tisotumab vedotin (Rx)

Brand and Other Names:Tivdak, tisotumab vedotin-tftv
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 40mg/vial

Cervical Cancer

Indicated for recurrent or metastatic cervical cancer in patients with disease progression during or following chemotherapy

2 mg/kg IV q3Weeks; not to exceed 200 mg/dose for patients ≥100 kg  

Continue until disease progression or unacceptable toxicity

Refer to Dosing Considerations for premedication and required eye care

Dosage Modifications

Dose reduction schedule

  • First reduction: 1.3 mg/kg
  • Second reduction: 0.9 mg/kg
  • Permanently discontinue if unable to tolerate 0.9 mg/kg

Keratitis

  • Superficial punctate keratitis (SPK), any occurrence: Monitor
  • Ulcerative keratitis or perforation: Permanently discontinue
  • Confluent superficial keratitis
    • First occurrence: Withhold until SPK or normal, then resume at next lower dose
    • Second occurrence: Permanently discontinue

Conjunctival ulceration

  • First occurrence: Withhold until complete conjunctival reepithelialization; resume at next lower dose
  • Second occurrence: Permanently discontinue

Conjunctival or corneal scarring or symblepharon

  • Any scarring or symblepharon: Permanently discontinue

Conjunctivitis and other ocular adverse reactions

  • Grade 1, any occurrence: Monitor
  • Grade 2-4
    • Grade 2, first occurrence: Withhold until Grade ≤1; resume at same dose
    • Grade 2, second occurrence: Withhold until Grade ≤1, then resume at next lower dose; if no resolution to Grade ≤1, permanently discontinue
    • Grade 2, third occurrence: Permanently discontinue
    • Grade 3 or 4: Permanently discontinue

Peripheral neuropathy

  • Grade 2, initial or worsening of preexisting condition: Withhold until Grade ≤1; resume at next lower dose
  • Grade 3 or 4: Permanently discontinue

Hemorrhage

  • Any grade pulmonary or CNS: Permanently discontinue
  • Any other location
    • Grade 2: Withhold until resolved; resume at same dose
    • Grade 3, first occurrence: Withhold until resolved; resume at same dose
    • Grade 3, second occurrence or grade 4: Permanently discontinue

Pneumonitis

  • Grade 2: Withhold until Grade ≤1 for persistent or recurrent pneumonitis; consider resuming at next lower dose
  • Grade 3 or 4: Permanently discontinue

Renal impairment

  • CrCl 30 to <90 mL/min: No dosage adjustment required
  • CrCl 15 to <30 mL/min or end-stage renal disease (ESRD) with or without dialysis: Pharmacokinetics unknown

Hepatic impairment

  • Mild (total bilirubin [TB] ≤ULN and AST >ULN or TB >1 to 1.5x ULN and any AST): Closely monitor for adverse effects; no dosage adjustment for starting dose
  • Moderate-to-severe (TB >1.5x ULN): Avoid use

Dosing Considerations

Verify pregnancy status in females of reproductive potential before initiating

Premedication and required eye care

  • Ophthalmic examination: Conduct ophthalmic examination including visual acuity and slit-lamp examination at baseline, before each dose, and as clinically indicated
  • Topical corticosteroid eye drops: Determine initial prescription and all renewals of any corticosteroid medication only after examination with a slit-lamp; administer first drop in each eye before to each infusion and instruct patients to continue administration in each eye for 72 hr after each infusion
  • Topical ocular vasoconstrictor drops: Administer in each eye immediately before each infusion
  • Cold-packs: Use cooling eye pads during IV infusion
  • Topical lubricating ophthalmic drops: Instruct patients to administer for duration of therapy and for 30 days after last dose
  • Contact lenses: Advise patients to avoid wearing contact lenses unless advised by their eye care provider for the entire duration of therapy

Safety and efficacy not established

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Interactions

Interaction Checker

and tisotumab vedotin

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    No Interactions Found
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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            All grades

            • Fatigue (50%)
            • Nausea (41%)
            • Peripheral neuropathy (39%)
            • Alopecia (39%)
            • Epistaxis (39%)
            • Conjunctival adverse reactions (37%)
            • Hemorrhage (32%)
            • Dry eye (29%)
            • Rash (25%)
            • Diarrhea (25%)
            • Constipation (23%)
            • Abdominal pain (23%)
            • Corneal adverse reactions (21%)
            • Myalgia (21%)
            • Vomiting (17%)
            • Periorbital adverse reactions (16%)
            • Pyrexia (16%)
            • Arthralgia (16%)
            • Decreased appetite (16%)
            • Urinary tract infection (14%)
            • Pain in extremity (13%)
            • Pruritus (13%)
            • Decreased weight (12%)

