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. It is indicated for use in adult patients with esophageal cancer, hepatocellular cancer, melanoma, mesothelioma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, non-small cell lung cancer (NSCLC), and renal cell carcinoma. In pediatric patients 12 years of age and older, ipilimumab is indicated for the treatment of advanced melanoma as a single agent or in combination with nivolumab and for MSI-H or dMMR metastatic colorectal cancer in combination with nivolumab. Ipilimumab may cause fatal immune-mediated adverse reactions such as enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy; an interruption or discontinuation of therapy may be necessary for suspected immune-mediated adverse reactions.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal
Route-Specific 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.
Intravenous (IV) Infusion:
-Administer the diluted solution through an IV line containing a sterile, non-pyrogenic, low-protein-binding, in-line filter.
-The administration time is as follows:
--Infuse IV over 90 minutes when administered as a 10 mg/kg dose for adjuvant therapy in melanoma patients
-Infuse IV over 30 minutes for all other doses (1 mg/kg or 3 mg/kg) and indications
-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.
Infection including upper respiratory tract infection (23% or less; grade 3 or 4, 0.3% or less), influenza (14% or less; grade 3 or 4, 2% or less), and pneumonia (14% or less; grade 3 or 4, 8% or less) occurred in patients who received ipilimumab in combination with nivolumab in clinical trials. The term upper respiratory tract infection included nasopharyngitis, pharyngitis, and rhinitis; the term pneumonia included both bacterial pneumonia and organizing pneumonia.
Immune-mediated pneumonitis occurred in 3.9% (grade 3, 1.4%) of patients with renal cell carcinoma (RCC) or colorectal cancer (CRC) (n = 666) and 9% (grade 3 or 4, 4%; grade 5, 0.7%) of patients with non-small cell lung cancer (NSCLC) (n = 576) who received ipilimumab 1 mg/kg with nivolumab in clinical trials. Additionally, immune-mediated pneumonitis occurred in 7% (grade 3 or 4, 2.2%) of patients who received ipilimumab 3 mg/kg with nivolumab (n = 456). Pneumonitis was also reported in patients with malignant pleural mesothelioma who received ipilimumab plus nivolumab therapy. Monitor patients for signs and symptoms of pneumonitis. If confirmed, ipilimumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. In clinical studies, all patients who developed pneumonitis following ipilimumab and nivolumab therapy received systemic corticosteroids; 8% of patients with RCC or CRC required the use of an additional immunosuppressant. Resolution of pneumonitis occurred in 72% to 94% of patients. In patients with NSCLC, the median duration of pneumonitis was 1.5 months (range, 5 days to more than 25 months). Across clinical studies, acute respiratory distress syndrome (ARDS) occurred in less than 1% of patients who received ipilimumab as a single agent at doses ranging from 0.3 mg/kg to 10 mg/kg.
Cough (13% to 37%; grade 3 or 4, 0.8% or less) and dyspnea (13% to 27%; grade 3 or 4, 4.7% or less) were reported in patients receiving ipilimumab in combination with nivolumab in clinical trials. The addition of ipilimumab and nivolumab to platinum-based chemotherapy slightly increased the incidence of cough (19% vs. 15%; grade 3 or 4, 0.6% vs. 0.9%) and dyspnea (18% vs. 14%; grade 3 or 4, 4.7% vs. 3.2%) compared with chemotherapy alone in patients with metastatic or recurrent non-small cell lung cancer in a randomized clinical trial.
Electrolyte abnormalities including hyponatremia (26% to 45%; grade 3 or 4, 5% to 12%), hyperkalemia (23% to 30%; grade 3 or 4, 0.9% to 4.3%), hypocalcemia (16% to 32%; grade 3 or 4, 1.7% or less), and hypomagnesemia (18% or less; grade 3 or 4, 0.4% or less) occurred in patient with colorectal cancer, esophageal cancer, mesothelioma, non-small cell lung cancer (NSCLC), or renal cell cancer treated with ipilimumab in combination with nivolumab in 4 clinical trials. Hypokalemia also occurred in 15% to 19% (grade 3 or 4, 1.8% to 5%) of patients with colorectal cancer or esophageal cancer; hypercalcemia was also reported in 15% (grade 3 or 4, 2%) of esophageal cancer patients. Incidences of hyponatremia (49%; grade 3 or 4, 32%), hypocalcemia (47%) and hypokalemia (26%; grade 3 or 4, 2.1%) were slightly higher in a subgroup of patients with hepatocellular cancer and Child-Pugh A cirrhosis who received ipilimumab plus nivolumab after progression or intolerance to sorafenib in one cohort of a clinical trial. The addition of ipilimumab and nivolumab to platinum-based chemotherapy in patients with NSCLC did not meaningfully increase the incidence of hypomagnesemia (29% vs. 33%; grade 3 or 4, 1.2% vs. 0.6%), hypocalcemia (26% vs. 22%; grade 3 or 4, 1.4% vs. 1.8%), or hyperkalemia (22% vs. 21%; grade 3 or 4, 1.7% vs. 2.1%) compared with chemotherapy alone; hyponatremia was more common in the ipilimumab/nivolumab arm (37% vs. 27%; grade 3 or 4, 10% vs. 7%).
