evere toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2)]
In genetically engineered mice in which the gene for CTLA-4 has been deleted (a “knockout mouse”), offspring lacking CTLA-4 were born apparently healthy, but died within 3–4 weeks due to multi-organ infiltration and damage by lymphocytes.
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.
8.3 Nursing Mothers
It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.
8.4 Pediatric Use
Safety and effectiveness of YERVOY have not been established in pediatric patients.
8.5 Geriatric Use
Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).
8.6 Renal Impairment
No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3)]
8.7 Hepatic Impairment
No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3)]
10 OVERDOSAGE
There is no information on overdosage with YERVOY.
11 DESCRIPTION
YERVOY (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.
YERVOY is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for intravenous infusion, which may contain a small amount of visible translucent-to-white, amorphous ipilimumab particulates. It is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
12.3Pharmacokinetics
The pharmacokinetics of ipilimumab was studied in 499 patients with unresectable or metastatic melanoma who received doses of 0.3
