TRODELVY: Package Insert and Label Information

TRODELVY- sacituzumab govitecan powder, for solution
Immunomedics, Inc.

WARNING: NEUTROPENIA AND DIARRHEA

  • Severe neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm 3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patient with febrile neutropenia without delay [see Warnings and Precautions (5.1)].
  • Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide [see Warnings and Precautions (5.2)]. If severe diarrhea occurs, withhold TRODELVY until resolved to < Grade 1 and reduce subsequent doses [see Dosage and Administration (2.3)].

1 INDICATIONS AND USAGE

TRODELVY is indicated for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease.

This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

2 DOSAGE AND ADMINISTRATION

2.1 Important Use Information

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

2.2 Recommended Dose and Schedule

The recommended dose of TRODELVY is 10 mg/kg administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles. Continue treatment until disease progression or unacceptable toxicity. Do not administer TRODELVY at doses greater than 10 mg/kg.

Administer TRODELVY as an intravenous infusion only. Do not administer as an intravenous push or bolus.

First infusion: Administer infusion over 3 hours. Observe patients during the infusion and for at least 30 minutes following the initial dose, for signs or symptoms of infusion-related reactions [see Warning and Precautions (5.3)].

Subsequent infusions: Administer infusion over 1 to 2 hours if prior infusions were tolerated. Observe patients during the infusion and for at least 30 minutes after infusion.

Premedication

Prior to each dose of TRODELVY, premedication for prevention of infusion reactions and prevention of chemotherapy-induced nausea and vomiting (CINV) is recommended.

  • Premedicate with antipyretics, H1 and H2 blockers prior to infusion, and corticosteroids may be used for patients who had prior infusion reactions.
  • Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist, as well as other drugs as indicated).

2.3 Dose Modifications for Adverse Reactions

Infusion-related Reactions

Slow or interrupt the infusion rate of TRODELVY if the patient develops an infusion-related reaction. Permanently discontinue TRODELVY for life-threatening infusion-related reactions [see Warnings and Precautions (5.3)]

Dose Modifications for Adverse Reactions

Withhold or discontinue TRODELVY to manage adverse reactions as described in Table 1. Do not re-escalate the TRODELVY dose after a dose reduction for adverse reactions has been made.

Table 1: Dose Modifications for Adverse Reactions
Adverse Reaction Occurrence Dose Modification
Severe Neutropenia [see Warnings and Precautions (5.1)]
Grade 4 neutropenia ≥7 days,ORGrade 3 febrile neutropenia (absolute neutrophil count <1000/mm3 and fever ≥38.5°C),ORAt time of scheduled treatment, Grade 3-4 neutropenia which delays dosing by 2 or 3 weeks for recovery to ≤ Grade 1 First 25% dose reduction and administer granulocyte-colony stimulating factor (G-CSF)
Second 50% dose reduction
Third Discontinue Treatment
At time of scheduled treatment, Grade 3-4 neutropenia which delays dosing beyond 3 weeks for recovery to ≤ Grade 1 First Discontinue treatment
Severe Non-Neutropenic Toxicity
Grade 4 non-hematologic toxicity of any duration,ORAny Grade 3-4 nausea, vomiting or diarrhea due to treatment that is not controlled with antiemetics and anti-diarrheal agents [see Warnings and Precautions (5.2, 5.4)],OROther Grade 3-4 non-hematologic toxicity persisting >48 hours despite optimal medical management,ORAt time of scheduled treatment, Grade 3-4 non-neutropenic hematologic or non-hematologic toxicity, which delays dose by 2 or 3 weeks for recovery to ≤ Grade 1 First 25% dose reduction
Second 50% dose reduction
Third Discontinue treatment
In the event of Grade 3-4 non-neutropenic hematologic or non-hematologic toxicity, which does not recover to ≤ Grade 1 within 3 weeks First Discontinue treatment

