TRILACICLIB: 226 Adverse Event Reports & Safety Profile

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

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 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 )]</span>.

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&apos;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.

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 )

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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . 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.

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 a 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 2 (10%) and Grade 3 (0.4%) adverse reactions (ARs). The median time to onset from start of COSELA was 15 days (range 1 to 542) and from the preceding dose of COSELA was 1 day (1 to 15). The median duration was 1 day (range 1 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 3 (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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

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 2 reactions (2%). One patient experienced a Grade 2 anaphylactic reaction 4 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 2 to 256) and from the preceding dose of COSELA was 1 day (range 1 to 28). The median duration was 6 days (range 1 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

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 1 (0.4%) of 272 patients receiving COSELA in clinical trials. The adverse reaction was Grade 3 and reported 2 months after discontinuing COSELA, in a patient receiving a 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

5.4 Embryo-Fetal Toxicity Based on its mechanism of action, COSELA can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should use an effective method of contraception during treatment with COSELA and for at least 3 weeks after the final dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span>.

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) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. 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.