            Laboratory abnormalities (all grades)

            • Hemoglobin decreased (52%)
            • Lymphocytes decreased (42%)
            • Leukocytes decreased (30%)
            • Creatinine increased (29%)
            • Prothrombin INR increased (26%)
            • aPTT prolonged (26%)
            • ALT increased (24%)
            • Lactate dehydrogenase increased (22%)
            • Neutrophils decreased (21%)
            • Urate increased (20%)
            • Sodium decreased (20%)
            • Glucose decreased (19%)
            • AST increased (18%)
            • Alkaline phosphatase increased (17%)
            • Magnesium decreased (17%)
            • Creatinine kinase increased (16%)
            • Albumin decreased (16%)

            1-10%

            All grades

            • Fatigue (7%)
            • Peripheral neuropathy (7%)
            • Hemorrhage (6%)
            • Corneal adverse reactions (3%)
            • Diarrhea (2%)
            • Constipation (2%)
            • Vomiting (2%)
            • Urinary tract infection (2%)
            • Pain in extremity (1%)
            • Decreased appetite (1%)
            • Abdominal pain (1%)
            • Pyrexia (1%)
            • Pruritus (1%)

            Laboratory abnormalities (grade 3-4)

            • Lymphocytes decreased (8%)
            • Hemoglobin decreased (7%)
            • Creatinine increased (4.1%)
            • Neutrophils decreased (3%)
            • Creatinine kinase increased (2.1%)
            • Magnesium decreased (2.1%)
            • aPTT prolonged (2%)
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            Warnings

            Black Box Warnings

            Ocular toxicity

            • Causes changes in corneal epithelium and conjunctiva resulting in vision changes, including severe vision loss, and corneal ulceration
            • Conduct ophthalmic examination at baseline, prior to each dose, and as clinically indicated
            • Adhere to premedication and required eye care before, during, and after infusion
            • Withhold until improvement and resume, reduce the dose, or permanently discontinue, based on severity

            Contraindications

            None

            Cautions

            Based on mechanism of action and findings in animal studies, can cause fetal harm

            Peripheral neuropathy

            • Peripheral neuropathy reported
            • Median time to onset of peripheral neuropathy reported to be 2.4 months (range, 0-11.3 months)
            • Monitor for signs and symptoms of neuropathy (eg, paresthesia, tingling or burning sensation, neuropathic pain, muscle weakness, dysesthesia)
            • If observed, withhold dose, then reduce dose or permanently discontinue

            Hemorrhage

            • Hemorrhage occurred in a majority of treated patients
            • Median time to onset of hemorrhage reported to be 0.3 months (range, 0-6.5 months)
            • Monitor and withhold or discontinue dose as recommended

            Pneumonitis

            • Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates
            • Pulmonary symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic examinations; infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations
            • Monitor for pulmonary symptoms and adjust dose, withhold treatment, or permanently discontinue as recommended

            Ocular adverse effects

            • Ocular adverse reactions reported; promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms
            • Conduct ophthalmic examination including visual acuity and slit lamp examination at baseline, before each dose, and as clinically indicated
            • Administer premedication and cold-pack regimen with each infusion
            • Common ocular adverse reactions included conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%)
            • Grade 3 ocular adverse reactions occurred in 3.8%, including severe ulcerative keratitis in 3.2% of patients
            • One patient experienced ulcerative keratitis with perforation requiring corneal transplantation
            • Symblepharon was reported in patients with other tumor types treated at the recommended dose
            • Median time to onset of first ocular adverse reaction was 1.2 months
            • Among patients who experienced ocular events, 55% had complete resolution, 30% had partial improvement, 6% discontinued treatment

            Drug interaction overview

            • Strong CYP3A4 inhibitors
              • Monitor closely if coadministered
              • Tisotumab vedotin is metabolized to monomethyl auristatin E (MMAE), a mitotic inhibitor and the cytotoxic component of the antibody-drug conjugate
              • MMAE is substrate of CYP3A4
              • Strong CYP3A4 inhibitors may increase unconjugated MMAE systemic exposure and increase risk of adverse effects
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            Pregnancy & Lactation

