Ipilimumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Yervoy: 50 mg/10 mL (10 mL); 200 mg/40 mL (40 mL) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Ipilimumab is a recombinant human IgG1 immunoglobulin monoclonal antibody that binds to the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). CTLA-4 is a down-regulator of T-cell activation pathways. Blocking CTLA-4 allows for enhanced T-cell activation and proliferation. In melanoma, ipilimumab may indirectly mediate T-cell immune responses against tumors. Combining ipilimumab (anti-CTLA-4) with nivolumab (anti-PD-1) results in enhanced T-cell function that is greater than that of either antibody alone, resulting in improved antitumor responses in metastatic melanoma and advanced renal cell carcinoma.

Pharmacokinetics/Pharmacodynamics

Half-Life Elimination

Terminal: 15.4 days

Use in Specific Populations

Special Populations Note

Body weight: Clearance is increased with increasing body weight.

Use: Labeled Indications

Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient): Treatment (in combination with nivolumab) of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan in adults and pediatric patients ≥12 years of age

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma in adult and pediatric patients ≥12 years of age

Melanoma, adjuvant treatment: Adjuvant treatment of cutaneous melanoma in patients with pathologic involvement of regional lymph nodes of >1 mm who have undergone complete resection, including total lymphadenectomy

Renal cell carcinoma, advanced: Treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma (in combination with nivolumab)

Use: Off Label

Melanoma, metastatic with brain metastasesb

Data from an open-label, multicenter, phase 2 trial supports the use of ipilimumab (in combination with nivolumab) in the treatment of patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis and no neurologic symptoms Tawbi 2018.

Melanoma, unresectable or metastatic, first-line combination therapya

Data from a large randomized, double blind phase 3 study in patients with untreated metastatic melanoma (comparing nivolumab monotherapy to nivolumab plus ipilimumab and to ipilimumab monotherapy) supports the use of ipilimumab (in combination with nivolumab) for this condition Larkin 2015.

Small cell lung cancer (progressive)b

Data from the phase II portion of a randomized phase I/II multicenter international study support the use of ipilimumab (in combination with nivolumab) in the treatment of small cell lung cancer (limited stage or extensive stage) with disease progression following at least one platinum-based chemotherapy regimen Antonia 2016.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to ipilimumab or any component of the formulation; active life-threatening autoimmune disease, or with organ transplantation graft where further immune activation is potentially imminently life-threatening

Dosage and Administration

Dosing: Adult

Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient): IV: 1 mg/kg once every 3 weeks (in combination with nivolumab) for up to 4 combination doses, followed by nivolumab monotherapy until disease progression or unacceptable toxicity (Overman 2018) (refer to Nivolumab monograph for nivolumab dosing information). Note: If ipilimumab therapy is withheld, nivolumab should also be withheld.

Melanoma, metastatic with brain metastases (off-label use): 3 mg/kg once every 3 weeks (in combination with nivolumab) for 4 combination doses, followed by nivolumab monotherapy; total duration of nivolumab therapy is up to 24 months, or until disease progression or unacceptable toxicity (Tawbi 2018).

Melanoma, unresectable or metastatic: IV: 3 mg/kg every 3 weeks for a maximum of 4 doses (Hodi 2010); doses may be delayed due to toxicity, but all doses must be administered within 16 weeks of the initial dose.

Melanoma, adjuvant treatment: IV: 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years unless disease progression or unacceptable toxicity occur (Eggermont 2016); if toxicity occurs, doses are omitted (not delayed).

Melanoma, unresectable or metastatic, first-line combination therapy (off-label use): IV: 3 mg/kg every 3 weeks for 4 combination doses (in combination with nivolumab; with nivolumab continued until disease progression or unacceptable toxicity) (Larkin 2015).

Renal cell cancer, advanced, combination therapy: IV: 1 mg/kg once every 3 weeks (in combination with nivolumab) for 4 combination doses, followed by nivolumab monotherapy (refer to nivolumab monograph for nivolumab dosing information) until disease progression or unacceptable toxicity (Motzer 2018). Note: If ipilimumab therapy is withheld, nivolumab should also be withheld.

Small cell lung cancer, progressive (off-label use): IV: 3 mg/kg every 3 weeks (in combination with nivolumab) for 4 combination doses, followed by nivolumab monotherapy (Antonia 2016).

