CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Trilaciclib is transient inhibitor of CDK and 6. Hematopoietic stem and progenitor cells (HSPCs) in the bone marrow give rise to circulating neutrophils, RBCs, and platelets. HSPC proliferation is dependent on CDK4/6 activity.. 12.2 Pharmacodynamics. Bone MarrowTrilaciclib exhibited dose-dependent inhibition of CD45+/CD3+ lymphocyte proliferation following administration of single-dose COSELA 96 or 192 mg/m2 (0.4 or 0.8 times the approved recommended dose) in healthy subjects.Trilaciclib increased the percentage of cells arrested in G1 up to 32 hours post-infusion for all bone marrow progenitor subsets evaluated (hematopoietic stem cell/multipotent progenitor, oligopotent progenitor, monocyte lineage, granulocyte lineage, erythroid lineage, and megakaryocyte lineage) following single dose of COSELA 192 mg/m2 (0.8 times the approved recommended dose) in healthy subjects. Partial recovery of the total bone marrow with resumption of proliferation of the bone marrow progenitor subsets was observed by 32 hours post-dose. This transient G1 arrest of hematopoietic stem cells contributed to the myeloprotective effect of trilaciclib.. Cardiac ElectrophysiologyCOSELA is associated with dose-dependent and delayed increase in the QTc interval. The underlying mechanism of the delayed QT effect is unknown. At the clinical dose of 240 mg/m2, COSELA did not have clinically relevant effect on QTc (i.e., >10 msec). QTc prolongation was observed at higher doses.. 12.3 Pharmacokinetics. The maximum concentration (Cmax) increased proportionally whereas the total plasma exposure (AUC0-last) increased slightly greater than proportional over dosage range of trilaciclib 200 mg/m2 to 700 mg/m2 (0.83 to 2.9 times the approved recommended dose). There was no accumulation of trilaciclib following repeated dosing.. DistributionProtein binding of trilaciclib has not been fully characterized in vitro. The blood/plasma ratio ranged from 1.21 to 1.53 for trilaciclib across concentrations of 0.5 ug/mL to 50 ug/mL in vitro. The volume of distribution at steady state was 1130 L.. EliminationThe mean terminal half-life of trilaciclib is approximately 14 hours. Clearance was estimated to be 158 L/hr.. MetabolismTrilaciclib undergoes extensive metabolism. Trilaciclib is the predominant circulating compound in plasma following intravenous administration, representing ~50% of plasma total radioactivity.. ExcretionAfter single dose of radiolabeled trilaciclib 192 mg/m2 (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 small contribution of the renal route.. Specific PopulationsNo 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 m2 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 m2), end stage renal disease or dialysis, or moderate or severe hepatic impairment (total bilirubin >1.5 ULN and any AST) on trilaciclib pharmacokinetics has not been studied.. 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) AUCinf and Cmax 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 substrate of BCRP and P-gp, but not bile salt export pump (BSEP), MATE1, MATE-2K, or OCT.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of COSELA was established in three randomized, double-blind, placebo-controlled trials in patients with extensive stage-small cell lung cancer (ES-SCLC). Study (G1T28-05; NCT03041311) enrolled adult patients receiving carboplatin, etoposide, and atezolizumab for newly diagnosed ES-SCLC. Study (G1T28-02; NCT02499770) enrolled adult patients receiving etoposide/carboplatin for newly diagnosed ES-SCLC. Study (G1T28-03; NCT02514447) enrolled adult patients receiving topotecan for previously treated ES-SCLC.During Cycle 1, all three studies prohibited primary prophylactic granulocyte-colony stimulating factor (G-CSF) and erythropoiesis-stimulating agent (ESA) use. Both ESAs and prophylactic G-CSF were allowed from Cycle onwards as clinically indicated. Therapeutic G-CSF, RBC, and platelet transfusions were allowed at any time during the studies as clinically indicated.. Study 1: COSELA Prior to Etoposide, Carboplatin, and Atezolizumab (E/P/A). Patients with newly diagnosed ES-SCLC not previously treated with chemotherapyStudy (G1T28-05) was 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.A total of 107 patients were randomized to receive COSELA (n=54) or placebo (n=53) prior to administration of