Trilaciclib

1 INDICATIONS AND USAGE COSELA is indicated to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). COSELA is a kinase inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer. ( 1 )

2 DOSAGE AND ADMINISTRATION COSELA is for intravenous use only. The recommended dose of COSELA is 240 mg/m 2 as a 30-minute intravenous infusion completed no more than 4 hours prior to the start of chemotherapy on each day chemotherapy is administered. ( 2.1 ) Reduce dose in patients with moderate or severe hepatic impairment. ( 2.2 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.3 ) 2.1 Recommended Dosage The recommended dose of COSELA is 240 mg/m 2 per dose. Administer as a 30-minute intravenous infusion completed no more than 4 hours prior to the start of chemotherapy on each day chemotherapy is administered. The interval between doses of COSELA on sequential days should not be greater than 28 hours. Missed Treatment Session(s) If the COSELA dose is missed, discontinue chemotherapy on the day the COSELA dose was missed. Consider resuming both COSELA and chemotherapy on the next scheduled day for chemotherapy. Discontinuation of Treatment If COSELA is discontinued, wait 96 hours from the last dose of COSELA before resumption of chemotherapy only. 2.2 Dose Modification Dose Modification for Adverse Reactions Withhold, discontinue, or alter the administration of COSELA to manage adverse reactions as described in Table 1 [see Warnings and Precautions ( 5 )]. Table 1: Recommended Actions for Adverse Reactions Adverse Reaction Severity Grade* Recommended Action * National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 Injection-site reactions including phlebitis and thrombophlebitis Grade 1: Tenderness with or without symptoms (e.g., warmth, erythema, itching) Interrupt or slow infusion of COSELA. If 0.9% Sodium Chloride Injection, USP is being used as a diluent/flush, consider changing to 5% Dextrose Injection, USP as appropriate for subsequent infusions. Grade 2: Pain; lipodystrophy; edema; phlebitis Interrupt infusion of COSELA. If pain not severe, follow instructions for Grade 1. Otherwise, stop infusion in extremity and rotate site of infusion to site in alternative extremity. If 0.9% Sodium Chloride Injection, USP is being used as a diluent/flush, consider changing to 5% Dextrose Injection, USP as appropriate for subsequent infusions. Central access may also be considered. Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated. OR Grade 4: Life-threatening consequences; urgent interventions indicated. Stop infusion and permanently discontinue COSELA. Acute drug hypersensitivity reactions Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting Activities of Daily Living (ADL). Stop infusion and hold COSELA until recovery to Grade ≤1 or baseline, then consider resuming COSELA. If Grade 2 recurs, permanently discontinue COSELA. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. OR Grade 4: Life-threatening consequences; urgent intervention indicated. Permanently discontinue COSELA. Interstitial lung disease/pneumonitis Grade 2 (symptomatic) Hold COSELA until recovery to Grade ≤1 or baseline, then consider resuming COSELA. If Grade 2 recurs, permanently discontinue COSELA. Grade 3: Severe symptoms; limiting self-care ADL; oxygen indicated. OR Grade 4: Life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation) Permanently discontinue COSELA. Other toxicities Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Hold COSELA until recovery to Grade ≤1 or baseline, then consider resuming COSELA. If Grade 3 recurs, permanently discontinue COSELA. Grade 4: Life-threatening consequences; urgent intervention indicated. Permanently discontinue COSELA. Dose Modifications for Hepatic Impairment Reduce the dose of COSELA to 170 mg/m 2 in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C). No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh class A) [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. 