Ipilimumab

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: Disulfide with human kappa-chain anti-human cytotoxic T lymphocyte antigen 4 (human lambda-chain) immunoglobulin G1 dimer
Molecular Formula: C6472H9972N1732O2004S40
CAS Number: 477202-00-9
Brands: Yervoy

Warning(s)

  • Immune-mediated Adverse Reactions
  • Severe, sometimes fatal, immune-mediated adverse reactions reported.1 (See Warnings under Cautions.)

  • These reactions may involve any organ system; most common, severe immune-mediated reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy.1

  • Frequently occur during treatment; may also occur weeks or months after discontinuing the drug.1

  • Evaluate patient for manifestations of enterocolitis, dermatitis, neuropathy, and endocrinopathy using appropriate clinical and laboratory tests (e.g., liver function and thyroid function tests) prior to each dose.1

REMS:

FDA approved a REMS for ipilimumab to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of ipilimumab and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antineoplastic agent; recombinant human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).1 7 8 10

Uses for Ipilimumab

Melanoma

Treatment of unresectable or metastatic melanoma (designated an orphan drug by FDA for this use).1 6 7

Slideshow: Flashback: FDA Drug Approvals 2013

Ipilimumab Dosage and Administration

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Ipilimumab injection concentrate must be diluted prior to IV infusion.1

Do not admix or infuse with other drugs.1

Administer using an in-line, sterile, nonpyrogenic, low-protein-binding filter.1 Flush IV line with 0.9% sodium chloride or 5% dextrose injection after each dose.1

Dilution

Prior to dilution, allow vials containing ipilimumab injection concentrate to stand at room temperature for approximately 5 minutes.1

Use strict aseptic technique since drug contains no preservative.1

Withdraw the appropriate dose from the vial(s) containing 5 mg/mL and inject into an IV bag.1 Dilute the injection concentrate with 0.9% sodium chloride or 5% dextrose injection to achieve a final ipilimumab concentration of 1–2 mg/mL.1

Mix diluted solution by gentle inversion; do not shake.1

Use diluted solution within 24 hours after dilution.1

Vials are intended for single use only; discard any unused portions.1

Rate of Administration

Administer over 90 minutes.1

Dosage

Adults

Melanoma
IV

3 mg/kg every 3 weeks for total of 4 doses.1

Dosage Modification for Toxicity

Permanently discontinue ipilimumab in patients experiencing any severe or life-threatening immune-mediated adverse reactions.1 (See Warnings under Cautions.)

Temporarily withhold therapy in patients experiencing any moderate immune-mediated adverse reactions or symptomatic endocrinopathy.1 (See Warnings/Precautions under Cautions.) If the adverse reaction completely or partially resolves to grade 0 or 1 and the patient is receiving ≤7.5 mg of prednisone daily (or equivalent), resume therapy at a dosage of 3 mg/kg every 3 weeks until all 4 planned doses are administered or 16 weeks have elapsed since the first dose, whichever occurs first.1 3

Permanently discontinue ipilimumab in patients experiencing persistent moderate immune-mediated adverse reactions or in those unable to reduce corticosteroid dosage to ≤7.5 mg of prednisone daily (or equivalent).1

Permanently discontinue ipilimumab in patients unable to complete full treatment course within 16 weeks after receiving first dose.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Ipilimumab

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Immune-mediated Adverse Reactions

Severe, sometimes fatal, immune-mediated adverse reactions reported.1 7 22 These reactions result from T-cell activation and proliferation, and may involve any organ system.1

Most common, severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy.1 These reactions generally occur during treatment; may also occur weeks or months after discontinuing the drug.1

Evaluate patients for manifestations of enterocolitis, dermatitis, neuropathy, and endocrinopathy using appropriate clinical and laboratory tests prior to each dose of drug.1

If severe immune-mediated adverse reactions occur, discontinue the drug and initiate high-dose systemic corticosteroid therapy.1 (See REMS and see Dosage Modification for Toxicity under Dosage and Administration.)

