Data from FDA - Curated by EPG Health - Last updated 30 April 2018

Indication(s)

1 INDICATIONS AND USAGE YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for: •Treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older). (1.1) •Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. (1.2) •Treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma, in combination with nivolumab. (1.3) 1.1 Unresectable or Metastatic Melanoma YERVOY is indicated for the treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older) [see Clinical Studies (14.1)]. 1.2 Adjuvant Treatment of Melanoma YERVOY is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy [see Clinical Studies (14.2)]. 1.3 Advanced Renal Cell Carcinoma YERVOY, in combination with nivolumab, is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC) [see Clinical Studies (14.3)].

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. •Immune-mediated enterocolitis/colitis [see Warnings and Precautions (5.1)]. •Immune-mediated hepatitis [see Warnings and Precautions (5.2)]. •Immune-mediated dermatitis/skin adverse reactions [see Warnings and Precautions (5.3)]. •Immune-mediated neuropathies [see Warnings and Precautions (5.4)]. •Immune-mediated endocrinopathies [see Warnings and Precautions (5.5)]. •Immune-mediated pneumonitis [see Warnings and Precautions (5.6)]. •Immune-mediated nephritis and renal dysfunction [see Warnings and Precautions (5.7)]. •Immune-mediated encephalitis [see Warnings and Precautions (5.8)]. •Infusion reactions [see Warnings and Precautions (5.9)]. •Other immune-mediated adverse reactions, including ocular manifestations [see Warnings and Precautions (5.10)]. •Embryo-fetal toxicity [see Warnings and Precautions (5.11)]. In patients receiving YERVOY 3 mg/kg for unresectable or metastatic melanoma in MDX010-20, 15% of patients receiving monotherapy and 12% of patients treated in combination with gp100 peptide vaccine experienced Grade 3 to 5 immune-mediated reactions. In patients receiving YERVOY 10 mg/kg for adjuvant treatment of melanoma in CA184-029, 41% experienced Grade 3 to 5 immune-mediated reactions. Most common adverse reactions (≥5%) with YERVOY as a single agent are fatigue, diarrhea, pruritus, rash, and colitis. Additional common adverse reactions at the 10 mg/kg dose (≥5%) include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia. (6.1) Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab are fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice. The data described below reflect exposure to YERVOY 3 mg/kg as a single agent in MDX010-20, a randomized trial in patients with unresectable or metastatic melanoma and to YERVOY 10 mg/kg as a single agent in CA184-029, a randomized trial in patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma. Also described below are the data from CHECKMATE-214 (NCT02231749), a randomized trial in previously untreated patients with advanced renal cell carcinoma. In this trial, nivolumab 3 mg/kg was given in combination with YERVOY 1 mg/kg. Clinically significant adverse reactions were evaluated in a total of 982 patients treated in MDX010-20 and CA184-029 and in 21 dose-ranging trials (n=2478) administering YERVOY at doses of 0.1 to 20 mg/kg [see Warnings and Precautions (5.6)]. Unresectable or Metastatic Melanoma The safety of YERVOY was evaluated in MDX010-20, a randomized, double-blind clinical trial in which 643 previously treated patients with unresectable or metastatic melanoma received YERVOY 3 mg/kg for 4 doses given by intravenous infusion as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (gp100) (n=380), or gp100 peptide vaccine as a single agent (n=132) [see Clinical Studies (14.1)]. Patients in the trial received a median of 4 doses (range: 1 to 4 doses). MDX010-20 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% white, and baseline ECOG performance status 0 (56%). YERVOY was discontinued for adverse reactions in 10% of patients. Table 2 presents selected adverse reactions from MDX010-20, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3 to 5 events. Table 2: Selected Adverse Reactions in MDX010-20 a Incidences presented in this table are based on reports of adverse events regardless of causality. Percentage (%) of Patientsa YERVOY 3 mg/kg n=131 YERVOY 3 mg/kg+gp100 n=380 gp100 n=132 System Organ Class/ Preferred Term Any Grade Grade 3 to 5 Any Grade Grade 3 to 5 Any Grade Grade 3 to 5 General Disorders and Administration-Site Conditions Fatigue 41 7 34 5 31 3 Gastrointestinal