Uses and indications

BAVENCIO is a programmed death ligand-1 (PD-L1) blocking antibody indicated for: Merkel Cell Carcinoma (MCC) • Adults and pediatric patients 12 years and older with metastatic MCC. (1.1, 14.1) Urothelial Carcinoma (UC) • Maintenance treatment of patients with locally advanced or…

Contraindications

None.

Side effects

BAVENCIO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral…

BAVENCIO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue BAVENCIO depending on severity [see Dosage and Administration (2.5)]. In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

The following clinically significant adverse reactions are described elsewhere in the labeling:

Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)]
Infusion-related reactions [see Warnings and Precautions (5.2)]
Complications of allogeneic HSCT [see Warnings and Precautions (5.3)]
Major adverse cardiovascular events [see Warnings and Precautions (5.4)]

Precautions

• Immune-Mediated Adverse Reactions (5.1) • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated…

• Immune-Mediated Adverse Reactions

(5.1)

• Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and may result in solid organ transplant rejection.

• Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.

• Withhold or permanently discontinue based on severity and type of reaction.

• Infusion-related reactions

: Interrupt, slow the rate of infusion, or permanently discontinue BAVENCIO based on severity of reaction. (5.2)

• Complications of allogeneic HSCT

: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3)

• Major adverse cardiovascular events

: Optimize management of cardiovascular risk factors. Discontinue BAVENCIO in combination with axitinib for Grade 3-4 events. (5.4)

• Embryo-fetal toxicity

: BAVENCIO can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.5, 8.1, 8.3) 5.1 Severe and Fatal Immune-Mediated Adverse Reactions

BAVENCIO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue BAVENCIO depending on severity

[see Dosage and Administration (2.5)].

In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis

BAVENCIO can cause immune-mediated pneumonitis. Immune-mediated pneumonitis occurred in 1.1% (21/1854) of patients receiving BAVENCIO, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%) and Grade 2 (0.6%) adverse reactions. Pneumonitis led to permanent discontinuation of BAVENCIO in 0.3% and withholding of BAVENCIO in 0.3% of patients.

Systemic corticosteroids were required in all (21/21) patients with pneumonitis. Pneumonitis resolved in 57% (12/21) of the patients. Of the 5 patients in whom BAVENCIO was withheld for pneumonitis, 5 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of pneumonitis.

With other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-Mediated Colitis

BAVENCIO can cause immune-mediated colitis. The primary component of the immune-mediated colitis consisted of diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 1.5% (27/1854) of patients receiving BAVENCIO, including Grade 3 (0.4%) and Grade 2 (0.8%) adverse reactions. Colitis led to permanent discontinuation of BAVENCIO in 0.5% and withholding of BAVENCIO in 0.4% of patients.

Systemic corticosteroids were required in all (27/27) patients with colitis. Colitis resolved in 70% (19/27) of the patients. Of the 8 patients in whom BAVENCIO was withheld for colitis, 5 reinitiated treatment with BAVENCIO after symptom improvement; of these, 40% had recurrence of colitis. Hepatotoxicity and Immune-Mediated Hepatitis BAVENCIO as a single agent

BAVENCIO can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.1% (20/1854) of patients receiving BAVENCIO, including fatal (0.1%), Grade 3 (0.8%), and Grade 2 (0.2%) adverse reactions. Hepatitis led to permanent discontinuation of BAVENCIO in 0.6% and withholding of BAVENCIO in 0.2% of patients.

Systemic corticosteroids were required in all (20/20) patients with hepatitis. Hepatitis resolved in 60% (12/20) of the patients. Of the 4 patients in whom BAVENCIO was withheld for hepatitis, 4 reinitiated treatment with BAVENCIO after symptom improvement; of these, 25% had recurrence of hepatitis. BAVENCIO with Axitinib

BAVENCIO in combination with axitinib can cause hepatotoxicity with higher-than-expected frequencies of Grade 3 and 4 ALT and AST elevation compared to BAVENCIO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. For elevated liver enzymes, interrupt BAVENCIO and axitinib and consider administering corticosteroids as needed

[see Dosage and Administration (2.5)].

In patients treated with BAVENCIO in combination with axitinib in the advanced RCC trials, increased ALT and increased AST were reported in 9% (Grade 3) and 7% (Grade 4) of patients. In patients with ALT ≥ 3 times ULN (Grades 2-4, n=82), ALT resolved to Grades 0-1 in 92%. Among the 73 patients who were rechallenged with either BAVENCIO (n=3) or axitinib (n=25) administered as a single agent or with both (n=45), recurrence of ALT ≥3 times ULN was observed in no patient receiving BAVENCIO, 6 patients receiving axitinib, and 15 patients receiving both BAVENCIO and axitinib.

