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Ipilimumab

Medically reviewed by Drugs.com. Last updated on Nov 13, 2020.

Pronunciation

(ip i LIM u mab)

Index Terms

  • Ipilimumab, inj
  • MDX-010
  • MDX-CTLA-4
  • MOAB-CTLA-4

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]

Brand Names: U.S.

  • Yervoy

Pharmacologic Category

  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

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.

Excretion

Clearance: Ipilimumab monotherapy: 16.8 mL/hour; compared to ipilimumab monotherapy, ipilimumab clearance is unchanged when administered every 3 weeks in combination with nivolumab, increased 30% when administered every 6 weeks in combination with nivolumab, and increased 22% when administered every 6 weeks in combination with nivolumab and platinum-based doublet chemotherapy.

Half-Life Elimination

Terminal: 15.4 days

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.

Hepatocellular carcinoma: Treatment of hepatocellular carcinoma (in combination with nivolumab) in patients who have been previously treated with sorafenib.

Malignant pleural mesothelioma, unresectable: First-line treatment (in combination with nivolumab) of unresectable malignant pleural mesothelioma in adults.

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.

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

Non-small cell lung cancer, metastatic: First-line treatment of metastatic non-small cell lung cancer (in combination with nivolumab) in adults whose tumors express PD-L1 (≥1%) as determined by an approved test, and with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

Non-small cell lung cancer, metastatic or recurrent: First-line treatment of metastatic or recurrent non-small cell lung cancer (in combination with nivolumab and 2 cycles of platinum doublet chemotherapy) in adults with no EGFR or ALK genomic tumor aberrations.

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

Off Label Uses

Melanoma, metastatic with brain metastases

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 therapy

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)

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

Dosing: Adult

Note: When given in combination with nivolumab, if nivolumab is withheld, ipilimumab should also be withheld, and if ipilimumab is withheld, nivolumab should be withheld.

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

Hepatocellular carcinoma: IV: 3 mg/kg once every 3 weeks (in combination with nivolumab) for 4 combination doses, followed by nivolumab monotherapy until disease progression or unacceptable toxicity (Yau 2019) (refer to Nivolumab monograph for nivolumab dosing information).

Malignant pleural mesothelioma, unresectable (first-line therapy): IV: 1 mg/kg once every 6 weeks (in combination with nivolumab) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression.

Melanoma, adjuvant treatment: IV: 10 mg/kg every 3 weeks for up to 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years unless disease progression or unacceptable toxicity occur (Eggermont 2016).

Off-label dosing: IV: 3 mg/kg once every 3 weeks for 4 doses (induction), followed by 3 mg/kg once every 12 weeks for up to 4 additional doses (maintenance) or until disease progression or unacceptable toxicity for up to a maximum of 60 weeks (Tarhini 2020).

Melanoma, metastatic with brain metastases (off-label use): IV: 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).

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; Larkin 2019).

Non-small cell lung cancer, metastatic, PD-L1 expressing: IV: 1 mg/kg once every 6 weeks (in combination with nivolumab; refer to Nivolumab monograph for nivolumab dosing information) until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression (Hellmann 2019).

Non-small cell lung cancer, metastatic or recurrent: IV: 1 mg/kg once every 6 weeks (in combination with nivolumab and 2 cycles of histology-based platinum-doublet chemotherapy; refer to Nivolumab monograph for nivolumab dosing information) until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression (Reck 2020).

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; Motzer 2019).

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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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 ipilimumab is withheld, nivolumab should also be withheld, and when nivolumab is withheld, ipilimumab should be withheld. Refer to Nivolumab monograph for information on nivolumab dosage adjustment for toxicity.

Immune-mediated adverse reactions (general information):Withhold ipilimumab for grade 3 immune-mediated adverse reactions and permanently discontinue ipilimumab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, persistent moderate (grade 2) or severe (grade 3) reactions lasting 12 weeks or longer beyond the last ipilimumab dose (excluding endocrinopathies), or inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating corticosteroids.

