Tisotumab vedotin caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required 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 (Coleman 2021).
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 the first drop in each eye prior to each tisotumab vedotin infusion. Instruct patients to continue eye drop administration in each eye as prescribed 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 packs 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 (unless advised by their eye care provider) for the duration of tisotumab vedotin treatment.
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 (total bilirubin >1.5 times ULN): Avoid tisotumab vedotin use.
Refer to adult dosing.
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 (ASCO [Griggs 2021]). Note: The manufacturer recommends a maximum dose of 200 mg for patients weighing ≥100 kg.
|
Usual initial dose |
2 mg/kg (maximum dose: 200 mg) |
|
First dose reduction |
1.3 mg/kg |
|
Second dose reduction |
0.9 mg/kg |
|
Permanently discontinue tisotumab vedotin if unable to tolerate 0.9 mg/kg. | |
|
Adverse reaction |
Severity |
Occurrence |
Dose modification |
|---|---|---|---|
|
a 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. b Promptly refer patients to an eye care provider for assessment of new or worsening ocular symptoms. | |||
|
GI toxicity: nausea |
Any |
Any |
Administer prophylactic antiemetics in subsequent cycles (Coleman 2021) |
|
Hemorrhage |
Pulmonary or CNS (any grade) |
Any |
Permanently discontinue tisotumab vedotin. |
|
Grade 2 in any other location |
Any |
Withhold tisotumab vedotin until resolveda, then resume at the same dose. | |
|
Grade 3 in any other location |
First occurrence |
Withhold tisotumab vedotin until resolveda, then resume at the same dose. | |
|
Second occurrence |
Permanently discontinue tisotumab vedotin. | ||
|
Grade 4 in any other location |
Any |
Permanently discontinue tisotumab vedotin. | |
|
Ocular toxicity: keratitisb |
Superficial punctate keratitis |
Any |
Monitor. |
|
Confluent superficial keratitis |
First occurrence |
Withhold tisotumab vedotin until superficial punctate keratitis or normal, then resume at the next lower dose level. | |
|
Second occurrence |
Permanently discontinue tisotumab vedotin. | ||
|
Ulcerative keratitis or perforation |
Any |
Permanently discontinue tisotumab vedotin. | |
|
Ocular toxicity: conjunctival ulcerationb |
Any ulceration |
First occurrence |
Withhold tisotumab vedotin until complete conjunctival re-epithelialization, then resume at the next lower dose level. |
|
Second occurrence |
Permanently discontinue tisotumab vedotin. | ||
|
Ocular toxicity: conjunctival or corneal scarring or symblepharonb |
Any scarring or symblepharon |
Any |
Permanently discontinue tisotumab vedotin. |
|
Ocular toxicity: conjunctivitis or other ocular adverse reactionsb |
Grade 1 |
Any |
Monitor. |
|
Grade 2 |
First occurrence |
Withhold tisotumab vedotin until ≤ grade 1, then resume at the same dose. | |
|
Second occurrence |
Withhold tisotumab vedotin until ≤ grade 1, then resume at the next lower dose level. If does not resolve to ≤ grade 1, permanently discontinue tisotumab vedotin. | ||
|
Third occurrence |
Permanently discontinue tisotumab vedotin. | ||
|
Grade 3 or 4 |
Any |
Permanently discontinue tisotumab vedotin. | |
|
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. | |
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
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/2021/761208Orig1s000lbledt.pdf#page=21
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 leave on during infusion; change cold packs as needed throughout infusion to ensure eye area remains cold.
Administer prophylactic antiemetics in subsequent cycles if patient experiences nausea (Coleman 2021).
Hazardous agent (NIOSH [group 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 2016; USP-NF 2020).
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, tivozanib.
