Sacituzumab Govitecan-hziy (Monograph)

Brand name: Trodelvy
Drug class: Antineoplastic Agents
Chemical name: (2R)-2-amino-3-[1-[[4-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[2-[[(2S)- 6-amino-1-[4-[[(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13- diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl]oxycarbonyloxymethyl]anilino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethox y]ethyl]triazol-4-yl]methylcarbamoyl]cyclohexyl]methyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid
Molecular formula: C₇₆H₁₀₄N₁₂O₂₄S
CAS number: 1491917-83-9

Medically reviewed by Drugs.com on Jul 17, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an anti-trophoblast antigen-2 (anti-Trop-2) antibody conjugated with a topoisomerase I inhibitor (SN-38).

Uses for Sacituzumab Govitecan-hziy

Breast Cancer

Treatment of metastatic triple-negative (i.e., estrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor type 2 [HER2]-negative) breast cancer (mTNBC) previously treated with at least 2 prior therapies for metastatic disease.

Accelerated approval based on tumor response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in a confirmatory study.

Sacituzumab Govitecan-hziy Dosage and Administration

General

• Do not substitute for or use with other drugs containing irinotecan or its active metabolite SN-38.

  Monitor patients during and for at least 30 minutes following each infusion. Administer in settings where emergency equipment and appropriate medical support are available for the management of potential infusion-related or hypersensitivity reactions. (See Hypersensitivity Reactions under Cautions.)

  Administer an antipyretic, a histamine H₁-receptor antagonist, and a histamine H₂-receptor antagonist prior to each infusion. If an infusion-related reaction occurs, may use corticosteroids for subsequent infusions.

  Administer a 2- or 3-drug antiemetic regimen (e.g., dexamethasone with either a type 3 serotonin [5-HT₃] receptor antagonist or a neurokinin-1 [NK₁] receptor antagonist, and other drugs as indicated) prior to each dose.

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.

  Consider secondary prophylaxis with G-CSFs.

Administration

For solution and drug compatibility information, see Compatibility under Stability.

IV Administration

Administer by IV infusion only. Do not administer by rapid IV injection, such as IV push or bolus. Flush line with 20 mL of 0.9% sodium chloride injection following completion of infusion.

Sacituzumab govitecan-hziy powder for injection must be reconstituted and diluted prior to administration.

Do not mix or administer simultaneously through the same IV line with any other drug.

Reconstitution

Remove appropriate number of vials from the refrigerator and allow to reach room temperature.

Use only 0.9% sodium chloride injection to reconstitute the powder for injection.

Reconstitute vial containing 180 mg of sacituzumab govitecan-hziy with 20 mL of 0.9% sodium chloride for injection to provide a solution containing 10 mg/mL solution. Gently swirl vial and allow to sit until completely dissolved (e.g., up to 15 minutes). Do not shake vial.

The reconstituted solution should be clear and yellow, and free of visible particulates.

Prepare diluted infusion solution immediately following reconstitution.

Dilution

Use only 0.9% sodium chloride injection to further dilute the reconstituted drug.

Dilute the required amount of reconstituted sacituzumab govitecan-hziy solution in a polypropylene IV infusion bag containing 0.9% sodium chloride injection to provide a final concentration of 1.1–3.4 mg/mL in a total volume of no more than 500 mL.

Slowly inject the reconstituted solution into the infusion bag to minimize foaming. Do not shake.

For patients weighing >170 kg, divide the total dose of sacituzumab govitecan-hziy equally between two 500-mL infusion bags and administer the 2 infusions sequentially.

Rate of Administration

Infuse initial dose over 3 hours; if infusion-related reactions do not occur, infuse subsequent doses over 1–2 hours.

Dosage

Calculate dosage based on body weight prior to each cycle. If body weight changes by >10% compared with the previous dose, more frequent dosage adjustment during treatment cycles may be necessary.

Adults

Breast Cancer

Metastatic Triple-negative Breast Cancer

IV

10 mg/kg by IV infusion on days 1 and 8 of each 21-day cycle. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Temporary interruption, dosage reduction, or permanent discontinuance may be necessary for adverse effects.

Do not re-escalate dosage following a dosage reduction.

