Tivdak Drug Information

® is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TIVDAK is a tissue factor-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

• The following serious adverse reactions are described elsewhere in the labeling:
• Ocular Adverse Reactions [see Boxed Warning , Warnings and Precautions (5.1) ]
• Peripheral Neuropathy [see Warnings and Precautions (5.2) ]
• Hemorrhage [see Warnings and Precautions (5.3) ]
• Pneumonitis [see Warnings and Precautions (5.4) ]
• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, peripheral neuropathy, conjunctival adverse reactions, nausea, fatigue, aspartate aminotransferase increased, epistaxis, alopecia, alanine aminotransferase increased, and hemorrhage. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Seagen Inc. at 1-855-4SEAGEN or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 practice. The data in the WARNINGS AND PRECAUTIONS section reflect exposure to TIVDAK in 425 patients with recurrent or metastatic cervical cancer who received at least one dose of TIVDAK at 2 mg/kg intravenously every 3 weeks in innovaTV 301, innovaTV 204, innovaTV 201 (NCT02001623), innovaTV 202 (NCT02552121), innovaTV 203 (NCT03245736), and innovaTV 206 (NCT03913741). The median duration of treatment with TIVDAK was 3.7 months (range: 0.4-40.2). In this pooled safety population, the most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (45%), peripheral neuropathy (39%), conjunctival adverse reactions (38%), nausea (37%), fatigue (36%), aspartate aminotransferase increased (33%), epistaxis (33%), alopecia (31%), alanine aminotransferase increased (30%), and hemorrhage (28%). The data described in this section reflect exposure to TIVDAK from innovaTV 301 and innovaTV 204. innovaTV 301 The safety of TIVDAK was evaluated in an open-label, randomized study in patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy [see Clinical Studies (14.1) ]. A total of 250 patients received TIVDAK 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment with TIVDAK was 3.7 months (range: 0.4-19). Serious adverse reactions occurred in 33% of patients receiving TIVDAK. The most common (≥2%) serious adverse reactions were urinary tract infection (4.8%), small intestinal obstruction (2.4%), sepsis (2%), abdominal pain (2%), and hemorrhage (2%). Fatal adverse reactions occurred in 1.6% of patients who received TIVDAK, including acute kidney injury (0.4%), pneumonia (0.4%), sepsis (0.4%) and Stevens-Johnson syndrome (0.4%). Adverse reactions leading to permanent discontinuation occurred in 15% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to permanent discontinuation were peripheral neuropathy (6%) and ocular adverse reactions (6%). Adverse reactions leading to dose interruption occurred in 39% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to dose interruption were ocular adverse reactions (16%) and peripheral neuropathy (6%). Adverse reactions leading to dose reduction occurred in 30% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to dose reduction were peripheral neuropathy (10%) and ocular adverse reactions (10%). The ocular adverse reactions included conjunctival disorders (4.8%), keratopathy (4%), and dry eye (0.8%). The most common (≥25%) adverse reactions, including laboratory abnormalities, in patients receiving TIVDAK were hemoglobin decreased, peripheral neuropathy, conjunctival adverse reactions, aspartate aminotransferase increased, nausea, alanine aminotransferase increased, fatigue, sodium decreased, epistaxis, and constipation. Table 4 summarizes the all grade and Grade 3-4 adverse reactions from innovaTV 301. Table 4: Adverse Reactions (≥10%) in Patients Who Received TIVDAK in innovaTV 301 Adverse Reaction TIVDAK N=250 Chemotherapy N=239 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Nervous system disorders Peripheral neuropathy Peripheral neuropathy includes peripheral sensory neuropathy, paresthesia, muscular weakness, peripheral sensorimotor neuropathy, peripheral motor neuropathy, neurotoxicity, gait disturbance, neuralgia, hypoaesthesia, neuropathy peripheral, and skin burning sensation 38 6 4.2 0.4 Eye disorders Conjunctival adverse reactions Conjunctival adverse reactions includes conjunctivitis, conjunctivitis bacterial, conjunctivitis viral, episcleritis, ocular hyperemia, conjunctival hemorrhage, conjunctival hyperemia, conjunctival ulcer, conjunctivitis allergic, conjunctival