Tivdak Drug Information

TIVDAK ® is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

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.

Premedication and Required Eye Care Adhere to the following recommendations to reduce the risk of ocular adverse reactions. • 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.

Dosage Modifications for Adverse Reactions

The recommended TIVDAK dose reduction schedule is provided in Table 1. Table 1: Dosage Reduction Schedule 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.

Conjunctival or corneal scarring or symblepharon Any scarring or symblepharon Any Permanently discontinue. Conjunctivitis and other ocular adverse reactions Severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS))

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. 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.

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. Visually inspect the infusion bag for any particulate matter or discoloration prior to use. 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. 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. 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

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. The median duration of treatment with TIVDAK was 3.7 months (range: 0.4-40.2).

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. A total of 250 patients received TIVDAK 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. Serious adverse reactions occurred in 33% of patients receiving TIVDAK.

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 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 4 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. Serious adverse reactions occurred in 43% of patients.

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 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 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).