TIVDAK

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)

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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.