Prescription Drug Information: TRODELVY (Page 2 of 5)

5.3 Hypersensitivity and Infusion-Related Reactions

Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with TRODELVY treatment. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions [see Contraindications (4)].

Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients treated with TRODELVY. Grade 3–4 hypersensitivity occurred in 2% of patients treated with TRODELVY. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.3%. The incidence of anaphylactic reactions was 0.3%.

Premedication for infusion reactions in patients receiving TRODELVY is recommended. Have medications and emergency equipment to treat infusion-related reactions, including anaphylaxis, available for immediate use when administering TRODELVY [see Dosage and Administration (2.2)].

Closely monitor patients for hypersensitivity and infusion-related reactions during each TRODELVY infusion and for at least 30 minutes after completion of each infusion [see Dosage and Administration (2.3)].

Permanently discontinue TRODELVY for Grade 4 infusion-related reactions [see Dosage and Administration (2.3)].

5.4 Nausea and Vomiting

TRODELVY is emetogenic. Nausea occurred in 66% of all patients treated with TRODELVY. Grade 3 nausea occurred in 4% of patients.

Vomiting occurred in 39% of all patients treated with TRODELVY. Grade 3–4 vomiting occurred in 3% of these patients.

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) for prevention of chemotherapy-induced nausea and vomiting (CINV) [see Dosage and Administration (2.2) ].

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 Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity

Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia; and may be at increased risk for other adverse reactions when treated with TRODELVY.

The incidence of neutropenia and anemia was analyzed in 701 patients who received TRODELVY and had UGT1A1 genotype results. In patients homozygous for the UGT1A1 *28 allele (n=87), the incidence of Grade 3–4 neutropenia was 67%. In patients heterozygous for the UGT1A1*28 allele (n=301), the incidence of Grade 3–4 neutropenia was 46%. In patients homozygous for the wild-type allele (n=313), the incidence of Grade 3–4 neutropenia was 46% [see Clinical Pharmacology (12.5)]. In patients homozygous for the UGT1A1 *28 allele, the incidence of Grade 3–4 anemia was 25%. In patients heterozygous for the UGT1A1*28 allele, the incidence of Grade 3–4 anemia was 10%. In patients homozygous for the wild-type allele, the incidence of Grade 3–4 anemia was 11%.

Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 enzyme activity [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:

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 pooled safety population described in the Warnings and Precautions section reflect exposure to TRODELVY as a single agent in 795 patients from three studies, IMMU-132-01, IMMU-132-05 and IMMU-132-06 which included 366 patients with mTNBC who had received prior systemic chemotherapy for advanced disease and 180 patients with mUC. TRODELVY was administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles at doses of 10 mg/kg until disease progression or unacceptable toxicity. Among the 795 patients treated with TRODELVY, the median duration of treatment was 4.1 months (range: 0 to 59 months). In this pooled safety population, the most common (≥ 25%) adverse reactions were neutropenia (61%), nausea (66%), diarrhea (65%), fatigue (62%), alopecia (45%), anemia (42%), vomiting (39%), constipation (37%), decreased appetite (34%), rash (32%) and abdominal pain (28%).

Metastatic Triple-Negative Breast Cancer

ASCENT Study

The safety of TRODELVY was evaluated in a randomized, active-controlled, open-label trial (ASCENT) in patients with mTNBC who had previously received a taxane and at least two prior therapies. Patients were randomized (1:1) to receive either TRODELVY (n=258) or single agent chemotherapy (n=224) and were treated until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. For patients treated with TRODELVY, the median duration of treatment was 4.4 months (range: 0 to 23 months).

Serious adverse reactions occurred in 27% of patients receiving TRODELVY. Serious adverse reactions in > 1% of patients receiving TRODELVY included neutropenia (7%), diarrhea (4%), and pneumonia (3%). Fatal adverse reactions occurred in 1.2% of patients who received TRODELVY, including respiratory failure (0.8%) and pneumonia (0.4%). TRODELVY was permanently discontinued for adverse reactions in 5% of patients. Adverse reactions leading to permanent discontinuation in ≥ 1 % of patients who received TRODELVY were pneumonia (1%) and fatigue (1%).

Adverse reactions leading to a treatment interruption of TRODELVY occurred in 63% of patients. The most frequent (≥5%) adverse reactions leading to a treatment interruption were neutropenia (47%), diarrhea (5%), respiratory infection (5%), and leukopenia (5%).

Adverse reactions leading to a dose reduction of TRODELVY occurred in 22% of patients. The most frequent (>4%) adverse reactions leading to a dose reduction were neutropenia (11%) and diarrhea (5%).

Granulocyte-colony stimulating factor (G-CSF) was used in 44% of patients who received TRODELVY.

Tables 2 and 3 summarize adverse reactions and select laboratory abnormalities, respectively, in the ASCENT study.