In general, if ipilimumab treatment interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to ≤ grade 1; upon improvement to grade 1 or lower, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroid therapy.

Ipilimumab Recommended Dosage Modifications for Adverse Reactions

Adverse reaction

Severity

Ipilimumab dosage modification

Immune-mediated adverse reactions

Colitis/Diarrhea

Grade 2

Withhold ipilimumab; resume ipilimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.

Grade 3 or 4

Permanently discontinue ipilimumab.

Dermatologic toxicity: Nonbullous/exfoliative rashes

Mild to moderate

Manage with topical emollients and/or topical corticosteroids. Withhold or permanently discontinue ipilimumab depending on severity; may require management with systemic corticosteroids.

Dermatologic toxicity: Exfoliative or bullous conditions

Grade 2

Withhold ipilimumab and refer for specialist assessment.

Grade 3 or 4

Permanently discontinue ipilimumab.

Endocrinopathies

Grade 2, 3, or 4

Withhold ipilimumab if not clinically stable. Moderate and life-threatening endocrinopathy may require long-term hormone replacement therapy (eg, adrenal or thyroid hormone therapy).

Hypophysitis (signs of mass effects, including headache, photophobia, or visual field cuts)

Grade 2, 3, or 4

Withhold ipilimumab; resume ipilimumab when acute symptoms have resolved. Initiate hormone replacement as clinically indicated. Depending on the severity, permanently discontinue ipilimumab.

Pneumonitis

Grade 2

Withhold ipilimumab; resume ipilimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.

Grade 3 or 4

Permanently discontinue ipilimumab.

Neurologic toxicities

Grade 2

Withhold ipilimumab; resume ipilimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue ipilimumab with signs of encephalitis or respiratory insufficiency due to neurologic toxicity (regardless of grade).

Grade 3 or 4

Permanently discontinue ipilimumab.

Myocarditis

Grade 2

Withhold ipilimumab; resume ipilimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.

Grade 3 or 4

Permanently discontinue ipilimumab.

Ophthalmologic

Grade 2, 3 or 4 that does not improve to grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment

Permanently discontinue ipilimumab.

Pancreatitis

Grade 3 or 4 amylase or lipase increases

Permanent ipilimumab discontinuation is recommended (Weber 2012).

Other adverse reactions

Infusion reactions

Grade 1 or 2

Interrupt or slow the rate of ipilimumab infusion.

Grade 3 or 4

Permanently discontinue ipilimumab.

Reconstitution

Prior to preparation, allow vial(s) to sit at room temperature for ~5 minutes. Inspect vial prior to use; solution may have a pale yellow color or may contain translucent-to-white or white amorphous ipilimumab particles; discard if cloudy or for pronounced discoloration. 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. Do not mix with other medications.

Administration

IV: Infuse through a sterile, nonpyrogenic, low protein-binding in-line filter. Do not administer with other medications. Flush with NS or D5W after each ipilimumab infusion.

Colorectal cancer (metastatic), hepatocellular carcinoma, malignant pleural mesothelioma, non-small cell lung cancer, 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 as nivolumab). Use separate infusion bags and filters for each infusion.

Combination therapy with nivolumab and platinum-based doublet chemotherapy: When administered in combination with nivolumab and platinum-based doublet chemotherapy, infuse nivolumab first, followed by ipilimumab, and then the platinum-based doublet chemotherapy (all on the same day). Use separate infusion bags and filters for each infusion.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Do not shake. 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 (from time of preparation to time of infusion) 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

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Dermatologic: Pruritus (24% to 45%) (Hodi 2010), skin rash (15% to 50%) (Hodi 2010)

Endocrine & metabolic: Weight loss (32%)

Gastrointestinal: Abdominal pain (15%) (Hodi 2010), colitis (≤31%), constipation (21%) (Hodi 2010), decreased appetite (14% to 27%) (Hodi 2010), diarrhea (≤49%), increased serum amylase (17%), increased serum lipase (26%), nausea (25% to 35%) (Hodi 2010), vomiting (13% to 24%) (Hodi 2010)