Disorders Diarrhea 32 5 37 4 20 1 Colitis 8 5 5 3 2 0 Skin and Subcutaneous Tissue Disorders Pruritus 31 0 21 <1 11 0 Rash 29 2 25 2 8 0 Table 3 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from MDX010-20. Table 3: Severe to Fatal Immune-Mediated Adverse Reactions in MDX010-20 a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. Percentage (%) of Patients YERVOY 3 mg/kg n=131 YERVOY 3 mg/kg+gp100 n=380 Any Immune-Mediated Adverse Reaction 15 12 Enterocolitisa,b 7 7 Hepatotoxicitya 1 2 Dermatitisa 2 3 Neuropathya 1 <1 Endocrinopathy 4 1 Hypopituitarism 4 1 Adrenal insufficiency 0 1 Other Pneumonitis 0 <1 Meningitis 0 <1 Nephritis 1 0 Eosinophiliac 1 0 Pericarditisa,c 0 <1 Adjuvant Treatment of Melanoma The safety of YERVOY was evaluated in CA184-029, a randomized (1:1), double-blind, placebo-controlled trial in which 945 patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma received YERVOY 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at Week 24 up to a maximum of 3 years [see Clinical Studies (14.2)]. In this trial, 36% of patients received YERVOY for longer than 6 months and 26% of patients received YERVOY for longer than 1 year. YERVOY-treated patients in the trial received a median of 4 doses (range: 1 to 16). CA184-029 excluded patients with prior systemic therapy for melanoma, autoimmune disease, a condition requiring systemic immunosuppression, or a positive test for hepatitis B, hepatitis C, or HIV. The trial population characteristics were: median age 51 years (range: 18 to 84 years), 62% male, 99% white, and baseline ECOG performance status 0 (94%). YERVOY was discontinued for adverse reactions in 52% of patients. Table 4 presents selected adverse reactions from CA184-029 which occurred in at least 5% of YERVOY-treated patients and with at least 5% increased incidence over the placebo group for all-grade events. Table 4: Selected Adverse Reactions in CA184-029 Percentage (%) of Patientsa YERVOY 10 mg/kg n=471 Placebo n=474 a Incidences presented in this table are based on reports of adverse events regardless of causality. b Includes 1 death. System Organ Class/ Preferred Term Any Grade Grade 3 to 5 Any Grade Grade 3 to 5 Skin and Subcutaneous Tissue Disorders Rash 50 2.1 20 0 Pruritus 45 2.3 15 0 Gastrointestinal Disorders Diarrhea 49 10 30 2.1 Nausea 25 0.2 18 0 Colitisb 16 8 1.5 0.4 Vomiting 13 0.4 6 0.2 Investigations Weight Decreased 32 0.2 9 0.4 General Disorders and Administration-Site Conditions Fatigue 46 2.3 38 1.5 Pyrexia 18 1.1 4.9 0.2 Nervous System Disorders Headache 33 0.8 18 0.2 Metabolism and Nutrition Disorders Decreased Appetite 14 0.2 3.4 0.2 Psychiatric Disorders Insomnia 10 0 4.4 0 Table 5 presents selected laboratory abnormalities from CA184-029 which occurred in at least 10% of YERVOY-treated patients at a higher incidence compared to placebo. Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of YERVOY-Treated Patients (CA184-029)a a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Excluding lipase and amylase, YERVOY group (range: 466 to 470 patients) and placebo group (range: 472 to 474 patients). b For lipase and amylase, YERVOY group (range: 447 to 448 patients) and placebo group (range: 462 to 464 patients). Percentage of Patients with Worsening Laboratory Test from Baselinea Test YERVOY Placebo All Grades Grade 3 to 4 All Grades Grade 3 to 4 Chemistry Increased ALT 46 10 16 0 Increased AST 38 9 14 0.2 Increased lipaseb 26 9 17 4.5 Increased amylaseb 17 2.0 7 0.6 Increased alkaline phosphatase 17 0.6 6 0.2 Increased bilirubin 11 1.5 9 0 Increased creatinine 10 0.2 6 0 Hematology Decreased hemoglobin 25 0.2 14 0 Table 6 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from CA184-029. Table 6: Severe to Fatal Immune-Mediated Adverse Reactions in CA184-029 Percentage (%) of Patients YERVOY 10 mg/kg n=471 a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. Any Immune-Mediated Adverse Reaction 41 Enterocolitisa,b 16 Hepatitis 11 Dermatitis 4.0 Neuropathya 1.7 Endocrinopathy 8 Hypopituitarism 7 Primary hypothyroidism 0.2 Hyperthyroidism 0.6 Other Myocarditisa 0.2 Meningitis 0.4 Pericarditisc 0.2 Pneumonitis 0.2 Uveitis 0.2 Other Clinical Experience Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Previously Untreated Renal Cell Carcinoma The safety of nivolumab 3 mg/kg, administered with YERVOY 1 mg/kg was evaluated in CHECKMATE-214, a randomized open-label trial in which 1082 patients with previously untreated advanced RCC received nivolumab 3 mg/kg in combination with YERVOY 1 