Tisotumab Vedotin-tftv (Monograph)

Brand name: Tivdak
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Warning

Tisotumab vedotin can cause severe ocular toxicities resulting in changes in vision, including severe vision loss and corneal ulceration.
Conduct an ophthalmic exam prior to initiation of tisotumab vedotin, prior to every cycle for the first 9 cycles, and as clinically indicated.
Adhere to the required premedication and eye care before, during, and after infusion.
If ocular toxicity occurs, withhold tisotumab vedotin until improvement, then resume, reduce dose, or permanently discontinue, based on severity.

Introduction

Antineoplastic agent; tissue factor (TF)-directed antibody conjugated with a microtubule inhibitor (monomethyl auristatin E [MMAE])

Uses for Tisotumab Vedotin-tftv

Cervical Cancer

Treatment of adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy; significantly improved overall survival, progression-free survival, and objective response rates compared to chemotherapy.

Treatment of recurrent or metastatic cervical cancer typically includes first-line systemic treatment with bevacizumab and chemotherapy (or pembrolizumab and chemotherapy with or without bevacizumab in eligible patients). Patients with disease progression on first-line therapy have limited treatment options; available therapies in this setting include single agent chemotherapies. Tisotumab vedotin provides another treatment option for such patients.

Tisotumab Vedotin-tftv Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential.
Conduct an ophthalmic exam prior to initiating tisotumab vedotin. The exam should include visual acuity, slit lamp examination of the anterior segment, and an assessment of eye movement.

Patient Monitoring

Monitor patients for ocular toxicity. Conduct an ophthalmic exam before each cycle for the first 9 cycles and as clinically indicated.
Monitor patients for signs and symptoms of neuropathy (e.g., paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, dysesthesia).
Monitor patients for signs and symptoms of hemorrhage.
Monitor patients for pulmonary symptoms indicative of pneumonitis (e.g., hypoxia, cough, dyspnea, interstitial infiltrates on radiologic exams).
Monitor patients for signs or symptoms of severe cutaneous adverse reactions including Stevens- Johnson Syndrome (SJS), which include target lesions, worsening skin reactions, blistering or peeling of the skin, painful sores in mouth, nose, throat, or genital area, fever or flu-like symptoms, and swollen lymph nodes.

Premedication and Prophylaxis

Administer topical corticosteroid and vasoconstrictor eye drops as premedication prior to each infusion of tisotumab vedotin to reduce the risk of ocular adverse reactions.
Instruct patients to administer one drop of the topical corticosteroid in each eye prior to each infusion and to continue to administer eye drops in each eye 3 times daily for 72 hours after each infusion. The initial prescription and all renewals of any corticosteroid medication should be made only after examination with a slit lamp.
Administer topical ocular vasoconstrictor drops in each eye immediately prior to each infusion of tisotumab vedotin. Apply cold packs fully over the eyes following administration of the vasoconstrictor eye drops; change cold packs as needed throughout infusion to ensure eye area remains cold during the entire 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.

Dispensing and Administration Precautions

Advise patients to avoid wearing contact lenses for the entire duration of therapy unless advised by their eye care provider.

Tisotumab vedotin is a hazardous drug. Follow applicable special handling and disposal procedures.

Administration

IV Administration

Administer by IV infusion only; do not administer as an IV push or bolus.

Commercially available as a lyophilized powder that must be reconstituted and diluted prior to administration.

Adhere to the required premedication and eye care recommendations before, during, and after infusion.

Use a 0.2 μm inline filter to administer the drug.

Do not mix with or administer as an infusion with any other medications.

Reconstitution

Calculate the dose based on patient weight to determine number of vials needed.

Reconstitute each 40-mg vial with 4 mL sterile water for injection to produce a concentration of 10 mg/mL. Swirl vial gently until dissolved, then allow contents to settle; do not shake or expose the vial to direct sunlight. Inspect for clarity; discard if discolored or contains particles.

