COSELA

Dosage and Administration ( 2.2 ) 8/2023

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 …

3 DOSAGE FORMS AND STRENGTHS For injection: Contains the equivalent of 300 mg of trilaciclib (provided as 349 mg of trilaciclib dihydrochloride) as a sterile, preservative-free, yellow, lyophilized cake in a single-dose vial for reconstitution and further dilution. For injection: 300 mg of trilaciclib as a lyophilized cake in a single-dose vial. ( 3 )

4 CONTRAINDICATIONS COSELA is contraindicated in patients with a history of serious hypersensitivity reactions to trilaciclib. Reactions have included anaphylaxis [see Warnings and Precautions ( 5.2 )] . Patients with a history of serious hypersensitivity reactions to COSELA. ( 4 )

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 …

7 DRUG INTERACTIONS Certain OCT2, MATE1, and MATE-2K substrates: Avoid concomitant use with certain OCT2, MATE1, and MATE-2K substrates where minimal concentration changes may lead to serious or life-threatening toxicities. ( 7.1 ) 7.1 Effect of COSELA on Other Drugs, Certain OCT2, MATE1, and MATE-2K Substrates COSELA is an inhibitor of OCT2, MATE1, and MATE-2K. Co-administration of COSELA may increase the concentration or net accumulation of OCT2, MATE1, and MATE-2K substrates in the kidney (e.g., dofetilide, dalfampridine, and cisplatin) [see Clinical Pharmacology ( 12.3 )]. Refer to the prescribing information for these concomitant medications for assessing the benefit and risk of concomitant use of COSELA. Table 4: Potentially Significant Drug Interactions with COSELA Drugs Recommendations Comments Dofetilide The potential benefits of taking COSELA concurrently with dofetilide should be considered against the risk of QT interval prolongation. Increased dofetilide blood levels may occur in patients who are also receiving COSELA. Increased plasma concentrations of dofetilide may cause serious ventricular arrhythmias associated with QT interval prolongation, including torsade de pointes. Dalfampridine The potential benefits of taking COSELA concurrently with dalfampridine should be considered against the risk of seizures in these patients. Increased dalfampridine blood levels may occur in patients who are also receiving COSELA. Elevated levels of dalfampridine increase the risk of seizure. Cisplatin Closely monitor for nephrotoxicity. Concurrent treatment with COSELA may increase the exposure and alter the net accumulation of cisplatin in the kidney, which may associate with dose-related nephrotoxicity.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on the mechanism of action, COSELA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12 )] . There are no available human or animal data on COSELA use to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 Summary There 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 3 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on its mechanism of action, COSELA can cause fetal harm if administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy testing is recommended for females of reproductive potential prior to initiating COSELA. Contraception COSELA 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 3 weeks after the final dose. Infertility No 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 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 in patients with mild hepatic impairment (Child-Pugh class A) [see Dosage and Administration ( 2.2 )]. Trilaciclib is mainly metabolized in the liver. Trilaciclib exposure increased with moderate and severe hepatic impairment (Child-Pugh classes B and C) [see Clinical Pharmacology ( 12.3 )].

12.1 Mechanism of Action Trilaciclib is a transient inhibitor of CDK 4 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.

11 DESCRIPTION COSELA for injection contains trilaciclib dihydrochloride, a kinase inhibitor. The chemical name for trilaciclib is 2'-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-7',8'-dihydro-6' H -spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3- d ]pyrimidin]-6'-one. Trilaciclib dihydrochloride is a water-soluble yellow solid, with molecular formula of C 24 H 30 N 8 O•2HCl, a molecular weight of 519.48 g/mol (Free base: 446.56 g/mol), and the following chemical structure: COSELA (trilaciclib) for injection is a sterile, preservative-free, yellow lyophilized cake in a single-dose vial for intravenous infusion after reconstitution and dilution. Each single-dose vial contains the equivalent of 300 mg of trilaciclib (provided as 349 mg of trilaciclib dihydrochloride) and the following inactive ingredients: citric acid monohydrate (75.6 mg) and mannitol (300 mg); hydrochloric acid and sodium hydroxide to adjust pH. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied COSELA (trilaciclib) for injection is a yellow lyophilized cake supplied in a single-dose vial. Each carton (NDC 73594-0101-1) contains one 300 mg strength single-dose vial. 16.2 Storage and Handling Store COSELA vials at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . The vial stopper is not made with natural rubber latex.

16.1 How Supplied COSELA (trilaciclib) for injection is a yellow lyophilized cake supplied in a single-dose vial. Each carton (NDC 73594-0101-1) contains one 300 mg strength single-dose vial.