Trilaciclib (Monograph)

Brand name: Cosela
Drug class: Protective Agents

Medically reviewed by Drugs.com on Nov 21, 2023. Written by ASHP.

Introduction

Kinase inhibitor; a myeloprotective agent.

Uses for Trilaciclib

Prevention of Chemotherapy-induced Myelosuppression

Used to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when given prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC).

Guidelines from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) provide recommendations on the use of myeloid growth factors (e.g., G-CSF) for patients undergoing myelosuppressive chemotherapy; however, trilaciclib is not addressed because the drug was approved after publication of the guidelines.

Trilaciclib Dosage and Administration

General

Pretreatment Screening

Perform pregnancy testing in females of reproductive potential prior to initiating trilaciclib.

Patient Monitoring

Monitor for signs and symptoms of injection-site reactions, phlebitis, and thrombophlebitis (including infusion-site pain and erythema) during trilaciclib infusion.
Monitor for pulmonary symptoms indicative of interstitial lung disease/pneumonitis during treatment.
Monitor for signs and symptoms of acute drug hypersensitivity reactions (e.g., facial, eye, and tongue edema; urticaria; pruritus; anaphylactic reactions) during treatment.

Administration

IV Administration

Administer by IV infusion over 30 minutes. Complete infusion no more than 4 hours prior to the start of chemotherapy on each day chemotherapy is administered.

Available as a lyophilized powder that must be reconstituted and further diluted prior to administration.

Administer 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 with a polytetrafluorethylene (PTFE) in-line filter; PTFE is acceptable for use in air vent filters.

Do not coadminister other drugs through the same infusion line, or through a central access device unless the device supports coadministration of incompatible drugs.

After infusion is complete, flush infusion line/cannula with at least 20 mL of sterile 0.9% sodium chloride or 5% dextrose injection.

If a dose is missed, discontinue chemotherapy on the day the dose was missed. Consider resuming both trilaciclib and chemotherapy on the next scheduled chemotherapy day. If trilaciclib is discontinued, wait 96 hours from the last trilaciclib dose before resuming chemotherapy only.

Reconstitution

Calculate dose based on patient’s body surface area, the total volume of reconstituted solution required, and the number of vials necessary.

Reconstitute each vial with 19.5 mL of 0.9% sodium chloride or 5% dextrose injection to achieve a concentration of 15 mg/mL.

Gently swirl vial for up to 3 minutes until lyophilized cake is completely dissolved; do not shake.

Dilution

Dilute reconstituted solution in 0.9% sodium chloride or 5% dextrose injection to a final concentration between 0.5–3 mg/mL.

Mix diluted solution by gentle inversion; do not shake.

If not used immediately, store diluted solution in the IV infusion bag (see Storage); discard if storage time exceeds these limits.

Rate of Administration

Administer diluted solution as a 30-minute IV infusion completed no more than 4 hours prior to start of chemotherapy.

Dosage

Dosage of trilaciclib dihydrochloride is expressed in terms of trilaciclib.

Adults

Prevention of Chemotherapy-induced Myelosuppression

IV:

240 mg/m²per dose; administer as a 30 minute IV infusion within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered. When given on sequential days, interval between doses should not be greater than 28 hours.

<C> Dosage Modification for Toxicity

Discontinue, withhold, or modify trilaciclib administration to manage specific adverse reactions (see Table 1).

Abbreviations: ADL, activities of daily living.

Table 1: Dosage Modification Recommendations for Adverse Reactions.1
Adverse Reaction	Severity Grade	Recommendation
Injection site reactions including phlebitis and thrombophlebitis	Grade 1: tenderness with or without symptoms (e.g., warmth, erythema, itching) Grade 2: pain, lipodystrophy, edema, phlebitis Grade 3: ulceration or necrosis; severe tissue damage; operative intervention indicated OR Grade 4: life-threatening consequences; urgent intervention indicated	Grade 1: Interrupt or slow infusion; if 0.9% sodium chloride is being used as a diluent/flush, consider changing to 5% dextrose as appropriate for subsequent infusions Grade 2: Interrupt infusion; if pain is 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 is being used as a diluent/flush, consider changing to 5% dextrose as appropriate for subsequent infusions; central access may also be considered Grade 3 or 4: Stop infusion and permanently discontinue
Acute drug hypersensitivity reactions	Grade 2: moderate; minimal, local, or noninvasive intervention indicated; limiting activities of daily living (ADL) 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	Grade 2: Stop infusion and hold until recovery to grade 1 or less or baseline, then consider resuming; if grade 2 recurs, permanently discontinue Grade 3 or 4: Permanently discontinue
Interstitial lung disease/pneumonitis	Grade 2 (symptomatic) Grade 3: severe symptoms; limiting self-care ADL; oxygen indicated OR Grade 4: life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy, intubation)	Grade 2: Hold until recovery to grade 1 or less or baseline, then consider resuming; if grade 2 recurs, permanently discontinue Grade 3 or 4: Permanently discontinue
Other toxicities	Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL Grade 4: life-threatening consequences; urgent intervention indicated	Grade 3: Hold until recovery to grade 1 or lower or baseline, then consider resuming; if grade 3 recurs, permanently discontinue Grade 4: Permanently discontinue

Special Populations

Hepatic Impairment

Moderate or severe hepatic impairment (Child-Pugh classes B and C): Reduce trilaciclib dosage to 170 mg/m².

