DRUG INTERACTIONS-

1. Effects of Other Drugs on POLIVY 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.

ADVERSE REACTIONS

 The most common adverse reactions (=20%) included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.

• Infusion-Related Reactions: Premedicate with an antihistamine and antipyretic. Monitor patients closely during infusions. Interrupt or discontinue infusion for reactions.

 • Myelosuppression: Monitor complete blood counts. Manage using dose delays or reductions and growth factor support. Monitor for signs of infection.

 • Serious and Opportunistic Infections: Closely monitor patients for signs of bacterial, fungal, or viral infections.

 • Progressive Multifocal Leukoencephalopathy (PML): Monitor patients for new or worsening neurological, cognitive, or behavioral changes suggestive of PML.

 • Tumor Lysis Syndrome: Closely monitor patients with high tumor burden or rapidly proliferative tumors.

 • Hepatotoxicity: Monitor liver enzymes and bilirubin.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 3 months after the last dose.

 PATIENT COUNSELING INFORMATION

Peripheral Neuropathy

Advise patients that POLIVY can cause peripheral neuropathy.

Advise patients to report to their healthcare provider any numbness or tingling of the hands or feet or any muscle weakness 

Infusion-Related Reactions

Advise patients to contact their healthcare provider if they experience signs and symptoms of infusion reactions including fever, chills, rash or breathing problems within 24 hours of infusion 

Myelosuppression

Advise patients to report signs or symptoms of bleeding or infection immediately. Advise patients of the need for periodic monitoring of blood counts 

Infections

Advise patients to contact their healthcare provider if a fever of 38°C (100.4°F) or greater or other evidence of potential infection such as chills, cough, or pain on urination develops.

Advise patients of the need for periodic monitoring of blood counts 

Progressive Multifocal Leukoencephalopathy

Advise patients to seek immediate medical attention for new or changes in neurological symptoms such as confusion, dizziness, or loss of balance; difficulty talking or walking; or changes in vision 

Tumor Lysis Syndrome

Advise patients to seek immediate medical attention for symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy 

Hepatotoxicity

Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice 

Advise females of reproductive potential of the potential risk to a fetus.

Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with POLIVY 

Females and Males of Reproductive Potential

Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with POLIVY and for at least 3 months and 5 months after the last dose, respectively 

Lactation

Advise women not to breastfeed while receiving POLIVY and for at 2 months after the last dose

Manufactured by:

Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

 CLINICAL PHARMACOLOGY

1 Mechanism of Action

Polatuzumab vedotin-piiq is a CD79b-directed antibody-drug conjugate with activity against dividing B cells. The small molecule, MMAE is an anti-mitotic agent covalently attached to the antibody via a cleavable linker.

2. Pharmacodynamics

Over polatuzumab vedotin-piiq dosages of 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approved recommended dosage), a higher exposure was associated with higher incidence of some adverse reactions (e.g., =Grade 2 peripheral neuropathy, =Grade 3 anemia) and a lower exposure was associated with lower efficacy.

Cardiac Electrophysiology

Polatuzumab vedotin-piiq did not prolong the mean QTc interval to any clinically relevant extent based on ECG data from two open-label studies in patients with previously treated B-cell malignancies at the recommended dosage.

3. Pharmacokinetics

The exposure parameters of antibody-conjugated MMAE (acMMAE) and unconjugated MMAE (the cytotoxic component of polatuzumab vedotin-piiq) are summarized. 

The plasma exposure of acMMAE and unconjugated MMAE increased proportionally over a polatuzumab vedotin-piiq dose range from 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approved recommended dosage).

Distribution

The acMMAE central volume of distribution estimated based on population PK analysis is 3.15 L. For human, MMAE plasma protein binding is 71% to 77% and the blood to plasma ratio is 0.79 to 0.98, in vitro.

