuation in > 1% of patients treated with Polivy plus R-CHP was pneumonia (1.1%).

The safety of Polivy has been evaluated in 151 patients in Study GO29365. The ADRs described in section 4.8 were identified:
•      during treatment and follow-up of previously treated DLBCL patients (n=151) from the pivotal clinical trial GO29365. This includes run-in phase patients (n=6), randomized patients (n=39), and extension cohort patients (n=106) who received Polivy plus BR compared to randomized patients (n=39) who received BR alone. Patients in the treatment arms received a median of 5 cycles of treatment while randomized patients in the comparator arm received a median of 3 cycles of treatment.

In previously treated DLBCL patients treated with Polivy plus BR:
•     The most frequently reported (≥ 30%) ADRs (all grades) in patients treated with Polivy plus BR in previously treated DLBCL were neutropenia (45.7%), diarrhoea (35.8%), nausea (33.1%), thrombocytopenia (32.5%), anaemia (31.8%) and neuropathy peripheral (30.5%).
•     Serious adverse reactions were reported in 41.7% of Polivy plus BR treated patients.
•     The most common serious adverse reactions reported in ≥ 5% of patients were: febrile neutropenia (10.6%), sepsis (9.9%), pneumonia (8.6%) and pyrexia (7.9%).
•     The ADR leading to treatment regimen discontinuation in > 5% of patients treated with Polivy plus BR was thrombocytopenia (7.9%).

Tabulated list of ADRs from clinical trials

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


Table 4       Tabulated list of ADRs in patients treated with Polivy in clinical trials 
Infections and infestations
Very common           pneumonia a, 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, dyspnoea c
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 edema c, 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

Description of selected adverse drug reactions

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

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

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

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

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

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

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

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

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

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

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

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: sideeffects.health.gov.il/