E/P/A; patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 to vs 2) and the presence of brain metastases. Carboplatin (AUC 5) and atezolizumab (1200 mg) were administered on Day and etoposide (100 mg/m2) and COSELA (240 mg/m2) or placebo were administered on Days 1, 2, and of 21-day cycle for maximum of cycles (induction). After induction, maintenance atezolizumab (1200 mg) monotherapy on Day of 21-day cycle continued until disease progression or unacceptable toxicity. COSELA was not administered during maintenance.The study population characteristics were: median age 64 years (range: 45 to 83); 70% male; 97% white; 14% ECOG performance status 2; 28% with history of brain metastases; 38% current smokers; 46% lactate dehydrogenase (LDH) >ULN.The mean relative dose intensities (RDIs) for E/P/A in patients receiving COSELA were 93%, 95%, and 93%, respectively. The mean RDIs for E/P/A in patients receiving placebo were 88%, 89%, and 91%, respectively. Dose reductions of carboplatin occurred in 2% of patients receiving COSELA and in 25% of patients receiving placebo; dose reductions of etoposide occurred in 6% of patients receiving COSELA and in 26% of patients receiving placebo. No dose reduction was allowed for COSELA or atezolizumab.The study demonstrated statistically significantly shorter duration of severe neutropenia (DSN) in Cycle (0 vs days) and lower proportion of patients with severe neutropenia (SN) (2% vs 49%) in patients receiving COSELA compared with placebo (Table 5). Nineteen percent of patients receiving COSELA had Grade or decreased hemoglobin compared with 28% of patients receiving placebo (adjusted relative risk 0.663 [95% CI: 0.336, 1.310]). The rate of RBC transfusions over time was 1.7/100 weeks for patients receiving COSELA and 2.6/100 weeks for patients receiving placebo (adjusted relative risk was not estimable). Six percent of patients receiving COSELA received erythropoiesis-stimulating agents (ESAs) compared with 11% of patients receiving placebo (adjusted relative risk 0.529 [95% CI: 0.145, 1.927]).Table 5: Study 1: Myeloprotective Efficacy Results in Patients Treated with COSELA or Placebo Prior to Chemotherapy (Intent-to-Treat Analysis)EndpointCOSELA 240 mg/m2 (N=54)Placebo(N=53)Treatment Effecta(Mean Difference or Adjusted Relative Risk)(95% CI)Adjusted 1-sided p-valuebANCOVA=analysis of covariance; CI=confidence interval; DSN=duration of severe neutropenia; G-CSF=granulocyte colony-stimulating factor; N=total number of patients in each treatment group; RBC=red blood cell; SD=standard deviationa The following statistical models were used to assess treatment effects: non-parametric ANCOVA (DSN in Cycle 1); modified Poisson regression (occurrence of SN and RBC transfusion on/after weeks); negative binomial regression (number of all-cause dose reductions). All models included the following as covariates: ECOG status, presence of brain metastases, and the corresponding baseline laboratory values.b One-sided adjusted p-value obtained from Hochberg-based gatekeeping procedure.Primary EndpointsDSN in Cycle (days): mean (SD)0 (1.0)4 (4.7)-3.6 (-4.9, -2.3)<0.0001Number (%) of patients with severe neutropenia1 (1.9%)26 (49.1%)0.038 (0.008, 0.195)<0.0001Key Secondary EndpointsNumber of all-cause dose reductions, event rate per cycle0.0210.0850.242(0.079, 0.742)0.0195Number (%) of patients with RBC transfusion on/after weeks7 (13.0%)11 (20.8%)0.642 (0.294, 1.404)--Number (%) of patients with G-CSF administration16 (29.6%)25 (47.2%)0.646(0.403, 1.034)--. Study 2: COSELA Prior to Etoposide and Carboplatin. Patients with newly diagnosed ES-SCLC not previously treated with chemotherapyStudy (G1T28-02) was randomized (1:1), double-blind, placebo-controlled evaluation 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. total of 77 patients were randomized to COSELA (n=39) or placebo (n=38) and stratified by ECOG performance status (0 to vs 2). Carboplatin (AUC 5) was administered on Day and etoposide (100 mg/m2) and COSELA (240 mg/m2) or placebo were administered on Days 1, 2, and of 21-day cycle until disease progression or unacceptable toxicity.Ten percent of patients receiving COSELA had Grade or decreased hemoglobin compared with 18% of patients receiving placebo. The rate of RBC transfusions over time was 0.5/100 weeks for patients receiving COSELA and 1.9/100 weeks for patients receiving placebo. Three percent of patients receiving COSELA