Hematologic & oncologic: Anemia (12%) (Hodi 2010)

Hepatic: Hepatitis (4% to 15%), increased serum alanine aminotransferase (≤46%) (Hodi 2010), increased serum alkaline phosphatase (17%), increased serum aspartate aminotransferase (≤38%) (Hodi 2010), increased serum bilirubin (11%)

Nervous system: Fatigue (41% to 46%), headache (15% to 33%) (Hodi 2010)

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

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

1% to 10%:

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

Endocrine & metabolic: Adrenocortical insufficiency (≤2%) (Hodi 2010), Cushing’s syndrome (≤2%), endocrine disease (4% to 28%), hyperthyroidism (≤2%), hypophysitis (2%) (Hodi 2010), hypothyroidism (≤2%) (Hodi 2010), pituitary insufficiency (2% to 7%)

Gastrointestinal: Pancreatitis (1%)

Genitourinary: Hypogonadism (≤2%)

Hematologic & oncologic: Cytopenia (3%), eosinophilia (2%)

Immunologic: Antibody development (1%)

Nervous system: Insomnia (10%), neuropathy (≤2%)

Renal: Increased serum creatinine (10%)

Miscellaneous: Infusion related reaction (3%)

<1%:

Cardiovascular: Arteritis (temporal), hypersensitivity vasculitis, myocarditis, pericarditis, peripheral angiopathy, vasculitis

Dermatologic: Erythema multiforme, psoriasis

Gastrointestinal: Duodenitis, esophagitis, gastritis, ulcerative bowel lesion

Hematologic & oncologic: Aplastic anemia, lymphadenitis (histiocytic necrotizing [Kikuchi lymphadenitis]), sarcoidosis

Immunologic: Organ transplant rejection

Infection: Systemic inflammatory response syndrome

Nervous system: Demyelinating disease, encephalitis, Guillain-Barré syndrome, meningitis, motor dysfunction, myasthenia gravis, nerve palsy

Neuromuscular & skeletal: Arthritis, myelitis, myositis (including orbital), polymyalgia rheumatica, polymyositis, rhabdomyolysis

Ophthalmic: Blepharitis, conjunctivitis, episcleritis, Graves' ophthalmopathy, iritis, scleritis, uveitis

Otic: Hypoacusis (neurosensory)

Renal: Renal failure syndrome

Respiratory: Acute respiratory distress syndrome

Frequency not defined: Ophthalmic: Vogt-Koyanagi-Harada disease

Postmarketing:

Cardiovascular: Capillary leak syndrome (Hodi 2010)

Dermatologic: Drug reaction with eosinophilia and systemic symptoms

Hematologic & oncologic: Immunological signs and symptoms (hemophagocytic lymphohistiocytosis) (Hantel 2018)

Immunologic: Graft versus host disease

Respiratory: Bronchiolitis obliterans organizing pneumonia (Barjaktarevic 2013)

Warnings/Precautions

Concerns related to adverse effects:

• Immune-mediated adverse effects: Severe and fatal immune-mediated adverse effects may occur with ipilimumab. While any organ system may be involved, the most 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 ipilimumab discontinuation. Evaluate liver function, serum creatinine, adrenocorticotropic hormone level, and thyroid function tests at baseline and prior to each ipilimumab dose. Assess for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy at baseline and prior to each dose. Monitor for signs/symptoms of manifestations of underlying immune-mediated adverse reactions (early identification and management are necessary to ensure ipilimumab safety). Medically manage immune-mediated adverse reactions promptly and refer for specialty consultation as appropriate. Depending on the severity, withhold or permanently discontinue ipilimumab. In general, if treatment interruption or discontinuation are required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to ≤ grade 1. Upon improvement to grade 1 or lower, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroid therapy. Institute hormone replacement therapy for endocrinopathies as clinically necessary.