Dosing: Pediatric

Colorectal cancer, metastatic (microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR): Children ≥12 years and Adolescents: IV: 1 mg/kg/dose once every 3 weeks (in combination with nivolumab) for up to 4 doses. Note: FDA approval through an accelerated process; continued approval is dependent on verification of clinical benefit in further trials.

Melanoma, unresectable or metastatic: Children ≥12 years and Adolescents: IV: 3 mg/kg every 3 weeks for a maximum of 4 doses; doses may be delayed due to toxicity, but all doses must be administered within 16 weeks of the initial dose.

Dosing adjustment for toxicity: Note: If receiving combination therapy with nivolumab, when nivolumab is withheld, ipilimumab should also be withheld. Refer to Nivolumab monograph for information on nivolumab dosage adjustment for toxicity.

Children ≥12 years and Adolescents:

Dermatologic toxicity: Treat symptomatically for mild to moderate dermatitis (eg, localized rash and pruritus); topical or systemic corticosteroids should be administered if not resolved within 1 week. Withhold ipilimumab for moderate to severe dermatologic symptoms. Permanently discontinue for Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by dermal ulceration (full thickness) or necrotic, bullous, or hemorrhagic manifestations; also initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent). When dermatitis is controlled, taper corticosteroid over at least 1 month.

Encephalitis (new onset moderate or severe neurologic toxicity): Withhold therapy and evaluate (rule out other causes); if confirmed, permanently discontinue and administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent), followed by a corticosteroid taper.

Endocrinopathy: Temporarily withhold ipilimumab for symptomatic endocrinopathy; initiate systemic corticosteroids (prednisone at 1 to 2 mg/kg/day or equivalent) and begin appropriate hormone replacement therapy. Resume treatment in patients with complete or partial resolution of toxicity (≤ grade 1) and who are receiving prednisone <7.5 mg daily (or equivalent). Permanently discontinue ipilimumab for symptomatic endocrinopathy lasting 6 weeks or longer, or if unable to reduce corticosteroid dose to prednisone ≤7.5 mg daily (or equivalent).

Gastrointestinal toxicity:

Moderate enterocolitis/colitis: Withhold ipilimumab and administer antidiarrheal treatment; if moderate enterocolitis persists for >1 week, initiate systemic corticosteroids (prednisone at 0.5 mg/kg/day or equivalent). May resume treatment in patients with complete or partial resolution of toxicity (≤ grade 1) and who are receiving prednisone <7.5 mg daily (or equivalent).

Severe enterocolitis/colitis: Permanently discontinue. Initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent). Upon improvement 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.

Infusion-related reaction:

Mild or moderate reaction: Interrupt or slow the infusion rate.

Severe or life-threatening reaction: Discontinue ipilimumab.

Neuropathy: Withhold therapy for moderate neuropathy (not interfering with daily activities). Permanently discontinue for severe neuropathy which interferes with daily activities, such as Guillain-Barré-like syndromes. Consider initiating systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) for severe neuropathies.

Ophthalmologic toxicity: Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue for grade 2 through 4 immune-mediated reactions which do not improve to ≤ grade 1 within 2 weeks while receiving topical therapy or which require systemic treatment.

Pancreatitis, immune-mediated: Permanent discontinuation is recommended for grades 3 or 4 amylase or lipase increases (Weber 2012)

Pneumonitis: Withhold ipilimumab for moderate (grade 2) or severe (grade 3) pneumonitis; permanently discontinue for life-threatening (grade 4) immune-mediated pneumonitis. Also administer corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) for grade 2 or higher pneumonitis, followed by a corticosteroid taper.

Other toxicity: Temporarily withhold ipilimumab for grade 2 adverse reactions. May resume treatment in patients (with grade 2 toxicity) with complete or partial resolution of toxicity (≤ grade 1) and who are receiving prednisone <7.5 mg daily (or equivalent). Initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) for severe immune-mediated adverse reactions. Permanently discontinue for clinically significant or severe immune-mediated adverse reactions, grade 2 reactions lasting 6 weeks or longer, grade 3 or 4 toxicity, or if unable to reduce corticosteroid dose to prednisone ≤7.5 mg daily (or equivalent).

Dosing: Adjustment for Toxicity

Note: If receiving combination therapy with nivolumab, when nivolumab is withheld, ipilimumab should also be withheld. Refer to nivolumab monograph for information on nivolumab dosage adjustment for toxicity.