Twenty-two (88%) patients with a recurrence of ALT ≥3 ULN subsequently recovered to Grade 0-1 from the event. Immune-mediated hepatitis was reported in 7% of patients, including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Hepatotoxicity led to permanent discontinuation in 6.5% and immune-mediated hepatitis led to permanent discontinuation of either BAVENCIO or axitinib in 5.3% of patients. Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidal immunosuppressant. Resolution of hepatitis occurred in 31 of the 35 patients at the time of data cut-off. Immune-Mediated Endocrinopathies Adrenal Insufficiency

BAVENCIO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Withhold BAVENCIO depending on severity [see Dosage and Administration (2.5)].

Immune-mediated adrenal insufficiency occurred in 0.6% (11/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%), and Grade 2 (0.4%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of BAVENCIO in 0.1% and withholding of BAVENCIO in 0.1% of patients.

Systemic corticosteroids were required in all (11/11) patients with adrenal insufficiency. Adrenal insufficiency resolved in 18% (2/11) of patients. Of the 2 patients in whom BAVENCIO was withheld for adrenal insufficiency, none reinitiated treatment with BAVENCIO. Hypophysitis

BAVENCIO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated. Withhold or permanently discontinue BAVENCIO depending on severity [see Dosage and Administration (2.5)].

Immune-mediated pituitary disorders occurred in 0.1% (1/1854) of patients receiving BAVENCIO which was a Grade 2 (0.1%) adverse reactions. Hypopituitarism did not lead to withholding of BAVENCIO in this patient. Systemic corticosteroids were not required in this patient. Thyroid Disorders

BAVENCIO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated. Withhold or permanently discontinue BAVENCIO depending on severity [see Dosage and Administration (2.5)].

Thyroiditis

occurred in 0.2% (4/1854) of patients receiving BAVENCIO, including Grade 2 (0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation or withholding of BAVENCIO in any patients. No patients with thyroiditis required systemic corticosteroids. Thyroiditis did not resolve in any patients (0/4).

Hyperthyroidism

occurred in 0.4% (8/1854) of patients receiving BAVENCIO, including Grade 2 (0.3%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of BAVENCIO in any patients and led to withholding of BAVENCIO in 0.1% of patients. Systemic corticosteroids were required in 25% (2/8) of patients with hyperthyroidism. Hyperthyroidism resolved in 88% (7/8) of the patients. Of the 2 patients in whom BAVENCIO was withheld for hyperthyroidism, 2 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of hyperthyroidism.

Hypothyroidism

occurred in 5% (97/1854) of patients receiving BAVENCIO, including Grade 3 (0.2%) and Grade 2 (3.6%) adverse reactions. Hypothyroidism led to permanent discontinuation of BAVENCIO in 0.1% and withholding of BAVENCIO in 0.4% of patients. Systemic corticosteroids were required in 6% (6/97) of patients with hypothyroidism. Hypothyroidism resolved in 6% (6/97) of the patients. Of the 8 patients in whom BAVENCIO was withheld for hypothyroidism, none reinitiated BAVENCIO.

Type I Diabetes Mellitus, which can present with Diabetic Ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO depending on severity [see Dosage and Administration (2.5)].

Immune-mediated Type I diabetes mellitus occurred in 0.2% (3/1854) of patients receiving BAVENCIO, including Grade 3 (0.2%) adverse reactions. Type I diabetes mellitus led to permanent discontinuation of BAVENCIO in 0.1% of patients. Type I diabetes mellitus did not lead to withholding of BAVENCIO in any patient. Systemic corticosteroids were not required in any patient with Type I diabetes mellitus. Type I diabetes mellitus resolved in no patient and all patients required ongoing insulin treatment. Immune-Mediated Nephritis with Renal Dysfunction

BAVENCIO can cause immune-mediated nephritis.

Immune-mediated nephritis with renal dysfunction occurred in 0.1% (2/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%) and Grade 2 (0.1%) adverse reactions. Nephritis with renal dysfunction led to permanent discontinuation of BAVENCIO in 0.1% of patients. Nephritis did not lead to withholding of BAVENCIO in any patient.

