ADMINISTRATION GUIDE

Transcription

1 DOSING AND ADMINISTRATION GUIDE INDICATION LARTRUVO is indicated, in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. Infusion-Related Reactions Infusion-related reactions (IRR) occurred in 70 (14%) of 485 patients who received at least one dose of LARTRUVO across clinical trials. For 68 of these 70 patients (97%), the first occurrence of IRR was in the first or second cycle. Grade 3 IRR occurred in 11 (2.3%) of 485 patients, with one (0.2%) fatality. Symptoms of IRR included flushing, shortness of breath, bronchospasm, or fever/chills, and in severe cases symptoms manifested as severe hypotension, anaphylactic shock, or cardiac arrest. Infusion-related reactions required permanent discontinuation in 2.3% of patients and interruption of infusion in 10% of patients. All 59 patients with Grade 1 or 2 IRR resumed LARTRUVO; 12 (20%) of these patients had a Grade 1 or 2 IRR with rechallenge. The incidence of IRR in the overall safety database (N = 485) was similar (18% versus 12%) between those who did (56%) and those who did not (44%) receive premedication. Monitor patients during and following LARTRUVO infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Immediately and permanently discontinue LARTRUVO for Grade 3 or 4 IRR.

2 2 DOSING AND ADMINISTRATION 1 RECOMMENDED DOSE AND SCHEDULE For the first 8 cycles, LARTRUVO is administered with doxorubicin, which is given on Day 1 of each cycle following the LARTRUVO infusion. Administer LARTRUVO until disease progression or unacceptable toxicity. Do not administer LARTRUVO as an intravenous push or bolus. Treatment Dosage Interval LARTRUVO Doxorubicin* 15 mg/kg IV 75 mg/m 2 IV Days 1 and 8 of 21-day cycle Day 1 of each 21-day cycle for the first 8 cycles Infusion Time 60 minutes <60 minutes * In the registration trial, all patients received dexrazoxane, a cardioprotectant, prior to doxorubicin in Cycles 5 to 8. See dexrazoxane prescribing information for dosing and administration. See doxorubicin prescribing information for additional information on dosing and administration. PREMEDICATION Premedicate with diphenhydramine (25 mg to 50 mg intravenously) and dexamethasone (10 mg to 20 mg intravenously) prior to LARTRUVO on Day 1 of Cycle 1 Infusion-Related Reactions Infusion-related reactions (IRR) occurred in 70 (14%) of 485 patients who received at least one dose of LARTRUVO across clinical trials. For 68 of these 70 patients (97%), the first occurrence of IRR was in the first or second cycle. Grade 3 IRR occurred in 11 (2.3%) of 485 patients, with one (0.2%) fatality. Symptoms of IRR included flushing, shortness of breath, bronchospasm, or fever/chills, and in severe cases symptoms manifested as severe hypotension, anaphylactic shock, or cardiac arrest. Infusion-related reactions required permanent discontinuation in 2.3% of patients and interruption of infusion in 10% of patients. All 59 patients with Grade 1 or 2 IRR resumed LARTRUVO; 12 (20%) of these patients had a Grade 1 or 2 IRR with rechallenge. The incidence of IRR in the overall safety database (N = 485) was similar (18% versus 12%) between those who did (56%) and those who did not (44%) receive premedication. Monitor patients during and following LARTRUVO infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Immediately and permanently discontinue LARTRUVO for Grade 3 or 4 IRR.

3 3 DOSING MODIFICATIONS 1 EVENT Infusion-Related Reactions Neutropenia DOSE MODIFICATION FOR TOXICITIES Permanently discontinue LARTRUVO for Grade 3 or 4 infusion-related reactions (IRR) Interrupt infusion of LARTRUVO for Grade 1 or 2 IRRs. After resolution, resume LARTRUVO infusion at 50% of the initial infusion rate For neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week, discontinue administration of LARTRUVO until the absolute neutrophil count is 1,000/µL or greater and then permanently reduce the dose to 12 mg/kg Embryo-Fetal Toxicity Based on animal data and its mechanism of action, LARTRUVO can cause fetal harm when administered to a pregnant woman. Animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-α) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-α antibody to pregnant mice during organogenesis caused malformations and skeletal variations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose.

