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Brand Name
Yervoy
Generic Name
Ipilimumab
View Brand Information FDA approval date: March 25, 2011
Classification: CTLA-4-directed Blocking Antibody
Form: Injection
What is Yervoy (Ipilimumab)?
YERVOY is a human cytotoxic T-lymphocyte antigen 4 -blocking antibody indicated for: Melanoma Treatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older.
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Brand Information
YERVOY (ipilimumab)
1DOSAGE FORMS AND STRENGTHS
Injection: 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL) as a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose vial.
2CONTRAINDICATIONS
None.
3ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Severe and fatal immune-mediated adverse reactions
- Infusion-related reactions
3.1Clinical 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The data described in the Warnings and Precautions section reflect exposure to YERVOY 3 mg/kg as a single agent (or in combination with an investigational gp100 peptide vaccine) in 511 patients in Study MDX010-20; YERVOY 1 mg/kg administered with nivolumab 3 mg/kg in 1,362 patients in CHECKMATE-214, CHECKMATE-142, CHECKMATE-227, and CHECKMATE-743; YERVOY 3 mg/kg administered with nivolumab 1 mg/kg in 456 patients enrolled in CHECKMATE-067, CHECKMATE-040, and another randomized trial; and to YERVOY 1 mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA.
3.1.1Unresectable or Metastatic Melanoma
The safety of YERVOY was evaluated in 643 previously treated patients with unresectable or metastatic melanoma in Study MDX010-20
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 4 presents adverse reactions from Study MDX010-20.
3.1.2Unresectable or Metastatic Melanoma: In Combination with Nivolumab
The safety of YERVOY, administered with nivolumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma
Patients were randomized to receive:
- YERVOY 3 mg/kg by intravenous infusion over 90 minutes with nivolumab 1 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (YERVOY and nivolumab arm; n=313), or
- Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm; n=313), or
- YERVOY 3 mg/kg by intravenous infusion over 90 minutes every 3 weeks for up to 4 doses (YERVOY arm; n=311).
The median duration of exposure to nivolumab was 2.8 months (range: 1 day to 36.4 months) for the YERVOY and nivolumab arm. In the YERVOY and nivolumab arm, 39% were exposed to nivolumab for ≥6 months and 30% exposed for >1 year.
Serious adverse reactions (74%), adverse reactions leading to permanent discontinuation (47%) or to dosing delays (58%), and Grade 3 or 4 adverse reactions (72%) occurred in patients treated with YERVOY and nivolumab.
The most frequent (≥10%) serious adverse reactions in the YERVOY and nivolumab arm were diarrhea (13%), colitis (10%), and pyrexia (10%). The most frequent adverse reactions leading to discontinuation of both drugs in the YERVOY and nivolumab arm were colitis (10%), diarrhea (8%), increased ALT (4.8%), increased AST (4.5%), and pneumonitis (1.9%).
The most common (≥20%) adverse reactions in the YERVOY and nivolumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases.
Tables 5 and 6 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.
Clinically important adverse reactions in <10% of patients who received YERVOY with nivolumab:
Gastrointestinal Disorders: stomatitis, intestinal perforation
Skin and Subcutaneous Tissue Disorders: vitiligo
Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)
Nervous System Disorders: neuritis, peroneal nerve palsy
3.1.3Adjuvant Treatment of Melanoma
The safety of YERVOY was evaluated in Study E1609, an open-label, multicenter, randomized trial for the adjuvant treatment of patients with completely resected node positive cutaneous melanoma
Fatal adverse reactions occurred in 1.4% of patients who received YERVOY, including gastric perforation (0.2%), and cardiac arrest (0.2%). Permanent discontinuation of YERVOY due to an adverse reaction occurred in 35% of patients.
The most common adverse reactions (≥20%) in the YERVOY arm were fatigue, diarrhea, rash, pruritus, nausea, and headache. Table 7 summarizes adverse reactions in E1609.
3.1.4Other Clinical Experience
Across clinical studies in which patients received YERVOY as a single agent at doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence <1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.
