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    Monoclonal Antibodies that Target the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) Receptor

    BOXED WARNING

    Immune-mediated reactions

    Ipilimumab administration can result in severe and fatal immune-mediated reactions. Reactions usually manifest during treatment although a minority have been reported weeks to months after treatment discontinuation. While any organ system can be affected, the most common severe reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. Prior to treatment initiation and before each dose is administered, asses for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy; also, evaluate clinical blood chemistries including liver function tests, adrenocorticotropic hormone (ACTH) concentrations, and thyroid function tests. Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

    DEA CLASS

    Rx

    DESCRIPTION

    Monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks its interaction with its ligands CD80/CD86
    Used for malignant melanoma, renal cell carcinoma, and microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer
    May cause fatal immune-mediated adverse reactions such as enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy

    COMMON BRAND NAMES

    YERVOY

    HOW SUPPLIED

    YERVOY Intravenous Inj Sol: 1mL, 5mg

    DOSAGE & INDICATIONS

    For the treatment of malignant melanoma.
    For the treatment of unresectable or metastatic melanoma, as a single-agent.
    Intravenous dosage
    Adults, Adolescents, and Children 12 years of age

    3 mg/kg IV over 90 minutes repeated every 3 weeks for a total of 4 doses. Doses may be delayed for toxicity; however, all treatment must be administered within 16 weeks of the first dose. In a multinational, randomized, double-blind, placebo-controlled, phase III study (the MDX010-20 study), treatment with ipilimumab (n = 137), a melanoma vaccine consisting of HLA-A*0201-restricted peptides derived from the melanosomal glycoprotein 100 (gp100) (n = 136), or ipilimumab plus gp100 (combination therapy arm; n = 403) was evaluated in adult patients with HLA-A*0201-positive, unresectable stage III or stage IV melanoma who had previously received at least 1 of the following therapies: carboplatin, dacarbazine, fotemustine, interleukin-2, or temozolomide. In this study, 31 evaluable patients with disease progression who had stable disease for 3 months at week 12 or a confirmed partial or complete response received additional courses (reinduction) of ipilimumab-containing therapy. For the primary end point comparison, the median overall survival (OS) time was significantly improved with combination therapy compared with gp100 alone (10 months vs. 6.4 months; hazard ratio (HR) = 0.68; 95% CI, 0.55 to 0.85; p < 0.001). In a pre-specified comparison, the OS time was significantly improved with ipilimumab alone compared with gp100 alone (10.1 months vs. 6.4 months; HR = 0.66; 95% CI, 0.51 to 0.87; p = 0.003) and there was no significant OS difference between the 2 ipilimumab-containing arms. The 12-, 18-, and 24-month OS rates for the single-agent ipilimumab arm were 45.6%, 33.2%, and 23.5%, respectively. The median progression-free survival (PFS) time for single-agent ipilimumab was 2.86 months and the 12-week PFS rate was 57.7%. In an analysis of all patients who survived at least 2 years (n = 94 of 474; 20%) or 3 years (n = 42 of 259; 16%), the 2- and 3-year OS rates were 25% (n = 24 of 95) and 25% (n = 13 of 53), respectively, for patients who received ipilimumab alone. Additionally, disease control (defined as a best response of stable disease or better) was 28.5% at week 24 and 83.3% in patients who received single-agent ipilimumab and survived at least 2 years.

    For the first-line treatment of unresectable or metastatic melanoma, in combination with dacarbazine†.
    Intravenous dosage
    Adults

    10 mg/kg IV plus dacarbazine 850 mg/m2 IV repeated every 3 weeks (at weeks 1, 4, 7, and 10) for 4 doses followed by dacarbazine 850 mg/m2 IV every 3 weeks through week 22 (if no progressive disease) as induction therapy resulted in favorable overall survival in a randomized, double-blind, placebo-controlled, phase III trial. At week 24, patients with stable disease or an objective response received maintenance therapy with ipilimumab 10 mg/kg IV every 12 weeks until progressive disease.