2.3 Preparation and Administration Instructions Reconstitute and further dilute COSELA prior to intravenous infusion as outlined below. Use aseptic technique for reconstitution and dilution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitution of COSELA Calculate the COSELA dose based on the patient's body surface area (BSA), the total volume of reconstituted COSELA solution required, and the number of COSELA vials needed. Reconstitute each 300 mg vial with 19.5 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP using a sterile syringe to obtain a concentration of 15 mg/mL of trilaciclib. Gently swirl the vial for up to 3 minutes until the sterile lyophilized cake is completely dissolved. Do not shake. Inspect the reconstituted solution for discoloration and particulate matter. Reconstituted COSELA solution should be a clear, yellow solution. Do not use if the reconstituted solution is discolored, cloudy, or contains visible particulates. Reconstituted solution in the vial can be stored at 20°C to 25°C (68°F to 77°F) for up to 4 hours prior to transfer to the infusion bag. Do not refrigerate or freeze. Discard any unused portion after use. Dilution of Reconstituted COSELA Solution Withdraw the required volume from the vial(s) of reconstituted COSELA solution and dilute into an intravenous infusion bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The final concentration of the diluted COSELA solution should be between 0.5 mg/mL and 3 mg/mL. Mix diluted solution by gentle inversion. Do not shake. The diluted COSELA solution for infusion is a clear, yellow solution. If not used immediately, store the diluted COSELA solution in the intravenous infusion bag as specified in Table 2 . Discard if storage time exceeds these limits. Do not refrigerate or freeze. Table 2: Diluted COSELA Solution Storage Conditions a To ensure product stability, do not exceed specified storage durations. Intravenous Infusion Bag Material Diluent Diluted COSELA Storage Duration a Polyvinyl chloride (PVC), Ethylene vinyl acetate (EVA), Polyolefin (PO), or Polyolefin/polyamide (PO/PA) 5% Dextrose for Injection, USP Up to 12 hours at 20°C to 25°C (68°F to 77°F) PVC, EVA, or PO 0.9% Sodium Chloride Injection, USP Up to 8 hours at 20°C to 25°C (68°F to 77°F) PO/PA 0.9% Sodium Chloride Injection, USP Up to 4 hours at 20°C to 25°C (68°F to 77°F) Administration Administer diluted COSELA solution as a 30-minute intravenous infusion completed no more than 4 hours prior to the start of chemotherapy. Diluted COSELA solution must be administered with an infusion set, including an in-line filter (0.2 or 0.22 micron). Compatible in-line filters include polyethersulfone (PES), polyvinylidene fluoride (PVDF), and cellulose acetate (CA). Do not administer diluted COSELA solution with a polytetrafluorethylene (PTFE) in-line filter as it is not compatible. PTFE is acceptable for use in air vent filters. Do not co-administer other drugs through the same infusion line. Do not co-administer other drugs through a central access device unless the device supports co-administration of incompatible drugs. Upon completion of infusion of diluted COSELA solution, the infusion line/cannula must be flushed with at least 20 mL sterile 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the label: Injection-Site Reactions, including phlebitis and thrombophlebitis [ s ee Warnings and Precautions ( 5.1 )] Acute Drug Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] ILD/Pneumonitis [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (≥10% of patients with ≥2% difference in incidence compared to placebo) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact G1 Therapeutics, Inc., at 1-800-790-4189 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of COSELA was evaluated in Studies 1, 2, and 3 [see Clinical Studies ( 14 )] . Patients received COSELA 240 mg/m 2 by 30-minute intravenous infusion prior to chemotherapy on each chemotherapy day. The data described in this section reflect exposure to COSELA among 240 patients (122 patients in the trilaciclib group and 118 patients in the placebo group) being treated for extensive stage-small cell lung cancer (ES-SCLC) in 3 randomized, double-blind, placebo-controlled trials: 32 patients with treatment naïve ES-SCLC received carboplatin (AUC 5 Day 1) + etoposide (100 mg/m 2 Days 1-3) every 21 days; 58 received carboplatin (AUC 5 Day 1) + etoposide (100 mg/m 2 Days 1-3) every 21 days + atezolizumab (1200 mg on Day 1) every 21 days; 32 patients with previously treated ES-SCLC received topotecan (1.5 mg/m 2 Days 1-5) every 21 days. Study 1: COSELA Prior to Etoposide, Carboplatin, and Atezolizumab (E/P/A) Patients with newly diagnosed ES-SCLC not previously treated with chemotherapy Study 1 (G1T28-05; NCT03041311) was an international, randomized (1:1), double-blind, placebo-controlled study of COSELA or placebo administered prior to treatment with etoposide, carboplatin, and atezolizumab (E/P/A) for patients with newly diagnosed ES-SCLC not previously treated with chemotherapy. The data presented below are for the 105 patients who received study treatment. Eighty-five percent of patients receiving COSELA and 91% receiving placebo completed 4 cycles of induction therapy. Study 2: