Version July 2025
Tisotumab vedotin can cause severe ocular toxicities resulting in changes in vision, including severe vision loss, and corneal ulceration. 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 tisotumab vedotin, prior to every cycle for the first nine cycles, and as clinically indicated. Adhere to the required premedication and eye care before, during, and after infusion. Withhold tisotumab vedotin until improvement and resume, reduce the dose, or permanently discontinue, based on severity.
Cervical cancer, recurrent or metastatic: IV: 2 mg/kg (maximum dose: 200 mg for patients ≥100 kg) once every 3 weeks until disease progression or unacceptable toxicity (Ref).
Ophthalmic care and premedication:
Topical corticosteroid ophthalmic drops: Initial prescription (and all renewals) for any corticosteroid should be made only after ophthalmic examination with a slit lamp. Administer 1 drop in each eye prior to each tisotumab vedotin infusion. Instruct patients to continue eye drop administration in each eye 3 times a day for 72 hours after each tisotumab vedotin infusion.
Topical vasoconstrictor ophthalmic drops: Administer in each eye immediately prior to each tisotumab vedotin infusion.
Cooling packs: Use cooling eye pads during each tisotumab vedotin infusion.
Topical lubricating ophthalmic drops: Instruct patients to administer during tisotumab vedotin treatment and for 30 days after the last tisotumab vedotin dose.
Contact lens: Patients should avoid wearing contact lens for the entire duration of tisotumab vedotin treatment (unless advised by their eye care provider).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney function estimated by Cockcroft-Gault equation.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling. However, no clinically significant differences in exposures of tisotumab vedotin and unconjugated microtubule-disrupting agent monomethyl auristatin E (MMAE) were observed in a pharmacokinetic study.
CrCl 15 to <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling.
CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (effect on tisotumab vedotin and unconjugated MMAE pharmacokinetics is unknown).
End-stage renal disease (with or without dialysis): There are no dosage adjustments provided in the manufacturer’s labeling (effect on tisotumab vedotin and unconjugated MMAE pharmacokinetics is unknown).
Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST): No initial dosage adjustment necessary; monitor closely for adverse reactions.
Moderate or severe impairment (AST >3 times ULN or total bilirubin >1.5 times ULN): Avoid tisotumab vedotin use.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 : Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref). Note: The manufacturer recommends a maximum dose of 200 mg for patients weighing ≥100 kg; dosage adjustments should be calculated using a maximum body weight of 100 kg.
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Usual initial dose |
2 mg/kg (maximum dose: 200 mg) |
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First dose reduction |
1.3 mg/kg (maximum dose: 130 mg) |
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Second dose reduction |
0.9 mg/kg (maximum dose: 90 mg) |
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Permanently discontinue tisotumab vedotin if unable to tolerate 0.9 mg/kg. | |
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Adverse reaction |
Severity |
Occurrence |
Dose modification |
|---|---|---|---|
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a SJS = Stevens-Johnson syndrome. | |||
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b Withhold tisotumab vedotin 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. | |||
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c Promptly refer patients to an eye care provider for assessment of new or worsening ocular symptoms. | |||
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Cutaneous adverse reactions, severe (including SJSa) |
Suspected (any grade) |
Any |
Immediately withhold tisotumab vedotin until etiology of adverse reaction has been determined. Consult a specialist to confirm the diagnosis. Early specialist consultation is recommended for diagnostic accuracy and appropriate management. |
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Confirmed grade 3 or 4 |
Any |
Permanently discontinue tisotumab vedotin. | |
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GI toxicity: nausea |
Any |
Any |
Administer prophylactic antiemetics in subsequent cycles (Coleman 2021). |
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Hemorrhage |
Pulmonary or CNS (any grade) |
Any |