    For the treatment of unresectable or metastatic melanoma, following no more than 1 prior therapy, in combination with sargramostim (GM-CSF)†.
    Intravenous dosage
    Adults

    10 mg/kg (actual body weight) IV on day 1 repeated every 3 weeks for 4 cycles in combination with sargramostim 250 micrograms (mcg) subcutaneously on days 1 to 14 repeated every 3 weeks for 4 cycles as induction therapy was evaluated in a randomized, phase IIb study. In patients with stable disease or better, maintenance therapy consisted of ipilimumab 10 mg/kg (actual body weight) IV on day 1 repeated every 12 weeks (starting on cycle 8) in combination with sargramostim 250 mcg subcutaneously on days 1 to 14 repeated every 3 weeks (starting on cycle 5). At a median follow-up of 13.3 months, median OS was significantly improved with combination therapy of ipilimumab plus GM-CSF compared to single-agent ipilimumab (17.5 months vs. 12.7 months; p = 0.01).

    For the treatment of unresectable or metastatic melanoma, in combination with nivolumab†.
    NOTE: Nivolumab is FDA approved in combination with ipilimumab for the treatment of unresectable or metastatic malignant melanoma.
    intravenous dosage
    Adults

    3 mg/kg IV over 90 minutes after the nivolumab 1 mg/kg IV infusion (over 30 minutes) repeated every 3 weeks for 4 doses followed by nivolumab 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Nivolumab and ipilimumab may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the nivolumab infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions.[58668] At a minimum follow-up of approximately 60 months, the median overall survival (60 months vs. 19.9 months; hazard ratio (HR) = 0.52; 95% CI 0.42 to 0.64) and progression-free survival (11.5 months vs. 2.9 months; HR = 0.42; 95% CI 0.35 to 0.51) times were significantly improved in patients with previously untreated, unresectable, stage III or stage IV melanoma who received nivolumab plus ipilimumab compared with ipilimumab in a 3-arm, randomized, double-blind, phase 3 trial (CheckMate 067 trial; n = 945).

    For the adjuvant treatment of cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm, in patients who have undergone complete resection, including total lymphadenectomy.
    Intravenous dosage
    Adults

    10 mg/kg IV over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg IV every 12 weeks until disease recurrence or unacceptable toxicity, for up to 3 years. In the event of toxicity, doses may be omitted but not delayed. At a median follow-up of 5.3 years, adjuvant treatment with ipilimumab led to a significantly improved median recurrence-free survival (RFS) time (primary endpoint) compared with placebo (27.6 months vs. 17.1 months; hazard ratio (HR) = 0.76; 95% CI, 0.64 to 0.89; p < 0.001) in patients with high-risk stage III melanoma after complete lymph-node dissection in a multinational, randomized, double-blind, placebo-controlled, phase III trial (n = 951; EORTC 18071 trial); the 5-year RFS rate was 40.8% and 30.3%, respectively. Treatment with ipilimumab also resulted in significantly improved 5-year overall survival (65.4% vs. 54.4%; HR = 0.72; 95.1% CI, 0.58 to 0.88; p = 0.001) and metastasis-free survival (48.3% vs. 38.9%; HR = 0.76; 95.8% CI, 0.64 to 0.92; p = 0.002) rates compared with placebo. In this study, patients had stage IIIA melanoma (with at least one metastasis measuring greater than 1 millimeter in the greatest dimension) or stage IIIB or IIIC melanoma with no in-transit metastases and had not received prior systemic therapy.

    For the treatment of unresectable advanced melanoma in patients eligible for local treatment of cutaneous, subcutaneous, and nodal lesions, in combination with talimogene laherparepvec†.
    Intravenous dosage
    Adults

    Dosage not established. Although overall response rate was improved with talimogene laherparepvec plus ipilimumab therapy compared with ipilimumab alone in a randomized clinical trial; there is not sufficient evidence to support the use of this drug combination for this indication. Ipilimumab 3 mg/kg IV every 3 weeks beginning on day 1 of week 6 for up to 4 infusions in combination with talimogene laherparepvec (given as a dose volume up to 4 mL at a concentration of 1 million plaque-forming units (PFU)/mL intralesionally on day 1 of week 1 followed by up to 4 mL at a concentration of 100 million PFU/mL on day 1 of week 4 and then every 2 weeks until complete response, all injectable tumors have disappeared, confirmed disease progression per modified immune-related response criteria, or intolerance) was evaluated in a multinational, randomized, phase 2 trial (n = 198).[63055]

