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Ipilimumab

Pronunciation

(ip i LIM u mab)

Index Terms

  • MDX-010
  • MDX-CTLA-4
  • MOAB-CTLA-4

Dosage Forms

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

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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 which 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.

Half-Life Elimination

Terminal: 15.4 days

Special Populations Note

Body weight

Ipilimumab clearance is increased with increasing body weight.

Use: Labeled Indications

US labeling:

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma

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

Canadian labeling:

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma

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

Melanoma, unresectable or metastatic: Adults: 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.

Melanoma, adjuvant treatment: Adults: IV: 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years; if toxicity occurs, doses are omitted (not delayed).

Melanoma, unresectable or metastatic, first-line combination therapy (off-label use): Adults: 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)

Dosage adjustment for toxicity:

US labeling:

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.

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: 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: 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.

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)

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).

Canadian labeling:

Temporarily withhold scheduled dose for the following:

Moderate immune-mediated reactions

Symptomatic endocrinopathy

Note: If receiving prednisone <7.5 mg daily (or equivalent), may resume with complete or partial resolution (to ≤ grade 1) of symptoms. Resume ipilimumab treatment at 3 mg/kg every 3 weeks until all 4 planned doses have been administered or until 16 weeks from initial dose, whichever occurs first.

Permanently discontinue for the following:

Failure to complete treatment course within 16 weeks of initial dose

Persistent moderate adverse reactions or unable to reduce corticosteroid dose to prednisone 7.5 mg daily (or equivalent)

Severe or life-threatening adverse reactions including:

Central nervous system or neuromuscular toxicity: Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis

Dermatologic toxicities: Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations

Gastrointestinal toxicities: Colitis with abdominal pain, fever, ileus, or peritoneal symptoms, increase in stool frequency (≥7 over baseline), stool incontinence, require IV hydration for >24 hours, or GI hemorrhage or perforation; grades 3/4 amylase or lipase increases (Weber, 2012)

Ophthalmic toxicities: Immune-mediated ocular disease unresponsive to topical immunosuppressive treatment

Severe immune-mediated reactions involving any organ system (eg, myocarditis [noninfectious], nephritis, pancreatitis, pneumonitis)

Dosage adjustment in renal impairment: No dosage adjustment necessary.

Dosage adjustment in 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.

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

Compatibility

Stable in NS, D5W

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 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%), headache (15% [Hodi 2010])

Dermatologic: Pruritus (24% to 31% [Hodi 2010]), skin rash (19% to 29%; grades 3 to 5: 2% [Hodi 2010]), dermatitis (grade 2: 12%; grades 3 to 5: 2% to 3% [includes Stevens-Johnson syndrome, toxic epidermal necrolysis, dermal ulceration, necrotic, bullous or hemorrhagic dermatitis])

Gastrointestinal: Nausea (35% [Hodi 2010]), diarrhea (32%; grades 3 to 5: 5%), decreased appetite (27% [Hodi 2010]), vomiting (24% [Hodi 2010]), constipation (21% [Hodi 2010]), abdominal pain (15% [Hodi 2010])

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

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

Miscellaneous: Fever (12% [Hodi 2010])

1% to 10%:

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

Endocrine & metabolic: Pituitary insufficiency (4%; grade ≥2: ≤2%; ), hypophysitis (2% [Hodi 2010]), adrenal insufficiency (≤2% [Hodi 2010]), hypothyroidism (≤2% [Hodi 2010])

Gastrointestinal: Colitis (8%; grades 3 to 5: 5%), enterocolitis (grade 2: 5%; grades 3 to 5: 7%), intestinal perforation (1%)

Hematologic & oncologic: Eosinophilia (1%)

Hepatic: Hepatotoxicity (grade 2: 3%; grades 3 to 5: 1% to 2%), ALT increased (≤2% [Hodi 2010])

Immunologic: Antibody development (1%)

Renal: Nephritis (≤1%)

<1% (Limited to important or life-threatening): Acute respiratory distress syndrome, adrenocortical insufficiency (Hodi 2010), arthritis, blepharitis, bronchiolitis obliterans organizing pneumonia (Barjaktarevic 2013), capillary leak syndrome (Hodi 2010), conjunctivitis, Cushing's syndrome, DRESS syndrome, encephalitis, episcleritis, erythema multiforme, esophagitis, gastrointestinal ulcer, giant-cell arteritis, Guillain-Barré syndrome, hemolytic anemia, hepatic failure, hepatitis (immune-mediated), hypersensitivity angiitis, hyperthyroidism, hypoacusis (neurosensory), hypogonadism, increased serum AST, increased serum bilirubin, increased thyroid stimulating hormone level, infusion related reaction, iritis, meningitis, myasthenia gravis, myelofibrosis, myocarditis, myositis, myositis (ocular), neuropathy (sensory and motor), pancreatitis, pericarditis, peritonitis, pneumonitis, polymyalgia rheumatica, polymyositis, psoriasis, renal failure, sarcoidosis, scleritis, sepsis, 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 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.

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

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

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

• 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.

• 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.

• Ophthalmic toxicity: Administer corticosteroid ophthalmic drops in patients who develop episcleritis, iritis, or uveitis; permanently discontinue ipilimumab if unresponsive to topical ophthalmic immunosuppressive treatments. 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).

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 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 and pruritus. 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).

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

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 diarrhea. Have patient report immediately to prescriber signs of hepatic impairment, signs of bowel problems, signs of hormonal imbalance, signs of renal impairment, signs of pancreatitis, paresthesia, asthenia, dyspnea, excessive weight gain, edema of extremities, angina, vision changes, ophthalmalgia, significant eye irritation, ecchymosis, hemorrhaging, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (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 healthcare 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.

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