2.4 Preparation for Administration

Reconstitution

  • TRODELVY is a cytotoxic drug.
  • Follow applicable special handling and disposal procedures1.
  • Calculate the required dose (mg) of TRODELVY based on the patient’s body weight at the beginning of each treatment cycle (or more frequently if the patient’s body weight changed by more than 10% since the previous administration) [see Dosage and Administration (2.1)].
  • Allow the required number of vials to warm to room temperature.
  • Using a sterile syringe, slowly inject 20 mL of 0.9% Sodium Chloride Injection, USP, into each 180 mg TRODELVY vial. The resulting concentration will be 10 mg/mL.
  • Gently swirl vials and allow to dissolve for up to 15 minutes. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be free of visible particulates, clear and yellow. Do not use the reconstituted solution if it is cloudy or discolored.
  • Use immediately to prepare a diluted TRODELVY infusion solution.

Dilution

  • Calculate the required volume of the reconstituted TRODELVY solution needed to obtain the appropriate dose according to patient’s body weight. Withdraw this amount from the vial(s) using a syringe. Discard any unused portion remaining in the vial(s).
  • Slowly inject the required volume of reconstituted TRODELVY solution into a polypropylene (PP) infusion bag, to minimize foaming. Do not shake the contents.
  • Adjust the volume in the infusion bag as needed with 0.9% Sodium Chloride Injection, USP, to obtain a concentration of 1.1 mg/mL to 3.4 mg/mL (total volume should not exceed 500 mL). For patients whose body weight exceeds 170 kg, divide the total dosage of TRODELVY equally between two 500 mL infusion bags and infuse sequentially via slow infusion.
  • Only 0.9% Sodium Chloride Injection, USP, should be used since the stability of the reconstituted product has not been determined with other infusion-based solutions. Use the diluted solution in the infusion bag immediately. If not used immediately, the infusion bag containing TRODELVY solution can be stored refrigerated 2°C to 8°C (36°F to 46°F) for up to 4 hours. After refrigeration, administer diluted solution within 4 hours (including infusion time).

Do Not Freeze or Shake. Protect from Light.

Administration

  • Administer TRODELVY as an intravenous infusion. Protect infusion bag from light.
  • An infusion pump may be used.
  • Do not mix TRODELVY, or administer as an infusion, with other medicinal products.
  • Upon completion of the infusion, flush the intravenous line with 20 mL 0.9% Sodium Chloride Injection, USP.

3 DOSAGE FORMS AND STRENGTHS

For injection: 180 mg off-white to yellowish lyophilized powder in a single-dose vial.

4 CONTRAINDICATIONS

TRODELVY is contraindicated in patients who have experienced a severe hypersensitivity reaction to TRODELVY [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Neutropenia

TRODELVY can cause severe or life-threatening neutropenia. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Dose modifications may be required due to neutropenia [see Dosage and Administration (2.3)].

Febrile neutropenia occurred in 6% (24/408) patients treated with TRODELVY, including 8% (9/108) patients with mTNBC after at least two prior therapies. Less than 1% (1/408) of patients had febrile neutropenia leading to permanent discontinuation.

The incidence of Grade 1-4 neutropenia was 64% in patients with mTNBC (n=108). In all patients treated with TRODELVY (n=408), the incidence of Grade1-4 neutropenia was 54%; Grade 4 neutropenia occurred in 13%. Less than 1% (2/408) of patients permanently discontinued treatment due to neutropenia.

5.2 Diarrhea

TRODELVY can cause severe diarrhea. Withhold TRODELVY for Grade 3-4 diarrhea at the time of scheduled treatment administration and resume when resolved to ≤ Grade 1 [see Dosage and Administration (2.3) ].

At the onset of diarrhea, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated.