    For the first-line treatment of intermediate or poor risk advanced renal cell cancer (RCC), in combination with nivolumab.
    Intravenous dosage
    Adults

    1 mg/kg IV over 30 minutes on day 1, preceded by nivolumab 3 mg/kg IV over 30 minutes, every 3 weeks for 4 doses. After completion of 4 doses of nivolumab plus ipilimumab, continue nivolumab as monotherapy until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a randomized, open-label study, treatment with nivolumab plus ipilimumab significantly improved median overall survival (not estimated vs. 25.9 months) and objective response rate (41.6% vs. 26.5%) compared with sunitinib in patients with intermediate/poor risk patients with previously untreated RCC; a complete response was achieved in 9.4% of patients in the nivolumab plus ipilimumab arm compared with 1.2% of those who received sunitinib. Median progression-free survival was 11.6 months compared with 8.4 months, respectively. In a separate analysis, the combination of nivolumab plus ipilimumab in patients with favorable risk disease did not significantly improve overall survival; efficacy in this population has not been established.

    For the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab.
    Intravenous dosage
    Adults

    1 mg/kg IV over 30 minutes following administration of nivolumab 3 mg/kg IV over 30 minutes, on day 1 every 3 weeks for 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab 240 mg IV over 30 minutes as a single agent every 2 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, non-randomized, multiple parallel-cohort, open-label study, treatment with nivolumab plus ipilimumab resulted in an overall response rate by independent radiographic review of 46% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 82), with 43% partial responses. The duration of response was 6 months or longer in 89% of these patients, and was 12 months or longer in 21% of patients.

    Children and Adolescents 12 to 17 years

    1 mg/kg IV over 30 minutes following administration of nivolumab 3 mg/kg IV over 30 minutes, on day 1 every 3 weeks for 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab 240 mg IV over 30 minutes as a single agent every 2 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult MSI-H or dMMR metastatic colorectal cancer patients with additional population pharmacokinetic data. In a multicenter, non-randomized, multiple parallel-cohort, open-label study, treatment with nivolumab plus ipilimumab resulted in an overall response rate by independent radiographic review of 46% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 82), with 43% partial responses. The duration of response was 6 months or longer in 89% of these patients, and was 12 months or longer in 21% of patients.

    MAXIMUM DOSAGE

    Adults

    10 mg/kg IV every 3 weeks.

    Geriatric

    10 mg/kg IV every 3 weeks.

    Adolescents

    3 mg/kg IV every 3 weeks.

    Children

    12 years: 3 mg/kg IV every 3 weeks.
    1 to 11 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild hepatic impairment (total bilirubin 1 to 1.5 times the upper limit of normal (ULN) or AST level greater than ULN): No ipilimumab dosage adjustment is required.
    Moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST level): Ipilimumab has not been evaluated in this patient population; specific guidelines for dosage adjustments in these patients are not available.
     
     
    Treatment-Related Hepatotoxicity
    Grade 2 hepatotoxicity (bilirubin 1.51 to 3 times ULN or AST/ALT 3 to 5 times ULN): Hold ipilimumab therapy; if administered in combination with nivolumab, also hold nivolumab. If hepatotoxicity resolves to grade 0 or 1 in less than 6 weeks and the patient is receiving less than prednisone 7.5 mg/day (or equivalent), resume therapy. If the hepatotoxicity lasts longer than 6 weeks or if the dose of corticosteroid cannot be reduced to the equivalent of prednisone 7.5 mg/day, permanently discontinue therapy.
    Grade 3 or 4 hepatotoxicity (bilirubin greater than 3 times ULN or AST/ALT greater than 5 times ULN): Initiate systemic high-dose corticosteroids with prednisone 1 to 2 mg/kg/day (or equivalent) and permanently discontinue ipilimumab therapy; if administered in combination with nivolumab, also discontinue nivolumab. When liver tests show sustained improvement or return to baseline, initiate a taper to last over 1 month. Across the clinical development program, mycophenolate has been administered to patients with persistent severe hepatitis despite high-dose corticosteroids.

