Dosing & Uses
Dosage Forms & Strengths
injectable solution, single-dose
- 5mg/mL (10mL, 40mL)
Melanoma
Unresectable or metastatic melanoma
- Indicated for treatment of unresectable or metastatic melanoma in adults and children aged ≥12 yr
- 3 mg/kg IV q3Weeks for a maximum of 4 doses
-
Combination with nivolumab
- Indicated in combination with nivolumab for unresectable or metastatic melanoma in adults
- Ipilimumab 3 mg/kg IV q3Weeks PLUS
- Nivolumab 1 mg/kg IV on the same day for maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier
- After completing 4 doses of combination therapy: Administer nivolumab 240 mg IV q2Weeks or 480 mg IV q4Weeks as a single agent until disease progression or unacceptable toxicity
Cutaneous Melanoma
- Indicated for adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy
- 10 mg/kg IV q3Weeks for 4 doses followed by 10 mg/kg q12Weeks for up to 3 yr
Renal Cell Carcinoma
Indicated in combination with nivolumab for patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma
Ipilimumab1 mg/kg IV q3Weeks following nivolumab on the same day for 4 doses
After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression
Also see nivolumab drug monograph for dose and continuation as monotherapy
Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer
Indicated in combination with nivolumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan
Ipilimumab 3 mg/kg IV immediately following nivolumab 1 mg/kg IV on the same day, q3Weeks for 4 doses
After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression
Also see nivolumab drug monograph for dose and continuation as monotherapy
Hepatocellular Carcinoma
Indicated in combination with nivolumab for hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib
Ipilimumab 3 mg/kg IV immediately following nivolumab 1 mg/kg IV on the same day, q3Weeks for 4 doses
After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression
Also see nivolumab drug monograph for dose and continuation as monotherapy
Non-small Cell Lung Cancer
Combination with nivolumab
- Indicated in combination with nivolumab for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in adults whose tumors express PD-L1 (≥1%) with no EGFR or ALK genomic tumor aberrations
- Nivolumab 3 mg/kg IV q2Weeks, plus
- Ipilimumab 1 mg/kg IV q6Weeks
- Continue until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression
Combination with nivolumab and platinum-based chemotherapy
- Indicated in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, for first-line treatment of metastatic or recurrent NSCLC in adults with no EGFR or ALK genomic tumor aberrations
- Nivolumab 360 mg/kg IV q3Weeks, PLUS
- Ipilimumab 1 mg/kg IV q6Weeks, PLUS
- Histology-based platinum doublet chemotherapy q3Weeks for 2 cycles
- Continue until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression
Malignant Pleural Mesothelioma
Indicated in combination with nivolumab for patients with unresectable malignant pleural mesothelioma, as first-line treatment
Ipilimumab 1 mg/kg IV q6Weeks, PLUS
Nivolumab 360 mg IV q3Weeks
Continue in combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression
Dosage Modifications
Note: No dose reduction is recommended for adverse reactions
Renal impairment
- All severities: No dosage adjustment required
Hepatic impairment
- Mild (TB >1 to 1.5x ULN or AST >ULN): No dose adjustment required
- Moderate-to-severe (TB >1.5x ULN and any AST): Not studied; caution advised
Pneumonitis
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Colitis
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Hepatitis with no tumor involvement of the liver
- AST or ALT increases to >3 and ≤8x ULN or total bilirubin increases to >1.5 and <3x ULN: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- AST or ALT increases to >8x ULN or total bilirubin increases to >3x ULN: Permanently discontinue
Hepatitis with tumor involvement of the liver
-
Withhold therapy
- Baseline AST or ALT >1 and ≤3x ULN and increases to >5 and ≤10x ULN
- Baseline AST or ALT >3 and ≤5x ULN and increases to >8 and ≤10x ULN
- Resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
-
Permanently discontinue
- AST or ALT increases to >10x ULN or total bilirubin increases to >3x ULN
Endocrinopathies
- Grade 3 or 4: Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with renal dysfunction
- Grade 2 or 3 increased blood creatinine: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 4 increased blood creatinine: Permanently discontinue
Exfoliative dermatologic conditions
- Suspected Steven Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Withhold therapy
- Confirmed SJS, TEN, or DRESS: Permanently discontinue
- Myocarditis H4
- Grade 2, 3, or 4: Permanently discontinue
Neurologic toxicities
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Infusion-related reactions H4
- Grade 1 or 2: Interrupt or slow infusion rate
- Grade 3 or 4: Permanently discontinue
Dosing Considerations
Patient selection