Table 2: Adverse Reactions in ≥10% of Patients with mTNBC in ASCENT
TRODELVY (n=258) Single Agent Chemotherapy (n=224)
Adverse Reaction All Grades% Grade 3 – 4% All Grades% Grade 3 – 4%
*Single agent chemotherapy included one of the following single-agents: eribulin (n=139), capecitabine (n=33), gemcitabine (n=38), or vinorelbine (except if patient had ≥Grade 2 neuropathy, n=52).
Graded per NCI CTCAE v.5.0.
*
Including neutropenia and neutrophil count decreased
Including anemia, hemoglobin decreased, and red blood cell count decreased
Including leukopenia and white blood cell count decreased
§
Including lymphopenia and lymphocyte count decreased
Including stomatitis, glossitis, mouth ulceration, and mucosal inflammation
#
Including fatigue and asthenia
Blood and lymphatic system disorders
Neutropenia * 64 52 44 34
Anemia 40 9 28 6
Leukopenia 17 11 12 6
Lymphopenia § 10 2 6 2
Gastrointestinal disorders
Diarrhea 59 11 17 1
Nausea 57 3 26 0.4
Vomiting 33 2 16 1
Constipation 37 0.4 23 0
Abdominal Pain 30 3 12 1
Stomatitis 17 2 13 1
General disorders and administration site conditions
Fatigue # 65 6 50 9
Pyrexia 15 0.4 14 2
Infections and infestation
Urinary tract infection 13 0.4 8 0.4
Upper respiratory tract infection 12 0 3 0
Investigations
Alanine aminotransferase increased 11 1 10 1
Metabolism and nutrition disorders
Decreased appetite 28 2 21 1
Hypokalemia 16 3 13 0.4
Hypomagnesaemia 12 0 6 0
Musculoskeletal and connective tissue disorders
Back pain 16 1 14 2
Arthralgia 12 0.4 7 0
Nervous system disorders
Headache 18 0.8 13 0.4
Dizziness 10 0 7 0
Psychiatric disorders
Insomnia 11 0 5 0
Respiratory, thoracic and mediastinal disorders
Cough 24 0 18 0.4
Skin and subcutaneous tissue disorders
Alopecia 47 0 16 0
Rash 12 0.4 5 0.4
Pruritus 10 0 3 0
Table 3: Select Laboratory Abnormalities in >10% of Patients with mTNBC in ASCENT
Laboratory Abnormality TRODELVY(n=258) Single Agent Chemotherapy(n=224)
All Grades(%) Grade 3 – 4(%) All Grades(%) Grade 3 – 4(%)
Decreased hemoglobin 94 9 57 6
Decreased leukocytes 86 41 53 25
Decreased neutrophils 78 49 48 36
Decreased lymphocytes 88 31 40 24
Decreased platelets 23 1.2 25 2.7

Study IMMU-132-01

The safety of TRODELVY was evaluated in a single-arm, open-label study (IMMU-132-01) in patients with mTNBC and other malignancies, which included 108 patients with mTNBC who had received at least two prior treatments for metastatic disease [see Clinical Studies (14.1)]. 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 median treatment duration in these 108 patients was 5.1 months (range: 0–51 months).

Serious adverse reactions occurred in 31% of the patients. Serious adverse reactions in >1% of patients receiving TRODELVY included 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 permanent discontinuation were anaphylaxis, anorexia/fatigue, headache (each 0.9%). 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 4.

Table 4: 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
*
Including abdominal pain, distention, pain (upper), discomfort, tenderness.
Including stomatitis, esophagitis, and mucosal inflammation
Including fatigue and asthenia.
§
Including edema; and peripheral, localized, and periorbital edema
Including rash; maculopapular, erythematous, generalized rash; dermatitis acneiform; skin disorder, irritation, and exfoliation
#
Including gait disturbance, hypoesthesia, muscular weakness, paresthesia, peripheral and sensory neuropathy
Þ
Including lower and upper respiratory tract infection, pneumonia, influenza, viral upper respiratory infection, bronchitis and respiratory syncytial virus infection
ß
Includes cough and productive cough
à
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 pain * 26 1
Mucositis 14 1
General disorders and administration site conditions 77 9
Fatigue 57 8
Edema § 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
Rash 31 3
Pruritus 17 0
Dry Skin 15 0
Nervous system disorders 56 4
Headache 23 1
Dizziness 22 0
Neuropathy # 24 0
Dysgeusia 11 0
Infections and infestations 55 12
Urinary Tract Infection 21 3
Respiratory Infection Þ 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
Cough ß 22 0
Dyspnea à 21 3
Psychiatric disorders 26 1
Insomnia 13 0
Table 5: 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

Locally Advanced or Metastatic Urothelial Cancer

Study IMMU-132-06

The safety of TRODELVY was evaluated in a single-arm, open-label study (IMMU-132-06) in patients (n=113) with mUC who had received previous platinum-based and anti-PD-1/PD-L1 therapy. TRODELVY was administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles at doses of 10 mg/kg until disease progression or unacceptable toxicity. (see Clinical Studies 14.2)

Serious adverse reactions occurred in 44% of patients. Serious adverse reactions in >1% of patients receiving TRODELVY included infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), sepsis or bacteremia (5%), diarrhea (4%), anemia, venous thromboembolism, and small intestinal obstruction (3% each), pneumonia, abdominal pain, pyrexia, and thrombocytopenia (2% each). Fatal adverse reactions occurred in 3.6% of patients, including sepsis, respiratory failure, epistaxis, and completed suicide.