            Pregnancy

            Based on mechanism of action and findings in animals, can cause fetal harm when administered to pregnant females

            Human data are not available to evaluate drug-associated risk

            Advise patients of potential risk to fetus and verify pregnancy status in females of reproductive potential before initiating

            Animal studies

            • Administration of MMAE (tisotumab vedotin active metabolite) to pregnant rats during organogenesis caused embryofetal mortality and structural abnormalities at exposures below the clinical exposure at the recommended dose

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for 2 months after last dose
            • Males with female partners of reproductive potential: Use effective contraception during treatment and for 4 months after last dose

            Infertility

            • Males: Based on findings from animal studies, may impair fertility

            Lactation

            Data are not available on presence in human milk, effects on breastfed children, or effects on milk production

            Advise lactating females not to breastfeed during treatment and for 3 weeks after last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Antibody-drug conjugate composed of a monoclonal antibody against human tissue factor that is covalently bound by a protease-cleavable peptide liner to monomethyl auristatin E (MMAE), an auristatin derivative

            MMAE is an agent that disrupts microtubules; disruption of the microtubule network of actively dividing cells leads to cell cycle arrest and apoptotic cell death

            Absorption

            Peak plasma concentration: 40.8 mcg/mL; 5.91 ng/mL (unconjugated MMAE)

            AUC: 57.5 day⋅mcg/mL; 50 day⋅ng/mL (unconjugated MMAE)

            Vd: 7.83 L

            Distribution

            Protein bound: 68-82% (MMAE)

            Metabolism

            Tisotumab vedotin undergoes catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites

            Unconjugated MMAE primarily metabolized by CYP3A4 (in vitro)

            Elimination

            Half-life: 4.04 days; 2.56 days (unconjugated MMAE)

            Clearance: 1.54 L/day; 45.9 L/day (unconjugated MMAE)

            Excretion (MMAE): 17% feces; 6% urine over 1 week

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            Administration

            IV Incompatibilities

            Do not mix with or administer with other medicinal products

            IV Compatibilities

            D5W

            NaCl 0.9%

            Lactated Ringer solution

            IV Preparation

            Follow applicable special handling and disposal procedures for hazardous drugs

            Reconstitute lyophilized powder

            • Calculate dose according to patient’s weight and determine number of single-dose vials needed
            • Reconstitute each 40-mg vial with 4 mL sterile water for injection; resulting concentration is 10 mg/mL
            • Slowly swirl each vial until contents are completely dissolved; allow reconstituted vial(s) to settle; do NOT shake vial or expose to direct sunlight
            • Inspect visually for particulate matter and discoloration; reconstituted solution should appear clear to slightly opalescent, colorless to brownish-yellow, and free of visible particles; discard if visible particles or discoloration observed
            • Add calculated dose from vial(s) to infusion bag immediately; if not used immediately, see storage recommendations below

            Dilution in infusion bag

            • Dilute with D5W, NaCl 0.9%, or Lactated Ringer solution in infusion bag to achieve final concentration of 0.7-2.4 mg/mL
            • Mix diluted solution by gentle inversion; do NOT shake bag or expose to direct sunlight
            • Visually inspect for any particulate matter or discoloration; discard if particulate matter or discoloration observed
            • Discard any unused portion left in vials

            IV Administration

            For IV infusion only; do NOT administer as IV push or bolus

            Confirm administration of steroid and vasoconstrictor ophthalmic drops

            Apply cold packs fully over eyes following administration of the vasoconstrictor eye drops and leave on during IV infusion; change cold packs as needed throughout infusion to ensure eye area remains cold

            Immediately administer IV infusion over 30 minutes via IV line containing a 0.2-μm inline filter

            If infusion not administered immediately, store diluted solution in refrigeration as specified in storage below

            Storage

            Does not contain preservatives

            Do NOT freeze or expose to direct sunlight

            Do not shake vials

            Unopened vial

            • Refrigerate at 2-8ºC (36-46ºF) in original carton to protect from light

            Reconstituted vial

            • Refrigerate at 2-8ºC (36-46ºF) for up to 24 hr, OR
            • Store at room temperature up to 25ºC (77ºF) for maximum of 8 hr before dilution

            Diluted infusion bag

            • Refrigerate at 2-8ºC (36-46ºF)
            • Duration of refrigeration depends on solution
              • Lactated Ringer solution: Up to 12 hr
              • 0.9% NaCl: Up to 18 hr
              • D5W: Up to 24 hr
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            Formulary

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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