received ESAs compared with 5% of patients receiving placebo.Table 6: Study 2: Myeloprotective Efficacy Results in Patients Treated with COSELA or Placebo Prior to Chemotherapy (Intent-to-Treat Analysis)EndpointCOSELA 240 mg/m2 (N=39)Placebo(N=38)DSN=duration of severe neutropenia; G-CSF=granulocyte colony-stimulating factor; N=total number of patients in each treatment group; RBC=red blood cell; SD=standard deviationDSN in Cycle (days): mean (SD)0 (0.5)3 (3.9)Number (%) of patients with severe neutropenia2 (5.1%)16 (42.1%)Number of all-cause dose reductions, event rate per cycle0.0220.084Number (%) of patients with RBC transfusion on/after weeks2 (5.1%)9 (23.7%)Number (%) of patients with G-CSF administration4 (10.3%)24 (63.2%). Study 3: COSELA Prior to Topotecan. Patients with ES-SCLC previously treated with chemotherapyStudy (G1T28-03) included randomized, double-blind, placebo-controlled evaluation of COSELA or placebo administered prior to topotecan in patients with ES-SCLC previously treated with chemotherapy. total of 61 patients were randomized to COSELA (n=32) or placebo (n=29). Patients were stratified by ECOG performance status (0 to vs 2) and sensitivity to first-line treatment. Topotecan (1.5 mg/m2) and COSELA (240 mg/m2) or placebo were administered on Days 1-5 of 21-day cycle. Treatment was administered until disease progression or unacceptable toxicity.Thirty-eight percent of patients receiving COSELA had Grade or decreased hemoglobin compared with 59% of patients receiving placebo. The rate of RBC transfusions over time was 2.6/100 weeks for patients receiving COSELA and 6.3/100 weeks for patients receiving placebo. Three percent of patients receiving COSELA received ESAs compared with 21% of patients receiving placebo.Table 7: Study 3: Myeloprotective Efficacy Results in Patients Treated with COSELA or Placebo Prior to Chemotherapy (Intent-to-Treat Analysis)EndpointCOSELA 240 mg/m2 (N=32)Placebo(N=29)DSN=duration of severe neutropenia; G-CSF=granulocyte colony-stimulating factor; N=total number of patients in each treatment group; RBC=red blood cell; SD=standard deviationPrimary EndpointsDSN in Cycle (days): mean (SD)2 (3.9)7 (6.2)Number (%) of patients with severe neutropenia13 (40.6%)22 (75.9%)Key Secondary EndpointsNumber of all-cause dose reductions, event rate per cycle0.0510.116Number (%) of patients with RBC transfusion on/after weeks10 (31.3%)12 (41.4%)Number (%) of patients with G-CSF administration16 (50.0%)19 (65.5%)Number (%) of patients with platelet transfusion8 (25.0%)9 (31.0%). Patient SubgroupsTreatment efficacy was examined across different subgroups, including those quantifying the risk of febrile neutropenia, anemia, and RBC transfusions; results were consistent across subgroups.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the label:Injection-Site Reactions, including phlebitis and thrombophlebitis [see Warnings and Precautions (5.1)] Acute Drug Hypersensitivity Reactions [see Warnings and Precautions (5.2)] ILD/Pneumonitis [see Warnings and Precautions (5.3)] Injection-Site Reactions, including phlebitis and thrombophlebitis [see 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 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 [see Clinical Studies (14)]. Patients received COSELA 240 mg/m2 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 randomized, double-blind, placebo-controlled trials: 32 patients with treatment naive ES-SCLC received carboplatin (AUC Day 1) etoposide (100 mg/m2 Days 1-3) every 21 days; 58 received carboplatin (AUC Day 1) etoposide (100 mg/m2 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/m2 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 chemotherapyStudy (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 cycles of induction therapy.. Study 2: COSELA Prior to Etoposide and Carboplatin (E/P). Patients with newly diagnosed ES-SCLC not previously treated with chemotherapyStudy (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 cycles of therapy. The median duration of treatment was cycles in each treatment group.. Study 3: COSELA Prior to Topotecan. Patients with ES-SCLC previously treated with chemotherapyStudy (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/m2 dose of topotecan.Thirty-eight percent of patients receiving COSELA and 29% of patients receiving placebo completed or more cycles of therapy. The median duration of treatment was