disorder, symblepharon, conjunctival erosion, conjunctival oedema, conjunctivochalasis, and conjunctival scar 37 0 1.7 0 Corneal adverse reactions Corneal adverse reactions includes keratitis, punctate keratitis, corneal erosion, ulcerative keratitis, corneal degeneration, corneal opacity, and keratopathy 21 3.2 0 0 Dry eye Dry eye includes dry eye, eye discharge, eye pruritus, eye pain, eye irritation, and lacrimation increased 21 0 1.7 0 Gastrointestinal disorders Nausea Nausea includes nausea and retching 33 0.4 40 2.1 Constipation 25 1.2 16 0 Diarrhea Diarrhea includes diarrhea and gastroenteritis 22 1.6 15 1.3 Abdominal Pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower 18 4 15 2.5 Vomiting 18 1.6 18 1.3 General Fatigue Fatigue includes fatigue and asthenia 28 6 32 6 Pyrexia 17 0.4 21 0.8 Pruritus 10 0.4 2.9 0 Vascular disorders Epistaxis 26 0 2.5 0 Hemorrhage Hemorrhage includes hematuria, vaginal hemorrhage, rectal hemorrhage, hemoptysis, anal hemorrhage, hemorrhage, gastrointestinal hemorrhage, hemorrhagic shock, lower gastrointestinal hemorrhage, gingival bleeding, tumor hemorrhage, intra-abdominal hemorrhage, gastric hemorrhage, genital hemorrhage, uterine hemorrhage, urinary tract hemorrhage, hemorrhoidal hemorrhage 21 2 11 2.5 Metabolism and nutrition disorders Decreased appetite 24 0.8 18 0.4 Decreased weight 10 0.4 5 0 Skin and subcutaneous tissue disorders Alopecia 24 0 2.9 0 Rash Rash includes rash maculo-papular, eczema, rash macular, rash pustular, dermatitis acneiform, erythema, rash, urticaria, dermatitis, and rash erythematous 17 1.6 16 1.3 Infections Urinary tract infection Urinary tract infection includes urinary tract infection, pyelonephritis acute, cystitis, and urinary tract infection bacterial 16 5 18 8 Clinically relevant adverse reactions in <10% of patients who received TIVDAK in innovaTV 301 include periorbital adverse reactions (9%) and intestinal obstruction (4.4%, including small bowel, large bowel, and malignant gastrointestinal obstruction). Table 5 summarizes the laboratory abnormalities in innovaTV 301. Table 5: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline In Patients Who Received TIVDAK in innovaTV 301 TIVDAK The denominator used to calculate the rate varied from 206 to 244 based on the number of patients with a baseline value and at least one post-treatment value. Chemotherapy All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3-4 (%) Hematology Hemoglobin decreased 41 7 70 23 Neutrophils decreased 16 3.3 39 17 Chemistry Aspartate aminotransferase increased 34 2.5 32 0.4 Alanine aminotransferase increased 30 3.3 35 2.6 Sodium decreased 27 0.4 27 0.4 Creatinine increased 23 2 26 2.2 Coagulation Activated partial thromboplastin time prolonged 16 1.9 17 0.5 innovaTV 204 The safety of TIVDAK was evaluated in a single arm study in patients (n=101) with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.1) ]. Patients received TIVDAK 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7-16). Serious adverse reactions occurred in 43% of patients. The most common (≥3%) serious adverse reactions were ileus (6%), hemorrhage (5%), pneumonia (4%), peripheral neuropathy, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock (1%), pneumonitis (1%), sudden death (1%), and multisystem organ failure (1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to permanent discontinuation were peripheral neuropathy (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most (≥3%) common adverse reactions leading to dose interruption were peripheral neuropathy (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) adverse reactions leading to dose reduction were conjunctival adverse reactions (9%) and corneal adverse reactions (8%). The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash. Table 6 summarizes the all grade and Grade 3-4 adverse reactions from innovaTV 204. Table 6: Adverse Reactions (≥10%) in Patients Who Received TIVDAK in innovaTV 204 Adverse Reaction TIVDAK N=101 All Grades % Grade 3-4 % General Fatigue Fatigue includes fatigue and asthenia 50 7 Pyrexia 16 1 Pruritus 13 1 Gastrointestinal disorders Nausea Nausea includes nausea and retching 41 0 Diarrhea Diarrhea includes diarrhea, gastroenteritis, and colitis 25 2 Constipation 23 2 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal distention and abdominal discomfort 23 1 Vomiting 17 2 Nervous system disorders Peripheral neuropathy Peripheral neuropathy includes