mg/kg every 3 weeks for 4 doses followed by nivolumab monotherapy at the 3 mg/kg dose (n=547) every 2 weeks or sunitinib administered orally 50 mg daily for 4 weeks followed by 2 weeks off, every cycle (n=535) [see Clinical Studies (14.3)]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in nivolumab plus YERVOY-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the nivolumab plus YERVOY arm were exposed to treatment for greater than 6 months, and 38% of patients were exposed to treatment for greater than 1 year. Study therapy was discontinued for adverse reactions in 31% of nivolumab plus YERVOY patients and in 21% of sunitinib patients. Fifty-four percent (54%) of patients receiving nivolumab plus YERVOY and 43% of patients receiving sunitinib had a drug delay for an adverse reaction. In the sunitinib group, 53% of patients required a dose reduction; dose reductions were not permitted in the nivolumab plus YERVOY treatment group. Serious adverse reactions occurred in 59% of patients receiving nivolumab plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in at least 2% of patients treated with nivolumab plus YERVOY were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in at least 20% of nivolumab plus YERVOY-treated patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. Table 7 summarizes adverse reactions that occurred in greater than 15% of nivolumab plus YERVOY-treated patients. Table 7: Grade 1-4 Adverse Reactions in >15% of Patients Receiving Nivolumab plus YERVOY (CHECKMATE-214) Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes peripheral edema, peripheral swelling. c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption. d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. Nivolumab plus YERVOY (n=547) Sunitinib (n=535) Percentage (%) of Patients Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Adverse Reaction 99 65 99 76 General Disorders and Administration Site Conditions Fatiguea 58 8 69 13 Pyrexia 25 0.7 17 0.6 Edemab 16 0.5 17 0.6 Respiratory, Thoracic, and Mediastinal Disorders Cough/productive cough 28 0.2 25 0.4 Dyspnea/exertional dyspnea 20 2.4 21 2.1 Gastrointestinal Disorders Diarrhea 38 4.6 58 6 Nausea 30 2.0 43 1.5 Vomiting 20 0.9 28 2.1 Abdominal pain 19 1.6 24 1.9 Constipation 17 0.4 18 0 Skin and Subcutaneous Tissue Disorders Rashc 39 3.7 25 1.1 Pruritus/generalized pruritus 33 0.5 11 0 Endocrine Disorders Hypothyroidism 18 0.4 27 0.2 Nervous System Disorders Headache 19 0.9 23 0.9 Metabolism and Nutrition Disorders Decreased appetite 21 1.8 29 0.9 Musculoskeletal and Connective Tissue Disorders Musculoskeletal paind 37 4.0 40 2.6 Arthralgia 23 1.3 16 0 The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of nivolumab plus YERVOY-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia. Table 8 summarizes the laboratory abnormalities that occurred in greater than 15% of nivolumab plus YERVOY-treated patients. Table 8: Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on Nivolumab plus YERVOY (CHECKMATE-214) a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: nivolumab plus YERVOY group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients). Percentage of Patients with Worsening Laboratory Test from Baseline a Laboratory Abnormality Nivolumab plus YERVOY Sunitinib Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Hematology Anemia 43 3.0 64 9 Lymphopenia 36 5 63 14 Chemistry Increased lipase 48 20 51 20 Increased creatinine 42 2.1 46 1.7 Increased ALT 41 7 44 2.7 Increased AST 40 4.8 60 2.1 Increased amylase 39 12 33 7 Hyponatremia 39 10 36 7 Increased alkaline phosphatase 29 2.0 32 1.0 Hyperkalemia 29 2.4 28 2.9 Hypocalcemia 21 0.4 35 0.6 Hypomagnesemia 16 0.4 26 1.6 In addition, among patients with TSH less than or equal to the ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH greater than the ULN in the nivolumab plus YERVOY group compared to the sunitinib group (31% and 61%, respectively). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of YERVOY. 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. Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) 6.3 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ipilimumab in the studies described below with the incidences of antibodies in other studies or to other products may be misleading. Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab (TE-ADAs) in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab and 7 (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for TE-ADAs using an ECL assay with improved drug tolerance. No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for TE-ADAs. Of the patients who were treated with ipilimumab and nivolumab and evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies was 6.3% and there were no patients with neutralizing antibodies against ipilimumab with nivolumab 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks. There was no evidence of increased incidence of infusion reactions in the presence of anti-ipilimumab antibodies. Of patients evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26.0% and the incidence of neutralizing antibodies against nivolumab was 0.5% with nivolumab 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Unresectable or metastatic melanoma: ∘3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses. (2.1) •Adjuvant melanoma: ∘10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity. (2.2) •Advanced renal cell carcinoma: ∘Nivolumab 3 mg/kg administered intravenously over 30 minutes followed by YERVOY 1 mg/kg administered intravenously over 30 minutes on the same day, every 3 weeks for a maximum of 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks, administered intravenously over 30 minutes. (2.3) •Permanently discontinue for severe adverse reactions. (2.4) 2.1 Recommended Dosing for Unresectable or Metastatic Melanoma The recommended dose of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a maximum of 4 doses. In the event of toxicity, doses may be delayed, but all treatment must be administered within 16 weeks of the first dose [see Clinical Studies (14.1)]. 2.2 Recommended Dosing for Adjuvant Treatment of Melanoma The recommended dose of YERVOY is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years [see Clinical Studies (14.2)]. In the event of toxicity, doses are omitted, not delayed. 2.3 Recommended Dosing for RCC The recommended dose of nivolumab in combination with YERVOY is nivolumab 3 mg/kg administered as an intravenous infusion over 30 minutes, followed by YERVOY 1 mg/kg administered as an intravenous infusion over 30 minutes on the same day, every 3 weeks for 4 doses [see Clinical Studies (14.3)]. After completing 4 doses of the combination, administer nivolumab as a single agent, either: • 240 mg every 2 weeks, or • 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. Review the Full Prescribing Information for nivolumab prior to initiation. 2.4 Recommended Dose Modifications Recommendations for YERVOY modifications are provided in Table 1. When YERVOY is administered in combination with nivolumab, if YERVOY is withheld, nivolumab should also be withheld. Review the Full Prescribing Information for nivolumab for recommended dose modifications. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue in patients with severe or life-threatening infusion reactions. Table 1: Recommended Treatment Modifications for Immune-Mediated Adverse Reactions of YERVOY Target/Organ System Adverse Reaction (CTCAE v4) Treatment Modification Endocrine Symptomatic endocrinopathy Withhold YERVOY Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day. •Symptomatic reactions lasting 6 weeks or longer •Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day Permanently discontinue YERVOY Ophthalmologic Grade 2 through 4 reactions •not improving to Grade 1 within 2 weeks while receiving topical therapy or •requiring systemic treatment Permanently discontinue YERVOY All Other Grade 2 Withhold YERVOY Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day. •Grade 2 reactions lasting 6 weeks or longer •Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day •Grade 3 or 4 Permanently discontinue YERVOY 2.5 Preparation and Administration •Do not shake product. •Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles. Preparation of Solution •Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion. •Withdraw the required volume of YERVOY and transfer into an intravenous bag. •Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion. •Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). •Discard partially used vials or empty vials of YERVOY. Administration Instructions •Do not mix YERVOY with, or administer as an infusion with, other medicinal products. •Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose. •Administer diluted solution over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter. When administered in combination with nivolumab, infuse nivolumab first followed by YERVOY on the same day. Use separate infusion bags and filters for each infusion.
