Ipilimumab, a Human Monoclonal Antibody for Treatment of Unresectable or Metastatic Melanoma

Approved Drug: Ipilimumab (Yervoy)

Indications

Drug is indicated for unresectable or metastatic melanoma.

Mechanism of Action

Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4). CTLA-4 normally turns off activation of the powerful cytotoxic T cells, which are able to kill cancer cells. T lymphocytes are immune cells that help with cell-mediated immunity. Theoretically, blocking CTLA-4 enables cytotoxic T cells to proliferate and work more effectively in fighting against melanoma cells. Ipilimumab is made using recombinant techniques in Chinese hamster ovarian cell cultures.

Metabolism

When the drug is given intravenously every 3 weeks, steady state is reached after the third dose. The terminal half-life is 14.7 days. In studies of the drug, systemic clearance increased with increasing body weight, but is clinically insignificant and does not require any dose adjustments. Neither renal nor hepatic impairment had a significant clinical impact on drug metabolism. While not studied in humans, animal testing of pregnant mothers showed no adverse reproductive effects; when the drug was received in the third trimester, however, there was a higher incidence of abortion, stillbirth, premature delivery, and infant mortality.

Drug Administration

Recommended dose is 3 mg/kg IV over 90 minutes every 3 weeks × 4 doses for no more than 16 weeks. Refer to package insert for detailed information about drug storage, preparation, and administration.

Dose Modifications

• If patient develops moderate to severe side effects, hold drug and anticipate physician or midlevel will order systemic corticosteroids.

• Drug dose should be held for moderate immune-mediated adverse reactions, or symptomatic endocrinopathy.

– If complete or partial resolution of adverse effects (grade 0–1), and patient is receiving < 7.5 mg of prednisone or equivalent per day, resume drug at the recommended 3 mg/kg dose every 3 weeks until all four doses have been administered, or 16 weeks, whichever comes first.

• Drug should be discontinued for any of the following:

– Persistent moderate adverse reactions, or inability to reduce corticosteroid to 7.5 mg prednisone/day or equivalent

– Failure to complete full treatment in 16 weeks from administration of first dose

– Severe or life-threatening adverse reactions:

• Colitis with abdominal pain, fever, ileus, peritoneal signs, seven or more stools over baseline, stool incontinence, need for IV hydration > 24 h, or GI hemorrhage and perforation

• Significantly abnormal LFTs: AST or ALT > five times ULN, or total bilirubin > three times ULN

• Stevens-Johnson syndrome, toxic epidermal necrolysis, rash complicated by full-thickness dermal ulceration, or necrotic bullous or hemorrhagic manifestations

• Severe motor or sensory neuropathy, Guillain-Barr syndrome, or myasthenia gravis

• Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, noninfectious myocarditis)

• Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy

Patient Education

• (Also see wallet card available for patient teaching, developed as part of Yervoy REMS [Risk Evaluation and Mitigation Strategy]; card is available online at www.YERVOY.com/hcp/rems.)

• Before you start ipilimumab, tell your doctor if you have any autoimmune disease (eg, ulcerative colitis, lupus, sarcoidosis), had an organ transplant, have liver damage, have other medical conditions, are pregnant, or are breast feeding. Women of childbearing age should use effective contraception to avoid pregnancy while receiving the drug. Women should not breast feed while receiving the drug.

• This drug is given intravenously every 3 weeks for four doses over a period of up to 16 weeks. It is given over 90 minutes, but the infusion time may be longer depending upon your body’s reaction to the drug.

• Your blood will be checked before each treatment.

• Try to keep all your appointments with your doctor, and report any side effects you may experience.

• Common side effects are fatigue, diarrhea, itching, and rash.

• Serious side effects can occur during treatment or after the therapy has ended. It is important to know about them so that you can work with your doctor or nurse to resolve them. They involve inflammation of any organ, and some can cause death. They may include inflammation of the:

– Intestines: colitis, with tears or holes in the lining of the colon, and bleeding

– Liver: hepatitis, and damage affecting liver function

– Skin: the side effect is like an allergic reaction, with rash, sores, or blisters on the skin and sores in the mouth

– Nerves: damage to the nerves, making you feel weak, and possibly unable to move your arms and legs (paralysis)

– Hormone glands: damage to the pituitary, adrenal, and/or thyroid glands, with symptoms based on the gland affected

– Eyes: changes in vision

• Call your doctor or nurse right away if you experience:

– Diarrhea of four or more stool episodes above baseline in 24 hours that does not respond to antidiarrheal medicine; blood in your stools, or dark, tarry, sticky stools; pain or tenderness in your abdomen

– Yellowing of your skin or the whites of your eyes, dark urine, nausea, vomiting, pain on the right side of your abdomen below the ribs, easy bruising or bleeding

– Rash on your skin, with or without itching; sores in your mouth; blisters on your skin, with or without peeling

– New weakness of your legs, arms, or face, or feeling that you cannot move your legs or arms; numbness and tingling of hands and feet

– Persistent or unusual headaches, feeling sluggish, feeling cold all the time, or gaining weight without trying; changes in mood or behavior (eg, decreased sex drive, irritability or forgetfulness); dizziness or fainting; fever

– Blurry or double vision, eye pain or redness; other visual problems

Drug Interactions

• No studies of drug interactions have been conducted.

Special Considerations

• Immune-mediated reactions can be severe and fatal. Assess LFTs, TFTs, and clinical chemistries at baseline and prior to each drug dose. The Yervoy Immune Mediated Adverse Reaction Management Guide is available online as part of the Yervoy REMS, at: www.YERVOY.com/hcp/rems

• Drug should be permanently discontinued for severe immune-mediated reactions, and the patient treated with systemic high-dose corticosteroid therapy (1–2 mg/kg/day prednisone or equivalent, followed by at least a 1-month steroid taper)

Contraindications/Precautions

• None

Adverse Reactions to Ipilimumab by Body System (boldface type indicates more common events, with 25% or higher incidence)

Cardiovascular: Rare myocarditis, pericarditis,
angiopathy, temporal arteritis, vasculitis

CNS: Rare hypopituitarism

Endocrine: Adrenal insufficiency/adrenal crisis,
hypothyroidism or hyperthyroidism, hypopituitarism,
autoimmune thyroiditis

GI: Diarrhea, enterocolitis (abdominal pain, mucus or blood in stool, diarrhea, fever), hepatitis, bowel perforation, ileus, nausea and vomiting with hepatitis, pancreatitis

Hematologic: Hemolytic anemia

Musculoskeletal: Arthritis, polymyalgia rheumatica

Neurologic: Motor and sensory neuropathy, rare Guillain Barr syndrome, rare myasthenia gravis; ocular changes (blepharitis, conjunctivitis, episcleritis, iritis, scleritis, uveitis)

Pulmonary: Rare pneumonitis

Renal: Nephritis

Reproductive: Harm to the fetus

Skin: Pruritis, rash, sores in mouth, rare blisters and peeling (eg, Stevens Johnson Syndrome, toxic epidermal necrolysis), psoriasis, leukocytoclastic vasculitis

General: Fatigue, fever

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; LFTs = liver function tests; TFTs = thyroid function tests; ULN = upper limit of normal.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.