Tivdak

• •
  TIVDAK can cause severe ocular toxicities resulting in changes in vision, including severe vision loss, and corneal ulceration.

  [see

  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)

  ].

  ].
• •
  Conduct an ophthalmic exam, including an assessment of ocular symptoms, visual acuity, and slit lamp exam of the anterior segment of the eye prior to initiation of TIVDAK, prior to every cycle for the first nine cycles, and as clinically indicated. 

  [see

  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.

   and

  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)

  ].

  ]

  .
• •
  Adhere to the required premedication and eye care before, during, and after infusion. 

  [see

  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.

  ].
• •
  Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity

  [see

  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/kgPermanently 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.

  ,

  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)

  ].

  ].

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

• •
  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 Instructions for Preparation and Administration

  • •
    Administer TIVDAK as an intravenous infusion only.
  • •TIVDAK is a hazardous drug. Follow applicable special handling and disposal procedures¹.
  • •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

  • 1.000000000000000e+00Calculate the recommended dose based on the patient’s weight to determine the number of vials needed.
  • 2.000000000000000e+00Reconstitute each 40 mg vial with 4 mL of Sterile Water for Injection, USP, resulting in 10 mg/mL TIVDAK.
  • 3.000000000000000e+00Slowly 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.
  • 4.000000000000000e+00Parenteral 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.
  • 5.000000000000000e+00Based 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

  • 1.000000000000000e+00Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.
  • 2.000000000000000e+00Dilute 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.
  • 3.000000000000000e+00Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight.
  • 4.000000000000000e+00Visually 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.
  • 5.000000000000000e+00Discard any unused portion left in the single-dose vials.

  Administration

  • 1.000000000000000e+00Confirm administration of steroid and vasoconstrictor eye drops
    [see Dosage and Administration (2.2)].
  • 2.000000000000000e+00Apply 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)].
  • 3.000000000000000e+00Immediately administer the infusion over 30 minutes through an intravenous line containing a 0.2 µm in-line filter.
  • 4.000000000000000e+00If 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)
  )
• •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 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.
  )

For Injection: 40 mg of tisotumab vedotin-tftv as a white to off-white lyophilized cake or powder in a single-dose vial for reconstitution.

• •Moderate or severe hepatic impairment: Exposure to MMAE and adverse reactions are increased. Avoid use. (
  8.6 Hepatic Impairment

  Avoid use of TIVDAK in patients with moderate or severe hepatic impairment [aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) or total bilirubin > 1.5 × ULN]

  [see Clinical Pharmacology (12.3)].

  In patients with mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin > 1 to 1.5 × ULN and any AST), closely monitor patients for adverse reactions of TIVDAK, but no dosage adjustment in the starting dose of TIVDAK is recommended.
  )
• •Lactation: Advise women not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There are no data on the presence of tisotumab vedotin-tftv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with TIVDAK and for 3 weeks after the last dose.
  )