In Trial 1, the most common laboratory abnormalities (��20%) were lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated aPTT, hypokalemia, and hypophosphatemia as shown in Table 2. Table 2: Laboratory Abnormalities Worsening from Baseline in >10% (All Grades) of Patients in the LARTRUVO plus Doxorubicin Arm and Occurring at a Higher Incidence than in the Doxorubicin Arm (Between Arm Difference ��5% for All Grades or ��2% for Grades 3 and 4) (Trial 1) Doxorubicina LARTRUVO plus Doxorubicina Laboratory Abnormality All Grades a The incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: LARTRUVO plus doxorubicin arm (range 60 to 63 patients) and doxorubicin arm (range 39 to 62 patients). b aPTT = activated partial thromboplastin time Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 13/370 (3.5%) of evaluable LARTRUVO-treated patients tested positive for treatment-emergent anti-olaratumab antibodies by an enzymelinked immunosorbent assay (ELISA). Neutralizing antibodies were detected in all patients who tested positive for treatment-emergent anti-olaratumab antibodies. The effects of anti-olaratumab antibodies on efficacy, safety, and exposure could not be assessed due to the limited number of patients with treatment-emergent anti-olaratumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to LARTRUVO with the incidences of antibodies to other products may be misleading. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on animal data and its mechanism of action, LARTRUVO can cause fetal harm. There are no available data on LARTRUVO use in pregnant women. No animal studies using olaratumab have been conducted to evaluate its effect on female reproduction and embryo-fetal development. Animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-��) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-����antibody to pregnant mice during organogenesis at exposures less than the exposure at the maximum recommended human dose caused malformations and skeletal variations see Data. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data No animal studies have been conducted using olaratumab to evaluate the effect of blocking PDGFR-���� signaling on reproduction and embryo-fetal development. In PDGFR-�� knockout mice, disruption of PDGFR-�� signaling resulted in embryo-fetal lethality and teratogenicity, including cleft face and spina bifida. Intravenous administration of an anti-murine PDGFR-�� antibody once every 3 days to pregnant mice during organogenesis at 50 and 150 mg/kg resulted in increased malformations (abnormal eyelid development) and skeletal variations (additional ossification sites in the frontal/parietal skull). Increased post-implantation loss occurred at a dose of 5 mg/kg. The effects on fetal development in mice administered this antibody occurred at exposures less than the AUC exposure at the maximum recommended human dose of 15 mg/kg LARTRUVO. Lactation Risk Summary There are no data on the presence of olaratumab in human milk, or its effects on the breastfed infant or on milk production. Because of the potential risk for serious adverse reactions in breastfeeding infants from olaratumab, advise women not to breastfeed during treatment with LARTRUVO and for 3 months following the last dose. Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, LARTRUVO can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose. Infertility Males Based on animal models, LARTRUVO may impair male fertility. Pediatric Use The safety and effectiveness of LARTRUVO in pediatric patients have not been established. Geriatric Use Clinical studies of LARTRUVO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. PATIENT COUNSELING INFORMATION Infusion-Related Reactions Advise patients to report signs and symptoms of infusion reactions. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential of the potential risk to the fetus, to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose, and to inform their healthcare provider of a known or suspected pregnancy. Lactation Advise patients not to breastfeed during treatment with LARTRUVO and for 3 months after the last dose. Additional information can be found at www.LARTRUVO.com/hcp. Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2016, Eli Lilly and Company. All rights reserved. OR HCP BS 21OCT2016 Chemistry Hyperglycemia Increased aPTTb Hypokalemia Hypophosphatemia Increased Alkaline Phosphatase Hypomagnesemia Hematology Lymphopenia Neutropenia Thrombocytopenia (%) All Grades (%) Grades 3-4 (%) 52 33 21 21 16 16 77 65 63 2 5 8 5 0 0 44 48 6 28 13 15 7 7 8 73 63 44 3 0 3 3 0 0 37 38 11 Grades 3-4 (%) LARTRUVOTM (olaratumab) injection OR HCP BS 21OCT2016 LARTRUVOTM (olaratumab) injection OR HCP BS 21OCT2016
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