Dermatologic toxicity: Treat symptomatically for mild to moderate dermatitis (eg, localized rash and pruritus); topical or systemic corticosteroids should be administered if not resolved within 1 week. Withhold ipilimumab for moderate to severe dermatologic symptoms. Permanently discontinue for Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by dermal ulceration (full thickness) or necrotic, bullous, or hemorrhagic manifestations; also initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent). When dermatitis is controlled, taper corticosteroid over at least 1 month.

Encephalitis (new onset moderate or severe neurologic toxicity): Withhold therapy and evaluate (rule out other causes); if confirmed, permanently discontinue and administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent), followed by a corticosteroid taper.

Endocrinopathy: Temporarily withhold ipilimumab for symptomatic endocrinopathy; initiate systemic corticosteroids (prednisone at 1 to 2 mg/kg/day or equivalent), and begin appropriate hormone replacement therapy. Resume treatment in patients with complete or partial resolution of toxicity (≤ grade 1) and who are receiving prednisone <7.5 mg daily (or equivalent). Permanently discontinue ipilimumab for symptomatic endocrinopathy lasting 6 weeks or longer, or if unable to reduce corticosteroid dose to prednisone ≤7.5 mg daily (or equivalent).

Gastrointestinal toxicity:

Moderate enterocolitis/colitis: Withhold ipilimumab and administer antidiarrheal treatment; if moderate enterocolitis persists for >1 week, initiate systemic corticosteroids (prednisone at 0.5 mg/kg/day or equivalent). May resume treatment in patients with complete or partial resolution of toxicity (≤ grade 1) and who are receiving prednisone <7.5 mg daily (or equivalent).

Severe enterocolitis/colitis: Permanently discontinue. Initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent). Upon improvement 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.

Infusion-related reaction:

Mild or moderate reaction: Interrupt or slow the infusion rate

Severe or life-threatening reaction: Discontinue ipilimumab.

Neuropathy: Withhold therapy for moderate neuropathy (not interfering with daily activities). Permanently discontinue for severe neuropathy which interferes with daily activities, such as Guillain-Barré-like syndromes. Consider initiating systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) for severe neuropathies.

Ophthalmologic toxicity: Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue for grade 2 through 4 immune-mediated reactions which do not improve to ≤ grade 1 within 2 weeks while receiving topical therapy or which require systemic treatment. Uveitis in combination with other immune-mediated adverse reactions may require systemic corticosteroids to reduce the risk of permanent visions loss.

Pancreatitis, immune-mediated: Permanent discontinuation is recommended for grades 3 or 4 amylase or lipase increases (Weber 2012)

Pneumonitis: Withhold ipilimumab for moderate (grade 2) or severe (grade 3) signs and symptoms of pneumonitis; permanently discontinue for life-threatening (grade 4) immune-mediated pneumonitis. Also administer corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) for grade 2 or higher pneumonitis, followed by a corticosteroid taper.

Other toxicity: Temporarily withhold ipilimumab for grade 2 adverse reactions. May resume treatment in patients (with grade 2 toxicity) with complete or partial resolution of toxicity (≤ grade 1) and who are receiving prednisone <7.5 mg daily (or equivalent). Initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) for severe immune-mediated adverse reactions. Permanently discontinue for clinically significant or severe immune-mediated adverse reactions, grade 2 reactions lasting 6 weeks or longer, grade 3 or 4 toxicity, or if unable to reduce corticosteroid dose to prednisone ≤7.5 mg daily (or equivalent). When used in combination with nivolumab, when toxicity improves to grade 1 or lower, may initiate a corticosteroid taper over at least 1 month; depending on the severity of the toxicity, may consider reinitiating ipilimumab (based on the toxicity severity).

Reconstitution

Prior to preparation, allow vials to sit at room temperature for ~5 minutes. Inspect vial prior to use; solution may have a pale yellow color or may contain translucent or white amorphous ipilimumab particles; discard if cloudy or discolored. Withdraw appropriate ipilimumab volume and transfer to IV bag, dilute with NS or D5W to a final concentration between 1 to 2 mg/mL. Mix by gently inverting, do not shake.

Administration

IV: Infuse through a non-pyrogenic, low protein-binding in-line filter. Do not administer with other medications. Flush with NS or D5W at the end of infusion.

Colorectal cancer (metastatic) or renal cell cancer (advanced): Infuse over 30 minutes.

Melanoma (unresectable/metastatic or adjuvant treatment): Infuse over 90 minutes.

Combination therapy with nivolumab: When administered in combination with nivolumab, infuse nivolumab first followed by ipilimumab on the same day (for treatment of renal cell cancer) or immediately following nivolumab (for treatment of colorectal cancer). Use separate infusion bags and filters for each infusion. If nivolumab therapy is withheld, ipilimumab should also be withheld.