cycles in each treatment group.. Integrated Safety AnalysisThe adverse reaction summary presented in Table are pooled safety results from Studies 1, 2, and 3. The patients included in the pooling are those randomized patients that received at least 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 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 >=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 ReactionCOSELA (N=122)Placebo (N=118)AllGradesa(%)Grade >=3 (%)AllGradesa(%)Grade >=3 (%)a Graded per NCI CTCAE v4.03xb Hypocalcemia=calcium decreased (lab) or treatment-emergent adverse event (TEAE) preferred term Hypocalcemiac Hypokalemia=potassium decreased (lab) or TEAE preferred terms Hypokalemia, Blood potassium decreasedd Hypophosphatemia=phosphate decreased (lab) or TEAE preferred terms Hypophosphatemia, Blood phosphorus decreasede Aspartate aminotransferase increased=aspartate aminotransferase increased (lab) or TEAE preferred term Blood aspartate aminotransferase increasedFatigue343272Hypocalcemiab 24<121<1Hypokalemiac 226183Hypophosphatemiad 217162Aspartate aminotransferase increasede 17<114<1Headache13090Pneumonia10787Rash9<160Infusion-related reaction8020Edema peripheral704<1Abdominal pain upper7030Thrombosis7322Hyperglycemia6230Grade 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. COSELA is for intravenous use only.The recommended dose of COSELA is 240 mg/m2 as 30-minute intravenous infusion completed within hours prior to the start of chemotherapy on each day chemotherapy is administered. (2.1)See Full Prescribing Information for instructions on preparation and administration. (2.3). 2.1 Recommended Dosage. The recommended dose of COSELA is 240 mg/m2 per dose. Administer as 30-minute intravenous infusion completed within 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 TreatmentIf COSELA is discontinued, wait 96 hours from the last dose of COSELA before resumption of chemotherapy only.. 2.2 Dose Modification for Adverse Reactions. Withhold, discontinue, or alter the administration of COSELA to manage adverse reactions as described in Table [see Warnings and Precautions (5)]. Table 1: Recommended Actions for Adverse ReactionsAdverse ReactionSeverity GradeRecommended Action National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03xInjection-site reactions including phlebitis and thrombophlebitisGrade 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 diluent/flush, consider changing to 5% Dextrose Injection, USP as appropriate for subsequent infusions.Grade 2: Pain; lipodystrophy; edema; phlebitisInterrupt 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 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.ORGrade 4: Life-threatening consequences; urgent interventions indicated.Stop infusion and permanently discontinue COSELA.Acute drug hypersensitivity reactionsGrade 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 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.ORGrade 4: Life-threatening consequences; urgent intervention indicated.Permanently discontinue COSELA.Interstitial lung disease/pneumonitisGrade (symptomatic)Hold COSELA until recovery to Grade <=1 or baseline, then consider resuming COSELA.If Grade recurs, permanently discontinue COSELA.Grade 3: Severe symptoms; limiting self-care ADL; oxygen indicated.ORGrade 4: Life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation)Permanently discontinue COSELA.Other toxicitiesGrade 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 recurs, permanently discontinue COSELA.Grade 4: Life-threatening consequences; urgent intervention indicated.Permanently discontinue COSELA.. 2.3 Preparation and Administration. 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 COSELACalculate the COSELA dose based on the patients 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 sterile syringe to obtain concentration of 15 mg/mL of trilaciclib.Gently swirl the vial for up to 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 clear, yellow solution. Do not use if the reconstituted solution is discolored, cloudy, or contains visible particulates.If needed, the unused reconstituted solution in the vial can be stored at 20C to 25C (68F to 77F) for up to hours prior to transfer to the infusion bag. Do not refrigerate or freeze.Discard any unused portion after use.. Calculate the COSELA dose based on the patients 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 