Hematologic Toxicity

For ANC <1500/mm³ on day 1 of any cycle, ANC <1000/mm³ on day 8 of any cycle, or febrile neutropenia, withhold therapy.

For the first occurrence of grade 4 neutropenia lasting ≥7 days, grade 3 febrile neutropenia (ANC <1000/mm³ and fever ≥38.5°C), or grade 3 or 4 neutropenia that delays scheduled dosing by 2 or 3 weeks until recovery to grade 1 or less, reduce dosage by 25% and initiate G-CSF therapy.

If these neutropenic events recur following a 25% reduction in dosage, reduce dosage by 50%. If these neutropenic events recur following a 50% reduction in dosage or if grade 3 or 4 neutropenia delays scheduled dosing beyond 3 weeks until recovery to grade 1 or less, discontinue therapy.

For other grade 3 or 4 hematologic toxicities that do not recover to grade 1 or less within 3 weeks, discontinue therapy.

GI Toxicity

If grade 3 or 4 nausea, vomiting, or diarrhea occurs, withhold therapy until the toxicity improves to grade 1 or less.

For the first occurrence of grade 3 or 4 nausea, vomiting, or diarrhea that persists despite antiemetic or antidiarrheal therapy, withhold therapy until toxicity improves to grade 1 or less, then reduce dosage by 25%.

For the second occurrence of grade 3 or 4 nausea, vomiting, or diarrhea that persists despite antiemetic or antidiarrheal therapy, withhold therapy until toxicity improves to grade 1 or less, then reduce dosage by 50%.

For the third occurrence of grade 3 or 4 nausea, vomiting, or diarrhea that persists despite antiemetic or antidiarrheal therapy, discontinue therapy.

Nonhematologic Toxicity

For the first occurrence of grade 4 nonhematologic toxicity of any duration or grade 3 or 4 nonhematologic toxicity persisting for >48 hours despite optimal medical management, or grade 3 or 4 nonhematologic toxicity that delays scheduled dosing by 2 or 3 weeks until recovery to grade 1 or less, reduce dosage by 25%.

If such nonhematologic effects recur following a 25% reduction in dosage, reduce dosage by 50%.

If such nonhematologic effects recur following a 50% reduction in dosage, discontinue therapy.

For grade 3 or 4 nonhematologic toxicity that does not recover to grade 1 or less within 3 weeks, discontinue therapy.

Infusion-related Reactions

If an infusion-related reaction occurs, interrupt infusion or reduce infusion rate. For life-threatening infusion-related reaction, permanently discontinue therapy.

Prescribing Limits

Adults

Breast Cancer

IV

Maximum 10 mg/kg per dose.

Special Populations

Dosage in Hepatic Impairment

Mild hepatic impairment (serum bilirubin concentration not exceeding the ULN and AST concentration exceeding the ULN, or serum bilirubin concentration 1–1.5 times the ULN and any AST concentration): No initial dosage adjustment needed.

Moderate or severe hepatic impairment: No specific dosage recommendation. (See Hepatic Impairment under Cautions.)

Dosage in Renal Impairment

No specific dosage recommendations. (See Renal Impairment under Cautions.)

Geriatric Use

No specific dosage recommendations.

Pharmacogenomic Dosage Considerations

Homozygous for UGT1A1*28: Increased risk of neutropenia and other toxicities; however, appropriate dosage not established. Closely monitor patients for severe neutropenia and adjust dosage based on individual patient tolerance. (See Pharmacogenomic Considerations under Cautions.)

The principal mTNBC efficacy study (IMMU-132-01) excluded patients with known Gilbert syndrome, a condition associated with UGT1A1 deficiency.

Cautions for Sacituzumab Govitecan-hziy

Contraindications

• Known severe hypersensitivity reaction to sacituzumab govitecan or any ingredient in the formulation.

Warnings/Precautions

Warnings

Neutropenia

Severe or life-threatening neutropenia, including febrile neutropenia, reported. In the IMMU-132-01 study, neutropenia was the most common cause of treatment interruption and dose reduction in patients with mTNBC.

Monitor CBCs periodically during therapy and consider secondary prophylaxis with a G-CSF agent. Promptly initiate anti-infective therapy if febrile neutropenia occurs.