• Dermatologic toxicity: Ipilimumab may cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens-Johnson S-syndrome, and toxic epidermal necrolysis. Mild to moderate nonbullous/exfoliative rashes may be managed with topical emollients and/or topical corticosteroids. Withhold or permanently discontinue ipilimumab depending on severity; may require management with systemic corticosteroids. Immune-mediated rash (including grade 2 or higher events) occurred with both single-agent ipilimumab and when ipilimumab was used in combination with nivolumab. Higher ipilimumab doses were generally associated with an increased incidence of rash. In one ipilimumab/nivolumab combination therapy study, the median time to onset of immune-mediated rash was 15 days (range: 6 days to 3.1 months); some of those patients received high-dose corticosteroids (at least 40 mg prednisone equivalents/day) for a median duration of 8 days (range: 1 to 15 days). Rash resolved in a majority of patients following treatment interruption (of at least 1 dose) or permanent discontinuation; systemic corticosteroids were administered to some patients. Some patients experienced a recurrence when ipilimumab was restarted after symptom improvement. Immune-mediated erythema multiforme has also been observed with ipilimumab (either as s single agent or in combination with nivolumab).

• Endocrinopathy: Single-agent ipilimumab has been associated with immune-mediated endocrinopathies; grades 3 to 4 endocrinopathies occurred in a small number of patients. The grade 3 and 4 events mostly consisted of hypopituitarism, with some patients also experiencing additional concomitant endocrinopathies (eg, adrenal insufficiency, hypogonadism, hyperthyroidism, hypothyroidism); grade 3 to 4 hyperthyroidism and primary hypothyroidism were also observed. Some patients required hospitalization for severe endocrinopathies. Grade 2 (moderate) endocrinopathy events included primary or secondary adrenal insufficiency, Cushing syndrome, hypogonadism, hypopituitarism, hyperthyroidism, hypothyroidism, and/or thyroiditis. Moderate and life-threatening endocrinopathy may require long-term hormone replacement therapy (eg, adrenal or thyroid hormone therapy) and may require systemic corticosteroids as immunosuppression. Some patients reported resolution of endocrinopathy.

- Ipilimumab has been associated with immune-mediated hypophysitis, which may present with acute mass effect symptoms, including headache, photophobia, or visual field cuts. Hypophysitis may lead to hypopituitarism. The median time to onset of hypophysitis in one study (using combination ipilimumab/nivolumab) was 3.7 months (range: 3 to 4.3 months). Initiate hormone replacement as clinically indicated and, depending on the severity, withhold or permanently discontinue ipilimumab; may also require treatment with systemic corticosteroids. Hypophysitis resolved in over half of patients. Some patients experienced a recurrence when treatment was restarted after symptom improvement.

- Adrenal insufficiency (grade 2 to 4) occurred with ipilimumab in combination with nivolumab. In one study, the median time to onset was 2.8 months (range: 1.4 to 8 months). Adrenal insufficiency led to ipilimumab/nivolumab treatment interruption or permanent discontinuation in a small number of patients. Most patients with adrenal insufficiency received hormone replacement therapy and systemic corticosteroids. Adrenal insufficiency resolved in some patients. Some patients experienced a recurrence when ipilimumab and/or nivolumab treatment was restarted after symptom improvement.

- Hyperthyroidism (grade 2 and 3) has occurred with ipilimumab in combination with nivolumab. In one study, the median time to onset was 1.4 months (range: 1.4 to 2.8 months). Although ipilimumab/nivolumab treatment interruption was necessary in some patients, no patients required ipilimumab discontinuation for hyperthyroidism. A thyroid synthesis inhibitor and/or systemic corticosteroids were necessary to manage hyperthyroidism in ~20% of patients. Hyperthyroidism resolved in most patients. Some patients experienced a recurrence when ipilimumab and/or nivolumab treatment was restarted after symptom improvement.