Immune-mediated hepatitis occurred in 4.1% (grade 3 or higher, 1.6%) and 15% (grade 3 or 4, 10.8%) of patients who received single-agent ipilimumab 3 mg/kg (n = 511) and 10 mg/kg (n = 471), respectively; 7% (grade 3 or 4, 6.1%) of patients who received ipilimumab 1 mg/kg plus nivolumab (n = 666); and 15% (grade 3 or 4, 13.4%) of patients who received ipilimumab 3 mg/kg with nivolumab (n = 456). 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 and other systemic immunosuppressants may be necessary. The safety and effectiveness of ipilimumab in combination with vemurafenib have not been established; however, in a dose-finding trial grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients treated with ipilimumab 3 mg/kg plus vemurafenib. Treatment with systemic corticosteroids was necessary for 29% of patients who received ipilimumab 3 mg/kg monotherapy. Systemic corticosteroids were required in 70% to 100% of patients in the other dosing cohorts, with up to 19% of patients requiring the use of an additional immunosuppressant. Overall, resolution occurred in 70% to 93% of patients. Hepatitis (including transaminitis, autoimmune hepatitis, increased bilirubin levels, hepatic failure, and hepatotoxicity) was additionally reported in 21% of patients receiving first-line therapy for metastatic non-small cell lung cancer treated with combination therapy (grade 3 or 4, 9%).
Elevated hepatic enzymes including increased ALT (33% to 66%; grade 3 or 4, 4.3% to 21%) and AST (30% to 66%; grade 3 or 4, 3.5% to 40%) levels and increased alkaline phosphatase level (17% to 41%; grade 3 or 4, 0.6% to 6%) and hyperbilirubinemia (55% or less; grade 3 or 4, 11 % or less) occurred in patients who received ipilimumab as a single agent or in combination with nivolumab (including NSCLC patients who also received 2 cycles of platinum-doublet chemotherapy) in clinical trials.
Immune-mediated colitis occurred in 12% (grade 3 or higher, 7%) and 31% (grade 3 or 4, 15.5%; grade 5, 0.2%) of patients who received single-agent ipilimumab 3 mg/kg (n = 511) and 10 mg/kg (n = 471), respectively; 9% (grade 3, 4.4%) of patients who received ipilimumab 1 mg/kg plus nivolumab (n = 666); and 25% (grade 3 or 4, 14.4%) of patients who received ipilimumab 3 mg/kg with nivolumab (n = 456). Additionally, cytomegalovirus (CMV) or CMV reactivation has been reported in patients who had steroid-refractory immune-mediated colitis. Monitor patients for symptoms of colitis. Ipilimumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In clinical studies, 60% to 100% of patients who developed colitis following ipilimumab therapy received systemic corticosteroids; 26% of patients or less required the use of an additional immunosuppressant. Overall, resolution of colitis occurred in 76% to 95% of patients. Diarrhea was reported in patients who received ipilimumab as a single-agent (3 mg/kg: 32%; grade 3 or 4, 5%; 10 mg/kg: 49%; grade 3 or 4, 10%), in combination with nivolumab (22% to 54%; grade 3 or 4, 1.9% to 11%), or in combination with nivolumab plus platinum-based chemotherapy (31%; grade 3 or 4, 6%) in clinical trials. The term diarrhea included colitis, ulcerative colitis, enteritis, and enterocolitis in some trials.
Serious cases of dehydration occurred in 2.5% of patients with esophageal cancer treated with ipilimumab in combination with nivolumab in a randomized clinical trial. Dehydration was also among the most frequently reported serious adverse reactions (2% or more) in patients with metastatic colorectal cancer treated with ipilimumab plus nivolumab in a single-arm cohort of a multicenter, open-label study.
Nausea (20% to 44%; grade 3 or higher, 2.8% or less) and vomiting (12% to 31%; grade 3 or higher, 3.8% or less) were reported in patients treated with ipilimumab 10 mg/kg monotherapy or ipilimumab plus nivolumab (including NSCLC patients who also received 2 cycles of platinum-doublet chemotherapy) in clinical trials. Dyspepsia occurred in 12% (grade 3 or 4, 2%) of patients with hepatocellular cancer treated with ipilimumab plus nivolumab in a clinical trial (n = 49).
Ascites occurred in 14% (grade 3 or 4, 6%) of patients with advanced hepatocellular cancer treated with ipilimumab plus nivolumab in one cohort of a clinical trial. Bleeding of esophageal varices also occurred in at least 4% of these patients.
