TIVDAK

1 INDICATIONS AND USAGE TIVDAK ® 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. ( 1 )

2 DOSAGE AND ADMINISTRATION • For intravenous infusion only. Do not administer TIVDAK as an intravenous push or bolus. Do not mix with, or administer as an infusion with, other medicinal products. ( 2.4 ) • The recommended dose of TIVDAK is 2 mg/kg (up to a maximum of 200 mg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. ( 2.1 ) 2.1 Recommended Dosage The recommended dose of TIVDAK is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. 2.2 Premedication and Required Eye Care Adhere to the following recommendations to reduce the risk of ocular adverse reactions [see Warnings and Precautions (5.1) ]. • Ophthalmic exam by eye care provider: Conduct an ophthalmic exam prior to initiation of TIVDAK, prior to every cycle for the first nine cycles, and as clinically indicated. The ophthalmic exam should include visual acuity, slit lamp exam of the anterior segment of the eye, and an assessment of normal eye movement. • Topical corticosteroid eye drops: Instruct patients to administer one drop in each eye prior to each infusion and to continue to administer eye drops in each eye three times daily for 72 hours after each infusion. The initial prescription and all renewals of any corticosteroid medication should be made only after examination with a slit lamp. • Topical ocular vasoconstrictor drops: Administer in each eye immediately prior to each infusion of TIVDAK. • Cold packs: Use cooling eye pads during each infusion of TIVDAK. • Topical lubricating eye drops: Instruct patients to administer for the duration of therapy and for 30 days after the last dose of TIVDAK. • Contact lenses: Advise patients to avoid wearing contact lenses for the entire duration of therapy unless advised by their eye care provider. 2.3 Dosage Modifications for Adverse Reactions The recommended TIVDAK dose reduction schedule is provided in Table 1 . Table 1: Dosage Reduction Schedule TIVDAK Dose Level Starting dose 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) First dose reduction 1.3 mg/kg (up to a maximum of 130 mg for patients ≥100 kg) Second dose reduction 0.9 mg/kg Permanently discontinue in patients who cannot tolerate 0.9 mg/kg (up to a maximum of 90 mg for patients ≥100 kg) The recommended dose modifications for adverse reactions are provided in Table 2 . Table 2: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Occurrence TIVDAK Dose Modification Keratitis Refer patients to an eye care provider promptly for an assessment of new or worsening ocular symptoms. [see Warnings and Precautions (5.1) ] Nonconfluent superficial keratitis Any Monitor. Confluent superficial keratitis, a corneal epithelial defect, or a 3 line or more loss in best corrected visual acuity First occurrence Withhold dose until resolution, or improvement to nonconfluent superficial keratitis, then resume treatment at the next lower dose level. Second occurrence Permanently discontinue. Ulcerative keratitis or perforation Any Permanently discontinue. Conjunctival or corneal scarring or symblepharon [see Warnings and Precautions (5.1) ] Any scarring or symblepharon Any Permanently discontinue. Conjunctivitis and other ocular adverse reactions [see Warnings and Precautions (5.1) ] Nonconfluent superficial punctate conjunctival defects, mild vasodilation Any Monitor. Confluent superficial punctate conjunctival defects, moderate to severe vasodilation First occurrence Withhold dose until resolution or improvement to nonconfluent superficial punctate conjunctival defects, mild vasodilation, then resume treatment at the same dose. Second occurrence Withhold dose until resolution or improvement to nonconfluent superficial punctate conjunctival defects, mild vasodilation, then resume treatment at the next lower dose level. If no resolution or improvement to nonconfluent superficial punctate conjunctival defects, mild vasodilation, permanently discontinue. Third occurrence Permanently discontinue. Conjunctival ulcer, conjunctival neovascularization, or fibrovascular scarring Any Permanently discontinue. Peripheral Neuropathy [see Warnings and Precautions (5.2) ] Grade 2 Any (initial or worsening of pre-existing condition) Withhold dose until Grade ≤1, then resume treatment at the next lower dose level. Grade 3 or 4 Any Permanently discontinue. Hemorrhage [see