sterile syringe to obtain concentration of 15 mg/mL of trilaciclib.. Gently swirl the vial for up to 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 clear, yellow solution. Do not use if the reconstituted solution is discolored, cloudy, or contains visible particulates.. If needed, the unused reconstituted solution in the vial can be stored at 20C to 25C (68F to 77F) for up to hours prior to transfer to the infusion bag. Do not refrigerate or freeze.. Discard any unused portion after use.. Dilution of Reconstituted COSELA SolutionWithdraw 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 mg/mL.Mix diluted solution by gentle inversion. Do not shake.The diluted COSELA solution for infusion is 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 Conditionsa To ensure product stability, do not exceed specified storage durations.Intravenous Infusion Bag MaterialDiluentDiluted COSELA Storage DurationaPolyvinyl chloride (PVC), Ethylene vinyl acetate (EVA), Polyolefin (PO), or Polyolefin/polyamide (PO/PA)5% Dextrose for Injection, USPUp to 12 hours at 20C to 25C (68F to 77F)PVC, EVA, or PO0.9% Sodium Chloride Injection, USPUp to hours at 20C to 25C (68F to 77F)PO/PA0.9% Sodium Chloride Injection, USPUp to hours at 20C to 25C (68F to 77F). 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 mg/mL.. Mix diluted solution by gentle inversion. Do not shake.. The diluted COSELA solution for infusion is 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.. AdministrationAdminister diluted COSELA solution as 30-minute intravenous infusion completed within 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 polyethylene sulfone, polyvinylidene fluoride, and cellulose acetate.Do not administer diluted COSELA solution with polytetrafluorethylene (PTFE) in-line filter. PTFE in-line filters are not compatible with diluted COSELA solution.Do not co-administer other drugs through the same infusion line.Do not co-administer other drugs through 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.. Administer diluted COSELA solution as 30-minute intravenous infusion completed within 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 polyethylene sulfone, polyvinylidene fluoride, and cellulose acetate.. Do not administer diluted COSELA solution with polytetrafluorethylene (PTFE) in-line filter. PTFE in-line filters are not compatible with diluted COSELA solution.. Do not co-administer other drugs through the same infusion line.. Do not co-administer other drugs through 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Injection-Site Reactions, Including Phlebitis and ThrombophlebitisInform patients of the signs and symptoms of injection-site reactions, including phlebitis and thrombophlebitis. Advise patients to contact their healthcare provider immediately for signs and symptoms of injection-site reactions, including phlebitis and thrombophlebitis [see Warnings and Precautions (5.1)]. Acute Drug Hypersensitivity ReactionsAdvise patients to contact their healthcare provider immediately for signs and symptoms of acute drug hypersensitivity reactions including facial, eye, and tongue edema, urticaria, pruritis, and anaphylactic reactions [see Warnings and Precautions (5.2)]. Interstitial Lung Disease/PneumonitisAdvise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.3) and Dosage and Administration (2.2)]. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with COSELA and for at least weeks after the final dose [see Use in Specific Populations (8.1, 8.3)].. LactationAdvise women not to breastfeed during treatment with COSELA and for at least weeks after the final dose of COSELA [see Use in Specific Populations (8.2)].. Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].Distributed by:G1 Therapeutics, Inc.Durham, NC 27709COSELATM is trademark of G1 Therapeutics, Inc.(C)2021 G1 Therapeutics, Inc.02599110003 Rev. 2/2021.