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POLIVY® Safety

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Adverse Reactions
Dose Reduction & Discontinuation Rates
Drug Interactions

The majority of adverse reactions ≥10% were generally comparable across treatment arms1,*

*Adverse reactions with ≥5% difference in all grades or grade ≥3 include (POLIVY + R-CHP vs R-CHOP): diarrhea (all grades: 31% vs 20%; grade ≥3: 3.9% vs 1.8%), febrile neutropenia (all grades and grade ≥3: 15% vs 9%), and nausea (all grades: 42% vs 37%; grade ≥3: 1.1% vs 0.5%).
Most common adverse reactions in ≥20% of patients
  • The rates of peripheral neuropathy between the POLIVY + R-CHP vs R-CHOP arms were 53% vs 54%, respectively1
  • The rates of febrile neutropenia between the POLIVY + R-CHP vs R-CHOP arms were 15% and 9% respectively (for all grades and grade ≥ 3)1
  • The rates of grade 3-4 infections were comparable between POLIVY + R-CHP vs R-CHOP arms (14% vs 11%)19
  • Serious ARs occurred in 34% of patients who received POLIVY + R-CHP vs 30.6% of patients who received R-CHOP1,15
  • Serious ARs in ≥5% of patients who received POLIVY + R-CHP included febrile neutropenia and pneumonia1
  • Fatal ARs within 90 days of last treatment occurred in 3% of patients who received POLIVY + R-CHP vs 2.3% of patients who received R-CHOP. These were primarily from infection, including pneumonia (0.9% and 0.7%, respectively) and sepsis (0.2% and 0.7%, respectively) in the POLIVY + R-CHP vs R-CHOP arms1,15
  • New or worsening Grade 3 to 4 laboratory abnormalities in ≥10% of patients were lymphopenia, neutropenia, hyperuricemia, and anemia1

Select adverse reactions occurring in ≥10% of patients treated with POLIVY + R-CHP in POLARIX1

  POLIVY + R-CHP (n=435) R-CHOP (n=438)

 

 All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Blood and lymphatic system disorders†
Lymphopenia 80 44 77 44
Anemia 68 14 67 11
Neutropenia 60 39 60 42
Thrombocytopenia 32 8 33 6
Febrile neutropenia‡ 15 15 9 9
Investigations†
Creatinine increased 66 0.7 64 0.9
Aspartate aminotransferase increased 26 0.7 23 1.1
Alanine aminotransferase increased 25 1.4 27 0.5
Alkaline phosphatase increased 23 0 22 0.5
Uric acid increased 19 18 17 16
Weight decreased 13 0.9 12 0.2
Nervous system disorders
Peripheral neuropathy§,‖ 53 1.6 54 1.1
Altered taste 14 0 16 0
Headache 13 0.2 14 0.9
Gastrointestinal disorders
Nausea 42 1.1 37 0.5
Diarrhea 31 3.9 20 1.8
Constipation 29 1.1 29 0.2
Mucositis 22 1.4 19 0.5
Abdominal pain# 16 1.1 14 1.6
Vomiting 15 1.1 14 0.7
General disorders
Fatigue 37 2.5 38 3.0
Pyrexia 16 1.4 13 0
Edema** 14 0.5 11 0.2
Infusion-related reaction†† 13 1.1 16 1.6
Skin and subcutaneous tissue disorders
Alopecia 24 0 24 0.2
Rash‡‡ 13 0.7 11 0
Musculoskeletal disorders
Musculoskeletal pain§§ 19 0.5 21 1.8
Infections
Upper respiratory tract infection‖‖ 17 0.5 16 0.5
Metabolism and nutrition disorders
Decreased Appetite 17 1.1 14 0.7
Respiratory disorders
Cough 15 0 14 0
Dyspnea 13 0.9 10 0.9