    Renal Impairment

    Baseline Renal Impairment
    No ipilimumab dosage adjustment is required in patients with renal impairment. No significant difference in ipilimumab clearance was observed in patients with mild (glomerular filtration rate (GFR), 60 to 90 mL/min/1.73 m2), moderate (GFR, 30 to 60 mL/min/1.73 m2), or severe (GFR, 15 to 30 mL/min/1.73 m2) renal impairment compared with patients with normal renal function (GFR, greater than or equal to 90 mL/min/1.73 m2) in a pharmacokinetic analysis.
     
    Treatment-Related Nephrotoxicity (including nephritis)
    Grade 2 or 3 toxicity: Hold nivolumab and administer prednisone 0.5 to 1 mg/kg per day (or equivalent) followed by a corticosteroid taper; if administered in combination with nivolumab, also hold nivolumab. Consider resuming therapy when the toxicity resolves to grade 1 or less. If the toxicity does not improve or worsens on prednisone 0.5 to 1 mg/kg per day (or equivalent), increase the prednisone dose to 1 to 2 mg/kg per day (or equivalent) and permanently discontinue therapy.
    Grade 4 toxicity: Permanently discontinue therapy and administer high-dose corticosteroids (e.g., prednisone 1 to 2 mg/kg per day or equivalent) followed by corticosteroid taper. If administered in combination with nivolumab, also discontinue nivolumab.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The ipilimumab solution may have a pale yellow color and may have translucent-to-white, amorphous particles. Discard the ipilimumab vial if the solution is cloudy, if there is pronounced discoloration, or if there is foreign particulate matter.
    Do not shake ipilimumab.

    Intravenous Administration

    Preparation:
    Allow the ipilimumab vials to stand at room temperature for approximately 5 minutes before infusion preparation.
    Withdraw the required volume of ipilimumab and transfer into an intravenous bag. Discard partially used vials or empty vials of ipilimumab.
    Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final ipilimumab concentration ranging from 1 to 2 mg/mL. Mix diluted solution by gentle inversion.
    Do not mix ipilimumab with other medicinal products.
    With combination therapy, infuse nivolumab first followed by ipilimumab; use separate infusion bags and filters for each drug.
    Storage: Once diluted, store for no more than 24 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) or at room temperature (20 to 25 degrees C or 68 to 77 degrees F).
     
    Intravenous infusion:
    Administer the diluted infusion over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding, in-line filter. Do not administer as an infusion with other medicinal products.
    After each infusion, flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 0.5% Dextrose Injection, USP.

    STORAGE

    YERVOY:
    - Diluted product is stable and sterile for 24 hours when stored refrigerated or at room temperature
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Colitis, Crohn's disease, diarrhea, inflammatory bowel disease, ulcerative colitis, viral infection

    Severe and fatal immune-mediated enterocolitis has been reported with ipilimumab use; monitor patients for signs and symptoms of enterocolitis (diarrhea, abdominal pain, and mucus or blood in stool) and bowel perforation (peritoneal signs and ileus). An interruption or discontinuation of therapy may be necessary for patients who develop enterocolitis; management includes treatment with antidiarrheal agents, high-dose corticosteroids, or other immunosuppressive agents. Evaluate patients with symptomatic enterocolitis for infection; consider endoscopic evaluation for persistent or severe symptoms. Patients with inflammatory bowel disease such as ulcerative colitis or Crohn's disease may have an increased risk of developing enterocolitis. The median time to onset of grade 3 or higher enterocolitis when used as monotherapy was 1.1 to 1.7 months; the median time to onset of immune-mediated colitis when administered in combination with nivolumab was 1.7 to 2.4 months. Cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis during ipilimumab therapy. In these patients, repeat the infectious workup to exclude alternative etiologies and consider the use of an alternative immunosuppressive agent instead of a corticosteroid if other causes are excluded.[60106]

    Serious rash

    Ipilimumab can result in severe and sometimes fatal serious rash or dermatitis, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Monitor patients for signs and symptoms of dermatitis, such as rash and pruritus; unless an alternate etiology has been identified, these should be considered immune-mediated. An interruption or discontinuation of therapy may be necessary, along with treatment with topical or systemic corticosteroids. The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis ranged from 11 days to 1.5 months.

