YERVOY
Clinical safety rating: caution
Comprehensive clinical and safety monograph for YERVOY (YERVOY).
Ipilimumab is a recombinant human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expressed on activated T cells. Blockade of CTLA-4 enhances T-cell activation and proliferation, including the activation and proliferation of tumor-infiltrating T cells, thereby augmenting anti-tumor immune responses.
| Metabolism | Metabolism of ipilimumab is not fully characterized. As a monoclonal antibody, it is expected to be degraded into small peptides and amino acids via catabolic pathways similar to endogenous IgG, not mediated by cytochrome P450 enzymes. |
| Excretion | YERVOY (ipilimumab) is eliminated primarily via catabolism. Renal excretion is negligible (<1%). Biliary/fecal excretion is not quantified; as a monoclonal antibody, it is expected to be degraded into amino acids and recycled or excreted in feces via the reticuloendothelial system. |
| Half-life | Terminal elimination half-life is approximately 14.0 days (range 9-19 days) following repeated doses. This long half-life supports a 3-week dosing interval. Clearance decreases over time due to target-mediated elimination (binding to CTLA-4), resulting in non-linear pharmacokinetics. |
| Protein binding | Ipilimumab is an IgG1 monoclonal antibody; it does not bind to serum proteins such as albumin. Instead, it binds specifically to CTLA-4. Non-specific plasma protein binding is negligible (<5%). |
| Volume of Distribution | Volume of distribution at steady state (Vss) is approximately 0.064 L/kg (range 0.044-0.088 L/kg), indicating distribution primarily in the vascular space with limited extravascular penetration, as expected for a large antibody. |
| Bioavailability | Bioavailability is 100% as YERVOY is administered only via intravenous infusion. No oral formulation exists. |
| Onset of Action | Time to clinical effect is not precisely defined; objective responses are typically observed after 2-3 doses (6-9 weeks) but may occur later due to immunomodulatory mechanism. Immune-related adverse events can manifest earlier (2-3 weeks). |
| Duration of Action | Duration of action is prolonged, with immune modulation persisting for weeks to months after last dose. Clinical response can continue after treatment discontinuation. The half-life of ~14 days indicates therapeutic concentrations persist for ~2-3 months after cessation. |
| Molecular Weight | 148000 |
3 mg/kg intravenously over 90 minutes every 3 weeks for a total of 4 doses.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | No dose adjustment for mild hepatic impairment (Child-Pugh A). Not recommended for moderate to severe hepatic impairment (Child-Pugh B or C) due to lack of data. |
| Pediatric use | Not approved for pediatric patients; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment; select dose cautiously due to age-related increased risk of immune-related adverse events. |
| 1st trimester | IPILIMUMAB is a monoclonal antibody (IgG1). IgG crosses the placenta during the first trimester, but fetal exposure is limited. However, as an immune checkpoint inhibitor, it may affect fetal immune development. Use only if potential benefit justifies potential risk to fetus. |
| 2nd trimester | Placental transfer of IgG increases from the second trimester onward. Based on mechanism of action, fetal exposure can cause immune-mediated adverse effects including fetal loss, stillbirth, or neonatal immune abnormalities. Avoid use unless no safer alternative. |
| 3rd trimester | High placental transfer of maternal IgG occurs in the third trimester. Potential risks include preterm birth, low birth weight, and neonatal immune dysregulation. Discontinue if possible; avoid use in third trimester unless absolutely necessary. |
Clinical note
Comprehensive clinical and safety monograph for YERVOY (YERVOY).
| Placental transfer | Human IgG1 antibodies are known to cross the placenta. The degree of placental transfer increases with gestational age, especially in the third trimester. Studies in animals have shown detectable fetal levels. In humans, indirect evidence of fetal exposure (e.g., neonatal immune suppression) suggests significant transfer. |
■ FDA Black Box Warning
Immune-mediated adverse reactions, including severe and fatal immune-mediated reactions, can occur in any organ system or tissue. These include immune-mediated enterocolitis, hepatitis, dermatitis, neuropathy, endocrinopathy, and pneumonitis. YERVOY can also cause severe and fatal immune-mediated adverse reactions from T-cell activation and proliferation.
| Serious Effects |
Known severe hypersensitivity to ipilimumab or any excipients
| Precautions | Immune-mediated enterocolitis, Immune-mediated hepatitis, Immune-mediated dermatitis, Immune-mediated endocrinopathies (including hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism), Immune-mediated pneumonitis, Immune-mediated nephritis and renal dysfunction, Immune-mediated ocular inflammation, Infusion-related reactions, Embryofetal toxicity |
| Food/Dietary | No specific food interactions. No dietary restrictions required. |
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| Breastfeeding | It is not known whether ipilimumab is excreted in human milk. Because many monoclonal antibodies are present in breast milk and due to the potential for serious adverse reactions in the breastfed child, breastfeeding should be discontinued during treatment and for at least 3 months after the last dose. |
| Lactation Rating | L5 |
| Teratogenic Risk | Based on its mechanism of action (CTLA-4 inhibitor), YERVOY (ipilimumab) can cause fetal harm when administered to a pregnant woman. Human IgG1 antibodies are known to cross the placenta; therefore, ipilimumab may be transmitted from the mother to the developing fetus. There are no adequate and well-controlled studies in pregnant women. In animal studies, administration of ipilimumab during gestation resulted in increased incidences of malformations and embryolethality. First trimester: The risk of miscarriage and teratogenicity is highest. Second and third trimesters: Potential for immune-mediated fetal injury including immune-mediated abortion. Advise pregnant women of the potential risk to the fetus. |
| Fetal Monitoring | Monitor pregnant women for signs of fetal distress. Consider serial ultrasounds to assess fetal growth and anatomy. Monitor for immune-related adverse events in the mother that may affect pregnancy. Postpartum: Monitor neonates for immune-mediated reactions, including hypophysitis, thyroiditis, and other endocrinopathies. |
| Fertility Effects | Based on animal studies, YERVOY may impair fertility in females. Reversible effects on female reproductive function (including ovarian failure) were observed in animal toxicology studies. The effects on male fertility are unknown. No fertility studies have been conducted in humans. |
| Clinical Pearls | Monitor for immune-mediated adverse events including colitis, hepatitis, pneumonitis, and dermatitis. Administer 3 mg/kg IV over 90 minutes every 3 weeks for 4 doses. For melanoma, use in combination with nivolumab or as monotherapy. Premedicate with antihistamines and acetaminophen if infusion reactions occur. Do not administer with live vaccines. |
| Patient Advice | Contact your healthcare provider immediately if you experience symptoms like new or worsening cough, shortness of breath, chest pain, severe diarrhea or bloody stools, abdominal pain, changes in urine color, yellowing of skin or eyes, severe nausea or vomiting, severe skin rash, or symptoms of thyroid problems such as weight changes or temperature sensitivity. · Avoid becoming pregnant during treatment and for at least 5 months after the last dose of Yervoy as it may harm the unborn baby. Use effective contraception. · Do not receive live vaccines during treatment and for up to 3 months after the last dose. · Keep all appointments for monitoring blood work and physical exams. · Tell your doctor about all medications you take, including prescription, over-the-counter, and herbal supplements. |