Warnings and Precautions (5.3) ] Any grade pulmonary or CNS Any Permanently discontinue. Grade 2 in any other location Any Withhold until resolved, then resume treatment at the same dose. Grade 3 in any other location First occurrence Withhold dose until resolved, then resume treatment at the same dose. Second occurrence Permanently discontinue. Grade 4 in any other location Any Permanently discontinue. Pneumonitis [see Warnings and Precautions (5.4) ] Grade 2 Any Withhold dose until Grade ≤1 for persistent or recurrent pneumonitis, consider resuming treatment at next lower dose level. Grade 3 or 4 Any Permanently discontinue. Severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS)) [see Warnings and Precautions (5.5) ] Suspected (any grade) Any Immediately withhold dose and consult a specialist to confirm the diagnosis. Confirmed Grade 3 or 4 Any Permanently discontinue. 2.4 Instructions for Preparation and Administration • Administer TIVDAK as an intravenous infusion only. • TIVDAK is a hazardous drug. Follow applicable special handling and disposal procedures 1 . • DO NOT administer TIVDAK as an intravenous push or bolus. • DO NOT mix TIVDAK with, or administer as an infusion with, other medicinal products. Use appropriate aseptic technique for reconstitution and preparation of dosing solutions. Prior to administration, the TIVDAK vial is reconstituted with Sterile Water for Injection, USP. The reconstituted solution is subsequently diluted in an intravenous infusion bag containing one of the following: 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP. Reconstitution in Single-dose Vial 1. Calculate the recommended dose based on the patient’s weight to determine the number of vials needed. 2. Reconstitute each 40 mg vial with 4 mL of Sterile Water for Injection, USP, resulting in 10 mg/mL TIVDAK. 3. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle. DO NOT SHAKE THE VIAL. Do not expose to direct sunlight. 4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colorless to brownish-yellow and free of visible particles. Discard any vial with visible particles or discoloration. 5. Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain a preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours in refrigeration at 2°C to 8°C (36 °F to 46 °F) or at room temperature up to 25°C (77°F) for up to a maximum of 8 hours prior to dilution. DO NOT FREEZE. Do not expose to direct sunlight. Discard unused vials with reconstituted solution beyond the recommended storage time. Dilution in Infusion Bag 1. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag. 2. Dilute TIVDAK with one of the following: 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP or Lactated Ringer's Injection, USP. The infusion bag size should allow enough diluent to achieve a final concentration of 0.7 mg/mL to 2.4 mg/mL TIVDAK. 3. Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight. 4. Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to brownish-yellow and free of visible particles. Discard the infusion bag if particulate matter or discoloration is observed. 5. Discard any unused portion left in the single-dose vials. Administration 1. Confirm administration of steroid and vasoconstrictor eye drops [see Dosage and Administration (2.2) ]. 2. Apply cold packs fully over the eyes following administration of the vasoconstrictor eye drops. Change cold packs as needed throughout infusion to ensure eye area remains cold during the entire infusion [see Dosage and Administration (2.2) ]. 3. Immediately administer the infusion over 30 minutes through an intravenous line containing a 0.2 µm in-line filter. 4. If the infusion is not administered immediately, store the diluted TIVDAK solution in refrigeration as specified in Table 3 . Discard if storage time exceeds these limits. DO NOT FREEZE. Once removed from refrigeration, complete administration of the diluted infusion solution of TIVDAK within 4 hours (including infusion time). Table 3: Diluted TIVDAK Solution Refrigeration Storage Conditions Diluent Used to Prepare Solution for Infusion Diluted TIVDAK Solution Storage Conditions (Including Infusion Time) 5% Dextrose Injection, USP Up to 24 hours at 2°C to 8°C (36°F to 46°F) 0.9% Sodium Chloride Injection, USP Up to 18 hours at 2°C to 8°C (36°F to 46°F) Lactated Ringer’s Injection, USP Up to 12 hours at 2°C to 8°C (36°F to 46°F)