- Patients selection should be based on PD-L1 expression
- Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics
Orphan Designations
Small cell lung cancer
Orphan sponsor
- Bristol-Myers Squibb Company; 5 Research Parkway; Wallingford, Connecticut 06492
Dosage Forms & Strengths
injectable solution, single-dose
- 5mg/mL (10mL, 40mL)
Malignant Melanoma
Indicated for treatment of unresectable or metastatic melanoma in adults and adolescents aged ≥12 yr
<12 years: Safety and efficacy not established
≥12 years: 3 mg/kg IV q3Week for a maximum of 4 doses
Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer
Indicated in combination with nivolumab for patients aged ≥12 years with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan
<12 years: Safety and efficacy not established
≥12 years: 1 mg/kg IV q3Weeks following nivolumab on the same day; repeat for up to 4 doses or until intolerable toxicity or disease progression
Also see nivolumab drug monograph for dose and continuation as monotherapy
Dosage Modifications
Renal impairment
- All severities: No dosage adjustment required
Hepatic impairment
- Mild (TB >1 to 1.5 x ULN or AST >ULN): No dose adjustment required
- Moderate-to-severe (TB >1.5 x ULN and any AST): Not studied; caution advised
Interrupt or slow rate of infusion
- Grade 1 or 2 infusion-related reactions
Withhold
-
Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper
- Grade 2 colitis or diarrhea
- Grade 2 pneumonitis
- Grade 2 or 3 increased blood creatinine nephritis with renal dysfunction
- Grade 2 neurological toxicities
- Grade 2 myocarditis
-
Resume when acute symptoms have resolved
- Grade 2 to 4 hypophysitis
-
Resume when AST/ALT returns to baseline
- Hepatitis (AST or ALT >3x to <5x ULN or total bilirubin >1.5x to <3x ULN)
Withhold until specialist assessment
- Grade 2 exfoliative or bullous dermatologic conditions
Withhold if not clinically stable
- Grade 2 to 4 endocrinopathies
Permanently discontinue
- Grade 3 or 4 colitis or diarrhea
- Hepatitis (AST or ALT >5x ULN or total bilirubin >3x ULN)
- Grade 3 or 4 exfoliative or bullous dermatologic conditions
- Grade 3 or 4 pneumonitis
- Grade 4 increased blood creatinine
- Grade 3 or 4 myocarditis
- Grade 2 to 4 ophthalmologic that does not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment
- Grade 3 or 4 neurological toxicities if signs of encephalitis or respiratory insufficiency due to neurological toxicity regardless of grade
- Grade 3 or 4 infusion-related reactions
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Dermatitis immune-mediated manifestations (up to 70%)
Fatigue (41%)
Diarrhea (32%)
Pruritus (31%)
Rash (29%)
1-10%
Colitis (8%)
Immune-mediated enterocolitis (7%)
Immune-mediated hepatitis (2%)
Endocrinopathies (1.8%) including adrenal insufficiency, hypogonadism, and hypothyroidism
<1%
Neurologic immune-mediated manifestations (eg, Guillain-Barre, peripheral motor neuropathy)
Ocular immune-mediated manifestations (eg, uveitis, iritis)
Nephrotic immune-mediated manifestations (nephritis)
Pulmonary immune-mediated manifestations (pneumonitis)
Other immune-mediated adverse reactions (<1%) include nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia
Meningitis
Pericarditis
Myocarditis
Angiopathy
Temporal arteritis
Vasculitis
Polymyalgia rheumatica
Conjunctivitis
Blepharitis
Episcleritis
Scleritis
Leukocytoclastic vasculitis
Erythema multiforme
Psoriasis
Pancreatitis
Arthritis
Autoimmune thyroiditis
Postmarketing Reports
Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH)
Immune System: Graft-versus-host disease, solid organ transplant rejection
Warnings
Contraindications
None
Cautions
Severe infusion-related reactions can occur; discontinue in patients with severe or life-threatening infusion reactions
Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive a CTLA-4 receptor blocking antibody either before or after allogeneic hematopoietic stem cell transplantation (HSCT); closely monitor for evidence of GVHD and intervene promptly; consider benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after allogeneic HSCT
May cause fetal harm when administered to pregnant females
When used in combination with nivolumab, refer to nivolumab prescribing information for additional risk information that applies to the combination use treatment
Immune-mediated adverse reactions
- Owing to the mechanism of action that blocks T-cell inhibitory signal via CTLA-4 pathway, thereby removing inhibition of the immune response to potential immune-mediated adverse reactions
- In general, if interruption or discontinuation is necessary, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less; upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month; consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy
- Therapy can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (drug rash with eosinophilia and systemic symptoms); topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes; withhold or permanently discontinue therapy depending on severity
