TIVDAK TM (tisotumab vedotin-tftv) for injection

TIVDAK (tisotumab vedotin-tftv) for injection

TIVDAK

Tisotumab vedotin-tftv is a Tissue Factor (TF) directed antibody drug conjugate (ADC) comprised of a human anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable vc (valine-citrulline) linker. The monoclonal antibody is produced in a mammalian cell cline (Chinese hamster ovary). MMAE and the linker are produced by chemical synthesis. Each monoclonal antibody molecule carries an average of 4 MMAE molecules. Tisotumab vedotin-tftv has an approximate molecular weight of 153 kDa.

TIVDAK (tisotumab vedotin-tftv) for injection, is provided as a sterile, preservative-free, white to off-white lyophilized cake or powder in a single-dose vial for infusion after dilution. Following reconstitution with 4 mL of Sterile Water for Injection, a clear to slightly opalescent, colorless to brownish-yellow solution containing 10 mg/mL tisotumab vedotin-tftv is produced. Each mL of reconstituted solution contains 10 mg of tisotumab vedotin-tftv, d-mannitol (30 mg), l-histidine (2.11 mg), l-histidine monohydrochloride (3.44 mg), and sucrose (30 mg), at pH 6.0.

INDICATIONS AND USAGE

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

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Mechanism of Action

Tisotumab vedotin-tftv is a tissue factor (TF)-directed antibody drug conjugate (ADC). The antibody is a human IgG1 directed against cell surface TF. TF is the primary initiator of the extrinsic blood coagulation cascade. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggests that the anticancer activity of tisotumab vedotin-tftv is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin-tftv also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

DOSAGE AND ADMINISTRATION

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.

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Premedication and Required Eye Care

Adhere to the following recommendations to reduce the risk of ocular adverse reactions

Ophthalmic exam: Conduct an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated.

Topical corticosteroid eye drops: The initial prescription and all renewals of any corticosteroid medication should be made only after examination with a slit lamp. Administer first drop in each eye prior to each infusion. Instruct patients to continue to administer eye drops in each eye as prescribed for 72 hours after each infusion.

Topical ocular vasoconstrictor drops: Administer in each eye immediately prior to each infusion.

Cold packs: Use cooling eye pads during the 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 unless advised by their eye care provider for the entire duration of therapy.

Instructions for Preparation and Administration

  • Administer TIVDAK as an intravenous infusion only.
  • TIVDAK is a hazardous drug. Follow applicable special handling and disposal procedures
  • DO NOT mix 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.
  2. Apply cold packs fully over the eyes following administration of the vasoconstrictor eye drops and leave on during the infusion. Change cold packs as needed throughout infusion to ensure eye area remains cold
  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 InfusionDiluted TIVDAK Solution Storage Conditions (Including Infusion Time)
0.9% Sodium Chloride Injection, USPUp to 18 hours at 2°C to 8°C (36°F to 46°F)
5% Dextrose Injection, USPUp to 24 hours at 2°C to 8°C (36°F to 46°F)
Lactated Ringer’s Injection, USPUp to 12 hours at 2°C to 8°C (36°F to 46°F)

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Ocular Adverse Reactions: Ocular adverse reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common ocular adverse reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose.

Peripheral Neuropathy: 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

Hemorrhage: 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.

Pneumonitis: 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.

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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.

DRUG INTERACTIONS

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.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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.

Lactation: 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.

Pediatric Use: Safety and effectiveness of TIVDAK in pediatric patients have not been established.

Geriatric Use: Of the 101 patients treated with TIVDAK in innovaTV 204, 13% were ≥65 years of age. Grade ≥3 adverse reactions occurred in 69% patients ≥65 years and in 59% patients <65 years. Serious adverse reactions occurred in 54% patients ≥65 years and in 41% patients <65 years. No patients aged ≥65 years treated with TIVDAK in innovaTV 204 experienced a tumor response.

Hepatic Impairment: Avoid use of TIVDAK in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN). 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.

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