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

    DEA CLASS

    Rx

    DESCRIPTION

    Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking monoclonal antibody
    Used for hepatocellular cancer, malignant melanoma, mesothelioma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, non-small cell lung cancer, and renal cell carcinoma
    Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued

    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. In a multinational, randomized, double-blind, placebo-controlled, phase 3 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). 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) 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; 20%) or 3 years (n = 42; 16%), the 2- and 3-year OS rates were 25% and 25%, 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 3 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 2b 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.
    intravenous dosage
    Adults

    3 mg/kg IV over 90 minutes repeated every 3 weeks for a maximum of 4 doses in combination with nivolumab; administer after the nivolumab infusion. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions or infusion-related reactions. Administer ipilimumab in combination with nivolumab as follows: 1 mg/kg IV over 30 minutes repeated every 3 weeks (maximum of 4 doses), then continue single-agent 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.[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. 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) in patients with high-risk stage III melanoma after complete lymph-node dissection in a multinational, randomized, double-blind, placebo-controlled, phase 3 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%) and metastasis-free survival (48.3% vs. 38.9%) 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 treatment of renal cell cancer (RCC).
    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, following administration of nivolumab (3 mg/kg IV over 30 minutes), every 3 weeks for up to 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 (the CHECKMATE-142 study), treatment with nivolumab plus ipilimumab resulted in an overall response rate by blinded independent central review (BICR) of 56% 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 13% complete responses. The duration of response was 6 months or longer in 87% of these patients and was 12 months or longer in 74% 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 (the CHECKMATE-142 study), treatment with nivolumab plus ipilimumab resulted in an overall response rate by blinded independent central review (BICR) of 56% 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 13% complete responses. The duration of response was 6 months or longer in 87% of these patients and was 12 months or longer in 74% of patients.

    For the treatment of hepatocellular cancer (HCC).
    For the treatment of hepatocellular cancer (HCC) in patients who have been previously treated with sorafenib, in combination with nivolumab.
    Intravenous dosage
    Adults

    3 mg/kg IV over 30 minutes on day 1 following administration of nivolumab (1 mg/kg IV over 30 minutes), every 3 weeks for up to 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab (240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks) as a single agent 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 multicohort, open-label clinical trial, treatment with ipilimumab plus nivolumab followed by nivolumab monotherapy resulted in an overall response rate of 33% (complete response [CR], 8%; partial response [PR], 24%) by RECIST v1.1 and 35% (CR, 12%; PR, 22%) by mRECIST for a median duration of 4.6 months; 88% of patients had a response of at least 6 months, 56% had a response of at least 12 months, and 31% had a response of at least 24 months.

    For the treatment of non-small cell lung cancer (NSCLC).
    For the first-line treatment of EGFR- and ALK-negative metastatic NSCLC in patients whose tumors express PD-L1 (1% or more), in combination with nivolumab.
    NOTE: Patients should be selected based on PD-L1 expression. Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    1 mg/kg IV over 30 minutes every 6 weeks in combination with nivolumab (3 mg/kg IV over 30 minutes every 2 weeks) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. 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, multi-part trial (CHECKMATE-227), first-line treatment with nivolumab in combination with ipilimumab significantly improved overall survival compared with treatment with a platinum-based doublet for patients with metastatic or recurrent NSCLC and PD-L1 expression of 1% or more (17.1 months vs. 14.9 months); patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy were excluded from the study. The median progression-free survival as assessed by a blinded independent central review (BICR) was 5.1 months versus 5.6 months, respectively; the confirmed objective response rate by BICR was 36% versus 30%, respectively, for a median duration of 23.2 months in the nivolumab/ipilimumab arm and 6.2 months in the platinum doublet arm.