neuropathy peripheral, peripheral sensorimotor neuropathy, polyneuropathy, peripheral sensory neuropathy, paresthesia, hypoesthesia, burning sensation, neuralgia, sensory loss, peripheral motor neuropathy, muscular weakness, gait disturbance, and hyperesthesia 39 7 Skin and subcutaneous tissue disorders Alopecia 39 0 Rash Rash includes rash, rash maculo-papular, rash macular, dermatitis acneiform, dermatitis allergic, and erythema 25 0 Vascular disorders Epistaxis 39 0 Hemorrhage Hemorrhage includes vaginal hemorrhage, hematuria, rectal hemorrhage, cystitis hemorrhagic, lower gastrointestinal hemorrhage, urinary bladder hemorrhage, hematochezia, anal hemorrhage, gingival bleeding, post procedural hemorrhage, radiation associated with hemorrhage, metrorrhagia, large intestinal hemorrhage, paranasal sinus hemorrhage, and hemoptysis 32 6 Eye disorders Conjunctival adverse reactions Conjunctival adverse reactions includes conjunctivitis, conjunctival abrasion, conjunctival erosion, conjunctival hyperemia, conjunctival scar, noninfective conjunctivitis, ocular hyperemia, and conjunctival hemorrhage 37 0 Dry eye Dry eye includes dry eye and lacrimation increased 29 0 Corneal adverse reactions Corneal adverse reactions includes keratitis, punctate keratitis, ulcerative keratitis, corneal erosion, corneal scar, keratopathy, and corneal bleeding 21 3 Periorbital adverse reactions Periorbital adverse reactions includes blepharitis, meibomianitis, eye pruritus, entropion, trichiasis, chalazion, and meibomian gland dysfunction 16 0 Musculoskeletal and connective tissue disorders Myalgia Myalgia includes myalgia, musculoskeletal discomfort, and musculoskeletal pain 21 0 Arthralgia 16 0 Pain in extremity Pain in extremity includes pain in extremity and limb discomfort 13 1 Metabolism and nutrition disorders Decreased appetite 16 1 Infections Urinary tract infection Urinary tract infection includes urinary tract infection, urinary tract infection bacterial, and cystitis 14 2 Investigations Weight decreased 12 0 Clinically relevant adverse reactions in <10% of patients who received TIVDAK in innovaTV 204 included venous thrombosis (3%), pulmonary embolism (3%), and pneumonitis (2%). Table 7 summarizes the laboratory abnormalities in innovaTV 204. Table 7: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline In Patients Who Received TIVDAK in innovaTV 204 Laboratory Abnormality TIVDAK The denominator used to calculate the rate varied from 96 to 101 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Hemoglobin decreased 52 7 Neutrophils decreased 21 3 Chemistry Creatinine increased 29 4.1 Alanine aminotransferase increased 24 0 Aspartate aminotransferase increased 18 0 Sodium decreased 20 0 Alkaline phosphatase increased 17 0 Creatinine kinase increased 16 2.1 Magnesium decreased 17 2.1 Coagulation Prothrombin international normalized ratio increased 26 0 Activated partial thromboplastin time prolonged 26 2

Effects of Other Drugs on

TIVDAK Strong CYP3A4 Inhibitors MMAE is a CYP3A4 substrate. Concomitant use of TIVDAK with strong CYP3A4 inhibitors may increase unconjugated MMAE exposure , which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for adverse reactions of TIVDAK when used concomitantly with strong CYP3A4 inhibitors.

Pregnancy Risk Summary Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman . There are no available human data on TIVDAK use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of the small molecule component of TIVDAK, MMAE, to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at exposures below the clinical exposure at the recommended dose (see Data ). Advise patients of the potential risk to a fetus. The 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. Data Animal Data No embryo-fetal development studies in animals have been performed with tisotumab vedotin-tftv. In an embryo-fetal development study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of TIVDAK, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve at the recommended dose).

Pediatric Use Safety and effectiveness of TIVDAK in pediatric patients have not been established. Nonclinical studies of tisotumab vedotin-tftv suggest a lack of anti-tumor activity and penetrance to brain based on limited in vivo data from tissue factor (TF)-expressing subcutaneous or orthotopic pediatric models of high‑grade gliomas/glioblastomas (HGG/GBM) and diffuse intrinsic pontine glioma (DIPG).