Immune-mediated GI Effects

Severe, life-threatening, and sometimes fatal immune-mediated enterocolitis reported.1 Incidence and severity appear to be dose dependent.1 Median onset occurs at 6 or 7 weeks (up to 19 weeks) after therapy initiation.1

Monitor patients for manifestations of enterocolitis (e.g., diarrhea, abdominal pain, mucus or blood in stool) and bowel perforation (e.g., peritoneal signs, ileus).1 Rule out infectious etiologies in symptomatic patients; consider endoscopic evaluation for severe or persistent symptoms.1

Permanently discontinue ipilimumab in patients with severe (grade 3–5) enterocolitis.1 After bowel perforation ruled out,3 initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg per day of prednisone (or equivalent).1 Once symptoms improve to mild or resolve to grade 0 or 1, taper corticosteroid dosage for ≥1 month to avoid recurrence or worsening of enterocolitis.1 If symptoms continue, consider alternative immunosuppressive therapy (e.g., infliximab).1 3 18 19

For moderate enterocolitis, temporarily withhold ipilimumab and initiate antidiarrheal therapy.1 If symptoms persist for >1 week, start systemic corticosteroid therapy at a dosage of 0.5 mg/kg day of prednisone (or equivalent).1 May resume therapy once symptoms resolve or improve to mild and daily prednisone dosage is ≤7.5 mg (or equivalent).1 3 (See Dosage Modification for Toxicity under Dosage and Administration.)

Permanently discontinue ipilimumab in patients unable to reduce daily corticosteroid dosage to ≤7.5 mg of prednisone (or equivalent) and in those unable to complete full treatment course within 16 weeks after receiving first dose.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Immune-mediated Hepatic Effects

Severe, life-threatening, and sometimes fatal hepatotoxicity (e.g., immune-mediated hepatitis) reported.1 7 22 Incidence and severity of hepatitis appear to be dose dependent.1

Evaluate serum AST, ALT, and total bilirubin concentrations and assess patients for manifestations of hepatotoxicity prior to each dose of drug.1 Rule out infectious and malignant etiologies. Evaluate serum AST, ALT, and total bilirubin concentrations more frequently in patients experiencing hepatotoxicity until resolved.1

Permanently discontinue ipilimumab for severe, life-threatening, or fatal (grade 3–5) hepatotoxicity and initiate systemic corticosteroid treatment at a dosage of 1–2 mg/kg per day of prednisone (or equivalent).1 Once liver function tests indicate improvement or return to baseline, taper corticosteroid dosage for ≥1 month.1 If severe or life-threatening hepatotoxicity persists, consider alternative immunosuppressive therapy.3

For moderate (grade 2) hepatotoxicity, temporarily withhold ipilimumab.1 May resume therapy once ALT and AST are <2.5 times the ULN and total bilirubin is <1.5 times the ULN, or these values have returned to baseline.1 3

Permanently discontinue ipilimumab in patients unable to reduce daily corticosteroid dosage to ≤7.5 mg of prednisone (or equivalent) and in those unable to complete full treatment course within 16 weeks after receiving first dose.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Immune-mediated Dermatologic Effects

Severe, life-threatening, and sometimes fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) reported.1 7 22 Median onset occurs at 3.1 weeks (up to 17.3 weeks) after initiating ipilimumab.1

Monitor patients for manifestations of dermatitis (e.g., rash, pruritus).1 Unless alternative etiology is identified, consider dermatitis to be immune mediated.1

Permanently discontinue ipilimumab for severe or life-threatening (grade 3–5) dermatitis and initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg per day of prednisone (or equivalent).1 Once dermatitis is controlled, taper corticosteroid dosage for ≥1 month.1

Withhold ipilimumab for moderate (diffuse, ≤50% of skin surface) manifestations of dermatitis.1 20 Administer topical or systemic corticosteroids if there is no symptomatic improvement within 1 week.1 May resume therapy once dermatitis resolves or improves to mild (localized rash) and daily prednisone dosage is ≤7.5 mg (or equivalent).1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Symptomatically treat mild dermatitis (e.g., localized rash, pruritus).1 20 Administer topical or systemic corticosteroids if there is no symptomatic improvement within 1 week.1

Immune-mediated Neurologic Effects

Severe, sometimes fatal, immune-mediated neurologic effects (e.g., Guillain-Barré syndrome, myasthenia gravis, peripheral motor neuropathy) reported.1 7 22

