General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications:

Pronunciation:
i-pil-li-moo-mab

Trade Name(s)

• Yervoy

Ther. Class.

antineoplastics

Pharm. Class.

monoclonal antibodies

cytotoxic t lymphocyte antigen 4 inhibitors

Indications

• Unresectable/metastatic melanoma (as monotherapy or in combination with nivolumab).
• Adjuvant treatment of cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm in patients who have undergone complete resection, including total lymphadenectomy.
• Previously untreated advanced renal cell carcinoma in patients who are at intermediate or poor risk (in combination with nivolumab).
•  Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Hepatocellular carcinoma in patients who have been previously treated with sorafenib (in combination with nivolumab).
•  First-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1(≥1%) and have no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations (in combination with nivolumab).
•  First-line treatment of metastatic or recurrent NSCLC in patients whose tumors have no EGFR or ALK genomic tumor aberrations (in combination with nivolumab and two cycles of platinum-based chemotherapy).
• First-line treatment of unresectable malignant pleural mesothelioma (in combination with nivolumab).
• First-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma in patients whose tumors express PD-L1(≥1) (in combination with nivolumab).

Action

Binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and prevents it from binding to CD80/CD86 ligands. CTLA-4 is a negative regulator of T-cell activation; binding results in augmented T-cell activation and proliferation as well as enhanced T-cell responsiveness.

Therapeutic Effect(s):

• ↓ spread or recurrence of melanoma and improved survival.
• Improved survival with renal cell carcinoma, NSCLC, malignant pleural mesothelioma, and esophageal squamous cell carcinoma.
• ↓ progression of MSI-H or dMMR metastatic colorectal cancer.
• ↓ progression of hepatocellular carcinoma.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism and Excretion: Unknown.

Half-life: 14.7 days.

TIME/ACTION PROFILE

Contraindication/Precautions

Contraindicated in:

• Lactation: Lactation.

Use Cautiously in:

• Patients undergoing allogeneic hematopoietic stem cell transplantation (↑ risk of graft-versus-host disease;
• OB:  Use only if potential maternal benefit justifies potential risk to the fetus;
• Rep:  Women of reproductive potential;
• Pedi:  Children <12 yr (safety and effectiveness not established).

Adverse Reactions/Side Effects

CV: MYOCARDITIS, pericarditis, vasculitis

Derm: pruritus, rash, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

EENT: hearing loss, immune-mediated iritis, immune-mediated uveitis

Endo: immune-mediated hypothyroidism, IMMUNE-MEDIATED ADRENAL INSUFFICIENCY, immune-mediated hyperthyroidism, immune-mediated hypoparathyroidism, immune-mediated hypophysitis, immune-mediated type 1 diabetes

GI: diarrhea, IMMUNE-MEDIATED COLITIS, immune-mediated gastritis, IMMUNE-MEDIATED HEPATITIS, immune-mediated pancreatitis

GU: immune-mediated nephritis

Hemat: immune-mediated hemolytic anemia

MS: immune-mediated myositis, IMMUNE-MEDIATED RHABDOMYOLYSIS

Neuro: fatigue, autoimmune neuropathy, Guillain-Barré syndrome, IMMUNE-MEDIATED ENCEPHALITIS, IMMUNE-MEDIATED MENINGITIS, immune-mediated myasthenic syndrome, immune-mediated myelitis

Resp: IMMUNE-MEDIATED PNEUMONITIS

Misc: INFUSION REACTIONS

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Concurrent use with  vemurafenib  may ↑ risk of hepatic impairment.

Route/Dosage

Unresectable/Metastatic Melanoma

IV (Adults and Children  ≥12 yr): As monotherapy:  3 mg/kg every 3 wk for up to 4 doses.  In combination with nivolumab:  3 mg/kg every 3 wk for up to 4 doses or unacceptable toxicity (administer after nivolumab on same day); after completing 4 doses of the combination, give nivolumab alone until disease progression or unacceptable toxicity.

Adjuvant Treatment of Melanoma

IV (Adults and Children  ≥12 yr): 3 mg/kg every 3 wk for up to 4 doses, then 3 mg/kg every 12 wk for up to 4 additional doses.

Advanced Renal Cell Carcinoma

IV (Adults): 1 mg/kg every 3 wk for up to 4 doses (administer after nivolumab on same day); after completing 4 doses of the combination, give nivolumab alone until disease progression or unacceptable toxicity.

Colorectal Cancer

IV (Adults): 1 mg/kg every 3 wk for 4 doses (administer after nivolumab on same day); after completing 4 doses of the combination, give nivolumab alone until disease progression or unacceptable toxicity.