Immune-mediated rash occurred in 15% (grade 3 or higher, 2.5%) and 25% (grade 3, 4%) of patients who received single-agent ipilimumab 3 mg/kg (n = 511) and 10 mg/kg (n = 471), respectively; 16% (grade 3, 3.5%) of patients who received ipilimumab 1 mg/kg plus nivolumab (n = 666); and 28% (grade 3, 4.8%) of patients who received ipilimumab 3 mg/kg plus nivolumab (n = 456). Monitor patients for suspected severe skin reactions including bullous or exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS); 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 and other systemic immunosuppressants may be necessary. In clinical studies, 12% to 100% of patients who developed rash following ipilimumab therapy received systemic corticosteroids. Overall, resolution of rash occurred in 65% to 81% of patients. Rash was reported in patients who received ipilimumab as a single-agent (3 mg/kg: 29%; grade 3 or 4, 2%; 10 mg/kg: 50%; grade 3 or 4, 2.1%), ipilimumab 1 mg/kg plus nivolumab (25% to 39%; grade 3 or 4, 2.7% to 4.7%), ipilimumab 1 mg/kg and nivolumab plus platinum-doublet chemotherapy (30%; grade 3 or 4, 4.7%), and ipilimumab 3 mg/kg plus nivolumab (53%; grade 3 or 4, 6%) in clinical trials. The term rash included acne vulgaris, acneiform rash, atopic dermatitis, bullous rash, contact dermatitis, eczema, erythema multiforme, exfoliative dermatitis, keratoderma blenorrhagica, maculopapular rash, morbilliform rash, palmar-plantar erythrodysesthesia (hand and foot syndrome), SJS, TEN, and urticaria. Urticaria occurred in 2% of patients who received ipilimumab as a single agent at doses ranging from 0.3 mg/kg to 10 mg/kg across clinical trials. Immune-mediated erythema multiforme and psoriasis were each reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in postmarketing experience with ipilimumab.
Pruritus was reported in patients who received ipilimumab as a single-agent (3 mg/kg: 31%; 10 mg/kg: 45%; grade 3 or 4, 2.3%), ipilimumab 1 mg/kg plus nivolumab (17% to 33%; grade 3 or 4, 0.5% to 1.7%), ipilimumab 1 mg/kg and nivolumab plus platinum-doublet chemotherapy (21%; grade 3 or 4, 0.8%), and ipilimumab 3 mg/kg plus nivolumab (53%; grade 3 or 4, 4%) in clinical trials.
Fatigue occurred in 27% to 62% (grade 3 or 4, 2% to 8%) of patients who received ipilimumab as a single agent or in combination with nivolumab (including NSCLC patients who also received 2 cycles of platinum-doublet chemotherapy) in clinical trials. Fatigue included asthenia and malaise in some trials.
Autoimmune neuropathy occurred in 2% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials. Other immune-mediated neurotoxicity that was reported in less than 1% of patients included meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, nerve paresis, and motor dysfunction. Ipilimumab therapy may need to be interrupted or discontinued in patients who develop grade 2 or higher neurotoxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Clinically meaningful cases of peripheral neuropathy were reported in patients with metastatic non-small cell lung cancer treated with ipilimumab in combination with nivolumab. Neuritis and peroneal nerve palsy occurred in less than 10% of patients with melanoma who received ipilimumab 3 mg/kg in combination with nivolumab (n = 313) in a randomized trial.
Immune-mediated adrenocortical insufficiency occurred in 7% (grade 3 or 4, 2.8%) of patients who received ipilimumab 1 mg/kg plus nivolumab (n = 666); and 8% (grade 3 or 4, 2.6%) of patients who received ipilimumab 3 mg/kg with nivolumab (n = 456) in clinical trials. Immune-mediated hypophysitis was reported in 4.4% (grade 3 or 4, 2.7%) and 9% (grade 3, 2.4%) in these patients, respectively. Hypophysitis can present with acute symptoms associated with mass effect such as photophobia or visual field defects. 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 be necessary. In patients who received ipilimumab 1 mg/kg plus nivolumab, 94% of patients with adrenal insufficiency and 72% of patients with hypophysitis received hormone replacement therapy and systemic corticosteroids; resolution of endocrinopathy occurred in 29% and 59%, respectively. In patients who received ipilimumab 3 mg/kg plus nivolumab, 71% of patients with adrenal insufficiency and 86% of patients with hypophysitis received hormone replacement therapy and systemic corticosteroids; resolution of endocrinopathy occurred in 37% and 38%, respectively.
Hypothyroidism (18%; grade 3, 0.6%), hyperthyroidism (12%; grade 3, 0.6%), and thyroiditis (2.7%; grade 3, 4.5%) occurred in patients who received ipilimumab 1 mg/kg plus nivolumab (n = 666) in clinical trials. Additionally, hypothyroidism (20%; grade 3, 0.4%) and hyperthyroidism (9%; grade 3, 0.9%) occurred in patients who received ipilimumab 3 mg/kg with nivolumab (n = 456). 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. In patients who received ipilimumab 1 mg/kg plus nivolumab, some patients with hypothyroidism received hormone replacement therapy (82%) and systemic corticosteroids (7%); resolution of hypothyroidism occurred in 27% of patients. Some patients with hyperthyroidism received a thyroid synthesis inhibitor (19%) and systemic corticosteroids (20%); resolution of hyperthyroidism occurred in 85% of patients. In patients who received ipilimumab 3 mg/kg plus nivolumab, levothyroxine (89%) and systemic corticosteroids (2.2%) were administered for hypothyroidism and methimazole (26%), carbimazole (21%), and systemic corticosteroids (17%) were administered for hyperthyroidism. Additionally, 41% and 91% of patients had resolution of hypothyroidism and hyperthyroidism, respectively.
