Ipilimumab

Severe and fatal immune-mediated adverse effects may occur. While any organ system may be involved, common severe effects include dermatitis (including toxic epidermal necrolysis), endocrinopathy, enterocolitis, hepatitis, and neuropathy. Reactions generally occur during treatment, although some reactions have occurred weeks to months after treatment discontinuation. Discontinue treatment (permanently) and initiate high-dose systemic corticosteroid treatment for severe immune-mediated reactions. Evaluate liver function, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and prior to each dose. Assess for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy at baseline and prior to each dose. Uncommon immune-mediated adverse effects reported include cytopenias, eosinophilia, hemolytic anemia, iritis, meningitis, myocarditis (fatal), nephritis, pancreatitis, pericarditis, pneumonitis, sarcoidosis, and uveitis. Other rare immune-mediated reactions reported in clinical trials include angiopathy, arthritis, autoimmune central neuropathy (encephalitis), autoimmune thyroiditis, blepharitis, conjunctivitis, episcleritis, erythema multiforme, leukocytoclastic vasculitis, myositis, neurosensory hypoacusis, ocular myositis, polymyalgia rheumatica, polymyositis, psoriasis, scleritis, temporal arteritis, and vasculitis. Initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) for severe reactions.

Severe, life-threatening, or fatal immune-mediated dermatitis has been reported. The median time to onset for dermatologic toxicity is 2 to 3 weeks. Monitor for signs/symptoms of dermatitis, including rash and pruritus; dermatitis should be considered immune-mediated unless identified otherwise. Mild-to-moderate dermatitis (localized rash and pruritus) should be treated symptomatically; topical or systemic corticosteroids should be administered if not resolved within 1 week. Withhold treatment for moderate to severe dermatologic symptoms. Permanently discontinue ipilimumab and initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) for Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by dermal ulceration (full thickness) or necrotic, bullous, or hemorrhagic manifestations; when dermatitis is controlled, taper corticosteroid over at least 1 month

Severe or life-threatening endocrine disorders (hypophysitis, adrenal insufficiency [including adrenal crisis], hyperthyroidism and hypothyroidism) have been reported; may require hospitalization. Endocrine disorders of moderate severity (including hypothyroidism, adrenal insufficiency, hypopituitarism, and less commonly hyperthyroidism and Cushing's syndrome) which have required hormone replacement therapy or medical intervention have also been reported. The median onset for moderate to severe endocrine disorders was 2.2 to 2.5 months; long-term hormone replacement therapy has been required in many cases. Monitor thyroid function tests, adrenocorticotropic hormone (ACTH) level, and serum chemistries prior to each dose and as clinically necessary; also monitor for signs of hypophysitis, adrenal insufficiency and thyroid disorders (eg, abdominal pain, fatigue, headache, hypotension, mental status changes, unusual bowel habits); rule out other potential causes such as underlying disease or brain metastases. Endocrine disorders should be considered immune-mediated unless identified otherwise; consider endocrinology referral for further evaluation. If symptomatic, withhold ipilimumab treatment and initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) and appropriate hormone replacement therapy.

Immune-mediated enterocolitis (including fatal cases) may occur. The median time to onset of grade 3 to 5 enterocolitis was 1.1 to 1.7 months. Monitor for signs and symptoms of enterocolitis (abdominal pain, blood in stool, diarrhea, or mucous in stool; with or without fever) and intestinal perforation (peritoneal signs, ileus). If enterocolitis develops, infectious causes should be ruled out; consider endoscopy for persistent or severe symptoms. Withhold ipilimumab treatment and administer antidiarrheals for moderate enterocolitis (diarrhea with ≤6 stools over baseline abdominal pain, mucous or blood in stool); if persists for >1 week, initiate systemic corticosteroids (prednisone at 0.5 mg/kg/day or equivalent). If severe enterocolitis (diarrhea ≥7 stools above baseline, fever, ileus, peritoneal signs) develops, permanently discontinue ipilimumab and initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent); when resolved to ≤ grade 1, taper corticosteroids slowly over ≥1 month (rapid tapering may cause recurrence or worsen symptoms). May consider adding anti-tumor necrosis factor (TNF) or other immunosuppressive therapy for management of immune-mediated enterocolitis unresponsive to 3 to 5 days of systemic corticosteroids or recurring after symptomatic improvement.

Severe, life-threatening or fatal hepatotoxicity and immune-mediated hepatitis have been observed. The median time to onset for grade 3 or 4 immune-mediated hepatitis in patients receiving ipilimumab for adjuvant treatment of melanoma was 2 months. Monitor liver function tests (LFTs) and evaluate for signs of hepatotoxicity prior to each dose; if hepatotoxicity develops, infectious or malignant causes should be ruled out and liver function should be monitored more frequently until resolves. Withhold treatment for grade 2 hepatotoxicity (ALT or AST 2.5 to 5 times ULN or total bilirubin 1.5 to 3 times ULN). If severe or grade 3 or 4 hepatotoxicity develops (ALT or AST >5 times ULN or total bilirubin >3 times ULN), permanently discontinue ipilimumab and initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent). If transaminases do not decrease within 48 hours of steroid initiation, consider adding mycophenolate mofetil (Weber 2012). May begin tapering corticosteroid (over 1 month) when LFTs show sustained improvement or return to baseline.

Immune-mediated neuropathies (some fatal) may occur. Severe peripheral motor neuropathy and fatal Guillain-Barré syndrome have been reported (rare). The median time to onset of grade 2 to 5 immune-mediated neuropathy in patients receiving ipilimumab for adjuvant treatment of melanoma was 1.4 to 27.4 months. Monitor for signs of motor or sensory neuropathy (unilateral or bilateral weakness, sensory changes or paresthesia). Withhold treatment in patients with neuropathy that does not interfere with daily activities (moderate neuropathy). Permanently discontinue for severe neuropathy (interferes with daily activities, including symptoms similar to Guillain-Barré syndrome) and treat accordingly. Consider initiating systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) for severe neuropathies.

Immune-mediated ocular toxicity may occur and may be associated with retinal detachment or permanent vision loss; monitor patients for signs and symptoms of ocular toxicity (including blurred vision and decreased visual acuity). Administer corticosteroid ophthalmic drops in patients who develop episcleritis, iritis, or uveitis; permanently discontinue ipilimumab if unresponsive to topical ophthalmic immunosuppressive treatments. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving ipilimumab and may require systemic corticosteroids to reduce the risk of permanent vision loss. For severe immune-mediated episcleritis or uveitis, initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent); taper over at least 1 month (Weber 2012).