    For the first-line treatment of EGFR- and ALK-negative metastatic or recurrent NSCLC, in combination with nivolumab and platinum-doublet chemotherapy.
    Intravenous dosage
    Adults

    1 mg/kg IV over 30 minutes every 6 weeks and nivolumab (360 mg IV over 30 minutes every 3 weeks) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression in combination with platinum-doublet chemotherapy given every 3 weeks for 2 cycles of therapy. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the ipilimumab infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The overall survival time was significantly improved (14.1 months vs. 10.7 months; hazard ratio (HR) = 0.69; 95% CI, 0.55 to 0.87; p = 0.0006) in patient with metastatic or recurrent NSCLC who received first-line treatment with nivolumab and ipilimumab in combination with 2 cycles of platinum-based doublet chemotherapy (n = 361) compared with 4 cycles of platinum-doublet chemotherapy (n = 358) in a randomized, open-label, phase 3 trial (CHECKMATE-9LA). In this trial, platinum-doublet chemotherapy was administered every 3 weeks and consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/mg2 OR cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC (plus optional pemetrexed maintenance therapy); or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. The progression-free survival time was also significantly improved in the nivolumab and ipilimumab plus platinum-based doublet chemotherapy arm compared with platinum-doublet chemotherapy alone arm (6.8 months vs. 5 months; HR = 0.7; 95% CI, 0.57 to 0.86; p = 0.0001).

    For the treatment of mesothelioma.
    NOTE: The FDA has designated ipilimumab as an orphan drug for the treatment of mesothelioma.
    For the first-line treatment of unresectable malignant pleural mesothelioma, in combination with nivolumab.
    Intravenous dosage
    Adults

    1 mg/kg IV over 30 minutes every 6 weeks, in combination with nivolumab (360 mg IV over 30 minutes every 3 weeks), until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. 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. Treatment with ipilimumab in combination with nivolumab significantly improved median overall survival compared with pemetrexed plus either cisplatin or carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma in a randomized, open-label trial (CHECKMATE-743) (18.1 months vs. 14.1 months). Median progression-free survival was 6.8 months in the nivolumab plus ipilimumab arm compared with 7.2 months in patients receiving chemotherapy. The overall response rate was 40% versus 43%, for a median duration of 11 months and 6.7 months, respectively.

    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

    Treatment-Related Immune-Mediated HepatitisNo Tumor Involvement of the Liver OR Tumor Involvement of the Liver and non-Hepatocellular Carcinoma (HCC)AST or ALT level of more than 3 to 5 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. AST or ALT level more than 5 times the ULN or a total bilirubin level more than 3-times the ULN: Permanently discontinue ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).Tumor Involvement of the Liver and HCCBaseline AST or ALT level at the ULN or less: Hold or permanently discontinue ipilimumab based on recommendations for hepatitis with no tumor involvement of the liver.Baseline AST or ALT level of more than 1 to 3 times the ULNAST or ALT level of more than 5 to 10 times the ULN: Hold ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Baseline AST or ALT level of more than 3 to 5 times the ULNAST or ALT level of more than 8 to 10 times the ULN: Hold ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Any Baseline AST or ALT levelAST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3 times the ULN: Permanently discontinue ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).

    Renal Impairment

    Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction Grade 2 or 3 increased serum creatinine (SCr) level: Hold ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Grade 4 increased SCr level: Permanently discontinue ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard the vial if the solution is cloudy, there is pronounced discoloration, or there is foreign particulate matter other than translucent-to white, amorphous particles.

    Intravenous Administration

    Do not shake undiluted product.
    When using combination therapy, administer nivolumab prior to ipilimumab (followed by platinum-based chemotherapy, if applicable); use separate infusion bags and filters for each drug.
     
    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 or 5% Dextrose injection to prepare a solution with a final concentration ranging from 1 to 2 mg/mL. Mix diluted solution by gentle inversion.
    Do not mix ipilimumab with other medicinal products.
    Storage: Once diluted, store 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) for no more than 24 hours from the time for preparation to the time of infusion.
     
    Administration:
    Administer the diluted infusion through an IV line containing a sterile, non-pyrogenic, low-protein-binding, in-line filter,
    Do not administer with other drugs through the same IV line.
    After each infusion, flush the intravenous line with 0.9% Sodium Chloride injection or 0.5% Dextrose injection.

    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

    Immune-mediated reactions

    Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to cytotoxic T-lymphocyte antigen 4 (CTLA-4), thus removing inhibition of the immune response. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously. Although usually occurring during treatment, immune-mediated reactions can occur at any time after starting therapy including after discontinuation of therapy. Because early identification and management is critical to safe usage, closely monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated reactions. Initiate an appropriate workup to exclude alternative etiologies including infection in cases of suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of ipilimumab therapy (and nivolumab if these agents are used together) may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary, administer systemic corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy.