Immune-mediated endocrinopathies occurred in 4% (grade 3 or 4, 1.8%) and 28% (grade 3 or 4, 8.6%) of patients who received single-agent ipilimumab 3 mg/kg (n = 511) and 10 mg/kg (n = 471), respectively, in clinical trials. Endocrinopathies included hypopituitarism, adrenal insufficiency, hypogonadism/gonadal suppression, hypothyroidism, hyperthyroidism, thyroiditis, Graves ophthalmopathy, and Cushing's syndrome. Hypophysitis may lead to hypopituitarism. Some patients were hospitalized due to severe endocrinopathies. Monitor adrenocorticotropic hormone at baseline and periodically during treatment. Initiate symptomatic treatment including adrenal or thyroid hormone replacement therapy as clinically indicated. Ipilimumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary.
Immune-mediated cardiovascular toxicity that was reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials included angiopathy, myocarditis, pericarditis, temporal arteritis, and vasculitis; cases may be severe or fatal. Ipilimumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Immune-mediated interstitial nephritis occurred in 4.1% (grade 3, 1.7%) of patients with renal cell carcinoma or colorectal cancer who received ipilimumab 1 mg/kg plus nivolumab (n = 666) in clinical trials. 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. All patients that developed immune-related nephritis with renal dysfunction received systemic corticosteroids; the toxicity resolved in 67% of patients. Of the 12 patients who had treatment interrupted, 10 patients resumed therapy after symptom improvement; of these, 4 patients had a recurrence of nephritis. Increased creatinine levels were reported in patients who received ipilimumab as a single-agent (10 mg/kg: 10%; grade 3 or 4, 0.2%), ipilimumab 1 mg/kg plus nivolumab (15% to 42%; grade 3 or 4, 0.3% to 3.6%), ipilimumab 1 mg/kg and nivolumab plus platinum-doublet chemotherapy (26%; grade 3 or 4, 1.2%), and ipilimumab 3 mg/kg plus nivolumab (21% to 26%; grade 3 or 4, 2.7% or less) in clinical trials. Renal failure (unspecified) occurred in less than 1% of patients who received ipilimumab as a single agent at doses ranging from 0.3 mg/kg to 10 mg/kg across clinical trials. Renal failure and acute kidney injury were reported in patients with non-small cell lung cancer who received ipilimumab plus nivolumab with or without platinum-doublet therapy; some cases were fatal.
Antibody formation was reported in 1.1% to 13.7% of patients who received ipilimumab with or without nivolumab in clinical trials; neutralizing antibodies were detected in 1.6% or less of patients. There was no evidence of an increased incidence of infusion reactions in the presence of anti-ipilimumab antibodies.
Immune-mediated ocular toxicity that was reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials included blepharitis, conjunctivitis, episcleritis, iritis, orbital myositis (ocular inflammation), scleritis, and uveitis; some cases may be associated with retinal detachment. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a diagnosis of Vogt-Koyanagi-Harada syndrome. Ipilimumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Patients may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss. Clinically relevant blurred vision has been reported in patients with non-small cell lung cancer treated with ipilimumab in combination with nivolumab.
Lymphopenia occurred in 25% to 53% (grade 3 or 4, 5% to 13%) of patients who were treated with ipilimumab in combination with nivolumab (including non-small cell lung cancer patients who also received 2 cycles of platinum-doublet chemotherapy) in clinical trials. Neutropenia occurred in 13% of patients with esophageal cancer (grade 3 or 4, 1.3%), 18% of patients with colorectal cancer and in 43% of patients with hepatocellular cancer (grade 3 or 4, 9%) who received ipilimumab plus nivolumab; 40% of patients with hepatocellular cancer also experienced leukopenia (grade 3 or 4, 2.1%). The addition of ipilimumab and nivolumab to platinum-based chemotherapy did not increase the incidence of lymphopenia (41% vs. 40%; grade 3 or 4, 6% vs. 11%), neutropenia (40% vs. 42%; grade 3 or 4, 15% vs. 15%), or leukopenia (36% vs. 40%; grade 3 or 4, 10% vs. 9%) compared with chemotherapy alone in a randomized clinical trial; febrile neutropenia occurred in more than 2% of patients in the ipilimumab plus nivolumab arm of this study. Immune-mediated cytopenias (2.5%) and eosinophilia (2.1%) were reported in patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials.
