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Ipilimumab

Medically reviewed on March 25, 2018

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.

Half-Life Elimination

Terminal: 15.4 days

Special Populations Note

Body weight: Clearance is increased with increasing body weight.

Use: Labeled Indications

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

Melanoma, adjuvant treatment: Adjuvant treatment of cutaneous melanoma in patients with pathologic involvement of regional lymph nodes of more than 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)

Off Label Uses

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

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 doses (in combination with nivolumab; with nivolumab continued until disease progression or unacceptable toxicity) (Larkin 2015).

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

Renal cell cancer, advanced, combination therapy: IV: 1 mg/kg once every 3 weeks (in combination with nivolumab) for 4 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.

Dosing: Pediatric

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: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Impairment at baseline:

Mild impairment (total bilirubin >1 to 1.5 x ULN or AST >ULN): No dosage adjustment necessary.

Moderate or severe impairment (total bilirubin >1.5 x ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Impairment during treatment:

AST or ALT >2.5 to ≤5 x ULN or bilirubin >1.5 to ≤3 x ULN: Temporarily withhold treatment.

ALT or AST >5 times ULN, or total bilirubin >3 times ULN: Permanently discontinue; also administer systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent). May begin tapering corticosteroid (over 1 month) when LFTs show sustained improvement or return to baseline.

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) 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 for renal cell carcinoma, 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.

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 over 90 minutes 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.

Combination therapy with nivolumab: When administered in combination with nivolumab, infuse nivolumab first followed by ipilimumab on the same day. 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% [includes Stevens-Johnson syndrome, toxic epidermal necrolysis, dermal ulceration, necrotic, bullous or hemorrhagic dermatitis])

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%)

<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, DRESS syndrome, encephalitis, episcleritis, erythema multiforme, esophagitis, gastrointestinal ulcer, giant-cell arteritis, Graves' ophthalmopathy, Guillain-Barré syndrome, hemolytic anemia, hepatic failure, hepatitis (immune-mediated), hypersensitivity angiitis, hyperthyroidism, hypoacusis (neurosensory), hypogonadism, increased thyroid stimulating hormone level, 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

ALERT: U.S. Boxed Warning

Immune-mediated adverse reactions:

Ipilimumab can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of ipilimumab.

Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries, including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.

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. The median time to onset for dermatologic toxicity is 2 weeks 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.

• Encephalitis: Immune-mediated encephalitis (without clear etiology) may occur when used in combination with nivolumab (has been reported after ~4 month 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. 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 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 1.4 to 3.4 months. 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.

• Gastrointestinal toxicity: Immune-mediated enterocolitis/colitis (including fatal cases) may occur. The median time to onset of grade 3 to 5 enterocolitis/colitis 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/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, 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/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). May consider adding anti-tumor necrosis factor (TNF) 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.

• 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 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.

• 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 2.5 months. Three-quarters of patients received high-dose systemic corticosteroids (at least 40 mg prednisone or equivalent per day) for a median duration of 15 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. 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 2.6 months in patients receiving ipilimumab in combination with nivolumab for the treatment of advanced renal cell carcinoma. 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. Some cases required the addition of infliximab to corticosteroid therapy. Withhold ipilimumab for moderate to severe signs and symptoms; permanently discontinue ipilimumab for life-threatening (grade 4) immune-mediated pneumonitis.

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 Considerations

Adverse effects were observed in animal reproduction studies. Ipilimumab is an IgG1 immunoglobulin and human IgG1 is known to cross the placenta, therefore, ipilimumab may be expected to reach the fetus. Ipilimumab may cause fetal harm if administered during pregnancy (based on the mechanism of action). 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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, diarrhea, nausea, vomiting, lack of appetite, insomnia, or weight loss. Have patient report immediately to prescriber signs of infusion reaction, signs of thyroid, pituitary, or adrenal gland problems (mood changes, behavioral changes, weight changes, constipation, deeper voice, dizziness, passing out, cold sensation, severe fatigue, hair loss, persistent headache, or decreased libido), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea), signs of hormonal imbalance (behavioral changes; dizziness or passing out; sensation of cold; sluggishness; memory impairment; mood changes; severe headache; or weight gain), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of myocarditis (excessive weight gain, abnormal heartbeat, angina, tachycardia, fever, flu-like signs, shortness of breath, swelling of arms or legs, severe dizziness, or passing out), signs of meningitis (headache with fever, stiff neck, nausea, confusion, or sensitivity to light), burning or numbness feeling, muscle weakness, paralysis, severe loss of strength and energy, vision changes, eye pain, severe eye irritation, bruising, bleeding, or change in bowel habits (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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

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