Bavencio Drug Information

Premedication

Premedicate patients with an antihistamine and with acetaminophen prior to the first 4 infusions of BAVENCIO. Premedication should be administered for subsequent BAVENCIO doses based upon clinical judgment and presence/severity of prior infusion reactions.

Recommended Dosage for MCC

The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Recommended Dosage for RCC

When axitinib is used in combination with BAVENCIO, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of two weeks or longer. Review the Full Prescribing Information for axitinib prior to initiation.

Dose Modifications

No dose reduction for BAVENCIO is recommended. In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.

Dosage modifications for BAVENCIO for adverse reactions that require management different from these general guidelines are summarized in Table 1. Table 1: Recommended Monotherapy Table 2 presents dosage modifications that are different from those described above in Table 1 for BAVENCIO used as monotherapy or in the Full Prescribing Information for the drug administered in combination. Table 2: Recommended Specific

Preparation and Administration Preparation

Visually inspect vial for particulate matter and discoloration. BAVENCIO is a clear, colorless to slightly yellow solution. Discard vial if the solution is cloudy, discolored, or contains particulate matter.

Withdraw the required volume of BAVENCIO from the vial(s) and inject it into a 250 mL infusion bag containing either 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection. Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing. Inspect the solution to ensure it is clear, colorless, and free of visible particles.

Discard any partially used or empty vials. Storage of diluted BAVENCIO solution Protect from light. Store diluted BAVENCIO solution: At room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution.

Or Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not freeze or shake diluted solution.

Administration Administer the diluted solution over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron). Do not co-administer other drugs through the same intravenous line.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The population characteristics of BAVENCIO in combination with axitinib are shown below. The following criteria were used to classify an adverse reaction as immune-mediated: onset within 90 days after last dose of BAVENCIO, no spontaneous resolution within 7 days of onset, treatment with corticosteroids or other immunosuppressant or hormone replacement therapy, biopsy consistent with immune-mediated reaction, and no other clear etiology.

Metastatic Merkel Cell Carcinoma The safety of BAVENCIO was evaluated in 204 patients enrolled in the JAVELIN Merkel 200 trial with metastatic MCC. The median duration of exposure to BAVENCIO was 4.1 months (range: 2 weeks to 48 months). Serious adverse reactions occurred in 52% of patients receiving BAVENCIO.

The most frequent serious adverse reactions (≥ 2% of patients) were general physical health deterioration, anemia, abdominal pain, acute kidney injury, sepsis, hyponatremia, and infusion-related reaction. Permanent discontinuation of BAVENCIO due to an adverse reaction occurred in 27% of patients. The most frequent adverse reactions (> 1% of patients) that resulted in permanent discontinuation were infusion-related reaction, anemia, increased ALT, and increased AST.

Dosage interruptions of BAVENCIO due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 29% of patients. The most frequent adverse reactions (> 1% of patients) that required dosage interruption were nasopharyngitis, anemia, diarrhea, lung infection, and ALT increased. The most common adverse reactions (≥ 20%) that occurred in patients receiving BAVENCIO were fatigue, musculoskeletal pain, infusion-related reaction, rash, nausea, constipation, cough, and diarrhea.

Table 3 and Table 4 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving BAVENCIO. Table 3: Adverse Reactions in ≥ 10% of Patients with Metastatic MCC Receiving BAVENCIO in the JAVELIN Merkel 6 Other clinically significant adverse reactions in < 10% of patients receiving BAVENCIO in the JAVELIN Merkel 200 trial were dizziness, headache, transaminase increased, creatine phosphokinase increased, and tubulointerstitial nephritis. Table 4: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with Metastatic MCC Receiving BAVENCIO in the JAVELIN Merkel 5 Locally Advanced or Metastatic Urothelial Carcinoma First-Line Maintenance Treatment of Urothelial Carcinoma The safety of BAVENCIO was evaluated in the JAVELIN Bladder 100 trial where patients received BAVENCIO 10 mg/kg every 2 weeks plus best supportive care (BSC) (N=344) or BSC alone (N=345).

Patients with autoimmune diseases or conditions requiring systemic immunosuppression were excluded. A fatal adverse reaction (sepsis) occurred in one (0.3%) patient receiving BAVENCIO plus BSC. Adverse reactions resulting in permanent discontinuation of BAVENCIO in > 1% of patients were myocardial infarction (including acute myocardial infarction and troponin T increased) (1.5%) and infusion-related reaction (1.2%).