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Prior to preparation, allow vials to sit at room temperature for ~5 minutes. Solutions diluted for infusion in NS or D5W are stable for up to 24 hours refrigerated or at room temperature.

Drug Interactions

Vemurafenib: Ipilimumab may enhance the hepatotoxic effect of Vemurafenib. Management: Consider alternatives to this combination when possible. Use of this combination should only be undertaken with extra close monitoring of liver function (hepatic transaminases and bilirubin) and signs/symptoms of hepatotoxicity. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Fatigue (41% to 46%), headache (15% to 33% [Hodi 2010])

Dermatologic: Skin rash (19% to 50% [Hodi 2010]), pruritus (24% to 45% [Hodi 2010]), dermatitis (3% to 21%)

Endocrine & metabolic: Weight loss (32%)

Gastrointestinal: Diarrhea (32% to 49%), nausea (25% to 35% [Hodi 2010]), decreased appetite (14% to 27% [Hodi 2010]), increased serum lipase (26%), vomiting (13% to 24% [Hodi 2010]), constipation (21% [Hodi 2010]), increased serum amylase (17%), colitis (8% to 16%), enterocolitis (5% to 16%), abdominal pain (15% [Hodi 2010])

Hematologic & oncologic: Decreased hemoglobin (25%), anemia (12% [Hodi 2010])

Hepatic: Increased serum alanine aminotransferase (≤46% [Hodi 2010]), increased serum aspartate aminotransferase (≤38% [Hodi 2010]), increased serum alkaline phosphatase (17%), increased serum bilirubin (11%), hepatitis (5% to 11%)

Respiratory: Cough (16% [Hodi 2010]), dyspnea (15% [Hodi 2010])

Miscellaneous: Fever (12% to 18% [Hodi 2010])

1% to 10%:

Central nervous system: Insomnia (10%), neuropathy (≤2%)

Dermatologic: Urticaria (2%), vitiligo (2% [Hodi 2010])

Endocrine & metabolic: Pituitary insufficiency (4%), hypophysitis (2% [Hodi 2010]), adrenocortical insufficiency (≤2% [Hodi 2010]), hypothyroidism (≤2% [Hodi 2010])

Gastrointestinal: Intestinal perforation (1% to 2%), pancreatitis (1%)

Hematologic & oncologic: Eosinophilia (1% to 2%)

Hepatic: Hepatotoxicity (grade 2: 3%)

Immunologic: Antibody development (1%)

Renal: Increased serum creatinine (10%), nephritis (≤1%)

Frequency Not Defined:

Dermatologic: Bullous dermatitis, dermal ulcer, skin or other tissue necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis

<1%, postmarketing, and/or case reports: Acute respiratory distress, arthritis, blepharitis, bronchiolitis obliterans organizing pneumonia (Barjaktarevic 2013), capillary leak syndrome (Hodi 2010), conjunctivitis, Cushing syndrome, drug reaction with eosinophilia and systemic symptoms, encephalitis, episcleritis, erythema multiforme, esophagitis, gastrointestinal ulcer, giant-cell arteritis, graft versus host disease, Graves' ophthalmopathy, Guillain-Barré syndrome, hemolytic anemia, hepatic failure, hepatitis (immune-mediated), hypersensitivity angiitis, hyperthyroidism, hypoacusis (neurosensory), hypogonadism, immunological signs and symptoms (hemophagocytic lymphohistiocytosis) (Hantel 2018), infusion related reaction, iritis, meningitis, myasthenia gravis, myocarditis, myositis (ocular), pericarditis, peripheral motor neuropathy, pneumonitis, polymyalgia rheumatica, polymyositis, psoriasis, renal failure syndrome, sarcoidosis, scleritis, thyroiditis (autoimmune), uveitis, vascular disease, vasculitis

Warnings/Precautions

Concerns related to adverse effects:

