Tivdak

Antineoplastic Monoclonal Antibodies Targeting Tissue Factor (TF)
Antineoplastic Monoclonal Antibody-Drug Conjugates (ADCs)

Hazardous Drugs Classification
Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
Observe and exercise appropriate cautions for preparing, handling, and administering solutions of cytotoxic drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Administer as an IV infusion only; do not administer as an IV push or bolus.
Do not mix with, or administer as an infusion with, other drugs.
Reconstitution:
Calculate the dose (mg) and the number of vials required.
Reconstitute each 40-mg tisotumab vedotin vial with 4 mL Sterile Water for Injection resulting in a concentration of 10 mg/mL.
Slowly swirl each vial until the contents are completely dissolved; do not shake. Allow the reconstituted vials to settle.
Do not expose to direct sunlight.
The reconstituted solution should be clear to slightly opalescent, colorless to brownish-yellow. Discard any vial with visible particles or discoloration.
Storage after reconstitution: If not used immediately, reconstituted vials may be refrigerated for up to 24 hours at 2 to 8 degrees C (36 to 46 degrees F) or at room temperature up to 25 degrees C (77 degrees F) for up to 8 hours prior to dilution.
Dilution:
Dilute the calculated dose/volume of reconstituted tisotumab vedotin with 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection in a volume sufficient to achieve a final concentration of 0.7 mg/mL to 2.4 mg/mL.
Mix the diluted solution by gentle inversion; do not shake the bag.
Do not expose to direct sunlight.
Discard any unused portion left in the reconstituted single-dose vials.
IV infusion:
Confirm administration of steroid and vasoconstrictor eye drops.
Apply cold packs fully over the eyes following administration of the vasoconstrictor eye drops and leave them on during the infusion. Change cold packs as needed throughout infusion to ensure eye area remains cold.
Immediately administer the infusion over 30 minutes through an IV line containing a 0.2 micromol in-line filter.
Storage after dilution in Lactated Ringer's Injection: If not administered immediately, the solution may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 12 hours including infusion time. Do not freeze. Administration of the diluted solution must be complete within 4 hours after removing from refrigeration (including infusion time).
Storage after dilution in 0.9% Sodium Chloride Injection: If not administered immediately, the solution may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 18 hours including infusion time. Do not freeze. Administration of the diluted solution must be complete within 4 hours after removing from refrigeration (including infusion time).
Storage after dilution in 5% Dextrose Injection: If not administered immediately, the solution may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours including infusion time. Do not freeze. Administration of the diluted solution must be complete within 4 hours after removing from refrigeration (including infusion time).

peripheral neuropathy / Delayed / 7.0-8.0
lymphopenia / Delayed / 8.0-8.0
fatigue / Early / 7.0-7.0
anemia / Delayed / 7.0-7.0
bleeding / Early / 5.0-6.0
ileus / Delayed / 6.0-6.0
pulmonary embolism / Delayed / 3.0-3.0
thrombosis / Delayed / 3.0-3.0
neutropenia / Delayed / 3.0-3.0
diarrhea / Early / 2.0-2.0
constipation / Delayed / 2.0-2.0
vomiting / Early / 2.0-2.0
prolonged bleeding time / Delayed / 0-2.0
abdominal pain / Early / 1.0-1.0
anorexia / Delayed / 1.0-1.0
pruritus / Rapid / 1.0-1.0
fever / Early / 1.0-1.0
pneumonitis / Delayed / 0.7-0.7
infection / Delayed / 2.0
hemorrhagic cystitis / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
corneal erosion / Delayed / Incidence not known
keratitis / Delayed / Incidence not known
visual impairment / Early / Incidence not known
Guillain-Barre syndrome / Delayed / Incidence not known

leukopenia / Delayed / 30.0-30.0
elevated hepatic enzymes / Delayed / 17.0-24.0
hyponatremia / Delayed / 20.0-20.0
hypoglycemia / Early / 19.0-19.0
hypomagnesemia / Delayed / 17.0-17.0
hypoalbuminemia / Delayed / 16.0-16.0
hematuria / Delayed / 10.0-10.0
vaginal bleeding / Delayed / 10.0-10.0
blepharitis / Early / 8.0-8.0
antibody formation / Delayed / 5.0-5.5
hemoptysis / Delayed / Incidence not known
keratopathy / Delayed / Incidence not known
entropion / Early / Incidence not known
conjunctival hyperemia / Early / Incidence not known
conjunctivitis / Delayed / Incidence not known
ocular toxicity / Delayed / Incidence not known
hyperesthesia / Delayed / Incidence not known
colitis / Delayed / Incidence not known
erythema / Early / Incidence not known