Temporary interruption, dosage reduction, or permanent discontinuance of therapy may be necessary if neutropenia occurs. (See Dosage Modification for Toxicity under Dosage and Administration.)

Diarrhea

Severe diarrhea reported; generally occurs within the first few days of therapy.

If diarrhea occurs, initiate appropriate therapy (e.g., antidiarrheal agents, fluid replacement). If early diarrhea of any severity occurs, therapy with atropine is recommended as appropriate. At the onset of late diarrhea, evaluate patients for infectious causes; if an infectious etiology is ruled out, initiate loperamide 4 mg, then loperamide 2 mg with every episode of diarrhea up to a maximum of 16 mg daily. Discontinue loperamide therapy 12 hours after diarrhea resolves. If an excessive cholinergic response (e.g., abdominal cramping, diarrhea, salivation) occurs, initiate appropriate premedication (e.g., atropine) prior to subsequent infusions.

Temporary interruption, dosage reduction, or permanent discontinuance of therapy may be necessary if diarrhea occurs. (See Dosage Modification for Toxicity under Dosage and Administration.)

Other Warnings and Precautions

Hypersensitivity Reactions

Severe or life-threatening hypersensitivity reactions and anaphylaxis reported.

Closely observe patients during infusions and for at least 30 minutes following completion of sacituzumab govitecan infusions. The manufacturer recommends premedication prior to each infusion. (See General under Dosage and Administration.)

Nausea and Vomiting

Nausea and vomiting reported.

Sacituzumab govitecan is moderately emetogenic; premedicate patients with a 2- or 3-drug antiemetic regimen prior to each dose.

Temporary interruption of therapy, dosage reduction, or permanent discontinuance of therapy may be necessary if nausea or vomiting occurs. (See Dosage Modification for Toxicity under Dosage and Administration.)

Pharmacogenomic Considerations

Genetic variants of the UGT1A1 gene, such as the UGT1A1*28 allele, may reduce UGT1A1 enzyme activity.

The small molecule component (SN-38) of the antibody-drug conjugate is metabolized via UGT1A1; therefore, individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia and other adverse reactions.

The manufacturer makes no specific recommendations for screening for UGT1A1 genetic variants prior to initiation of therapy; however, some clinicians state that management of a neutropenic event is more appropriate than screening for UGT1A1 genetic variants.

Appropriate dosage not established for patients who are homozygous for UGT1A1*28. Closely monitor such patients for severe neutropenia and modify dosage based on individual patient tolerance. In the IMMU-132-01 study, patients with known Gilbert syndrome (condition associated with UGT1A1 deficiency) were excluded.

Fetal/Neonatal Morbidity and Mortality

May cause embryofetal mortality and/or teratogenicity based on mechanism of action.

Avoid pregnancy during therapy. Perform pregnancy testing prior to initiation of therapy in females of reproductive potential. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the last dose. Men with such female partners should use effective methods of contraception during therapy and for 3 months after the last dose. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Impairment of Fertility

Based on animal studies, may impair female fertility.

Immunogenicity

Potential for immunogenicity.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether sacituzumab govitecan or SN-38 is distributed into milk or if drug has any effect on milk production or the breast-fed infant. Women should not breast-feed during therapy or for 1 month after drug discontinuance.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

In the IMMU-132-01 study, 18 or 35% of patients who received sacituzumab govitecan-hziy in the mTNBC cohort or total study population, respectively, were ≥65 years of age. No overall differences in safety and efficacy were observed between these patients and younger adults.

Hepatic Impairment

Mild hepatic impairment: Pharmacokinetics not substantially altered. No dosage adjustment needed.

Moderate or severe hepatic impairment: Pharmacokinetics not studied. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Renal impairment or end-stage renal disease (Cl_cr ≤30 mL/minute): Pharmacokinetics not studied. Renal elimination of SN-38 is minimal.

Common Adverse Effects

Nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, abdominal pain.

Drug Interactions

SN-38 is metabolized by UGT1A1. No formal drug interaction studies performed to date.

Drugs Affecting UGT

UGT1A1 inhibitors: Possible increased systemic exposure to SN-38 and increased risk of adverse reactions. Avoid concomitant use.