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The maximum concentration (Cmax) increased proportionally whereas the total plasma exposure (AUC0-last) increased slightly greater than proportional over dosage range of trilaciclib 200 mg/m2 to 700 mg/m2 (0.83 to 2.9 times the approved recommended dose). There was no accumulation of trilaciclib following repeated dosing.. DistributionProtein binding of trilaciclib has not been fully characterized in vitro. The blood/plasma ratio ranged from 1.21 to 1.53 for trilaciclib across concentrations of 0.5 ug/mL to 50 ug/mL in vitro. The volume of distribution at steady state was 1130 L.. EliminationThe mean terminal half-life of trilaciclib is approximately 14 hours. Clearance was estimated to be 158 L/hr.. MetabolismTrilaciclib undergoes extensive metabolism. Trilaciclib is the predominant circulating compound in plasma following intravenous administration, representing ~50% of plasma total radioactivity.. ExcretionAfter single dose of radiolabeled trilaciclib 192 mg/m2 (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 small contribution of the renal route.. Specific PopulationsNo 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 m2 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 m2), end stage renal disease or dialysis, or moderate or severe hepatic impairment (total bilirubin >1.5 ULN and any AST) on trilaciclib pharmacokinetics has not been studied.. 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) AUCinf and Cmax 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 substrate of BCRP and P-gp, but not bile salt export pump (BSEP), MATE1, MATE-2K, or OCT.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on the mechanism of action, COSELA can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12)]. There are no available human or animal data on COSELA use to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. However, the background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the United States general population.. 8.2 Lactation. Risk SummaryThere are no data on the presence of trilaciclib in either human or animal milk, the effects on the breastfed child or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise lactating women to not breastfeed while taking COSELA and for at least weeks after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingBased on its mechanism of action, COSELA can cause fetal harm if administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy testing is recommended for females of reproductive potential prior to initiating COSELA.. ContraceptionCOSELA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with COSELA and for at least weeks after the final dose.. InfertilityNo studies have been performed in humans to evaluate the effects of COSELA on fertility in either sex.Based on animal toxicology studies, COSELA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13)]. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. In the pooled efficacy dataset from Studies 1, 2, and 3, 46% of 123 patients randomized to COSELA were >=65 years of age, and 49% of 119 patients randomized to placebo were >=65 years of age. No overall differences in safety or effectiveness of COSELA were observed between these patients and younger patients.. 8.6 Hepatic Impairment. Use of COSELA is not recommended in patients with moderate or severe hepatic impairment. No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin <= upper limit of normal [ULN] and aspartate aminotransferase [AST] ULN, or total bilirubin >1.0 to 1.5 ULN, irrespective of AST). The pharmacokinetics of COSELA have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN, irrespective of AST) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Injection-Site Reactions, Including Phlebitis and Thrombophlebitis: Monitor for signs and symptoms of injection-site reactions, including phlebitis and thrombophlebitis during infusion. Stop infusion and permanently discontinue COSELA for severe or life-threatening reactions. (5.1)Acute Drug Hypersensitivity Reactions: Monitor for signs and symptoms of acute drug hypersensitivity reactions, including edema (facial, eye, and tongue), urticaria, pruritus, and anaphylactic reactions. Withhold COSELA for moderate reactions, and permanently discontinue for severe or life-threatening reactions. (5.2)Interstitial Lung Disease (ILD)/Pneumonitis: Patients treated with CDK4/6 inhibitors should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Interrupt and evaluate patients with new or worsening symptoms suspected to be due to ILD/pneumonitis. Permanently discontinue COSELA in patients with recurrent symptomatic or severe/life-threatening ILD/pneumonitis. (5.3)Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.4). Injection-Site Reactions, Including Phlebitis and Thrombophlebitis: Monitor for signs and symptoms of injection-site reactions, including phlebitis and