epistaxis / Delayed / 39.0-44.0
nausea / Early / 41.0-41.0
alopecia / Delayed / 39.0-39.0
xerophthalmia / Early / 29.0-29.0
rash / Early / 25.0-25.0
myalgia / Early / 21.0-21.0
arthralgia / Delayed / 16.0-16.0
weight loss / Delayed / 12.0-12.0
weakness / Early / 3.0-3.0
ocular pruritus / Rapid / Incidence not known
chalazion (meibomian cyst) / Delayed / Incidence not known
lacrimation / Early / Incidence not known
hypoesthesia / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
gait disturbance / Delayed / Incidence not known
asthenia / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
acneiform rash / Delayed / Incidence not known
musculoskeletal pain / Early / Incidence not known

Ocular toxicity can occur during treatment with tisotumab vedotin. Use caution in patients with ocular disease or visual impairment. Patients should avoid wearing contact lenses for the entire duration of therapy unless advised by their eye care provider. Patients treated with tisotumab vedotin experienced changes in the corneal epithelium and conjunctiva in 4 clinical trials (n = 158) resulting in vision changes including severe vision loss and corneal ulceration. Conduct an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Administer topical corticosteroid eye drops with the first drop in each eye prior to infusion, continuing drops in each eye as prescribed for 72 hours after each infusion; the initial prescription and all renewals of any corticosteroid medication should be made only after slit lamp exam. Administer topical ocular vasoconstrictor drops in each eye immediately prior to each infusion and use cooling eye pads during the infusion. Instruct patients to administer topical lubricating eye drops for the duration of therapy and for 30 days after the last dose of tisotumab vedotin. Promptly refer patients to an eye care provider for any new or worsening ocular symptoms; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if ocular toxicity occurs.

Tivdak

Rx

Tissue factor-directed antibody and microtubule inhibitor conjugate
Used for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy
Ocular adverse reactions are common; adhere to recommendations for required eye care before, during, and after each infusion

2 mg/kg (maximum, 200 mg) IV every 3 weeks until disease progression or unacceptable toxicity; closely adhere to recommendations to reduce the risk of ocular adverse reactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, noncomparative trial (innovaTV 204), treatment with tisotumab vedotin resulted in an overall response rate of 24% (complete response, 7%) for a median duration of 8.3 months in patients with recurrent or metastatic cervical cancer who had received no more than 2 prior systemic regimens in the recurrent or metastatic setting including at least one prior platinum-based regimen; 69% of patients previously received bevacizumab as part of their prior therapy.

Mild hepatic impairment (total bilirubin at the upper limit of normal [ULN] or less and AST greater than ULN; OR total bilirubin 1.1 to 1.5 times ULN and any AST): No adjustment to the starting dose of tisotumab vedotin is recommended; closely monitor patients for adverse reactions.
Moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN): Avoid use of tisotumab vedotin.

Mild to moderate renal impairment (CrCl 30 to 89 mL/min): No dosage adjustment is recommended.
Severe renal impairment (CrCl 15 to 29 mL/min) or end-stage renal disease (ESRD) with or without dialysis: The effect of severe renal impairment or ESRD on the pharmacokinetics of tisotumab vedotin and unconjugated MMAE is unknown.

Adagrasib: (Moderate) Closely monitor for tisotumab vedotin-related adverse reactions if concomitant use with adagrasib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with clarithromycin is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Atazanavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with atazanavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Atazanavir; Cobicistat: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with atazanavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%. (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with cobicistat is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Ceritinib: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ceritinib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Chloramphenicol: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with chloramphenicol is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with clarithromycin is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Cobicistat: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with cobicistat is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Darunavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with darunavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Darunavir; Cobicistat: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with cobicistat is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%. (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with darunavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with cobicistat is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%. (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with darunavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Delavirdine: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with delavirdine is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with cobicistat is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with cobicistat is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Grapefruit juice: (Major) Advise patients to avoid grapefruit juice while taking tisotumab vedotin due to the risk of increased exposure to monomethyl auristatin E (MMAE) which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and grapefruit juice is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 34%.
Idelalisib: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with idelalisib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Indinavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with indinavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Itraconazole: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with itraconazole is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Ketoconazole: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ketoconazole is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with ketoconazole increased unconjugated MMAE exposure by 34%.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with clarithromycin is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Letermovir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with letermovir in combination with cyclosporine is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Levoketoconazole: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ketoconazole is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with ketoconazole increased unconjugated MMAE exposure by 34%.
Lonafarnib: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with lonafarnib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Lopinavir; Ritonavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ritonavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Mifepristone: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with mifepristone is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Nefazodone: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with nefazodone is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Nelfinavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with nelfinavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ritonavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Posaconazole: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with posaconazole is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Ribociclib: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ribociclib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Ribociclib; Letrozole: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ribociclib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Ritonavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ritonavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Saquinavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with saquinavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tipranavir: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with tipranavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tucatinib: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with tucatinib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with clarithromycin is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Voriconazole: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with voriconazole is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.