• Immune-mediated adverse effects: [US Boxed Warning]: 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. Immune-mediated reactions have been reported when used in combination with nivolumab (may occur after discontinuation of therapy). Reactions reported (either as nivolumab monotherapy or in combination with ipilimumab) include myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatic, autoimmune neuropathy, Guillain-Barre syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome. If immune-mediated adverse effects are suspected, exclude other causes. Based on the severity of the reaction, permanently discontinue or withhold ipilimumab and/or nivolumab and administer high-dose corticosteroids (and hormone replacement therapy, if appropriate). Upon improvement to ≤ grade 1, initiate corticosteroid taper (over at least 1 month). After corticosteroid taper is completed and based on the severity of the reaction, may consider reinitiating therapy.
• Dermatologic toxicity: Severe, life-threatening, or fatal immune-mediated dermatitis or rash has been reported. For single-agent ipilimumab, the median time to onset for dermatologic toxicity was 11 to 22 days; the median time to onset of immune-mediated dermatitis when ipilimumab was used in combination with nivolumab was 1 to 1.5 months. 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. When required, the duration of systemic corticosteroid treatment ranged from 15 days to 3.4 months (followed by a taper).
• Encephalitis: Immune-mediated encephalitis (without clear etiology) may occur when used in combination with nivolumab (has been reported after ~0.5 to 4 months of treatment exposure). Withhold for new-onset moderate to severe neurologic signs/symptoms; evaluate to rule out other neurologic causes or infection. Evaluate with neurology consultation, brain MRI, and lumbar puncture. For confirmed immune-mediated encephalitis felt to be caused by ipilimumab/nivolumab (if other etiologies are ruled out), administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent), followed by a corticosteroid taper. One case required the addition of infliximab to corticosteroid therapy. Permanently discontinue if immune-mediated encephalitis occurs.
• Endocrinopathy: 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. When used as a single-agent for the treatment of melanoma, 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. When used in combination with nivolumab, the median time to onset for various endocrinopathies (eg, hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus) ranged from 1.1 to 3.7 months. Monitor thyroid function tests, 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.
• Gastrointestinal toxicity: Immune-mediated enterocolitis/colitis (including fatal cases) may occur. For single-agent ipilimumab, the median time to onset of ≥ grade 3 enterocolitis/colitis was 1.1 to 1.7 months (range: 1 day to 33.1 months); the median time to onset of immune-mediated colitis when ipilimumab was used in combination with nivolumab was 1.7 to 2.4 months (range: 2 days to 19 months). Monitor for signs and symptoms of enterocolitis (abdominal pain, blood or mucus in stool, or diarrhea; with or without fever) and intestinal perforation (peritoneal signs, ileus). If enterocolitis/colitis develops, infectious causes should be ruled out; consider endoscopy for persistent or severe symptoms. Withhold ipilimumab treatment and administer antidiarrheals for moderate enterocolitis/colitis (diarrhea with ≤6 stools over baseline abdominal pain, mucus or blood in stool); if persists for >1 week, initiate systemic corticosteroids (prednisone at 0.5 mg/kg/day or equivalent). If severe enterocolitis/colitis (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). When required, the median durations of systemic corticosteroid treatment ranged from 10 days to 4.7 months (followed by a taper). Corticosteroid-refractory immune-mediated colitis has been reported. Cytomegalovirus infection/reactivation has been reported with ipilimumab in patients who develop corticosteroid-refractory immune-mediated colitis; if corticosteroid refractory colitis develops, consider repeat infection workup to exclude other etiologies. If other causes have been excluded, consider replacement of corticosteroid therapy or the addition of an anti-tumor necrosis factor or other immunosuppressive therapy for management of immune-mediated enterocolitis/colitis unresponsive to 3 to 5 days of systemic corticosteroids or recurring after symptomatic improvement.
• Graft-versus-host disease: Serious and potentially fatal graft-versus-host disease can occur in patients receiving ipilimumab before or after allogeneic hematopoietic stem cell transplantation; monitor closely.
• Hepatotoxicity: 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 single-agent ipilimumab for adjuvant treatment of melanoma was 2 months; the median time to onset of immune-mediated hepatitis when ipilimumab was used in combination with nivolumab was ~2 months. Monitor 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. If grade 3 or 4 hepatotoxicity develops, permanently discontinue ipilimumab and initiate systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent). When required, the median durations of systemic corticosteroid treatment ranged from 1 to 4.4 months (followed by a taper). 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.
• Infusion-related reactions: Infusion-related reactions have occurred when used in combination with nivolumab; may be severe. Monitor closely; discontinue for severe or life-threatening reactions. Mild or moderate reactions may be managed by interrupting or decreasing the infusion rate.
• Nephrotoxicity: Renal dysfunction has occurred with the combination of ipilimumab and nivolumab therapy. Immune-mediated nephritis (defined as renal dysfunction or ≥ grade 2 creatinine elevations with no other clear etiology and requiring corticosteroid use) may occur. The median time to onset was 3 months. Approximately three-quarters of patients with immune-mediated nephritis and renal dysfunction received high-dose systemic corticosteroids (≥40 mg prednisone or equivalent per day) for a median duration of 17 days; complete resolution occurred in close to two-thirds of patients, some patients resumed combination therapy with no recurrence. Monitor serum creatinine at baseline and periodically during treatment. Initiate corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper for life-threatening (grade 4) serum creatinine elevation and permanently discontinue ipilimumab. Withhold ipilimumab for moderate (grade 2) and severe (grade 3) creatinine elevations and administer corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; if toxicity worsens or does not improve, increase to prednisone 1 to 2 mg/kg daily (or equivalent).
• Neuropathy: Immune-mediated neuropathies (some fatal) may occur. Grade 3 paresthesia/hypoesthesia, 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.
• Ocular toxicity: 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).
• Pulmonary toxicity: Ipilimumab in combination with nivolumab may cause immune-mediated pneumonitis (severe pneumonitis or interstitial lung disease); fatal cases have been reported. Immune-mediated pneumonitis is defined as no other clear etiology and requiring corticosteroid use. The median time to onset was 1.9 to 2.6 months in patients receiving ipilimumab in combination with nivolumab. Monitor for signs (with radiographic imaging) and symptoms of pneumonitis. May require treatment interruption, corticosteroid therapy, and/or permanent discontinuation. Grades 2, 3, or 4 pneumonitis should be managed with corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. The median duration of systemic corticosteroid treatment was 19 days (range: 4 days to 3.2 months). Some cases required the addition of infliximab to corticosteroid therapy. Complete resolution of pneumonitis occurred in a majority of patients. Withhold ipilimumab for moderate to severe signs and symptoms; permanently discontinue ipilimumab for life-threatening (grade 4) immune-mediated pneumonitis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Monitoring Parameters