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS • Peripheral neuropathy: Monitor patients for new or worsening peripheral neuropathy. Withhold, reduce the dose, or permanently discontinue TIVDAK based on severity. ( 2.3 , 5.2 ) • Hemorrhage: Monitor patients for signs and symptoms of hemorrhage. Withhold, reduce the dose, or permanently discontinue TIVDAK based on severity. ( 2.3 , 5.3 ) • Pneumonitis: Severe, life-threatening, or fatal pneumonitis may occur. Withhold TIVDAK for persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK for Grade 3 or 4 pneumonitis. ( 2.3 , 5.4 ) • Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions, including events of fatal or life-threatening Stevens-Johnson syndrome (SJS), can occur in patients treated with TIVDAK. Immediately withhold TIVDAK for suspected severe cutaneous adverse reactions, including SJS. Permanently discontinue TIVDAK for confirmed Grade 3 or 4 severe cutaneous adverse reactions, including SJS. ( 2.3 , 5.5 ) • Embryo-fetal toxicity: TIVDAK can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Ocular Adverse Reactions TIVDAK can cause severe ocular adverse reactions, including conjunctivitis, keratopathy (keratitis, punctate keratitis, and ulcerative keratitis), and dry eye (increased lacrimation, eye pain, eye discharge, pruritus, irritation, and foreign body sensation), that may lead to changes in vision and/or corneal ulceration. Ocular adverse reactions occurred in 55% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common ocular adverse reactions were conjunctivitis (32%), dry eye (24%), keratopathy (17%), and blepharitis (5%). Grade 3 ocular adverse reactions occurred in 3.3% of patients, including severe ulcerative keratitis in 1.2% of patients. Nine patients (2.1%) experienced ulcerative keratitis (including one with perforation requiring corneal transplantation), six (1.4%) conjunctival ulcer, four (0.9%) corneal erosion, two (0.5%) conjunctival erosion, and two (0.5%) symblepharon. The median time to onset of the first ocular adverse reaction was 1.2 months (range, 0-17.1). Of the patients who experienced ocular events, 59% had complete resolution and 31% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Ocular adverse reactions led to permanent discontinuation of TIVDAK in 6% of patients with cervical cancer. In innovaTV 301, 8 (3.2%) patients experienced delayed ocular adverse reactions occurring more than 30 days after discontinuation of TIVDAK. These adverse reactions included 3 patients with ulcerative keratitis, and one patient (each) with keratitis, punctate keratitis and corneal erosion, blepharitis and conjunctival hyperemia, conjunctival scar, and conjunctivitis and xerophthalmia. Refer patients to an eye care provider to conduct an ophthalmic exam prior to initiation of TIVDAK, prior to every cycle for the first nine cycles, and as clinically indicated. The exam should include visual acuity, slit lamp exam of the anterior segment of the eye, and an assessment of normal eye movement and ocular signs or symptoms which include dry or irritated eyes, eye secretions or blurry vision. Adhere to the required premedication and eye care before, during, and after infusion to reduce the risk of ocular adverse reactions [see Dosage and Administration (2.2) ]. Monitor for ocular toxicity and promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold, reduce, or permanently discontinue TIVDAK based on the severity or persistence of the ocular adverse reaction [see Dosage and Administration (2.3) ]. 5.2 Peripheral Neuropathy Peripheral neuropathy occurred in 39% of patients with cervical cancer treated with TIVDAK across clinical trials; 6% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral sensory neuropathy (23%), peripheral neuropathy (5%), paresthesia (3.8%), peripheral sensorimotor neuropathy (3.3%), muscular weakness (2.8%), and peripheral motor neuropathy (2.4%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain-Barre syndrome. The median time to onset of peripheral neuropathy was 2.4 months (range, 0-11.3). Of the patients who experienced peripheral neuropathy, 18% had complete resolution and 21% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Peripheral neuropathy led to discontinuation of TIVDAK in 7% of patients with cervical cancer. Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, withhold dose, then dose reduce, or permanently discontinue TIVDAK based on the severity of peripheral neuropathy [see Dosage and Administration (2.3) ] . 5.3 Hemorrhage Hemorrhage occurred in 51% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reaction was epistaxis (33%). Grade 3 hemorrhage occurred in 4% of patients. The median time to onset of hemorrhage was 0.3 months (range, 0-10.4). Of the patients who experienced hemorrhage, 71% had complete resolution and 12% had partial resolution (defined as a decrease in severity by one or more grades from the worst grade) at last follow-up. Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK [see Dosage and Administration (2.3) ] . 5.4 Pneumonitis Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody drug conjugates containing vedotin including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 4 patients (0.9%) experienced pneumonitis, including 1 patient who had a fatal outcome. Monitor patients for pulmonary symptoms indicative of pneumonitis. Symptoms may include hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations. Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis [see Dosage and Administration (2.3) ] . 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including events of fatal or life-threatening SJS, can occur in patients treated with TIVDAK. Severe cutaneous adverse reactions occurred in 1.6% of patients with cervical cancer treated with TIVDAK across clinical trials. Grade ≥3 severe cutaneous adverse reactions occurred in 0.5% of patients, including 1 patient who had a fatal outcome. Monitor patients for signs or symptoms of severe cutaneous adverse reactions, which include target lesions, worsening skin reactions, blistering or peeling of the skin, painful sores in mouth, nose, throat, or genital area, fever or flu-like symptoms, and swollen lymph nodes. If signs or symptoms of severe cutaneous adverse reactions occur, withhold TIVDAK until the etiology of the reaction has been determined. Early consultation with a specialist is recommended to ensure greater diagnostic accuracy and appropriate management. Permanently discontinue TIVDAK for confirmed Grade 3 or 4 severe cutaneous adverse reactions, including SJS [see Dosage and Administration (2.3) ] . 5.6 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman. The small molecule component of TIVDAK, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose [see Use in Specific Populations (8.1 , 8.3 ), and Clinical Pharmacology (12.1) ].

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Closely monitor for TIVDAK adverse reactions. ( 7.1 ) 7.1 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 [see Clinical Pharmacology (12.3) ] , which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for adverse reactions of TIVDAK when used concomitantly with strong CYP3A4 inhibitors.

6 ADVERSE REACTIONS 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

8.1 Pregnancy Risk Summary Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . 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 [AUC] at the recommended dose).