    Hepatic disease, hepatitis

    Severe, life-threatening, and sometimes fatal hepatotoxicity has been reported with ipilimumab use, including immune-mediated hepatitis. Evaluate liver function tests (LFTs) and for signs or symptoms of hepatotoxicity prior to each ipilimumab dose. If hepatotoxicity develops, monitor LFTs frequently until resolution; rule out infection or malignancy. An interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids. In the clinical development program for ipilimumab, mycophenolate treatment was administered in patients with persistent severe hepatitis despite high-dose corticosteroids. Use ipilimumab with caution in patients with hepatic disease; it has not been evaluated in patients with moderate or severe hepatic impairment. Concomitant treatment with vemurafenib may increase the risk of hepatotoxicity; in a dose-finding trial which was closed due to hepatotoxicity, grade 3 increases in transaminases (with or without concomitant increases in bilirubin) occurred in 6 of 10 patients receiving concomitant ipilimumab and vemurafenib therapy.

    Guillain-Barre syndrome, myasthenia gravis, peripheral neuropathy

    Ipilimumab can result in severe and fatal immune-mediated neuropathies, including Guillain-Barre syndrome. Monitor patients for symptoms of motor or sensory neuropathy, such as unilateral or bilateral weakness, sensory alterations, or paresthesia. An interruption or discontinuation of therapy may be necessary, along with administration of high-dose corticosteroids. In patients receiving adjuvant treatment for melanoma with ipilimumab 10 mg/kg, the time to onset for patients who developed grade 2 to 5 immune-mediated neuropathy ranged from 1.4 to 27.4 months. Cautious use of ipilimumab by patients with pre-existing Guillain-Barre syndrome, peripheral neuropathy, or myasthenia gravis may be warranted.

    Adrenal insufficiency, hyperthyroidism, hypophysitis, hypopituitarism, hypothyroidism, thyroid disease

    Cautious use of ipilimumab may be warranted for patients with thyroid disease or Addison's disease. Ipilimumab can result in severe and life-threatening immune-mediated endocrinopathies. Ipilimumab treatment should be withheld and high-dose corticosteroids initiated in patients with symptomatic endocrinopathies; begin appropriate hormone replacement therapy if necessary. Discontinuation of therapy may be necessary if, after 6 weeks, symptoms are unresolved or corticosteroids are unable to be tapered to less than prednisone 7.5 mg/day (or equivalent). Assess patients for signs and symptoms of endocrinopathy such as hypophysitis, hypopituitarism, adrenal insufficiency (including adrenal crisis), hyperthyroidism, and hypothyroidism; presentation may include fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, hypotension, or other nonspecific symptoms. Evaluate clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline, before each dose, and as clinically indicated; in a limited number of patients, hypophysitis was diagnosed by imaging studies through pituitary gland enlargement. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related. The median time to onset of moderate to severe endocrinopathy was 2.1 to 3.7 months, whether administered as monotherapy or in combination with nivolumab; however, in some patients, endocrinopathies occurred up to 22.3 months after initiation of therapy. Some patients required treatment with long-term hormone replacement therapy.[60106]

    Renal disease, renal impairment

    Use caution in patients with renal disease or baseline renal impairment who require treatment with ipilimumab in combination with nivolumab. Immune-mediated nephritis or renal impairment/dysfunction has been reported with nivolumab/ipilimumab combination therapy with a median time to onset of 3 months. Monitor renal function (e.g., serum creatinine levels) at baseline and periodically during therapy. For grade 2 or higher renal toxicity, hold ipilimumab therapy and administer corticosteroids followed by a corticosteroid taper. Permanently discontinue ipilimumab in patients who develop grade 4 renal toxicity.[60106]

    Pancreatitis

    Cautious use of ipilimumab by patients with pre-existing pancreatitis may be warranted. Ipilimumab can result in severe and fatal immune-mediated adverse reactions, including immune-mediated pancreatitis. An interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.

    Iritis, ocular disease, uveitis

    Immune-mediated ocular toxicity has been reported with ipilimumab therapy; monitor patients for signs or symptoms of ocular toxicity (e.g., blurred vision and reduced visual acuity). Administer corticosteroid eye drops to patients who develop ocular disease such as uveitis, iritis, or episcleritis. Permanently discontinue ipilimumab in patients who develop grade 2 to 4 ophthalmologic adverse events that do not improve to grade 1 or less within 2 weeks while receiving topical therapy or who require systemic high-dose corticosteroid therapy. Consider a diagnosis of Vogt-Koyanagi-Harada-like syndrome if uveitis occurs in combination with other immune-mediated adverse reactions; this syndrome has been reported with ipilimumab therapy. Patients with Vogt-Koyanagi-Harada-like syndrome may require treatment with systemic steroids to reduce the risk of permanent vision loss.