thrombophlebitis during infusion. Stop infusion and permanently discontinue COSELA for severe or life-threatening reactions. (5.1). Acute Drug Hypersensitivity Reactions: Monitor for signs and symptoms of acute drug hypersensitivity reactions, including edema (facial, eye, and tongue), urticaria, pruritus, and anaphylactic reactions. Withhold COSELA for moderate reactions, and permanently discontinue for severe or life-threatening reactions. (5.2). Interstitial Lung Disease (ILD)/Pneumonitis: Patients treated with CDK4/6 inhibitors should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Interrupt and evaluate patients with new or worsening symptoms suspected to be due to ILD/pneumonitis. Permanently discontinue COSELA in patients with recurrent symptomatic or severe/life-threatening ILD/pneumonitis. (5.3). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.4). 5.1 Injection-Site Reactions, Including Phlebitis and Thrombophlebitis. COSELA administration can cause injection-site reactions including phlebitis and thrombophlebitis. Injection-site reactions including phlebitis and thrombophlebitis occurred in 56 (21%) of 272 patients receiving COSELA in clinical trials, including Grade (10%) and Grade (0.4%) adverse reactions (ARs). The median time to onset from start of COSELA was 15 days (range to 542) and from the preceding dose of COSELA was day (1 to 15).The median duration was day (range to 151 for the resolved cases). Injection-site reactions including phlebitis and thrombophlebitis resolved in 49 (88%) of the 56 patients and led to discontinuation of treatment in (1%) of the 272 patients.Monitor patients for signs and symptoms of injection-site reactions, phlebitis, and thrombophlebitis, including infusion-site pain and erythema during infusion. For mild (Grade 1) to moderate (Grade 2) injection-site reactions, flush line/cannula with at least 20 mL of sterile 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after end of infusion. For severe (Grade 3) or life-threatening (Grade 4) injection-site reactions, stop infusion and permanently discontinue COSELA [see Dosage and Administration (2.2)].. 5.2 Acute Drug Hypersensitivity Reactions. COSELA administration can cause acute drug hypersensitivity reactions, including facial edema and urticaria. Acute drug hypersensitivity reactions occurred in 16 (6%) of 272 patients receiving COSELA in clinical trials, including Grade reactions (2%). One patient experienced Grade anaphylactic reaction days after receiving COSELA, which resolved with epinephrine, and treatment with COSELA was continued. The median time to onset from start of COSELA was 77 days (range to 256) and from the preceding dose of COSELA was day (range to 28). The median duration was days (range to 69 for the resolved cases). Acute drug hypersensitivity reactions resolved in 12 (75%) of the 16 patients.Monitor patients for signs and symptoms of acute drug hypersensitivity reactions including facial, eye, and tongue edema, urticaria, pruritus, and anaphylactic reactions. For moderate (Grade 2) acute drug hypersensitivity reactions, stop infusion and hold COSELA until the adverse reaction recovers to Grade <=1. For severe (Grade 3) or life-threatening (Grade 4) acute drug hypersensitivity reactions, stop infusion and permanently discontinue COSELA [see Dosage and Administration (2.2)].. 5.3 Interstitial Lung Disease/Pneumonitis. Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with cyclin-dependent kinases (CDK)4/6 inhibitors, the same drug class as COSELA. ILD/pneumonitis occurred in (0.4%) of 272 patients receiving COSELA in clinical trials. The adverse reaction was Grade and reported months after discontinuing COSELA, in patient receiving confounding medication. The adverse reaction did not resolve.Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis such as cough, dyspnea, and hypoxia. For recurrent moderate (Grade 2) ILD/pneumonitis, permanently discontinue COSELA. For severe (Grade 3) or life-threatening (Grade 4) ILD/pneumonitis, permanently discontinue COSELA [see Dosage and Administration (2.2)].. 5.4 Embryo-Fetal Toxicity. Based on its mechanism of action, COSELA can cause fetal harm when administered to pregnant woman. Females of reproductive potential should use an effective method of contraception during treatment with COSELA and for at least weeks after the final dose [see Use in Specific Populations (8.1, 8.3)].