3.1.5Advanced Renal Cell Carcinoma: In Combination with Nivolumab
The safety of YERVOY in combination with nivolumab was evaluated in 1082 patients with previously untreated advanced RCC in CHECKMATE-214
Serious adverse reactions occurred in 59% of patients receiving YERVOY with nivolumab. The most frequent serious adverse reactions reported in ≥2% of patients treated with YERVOY and nivolumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis.
In patients who received YERVOY with nivolumab, study therapy was discontinued for adverse reactions in 31% and delayed for adverse reactions in 54%.
The most common adverse reactions (≥20%) in the YERVOY and nivolumab arm were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, vomiting, dyspnea, and decreased appetite. Table 8 summarizes adverse reactions in CHECKMATE-214.
Table 9 summarizes the laboratory abnormalities in CHECKMATE-214.
In addition, among patients with TSH ≤ ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the YERVOY with nivolumab group compared to the sunitinib group (31% and 61%, respectively).
3.1.6First-line Treatment of Metastatic NSCLC: In Combination with Nivolumab
The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations
Serious adverse reactions occurred in 58% of patients. YERVOY and nivolumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.
The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (≥20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.
Tables 16 and 17 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.
Other clinically important adverse reactions in CHECKMATE-227 were:
Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligo
Gastrointestinal: stomatitis, pancreatitis, gastritis
Musculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysis
Nervous System: peripheral neuropathy, autoimmune encephalitis
Blood and Lymphatic System: eosinophilia
Eye Disorders: blurred vision, uveitis
Cardiac: atrial fibrillation, myocarditis
3.1.7First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Nivolumab and Platinum-Doublet Chemotherapy
The safety of YERVOY in combination with nivolumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA
Serious adverse reactions occurred in 57% of patients who were treated with YERVOY in combination with nivolumab and platinum-doublet chemotherapy. The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.
Study therapy with YERVOY in combination with nivolumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.
Tables 18 and 19 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.
3.1.8First-line Treatment of Unresectable Malignant Pleural Mesothelioma: In Combination with Nivolumab
The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma
Serious adverse reactions occurred in 54% of patients who were treated with YERVOY in combination with nivolumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.
Both YERVOY and nivolumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction. An additional 4.7% of patients permanently discontinued YERVOY alone due to adverse reactions.
The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.
Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.
3.1.9First-line Treatment of Unresectable Advanced or Metastatic ESCC: In Combination with Nivolumab
The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC
- YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks.
- 5-FU (fluorouracil) 800 mg/m
Among patients who received YERVOY and nivolumab, the median duration of exposure was 2.8 months (range: 0 to 24 months).
Serious adverse reactions occurred in 69% of patients receiving YERVOY in combination with nivolumab.
The most frequent serious adverse reactions reported in ≥2% of patients who received YERVOY with nivolumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).
Fatal adverse reactions occurred in 5 (1.6%) patients who received YERVOY in combination with nivolumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.
YERVOY and/or nivolumab were discontinued in 23% of patients and delayed in 46% of patients for an adverse reaction.
The most common adverse reactions reported in ≥20% of patients treated with YERVOY in combination with nivolumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.
Tables 22 and 23 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648.
3.2Postmarketing Experience
The following adverse reactions have been identified during post-approval 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.
Blood and lymphatic system disorders: hemophagocytic lymphohistiocytosis (HLH)
Immune System: graft-versus-host disease, solid organ transplant rejection
Skin and Subcutaneous Tissue: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
4DESCRIPTION
Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody. Ipilimumab is a recombinant IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.
YERVOY (ipilimumab) injection, for intravenous use is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution, which may contain a small amount of visible translucent-to-white, amorphous ipilimumab particulates. It is supplied in single-dose vials of 50 mg/10 mL or 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.
5HOW SUPPLIED/STORAGE AND HANDLING
YERVOY (ipilimumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution. YERVOY is available as follows:
Store YERVOY under refrigeration at 2°C to 8°C (36°F to 46°F). Protect YERVOY from light by storing in the original carton until time of use. Do not freeze or shake.
6PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
7YERVOY 50 mg/10 mL Representative Packaging
See
NDC 0003-2327-11
8YERVOY 200 mg/40 mL Representative Packaging
NDC 0003-2328-22