Decreased hemoglobin occurred in 25% (grade 3 or 4, 0.2%) of patients with metastatic melanoma who received ipilimumab 10 mg/kg monotherapy compared with 14% of those receiving placebo in a randomized clinical trial. Anemia was reported in 10% to 52% (grade 3 or 4, 2.4% to 9%) of patients treated with ipilimumab plus nivolumab in clinical trials. The addition of ipilimumab and nivolumab to platinum-based chemotherapy did not increase the incidence of anemia compared with chemotherapy alone in a randomized clinical trial (70% vs. 74%; grade 3 or 4, 9% vs. 16%). Immune-mediated aplastic anemia was reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials.
Immune-mediated pancreatitis occurred in 1.3% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials. Ipilimumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Increased amylase levels/hyperamylasemia occurred in patients who received ipilimumab as a single-agent (10 mg/kg: 17%; grade 3 or 4, 2%), ipilimumab 1 mg/kg plus nivolumab (26% to 39%; grade 3 or 4, 3.4% to 12%), ipilimumab 1 mg/kg and nivolumab plus platinum-doublet chemotherapy (30%; grade 3 or 4, 7%), and ipilimumab 3 mg/kg plus nivolumab (27% to 38%; grade 3 or 4, 10% to 15%) in clinical trials. Increased lipase levels were reported in patients who received ipilimumab as a single-agent (10 mg/kg: 26%; grade 3 or 4, 9%), ipilimumab 1 mg/kg plus nivolumab (34% to 48%; grade 3 or 4, 12% to 20%), ipilimumab 1 mg/kg and nivolumab plus platinum-doublet chemotherapy (31%; grade 3 or 4, 12%), and ipilimumab 3 mg/kg plus nivolumab (43% to 51%; grade 3 or 4, 22% to 26%) in clinical trials.
Immune-mediated neurosensory hypoacusis (hearing loss) was reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials. Ipilimumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Headache was reported in 33% (grade 3 or 4, 0.8%) of patients with malignant melanoma who received ipilimumab 10 mg/kg monotherapy in a randomized clinical trial. Headache was also reported in 11% to 22% of patients treated with ipilimumab in combination with nivolumab in 4 clinical trials (grade 3 or 4, 1.7% or less); the addition of ipilimumab and nivolumab to platinum-based chemotherapy slightly increased the incidence of headache in patients with non-small cell lung cancer compared with chemotherapy alone in another randomized clinical trial (11% vs. 7%; grade 3 or 4, 0.6% vs. 0%).
Insomnia occurred in 10% to 18% (grade 3 or 4, 0.8% or less) of patients treated with ipilimumab as monotherapy or in combination with nivolumab in 3 randomized clinical trials.
Severe infusion-related reactions can occur with ipilimumab treatment. Infusion-related reactions occurred in 2.9% of patients who received ipilimumab monotherapy at a dose of 3 mg/kg or 10 mg/kg for the treatment of melanoma. The incidence was 5% in patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg every 3 weeks for the treatment of renal cell cancer or colorectal cancer; 8% in patients who received ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks for the treatment of hepatocellular cancer; and 12% in patients who received ipilimumab 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 3 weeks for the treatment of mesothelioma. Across clinical studies in which patients received ipilimumab as a single agent at doses ranging from 0.3 mg/kg to 10 mg/kg, infusion reactions occurred in less than 1% of patients.
Immune-mediated type 1 diabetes mellitus occurred in 2.7% (grade 3 or 4, 0.9%) of patients with renal cell carcinoma or colorectal cancer who received ipilimumab 1 mg/kg plus nivolumab (n = 666) in clinical trials. Of patients that experienced diabetes, 7% received systemic corticosteroids; resolution of diabetes occurred in 27% of patients. In 3 patients who had ipilimumab or nivolumab held for diabetes, 2 resumed therapy after symptoms improvement; of these, none had a recurrence of diabetes. Hyperglycemia was reported in 6% to 53% (grade 3 or 4, 7% or less) of patients who received ipilimumab in combination with nivolumab (including NSCLC patients who also received 2 cycles of platinum-doublet chemotherapy) in clinical trials. Patients with MSI-H or dMMR colorectal cancer (6%; grade 3 or 4, 1%) or hepatocellular cancer (8%) experienced less hyperglycemia compared with other patient populations who received combination therapy. Additionally, 15% of patients with esophageal cancer treated with ipilimumab plus nivolumab experienced hypoglycemia (grade 3 or 4, 1.2%).
Musculoskeletal pain (including back pain, bone pain, extremity pain, muscle spasms, musculoskeletal chest pain, myalgia, neck pain, non-cardiac chest pain, polymyalgia rheumatica, and spinal pain) occurred in 14% to 41% (grade 3 or 4, 0.6% to 4%) and arthralgia in 10% to 23% (grade 3 or 4, 1.3% or less) of patients treated with ipilimumab in combination with nivolumab in clinical trials. Necrotizing myositis occurred in 0.8% of patients with metastatic colorectal cancer treated with ipilimumab 1 mg/kg plus nivolumab in a single-arm cohort of a multicenter, open-label study. The addition of ipilimumab and nivolumab to platinum-based chemotherapy increased the incidence of musculoskeletal pain (including the previously listed terms as well as muscle cramps, arthralgia, arthritis, arthropathy, joint effusion, and synovitis) compared with chemotherapy alone in patients with non-small cell lung cancer (39% vs. 27%; grade 3 or 4, 4.5% vs. 2%). Immune-mediated arthritis was reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials. Myopathy, Sjogren's syndrome, and spondyloarthropathy occurred in less than 10% of patients with melanoma who received ipilimumab 3 mg/kg in combination with nivolumab (n = 313) in a randomized trial.