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Lactation: Discontinue breastfeeding during treatment with YERVOY. (8.2) 8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner (see Data). The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. There is insufficient human data for YERVOY exposure in pregnant women. Advise pregnant women 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 2% to 4% and 15% to 20%, respectively. A Pregnancy Safety Surveillance Study has been established to collect information about pregnancies in women who have received YERVOY. Healthcare providers are encouraged to enroll patients or have their patients enroll directly by calling 1-844-593-7869. Data Animal Data In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality. In addition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the 3 mg/kg dose). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema. Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3 to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction. 8.2 Lactation Risk Summary It is not known whether YERVOY is present in human milk. In monkeys, ipilimumab was present in milk (see Data). There are no data to assess the effects of YERVOY on milk production. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose. Data In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at a 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0.1 mcg/mL and 0.4 mcg/mL, representing a ratio of up to 0.3% of the steady-state serum concentration of the drug. 8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months following the last dose of YERVOY. 8.4 Pediatric Use The safety and effectiveness of YERVOY have been established in pediatric patients 12 years and older. Use of YERVOY in this age group is supported by evidence from adequate and well-controlled studies of YERVOY in adults and population pharmacokinetic data demonstrating that the exposure at a dose of 3 mg/kg in the pediatric and adult populations is comparable. In addition, the tumor biology and course of advanced melanoma is sufficiently similar in adults and pediatric patients 12 years and older to allow extrapolation of data from adults to pediatric patients. The safety and effectiveness for pediatric patients less than 12 years of age has not been established [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. YERVOY was evaluated in a total of 45 pediatric patients across two clinical trials. In a dose-finding trial, 33 pediatric patients with relapsed or refractory solid tumors were evaluated. The median age was 13 years (range 2 to 21 years), and 20 patients were >12 years old. YERVOY was administered at doses of 1, 3, 5, and 10 mg/kg intravenously over 90 minutes every 3 weeks for 4 doses and then every 12 weeks thereafter until progression or treatment discontinuation. YERVOY was also evaluated in an open-label, single-arm, trial in 12 pediatric patients >12 years old (range 12 to 16 years) with previously treated or untreated, unresectable Stage 3 or 4 malignant melanoma. Patients received YERVOY 3 mg/kg (4 patients) or 10 mg/kg (8 patients) intravenously over 90 minutes every 3 weeks for 4 doses. Of the 17 patients >12 years of age with melanoma treated with YERVOY across both studies, two patients experienced objective responses including one partial response that was sustained for 16 months. There were no responses in patients with non-melanoma solid tumors. The overall safety profile of YERVOY in children and adolescents was consistent with the safety profile in adults. Pediatric Pharmacokinetics (PK) Based on a population PK analysis using available pooled data from 565 patients from 4 phase 2 adult studies (N=521) and 2 pediatric studies (N=44), body weight normalized clearance of ipilimumab is comparable between adult and pediatric patients. In pediatric patients with a dosing regimen of 3 mg/kg every 3 weeks, the model simulated geometric mean (CV%) steady-state serum peak and trough concentrations of ipilimumab were 65.8 (17.6%) and 20.7 (33.1%) mcg/mL (for 2 to 6 years old), 70.1 (19.6%) and 19.6 (42.9%) mcg/mL (for 6 to <12 years old), and 73.3 (20.6%) and 17.8 (50.8%) mcg/mL (for 12 years and older), which are comparable to those in adult patients. 8.5 Geriatric Use Of the 511 patients treated with YERVOY in MDX010-20 (Unresectable or Metastatic Melanoma), 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). CA184-029 (Adjuvant Treatment of Melanoma) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 550 patients randomized to nivolumab 3 mg/kg administered with YERVOY 1 mg/kg in CHECKMATE-214 (Renal Cell Carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. In elderly patients with intermediate or poor risk, no overall difference in effectiveness was reported. 8.6 Renal Impairment No dose adjustment is needed for patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 to 1.5 times the upper limit of normal [ULN] or AST >ULN). YERVOY has not been studied in patients with moderate (TB >1.5 to 3.0 times ULN and any AST) or severe (TB >3 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.

More information

Category Value
Authorisation number BLA125377
Agency product number 6T8C155666
Orphan designation No
Product NDC 0003-2328,0003-2327
Date Last Revised 16-04-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder E.R. Squibb & Sons, L.L.C.
Warnings WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions [see Dosage and Administration (2.4)]. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5)]. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS See full prescribing information for complete boxed warning. YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. (2.4) Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose. (5.1, 5.2, 5.3, 5.4, 5.5)