Monitor patients for symptoms of motor or sensory neuropathy (e.g., unilateral or bilateral weakness, sensory alterations, paresthesia).1 Consider such symptoms to be immune mediated unless alternative etiology is identified.3

Permanently discontinue ipilimumab in patients experiencing severe neuropathy that interferes with daily activities (e.g., Guillain-Barré syndrome).1 Initiate appropriate medical intervention for management of severe neuropathy and consider initiating systemic corticosteroid therapy at a dosage of 1–2 mg/kg per day of prednisone (or equivalent).1

Withhold ipilimumab for moderate neuropathy that does not interfere with daily activities.1 May resume therapy once symptoms have resolved or returned to baseline.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Permanently discontinue the drug in patients unable to reduce daily corticosteroid dosage to ≤7.5 mg of prednisone (or equivalent) and in those unable to complete full treatment course within 16 weeks after receiving first dose.1

Immune-mediated Endocrine Effects

Severe or life-threatening immune-mediated endocrinopathies (e.g., hypopituitarism with concomitant adrenal insufficiency, hypogonadism, or hypothyroidism) reported.1 7 Median onset occurs at 11 weeks (up to 19.3 weeks) after therapy initiation.1

Monitor patients for manifestations of hypophysitis, adrenal insufficiency (including adrenal crisis), hyperthyroidism, and hypothyroidism.1 Perform laboratory testing (e.g., thyroid function tests) prior to each dose of ipilimumab and as clinically indicated throughout treatment.1 Consider such endocrinopathies to be immune mediated unless alternative etiology is identified.1

Withhold ipilimumab in symptomatic patients and initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg per day of prednisone (or equivalent) in conjunction with appropriate hormone replacement therapy.1 May resume therapy once symptoms have resolved or returned to baseline, patient is stable on hormone replacement therapy (if indicated), and daily corticosteroid dosage is ≤7.5 mg of prednisone (or equivalent).1 3 (See Dosage Modification for Toxicity under Dosage and Administration.)

Permanently discontinue ipilimumab in patients unable to reduce daily corticosteroid dosage to ≤7.5 mg of prednisone (or equivalent) and in those unable to complete full treatment course within 16 weeks after receiving first dose.1

Other Immune-mediated Effects

Other immune-mediated adverse reactions (e.g., nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, hemolytic anemia) reported.1 Myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis reported rarely.1

Permanently discontinue ipilimumab in patients experiencing clinically important or severe immune-mediated adverse reactions.1 In such patients, administer systemic corticosteroid therapy at a dosage of 1–2 mg/kg per day of prednisone (or equivalent).1

In patients experiencing uveitis, iritis, or episcleritis, administer an ophthalmic corticosteroid.1 Permanently discontinue ipilimumab if immune-mediated ocular disease is unresponsive to topical corticosteroid therapy.1

Other Warnings and Precautions

Immunogenicity

There is potential for immunogenicity with ipilimumab.1 Development of binding antibodies to ipilimumab reported during clinical trials in up to 6.9% of patients; neutralizing antibodies not detected.1 Infusion-related reactions associated with hypersensitivity or anaphylaxis not observed in antibody-positive patients.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether ipilimumab is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1

Renal Impairment

Not studied in patients with renal impairment.1

Common Adverse Effects

Fatigue, diarrhea, pruritus, rash, colitis.1 7 22

Interactions for Ipilimumab

No formal drug interaction studies to date.1

Ipilimumab Pharmacokinetics

Distribution

Extent

Not known whether ipilimumab is distributed into milk.1 (See Lactation under Cautions.)

Elimination

Half-life

Terminal half-life: 14.7 days.1

Special Populations

Various degrees of hepatic impairment (based on plasma AST, ALT, and total bilirubin concentrations) do not have a clinically important effect on pharmacokinetics.1

Renal impairment (i.e., CLcr ≥29 mL/minute) does not have a clinically important effect on pharmacokinetics.1

Stability

Storage

Parenteral

Injection Concentrate

2–8°C.1 Do not freeze; protect from light.1 Discard unused solution after initial entry into vial.1

Diluted solution may be stored for up to 24 hours in refrigerator or at controlled room temperature.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water1

Sodium chloride 0.9%1

Actions

  • IgG1 kappa immunoglobulin produced in mammalian (Chinese hamster ovary) cells.1 8 10