Immune-mediated musculoskeletal toxicity that was reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials included myositis, polymyalgia rheumatica, polymyositis, and rhabdomyolysis. Ipilimumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Clinically important increases in blood creatine phosphokinase (CPK) were reported in 2% of patients with hepatocellular cancer treated with ipilimumab 3 mg/kg plus nivolumab.
Edema (including eyelid edema, facial edema, peripheral edema, periorbital edema, and swelling) occurred in 7% to 17% (grade 3 or 4, 2% or less) of patients with renal cell cancer, colorectal cancer, hepatocellular cancer, or non-small cell lung cancer treated with ipilimumab in combination with nivolumab in 5 clinical trials.
Graft-versus-host disease (GVHD) was reported in postmarketing surveillance of ipilimumab. Fatal or serious 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. Monitor patients closely for evidence of GVHD; treat promptly. Complications may occur despite intervening therapy between CTLA-4 receptor blockade and allogeneic SCT.
Hepatitis B exacerbation and hepatitis C exacerbation have occurred in patients with hepatocellular cancer treated with ipilimumab in combination with nivolumab. In these patients, a virologic breakthrough defined as at least a 1 log increase in hepatitis B (HBV) DNA occurred in 14% of patients with active HBV at baseline (n = 28). A virologic breakthrough defined as at least a 1 log increase in hepatitis C (HCV) DNA occurred in 50% of patients with active HCV at baseline (n = 4).
Decreased appetite/anorexia (14% to 35%; grade 3 or 4, 0.2% to 4%) and weight loss (10% to 32%; grade 3 or 4, 1.9% or less) occurred in patients treated with ipilimumab 10 mg/kg monotherapy or ipilimumab plus nivolumab (including NSCLC patients who also received 2 cycles of platinum-doublet chemotherapy) in clinical trials.
Constipation was reported in 14% to 20% (grade 3 or 4, 0.4% or less) of patients with who received combination therapy with ipilimumab and nivolumab in 6 clinical trials. Constipation was reported in 21% (grade 3 or 4, 0.6%) of patients with NSCLC who received ipilimumab plus nivolumab in combination with 2 cycles of platinum-doublet chemotherapy (n = 358) in a randomized trial.
Dysphagia occurred with a similar incidence in patients with esophageal cancer treated with ipilimumab plus nivolumab and in patients treated with cisplatin and fluorouracil (12% vs. 12%; grade 3 or 4, 5% vs. 4.9%).
Hypertension occurred in 7% (grade 3 or 4, 2.2%) of patients with melanoma who received ipilimumab 3 mg/kg in combination with nivolumab (n = 313) in a randomized trial. Hypotension was reported in 10% of patients with hepatocellular cancer treated with ipilimumab 3 mg/kg plus nivolumab in a clinical trial (n = 49).
Pulmonary embolism occurred in at least 2% of patients with metastatic non-small cell lung cancer (NSCLC) or mesothelioma treated with ipilimumab in combination with nivolumab in 2 randomized clinical trials.
Atrial fibrillation was reported in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab in combination with ipilimumab in a randomized clinical trial.
Alopecia was reported in 11% of patients with metastatic non-small cell lung cancer (NSCLC) treated with ipilimumab 1 mg/kg in combination with nivolumab and platinum-doublet chemotherapy in a randomized clinical trial (grade 3 or 4, 0.8%). It was also reported in another randomized trial of patients with metastatic NSCLC treated with ipilimumab plus nivolumab, without chemotherapy.
Fever occurred in 14% to 40% (grade 3 or 4, 1.6% or less) of patients who received ipilimumab as a single agent or in combination with nivolumab (including NSCLC patients who also received 2 cycles of platinum-doublet chemotherapy) in clinical trials. Fever included tumor-related fever in mesothelioma patients. Chills were reported in 10% of patients with hepatocellular cancer treated with ipilimumab plus nivolumab in a clinical trial (n = 49).
Massive hemoptysis in the setting of low blood platelet levels resulting in death occurred in a patient with NSCLC who received ipilimumab plus nivolumab in combination with 2 cycles of platinum-doublet chemotherapy (n = 358) in a randomized trial.
Abdominal pain was reported in 10% to 30% (grade 3 or 4, 0.2% to 6%) of patients treated with ipilimumab in combination with nivolumab in clinical trials.
Xerostomia occurred in 12% of a subgroup of patients with hepatocellular cancer and Child-Pugh A cirrhosis who received ipilimumab plus nivolumab after progression or intolerance to sorafenib in one cohort of a clinical trial.