    Autoimmune disease, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus (SLE)

    Use ipilimumab with caution in patients with active autoimmune disease including rheumatoid arthritis, sarcoidosis, or systemic lupus erythematosus (SLE), as these patients were excluded from clinical trials of ipilimumab and the mechanism of action for ipilimumab involves inhibition of CTLA-4 signaling, which may increase T-cell responsiveness. Ipilimumab can result in severe and fatal immune-mediated adverse reactions, including immune-mediated sarcoidosis, myocarditis, arthritis, and polymyalgia rheumatica; an interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.[60106]

    Immunosuppression, organ transplant

    Ipilimumab works by T-cell activation and proliferation. Patients receiving systemic immunosuppression for organ transplant were excluded from the clinical development program.

    Immune-mediated reactions

    Ipilimumab administration can result in severe and fatal immune-mediated reactions. Reactions usually manifest during treatment although a minority have been reported weeks to months after treatment discontinuation. While any organ system can be affected, the most common severe reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. Prior to treatment initiation and before each dose is administered, asses for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy; also, evaluate clinical blood chemistries including liver function tests, adrenocorticotropic hormone (ACTH) concentrations, and thyroid function tests. Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

    Pneumonitis, pulmonary disease

    Use ipilimumab with caution in patients with pre-existing pulmonary disease. Immune-mediated pneumonitis, including interstitial lung disease, has been reported with ipilimumab when administered in combination with nivolumab therapy; some cases were fatal. Monitor patients for signs (e.g., chest X-ray) or symptoms (e.g., new or worsening chest pain or shortness of breath) of pneumonitis. Therapy interruption or permanent discontinuation of therapy may be necessary in patients who develop pneumonitis; administer high-dose corticosteroids (followed by a corticosteroid taper) for grade 2 or higher pneumonitis. The median time of onset of immune-mediated pneumonitis was 1.9 to 2.6 months from initiation of therapy.[60106]

    Diabetes mellitus, type 1 diabetes mellitus

    Use ipilimumab with caution in patients with pre-existing diabetes mellitus. Immune-mediated type 1 diabetes mellitus occurred in patients treated with nivolumab in combination with ipilimumab in clinical trials. The median time to onset was 3.2 months (range, 19 days to 16.8 months).

    Encephalopathy, mental status changes

    Immune-mediated encephalitis has been reported in patients who received ipilimumab in combination with nivolumab in clinical trials. Monitor patients for signs or symptoms of encephalopathy or mental status changes. For any new-onset moderate to severe neurologic signs or symptoms, hold ipilimumab therapy and evaluate (e.g., neurology consult, brain MRI, lumbar puncture) to rule out infectious or other causes. If immune-mediated encephalitis is diagnosed, permanently discontinue ipilimumab therapy and administer high-dose corticosteroids followed by a corticosteroid taper.

    Infusion-related reactions

    Severe or life-threatening infusion-related reactions have occurred during the administration of ipilimumab in clinical trials. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for mild to moderate reactions. Permanently discontinue ipilimumab for severe or life-threatening infusion-related reactions.[60106]

    Allogeneic stem cell transplant

    Fatal or serious graft-versus-host disease (GVHD) may occur in patients who receive an allogeneic stem cell transplant before or after receiving a CTLA-4 receptor blocking antibody, such as ipilimumab. Consider the benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after an allogeneic stem-cell transplantation; monitor patients closely for evidence of GVHD and treat promptly if GVHD develops.