This table includes a combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.0.
†Laboratory values are based on integrated analysis of laboratory and adverse reaction data. Reported investigations exclude electrolytes.
‡Febrile neutropenia includes febrile neutropenia, febrile bone marrow aplasia, and neutropenic sepsis.
§At last assessment, peripheral neuropathy was unresolved in 42% in the POLIVY + R-CHP arm and in 33%in the R-CHOP arm.
‖Peripheral neuropathy includes all terms containing “neuropathy”, neuralgia, dysesthesia, paresthesia, hypoesthesia, peroneal nerve palsy, hypotonia, hyporeflexia, neuromyopathy, and hyperesthesia.
Mucositis includes stomatitis, oropharyngeal pain, mucosal inflammation, mouth ulceration, oral pain, oropharyngeal discomfort, aphthous ulcer, odynophagia, oral discomfort, tongue blistering, and tongue ulceration.
#Abdominal pain includes abdominal pain, abdominal discomfort, gastrointestinal pain, epigastric discomfort, and related terms.
**Edema includes edema, face edema, swelling face, edema peripheral, fluid overload, fluid retention, pulmonary edema, peripheral swelling, and swelling.
††Infusion related reaction is reflective of the combination regimen due to same-day administration.
‡‡Rash includes rash, dermatitis, and related terms.
§§Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, myalgia, and bone pain.
‖‖Upper respiratory tract infection incudes sinusitis, laryngitis, pharyngitis, nasopharyngitis, rhinitis, and specific infections.

Other clinically relevant adverse reactions in <10% of patients who received POLIVY + R-CHP included pneumonia, herpesvirus infection, sepsis, cytomegalovirus infection, tumor lysis syndrome, renal insufficiency, and pneumonitis.

Dose reductions & discontinuation rates with POLIVY + R-CHP vs R-CHOP1,15,19

  POLIVY (n=435) Vincristine (n=438)
ARs leading to dose reduction 6% 10.3%
ARs leading to permanent discontinuation 4.4% 5%
ARs leading to dose interruption 18% 15.3%
More patients received 6 cycles of POLIVY vs vincristine (92% vs 89%)15

Drug interactions

Strong CYP3A inhibitors
  • Concomitant use with a strong CYP3A4 inhibitor may increase unconjugated MMAE AUC, which may increase POLIVY toxicities. Monitor patients for signs of toxicity
Strong CYP3A inducers
  • Concomitant use with a strong CYP3A4 inducer may decrease unconjugated MMAE AUC

AR = adverse reaction; AUC = area under the construction-time curve; CYP3A = cytochrome P450 family 3 subfamily A; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.

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NEXT: Important Safety Information
Important Safety Information and Indication

Indication

POLIVY in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) is indicated for the treatment of adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index score of 2 or greater.

POLIVY in combination with bendamustine and a rituximab product (BR) is indicated for the treatment of adult patients with relapsed or refractory DLBCL, NOS, after at least two prior therapies.

Important Safety Information

Peripheral Neuropathy

POLIVY can cause severe peripheral neuropathy. Peripheral neuropathy occurs as early as the first cycle of treatment and is cumulative. POLIVY may exacerbate preexisting peripheral neuropathy.

In POLARIX, of 435 patients treated with POLIVY plus R-CHP, 53% reported new or worsening peripheral neuropathy, with a median time to onset of 2.3 months. Peripheral neuropathy was Grade 1 in 39% of patients, Grade 2 in 12%, and Grade 3 in 1.6%. Peripheral neuropathy resulted in dose reduction in 4% of treated patients and treatment discontinuation in 0.7%. Among patients with peripheral neuropathy after POLIVY, 58% reported resolution after a median of 4 months.

In Study GO29365, of 173 patients treated with POLIVY, 40% reported new or worsening peripheral neuropathy, with a median time to onset of 2.1 months. Peripheral neuropathy was Grade 1 in 26% of patients, Grade 2 in 12%, and Grade 3 in 2.3%. Peripheral neuropathy resulted in POLIVY dose reduction in 2.9% of treated patients, dose delay in 1.2%, and permanent discontinuation in 2.9%. Sixty-five percent of patients reported improvement or resolution of peripheral neuropathy after a median of 1 month, and 48% reported complete resolution.

The peripheral neuropathy is predominantly sensory; however, motor and sensorimotor peripheral neuropathy also occur. Monitor for symptoms of peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, or gait disturbance. Patients experiencing new or worsening peripheral neuropathy may require a delay, dose reduction, or discontinuation of POLIVY.

Infusion-Related Reactions

POLIVY can cause severe infusion reactions. Delayed infusion-related reactions as late as 24 hours after receiving POLIVY have occurred.

With premedication, 13% of patients (58/435) in POLARIX reported infusion-related reactions after the administration of POLIVY plus R-CHP. The reactions were Grade 1 in 4.4% of patients, Grade 2 in 8%, and Grade 3 in 1.1%.