Permanently discontinue tisotumab vedotin. |
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Grade 2 in any other location |
Any |
Withhold tisotumab vedotin until resolved,b then resume at the same dose. | |
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Grade 3 in any other location |
First occurrence |
Withhold tisotumab vedotin until resolved,b then resume at the same dose. | |
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Second occurrence |
Permanently discontinue tisotumab vedotin. | ||
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Grade 4 in any other location |
Any |
Permanently discontinue tisotumab vedotin. | |
|
Ocular toxicity: keratitisc |
Nonconfluent superficial keratitis |
Any |
Monitor. |
|
Confluent superficial keratitis, corneal epithelial defect, or a ≥3 line loss in best corrected visual acuity |
First occurrence |
Withhold tisotumab vedotin until resolution or improvement to nonconfluent superficial keratitis, then resume at the next lower dose level. | |
|
Second occurrence |
Permanently discontinue tisotumab vedotin. | ||
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Ulcerative keratitis or perforation |
Any |
Permanently discontinue tisotumab vedotin. | |
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Ocular toxicity: conjunctival or corneal scarring or symblepharonc |
Any scarring or symblepharon |
Any |
Permanently discontinue tisotumab vedotin. |
|
Ocular toxicity: conjunctivitis or other ocular adverse reactionsc |
Nonconfluent superficial punctate conjunctival defects, mild vasodilation |
Any |
Monitor. |
|
Confluent superficial punctate conjunctival defects, moderate to severe vasodilation |
First occurrence |
Withhold tisotumab vedotin until resolution or improvement to nonconfluent superficial punctate conjunctival defects, mild vasodilation, then resume at the same dose. | |
|
Second occurrence |
Withhold tisotumab vedotin until resolution or improvement to nonconfluent superficial punctate conjunctival defects, mild vasodilation, then resume at the next lower dose level. If does not resolve or improve to nonconfluent superficial punctate conjunctival defects, mild vasodilation, permanently discontinue tisotumab vedotin. | ||
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Third occurrence |
Permanently discontinue tisotumab vedotin. | ||
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Conjunctival ulcer, conjunctival neovascularization, or fibrovascular scarring |
Any |
Permanently discontinue tisotumab vedotin. | |
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Peripheral neuropathy |
Grade 2 |
Any (initial or worsening of preexisting neuropathy) |
Withhold tisotumab vedotin until ≤ grade 1, then resume at the next lower dose level. |
|
Grade 3 or 4 |
Any |
Permanently discontinue tisotumab vedotin. | |
|
Pulmonary toxicity: pneumonitis |
Grade 2 |
Any |
Withhold tisotumab vedotin until ≤ grade 1 for persistent or recurrent pneumonitis; consider resuming at the next lower dose level. |
|
Grade 3 or 4 |
Any |
Permanently discontinue tisotumab vedotin. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Increased serum creatinine kinase (16%)
Dermatologic: Alopecia (24% to 39%), pruritus (10% to 13%), skin rash (17% to 25%)
Endocrine & metabolic: Decreased serum magnesium (17%), decreased serum sodium (20% to 27%), weight loss (10% to 12%)
Gastrointestinal: Abdominal pain (18% to 23%), constipation (23% to 25%), decreased appetite (16% to 24%), diarrhea (22% to 25%; grades 3/4: 2%), nausea (33% to 41%; grades 3/4: <1%), vomiting (17% to 18%; grades 3/4: 2%)
Genitourinary: Urinary tract infection (14% to 16%)
Hematologic & oncologic: Decreased hemoglobin (41% to 52%; grades 3/4: 7%), decreased neutrophils (16% to 21%; grades 3/4: 3%), hemorrhage (21% to 51%; grades 3/4: 2% to 6%; including gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhagic cystitis, uterine hemorrhage, vaginal hemorrhage), increased INR (26%), leukopenia (≥25%), lymphocytopenia (≥25%), prolonged partial thromboplastin time (16% to 26%; grades 3/4: 2%)
Hepatic: Increased serum alanine aminotransferase (24% to 30%), increased serum alkaline phosphatase (17%), increased serum aspartate aminotransferase (18% to 34%)
Nervous system: Fatigue (28% to 50%; including asthenia), peripheral neuropathy (38% to 39%; grades 3/4: 6% to 7%; including abnormal gait, hyperesthesia, hypoesthesia, myasthenia [3%], neuralgia, paresthesia [4%], peripheral motor neuropathy [2%], peripheral sensory neuropathy [23%], sensorimotor neuropathy [3%])
Neuromuscular & skeletal: Arthralgia (16%), limb pain (13%), myalgia (21%)