Systemic corticosteroids were required in 100% of patients with nephritis with renal dysfunction. Nephritis with renal dysfunction resolved in 50% of the patients. Immune-Mediated Dermatologic Adverse Reactions

BAVENCIO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue BAVENCIO depending on severity [see Dosage and Administration (2.5)].

Immune-mediated dermatologic adverse reactions occurred in 6% (108/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%) and Grade 2 (1.9%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of BAVENCIO in 0.3% of patients and withholding of BAVENCIO in 0.4% of patients.

Systemic corticosteroids were required in 25% (27/108) of patients with dermatologic adverse reactions. One patient required the addition of tacrolimus to high-dose corticosteroids.

Dermatologic adverse reactions resolved in 46% (50/108) of the patients. Of the 8 patients in whom BAVENCIO was withheld for dermatologic adverse reactions, 4 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of dermatologic adverse reaction. Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% (unless otherwise noted) in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies.

Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis,

vasculitis.

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis.

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica.

Endocrine: Hypoparathyroidism.

Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Other

: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reported as the co-occurrence of either two or all three adverse reactions. 5.2 Infusion-Related Reactions

BAVENCIO can cause severe or life-threatening infusion-related reactions [see Adverse Reactions (6.1)]. Premedicate with antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Infusion-related reactions occurred in 26% of patients treated with BAVENCIO including 3 (0.2%) Grade 4 and 10 (0.5%) Grade 3 infusion-related reactions. Ninety-three percent of patients received premedication with antihistamine and acetaminophen. Eleven (85%) of the 13 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids. Fifteen percent of patients had infusion-related reactions that occurred after the BAVENCIO infusion was completed. 5.3 Complications of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT. 5.4 Major Adverse Cardiovascular Events (MACE)

BAVENCIO in combination with axitinib can cause severe and fatal cardiovascular events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events.

MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib in a randomized trial, JAVELIN Renal 101. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%). Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months). 5.5 Embryo-Fetal Toxicity

Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking BAVENCIO, inform the patient of the potential risk to a fetus. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least one month after the last dose of BAVENCIO [see Use in Specific Populations (8.1, 8.3)].

Dosage

• Premedicate for the first 4 infusions and subsequently as needed. (2.1) • Merkel Cell Carcinoma : 800 mg every 2 weeks. (2.2) • Urothelial Carcinoma; 800 mg every 2 weeks. (2.3) • Renal Cell Carcinoma : 800 mg every 2 weeks in combination with axitinib 5 mg orally twice daily…

• Premedicate for the first 4 infusions and subsequently as needed. (2.1) • Merkel Cell Carcinoma : 800 mg every 2 weeks. (2.2) • Urothelial Carcinoma; 800 mg every 2 weeks. (2.3) • Renal Cell Carcinoma : 800 mg every 2 weeks in combination with axitinib 5 mg orally twice daily. (2.4) Administer BAVENCIO as an intravenous infusion over 60 minutes. 2.1 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 [see Dosage and Administration (2.5) and Warnings and Precautions (5.2)]. 2.2 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. 2.3 Recommended Dosage for UC 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. 2.4 Recommended Dosage for RCC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity. 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. 2.5 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 Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 Dosage Modification ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrosis, DRESS = drug rash with eosinophilia and systemic symptoms Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis Grade 2 Withhold Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids. Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withhold Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy, see Table 2 AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue BAVENCIO based on recommendations for hepatitis where there is no tumor involvement of the liver. Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2)] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue 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 Dosage Modifications for Adverse Reactions for Combination Therapy [see Warnings and Precautions (5.1)] Treatment Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 Dosage Modification BAVENCIO in combination with axitinib Liver enzyme elevations ALT or AST at least 3 times ULN but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both BAVENCIO and axitinib until adverse reactions recover to Grades 0-1 Consider corticosteroid therapy Consider rechallenge with BAVENCIO or axitinib or sequential rechallenge with both BAVENCIO and axitinib after recovery Dose reduction according to the axitinib Full Prescribing Information should be considered if rechallenging with axitinib. ALT or AST at least 10 times ULN or more than 3 times ULN with concurrent total bilirubin at least 2 times ULN Permanently discontinue both BAVENCIO and axitinib 2.6 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.

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.

The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.

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.

Injection: 200 mg/10 mL (20 mg/mL), clear, colorless to slightly yellow solution in a single-dose vial.

References

Source: DailyMed, U.S. National Library of Medicine. Additional information compiled from online sources.

Bavencio Injection, Solution, Concentrate