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment necessary.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

No specific dosage recommendations at this time.

Cautions for Trilaciclib

Contraindications

History of serious hypersensitivity reactions to trilaciclib, including anaphylaxis.

Warnings/Precautions

Injection-site Reactions

Injection-site reactions (including phlebitis and thrombophlebitis) may occur. Grade 2 and grade 3 events reported.

Monitor for signs and symptoms of injection-site reactions, phlebitis, and thrombophlebitis (including infusion-site pain and erythema) during infusion. For Grade 1 (mild) or grade 2 (moderate) reactions, flush the line/cannula with ≥20 mL of sterile 0.9% sodium chloride or 5% dextrose injection after end of infusion. For grade 3 (severe) or grade 4 (life-threatening) reactions, stop the infusion and permanently discontinue.

Acute Drug Hypersensitivity Reactions

Acute hypersensitivity reactions, including facial edema and urticaria, reported.

Monitor for signs and symptoms of acute drug hypersensitivity reactions (e.g., facial, eye, and tongue edema; urticaria, pruritus, anaphylactic reactions). For grade 2 (moderate) reactions, stop infusion and hold trilaciclib until reaction recovers to grade 1 or lower. For grade 3 (severe) or grade 4 (life-threatening) reactions, stop infusion and permanently discontinue.

Interstitial Lung Disease/Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis may occur.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis (e.g., cough, dyspnea, hypoxia). For recurrent grade 2 (moderate) ILD/pneumonitis, and for grade 3 (severe) or grade 4 (life-threatening) ILD/pneumonitis, permanently discontinue. See Table 1 in the Dosage section for additional information.

Fetal/Neonatal Morbidity and Mortality

Use during pregnancy can cause fetal harm.

Perform pregnancy testing in females of reproductive potential prior to initiating trilaciclib.

Advise females of reproductive potential to use effective contraception during treatment and for ≥3 weeks after the last dose.

Specific Populations

Pregnancy

Use during pregnancy can cause fetal harm based on the mechanism of action.

No available human or animal data to assess the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Advise pregnant women of the potential risk to a fetus.

Lactation

Unknown whether distributes into human or animal milk, or affects milk production or the breast-fed infant.

Advise women to not breast-feed during treatment and for ≥3 weeks after the last dose.

Females and Males of Reproductive Potential

Perform pregnancy testing in females of reproductive potential prior to initiating trilaciclib.

Advise females of reproductive potential to use effective contraception during treatment and for ≥3 weeks after the last dose.

No human studies on effects on fertility in males or females; animal studies indicate impaired fertility in females of reproductive potential.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety or efficacy between geriatric (≥65 years of age) and younger patients.

No clinically important differences in trilaciclib pharmacokinetics observed based on age (range, 19–80 years).

Hepatic Impairment

Principally metabolized in the liver.

Trilaciclib (unbound) exposure increased by 40 and 63%, respectively, in patients with moderate and severe hepatic impairment (Child-Pugh classes B and C). No clinically important differences in trilaciclib pharmacokinetics observed in patients with mild hepatic impairment.

Renal Impairment

Eliminated to a small extent via renal route.

No clinically important differences in trilaciclib pharmacokinetics observed with mild to moderate renal impairment (eGFR 30–89 mL/min per 1.73 m²).

Effect of severe renal impairment (eGFR <30 mL/min per 1.73 m²), end stage renal disease, or dialysis on trilaciclib pharmacokinetics not yet studied.

Common Adverse Effects

Most common adverse effects (≥10%): fatigue, headache, pneumonia, hypocalcemia, hypokalemia, hypophosphatemia, increased AST.

Drug Interactions

Does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. Induces CYP isoenzyme 1A2, but not CYP isoenzymes 2B6 or 3A4.

Inhibits organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) transporter 1, and MATE-2K.

Does not inhibit p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, or OAT3.

Substrate of P-gp and BCRP, but not bile salt export pump, MATE1, MATE-2K, or OCT.