Ophthalmic: Conjunctivitis (32%), dry eye syndrome (21% to 29%; including eye discharge, eye irritation, eye pain, foreign body sensation of eye), ocular toxicity (55%; including conjunctival erosion [<1%], conjunctival hemorrhage, conjunctival hyperemia, conjunctival scarring, conjunctival ulcer [1%], corneal abrasion, corneal erosion [<1%], corneal ulcer, epithelial keratopathy [17%; including keratitis, punctuate keratitis, ulcerative keratitis (2%)], noninfective conjunctivitis, ocular hyperemia, severe vision loss, symblepharon [<1%]), ophthalmic signs and symptoms (periorbital: 16%; including blepharitis [5%], chalazion, eye pruritus, eyelid entropion, meibomianitis [including meibomian gland dysfunction], misdirected growth of eyelashes)
Renal: Increased serum creatinine (23% to 29%)
Respiratory: Epistaxis (26% to 39%)
Miscellaneous: Fever (16% to 17%)
1% to 10%:
Cardiovascular: Pulmonary embolism (3%), venous thrombosis (3%)
Dermatologic: Dermatological reaction (severe: 2%; including Stevens-Johnson syndrome [<1%])
Gastrointestinal: Intestinal obstruction (4%)
Immunologic: Antibody development (5% to 6%; neutralizing: 2%)
Infection: Sepsis (2% to 3%)
Respiratory: Pneumonia (4%), pneumonitis (≤2%)
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Dermatologic toxicity: Severe cutaneous adverse reactions, including Stevens Johnson syndrome (which may be severe, life-threatening, or fatal) may occur rarely. Signs/symptoms of severe cutaneous adverse reactions include target lesions, worsening skin reactions, skin blistering/peeling, painful sores in the mouth, nose, throat, or genital area, fever/flu-like symptoms, and/or swollen lymph nodes.
• Hemorrhage: Hemorrhage occurred in over one-half of patients with cervical cancer who received tisotumab vedotin. The most common hemorrhagic adverse reaction (all grades) was epistaxis. Grade 3 hemorrhage occurred in a small percentage of patients. The median time to onset of hemorrhage was 0.3 months (range: up to 10.4 months). Of the patients who experienced hemorrhage, a majority had complete resolution and some experienced partial resolution (defined as a decrease in severity by one or more grades from the worst grade) at last follow-up.
• Ocular toxicity: Tisotumab vedotin may 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) which may lead to changes in vision and/or corneal ulceration. Ocular adverse reactions occurred in over half of patients with cervical cancer treated with tisotumab vedotin in clinical studies. The most common ocular adverse reactions were conjunctivitis, dry eye, keratopathy, and blepharitis. Grade 3 ocular adverse reactions occurred in a small percentage of patients, including cases of severe ulcerative keratitis, ulcerative keratitis (including one with perforation requiring corneal transplantation), conjunctival ulcer, corneal erosion, conjunctival erosion, and symblepharon. The median time to onset of the first ocular adverse reaction was 1.2 months (range: up to 17.1 months). Of the patients who experienced ocular events, over half experienced complete resolution and nearly one-third experienced partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow-up. Some patients required permanent discontinuation of tisotumab vedotin due to ocular adverse events. Delayed ocular adverse events (eg, ulcerative keratitis, keratitis, punctate keratitis, corneal erosion, blepharitis, conjunctival hyperemia, conjunctival scar, and conjunctivitis and xerophthalmia) have also been reported more than 30 days after discontinuation of therapy.
• Peripheral neuropathy: Peripheral neuropathy occurred in over one-third of patients with cervical cancer who received tisotumab vedotin; grade 3 peripheral neuropathy was reported. Peripheral neuropathy adverse reactions included peripheral sensory neuropathy, peripheral neuropathy, paresthesia, peripheral sensorimotor neuropathy, muscular weakness, and peripheral motor neuropathy. A case of Guillain-Barre syndrome developed in a patient with a different tumor type (not cervical cancer) who received tisotumab vedotin at the recommended dose. The median time to onset of peripheral neuropathy was 2.4 months (range: up to ~11 months). Of the patients who developed peripheral neuropathy, some patients experienced complete resolution or partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow-up.
• Pulmonary toxicity: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody drug conjugates containing vedotin, including tisotumab vedotin. Among patients with cervical cancer treated who received tisotumab vedotin, a small percentage experienced pneumonitis, including a fatal case. Pulmonary symptoms indicative of pneumonitis may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams.
