DRUG INTERACTIONS-(details)

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)

 Refer to the prescribing information for these concomitant medications for assessing the benefit and risk of concomitant use of COSELA.

 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.

BRIEF SUMMARY

TRILACICLIB-(Feb 2021)

 Indn-  To mitigate chemotheraphy induced   myelosuppressiion in adult patients                        with small lung cancer       

Comp-  For injection: 300 mg of trilaciclib as a lyophilized cake in a single-dose vial.     recommended dose  is 240 mg/m2 as a 30-minute intravenous infusion completed within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered.

ADR-  most common adverse reactions, were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia.

CI- Patients with a history of serious hypersensitivity reactions to the drug

WARNINGS -

 • Injection-Site Reactions, Including Phlebitis and Thrombophlebitis:                     Monitor for signs and symptoms of injection-site reactions, including phlebitis and thrombophlebitis during infusion

Pat Inform-

Injection-Site Reactions, Including Phlebitis and Thrombophlebitis - Inform 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 acute drug hypersensitivity reactions including facial, eye, and tongue edema, urticaria, pruritis, and anaphylactic reactions 

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 7

Name of the Drug-    COSELA

Active Ingredient -    Trilacicilib

Pharmacological Classification-   To mitigate chemotheraphy induced                                                                                 myelosuppressiion in adult patients                                                                               with small lung cancer                                                                          

Date of Approval-          2/12/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION-                                                     These highlights do not include all the information needed to use                          COSELA safely and effectively.                                                                                      See full prescribing information for COSELA. COSELA? (trilaciclib) for injection, for intravenous use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

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.

DOSAGE AND ADMINISTRATION-

 COSELA is for intravenous use only. The recommended dose of COSELA is 240 mg/m2 as a 30-minute intravenous infusion completed within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered.

 See Full Prescribing Information for instructions on preparation and administration.

 DOSAGE FORMS AND STRENGTHS-                                                                         For injection: 300 mg of trilaciclib as a lyophilized cake in a single-dose vial. 

CONTRAINDICATIONS

Patients with a history of serious hypersensitivity reactions to COSELA. 

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. 

ADVERSE REACTIONS

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.

CONTRAINDICATIONS

Patients with a history of serious hypersensitivity reactions to COSELA. 

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. 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.

 • 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.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. 

 PATIENT COUNSELING INFORMATION-   

  Injection-Site Reactions, Including Phlebitis and Thrombophlebitis -              Inform 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 

Acute Drug Hypersensitivity Reactions-                                                                     Advise 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 

Interstitial Lung Disease/Pneumonitis -                                                                         Advise patients to immediately report new or worsening respiratory symptoms

Advise  females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy 

Advise females of reproductive potential to use effective contraception during treatment with COSELA and for at least 3 weeks after the final dose 

Lactation-                                                                                                                  Advise women not to breastfeed during treatment with COSELA and for at least 3 weeks after the final dose of COSELA 

Drug Interactions-                                                                                                          Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products 

 Distributed by: G1 Therapeutics, Inc. Durham, NC 27709 025991 10003 Rev. 2/2021

 CLINICAL PHARMACOLOGY

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.

2 Pharmacodynamics Bone Marrow Trilaciclib 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.

Cardiac Electrophysiology- COSELA 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 a clinically relevant effect on QTc (i.e., >10 msec). QTc prolongation was observed at higher doses.

3. Pharmacokinetics-                                                                                                        The maximum concentration (Cmax) increased proportionally whereas the total plasma exposure (AUC0-last) increased slightly greater than proportional over a 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.

Distribution -                                                                                                                 Protein 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 0.5µg/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.

Excretion-                                                                                                                        After a 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 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 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.

 USE IN SPECIFIC POPULATIONS

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.

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.

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 . Pregnancy testing is recommended for females of reproductive potential prior to initiating COSELA.

Contraception COSELA can cause fetal harm when administered to pregnant women . 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 

4 Pediatric Use-                                                                                                        Safety and effectiveness in pediatric patients have not been established

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.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)