Esophagitis was reported in less than 1% of patients who received ipilimumab as a single agent at doses ranging from 0.3 mg/kg to 10 mg/kg across clinical trials. Stomatitis occurred in 11% or fewer patients who received ipilimumab plus nivolumab in clinical studies (grade 3 or 4, 0.6% or less), including aphthous ulcers, oral ulceration, and mucosal inflammation.
Large intestinal ulcers (peptic ulcer) were reported in less than 1% of patients who received ipilimumab as a single agent at doses ranging from 0.3 mg/kg to 10 mg/kg across clinical trials. GI perforation occurred in less than 10% of patients with melanoma who received ipilimumab 3 mg/kg in combination with nivolumab (n = 313) in a randomized trial.
Vitiligo/skin hypopigmentation occurred in 9% of patients with melanoma who received ipilimumab 3 mg/kg in combination with nivolumab (n = 313) in a randomized trial. Vitiligo was also reported in patients with metastatic non-small cell lung cancer treated with ipilimumab 1 mg/kg in combination with nivolumab in another randomized trial.
Xerosis occurred in 11% of patients with metastatic colorectal cancer treated with ipilimumab 1 mg/kg in combination with nivolumab in a non-randomized, multiple parallel-cohort, open-label study.
Immune-mediated gastrointestinal toxicity that was reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials included duodenitis and gastritis. Ipilimumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Thrombocytopenia occurred in 12% of esophageal cancer patients treated with ipilimumab plus nivolumab compared with 29% of those who received cisplatin plus fluorouracil (grade 3 or 4, 1% vs. 2.8%) in a randomized clinical trial. Thrombocytopenia occurred in 26% of patients with metastatic colorectal cancer (grade 3 or 4, 0.9%) and in 34% of patients with hepatocellular cancer (grade 3 or 4, 4.3%) who received treatment with ipilimumab plus nivolumab in 2 single-arm studies. The addition of ipilimumab and nivolumab to platinum-based chemotherapy did not increase the incidence of thrombocytopenia compared with chemotherapy alone in a randomized clinical trial (23% vs. 24%; grade 3 or 4, 4.3% vs. 5%).
Dizziness occurred in 11% of patients with metastatic colorectal cancer treated with ipilimumab 1 mg/kg in combination with nivolumab in a single-arm cohort of a multicenter, open-label study. It was also reported in 20% of a subgroup of patients with hepatocellular cancer and Child-Pugh A cirrhosis who received ipilimumab plus nivolumab after progression or intolerance to sorafenib in one cohort of a clinical trial. The addition of ipilimumab and nivolumab to platinum-based chemotherapy in patients with non-small cell lung cancer slightly increased the incidence of dizziness (including vertigo) compared with chemotherapy alone (11% vs. 6%; grade 3 or 4, 0.6% vs. 0%).
Hemophagocytic lymphohistiocytosis has been reported in postmarketing surveillance of ipilimumab.
Immune-mediated adverse reactions that were reported in less than 1% of patients who received ipilimumab as a single agent or in combination with nivolumab in clinical trials included histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, systemic inflammatory response syndrome, and solid organ transplant rejection. Ipilimumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Solid organ transplant rejection has been reported in postmarketing experience with ipilimumab.
Pleural effusion occurred in at least 2% of patients with malignant pleural mesothelioma treated with ipilimumab in combination with nivolumab in a randomized clinical trial.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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. .
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).
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 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.
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.
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.
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.
For the treatment of malignant melanoma:
-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 or metastatic melanoma, as a single-agent:
Intravenous dosage:
Adults: 3 mg/kg IV over 30 minutes repeated every 3 weeks for a total of 4 doses. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions or infusion-related reactions. 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.
Children and Adolescents 12 years and older: 3 mg/kg IV over 30 minutes repeated every 3 weeks for a total of 4 doses. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions or infusion-related reactions. Use of ipilimumab in pediatric patients aged 12 and older is based on evidence from adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.
-for the treatment of unresectable or metastatic melanoma, in combination with nivolumab:
intravenous dosage:
Adults: 3 mg/kg IV over 30 minutes repeated every 3 weeks for a maximum of 4 doses in combination with nivolumab 1 mg/kg IV repeated every 3 weeks (maximum of 4 doses) followed by single-agent nivolumab until disease progression. Administer ipilimumab 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. 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).
Children and Adolescents 12 years and older: 3 mg/kg IV over 30 minutes repeated every 3 weeks for a maximum of 4 doses in combination with nivolumab 1 mg/kg IV repeated every 3 weeks (maximum of 4 doses) followed by single-agent nivolumab until disease progression. Administer ipilimumab 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. Use of ipilimumab in pediatric patients aged 12 and older is based on evidence from adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.
-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 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).
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 (360 mg IV every 3 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.