COSELA Prior to Etoposide and Carboplatin (E/P) Patients with newly diagnosed ES-SCLC not previously treated with chemotherapy Study 2 (G1T28-02; NCT02499770) was an international, randomized (1:1), double-blind, placebo-controlled study of COSELA or placebo administered prior to treatment with etoposide and carboplatin (E/P) for patients with newly diagnosed ES-SCLC not previously treated with chemotherapy. The data presented below are for the 75 patients who received study treatment. Seventy-six percent of patients in the COSELA group and 87% of patients in the placebo group completed at least 4 cycles of therapy. The median duration of treatment was 6 cycles in each treatment group. Study 3: COSELA Prior to Topotecan Patients with ES-SCLC previously treated with chemotherapy Study 3 (G1T28-03; NCT02514447) was an international, randomized (2:1), double-blind, placebo-controlled study of COSELA or placebo administered prior to treatment with topotecan for patients with ES-SCLC previously treated with chemotherapy. The data presented below are for the 60 patients who received study treatment with the 1.5 mg/m 2 dose of topotecan. Thirty-eight percent of patients receiving COSELA and 29% of patients receiving placebo completed 5 or more cycles of therapy. The median duration of treatment was 3 cycles in each treatment group. Integrated Safety Analysis The adverse reaction summary presented in Table 3 are pooled safety results from Studies 1, 2, and 3. The patients included in the pooling are those randomized patients that received at least 1 dose of COSELA (122 patients) or placebo (118 patients). Seventy-one percent of patients receiving COSELA and 78% of patients receiving placebo completed at least 4 cycles of therapy. The median duration of treatment was the same (4 cycles) for patients receiving COSELA and placebo. Serious adverse reactions occurred in 30% of patients receiving COSELA. Serious adverse reactions reported in >3% of patients who received COSELA included respiratory failure, hemorrhage, and thrombosis. Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received COSELA. Adverse reactions leading to permanent discontinuation of any study treatment for patients receiving COSELA included pneumonia (2%), asthenia (2%), injection-site reaction, thrombocytopenia, cerebrovascular accident, ischemic stroke, infusion-related reaction, respiratory failure, and myositis (<1% each). Fatal adverse reactions were observed in 5% of patients receiving COSELA. Fatal adverse reactions for patients receiving COSELA included pneumonia (2%), respiratory failure (2%), acute respiratory failure (<1%), hemoptysis (<1%), and cerebrovascular accident (<1%). Infusion interruptions due to an adverse reaction occurred in 4.1% of patients who received COSELA. The most common adverse reactions (≥10%) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia. The most frequently reported Grade ≥3 adverse reaction (≥5%) in patients receiving COSELA occurring at the same or higher incidence than in patients receiving placebo was hypophosphatemia. The most common adverse reactions reported in at least 5% of patients receiving COSELA with a ≥2% higher incidence compared to patients receiving placebo are shown in Table 3 . Table 3: Adverse Reactions in ≥5% Patients with SCLC Receiving COSELA (with ≥2% Higher Incidence in COSELA Compared to Placebo) Adverse Reaction COSELA (N=122) Placebo (N=118) All Grades a (%) Grade ≥3 (%) All Grades a (%) Grade ≥3 (%) a Graded per NCI CTCAE v4.03 b Hypocalcemia=calcium decreased (lab) or treatment-emergent adverse event (TEAE) preferred term 'Hypocalcemia' c Hypokalemia=potassium decreased (lab) or TEAE preferred terms 'Hypokalemia,' 'Blood potassium decreased' d Hypophosphatemia=phosphate decreased (lab) or TEAE preferred terms 'Hypophosphatemia,' 'Blood phosphorus decreased' e Aspartate aminotransferase increased=aspartate aminotransferase increased (lab) or TEAE preferred term 'Blood aspartate aminotransferase increased' Fatigue 34 3 27 2 Hypocalcemia b 24 <1 21 <1 Hypokalemia c 22 6 18 3 Hypophosphatemia d 21 7 16 2 Aspartate aminotransferase increased e 17 <1 14 <1 Headache 13 0 9 0 Pneumonia 10 7 8 7 Rash 9 <1 6 0 Infusion-related reaction 8 0 2 0 Edema peripheral 7 0 4 <1 Abdominal pain upper 7 0 3 0 Thrombosis 7 3 2 2 Hyperglycemia 6 2 3 0 Grade 3/4 hematological adverse reactions occurring in patients treated with COSELA and placebo included neutropenia (32% and 69%), febrile neutropenia (3% and 9%), anemia (16% and 34%), thrombocytopenia (18% and 33%), leukopenia (4% and 17%), and lymphopenia (<1% and <1%), respectively.