Hepatocellular Carcinoma

IV (Adults): 3 mg/kg every 3 wk for 4 doses (administer after nivolumab on same day); after completing 4 doses of the combination, give nivolumab alone until disease progression or unacceptable toxicity.

Metastatic or Recurrent Non-Small Cell Lung Cancer

IV (Adults): 1 mg/kg every 6 wk until disease progression, unacceptable toxicity, or for up to 2 yr (if no disease progression) (administer after nivolumab, but before platinum-based chemotherapy [if being given] on same day).

Malignant Pleural Mesothelioma

IV (Adults): 1 mg/kg every 6 wk until disease progression, unacceptable toxicity, or for up to 2 yr (if no disease progression) (administer after nivolumab on same day).

Esophageal Squamous Cell Carcinoma

IV (Adults): 1 mg/kg every 6 wk until disease progression, unacceptable toxicity, or for up to 2 yr (administer after nivolumab on same day).

Availability

Solution for injection: 5 mg/mL

Assessment

• Monitor for signs and symptoms of colitis (diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and bowel perforation (peritoneal signs, ileus). Rule out infection and consider endoscopic evaluation.  If Grade 2 colitis occurs,  hold therapy and administer corticosteroids (initial dose of 1–2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper). Resume therapy if Grade ≤1 after corticosteroid taper. Permanently discontinue ipilimumab if no complete or partial resolution within 12 wk of last dose or inability to reduce prednisone to ≤10 mg per day (or equivalent) within 12 wk of initiating steroids.  If Grade 3 or 4 colitis occurs,  permanently discontinue ipilimumab.
• Assess for skin reactions, including SJS, TEN, and DRESS (prodrome of fever, malaise, mucosal lesions, progressive skin rash, blisters, lymphadenopathy, conjunctivitis, myalgias, hepatitis, eosinophilia), during therapy. Treat mild to moderate nonexfoliative rashes with topical emollients and/or topical corticosteroids.  If SJS, TEN, or DRESS is suspected,  hold ipilimumab.  If SJS, TEN, or DRESS is confirmed,  permanently discontinue ipilimumab.
• Monitor for signs and symptoms of pneumonitis (new or worsening cough, chest pain, shortness of breath) during therapy. Evaluate with x-ray. Administer corticosteroids (initial dose of 1–2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper).  For Grade 2 pneumonitis,  hold ipilimumab and resume if complete or partial resolution (Grade ≤1) after corticosteroid taper.  For Grade 3 or 4 or recurrent Grade 2 pneumonitis,  permanently discontinue ipilimumab.
• Monitor for signs and symptoms of neurologic toxicity (headache, neck stiffness, change in consciousness, weakness) periodically during therapy.  If Grade 2 symptoms occur,  hold ipilimumab.  If Grade 3 or 4 symptoms occur,  permanently discontinue ipilimumab.
• Monitor for signs and symptoms of hypophysitis (headache, photophobia, visual field defects) during therapy. May cause hypopituitarism. Begin hormone replacement therapy. Hold or permanently discontinue ipilimumab based on severity.
• Assess eyes for signs and symptoms of uveitis, iritis, or episcleritis. Administer corticosteroid eye drops if these occur. Consider Vogt-Koyanagi-Harada-like syndrome if uveitis occurs with other immune-mediated adverse reactions. May require treatment with systemic steroids to ↓ the risk of permanent vision loss.  If Grade 2–4 ophthalmologic symptoms occur that do not improve to Grade 1 within 2 wk while receiving topical therapy or that requires systemic treatment,  permanently discontinue ipilimumab.
• Monitor for signs and symptoms of infusion-related reactions (fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, urticaria) during infusion.  If Grade 1 or 2 infusion-related reactions occur,  interrupt or slow rate of infusion.  If Grade 3 or 4 infusion-related reactions occur,  stop infusion and permanently discontinue ipilimumab.
• Monitor for signs and symptoms of cardiovascular events during therapy. Assess left ventricular ejection fraction at baseline and periodically during therapy. Manage cardiovascular risk factors (hypertension, diabetes, dyslipidemia).  If Grade 2–4 cardiovascular events occur, permanently discontinue ipilimumab.
• Monitor for signs and symptoms of graft-versus-host disease (fatigue, rash, pruritus, nausea, vomiting, diarrhea, jaundice, scleral icterus, xerostomia, arthralgias).