Patients who exhibit an excessive cholinergic response to treatment with TRODELVY (e.g., abdominal cramping, diarrhea, salivation, etc.) can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Diarrhea occurred in 63% (68/108) of patients with mTNBC and 62% (254/408) of all patients treated with TRODELVY. In each population, events of Grade 3-4 occurred in 9% (10/108) of mTNBC patients and 9% (36/408) of all patients treated with TRODELVY. Four out of 408 patients (<1%) discontinued treatment because of diarrhea. Neutropenic colitis was observed in 2% (2/108) of patients in the mTNBC cohort and 1% of all patients treated with TRODELVY.

5.3 Hypersensitivity

TRODELVY can cause severe and life-threatening hypersensitivity. Anaphylactic reactions have been observed in clinical trials with TRODELVY.

Hypersensitivity reactions within 24 hours of dosing occurred in 37% (151/408) of patient treated with TRODELVY. Grade 3-4 hypersensitivity occurred in 1% (6/408) of patients treated with TRODELVY. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 1% (3/408).

Pre-infusion medication for patients receiving TRODELVY is recommended. Observe patients closely for infusion-related reactions during each TRODELVY infusion and for at least 30 minutes after completion of each infusion [see Dosage and Administration (2.3)]. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use.

5.4 Nausea and Vomiting

TRODELVY is emetogenic. Nausea occurred in 69% (74/108) of patients with mTNBC and 69% (281/408) of all patients treated with TRODELVY. Grade 3 nausea occurred in 6% (7/108) and 5% (22/408) of these populations, respectively.

Vomiting occurred in 49% (53/108) of patients with mTNBC and 45% (183/408) of all patients treated with TRODELVY. Grade 3 vomiting occurred in 6% (7/108) and 4% (16/408) of these patients, respectively.

Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK-1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV).

Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment administration and resume with additional supportive measures when resolved to Grade ≤ 1 [see Dosage and Administration (2.3)].

Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

5.5 Use in 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 and may be at increased risk for other adverse reactions following initiation of TRODELVY treatment.

In 84% (343/408) of patients who received TRODELVY (up to 10 mg/kg on Days 1 and 8 of a 21-day cycle) and had retrospective UGT1A1 genotype results available, the incidence of Grade 4 neutropenia was 26% (10/39) in patients homozygous for the UGT1A1*28 allele, 13% (20/155) in patients heterozygous for the UGT1A1*28 allele and 11% (16/149) in patients homozygous for the wild-type allele [see Clinical Pharmacology (12.5)].

Closely monitor patients with reduced UGT1A1 activity for severe neutropenia. The appropriate dose for patients who are homozygous for UGT1A1*28 is not known and should be considered based on individual patient tolerance to treatment [see Dosage and Administration (2.3)].

5.6 Embryo-Fetal Toxicity

Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. 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 [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

  • Neutropenia [see Warnings and Precautions (5.1)]
  • Diarrhea [see Warnings and Precautions (5.2)]
  • Hypersensitivity [see Warnings and Precautions (5.3)]
  • Nausea and Vomiting [see Warnings and Precautions (5.4)]

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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described in the Warnings and Precautions section reflect exposure to TRODELVY as a single agent in a single-arm, open-label study (IMMU-132-01) in 408 patients with mTNBC and other malignancies who had received prior systemic therapeutic regimen for advanced disease. TRODELVY was administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles at doses up to 10 mg/kg until disease progression or unacceptable toxicity.

The data in Table 2 reflect exposure to TRODELVY in a subset of 108 patients with mTNBC who had received at least two prior treatments for metastatic disease in study (IMMU-132-01). Patients received TRODELVY 10 mg/kg via intravenous infusion on Days 1 and 8 of 21-day treatment cycles until disease progression or unacceptable toxicity. The median treatment duration in these 108 patients was 5.1 months (range: 0-51 months).

Serious adverse reactions were reported in 31% of the patients. The most frequent serious adverse reactions (reported in >1%) of the patients receiving TRODELVY were febrile neutropenia (6%) vomiting (5%), nausea (3%), dyspnea (3%), diarrhea (4%), anemia (2%), pleural effusion, neutropenia, pneumonia, dehydration (each 2%).