Dose interruptions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 41% of patients receiving BAVENCIO plus BSC. Adverse reactions leading to interruption of BAVENCIO in > 2% of patients were urinary tract infection (including pyelonephritis) (4.7%) and blood creatinine increased (including acute kidney injury, renal impairment, and renal failure) (3.8%). The most common adverse reactions (≥ 20%) in patients receiving BAVENCIO plus BSC were fatigue, musculoskeletal pain, urinary tract infection, and rash.

Thirty-one (9%) patients treated with BAVENCIO plus BSC received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction. Infusion-related reactions occurred in 10% (Grade 3: 0.9%) of patients treated with BAVENCIO plus BSC. Table 6: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥ Previously-treated Urothelial Carcinoma The safety of BAVENCIO was evaluated in 242 patients with locally advanced or metastatic UC receiving BAVENCIO at 10 mg/kg every 2 weeks in the UC cohorts of the JAVELIN Solid Tumor trial.

Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. The median duration of exposure to BAVENCIO was 12 weeks (range: 2 weeks to 92 weeks). Fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.

Grade 1-4 serious adverse reactions were reported in 41% of patients. The most frequent serious adverse reactions reported in ≥ 2% of patients were urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestine obstruction, and pyrexia. The adverse reaction that resulted in permanent discontinuation in > 1% of patients was fatigue.

Adverse reactions leading to interruption of BAVENCIO in > 1% of patients were diarrhea, fatigue, dyspnea, urinary tract infection, and rash. The most common Grade 3 and 4 adverse reactions (≥ 3%) were anemia, fatigue, hyponatremia, hypertension, urinary tract infection, and musculoskeletal pain. The most common adverse reactions (≥ 20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Eleven (4.5%) patients received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction. Advanced Renal Cell Carcinoma The safety of BAVENCIO was evaluated in JAVELIN Renal 101. Patients with autoimmune disease other than type I diabetes mellitus, vitiligo, psoriasis, or thyroid disorders not requiring immunosuppressive treatment were excluded.

Fatal adverse reactions occurred in 1.8% of patients receiving BAVENCIO in combination with axitinib. The most common adverse reactions (> 1%) resulting in permanent discontinuation of BAVENCIO or the combination were hepatotoxicity (6%) and infusion-related reaction (1.8%). Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 76% of patients receiving BAVENCIO in combination with axitinib.

This includes interruption of BAVENCIO in 50% of patients. Axitinib was interrupted in 66% and dose reduced in 19% of patients. The most common adverse reactions (≥ 20%) in patients receiving BAVENCIO in combination with axitinib were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.

Forty-eight (11%) patients treated with BAVENCIO in combination with axitinib received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction. Table 7 summarizes adverse reactions that occurred in ≥ 20% of BAVENCIO in combination with axitinib-treated patients. Table 7: Adverse Reactions (≥ 20%) of Patients Receiving BAVENCIO in Combination with Axitinib JAVELIN Renal Other clinically important adverse reactions that occurred in less than 20% of patients in JAVELIN Renal 101 included arthralgia, weight decreased, and chills.

Table 8 summarizes selected laboratory abnormalities that occurred in ≥ 20% of BAVENCIO in combination with axitinib-treated patients. Table 8: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving BAVENCIO in Combination with Axitinib JAVELIN Renal 8

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of BAVENCIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: neutropenia Hepatobiliary disorders: sclerosing cholangitis

Pregnancy Risk Summary Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of BAVENCIO in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death.

Human IgG1 immunoglobulins (IgG1) are known to cross the placenta. Therefore, BAVENCIO has the potential to be transmitted from the mother to the developing fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data Animal reproduction studies have not been conducted with BAVENCIO to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus.

In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering BAVENCIO during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to BAVENCIO may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Pediatric Use The safety and effectiveness of BAVENCIO have been established in pediatric patients aged 12 years and older for metastatic MCC. Use of BAVENCIO in this age group is supported by evidence from adequate and well-controlled studies of BAVENCIO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of avelumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MCC is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. The recommended dose in pediatric patients 12 years of age or greater is the same as that in adults.

Safety and effectiveness of BAVENCIO have not been established in pediatric patients less than 12 years of age.