Drugs Affected by Transport Systems

Trilaciclib may increase concentration or net accumulation of OCT2, MATE1, and MATE-2K substrates in the kidney (e.g., cisplatin, dalfampridine, dofetilide).

Avoid concomitant use of trilaciclib with certain OCT2, MATE1, and MATE-2K substrates where minimal changes in concentrations may result in serious or life-threatening toxicities.

Refer to the prescribing information for concomitant drugs to assess the risks and benefits of concomitant use of trilaciclib.

Specific Drugs

Drug	Interaction	Comments
Cisplatin	Increased exposure and altered net accumulation of cisplatin in the kidney	Closely monitor for dose-related nephrotoxicity
Dalfampridine	Increased dalfampridine serum concentration, which may increase risk of seizure	Weigh risk of seizures against the potential benefits of concurrent use
Dofetilide	Increased dofetilide serum concentration, which may cause serious ventricular arrhythmias associated with QT interval prolongation, including torsade de pointes	Weigh the risk of QT prolongation against the potential benefits of concurrent use
Itraconazole	No clinically important differences in trilaciclib pharmacokinetics observed when used concomitantly with itraconazole (strong CYP3A inhibitor)
Metformin	Increased metformin exposure and peak plasma concentrations; decreased renal clearance of metformin
Midazolam	No clinically important differences in midazolam (CYP3A substrate) pharmacokinetics observed
Rifampin	No clinically important differences in trilaciclib pharmacokinetics observed when used concomitantly with rifampin (strong CYP3A inducer)
Topotecan	No clinically important differences in topotecan (MATE1 and MATE-2K substrate) pharmacokinetics observed

Trilaciclib Pharmacokinetics

Absorption

Plasma Concentrations

Peak plasma concentrations increased proportionally, and total plasma exposure increased slightly more than proportionally, over a dosage range of 200–700 mg/m² (0.83–2.9 times the usual dosage). No accumulation observed following repeated dosing.

Special Populations

No clinically important differences in trilaciclib pharmacokinetics observed based on age (range, 19–80 years), sex, race, mild to moderate renal impairment (eGFR 30–89 mL/min per 1.73 m²), or mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0–1.5 times ULN, irrespective of AST).

Distribution

Plasma Protein Binding

69% (independent of concentration).

Elimination

Metabolism

Undergoes extensive metabolism. Primarily metabolized by aldehyde oxidase and CYP isoenzymes 3A4 and 2C8.

Elimination Route

Mainly via fecal route; minimally via renal route.

Following a single radiolabeled dose of trilaciclib 192 mg/m², approximately 79.1% (7% unchanged) and 14% (2% unchanged) recovered in feces and urine, respectively.

Half-life

Approximately 14 hours.

Stability

Storage

Parenteral

For injection, for IV infusion

Unopened vial: 20–25ºC (excursions permitted between 15–30ºC).

Reconstituted solution in vial: 20–25ºC for up to 4 hours prior to transfer to the infusion bag; do not refrigerate or freeze.

Diluted solution with 5% dextrose in IV bag made of polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyolefin (PO), or polyolefin/polyamide (PO/PA): store up to 12 hours at 20–25ºC. Do not refrigerate or freeze.

Diluted solution with 0.9% sodium chloride in IV bag made of PVC, EVA, or PO: store up to 8 hours at 20–25ºC. Do not refrigerate or freeze.

Diluted solution with 0.9% sodium chloride in IV bag made of PO/PA: store up to 4 hours at 20–25ºC. Do not refrigerate or freeze.

Actions

Selective, reversible (transient) inhibitor of cyclin-dependent kinase (CDK) 4 and 6.
Administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells (HSPCs) and lymphocytes during chemotherapy.
By inhibiting CDK4/6, transiently induces HSPC G1 cell cycle arrest, preventing the cells from proliferating in the presence of cytotoxic chemotherapy and thus resulting in myelopreservation.

Advice to Patients

Advise patients to contact their clinician immediately if they experience signs and symptoms of injection-site reactions, including phlebitis and thrombophlebitis.
Advise patients to contact their clinician immediately if they experience signs and symptoms of acute drug hypersensitivity reactions (e.g, facial, eye, and tongue edema; urticaria, pruritis, anaphylactic reactions).
Advise patients to contact their clinician immediately to report any new or worsening respiratory symptoms, since severe or life-threatening interstitial lung disease/pneumonitis may occur with trilaciclib therapy.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise females of reproductive potential that trilaciclib may cause fetal harm. Advise females of reproductive potential to inform their clinician of a known or suspected pregnancy, and to use effective contraception during trilaciclib therapy and for ≥3 weeks after the last dose.
Advise women to inform their clinician if they are or plan to breast-feed. Advise women to not breast-feed during trilaciclib therapy and for ≥3 weeks after the last dose.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.