12.3 Pharmacokinetics The maximum concentration (C max ) increased proportionally whereas the total plasma exposure (AUC 0-last ) increased slightly greater than proportional over a dosage range of trilaciclib 200 mg/m 2 to 700 mg/m 2 (0.83 to 2.9 times the approved recommended dose). There was no accumulation of trilaciclib following repeated dosing. Distribution The in vitro human plasma protein binding of trilaciclib is 69% and appeared independent of trilaciclib concentration from 0.75 to 3.0 μg/mL. The blood/plasma ratio ranged from 1.21 to 1.53 for trilaciclib across concentrations of 0.5 μg/mL to 50 μg/mL in vitro. The volume of distribution at steady state was 1130 L. Elimination The mean terminal half-life of trilaciclib is approximately 14 hours. Clearance was estimated to be 158 L/hr. Metabolism Trilaciclib undergoes extensive metabolism. Trilaciclib is the predominant circulating compound in plasma following intravenous administration, representing ~50% of plasma total radioactivity. In vitro studies indicated that trilaciclib is primarily metabolized by aldehyde oxidase (AO), cytochrome P450 (CYP) 3A4 and CYP2C8. Excretion After a single dose of radiolabeled trilaciclib 192 mg/m 2 (0.8 times the approved recommended dosage), approximately 79.1% of the dose was recovered in feces (7% unchanged) and 14% was recovered in urine (2% unchanged). Trilaciclib is eliminated mainly via the fecal route, with a small contribution of the renal route. Specific Populations No clinically significant differences in the pharmacokinetics of trilaciclib were observed based on age (range: 19 to 80 years), sex, race, mild to moderate renal impairment (30 to 89 mL/min/1.73 m 2 measured by estimated glomerular filtration rate [eGFR]), or mild hepatic impairment (total bilirubin ≤ULN and AST >ULN, or total bilirubin >1.0 to 1.5 × ULN, irrespective of AST). The effect of severe renal impairment (<30 mL/min/1.73 m 2 ), end stage renal disease, or dialysis on trilaciclib pharmacokinetics has not been studied. Subjects with Hepatic Impairment Trilaciclib unbound AUC inf increased by 40% and 63%, respectively, in subjects with moderate and severe hepatic impairment (Child-Pugh classes B and C). No clinically significant differences were observed in trilaciclib systemic exposures in subjects with mild hepatic impairment [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )]. Drug Interaction Studies Clinical Studies Cytochrome P450 (CYP) Enzymes : There were no clinically significant differences in trilaciclib pharmacokinetics when used concomitantly with itraconazole (strong CYP3A inhibitor) or rifampin (strong CYP3A inducer). There were no clinically significant differences in midazolam (CYP3A substrate) pharmacokinetics when used concomitantly with trilaciclib. Transporter Systems : Concomitant use of trilaciclib increased metformin (OCT2, MATE1, and MATE-2K substrate) AUC inf and C max by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. There were no clinically significant differences in topotecan (MATE1 and MATE-2K substrate) pharmacokinetics when used concomitantly with trilaciclib. In Vitro Studies CYP Enzymes : Trilaciclib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Trilaciclib is an inducer for CYP1A2, and is not an inducer for CYP2B6 or CYP3A4. Transporter Systems : Trilaciclib did not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OAT1, or OAT3. Trilaciclib was a substrate of BCRP and P-gp, but not bile salt export pump (BSEP), MATE1, MATE-2K, or OCT.