- Immune-mediated adverse reactions (eg, hepatitis, dermatologic adverse reactions, endocrinopathies, pneumonitis, immune-mediated nephritis with renal dysfunction), which may be severe or fatal, can occur in any organ system or tissue
- Therapy can cause immune-mediated colitis, which may be fatal; cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis; in cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies
- Immune-mediated hypophysitis; hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts; hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated; withhold or permanently discontinue therapy depending on severity
- May occur at any time after initiating therapy
- Immune-mediated adverse reactions usually manifest during treatment, but can also manifest after discontinuation
- Early detection and management are essential to ensure safe use
- Monitor for signs and symptoms of underlying immune-mediated adverse reactions
- Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose
- Institute medical management promptly, including specialty consultation as appropriate
Pregnancy & Lactation
Pregnancy
Based on findings from animal studies and its mechanism of action, may cause fetal harm when administered to pregnant females
There is insufficient human data for drug exposure in pregnant females
Advise pregnant females of the potential risk to a fetus
Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus
Verify pregnancy status in females of reproductive potential prior to initiation
Report pregnancies to Bristol-Myers Squibb at 1-844-593-7869
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 3 months following last dose
Animal data
Administration of ipilimumab to cynomolgus monkeys from onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner
- Effects of ipilimumab are likely to be greater during second and third trimesters of pregnancy
Lactation
Unknown whether distributed in human breast milk
Advise women to discontinue breastfeeding during treatment and for 3 months after last dose
In monkeys, ipilimumab was present in milk
There are no data to assess the effects on milk production
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Recombinant, human cytotoxic T-lymphocyte antigen 4 (CTLA-4) - blocking antibody
CTLA-4 is a negative regulator of T-cell activation; ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86
Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation
Proposed mechanism of action is indirect, possibly through inhibition of CTLA-4 signaling, which can in turn reduce T-regulatory cell function and may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response
IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kd; produced in mammalian (Chinese hamster ovary) cell culture
Absorption
Minimum plasma concentration: 19.4 mcg/mL (steady-state)
Distribution
Vd: 7.21 L (steady-state)
Elimination
Half-life (terminal): 15.4 days
Clearance: 16.8 mL/hr
When administered in combination with nivolumab, ipilimumab clearance was unchanged in presence of antiipilimumab antibodies and the CL of nivolumab increased by 20% in the presence of antinivolumab antibodies
Administration
IV Incompatibilities
Do not coadminister with other drugs through same IV line
IV Compatibilities
0.9% NaCl
Dextrose 5% (D5W)
IV Preparation
Do not shake vial
Allow vials to stand at room temperature for ~5 minutes
Withdraw required volume and transfer into an IV bag
Dilute with 0.9% NaCl or D5W to prepare a diluted solution with a final concentration ranging from 1-2 mg/mL
Mix diluted solution by gentle inversion
Discard partially used or empty vials
IV Administration
Do not mix with, or administer as an infusion with, other medicinal products
Flush the IV line with 0.9% NaCl or D5W after each dose
Infusion rate
- Melanoma: Infuse over 90 minutes
- Renal cell carcinoma, MSI-H dMMR, hepatocellular carcinoma, NSCLC, malignant pleural mesothelioma: Infuse over 30 minutes
- Infuse through an IV line containing a sterile, nonpyrogenic, low-protein-binding in-line filter
Administration with nivolumab
- When administered in combination with nivolumab, infuse nivolumab first followed by ipilimumab on the same day
- Use separate infusion bags and filters for each infusion
Storage
Unopened vials
- Store refrigerated at 2-8°C (36-46°F)
- Do not freeze
- Protect vials from light
Diluted solution
- Store the diluted solution refrigerated (2-8°C; 36-46°F) or at room temperature (20-25°C; 68-77°F) for up to 24 hr
- Discard partially used vials or empty vials
Images
Patient Handout
Formulary
Adding plans allows you to compare formulary status to other drugs in the same class.
To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.
Adding plans allows you to:
- View the formulary and any restrictions for each plan.
- Manage and view all your plans together – even plans in different states.
- Compare formulary status to other drugs in the same class.
- Access your plan list on any device – mobile or desktop.