TRODELVY was permanently discontinued for adverse reactions in 10% of patients. The most frequent adverse reaction leading to permanent discontinuation of study drug was neutropenia (4%, including febrile neutropenia in 2%). Adverse reactions leading to dose interruption occurred in 52% of patients. The most common adverse reactions leading to dose interruption were neutropenia (27%, including febrile neutropenia in 2%), infection (12%), and acute kidney injury (8%). Adverse reactions leading to a dose reduction of TRODELVY occurred in 42% of patients. The most common (>4%) adverse reactions leading to a dose reduction were neutropenia (13%, including febrile neutropenia in 3%), diarrhea (11%), fatigue (8%), and infection (4%). Granulocyte-colony stimulating factor (G-CSF) was used in 47% of patients who received TRODELVY.

The most common adverse reactions (incidence ≥25%) were: diarrhea, fatigue, neutropenia, nausea, alopecia, anemia, decreased appetite, constipation, vomiting, and abdominal pain.

Table 6: Adverse Reactions Reported in ≥15% (Grade 1–4) or ≥5% (Grade ≥3) of Patients Treated with TRODELVY in IMMU-132-06
Adverse Reaction TRODELVYn=113
Grade 1–4% Grade 3–4%
*
Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain
Includes fatigue and asthenia
Includes edema genital, edema peripheral, peripheral swelling
§
Includes dermatitis acneiform, dermatitis bullous, erythema, lichen planus, photosensitivity reaction, pruritus, pruritus generalised, rash, rash macular, rash maculo-papular, rash pruritic, skin papilloma, skin toxicity
Includes failure to thrive and weight decreased
#
Includes acute kidney injury, blood creatinine increased, nephropathy toxic, renal failure, renal impairment
Þ
Includes bacteremia, body tinea, bronchitis, candida infection, cellulitis, clostridium difficile infection, corona virus infection, device related infection, diverticulitis, escherichia bacteremia, escherichia pyelonephritis, folliculitis, gastroenteritis, gastroenteritis escherichia coli, herpes zoster, kidney infection, klebsiella sepsis, lung infection, nasopharyngitis, oral candidiasis, oral herpes, pneumonia, pyelonephritis, pyelonephritis acute, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, tooth abscess, upper respiratory tract infection, urinary tract infection, urosepsis, vascular device infection, viral infection, viral pharyngitis, vulvovaginal mycotic infection
ß
Includes cough, productive cough, upper-airway cough syndrome
à
Includes deep vein thrombosis, embolism, and pulmonary embolism
Any 94 80
Gastrointestinal disorders
Diarrhea 72 12
Nausea 66 4
Constipation 34 1
Vomiting 34 1
Abdominal pain * 31 2
General disorders and administration site conditions
Fatigue 68 5
Pyrexia 19 0
Edema 17 2
Skin and subcutaneous tissue disorders
Alopecia 49 0
Rash § 32 2
Metabolism and nutrition disorders
Decreased appetite 41 3
Weight loss 17 2
Renal and urinary disorders
Acute kidney injury # 24 7
Hematuria 16 1
Infections and infestations
Any infection Þ 50 25
Urinary tract infection 19 12
Respiratory, thoracic and mediastinal disorders
Cough ß 17 0
Dyspnea 16 0
Musculoskeletal
Back pain 16 0
Vascular disorders
Venous thromboembolism à 9 6

Other clinically significant adverse reactions (≤15%) include: peripheral neuropathy (12%), sepsis or bacteremia (9%), and pneumonia (4%).

Table 7: Selected Laboratory Abnormalities Reported in ≥ 20% (Any Grade) or ≥ 5% (Grade 3–4) of Patients Treated with TRODELVY in IMMU-132-06
Adverse Reaction TRODELVYn = 113
Any Grade *% Grade 3–4*%
*
Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available (range: 66 to 111 patients).
Hematology
Leukocytes decreased 78 38
Lymphocytes decreased 71 35
Hemoglobin decreased 71 18
Neutrophils decreased 67 43
Platelets decreased 25 2
Chemistry
Glucose increased 59 8
Albumin decreased 51 4
Calcium decreased 46 9
Sodium decreased 43 1
Phosphate decreased 41 15
Alkaline phosphatase increased 36 0
Creatinine increased 32 5
Magnesium decreased 31 2
Alanine aminotransferase increased 28 2
Lactate dehydrogenase increased 28 0
Potassium decreased 27 0
Aspartate aminotransferase increased 26 2
Coagulation
Activated partial thromboplastin time increased 33 6

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