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

    Immune-mediated colitis has been reported with ipilimumab therapy. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Use ipilimumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Ipilimumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

    Serious rash

    Immune-mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) may occur in patients treated with ipilimumab. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Ipilimumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary.

    Hepatitis

    Immune-mediated hepatitis has been reported with ipilimumab therapy. Monitor hepatic function at baseline and periodically during treatment. Ipilimumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary.

    Guillain-Barre syndrome, myasthenia gravis, neurological disease

    Immune-mediated neurotoxicity has rarely been reported with ipilimumab as monotherapy or in combination with nivolumab, a PD-1/PD-L1 inhibitor. Use ipilimumab with caution in patients who have a history of neurological disease such as myasthenia gravis or Guillain-Barre syndrome. Ipilimumab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.

    Hyperthyroidism, hypothyroidism

    Ipilimumab can cause immune-mediated thyroid disorders. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Ipilimumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.[60106]

    Renal failure, renal impairment

    Immune-mediated nephritis has been reported with ipilimumab therapy; renal failure has been reported. Monitor renal function at baseline and periodically during treatment. Ipilimumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.[60106]

    Ocular disease

    Immune-mediated ocular disease has been reported with ipilimumab therapy. 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 (e.g., corticosteroid eye drops) or who require systemic high-dose corticosteroid therapy.

    Adrenal insufficiency, hypophysitis, hypopituitarism

    Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with ipilimumab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Monitor adrenocorticotropic hormone at baseline and periodically during treatment. Initiate symptomatic treatment including hormone replacement therapy as clinically indicated. Ipilimumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.

    Autoimmune disease, organ transplant, systemic lupus erythematosus (SLE)

    Use ipilimumab with caution in patients who have previously had an organ transplant or who have autoimmune disease such as systemic lupus erythematosus (SLE). Immune-mediated organ transplant rejection has been reported with ipilimumab as monotherapy or in combination with nivolumab, a PD-1/PD-L1 inhibitor.

    Pneumonitis

    Immune-mediated pneumonitis has been reported with ipilimumab therapy; some cases were fatal. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, ipilimumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary. .[60106]

    Infusion-related reactions

    Severe infusion-related reactions have occurred with ipilimumab. Monitor patients for signs and symptoms of infusion reactions including fever, chills, wheezing, pruritus, rash, and flushing. Interrupt or slow the rate of infusion for mild or moderate infusion related reactions (grade 1 or 2); stop the infusion and permanently discontinue ipilimumab for severe or life-threatening infusion-related reactions (grade 3 or 4).[60106]

    Allogeneic stem cell transplant

    Fatal and serious graft-versus-host-disease (GVHD) has been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with ipilimumab, a CTLA-4 receptor blocking antibody. Perform a risk/benefit analysis prior to starting treatment with ipilimumab in patients with a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of GVHD and intervene promptly. Complications may occur despite intervening therapy between CTLA-4 receptor blockade and allogeneic SCT.

    Geriatric

    Geriatric patients treated with ipilimumab in combination with nivolumab may have a higher rate of serious adverse reactions compared to younger patients. Patients aged 75 years or older with malignant pleural mesothelioma treated with nivolumab plus ipilimumab had higher rates of serious adverse reactions compared to all patients who received combination therapy (68% vs. 54%); discontinuation rates due to adverse reactions were also more common in older patients (35% vs. 28%). Patients with NSCLC aged 75 years or older also had a higher discontinuation rate (29% to 43%) compared to younger patients (18% to 24%) when treated with ipilimumab in combination with nivolumab (with or without concomitant platinum-doublet chemotherapy) in 2 randomized clinical trials. No overall differences in safety were reported between geriatric patients and younger patients with melanoma, colorectal cancer, or renal cell cancer; there were not sufficient numbers of patients with hepatocellular cancer aged 65 and over to determine whether they respond differently from younger patients.

