lation pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with renal impairment and patients with normal renal function. [See Use in Specific Populations (8.6).]
Hepatic Impairment: The effect of hepatic impairment on the CL of ipilimumab was eva luated in patients with mild hepatic impairment (TB 1.0 × to 1.5 × ULN or AST >ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n=76) compared to patients with normal hepatic function (TB and AST ≤ULN; n=708) in the population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with mild hepatic impairment and normal hepatic function. Yervoy has not been studied in patients with moderate (TB >1.5 × to 3 × ULN and any AST) or severe hepatic impairment (TB >3 × ULN and any AST). [See Use in Specific Populations (8.7).]
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of ipilimumab has not been eva luated in long-term animal studies.
Mutagenesis
The genotoxic potential of ipilimumab has not been eva luated.
Impairment of Fertility
Fertility studies have not been performed with ipilimumab.
Animal Toxicology and/or Pharmacology
In addition to the severe findings of abortion, stillbirths, and postnatal deaths observed in pregnant cynomolgus monkeys that received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition [see Use in Specific Populations (8.1)], developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the clinically recommended dose). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.
Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3–4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.
CLINICAL STUDIES
The safety and efficacy of Yervoy were investigated in a randomized (3:1:1), double-blind, double-dummy study (Study 1) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were randomized to receive Yervoy at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were randomized to receive Yervoy at 3 mg/kg, and 136 were randomized to receive gp100 alone. The study enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The study excluded patients with |