Tisotumab vedotin Intravenous Inj Pwd: 40mg

2 mg/kg IV (Max: 200 mg)

2 mg/kg IV (Max: 200 mg)

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Tisotumab vedotin is a tissue factor (TF)-directed antibody-drug conjugate (ADC) consisting of 3 components including a human anti-TF IgG1-kappa antibody directed against cell surface TF; a microtubule-disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable vc (valine-citrulline) linker. TF is the primary initiator of the extrinsic blood coagulation cascade. Nonclinical data suggests that the anticancer activity of tisotumab vedotin is due to the ADC binding 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 apoptosis. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

Tisotumab vedotin is administered intravenously. Plasma protein binding of monomethyl auristatin E (MMAE) ranged from 68% to 82% in vitro. The steady-state volume of distribution for tisotumab vedotin is 7.83 L (CV, 19.1%). The median terminal half-life of tisotumab vedotin and unconjugated MMAE is 4.04 (range, 2.26 to 7.25) days and 2.56 (range, 1.81 to 4.1) days, respectively. Steady-state concentrations of tisotumab vedotin and unconjugated MMAE were reached after 1 treatment cycle. The linear clearance of tisotumab vedotin was 1.54 L/day (CV, 28.8%); the linear clearance of MMAE was 45.9 L/day (CV, 61.1%). Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin. The excretion of tisotumab vedotin is not fully characterized. After a single dose of another antibody-drug conjugate that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
Tisotumab vedotin is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and catabolites related to unconjugated MMAE. MMAE is released from tisotumab vedotin via proteolytic cleavage. In vitro, unconjugated MMAE is primarily metabolized by CYP3A4. At the time of FDA approval, drug interaction studies for tisotumab vedotin had not been conducted. However, the Cmax and AUC of unconjugated MMAE increased by 25% and 34%, respectively, when another antibody-drug conjugate containing MMAE was administered with a strong CYP3A4 inhibitor. The Cmax and AUC of unconjugated MMAE decreased by 44% and 46%, respectively, when another antibody-drug conjugate containing MMAE was administered with a strong CYP3A4 inducer. In vitro, MMAE is also a P-gp substrate.

The mean Cmax after one 3-week cycle at the recommended dose was 40.8 mcg/mL (+/- 8.12 mcg/mL) for tisotumab vedotin and 5.91 ng/mL (+/- 4.2 ng/mL) for unconjugated MMAE. The Tmax of tisotumab vedotin was near the end of the infusion; unconjugated MMAE concentrations peaked approximately 2 to 3 days after administration. The mean AUC was 57.5 mcg x day/mL (+/- 13.4 mcg x day/mL) for tisotumab vedotin and 50 ng x day/mL (+/- 35.8 ng x day/mL) for MMAE. The Cmax of tisotumab vedotin increased proportionally, while the AUC increased in a more than dose-proportional manner. There was no accumulation of tisotumab vedotin and unconjugated MMAE.

Pregnancy should be avoided by females of reproductive potential during tisotumab vedotin treatment and for at least 2 months after the last dose. Although there are no adequately controlled studies in pregnant women, tisotumab vedotin can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving tisotumab vedotin should be apprised of the potential hazard to the fetus. Embryofetal development studies in animals have not been performed with tisotumab vedotin. However, administration of the active component of tisotumab vedotin, monomethyl auristatin E (MMAE), to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities (e.g., protruding tongue, malrotated limbs, gastroschisis, and agnathia) at exposures below the clinical exposure at the recommended dose.

Due to the potential for serious adverse reactions in nursing infants from tisotumab vedotin, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether tisotumab vedotin is present in human milk.