Tivdak may be confused with Tivicay, tivozanib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
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 (39%), pruritus (13%), skin rash (25%)
Endocrine & metabolic: Decreased serum albumin (16%), decreased serum glucose (19%), decreased serum magnesium (17%), decreased serum sodium (20%), increased lactate dehydrogenase (22%), increased uric acid (20%), weight loss (12%)
Gastrointestinal: Abdominal pain (23%), constipation (23%), decreased appetite (16%), diarrhea (25%; grade 3/4: 2%), nausea (41%), vomiting (17%; grade 3/4: 2%)
Genitourinary: Urinary tract infection (14%)
Hematologic & oncologic: Decreased hemoglobin (52%; grade 3/4: 7%), decreased neutrophils (21%; grade 3/4: 3%), hemorrhage (32% to 62%; grade 3: 5%; grade 3/4: 6%; including gastrointestinal hemorrhage, hematochezia, hemoptysis, hemorrhagic cystitis, uterine hemorrhage), increased INR (26%), leukopenia (30%), lymphocytopenia (42%; grade 3/4: 8%), prolonged partial thromboplastin time (26%; grade 3/4: 2%)
Hepatic: Increased serum alanine aminotransferase (24%), increased serum alkaline phosphatase (17%), increased serum aspartate aminotransferase (18%)
Nervous system: Fatigue (≤50%), peripheral neuropathy (20% to 42%; grade 3/4: 7% to 8%; including abnormal gait, hyperesthesia, hypoesthesia, neuralgia, paresthesia, severe peripheral neuropathy), peripheral sensory neuropathy (11%)
Neuromuscular & skeletal: Arthralgia (16%), asthenia (≤50%), limb pain (13%), myalgia (21%)
Ophthalmic: Blepharitis (≤16%), chalazion (≤16%), conjunctival abnormalities (37% to 40%; including conjunctival hemorrhage, conjunctival hyperemia, conjunctival scarring, conjunctivitis, corneal abrasion, corneal erosion, noninfective conjunctivitis, ocular hyperemia), dry eye syndrome (29%), epithelial keratopathy (≤21%; including keratitis, punctuate keratitis, and ulcerative keratitis), eye pruritus (≤16%), eyelid entropion (≤16%), meibomianitis (≤16%; including meibomian gland dysfunction), misdirected growth of eye lashes (≤16%), ocular toxicity (60%; including corneal ulcer, severe vision loss)
Renal: Increased serum creatinine (29%)
Respiratory: Epistaxis (39% to 44%)
Miscellaneous: Fever (16%)
1% to 10%:
Cardiovascular: Pulmonary embolism (3%), venous thrombosis (3%)
Gastrointestinal: Intestinal obstruction (6%)
Genitourinary: Hematuria (10%), vaginal hemorrhage (10%)
Immunologic: Antibody development (5% to 6%; neutralizing: 2%)
Infection: Sepsis (3%)
Nervous system: Myasthenia (3%), peripheral demyelinating polyneuropathy (1%), peripheral motor neuropathy (3%), sensorimotor neuropathy (5%)
Ophthalmic: Decreased visual acuity (changes to 20/50: 4%; changes to 20/200: 1%)
Respiratory: Pneumonia (4%), pneumonitis (2%)
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Hemorrhage: Hemorrhage commonly occurred in patients with cervical cancer who received tisotumab vedotin. The most common hemorrhagic adverse reactions (all grades) were epistaxis, hematuria, and vaginal hemorrhage. Grade 3 hemorrhage occurred in a small percentage of patients. The median time to onset of hemorrhage was 0.3 months (range: up to 6.5 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: Ocular adverse reactions occurred in over half of patients with cervical cancer who were treated with tisotumab vedotin. The most common ocular adverse reactions were conjunctival adverse reactions, dry eye, corneal adverse reactions, and blepharitis. Grade 3 ocular adverse reactions (including severe ulcerative keratitis) occurred in a small percentage of patients. A case of ulcerative keratitis with perforation requiring corneal transplantation was reported and cases of symblepharon have been reported. The median time to onset of the first ocular adverse reaction was 1.2 months (range: up to 6.5 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. Visual acuity changes to 20/50 or worse have been reported in a small number of patients, including rare visual acuity changes to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, a majority of cases resolved.
• Peripheral neuropathy: Peripheral neuropathy occurred in almost half of patients with cervical cancer who received tisotumab vedotin; grade 3 peripheral neuropathy was reported. Peripheral neuropathy adverse reactions included peripheral neuropathy, peripheral sensory neuropathy, peripheral sensorimotor neuropathy, motor neuropathy, muscular weakness, and demyelinating peripheral polyneuropathy. 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 or partial resolution improvement (partial resolution is 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 and higher and serious adverse reactions (compared to patients <65 years of age).
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tisotumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor therapy
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Verify pregnancy status prior to treatment initiation.
Patients who could become pregnant should use effective contraception during therapy and for at least 2 months after the last tisotumab vedotin dose. Patients with partners who could become pregnant should also use effective contraception during therapy and for at least 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 and slit lamp exam) at baseline, prior to each dose, 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, 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 AST < ULN or bilirubin ≤ ULN and AST > ULN, compared to patients with normal hepatic function.
Solution (reconstituted) (Tivdak Intravenous)
40 mg (per each): $7,336.80
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