TRODELVY was permanently discontinued for adverse reactions in 2% of patients. Adverse reactions leading to discontinuation were anaphylaxis, anorexia/fatigue, headache (each <1%, 1 patient for each event). Forty- five percent (45%) of patients experienced an adverse reaction leading to treatment interruption. The most common adverse reaction leading to treatment interruption was neutropenia (33%). Adverse reactions leading to dose reduction occurred in 33% of patients treated with TRODELVY, with 24% having one dose reduction and 9% with two dose reductions. The most common adverse reaction leading to dose reductions was neutropenia/febrile neutropenia.

Adverse reactions occurring in ≥10% of patients with mTNBC in the IMMU-132-01 study are summarized in Table 2.

Table 2: Adverse Reactions in ≥ 10% of Patients with mTNBC in IMMU-132-01
Adverse Reaction TRODELVY (n=108)
Grade 1-4(%) Grade 3-4(%)

Graded per NCI CTCAE v. 4.0

i. Including abdominal pain, distention, pain (upper), discomfort, tenderness

ii Including stomatitis, esophagitis, and mucosal inflammation

iii Including fatigue and asthenia

iv Including edema; and peripheral, localized, and periorbital edema

v Including rash; maculopapular, erythematous, generalized rash; dermatitis acneiform; skin disorder, irritation, and exfoliation

vi Including gait disturbance, hypoesthesia, muscular weakness, paresthesia, peripheral and sensory neuropathy

vii Including lower and upper respiratory tract infection, pneumonia, influenza, viral upper respiratory infection, bronchitis and respiratory syncytial virus infection

viii Includes cough and productive cough

ix Includes dyspnea and exertional dyspnea

Any adverse reaction 100 71
Gastrointestinal disorders 95 21
Nausea 69 6
Diarrhea 63 9
Vomiting 49 6
Constipation 34 1
Abdominal paini 26 1
Mucositisii 14 1
General disorders and administration site conditions 77 9
Fatigueiii 57 8
Edemaiv 19 0
Pyrexia 14 0
Blood and lymphatic system disorders 74 37
Neutropenia 64 43
Anemia 52 12
Thrombocytopenia 14 3
Metabolism and nutrition disorders 68 22
Decreased appetite 30 1
Hyperglycemia 24 4
Hypomagnesemia 21 1
Hypokalemia 19 2
Hypophosphatemia 16 9
Dehydration 13 5
Skin and subcutaneous tissue disorders 63 4
Alopecia 38 0
Rashv 31 3
Pruritus 17 0
Dry Skin 15 0
Nervous system disorders 56 4
Headache 23 1
Dizziness 22 0
Neuropathyvi 24 0
Dysgeusia 11 0
Infections and infestations 55 12
Urinary Tract Infection 21 3
Respiratory Infectionvii 26 3
Musculoskeletal and connective tissue disorders 54 1
Back pain 23 0
Arthralgia 17 0
Pain in extremity 11 0
Respiratory, thoracic and mediastinal disorders 54 5
Coughviii 22 0
Dyspneaix 21 3
Psychiatric disorders 26 1
Insomnia 13 0
Table 3: Laboratory Abnormalities observed in >10% of Patients while receiving TRODELVY
Laboratory Abnormality TRODELVY (n=108)
All Grades (%) Grade 3-4 (%)
Hematology
Decreased hemoglobin 93 6
Decreased leukocytes 91 26
Decreased neutrophils 82 32
Increased activated partial thromboplastin time 60 12
Decreased platelets 30 3
Chemistry
Increased alkaline phosphatase 57 2
Decreased magnesium 51 3
Decreased calcium 49 3
Increased glucose 48 3
Increased aspartate aminotransferase 45 3
Decreased albumin 39 1
Increased alanine aminotransferase 35 2
Decreased potassium 30 3
Decreased phosphate 29 5
Decreased sodium 25 4.7
Increased magnesium 24 4
Decreased glucose 19 2
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