    Pregnancy

    Ipilimumab may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. There is little data regarding the effects of ipilimumab exposure in pregnant women. The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Ipilimumab is an IgG1 kappa immunoglobulin and human IgG1 is known to cross the placental barrier; therefore, ipilimumab may be transmitted from the mother to the developing fetus. Patients with a known or suspected pregnancy should contact their healthcare provider. Advise women who may have been exposed to ipilimumab during pregnancy to contact Bristol-Myers Squibb at 1-800-721-5072. Advise pregnant women of the potential risk to a fetus and to enroll in a Pregnancy Safety Surveillance Study by calling 1-844-593-7869. No treatment-related adverse effects on reproduction were observed in the first two trimesters of pregnancy in pregnant cynomolgus monkeys who received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition. However, dose-related increases in the rate of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and infant mortality occurred at ipilimumab doses resulting in approximately 2.6 to 7.2 times the human exposure (of 3 mg/kg) administered during the third trimester. Developmental abnormalities including 1 case of unilateral renal agenesis of the left kidney and ureter and 1 case of an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema were also reported. Mice that were genetically engineered to be heterozygous for the target of ipilimumab, CTLA4 (CTLA4 +/-), appeared healthy and gave birth to healthy CTLA4 +/- heterozygous offspring. These mice produced offspring deficient in CTLA4 (homozygous negative, CTLA-4 -/-), which after appearing healthy at birth, exhibited signs of multi-organ lymphoproliferative disease by 2 weeks of age and died by 3 to 4 weeks of age due to massive lymphoproliferation and multi-organ tissue destruction.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ipilimumab treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 3 months after the last ipilimumab dose.

    Breast-feeding

    It is not known whether ipilimumab is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from ipilimumab, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose.

    ADVERSE REACTIONS

    Severe

    enterocolitis / Delayed / 7.0-16.0
    elevated hepatic enzymes / Delayed / 4.8-12.0
    diarrhea / Early / 3.4-10.0
    hyponatremia / Delayed / 0-10.0
    anemia / Delayed / 0-9.0
    colitis / Delayed / 2.0-8.0
    hypopituitarism / Delayed / 1.0-7.4
    fatigue / Early / 2.3-7.0
    abdominal pain / Early / 0-5.0
    hyperbilirubinemia / Delayed / 0-5.0
    hepatitis / Delayed / 2.0-5.0
    lymphopenia / Delayed / 0-5.0
    pneumonitis / Delayed / 0.2-4.4
    rash / Early / 2.0-4.2
    musculoskeletal pain / Early / 0-4.0
    renal failure (unspecified) / Delayed / 0-3.6
    dyspnea / Early / 0-2.4
    hyperkalemia / Delayed / 0-2.4
    pruritus / Rapid / 0-2.3
    eosinophilia / Delayed / 0-2.1
    nausea / Early / 0.2-2.0
    hyperamylasemia / Delayed / 0-2.0
    anorexia / Delayed / 0.2-1.8
    hypokalemia / Delayed / 0-1.8
    vomiting / Early / 0.4-1.7
    GI perforation / Delayed / 1.0-1.5
    pancreatitis / Delayed / 0-1.3
    arthralgia / Delayed / 0-1.3
    fever / Early / 0-1.1
    acute respiratory distress syndrome (ARDS) / Early / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    Guillain-Barre syndrome / Delayed / 0-1.0
    adrenocortical insufficiency / Delayed / 0-1.0
    meningitis / Delayed / 0.4-1.0
    myocarditis / Delayed / 0-1.0
    pericarditis / Delayed / 0-1.0
    Vogt-Koyanagi-Harada syndrome / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    hearing loss / Delayed / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    rhabdomyolysis / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-0.9
    hypothyroidism / Delayed / 0.2-0.8
    headache / Early / 0-0.8
    insomnia / Early / 0-0.8
    hyperthyroidism / Delayed / 0.2-0.6
    edema / Delayed / 0-0.5
    constipation / Delayed / 0-0.4
    hypomagnesemia / Delayed / 0-0.4
    hypocalcemia / Delayed / 0-0.4
    cough / Delayed / 0-0.2
    weight loss / Delayed / 0-0.2
    hepatic failure / Delayed / 0-0.2
    toxic epidermal necrolysis / Delayed / 0-0.2
    ileus / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    retinal detachment / Delayed / Incidence not known
    graft-versus-host disease (GVHD) / Delayed / Incidence not known