  • Binds to CTLA-4 receptors on cytotoxic T-lymphocytes and blocks interaction with ligands CD80 and CD86 resulting in T-cell activation and proliferation.1 8 10

  • Indirect effect on melanoma may be a result of augmented T-cell-mediated antitumor immune response.1 12

  • Variable patterns of clinical response observed (e.g., disease regression shortly after initiating therapy, durable stable disease, response after apparent disease progression, reduced total tumor burden despite development of new lesions); all such patterns associated with improved survival.8 11 12 16

  • Increase in total tumor burden after initial therapy (e.g., enlargement of baseline lesions, development of new lesions) may result from lymphocytic infiltration of lesions or tumor growth prior to full immune system activation.11

  • Definitive criteria (e.g., biomarkers, genetic polymorphisms, preexisting antitumor immune response) to reliably identify patients who are likely to respond favorably to ipilimumab not established to date.8 9

Advice to Patients

  • Risk of severe, and potentially fatal, immune-mediated adverse reactions (e.g., enterocolitis, hepatitis, dermatitis, neuropathy, endocrinopathy).1 21

  • Importance of promptly contacting clinician if signs or symptoms of immune-mediated reactions (e.g., changes in bowel movements or diarrhea, rash or pruritus, weakness or paresthesia, fatigue, headache, mental status changes, abdominal pain, hypotension) occur.1 3 21

  • Importance of advising patient to read the medication guide before beginning treatment and each time the drug is administered.1 21

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 21 Ipilimumab may cause fetal harm.1 21 Importance of advising nursing women not to breast-feed during therapy with the drug.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses, including autoimmune disease, history of organ transplantation, or liver damage.1 21

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ipilimumab (recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection concentrate, for IV infusion only

5 mg/mL (50 or 200 mg)

Yervoy

Bristol-Myers Squibb

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 23, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Bristol-Myers Squibb. Yervoy (ipilimumab) injection prescribing information. Princeton, NJ. 2011 Mar.

2. Bristol-Myers Squibb. BLA 125377: Yervoy (ipilimumab) injection Risk Evaluation and Mitigation Strategy (REMS). Princeton, NJ. 2011 Mar.

3. Bristol-Myers Squibb. Yervoy (ipilimumab) immune-mediated adverse reaction management guide. 2011 Mar.

4. Bristol-Myers Squibb. Yervoy (ipilimumab) nursing immune-mediated adverse reaction checklist. 2011 Mar.

5. Bristol-Myers Squibb. Yervoy (ipilimumab) patient wallet card. 2011 Mar.

6. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website . Accessed 2011 Aug 18.

7. Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711-23. [PubMed 20525992]

8. Callahan MK, Wolchok JD, Allison JP. Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol. 2010; 37:473-84. [PubMed 21074063]

9. Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol. 2008; 26:5275-83. [PubMed 18838703]

10. Morse MA. Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb. Curr Opin Mol Ther. 2005; 7:588-97. [PubMed 16370382]

11. Wolchok JD, Hoos A, O’Day S et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 15:7412-20. [PubMed 19934295]

12. Saenger YM, Wolchok JD. The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun. 2008; 8:1. [PubMed 18198818]

13. Weber J, Thompson JA, Hamid O et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009; 15:5591-8. [PubMed 19671877]

14. Ribas A, Chmielowski B, Glaspy JA. Do we need a different set of response assessment criteria for tumor immunotherapy?. Clin Cancer Res. 2009; 15:7116-8. [PubMed 19934296]

15. Wolchok JD, Neyns B, Linette G et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010; 11:155-64. [PubMed 20004617]

16. Pennock GK, Waterfield W, Wolchok JD. Patient Responses to Ipilimumab, a Novel Immunopotentiator for Metastatic Melanoma: How Different are these From Conventional Treatment Responses?. Am J Clin Oncol. 2011; :.

18. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007; 12:864-72. [PubMed 17673617]

19. Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. 2009; 58:823-30. [PubMed 19198837]

20. Bristol-Myers Squibb. Personal communication. Princeton, NJ.

21. Bristol-Myers Squibb. Yervoy (ipilimumab) medication guide. Princeton, NJ. 2011 Mar.

22. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011; 364:2517-26. [PubMed 21639810]

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