Special populations:
• Older age: Patients ≥65 years of age experienced a higher incidence of ≥ grade 3 adverse reactions and discontinuations due to adverse reactions (compared to patients <65 years of age).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Tivdak: Tisotumab vedotin-tftv 40 mg (1 ea)
No
Solution (reconstituted) (Tivdak Intravenous)
40 mg (per each): $8,547.60
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
IV: Infuse over 30 minutes using an infusion line containing a 0.2 micron inline filter. Do not infuse as an IV push or bolus. Do not infuse with other medications.
Confirm that topical ophthalmic corticosteroids and vasoconstrictor eye drops have been administered prior to initiating infusion. After administration of vasoconstrictor eye drops, apply cold packs fully over eyes and change cold packs throughout the infusion to ensure the eye area remains cold during the entire infusion.
Administer prophylactic antiemetics in subsequent cycles if patient experiences nausea (Ref). Consider a scalp cooling system (according to guidelines) to prevent alopecia/hair loss (Ref).
Hazardous agent (NIOSH 2024 [table 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Tivdak: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761208s005lbl.pdf#page=21
Cervical cancer, recurrent or metastatic: Treatment of recurrent or metastatic cervical cancer in adults with disease progression on or after chemotherapy.
Tisotumab vedotin may be confused with brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, tafasitamab, teclistamab, tislelizumab, tivozanib, toripalimab, trastuzumab, tremelimumab.
Tivdak may be confused with Tivicay, tivozanib.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Substrate of CYP3A4 (Major with inhibitors), CYP3A4 (Minor with inducers), P-glycoprotein (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase serum concentration of Tisotumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor
Efgartigimod Alfa: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification
Nipocalimab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Rozanolixizumab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Verify pregnancy status prior to treatment initiation.
Patients who could become pregnant should use effective contraception during therapy and for 2 months after the last tisotumab vedotin dose. Patients with partners who could become pregnant should also use effective contraception during therapy and for 4 months after the last dose of tisotumab vedotin.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to tisotumab vedotin may cause fetal harm.
It is not known if tisotumab vedotin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 3 weeks after the last tisotumab vedotin dose.
Ophthalmic exam (including visual acuity, slit lamp exam of the anterior segment of the eye, and assessment of normal eye movement, as well as ocular signs/symptoms including dry or irritated eyes, eye secretions or blurry vision) at baseline, prior to every cycle for the first nine cycles, and as clinically indicated. Verify pregnancy status prior to treatment initiation (in patients who could become pregnant). Monitor patients for signs/symptoms of hemorrhage, neuropathy (eg, paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia), ocular toxicity, cutaneous adverse reactions (including Stevens-Johnson syndrome and/or target lesions, worsening skin reactions, skin blistering/peeling, painful sores in the mouth, nose, throat, or genital area, fever/flu-like symptoms, and/or swollen lymph nodes), and for pulmonary symptoms indicative of pneumonitis (eg, hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams); exclude infectious, neoplastic, and other causes for pulmonary symptoms via appropriate investigations.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Tisotumab vedotin is a tissue factor (TF)-directed antibody drug conjugate (ADC) comprised of an anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE), via a protease-cleavable valine-citrulline linker. The antibody is directed against cell surface TF, which is the primary initiator of the extrinsic blood coagulation cascade. Tisotumab vedotin’s anticancer activity is likely 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. Tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.
Duration: Median duration of response: 8.3 months.
Distribution: Tisotumab vedotin: Vdss: 7.83 L.
Protein binding: Microtubule-disrupting agent monomethyl auristatin E (MMAE): 68% to 82%.
Metabolism: Tisotumab vedotin is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related metabolites; tisotumab vedotin releases unconjugated MMAE via proteolytic cleavage, and unconjugated MMAE is primarily metabolized via CYP3A4.
Half-life elimination: Tisotumab vedotin: ~4 days; unconjugated MMAE: ~2.5 days.
Time to peak: Tisotumab vedotin: Near the end of the infusion; unconjugated MMAE: 2 to 3 days after the tisotumab vedotin dose.
Excretion: Clearance: Tisotumab vedotin: 1.54 L/day; unconjugated MMAE: ~46 L/day.
Hepatic function impairment: Although there were no clinically significant differences in tisotumab vedotin exposure, unconjugated microtubule-disrupting agent monomethyl auristatin E exposures were 37% higher in patients with mild hepatic impairment (bilirubin 1 to 1.5 times ULN and any AST or bilirubin ≤ ULN and AST > ULN), compared to patients with normal hepatic function.