    Pregnancy

    Based on its mechanism of action and data from animal studies, ipilimumab may cause fetal harm if used during pregnancy. Ipilimumab is an immunoglobulin G1 antibody and may cross the placental barrier. The risk of fetal harm is likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Report any pregnancies to Bristol-Myers Squibb at 1-844-593-7869. There have been reports of healthy infants born following exposure to ipilimumab or ipilimumab plus nivolumab in utero.  A prematurely infant (gestational age, 24 weeks) with no signs of intrauterine growth inhibition was delivered via cesarean section after maternal use of ipilimumab plus nilotinib during pregnancy. During the first year, the infant had some typical preterm issues. At 6 months of corrected age, the infant had modestly elevated tonus of the lower extremities combined with a slight delay in motor development but showed age-appropriate speech and social emotional development and no evidence of melanoma. Immune checkpoint inhibitors, such as ipilimumab, may affect immune regulatory pathways play a role in autoimmune disease. However, there is a lack of preclinical evidence that the CTLA-4 axis plays a critical role in fetal-immune tolerance. In animal reproduction studies in pregnant cynomolgus monkeys, dose-related increases in the rate of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and infant mortality were observed when ipilimumab was administered during the third trimester at doses resulting in AUC values of 2.6 to 7.2 times higher than the clinical human dose of 3 mg/kg. 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.

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ipilimumab treatment. Ipilimumab can cause fetal harm if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 months after treatment with ipilimumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of ipilimumab. Women who become pregnant while receiving ipilimumab should be apprised of the potential hazard to the fetus. Report any pregnancies to Bristol-Myers Squibb at 1-844-593-7869.

    Breast-feeding

    Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during ipilimumab therapy and for 3 months after the final dose. It is not known if it has effects on the breastfed child or on milk production. Use ipilimumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because ipilimumab is a large protein molecule (molecular weight of 148,000 Daltons), the amount of drug in milk is likely to be very low but may increase with additional doses. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 3.5-40.0
    hyponatremia / Delayed / 0-32.0
    colitis / Delayed / 0-15.7
    hyperamylasemia / Delayed / 2.0-15.0
    hepatitis B exacerbation / Delayed / 0-14.0
    hepatitis / Delayed / 0-13.4
    lymphopenia / Delayed / 5.0-13.0
    hyperbilirubinemia / Delayed / 0-11.0
    diarrhea / Early / 3.4-11.0
    GI perforation / Delayed / 0-10.0
    neutropenia / Delayed / 0-9.0
    anemia / Delayed / 0-9.0
    hypopituitarism / Delayed / 0-8.6
    rash / Early / 2.0-8.0
    fatigue / Early / 2.0-8.0
    infection / Delayed / 0-7.0
    hyperglycemia / Delayed / 0-7.0
    abdominal pain / Early / 0-6.0
    pneumonitis / Delayed / 0-4.8
    dyspnea / Early / 0-4.7
    hyperkalemia / Delayed / 0-4.3
    thrombocytopenia / Delayed / 0-4.3
    pruritus / Rapid / 0-4.0
    musculoskeletal pain / Early / 0-4.0
    vomiting / Early / 0-3.8
    nausea / Early / 0-2.8
    adrenocortical insufficiency / Delayed / 0-2.8
    hypophysitis / Delayed / 0-2.7
    anorexia / Delayed / 0.2-2.3
    hypertension / Early / 0-2.2
    hypokalemia / Delayed / 0-2.1
    leukopenia / Delayed / 0-2.1
    influenza / Delayed / 0-2.0
    dyspepsia / Early / 0-2.0
    edema / Delayed / 0-2.0
    interstitial nephritis / Delayed / 1.7-1.7
    headache / Early / 0.8-1.7
    hypocalcemia / Delayed / 0-1.4
    pancreatitis / Delayed / 1.3-1.3
    arthralgia / Delayed / 0-1.3
    hypomagnesemia / Delayed / 0-1.2
    acute respiratory distress syndrome (ARDS) / Early / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    myasthenia gravis / Delayed / 0-1.0
    myelitis / Delayed / 0-1.0
    Guillain-Barre syndrome / Delayed / 0-1.0
    pericarditis / Delayed / 0-1.0
    myocarditis / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    renal failure (unspecified) / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    Vogt-Koyanagi-Harada syndrome / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    hearing loss / Delayed / 0-1.0
    rhabdomyolysis / Delayed / 0-1.0
    peptic ulcer / Delayed / 0-1.0
    organ transplant rejection / Delayed / 0-1.0
    hyperthyroidism / Delayed / 0-0.9
    diabetes mellitus / Delayed / 0-0.9
    cough / Delayed / 0-0.8
    insomnia / Early / 0-0.8
    alopecia / Delayed / 0-0.8
    hypothyroidism / Delayed / 0-0.6
    weight loss / Delayed / 0-0.2
    hepatic failure / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    retinal detachment / Delayed / Incidence not known
    graft-versus-host disease (GVHD) / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    hemophagocytic lymphohistiocytosis / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 1.1-13.7
    infusion-related reactions / Rapid / 0-12.0
    neuritis / Delayed / 0-10.0
    hypotension / Rapid / 0-10.0
    stomatitis / Delayed / 0-10.0
    eosinophilia / Delayed / 2.1-2.1
    psoriasis / Delayed / 0-1.0
    meningitis / Delayed / 0-1.0
    paresis / Delayed / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    ocular inflammation / Early / 0-1.0
    blepharitis / Early / 0-1.0
    iritis / Delayed / 0-1.0
    esophagitis / Delayed / 0-1.0
    gastritis / Delayed / 0-1.0
    dehydration / Delayed / Incidence not known
    ascites / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    atopic dermatitis / Delayed / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    photophobia / Early / Incidence not known
    Cushing's syndrome / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    bone pain / Delayed / Incidence not known
    synovitis / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known

