DRUG INTERACTIONS

­ • UGT1A1 inhibitors or inducers: Avoid concomitant use. 

 DRUG INTERACTIONS - details

1. Effect of Other Drugs on TRODELVY UGT1A1 Inhibitors-                               Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38

Avoid administering UGT1A1 inhibitors with TRODELVY. UGT1A1 Inducers Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers

Avoid administering UGT1A1 inducers with TRODELVY.

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  15

ADVERSE REACTIONS

­ Most common adverse reactions (incidence >25%) in patients with mTNBC are nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain.

CONTRAINDICATIONS

­ Severe hypersensitivity reaction to TRODELVY. 

WARNINGS AND PRECAUTIONS 

 ­ • Hypersensitivity:                                                                                           Hypersensitivity reactions including severe anaphylactic reactions have been observed. Monitor patients for infusion-related reactions. Permanently discontinue TRODELVY if severe or lifethreatening reactions occur. 

• Nausea/Vomiting:                                                                                                    Use antiemetic preventive treatment and withhold TRODELVY for patients with Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment. 

• Patients with Reduced UGT1A1 Activity:                                                        Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia following initiation of TRODELVY treatment. 

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

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information)

Neutropenia-                                                                                                           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

Diarrhea-                                                                                                                       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 get diarrhea under control within 24 hours 

Hypersensitivity-                                                                                                    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, that occur during or within 24 hours following the infusion 

Nausea/Vomiting-                                                                                                  Advise patients of the risk of nausea and vomiting.                                             Premedication according to established guidelines with a two or three 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

Embryo-Fetal Toxicity-                                                                                          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 

Contraception -                                                                                                     Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of TRODELVY 

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

Lactation-                                                                                                              Advise women not to breastfeed during treatment and for 1 month after the last dose of TRODELVY [see Use in Specific Populations (8.2)].

Infertility-                                                                                                               Advise females of reproductive potential that TRODELVY may impair fertility 

Manufactured by: Immunomedics, Inc. 300 The American Road Morris Plains, NJ 07950, USA U.S. License No. 1737

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                           Sacituzumab govitecan-hziy is a Trop-2-directed antibody-drug conjugate. Sacituzumab is a humanized antibody that recognizes Trop-2. The small molecule, SN-38, is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker.

2. Pharmacodynamics-                                                                                   Exposure-response relationships and the time course of pharmacodynamics response are unknown for sacituzumab govitecan-hziy.

3. Pharmacokinetics-                                                                                                The serum pharmacokinetics of sacituzumab govitecan-hziy and SN-38 were evaluated in a study in a population of mTNBC patients who received sacituzumab govitecan-hziy as a single agent at a dose of 10 mg/kg.

Cmax: maximum plasma concentration AUC0-168: area under plasma concentration curve through 168 hours 

Distribution-                                                                                                               The mean volume of distribution for sacituzumab govitecan-hziy was 0.045 L/kg.

Elimination-                                                                                                                The mean half-life of sacituzumab govitecan-hziy and free SN-38 was 16 and 18 hours, respectively. The clearance of the sacituzumab govitecan-hziy was 0.002 L/h/kg.

Metabolism-                                                                                                                 No metabolism studies with sacituzumab govitecan-hziy have been conducted. SN-38 (the small molecule moiety of sacituzumab govitecan-hziy) is metabolized via UGT1A1. The glucuronide metabolite of SN-38 (SN-38G) was detectable in the serum of patients.

Specific Populations Pharmacokinetic analyses in a limited number of patients with mTNBC (n = 57) did not identify an effect of age or race on the pharmacokinetics of sacituzumab govitecan-hziy.

Renal elimination is known to contribute minimally to the excretion of SN-38, the small molecule moiety of sacituzumab govitecan-hziy.

There are no data on the pharmacokinetics of sacituzumab govitecan-hziy in patients with renal impairment or end-stage renal disease (CLcr = 30 mL/min).

The exposure of sacituzumab govitecan-hziy is similar in patients with mild hepatic impairment (bilirubin less than or equal to ULN and AST greater than ULN, or bilirubin greater than 1.0 to less than 1.5 ULN and AST of any level; n=12) to patients with normal hepatic function (bilirubin or AST less than ULN; n=45).

Sacituzumab govitecan-hziy exposure is unknown in patients with moderate or severe hepatic impairment. SN-38 exposure may be elevated in such patients due to decreased hepatic UGT1A1 activity.

Drug Interaction Studies

No drug-drug interaction studies were conducted with sacituzumab govitecan-hziy or its components Inhibitors or inducers of UGT1A1 are expected to increase or decrease SN-38 exposure, respectively.

4. Pharmacogenomics

SN-38 is metabolized via UGT1A1 .                                                                      Genetic variants of the UGT1A1 gene such as the UGT1A1*28 allele lead to reduced UGT1A1 enzyme activity. Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia from TRODELVY 

Approximately 20% of the Black or African American population, 10% of the White population, and 2% of the East Asian population are homozygous for the UGT1A1*28 allele.

Decreased function alleles other than UGT1A1*28 may be present in certain populations.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                               Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman.

There are no available data in pregnant women to inform the drug-associated risk. TRODELVY contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells 

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively.

3. Females and Males of Reproductive Potential -                                        Pregnancy Testing                                                                                                   Verify the pregnancy status of females of reproductive potential prior to the initiation of TRODELVY.

Contraception Females                                                                                   TRODELVY can cause fetal harm when administered to a pregnant woman 

Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose.

Males-                                                                                                                  Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose. Infertility

Females-                                                                                                                Based on findings in animals, TRODELVY may impair fertility in females of reproductive potential.

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

5. Geriatric Use-                                                                                                           Of the patients who received TRODELVY, 19/108 (18%) patients with mTNBC and 144/408 (35%) of all patients were = 65 years old. No overall differences in safety and effectiveness were observed between these patients and younger patients.

6. Hepatic Impairment-                                                                                               No adjustment to the starting dose is required when administering TRODELVY to patients with mild hepatic impairment (bilirubin less than or equal to 1.5 ULN and AST/ALT < 3 ULN).

The exposure of TRODELVY in patients with mild hepatic impairment (bilirubin less than or equal to ULN and AST greater than ULN, or bilirubin greater than 1.0 to 1.5 ULN and AST of any level; n=12) was similar to patients with normal hepatic function (bilirubin or AST less than ULN; n=45).

The safety of TRODELVY in patients with moderate or severe hepatic impairment has not been established.

TRODELVY has not been tested in patients with serum bilirubin > 1.5 ULN, or AST and ALT > 3 ULN, or AST and ALT > 5 ULN and associated with liver metastases.

No dedicated trial was performed to investigate the tolerability of TRODELVY in patients with moderate or severe hepatic impairment.

No recommendations can be made for the starting dose in these patients.

 OVERDOSAGE-                                                                                                            In a clinical trial, planned doses of up to 18 mg/kg (approximately 1.8 times the maximum recommended dose of 10 mg/kg) of TRODELVY were administered. In these patients, a higher incidence of severe neutropenia was observed.