Dosing & Uses
Dosing Form & Strengths
injectable solution, single-dose
- 5mg/mL (10mL, 40mL)
Malignant Melanoma
Unresectable or metastatic melanoma
- Indicated for treatment of unresectable or metastatic melanoma in adults and children aged ≥12 yr
- 3 mg/kg IV q3Week for a maximum of 4 doses
Adjuvant treatment
- Indicated for the 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 q3Week for 4 doses followed by 10 mg/kg q12Week 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
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
Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer
Indicated in combination with nivolumab is indicated for adults with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) which progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
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
Hepatocellular Carcinoma
Indicated in combination with nivolumab for hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib
3 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
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
Dosage Modifications
Renal impairment
- Moderate renal impairment (CrCl 30 - 59 mL/min): 0.75 mg IV qDay
- Severe renal impairment (CrCl 15 - 29 mL/min): 0.5 mg IV qDay
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
Modifications for use with P-glycoprotein (P-gp) Inhibitors
- Avoid coadministration if possible
- Reduce dose to 0.75 mg IV qDay when coadministered with certain P-gp inhibitors, including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil
- When P-gp inhibitor discontinued, increase dose (after 3–5 half-lives of P-gp inhibitor) to dose used prior to initiation of P-gp inhibitor
Withhold dosing
- When administered with nivolumab, if ipilimumab is withheld, nivolumab should also be withheld
- Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions
- Symptomatic endocrine adverse effects and all other grade 2 adverse effects
- Resume dosing in patients with complete or partial resolution of adverse reactions (grade <1) and who are receiving <7.5 mg prednisone or equivalent per day
Permanently discontinue
- Severe or life-threatening infusion reactions
-
Endocrine
- Symptomatic reactions lasting ≥6 weeks
- Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day
-
Ophthalmologic
- Grade 2-4 reactions that do not improve to grade 1 within 2 weeks while receiving topical therapy
- Grade 2-4 reactions requiring systemic treatment
-
All other
- Grade 2 reactions lasting ≥6 weeks
- Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day
- Grade 3 or 4 reactions
Dosing Considerations
Patient selection
- Combination therapy with nivolumab for metastatic NSCLC should be based on PD-L1 expression
- Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is
- available at: http://www.fda.gov/CompanionDiagnostics
Orphan Designations
Mesothelioma (with nivolumab)
Small cell lung cancer
Orphan sponsor
- Bristol-Myers Squibb Company; 5 Research Parkway; Wallingford, Connecticut 06492
Dosing Form & 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, is indicated for adult and pediatric patients (≥12 years) with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) which progressed following treatment with a 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: No dose 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
Withhold dosing
- Symptomatic endocrine adverse effects and all other grade 2 adverse effects
- Resume dosing in patients with complete or partial resolution of adverse reactions (grade 0 to 1) and who are receiving <7.5 mg prednisone or equivalent per day
Permanently discontinue
-
Endocrine
- Symptomatic reactions lasting ≥6 weeks
- Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day
-
Ophthalmologic
- Grade 2-4 reactions that do not improve to grade 1 within 2 weeks while receiving topical therapy
- Grade 2-4 reactions requiring systemic treatment
-
All other
- Grade 2 reactions lasting ≥6 weeks
- Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day
- Grade 3 or 4 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)
Immune system disorders: Graft-versus-host disease
Warnings
Black Box Warnings
Immune-mediated adverse reactions
- Severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation may involve any organ system
- The most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy
- Other immune-mediated adverse reactions include ocular manifestations include autoimmune central neuropathy (encephalitis), neurosensory hypoacusis, myositis, polymyositis, ocular myositis, and sarcoidosis
- These reactions typically manifest during treatment but may occur weeks to months after discontinuation
- If severe immune-mediated reactions occur, permanently discontinue and initiate systemic high-dose corticosteroid therapy
- Assess signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries, including liver function
Contraindications
No known contraindications
Cautions
May cause immune-mediated adverse reactions including enterocolitis, hepatitis, dermatitis, neuropathies, endocrinopathies, ocular, and other significant or severe immune-mediated manifestations; may require initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent
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); follow patients closely for evidence of GVHD and intervene promptly; consider benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after allogeneic HSCT
Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg/day prednisone or equivalent
Cytomegalovirus (CMV) infection/reactivation reported in patients with corticosteroid-refractory immune-mediated colitis; in cases of corticosteroid-refractory colitis, consider repeating an infectious workup to exclude alternative etiologies; consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3 to 5 days or recurring after symptom improvement, if other causes are excluded
Immune-mediated pneumonitis, including fatal cases, reported; monitor patients for signs with radiographic imaging and for symptoms of pneumonitis; administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or more severe (Grade 3-4) pneumonitis, followed by corticosteroid taper; withhold dosing in patients with moderate to severe signs and symptoms; permanently discontinue for life-threatening (Grade 4) pneumonitis
Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions
Evaluate liver function tests before each dose; permanently discontinue with Grade 3-4 hepatotoxicity
Monitor thyroid function tests and clinical chemistries prior to each dose
Evaluate at each visit for signs and symptoms of endocrinopathy and institute hormone replacement therapy as needed
Binding antibodies against ipilimumab may develop
Based on its mechanism of action and data from animal studies, can cause fetal harm when administered to a pregnant woman (see Pregnancy); advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ipilimumab
Severe infusion reactions may occur when ipilimumab is used in combination with nivolumab; discontinue with severe or life-threatening reactions; interrupt or slow infusion rate with mild or moderate reactions (see Dosage Modifications)
Ocular toxicity
- Monitor patients for signs or symptoms of ocular toxicity, which may include blurred vision and reduced visual acuity
- Immune-mediated ocular toxicity may be associated with retinal detachment or permanent vision loss
- Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis
- Permanently discontinue therapy for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy
- If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt Koyanagi-Harada-like syndrome, which has been observed in patients receiving drug and may require treatment with systemic steroids to reduce risk of permanent vision loss
Pregnancy & Lactation
Pregnancy
A Pregnancy Safety Surveillance Study has been established to collect information about pregnancies in women who have received therapy;. healthcare providers are encouraged to enroll patients or have their patients enroll directly by calling 1-844-593-7869
Based on data from animal studies and its mechanism of action, can cause fetal harm when administered to a pregnant woman
Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose
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
Animal studies
- In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the 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
- The effects are likely to be greater during the second and third trimesters of pregnancy
Lactation
Unknown whether distributed in human breast milk
Advise women to discontinue nursing during treatment and for 3 months after the final 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 Compatibility
0.9% NaCl (normal saline)
Dextrose 5% (D5W)
IV Preparation
Do not shake vial
Allow the vials to stand at room temperature for ~5 minutes prior to preparation of infusion
Withdraw the required volume and transfer into an intravenous 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
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.
Administer diluted solution over 90 minutes (melanoma) or 30 minutes (renal cell carcinoma) 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
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