    Moderate

    neutropenia / Delayed / 0-18.0
    antibody formation / Delayed / 1.1-6.3
    hypophysitis / Delayed / 0-4.6
    diabetes mellitus / Delayed / 0-2.7
    gastritis / Delayed / 0-1.0
    esophagitis / Delayed / 0-1.0
    psoriasis / Delayed / 0-1.0
    myasthenia / Delayed / 0-1.0
    encephalopathy / Delayed / 0-1.0
    ocular inflammation / Early / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    iritis / Delayed / 0-1.0
    blepharitis / Early / 0-1.0
    infusion-related reactions / Rapid / 0-1.0
    Cushing's syndrome / Delayed / 0-0.2
    dehydration / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    xerosis / Delayed / 0-11.0
    dizziness / Early / 0-11.0
    infection / Delayed / 0-9.0
    urticaria / Rapid / 0-2.0
    rhinitis / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    myalgia / Early / Incidence not known

    DRUG INTERACTIONS

    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Vemurafenib: (Moderate) Concurrent use of vemurafenib and ipilimumab led to elevated transaminase levels in the majority of patients with BRAF V600-mutation positive melanoma in a small dose finding study; this study was closed due to adverse hepatic effects. Grade 3 elevated transaminase levels occurred in 6 of 10 patients who received combination therapy with vemurafenib (960 mg or 720 mg PO twice daily) plus ipilimumab (3 mg/kg IV every 3 weeks) in a phase I dose finding study; grade 2 or 3 elevated total bilirubin levels were reported in 2 patients in this study.

    PREGNANCY AND LACTATION

    Pregnancy

    Ipilimumab may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. There is little data regarding the effects of ipilimumab exposure in pregnant women. The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Ipilimumab is an IgG1 kappa immunoglobulin and human IgG1 is known to cross the placental barrier; therefore, ipilimumab may be transmitted from the mother to the developing fetus. Patients with a known or suspected pregnancy should contact their healthcare provider. Advise women who may have been exposed to ipilimumab during pregnancy to contact Bristol-Myers Squibb at 1-800-721-5072. Advise pregnant women of the potential risk to a fetus and to enroll in a Pregnancy Safety Surveillance Study by calling 1-844-593-7869. No treatment-related adverse effects on reproduction were observed in the first two trimesters of pregnancy in pregnant cynomolgus monkeys who received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition. However, dose-related increases in the rate of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and infant mortality occurred at ipilimumab doses resulting in approximately 2.6 to 7.2 times the human exposure (of 3 mg/kg) administered during the third trimester. Developmental abnormalities including 1 case of unilateral renal agenesis of the left kidney and ureter and 1 case of an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema were also reported. Mice that were genetically engineered to be heterozygous for the target of ipilimumab, CTLA4 (CTLA4 +/-), appeared healthy and gave birth to healthy CTLA4 +/- heterozygous offspring. These mice produced offspring deficient in CTLA4 (homozygous negative, CTLA-4 -/-), which after appearing healthy at birth, exhibited signs of multi-organ lymphoproliferative disease by 2 weeks of age and died by 3 to 4 weeks of age due to massive lymphoproliferation and multi-organ tissue destruction.

    It is not known whether ipilimumab is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from ipilimumab, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose.

    MECHANISM OF ACTION

    Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction of CTLA-4 with its ligands CD80/CD86. Blockade of CTLA-4 augments T-cell activation and proliferation, including tumor infiltrating T-effector cells. The inhibition of CTLA-4 signaling may cause a decrease in T-cell regulatory function resulting in an increase in T-cell antitumor responsiveness.

    PHARMACOKINETICS

    Ipilimumab is administered intravenously. The pharmacokinetic parameters of ipilimumab were studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses; the pharmacokinetics of ipilimumab are linear over this dose range. Upon repeated dosing of ipilimumab every 3 weeks, ipilimumab clearance was found to be time-invariant and minimal systemic accumulation (1.5-fold or less) was observed. Steady state concentration was reached by the third dose. In a population pharmacokinetic analysis, the terminal half-life was 15.4 days (coefficient of variance (CV), 34%) and the systemic clearance was 16.8 mL/hour (CV, 38%). Ipilimumab clearance was unchanged when administered in combination with nivolumab; it was also unchanged in the presence of anti-ipilimumab antibodies.

    Intravenous Route

    In a pharmacokinetic study, peak concentration, trough concentration (Cmin), and area under the curve of ipilimumab were found to be dose proportional within the dose range examined; steady-state concentrations were reached by the third dose. The mean ipilimumab Cmin achieved at steady-state with the 3 mg/kg regimen was 19.4 mcg/mL; the mean Cmin at 10 mg/kg was 58.1 mcg/mL.