- Hypothyroidism (or thyroiditis resulting in hypothyroidism) has occurred with ipilimumab in combination with nivolumab, including grade 2 and 3 hypothyroidism. Median time to onset of hypothyroidism in one study was 3.3 months (range: 1.4 to 16.2 months). Hypothyroidism led to ipilimumab/nivolumab treatment interruption or permanent discontinuation in some patients. Most patients were managed with thyroid hormone replacement therapy; systemic corticosteroids were required in some patients. Hypothyroidism resolved in less than half of patients. Recurrence of hypothyroidism occurred rarely when ipilimumab and/or nivolumab treatment was restarted after symptom improvement. Thyroiditis has been reported with ipilimumab in combination with nivolumab, including grade 2 and 3 thyroiditis. Thyroiditis led to ipilimumab/nivolumab treatment interruption or permanent discontinuation in some cases; some patients required systemic corticosteroids. Thyroiditis resolved in a majority of patients. Thyroiditis did not recur in patients whose treatment was restarted after symptom improvement.

- Type 1 diabetes (grade 2 to 4) has also been observed with ipilimumab in combination with nivolumab. Diabetes led to ipilimumab/nivolumab treatment interruption or permanent discontinuation in some cases and systemic corticosteroids were required in some cases. Diabetes resolved in about one quarter of patients. Diabetes did not recur in patients whose treatment was restarted after symptom improvement.

• GI toxicity: Ipilimumab may cause immune-mediated diarrhea/colitis, which may be fatal. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated diarrhea/colitis. In cases of corticosteroid-refractory diarrhea/colitis, consider repeating infectious workup to exclude alternative etiologies. If other causes are excluded, consider addition of an alternative immunosuppressive agent to the corticosteroid therapy or replacement of the corticosteroid therapy in corticosteroid-refractory immune-mediated colitis. Immune-mediated diarrhea/colitis (grade 2 to 5) has occurred with single-agent ipilimumab. Diarrhea/colitis has led to ipilimumab treatment interruption (of at least 1 dose) or permanent discontinuation. Systemic corticosteroids were required in most patients with immune-mediated diarrhea/colitis; some patients required coadministration of an additional immunosuppressant to manage diarrhea/colitis. Resolution of diarrhea/colitis occurred in a majority of patients. Upon ipilimumab reinitiation (following therapy interruption for diarrhea/colitis), recurrence of diarrhea/colitis commonly occurred. Immune-mediated diarrhea/colitis has occurred in ≤10% of patients who received ipilimumab in combination with nivolumab; grade 2 to 4 events have been reported. In one study, the median time to onset was 2 months (range: 1.1 to 19 months). Diarrhea/colitis led to ipilimumab/nivolumab treatment interruption or permanent discontinuation in a small percentage of patients; systemic corticosteroids were required in most patients experiencing diarrhea/colitis and some patients required coadministration of an additional immunosuppressant for management. Diarrhea/colitis resolved in most patients. When ipilimumab or nivolumab was withheld for diarrhea/colitis, treatment was restarted after symptom improvement in some patients and recurrence of diarrhea/colitis commonly occurred. Immune-mediated duodenitis, gastritis, pancreatitis have also been reported (rarely).

• Graft-vs-host disease: Serious and potentially fatal graft-vs-host disease (GVHD) can occur in patients receiving ipilimumab either before or after allogeneic hematopoietic stem cell transplantation (HSCT). These complications may occur despite intervening therapy between CTLA-4 receptor blocking antibody and allogeneic HSCT. Monitor closely for evidence of GVHD and manage promptly. Consider the benefit versus risks of ipilimumab treatment following allogeneic HSCT.