With premedication, 7% of patients (12/173) in Study GO29365 reported infusion-related reactions after the administration of POLIVY. The reactions were Grade 1 in 4.6% of patients, Grade 2 in 1.7%, and Grade 3 in 0.6%.

Symptoms occurring in ≥1% of patients included chills, dyspnea, pyrexia, pruritus, rash, and chest discomfort. Administer an antihistamine and antipyretic prior to the administration of POLIVY, and monitor patients closely throughout the infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management.

Myelosuppression

Treatment with POLIVY can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia.

In POLARIX, 90% of patients treated with POLIVY plus R-CHP had primary prophylaxis with granulocyte colony-stimulating factor (G-CSF). Grade 3–4 hematologic adverse reactions included lymphopenia (44%), neutropenia (39%), febrile neutropenia (15%), anemia (14%), and thrombocytopenia (8%).

In Study GO29365, in patients treated with POLIVY plus BR (n = 45), 42% received primary prophylaxis with G-CSF. Grade 3 or higher hematologic adverse reactions included neutropenia (42%), thrombocytopenia (40%), anemia (24%), lymphopenia (13%), and febrile neutropenia (11%). Grade 4 hematologic adverse reactions included neutropenia (24%), thrombocytopenia (16%), lymphopenia (9%), and febrile neutropenia (4.4%). Cytopenias were the most common reason for treatment discontinuation (18% of all patients).

Monitor complete blood counts throughout treatment. Cytopenias may require a delay, dose reduction, or discontinuation of POLIVY. Administer prophylactic G-CSF for neutropenia in patients receiving POLIVY plus R-CHP. Consider prophylactic G-CSF administration in patients receiving POLIVY plus bendamustine and a rituximab product.

Serious and Opportunistic Infections

Fatal and/or serious infections, including opportunistic infections such as sepsis, pneumonia (including Pneumocystis jiroveci and other fungal pneumonia), herpesvirus infection, and cytomegalovirus infection have occurred in patients treated with POLIVY.

In POLARIX, Grade 3–4 infections occurred in 14% (61/435) of patients treated with POLIVY plus R-CHP, and infection-related deaths were reported in 1.1% of patients.

In Study GO29365, Grade 3 or higher infections occurred in 32% (55/173) of patients treated with POLIVY, and infection-related deaths were reported in 2.9% of patients within 90 days of last treatment.

Closely monitor patients during treatment for signs of infection. Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus. Administer prophylactic G-CSF for neutropenia as recommended.

Progressive Multifocal Leukoencephalopathy (PML)

PML has been reported after treatment with POLIVY plus bendamustine and obinutuzumab in Study GO29365 (0.6%, 1/173). Monitor for new or worsening neurological, cognitive, or behavioral changes. Hold POLIVY and any concomitant chemotherapy if PML is suspected, and permanently discontinue if the diagnosis is confirmed.

Tumor Lysis Syndrome

POLIVY may cause tumor lysis syndrome. Patients with high tumor burden and rapidly proliferative tumor may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures, including tumor lysis syndrome prophylaxis.

Hepatotoxicity

Serious cases of hepatotoxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with POLIVY.

In recipients of POLIVY plus R-CHP, Grade 3–4 elevation of ALT and AST developed in 1.4% and 0.7% of patients, respectively.

In Study GO29365, Grade 3 and Grade 4 transaminase elevations each developed in 1.9% of patients.

Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk of hepatotoxicity. Monitor liver enzymes and bilirubin level.

Embryo-Fetal Toxicity

Based on the mechanism of action and findings from animal studies, POLIVY can cause fetal harm when administered to a pregnant woman. The small molecule component of POLIVY, monomethyl auristatin E, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for 5 months after the last dose.

The Most Common Adverse Reactions

The most common adverse reactions (≥20%), excluding laboratory abnormalities, in patients with previously untreated DLBCL treated with POLIVY in combination with R-CHP are peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. The most common Grade 3 to 4 laboratory abnormalities (≥10%) are lymphopenia, neutropenia, hyperuricemia, and anemia.

The most common adverse reactions (≥20%) in patients with relapsed or refractory DLBCL treated with POLIVY in combination with BR are neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.

Lactation

Advise women not to breastfeed during treatment with POLIVY and for 2 months after the last dose.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.
Please see the full Prescribing Information for additional Important Safety Information.

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