    Mild

    dizziness / Early / 0-20.0
    xerostomia / Early / 0-12.0
    xerosis / Delayed / 11.0-11.0
    skin hypopigmentation / Delayed / 0-8.0
    urticaria / Rapid / 0-2.0
    pharyngitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    arthropathy / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    malaise / Early / Incidence not known
    vertigo / Early / Incidence not known

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    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.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    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

    Based on its mechanism of action and data from animal studies, ipilimumab may cause fetal harm if used during pregnancy. Ipilimumab is an immunoglobulin G1 antibody and may cross the placental barrier. The risk of fetal harm is likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Report any pregnancies to Bristol-Myers Squibb at 1-844-593-7869. There have been reports of healthy infants born following exposure to ipilimumab or ipilimumab plus nivolumab in utero.  A prematurely infant (gestational age, 24 weeks) with no signs of intrauterine growth inhibition was delivered via cesarean section after maternal use of ipilimumab plus nilotinib during pregnancy. During the first year, the infant had some typical preterm issues. At 6 months of corrected age, the infant had modestly elevated tonus of the lower extremities combined with a slight delay in motor development but showed age-appropriate speech and social emotional development and no evidence of melanoma. Immune checkpoint inhibitors, such as ipilimumab, may affect immune regulatory pathways play a role in autoimmune disease. However, there is a lack of preclinical evidence that the CTLA-4 axis plays a critical role in fetal-immune tolerance. In animal reproduction studies in pregnant cynomolgus monkeys, dose-related increases in the rate of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and infant mortality were observed when ipilimumab was administered during the third trimester at doses resulting in AUC values of 2.6 to 7.2 times higher than the clinical human dose of 3 mg/kg. 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.

    Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during ipilimumab therapy and for 3 months after the final dose. It is not known if it has effects on the breastfed child or on milk production. Use ipilimumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because ipilimumab is a large protein molecule (molecular weight of 148,000 Daltons), the amount of drug in milk is likely to be very low but may increase with additional doses. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.

    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%). The clearance of ipilimumab was unchanged when ipilimumab 1 mg/kg or 3 mg/kg was administered every 3 weeks in combination with nivolumab (3 mg/kg or 1 mg/kg). Ipilimumab clearance values increased by 30% when administered every 6 weeks in combination with nivolumab 3 mg/kg IV every 2 weeks and increased by 22% when administered every 6 weeks in combination with nivolumab 360 mg IV every 3 weeks plus chemotherapy compared to ipilimumab monotherapy. Ipilimumab clearance 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.