4 4 STEP-BY-STEP PREPARATION AND ADMINISTRATION OF THE LARTRUVO INFUSION 1 1. Calculate the dose and required volume of LARTRUVO needed to prepare the infusion solution Vials contain 190 mg/19 ml or 500 mg/50 ml of LARTRUVO at a concentration of 10 mg/ml 2. Inspect the vial Inspect vial contents for particulate matter and discoloration prior to dilution LARTRUVO is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution Discard the vial if particulate matter or discolorations are identified 3. Dilute the infusion solution Withdraw the calculated dose and further dilute with 0.9% Sodium Chloride Injection, United States Pharmacopeia (USP) to a final volume of 250 ml for intravenous infusion DO NOT use dextrose-containing solutions or other solutions Gently invert but do not shake DO NOT FREEZE the diluted solution Store the diluted solution for up to 24 hours under refrigeration at 2 C to 8 C (36 F to 46 F) and for up to an additional 4 hours at room temperature (below 25 C [77 F]) Storage times include the duration of infusion If refrigerated, allow the diluted solution to come to room temperature prior to administration. The density of olaratumab is g/ml at room temperature 2 Discard vial with any unused portion of LARTRUVO 4. Administer the solution Do not administer LARTRUVO as an intravenous push or bolus. Do not co-infuse with electrolytes or other medications through the same intravenous line Visually inspect the diluted solution If particulate matter or discolorations are identified, discard the solution Administer diluted solution as an intravenous infusion over 60 minutes Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the infusion Most Common Adverse Reactions The most commonly reported adverse reactions (all grades; grade 3-4) occurring in 20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were nausea (73% vs 52%; 2% vs 3%), fatigue (69% vs 69%; 9% vs 3%), musculoskeletal pain (64% vs 25%; 8% vs 2%), mucositis (53% vs 35%; 3% vs 5%), alopecia (52% vs 40%; 0% vs 0%), vomiting (45% vs 19%; 0% vs 0%), diarrhea (34% vs 23%; 3% vs 0%) decreased appetite (31% vs 20%; 2% vs 0%), abdominal pain (23% vs 14%; 3% vs 0%), neuropathy (22% vs 11%; 0% vs 0%), and headache (20% vs 9%; 0% vs 0%).

5 5 STORAGE AND HANDLING REQUIREMENTS 1 DO NOT FREEZE OR SHAKE Store vials in a refrigerator at 2 C to 8 C (36 F to 46 F) until time of use Keep the vial in the outer carton in order to protect from light Store the diluted solution for up to 24 hours under refrigeration at 2 C to 8 C (36 F to 46 F) and for up to an additional 4 hours at room temperature (below 25 C [77 F]). Storage times include the duration of infusion Most Common Lab Abnormalities The most common laboratory abnormalities (all grades; grade 3-4) occurring in 20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were lymphopenia (77% vs 73%; 44% vs 37%), neutropenia (65% vs 63%; 48% vs 38%), thrombocytopenia (63% vs 44%; 6% vs 11%), hyperglycemia (52% vs 28%; 2% vs 3%), elevated aptt (33% vs 13%; 5% vs 0%), hypokalemia (21% vs 15%; 8% vs 3%), and hypophosphatemia (21% vs 7%; 5% vs 3%).

6 6 IMPORTANT SAFETY INFORMATION FOR LARTRUVO WARNINGS AND PRECAUTIONS Infusion-Related Reactions Infusion-related reactions (IRR) occurred in 70 (14%) of 485 patients who received at least one dose of LARTRUVO across clinical trials. For 68 of these 70 patients (97%), the first occurrence of IRR was in the first or second cycle. Grade 3 IRR occurred in 11 (2.3%) of 485 patients, with one (0.2%) fatality. Symptoms of IRR included flushing, shortness of breath, bronchospasm, or fever/chills, and in severe cases symptoms manifested as severe hypotension, anaphylactic shock, or cardiac arrest. Infusion-related reactions required permanent discontinuation in 2.3% of patients and interruption of infusion in 10% of patients. All 59 patients with Grade 1 or 2 IRR resumed LARTRUVO; 12 (20%) of these patients had a Grade 1 or 2 IRR with rechallenge. The incidence of IRR in the overall safety database (N = 485) was similar (18% versus 12%) between those who did (56%) and those who did not (44%) receive premedication. Monitor patients during and following LARTRUVO infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Immediately and permanently discontinue LARTRUVO for Grade 3 or 4 IRR. Embryo-Fetal Toxicity Based on animal data and its mechanism of action, LARTRUVO can cause fetal harm when administered to a pregnant woman. Animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-α) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-α antibody to pregnant mice during organogenesis caused malformations and skeletal variations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose. MOST COMMON ADVERSE REACTIONS/LAB ABNORMALITIES The most commonly reported adverse reactions (all grades; grade 3-4) occurring in 20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were nausea (73% vs 52%; 2% vs 3%), fatigue (69% vs 69%; 9% vs 3%), musculoskeletal pain (64% vs 25%; 8% vs 2%), mucositis (53% vs 35%; 3% vs 5%), alopecia (52% vs 40%; 0% vs 0%), vomiting (45% vs 19%; 0% vs 0%), diarrhea (34% vs 23%; 3% vs 0%) decreased appetite (31% vs 20%; 2% vs 0%), abdominal pain (23% vs 14%; 3% vs 0%), neuropathy (22% vs 11%; 0% vs 0%), and headache (20% vs 9%; 0% vs 0%). The most common laboratory abnormalities (all grades; grade 3-4) occurring in 20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were lymphopenia (77% vs 73%; 44% vs 37%), neutropenia (65% vs 63%; 48% vs 38%) and thrombocytopenia (63% vs 44%; 6% vs 11%), hyperglycemia (52% vs 28%; 2% vs 3%), elevated aptt (33% vs 13%; 5% vs 0%), hypokalemia (21% vs 15%; 8% vs 3%), and hypophosphatemia (21% vs 7%; 5% vs 3%). USE IN SPECIFIC POPULATIONS Lactation: Because of the potential risk for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LARTRUVO and for at least 3 months following the last dose. Please see OR HCP ISI 19OCT2016

7 7 REFERENCES 1. LARTRUVO (olaratumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; Data on file. Lilly Research Laboratories (OLA ). PP-OR-US /2017 Lilly USA, LLC All rights reserved. LARTRUVO TM is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.