YERVOY can result in severe and fatal immune-mediated reactions [see Boxed Warning].
5.1 Immune-Mediated Enterocolitis
Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY.
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.
Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3 to 5 days or recurring after symptom improvement.
Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent [see Dosage and Administration (2.3)].
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3 to 5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%), and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOY-treated patients (n=511), 5 patients (1%) developed intestinal perforation, 4 patients (0.8%) died as a result of complications, and 26 patients (5%) were hospitalized for severe enterocolitis.
The median time to onset of Grade 3 to 5 enterocolitis was 1.7 months (range: 11 days to 3.1 months) and for Grade 2 enterocolitis was 1.4 months (range: 2 days to 4.3 months).
Twenty-nine patients (85%) with Grade 3 to 5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 16 days (ranging up to 3.2 months) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 1.2 months, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.
Of the 34 patients with Grade 3 to 5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%). Seven patients (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications [see Adverse Reactions (6.1)].
The median time to onset for Grade 3 to 4 enterocolitis was 1.1 months (range: 1 day to 33.1 months) and for Grade 2 enterocolitis was 1.1 months (range: 1 day to 20.6 months).
Seventy-one patients (95%) with Grade 3 to 4 enterocolitis were treated with systemic corticosteroids. The median duration of treatment was 4.7 months (ranging up to 52.3 months).
Of the 68 patients with moderate enterocolitis, 51 patients (75%) were treated with systemic corticosteroids with a median duration of treatment of 3.5 months (ranging up to 52.2 months). Non-corticosteroids immunosuppression, consisting almost exclusively of infliximab, was used to treat 36% of patients with Grade 3 to 4 enterocolitis and 15% of patients with a Grade 2 event.
Of the 75 patients with Grade 3 to 4 immune-mediated enterocolitis, 86% experienced complete resolution, 3% experienced improvement to Grade 1, and 11% did not improve. Among the 68 patients with Grade 2 enterocolitis, 94% experienced complete resolution, 3% experienced improvement to Grade 1, and 3% did not improve.
5.2 Immune-Mediated Hepatitis
Immune-mediated hepatitis, including fatal cases, can occur with YERVOY.
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.
Permanently discontinue YERVOY in patients with Grade 3 to 4 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity [see Dosage and Administration (2.3)].
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3 to 5) occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3 to 4 hepatitis showed evidence of toxic or autoimmune hepatitis. The median time to onset for Grade 3 to 4 hepatitis was 2.0 months (range: 1 day to 4.2 months) and for Grade 2 hepatitis was 1.4 months (range: 13 days to 6.5 months). Of the 51 patients with Grade 3 to 4 immune-mediated hepatitis, 94% experienced complete resolution, 4% experienced improvement to Grade 1, and 2% did not improve. Of the 22 patients with Grade 2 immune-mediated hepatitis, 91% experienced complete resolution and 9% did not improve.
Forty-six patients (90%) with Grade 3 to 4 hepatitis were treated with systemic corticosteroids. The median duration of treatment was 4.4 months (ranging up to 56.1 months). Sixteen patients (73%) with moderate hepatitis were treated with systemic corticosteroids. The median duration of treatment was 2.6 months (ranging up to 41.4 months).
Concurrent Administration with Vemurafenib
In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).
5.3 Immune-Mediated Dermatitis
Immune-mediated dermatitis, including fatal cases, can occur with YERVOY.
Monitor patients for signs and symptoms of dermatitis, such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.
Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms [see Dosage and Administration (2.3)].
For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3 to 5) occurred in 13 YERVOY-treated patients (2.5%). One patient (0.2%) died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis.
The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 22 days and ranged up to 4.0 months from the initiation of YERVOY.
Seven YERVOY-treated patients (54%) with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 3.4 months followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 3.6 months.
Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 15 days, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four patients (70%) with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate (Grade 2) dermatitis. The median time to onset for Grade 3 to 4 dermatitis was 14 days (range: 5 days to 11.3 months) and for Grade 2 dermatitis was 11 days (range: 1 day to 16.6 months).
Sixteen patients (84%) with Grade 3 to 4 dermatitis were treated with systemic corticosteroids for a median of 21 days (ranging up to 49.2 months) resulting in complete resolution of dermatitis within a median time of 4.3 months (range up to 44.4 months). Of the 3 patients (16%) not treated with systemic or topical corticosteroids, 2 (11%) had complete resolution and 1 had improvement to Grade 1.
Of the 99 patients with Grade 2 dermatitis, 67 (68%) were treated with systemic corticosteroids for a median of 2.6 months, 16 (16%) were treated with only topical corticosteroids and 16 (16%) did not receive systemic or topical corticosteroids. Seventy-seven patients (78%) had complete resolution, 15 (15%) improved to mild (Grade 1) severity, and 7 (7%) did not improve.
5.4 Immune-Mediated Neuropathies
Immune-mediated neuropathies, including fatal cases, can occur with YERVOY.
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities) [see Dosage and Administration (2.3)].
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome [see Adverse Reactions (6.1)]. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).
The time to onset across the 9 patients with Grade 2 to 5 immune-mediated neuropathy ranged from 1.4 to 27.4 months. All 8 patients with Grade 3 to 5 neuropathy were treated with systemic corticosteroids (range: 3 days to 38.3 months) and 3 also received tacrolimus. Four of the 8 patients with Grade 3 to 5 immune-mediated neuropathy experienced complete resolution, 1 improved to Grade 1, and 3 did not improve. The single patient with Grade 2 immune-mediated neuropathy experienced complete resolution without the use of corticosteroids.
5.5 Immune-Mediated Endocrinopathies
Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY.
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.
Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.
Withhold YERVOY dosing in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy [see Dosage and Administration (2.3)].
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3 to 4) occurred in 9 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY.
Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).
Adjuvant Treatment of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies in 93 patients (20%). Of the 39 patients with Grade 3 to 4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with one or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3 to 4 immune-mediated endocrinopathy was 2.2 months (range: 2 days to 8 months). Twenty-seven of the 39 patients (69%) were hospitalized for immune-mediated endocrinopathies, and 4 patients (10%) were reported to have resolution.
Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with one or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days to 19.3 months), and 20% were reported to have resolution.
One hundred twenty-four patients received systemic corticosteroids as immunosuppression and/or adrenal hormone replacement for Grade 2 to 4 immune-mediated endocrinopathy. Of these, 42 (34%) were able to discontinue corticosteroids. Seventy-three patients received thyroid hormones for treatment of Grade 2 to 4 immune-mediated hypothyroidism. Of these, 14 patients (19%) were able to discontinue thyroid replacement therapy.
5.6 Other Immune-Mediated Adverse Reactions, Including Ocular Manifestations
Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy [see Dosage and Administration (2.3)].
Metastatic Melanoma
In Trial 1, the following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.
Adjuvant Treatment of Melanoma
In Trial 2, the following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients unless specified: eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal myocarditis [see Adverse Reactions (6.1)].
Other Clinical Experience
Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.
5.7 Embryo-fetal Toxicity
Based on its mechanism of action and data from animal studies, YERVOY can cause fetal harm when administered to a pregnant woman. 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. The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with a YERVOY-containing regimen and for 3 months after the last dose of YERVOY [see Use in Specific Populations (8.1, 8.3)].
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