UGT1A1 inducers: Possible decreased systemic exposure to SN-38. Avoid concomitant use.

Sacituzumab Govitecan-hziy Pharmacokinetics

Absorption

Bioavailability

Sacituzumab govitecan releases >90% of SN-38 over approximately 3 days.

Plasma concentrations of sacituzumab govitecan are considerably higher than those of free SN-38, suggesting the majority of circulating SN-38 remains bound to the antibody.

Special Populations

Mild hepatic impairment: No clinically important changes in the pharmacokinetics of sacituzumab govitecan.

Moderate or severe hepatic impairment: Pharmacokinetics of sacituzumab govitecan not studied; however, systemic exposure to SN-38 may be increased due to decreased hepatic UGT1A1 activity.

Renal impairment or end-stage renal disease (Cl_cr ≤30 mL/minute): Pharmacokinetics not studied.

Age and race do not substantially affect pharmacokinetics of sacituzumab govitecan.

Distribution

Extent

Sacituzumab govitecan maintains SN-38 in its most active form until the antibody-drug conjugate binds to Trop-2; therefore, higher concentrations of SN-38 are delivered to tumors compared with irinotecan-derived SN-38 therapy.

Not known whether sacituzumab govitecan or SN-38 distributes into human milk.

Elimination

Metabolism

No metabolism studies have been conducted. SN-38 is metabolized via UGT1A1 to the glucuronide metabolite SN-38G.

Elimination Route

Renal elimination of SN-38 is minimal.

Half-life

Antibody-drug conjugate: 16 hours.

Free SN-38: 18 hours.

Stability

Storage

Parenteral

Powder for Injection

2–8°C in original carton to protect from light. Do not freeze.

Reconstituted drug: Dilute immediately.

Diluted infusion solution: May refrigerate at 2–8°C for up to 4 hours. Following removal from refrigeration, use within 4 hours (including infusion time). Do not freeze or shake. Protect infusion bag from light.

Compatibility

Parenteral

Solution Compatibility

Actions

• Trop-2-directed antibody-drug conjugate consisting of a humanized immunoglobulin G1 (IgG₁) kappa monoclonal antibody (sacituzumab) covalently linked to the topoisomerase I inhibitor SN-38.

• High drug-to-antibody ratio (approximately 7–8 molecules of SN-38 attached to each antibody molecule).

• Binds to Trop-2-expressing cancer cells and resultant complex is internalized by the cell. SN-38 is subsequently released via hydrolysis of the maleimide-containing crosslinker CL2A. SN-38 also may be released extracellularly into the tumor microenvironment.

• SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single-strand breaks. The resulting DNA damage leads to apoptosis and cell death.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling.

• Advise patients of the risk of neutropenia. Instruct patients to immediately contact their healthcare provider if they experience fever, chills, or other signs of infection.

• Advise patients of the risk of diarrhea. Instruct patients to immediately contact their healthcare provider if they experience diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to control diarrhea within 24 hours.

• Inform patients of the risk of serious infusion reactions and anaphylaxis. Instruct patients to immediately contact their healthcare provider if they experience facial, lip, tongue, or throat swelling, urticaria, difficulty breathing, lightheadedness, dizziness, chills, rigors, wheezing, pruritus, flushing, rash, hypotension, or fever during or within 24 hours following the infusion.

• Advise patients of the risk of nausea and vomiting. Premedication according to established guidelines with a 2- or 3-drug regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) is also recommended. Additional antiemetics, sedatives, and other supportive measures may also be employed as clinically indicated. All patients should receive take-home medications for preventing and treating delayed nausea and vomiting, with clear instructions. Instruct patients to immediately contact their healthcare provider if they experience uncontrolled nausea or vomiting.

• Advise female patients to contact their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy.

• Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of sacituzumab govitecan.

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of sacituzumab govitecan.

• Advise women not to breast-feed during treatment and for 1 month after the last dose of sacituzumab govitecan.

• Advise females of reproductive potential that sacituzumab govitecan may impair fertility.

• Advise patients of the importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients of other important precautionary information. (See Cautions.)

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.

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