ipilimumab

High Alert

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 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 effects:

↓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: Crosses the placenta.

Metabolism/Excretion: Unknown.

Half-Life: 14.7 days.

Time/Action Profile ⬆ ⬇

ROUTE	ONSET	PEAK	DURATION
IV	unknown	unknown	unknown

Contraind./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).

Adv. 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

Interactions ⬆ ⬇

Drug-drug:

Concurrent use with vemurafenib may ↑ risk of hepatic dysfunction.

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): 10 mg/kg every 3 wk for up to 4 doses, then 10 mg/kg every 12 wk for up to 3 yr.

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 at Grade 0 or 1 after corticosteroid taper. Permanently discontinue 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, flu-like symptoms, mucosal lesions, progressive skin rash) 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 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 with complete or partial resolution (Grade 0–1) 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, discontinue ipilimumab permanently.
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 reduce the risk of permanent vision loss. If Grade 2, 3, or 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 (pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, urticaria) during infusion. For Grade 1 or 2 infusion-related reactions: interrupt or slow rate of infusion. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions: 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). Discontinue ipilimumab for Grade 2, 3, or 4 cardiovascular events.

Lab Test Considerations:

Patient selection with metastatic NSCLC 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 in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
Verify negative pregnancy status before starting therapy.
May cause hepatitis; monitor liver function tests prior to and periodically during therapy. If levels increase: 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/non-hepatocellular carcinoma: If AST or ALT ↑ >3 times to <5 times upper limit of normal (ULN) or total bilirubin ↑ >1.5 times to <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: discontinue ipilimumab permanently. For hepatitis with tumor involvement of the liver/hepatocellular carcinoma: If baseline AST or ALT >1–<3 times ULN and increases to >5–<10 times ULN or if baseline AST or ALT >3–<5 times ULN and increases to >8 to <10 times ULN: hold ipilimumab and resume with complete or partial resolution (Grade 0 to 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 base on severity, treat low levels, and resume with complete or partial resolution (Grade 0–1) after corticosteroid taper.
- May cause nephritis; monitor for ↑ serum creatinine prior to 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 increased blood creatinine occurs: hold ipilimumab and resume with complete or partial resolution (Grade 0–1) of nephritis and renal dysfunction after corticosteroid taper. If Grade 4 increased blood 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.
Hold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy. For patients with complete or partial resolution of adverse reactions (Grade 0–1), who are receiving equivalents of <7.5 mg prednisone/day, resume ipilimumab therapy.
Permanently discontinue if persistent moderate adverse reactions or inability to reduce corticosteroid dose to equivalent of prednisone 7.5 mg/day, failure to complete full treatment course within 16 wk from infusion of 1st dose, or severe or life-threatening adverse reactions occur including: Colitis with abdominal pain, fever, or peritoneal signs; ↑ in stool frequency of 7 or more over baseline, stool incontinence. Need for IV hydration for >24 hrs, GI hemorrhage and GI perforation; AST or ALT >5 times the upper limits of normal or total bilirubin >3 times the upper limit of normal; Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis; Severe immune-mediated reactions involving any organ system (nephritis, pneumonitis, pancreatitis, noninfectious myocarditis); and immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy.
Allow vial to stand at room temperature for 5 min prior to preparation of infusion. Withdraw amount of ipilimumab required and transfer to IV bag. Diluent: Dilute with 0.9% NaCl or D5W.Concentration: 1 mg/mL–2 mg/mL. Mix slowly by gentle inversion; do not shake. Solution is clear, pale yellow, and may contain translucent-to-white amorphous particles; do not administer if cloudy, discolored, or contains particulate matter. Store for up to 24 hr at room temperature or refrigerated; do not freeze, protect from light. Discard partially used vials.
Melanoma: For unresectable or metastatic melanoma: infuse over 30 min and for adjuvant treatment of melanoma: infuse over 90 min, through a sterile, nonpyrogenic, low-protein-binding in-line filter. Flush the IV line with 0.9% NaCl or D5W after each dose.
- Renal cell carcinoma, hepatocellular carcinoma, NSCLC, malignant pleural mesothelioma, esophageal squamous cell carcinoma, or colorectal cancer
  Infuse over 30 min immediately following nivolumab infusion through a sterile, nonpyrogenic, low-protein-binding in-line filter. Flush the IV line with 0.9% NaCl or D5W after each dose.
Y-Site Incompatibility: Do not mix with or infuse with other solutions or products.

Patient/Family Teaching ⬆ ⬇

Explain purpose and potential adverse effects of ipilimumab to patient.
Inform patient of the risk of immune-mediated reactions due to T-cell activation and proliferation. Advise patients these may be severe and fatal. Instruct patient to notify health care professional immediately if signs and symptoms occur.
Instruct patient to read the Medication Guide before starting therapy and with each Rx refill in case of changes.
Advise patient to notify health care professional 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 or nose, throat, or genital area), endocrinopathies (persistent or unusual headache, eye sensitivity to light, eye problems, rapid heartbeat, increased sweating, extreme tiredness, weight gain or weight loss, feeling more hungry or thirsty than usual, urinating more often than usual, hair loss, feeling cold, constipation, deepening of voice, dizziness or fainting, changes in mood or behavior, decreased sex drive, irritability, or forgetfulness), pneumonitis (new or worsening cough, shortness of breath, chest pain), nephritis (decrease in amount of urine, blood in urine, swelling of ankles, loss of appetite), or eye problems (blurry vision, double vision, or other vision problems, eye pain or redness) occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, herbal products.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception and avoid breastfeeding during and for 3 mo following last dose. Women must choose to discontinue breastfeeding or ipilimumab. Advise female patients to notify health care professional if pregnancy is planned or suspected. Encourage women who become pregnant during therapy to contact Bristol-Myers Squibb by calling 1-844-593-7869.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