Monitor liver function and evaluate for signs of hepatotoxicity prior to each dose; if hepatotoxicity develops, liver function should be monitored more frequently until resolves. If liver functions tests are >8 times ULN, monitor every other day until begin to fall, then weekly until normal (Weber 2012). Monitor serum chemistries and adrenocorticotropic hormone (ACTH) prior to each dose. Monitor serum creatinine (baseline and periodic). Monitor for signs of hypophysitis, adrenal insufficiency and thyroid disorders (eg, abdominal pain, fatigue, headache, hypotension, mental status changes, unusual bowel habits). Monitor TSH, free T₄ and cortisol levels (morning) at baseline, prior to dose, and as clinically indicated. Monitor for signs and symptoms of enterocolitis (abdominal pain, blood or mucus in stool or diarrhea), and intestinal perforation (peritoneal signs, ileus). Monitor for rash, pruritus, and other signs of dermatologic toxicity. Monitor for signs of motor or sensory neuropathy (unilateral or bilateral weakness, sensory changes or paresthesia). Monitor for ocular toxicity at baseline, then at 4 to 8 weeks with further evaluations as clinically indicated (Renouf 2012). Monitor for signs/symptoms of pneumonitis, encephalitis, and infusion-related reactions.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to ipilimumab may cause fetal harm. Ipilimumab is a humanized monoclonal antibody (IgG₁). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Females of reproductive potential should use effective contraception during treatment and for 3 months following the last ipilimumab dose.

A pregnancy registry has been established to collect information about women exposed to ipilimumab during pregnancy. Advise pregnant women to enroll in the Pregnancy Safety Surveillance Study by calling 1-844-593-7869.

Patient Education

What is this drug used for?

• It is used to treat cancer.

Frequently reported side effects of this drug

• Headache
• Diarrhea
• Nausea
• Vomiting
• Lack of appetite
• Trouble sleeping
• Back pain
• Bone pain
• Joint pain
• Weight loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Brain problem like change in balance, confusion, trouble with memory, muscle weakness, seizures, stiff neck, severe nausea, or vomiting.
• Thyroid, pituitary, or adrenal gland problems like mood changes, behavioral changes, weight changes, constipation, deeper voice, dizziness, passing out, cold sensation, severe fatigue, hair loss, persistent headache, or decreased sex drive.
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Bowel problems like black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Burning or numbness feeling
• Muscle weakness
• Paralysis
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Shortness of breath
• Swelling in arms or legs
• Severe loss of strength and energy
• Vision changes
• Eye pain
• Severe eye irritation
• Bruising
• Bleeding
• Change in bowel habits
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.