Elimination

The acMMAE terminal half-life is approximately 12 days (95% CI: 8.1 to 19.5 days) at Cycle 6 with predicted clearance of 0.9 L/day. The unconjugated MMAE terminal half-life is approximately 4 days after the first polatuzumab vedotin-piiq dose.

Metabolism

Polatuzumab vedotin-piiq catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. MMAE is a substrate for CYP3A4.

Specific Populations

No clinically significant differences in the pharmacokinetics of polatuzumab vedotin-piiq were observed based on age (20 to 89 years), sex, or race/ethnicity (Asian and non-Asian).

No clinically significant differences in the pharmacokinetics of acMMAE or unconjugated MMAE were observed based on mild to moderate renal impairment (CLcr 30 to 89 mL/min).

In mild hepatic impairment (AST or ALT >1.0 to 2.5 × ULN or total bilirubin >1.0 to 1.5 × ULN), there was a 40% increase in MMAE exposure, which was not deemed clinically significant.

The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease with or without dialysis, moderate to severe hepatic impairment (AST or ALT >2.5 × ULN or total bilirubin >1.5 × ULN), or liver transplantation on the pharmacokinetics of acMMAE or unconjugated MMAE is unknown.

Drug Interaction Studies

No dedicated clinical drug–drug interaction studies with POLIVY in humans have been conducted.

Strong CYP3A Inhibitor:

Concomitant use of polatuzumab vedotin-piiq with ketoconazole (strong CYP3A inhibitor) is predicted to increase unconjugated MMAE AUC by 45%.

Strong CYP3A Inducer:

Concomitant use of polatuzumab vedotin-piiq with rifampin (strong CYP3A inducer) is predicted to decrease unconjugated MMAE AUC by 63%.

Sensitive CYP3A substrate:

Concomitant use of polatuzumab vedotin-piiq is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate).

Cytochrome P450 (CYP) Enzymes:

MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. MMAE does not induce major CYP enzymes. 

Transporter Systems:

MMAE does not inhibit P-gp. MMAE is a P-gp substrate.

1. Pregnancy Risk Summary-

Based on findings from animal studies and its mechanism of action], POLIVY can cause fetal harm.

Advise a pregnant woman of the potential risks to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

2. Lactation Risk Summary-                                                                                          There is no information regarding the presence of polatuzumab vedotin-piiq in human milk, the effects on the breastfed child, or milk production.

Because of the potential for serious adverse Reference ID: 4446006 reactions in a breastfed children, advise women not to breastfeed during treatment with POLIVY and for at least 2 months after the last dose.

3. Females and Males of Reproductive Potential -

Pregnancy Testing- Verify pregnancy status in females of reproductive potential prior to initiating POLIVY 

Contraception- Females-                                                                                             POLIVY can cause embryo-fetal harm when administered to pregnant women.

Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the final dose ..

Males -                                                                                                                        Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for at least 5 months after the final dose.

Infertility-                                                                                                                        Based on findings from animal studies, POLIVY may impair male fertility. The reversibility of this effect is unknown.

4 Pediatric Use-

Safety and effectiveness of POLIVY have not been established in pediatric patients.

5. Geriatric Use -                                                                                                          Among 173 patients treated with POLIVY in Study GO29365, 95 (55%) were =65 years of age. Patients aged =65 had a numerically higher incidence of serious adverse reactions (64%) than patients aged <65 (53%).

Clinical studies of POLIVY did not include sufficient numbers of patients aged =65 to determine whether they respond differently from younger patients.

6. Hepatic Impairment-                                                                                                 Avoid the administration of POLIVY in patients with moderate or severe hepatic impairment (bilirubin greater than 1.5 × ULN). Patients with moderate or severe hepatic impairment are likely to have increased exposure to MMAE, which may increase the risk of adverse reactions.

POLIVY has not been studied in patients with moderate or severe hepatic impairment 

No adjustment in the starting dose is required when administering POLIVY to patients with mild hepatic impairment (bilirubin greater than ULN to less than or equal to 1.5 × ULN or AST greater than ULN).