Trisela Injection

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

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.

Bone Marrow: Trilaciclib exhibited dose-dependent inhibition of CD45+/CD3+ lymphocyte proliferation following administration of single-dose Trilaciclib 96 or 192 mg/m 2 (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 a single dose of Trilaciclib 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 Electrophysiology: Trilaciclib 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/m 2, Trilaciclib did not have a clinically relevant effect on QTc (i.e., >10 msec). QTc prolongation was observed at higher doses.

Recommended Dosage The recommended dose of Trilaciclib is 240 mg/m 2 per dose. Administer as a 30-minute intravenous infusion completed within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered. The interval between doses of Trilaciclib on sequential days should not be greater than 28 hours.

Missed Treatment Session(s): If the Trilaciclib dose is missed, discontinue chemotherapy on the day the Trilaciclib dose was missed. Consider resuming both Trilaciclib and chemotherapy on the next scheduled day for chemotherapy.

Discontinuation of Treatment: If Trilaciclib is discontinued, wait 96 hours from the last dose of Trilaciclib before resumption of chemotherapy only.

Preparation & Administration: Reconstitute and further dilute Trilaciclib 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.

Administer diluted Trilaciclib solution as a 30-minute intravenous infusion completed within 4 hours prior to the start of chemotherapy. Diluted Trilaciclib 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 Trilaciclib solution with a polytetrafluorethylene (PTFE) in-line filter. PTFE in-line filters are not compatible with diluted Trilaciclib solution. 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 Trilaciclib 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.

Trisela is an inhibitor of OCT2, MATE1, and MATE-2K. Co-administration of Trisela may increase the concentration or net accumulation of OCT2, MATE1, and MATE-2K substrates in the kidney (e.g., Dofetilide, Dalfampridine, and Cisplatin).

Trilaciclib is contraindicated in patients with a history of serious hypersensitivity reactions to Trilaciclib. Reactions have included anaphylaxis.

• Injection-Site Reactions, including phlebitis and thrombophlebitis
• Acute Drug Hypersensitivity Reactions
• ILD/Pneumonitis

Based on the mechanism of action, Trilaciclib can cause fetal harm when administered to a pregnant woman. There are no available human or animal data on Trilaciclib 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.

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 Trilaciclib and for at least 3 weeks after the last dose.

Injection-Site Reactions, Including Phlebitis and Thrombophlebitis: Trisela 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 Trisela in clinical trials, including Grade 2 (10%) and Grade 3 (0.4%) adverse reactions (ARs). The median time to onset from start of Trisela was 15 days (range 1 to 542) and from the preceding dose of Trisela 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 Trisela.

Acute Drug Hypersensitivity Reactions: Trisela administration can cause acute drug hypersensitivity reactions, including facial edema and urticaria. Acute drug hypersensitivity reactions occurred in 16 (6%) of 272 patients receiving Trisela in clinical trials, including Grade 2 reactions (2%). One patient experienced a Grade 2 anaphylactic reaction 4 days after receiving Trisela, which resolved with epinephrine, and treatment with Trisela was continued. The median time to onset from start of Trisela was 77 days (range 2 to 256) and from the preceding dose of Trisela 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 Trisela 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 Trisela.

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 Trisela. ILD/pneumonitis occurred in 1 (0.4%) of 272 patients receiving Trisela in clinical trials. The adverse reaction was Grade 3 and reported 2 months after discontinuing Trisela, 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 Trisela. For severe (Grade 3) or life-threatening (Grade 4) ILD/pneumonitis, permanently discontinue Trisela

Embryo-Fetal Toxicity: Based on its mechanism of action, Trisela can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should use an effective method of contraception during treatment with Trisela and for at least 3 weeks after the final dose.

Manifestations Symptoms of over dosage may include drowsiness, disorientation and extrapyramidal reactions. Treatment Anticholinergic drugs, antiparkinsonism drugs or antihistamine drugs with anticholinergic properties may be useful in controlling the extrapyramidal reactions. Symptoms are generally self-limiting and usually disappear within 24 hours.

Transient inhibitor

Reconstitution: Calculate the Trisela dose based on the patient’s Body Surface Area (BSA), the total volume of reconstituted Trisela solution required, and the number of Trisela 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 Trisela. 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 Trisela solution should be a 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 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 Trisela Solution: Withdraw the required volume from the vial(s) of reconstituted Trisela 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 Trisela solution should be between 0.5 mg/mL and 3 mg/mL. Mix diluted solution by gentle inversion. Do not shake. The diluted Trisela solution for infusion is a clear, yellow solution If not used immediately, store the diluted Trisela solution in the intravenous infusion bag as specified in Table Discard if storage time exceeds these limits. Do not refrigerate or freeze.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.