ipilimumab (Rx)

Brand and Other Names:Yervoy
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Dosing & Uses

AdultPediatric

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 
  • Infuse IV over 90 minutes
  • In the event of toxicity, doses may be delayed, but all treatment must be administered within 16 weeks of the first dose

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 
  • Infuse IV over 90 minutes
  • In the event of toxicity, doses are omitted, not delayed

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 infused over 30 min immediately following nivolumab on the same day; repeat q3Weeks 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 infused over 30 minutes immediately following nivolumab on the same day; repeat q3Weeks 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 1.5 x ULN or AST >ULN): No dose adjustment required
  • Moderate-to-severe (TB >1.5 x ULN and any AST): Not studied; caution advised

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 0 to 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 through 4 reactions that do not improve to grade 1 within 2 weeks while receiving topical therapy
    • Grade 2 through 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

Mesothelioma (Orphan)

Orphan designation for treatment of mesothelioma (with nivolumab)

Sponsor

  • Bristol-Myers Squibb Company; 5 Research Parkway; Wallingford, Connecticut 06492

Dosing Considerations

Indications for MSI-H or dMMR metastatic CRC is approved under accelerated approval based on overall response rate and duration of response

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

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 

Infuse IV over 90 minutes

In the event of toxicity, doses may be delayed, but all treatment must be administered within 16 weeks of the first dose

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 infused over 30 minutes immediately following nivolumab on the same day; repeat q3Weeks for up to 4 doses or until intolerable toxicity or disease progression

Also see nivolumab drug monograph for dose and continuation with monotherapy

Dosage Modifications

Renal impairment: No dose 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

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 through 4 reactions that do not improve to grade 1 within 2 weeks while receiving topical therapy
    • Grade 2 through 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

Indications for MSI-H or dMMR metastatic CRC is approved under accelerated approval based on overall response rate and duration of response

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

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Interactions

Interaction Checker

and ipilimumab

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

            All Interactions Sort By:
             activity indicator 
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            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)

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            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

            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 the risk of permanent vision loss

            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

            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)

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            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.

            more...
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            Pharmacology

            Mechanism of Action

            Targeted T-cell antibody; recombinant, human cytotoxic T-lymphocyte antigen 4 (CTLA-4) - blocking antibody indicated for unresectable or metastatic melanoma

            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

            Adsorption

            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

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            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 (normal saline) or 5% dextrose (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 for no more than 24 hours under refrigeration (2-8°C, 36-46°F) or at room temperature (20-25°C, 68-77°F)
            • Discard partially used vials or empty vials
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            Images

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            Formulary

            FormularyPatient Discounts

            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.

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            • 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.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.