For the first-line treatment of esophageal cancer, in particular unresectable advanced or metastatic esophageal squamous cell cancer (ESCC), in combination with nivolumab:
Intravenous dosage:
Adults: 1 mg/kg IV over 30 minutes every 6 weeks in combination with nivolumab (3 mg/kg IV every 2 weeks OR 360 mg IV every 3 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. Treatment with ipilimumab plus nivolumab significantly improved the median overall survival time compared with fluorouracil plus cisplatin (13.7 months vs. 9.1 months) in patients with previously untreated, unresectable advanced, recurrent or metastatic esophageal squamous cell cancer and at least 1% of tumor cells expressing PD-L1 in a multicenter, randomized, open-label, phase 3 clinical trial (CHECKMATE-648); median overall survival was also significantly improved with ipilimumab and nivolumab in the overall population (12.8 months vs. 10.7 months). Median progression-free survival (PFS) was shorter with immunotherapy compared with chemotherapy in patients with at least 1% PD-L1 expression (4 months vs. 4.4 months) and in those in the overall population (2.9 months vs. 5.6 months). The overall response rate was also higher in patients treated with nivolumab plus ipilimumab in both the PD-L1 positive population (35.4% vs. 20%) and the overall population (27.7% vs. 27%). Complete responses (CR) occurred in 17.7% of PD-L1 positive immunotherapy patients and in 11.1% of those in the overall population; CR occurred in 5.1% of PD-L1 positive patients who received chemotherapy and in 6.2% of those in the overall population. The median duration of response for PD-L1 positive patients was 11.8 months versus 5.7 months, respectively; the median duration of response in the overall population was 11.1 versus 7.1 months, respectively.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Immune-Mediated Reactions
NOTE: Corticosteroid therapy consists of 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. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. 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. When ipilimumab is administered in combination with nivolumab, withhold or permanently discontinue both ipilimumab and nivolumab for toxicity.
Colitis
Grade 2 toxicity: Hold ipilimumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue ipilimumab and administer corticosteroids.
Endocrinopathies (including Type 1 diabetes, Hypophysitis, Hypothyroidism, Hyperthyroidism, and Adrenal Insufficiency)
Grade 2 toxicity: Consider holding ipilimumab until symptoms improve with hormone replacement therapy. Resume therapy when acute symptoms resolve.
Grade 3 or 4 toxicity: Hold ipilimumab until the patient is clinically stable; administer appropriate treatment (e.g., hormone replacement therapy, corticosteroids, insulin). Permanently discontinue ipilimumab for severe toxicity.
Exfoliative Skin Reactions
Suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS): Hold ipilimumab and administer corticosteroids as applicable.
Confirmed SJS, TEN, or DRESS: Permanently discontinue ipilimumab and administer corticosteroids as applicable.
Infusion-Related Reactions
Grade 1 or 2 toxicity: Hold ipilimumab or slow the infusion rate.
Grade 3 or 4 toxicity: Permanently discontinue ipilimumab.
Myocarditis
Grade 2, 3, or 4 toxicity: Permanently discontinue ipilimumab and administer corticosteroids.
Neurologic Toxicity
Grade 2 toxicity: Hold ipilimumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue ipilimumab and administer corticosteroids.
Ophthalmologic Toxicity
Grade 2, 3, or 4 toxicity: If the adverse event does not improve to grade 1 within 2 weeks while receiving topical therapy or if systemic treatment is required, permanently discontinue ipilimumab.
Pneumonitis
Grade 2 toxicity: Hold ipilimumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue ipilimumab and administer corticosteroids.
Other Immune-Mediated Adverse Reactions
Grade 3 toxicity: Hold ipilimumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Persistent grade 2 or 3 toxicity lasting 12 weeks or longer after last ipilimumab dose: permanently discontinue ipilimumab.
Recurrent grade 3 toxicity that requires treatment with systemic immunosuppressants: Permanently discontinue ipilimumab.
Grade 4 toxicity: Permanently discontinue ipilimumab and administer corticosteroids.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Treatment-Related Immune-Mediated Hepatitis
No 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 HCC
Baseline 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 ULN
AST 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 ULN
AST 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 level
AST 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).
Patients with Renal Impairment Dosing
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).
*non-FDA-approved indication
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.
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.
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.
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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (bilirubin 1.1 to 1.5 times the upper limit of normal (ULN) or AST greater than ULN) did not have a clinically meaningful effect on the clearance of ipilimumab. Ipilimumab has not been studied in patients with moderate (bilirubin 1.6 to 3 times ULN and any AST) or severe (bilirubin greater than 3 times ULN and any AST) hepatic impairment.
Renal Impairment
Renal impairment (glomerular filtration rate 15 mL/min/1.72 m2 or more) did not have a clinically meaningful effect on the clearance of ipilimumab.
Pediatrics
When administered at the recommended dosage, ipilimumab exposures in pediatric patients 12 years and older are comparable with the exposures in adult patients.
Geriatric
Age had no clinically meaningful effect on the clearance of ipilimumab among patients 23 to 88 years old.
Gender Differences
Gender had no clinically meaningful effect on the clearance of ipilimumab.
Obesity
The clearance of ipilimumab increased with increasing body weight, supporting the recommended weight-based dosing.
Other
Performance status, prior cancer therapy, or baseline lactate dehydrogenase (LDH) concentrations had no clinically meaningful effect on the clearance of ipilimumab.