Lab Test Considerations:

•  Patient selection with metastatic NSCLC or unresectable advanced or metastatic esophageal squamous cell carcinoma for treatment with ipilimumab in combination with nivolumab is based on PD-L1 expression. Information on FDA-approved tests for the determination of PD-L1 expression is available at https://www.fda.gov/CompanionDiagnostics.
• Verify negative pregnancy status before starting therapy.
• May cause hepatitis; monitor liver function tests prior to therapy and before each dose during therapy.  If levels ↑,  administer corticosteroids (initial dose of 1–2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper). For hepatitis with no tumor involvement of the liver or hepatitis with tumor involvement of liver/nonhepatocellular carcinoma:  If AST or ALT ↑ >3–<5 times upper limit of normal (ULN) or total bilirubin ↑ >1.5–<3 times ULN,  hold ipilimumab and resume with complete or partial resolution (Grade 0–1) after corticosteroid taper.  If AST or ALT >5 times ULN or total bilirubin >3 times ULN,  permanently discontinue ipilimumab. For hepatitis with tumor involvement of the liver/hepatocellular carcinoma:  If baseline AST or ALT >1–<3 times ULN and ↑ to >5–<10 times ULN or if baseline AST or ALT >3–<5 times ULN and ↑ to >8 to <10 times ULN,  hold ipilimumab and resume with complete or partial resolution (Grade 0–1) after corticosteroid taper.  If AST or ALT >10 times ULN or if total bilirubin >3 times ULN,  permanently discontinue ipilimumab.
  • Monitor for signs and symptoms of adrenal insufficiency, including but not limited to hypothyroidism, hyperthyroidism, adrenal insufficiency, and hyperglycemia during and after treatment. Administer corticosteroids as appropriate, followed by a corticosteroid taper.  If Grade 3 or 4 endocrinopathies occur,  hold ipilimumab until clinically stable or permanently discontinue ipilimumab based on severity.
  • May cause nephritis; monitor for ↑ serum creatinine before and periodically during therapy. Administer corticosteroids (initial dose of 1–2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper).  If Grade 2 or 3 ↑ serum creatinine occurs,  hold ipilimumab and resume with complete or partial resolution (Grade 0–1) of nephritis and renal impairment after corticosteroid taper.  If Grade 4 ↑ serum creatinine occurs,  permanently discontinue ipilimumab.

Implementation

• For unresectable/metastatic melanoma, doses may be delayed in the event of toxicity, but must be administered within 16 wk from 1st dose. For adjuvant treatment of melanoma, doses can be omitted, but not delayed in the event of toxicity.

Patient/Family Teaching

• Explain purpose and potential adverse effects of ipilimumab to patient. Do not stop receiving drug without consulting health care provider. If an appointment is missed, contact health care provider as soon as possible to reschedule. Advise patient to read  Medication Guide  before starting and periodically during therapy in case of changes.
• Inform patient of the risk of immune-mediated reactions due to T-cell activation and proliferation. Advise patients these reactions may be severe and fatal. Advise patient to notify health care provider if signs and symptoms of colitis (diarrhea; black, tarry, sticky, bloody, or mucus in stools; severe abdominal pain or tenderness), hepatitis (yellowing of skin or the whites of eyes, severe nausea or vomiting, pain on right side of abdomen), skin reactions (rash; itching; skin blistering or peeling; painful sores in mouth, nose, throat, or genital area), endocrinopathies (persistent or unusual headache, eye sensitivity to light, eye problems, rapid heartbeat, ↑ sweating, extreme tiredness, weight gain or weight loss, feeling hungrier or thirstier than usual, urinating more often than usual, hair loss, feeling cold, constipation, deepening of voice, dizziness or fainting, changes in mood or behavior, ↓ sex drive, irritability, forgetfulness), pneumonitis (new or worsening cough, shortness of breath, chest pain), nephritis (↓ in amount of urine, blood in urine, swelling of ankles, loss of appetite), or eye problems (blurry vision, double vision, other vision problems, eye pain or redness) occur.
• Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other Rx, OTC, herbal products.
• Rep:  May cause fetal harm. Advise women of reproductive potential to use effective contraception and avoid breastfeeding during therapy and for 3 mo following last dose. Encourage women who become pregnant during therapy to contact Bristol Myers Squibb by calling 1-844-593-7869.

Evaluation/Desired Outcomes

• ↓ spread or recurrence of melanoma and improved survival.
• Improved survival with renal cell carcinoma, NSCLC, malignant pleural mesothelioma, and esophageal squamous cell carcinoma.
• ↓ progression of MSI-H or dMMR metastatic colorectal cancer.
• ↓ progression of hepatocellular carcinoma.