• Hepatitis B virus screening: The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

• Hepatotoxicity: Immune-mediated hepatitis (grade 2 to 5) has occurred with single-agent ipilimumab. Hepatitis has led to ipilimumab treatment interruption (of at least 1 dose) or permanent discontinuation. Systemic corticosteroids have been used to manage immune-mediated hepatitis; some patients required coadministration of another immunosuppressant with corticosteroids to manage hepatitis. If transaminases do not decrease within 48 hours of steroid initiation, consider adding mycophenolate mofetil; may begin tapering corticosteroid (over 1 month) when LFTs show sustained improvement or return to baseline (Weber 2012). Hepatitis resolved in most patients. When ipilimumab was withheld for hepatitis, some patients experienced recurrence of hepatitis when treatment was restarted after symptom improvement. Immune-mediated hepatitis (grade 2 to 4) has also been observed in patients who received ipilimumab in combination with nivolumab. In one study, the median time to onset was 1.3 months (range: 22 days to 4.1 months). Hepatitis has led to ipilimumab or nivolumab treatment interruption (of at least 1 dose) or permanent discontinuation. Systemic corticosteroids were required in most ipilimumab/nivolumab patients experiencing hepatitis; some patients required co-administration of an additional immunosuppressant for management. Hepatitis resolved in most patients. When ipilimumab or nivolumab was withheld for hepatitis, recurrence of hepatitis occurred in most patients whose treatment was restarted after symptom improvement.

• Infusion-related reactions: Infusion-related reactions may occur with ipilimumab; may be severe. Monitor closely; discontinue ipilimumab for severe or life-threatening reactions. Mild or moderate reactions may be managed by interrupting or slowing the ipilimumab infusion rate.

• Nephrotoxicity: Immune-mediated nephritis with renal dysfunction (grade 2 to 4) has occurred with ipilimumab when used in combination with nivolumab, and has led to ipilimumab or nivolumab treatment interruption or permanent discontinuation in some patients. Systemic corticosteroids were used to manage immune-mediated nephritis. Nephritis with renal dysfunction resolved in two-thirds of patients. Nephritis recurred in some patients whose treatment was restarted after symptom improvement.

• Neurotoxicity: Immune-mediated neuropathy, meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, neurosensory hypoacusis, nerve paresis, and motor dysfunction have been observed (rarely) with ipilimumab, either as a single agent or in combination with nivolumab (some have been fatal). Depending on the severity, withhold or permanently discontinue ipilimumab; systemic corticosteroid administration may be necessary.

• Ocular toxicity: Immune-mediated blepharitis, episcleritis, iritis, orbital myositis, scleritis, and uveitis have been observed (rarely) with ipilimumab, either as a single agent or in combination with nivolumab. Some cases can be associated with retinal detachment. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed with ipilimumab and may require treatment with 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). Ocular toxicity may require permanent discontinuation.

• Pulmonary toxicity: Immune-mediated pneumonitis (grade 2 to 4) has occurred with ipilimumab when used in combination with nivolumab; some cases were fatal. In one study, the median time to onset of pneumonitis was 8.3 months (range: 1.2 to 17 months). Pneumonitis has led to ipilimumab and nivolumab treatment interruption or permanent discontinuation. Systemic corticosteroids (eg, at least 40 mg prednisone equivalents/day) were used to treat immune-mediated pneumonitis, followed by a corticosteroid taper; some patients required coadministration of another immunosuppressant (with corticosteroids) to manage pneumonitis. In one study, the median duration of systemic corticosteroid therapy was 23 days (range: 12 days to 1.4 months). Pneumonitis resolved in a majority of patients. In patients receiving ipilimumab with nivolumab for the treatment of non-small cell lung cancer, the median duration of pneumonitis was 1.5 months (range: 5 days to >25 months). Some patients experienced recurrence when treatment was restarted after symptom improvement.

• Other immune-mediated toxicities: Other clinically significant immune-mediated adverse reactions have been observed (rarely although sometimes fatal) with ipilimumab (either as a single agent or in combination with nivolumab), including angiopathy, myocarditis, pericarditis, temporal arteritis, vasculitis, arthritis, myositis, polymyalgia rheumatica, polymyositis, rhabdomyolysis, aplastic anemia, conjunctivitis, cytopenias, eosinophilia, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), hypersensitivity vasculitis, psoriasis, sarcoidosis, systemic inflammatory response syndrome, and solid organ transplant rejection.

Special populations:

• Elderly: In patients with non-small cell lung cancer (NSCLC) who received ipilimumab/nivolumab or ipilimumab/nivolumab with platinum-based doublet chemotherapy, patients ≥75 years of age experienced a higher discontinuation rate due to adverse reactions compared to younger patients with NSCLC. In the malignant pleural mesothelioma study of ipilimumab in combination with nivolumab, patients ≥75 years of age experienced a higher rate of serious adverse reactions and discontinuation due to adverse reactions.

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.

Other warnings/precautions:

• Appropriate use: Select patients for first-line ipilimumab/nivolumab treatment of metastatic NSCLC based on PD-L1 expression. Information on tests to detect PD-L1 expression may be found at http://www.fda.gov/companiondiagnostics.

Monitoring Parameters

PD-L1 expression (first-line ipilimumab/nivolumab treatment of metastatic non-small cell lung cancer). Monitor liver function and evaluate for signs of hepatotoxicity prior to each dose; if hepatotoxicity develops, liver function should be monitored more frequently until resolution. If LFTs are >8 times ULN, monitor every other day until they 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). Hepatitis B virus screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning systemic anticancer therapy (ASCO [Hwang 2020]). Verify pregnancy status prior to ipilimumab treatment initiation (in females of reproductive potential). Monitor for signs/symptoms of manifestations of underlying immune-mediated adverse reactions. 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. Monitor closely for evidence of graft-vs-host disease in patients receiving ipilimumab either before or after allogeneic hematopoietic stem cell transplantation.

Reproductive Considerations

Verify pregnancy status in females of reproductive potential prior to ipilimumab treatment initiation. Females of reproductive potential should use effective contraception during treatment and for 3 months following the last ipilimumab dose.

Pituitary dysfunction, secondary to autoimmune hypophysitis, may occur with ipilimumab therapy; male and female fertility may be impaired (Grunewald 2015).

Pregnancy Considerations

Based on the mechanism of action and findings 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).

Information related to ipilimumab in pregnancy is limited to case reports describing use in patients with metastatic melanoma (Burotto 2018; Mehta 2018; Menzer 2018).

Guidelines are available for the diagnosis, treatment, and follow-up of cancer during pregnancy; the guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team) (ESMO [Peccatori 2013]; Swetter 2019). Until additional information is available, use of ipilimumab for the treatment of melanoma during pregnancy is not recommended (ESMO [Peccatori 2013]).

A pregnancy registry has been established to collect information about women exposed to ipilimumab during pregnancy. Ipilimumab exposures during pregnancy should be reported to the manufacturer by calling 1-844-593-7869.

Patient Education

What is this drug used for?

• It is used to treat cancer.

• This drug may be used with another drug called nivolumab. Some side effects may happen more often when this drug is used with nivolumab. Some side effects can be deadly. If you are also using nivolumab, talk with your doctor about the risks and side effects that may happen.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Constipation

• Stomach pain

• Headache

• Diarrhea

• Upset stomach

• Throwing up

• Not hungry

• Trouble sleeping

• Back pain

• Bone pain

• Joint pain

• Weight loss

• Muscle pain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Infusion reaction like back or neck pain, chills, shaking, dizziness, passing out, fever, flushing, itching, rash, shortness of breath, swelling of the face, or wheezing

• Brain problem like change in balance, confusion, trouble with memory, muscle weakness, seizures, stiff neck, severe upset stomach, or throwing up

• 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

• Lung or breathing problems like trouble breathing, shortness of breath, or cough that is new or worse

• Liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes

• Bowel problems like black, tarry, or bloody stools; fever; mucus in stools; throwing up; throwing up blood; severe stomach pain; constipation; or diarrhea

• Nerve problems like burning, numbness, or tingling feeling that is not normal; weakness; or not being able to move a part of the body (paralysis)

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or 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

• Swelling

• Feeling very tired or weak

• Vision changes

• Eye pain

• Severe eye irritation

• Bruising

• Bleeding

• Change in bowel habits

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.