If not used immediately, observe manufacturer's recommended storage instructions.

Dilution

Withdraw the calculated dose from the vial(s) and transfer to an infusion bag. Dilute with 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer's injection to a concentration of 0.7-2.4 mg/mL. Mix by gently inverting bag without shaking; avoid sunlight. Inspect for particles or discoloration; discard if present.

Dispose of any unused solution left in single-dose vials.

If not used immediately, observe manufacturer's recommended storage instructions for diluted solutions.

Rate of Administration

Administer by IV infusion over 30 minutes.

Dosage

Adults

Cervical Cancer

IV

2 mg/kg (maximum 200 mg for patients ≥100 kg) administered as a 30-minute IV infusion every 3 weeks until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

If an adverse reaction occurs, treatment interruption, dosage reduction, and/or discontinuance of therapy may be necessary based on type and severity of the adverse effect.

Adjust dosage according to the severity and occurrence of toxicity (see Tables 1 and 2).

For ocular adverse reactions (keratitis; conjunctival or corneal scarring or symblepharon; conjunctivitis and other ocular adverse reactions), refer patients to an eye care provider promptly for an assessment of new or worsening ocular symptoms.

Table 1: Dosage Reduction Schedule1
	Tisotumab Vedotin-tftv Dose Level
Starting dose	2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg).
First dose reduction	1.3 mg/kg (up to a maximum of 130 mg for patients ≥100 kg).
Second dose reduction	0.9 mg/kg (up to a maximum of 90 mg for patients ≥100 kg); permanently discontinue in patients who cannot tolerate 0.9 mg/kg.

Table 2: Dosage Modifications for Adverse Reactions1
Adverse Reaction	Severity, Occurrence, and Recommendation
Keratitis	Nonconfluent superficial keratitis (any occurrence): monitor. Confluent superficial keratitis, a corneal epithelial defect, or a 3 line or more loss in best corrected visual acuity (first occurrence): withhold dose until resolution or improvement to nonconfluent superficial keratitis, then resume treatment at the next lower dose level. Confluent superficial keratitis, a corneal epithelial defect, or a 3 line or more loss in best corrected visual acuity (second occurrence): permanently discontinue. Ulcerative keratitis or perforation (any occurrence): permanently discontinue.
Conjunctival or corneal scarring or symblepharon	Any scarring or symblepharon (any occurrence): permanently discontinue.
Conjunctivitis and other ocular adverse reactions	Nonconfluent superficial punctate conjunctival defects, mild vasodilation (any occurrence): monitor. Confluent superficial punctate conjunctival defects, moderate to severe vasodilation (first occurrence): withhold dose until resolution or improvement to nonconfluent superficial punctate conjunctival defects, mild vasodilation, then resume treatment at the same dose. Confluent superficial punctate conjunctival defects, moderate to severe vasodilation (second occurrence): withhold dose until resolution or improvement to nonconfluent superficial punctate conjunctival defects, mild vasodilation, then resume treatment at the next lower dose level; if no resolution or improvement to nonconfluent superficial punctate conjunctivaldefects, mild vasodilation, permanently discontinue. Confluent superficial punctate conjunctival defects, moderate to severe vasodilation (third occurrence): permanently discontinue. Conjunctival ulcer, conjunctival neovascularization, or fibrovascular scarring (any occurrence): permanently discontinue.
Peripheral neuropathy	Grade 2 (any occurrence, either initial or worsening of pre-existing condition): withhold dose until grade ≤1, then resume treatment at the next lower dose level. Grade 3 or 4 (any occurrence): permanently discontinue.
Hemorrhage	Any grade pulmonary or CNS hemorrhage (any occurrence): permanently discontinue. Grade 2 in any other location (any occurrence): withhold until resolved, then resume treatment at the same dose. Grade 3 in any other location (first occurrence): withhold dose until resolved, then resume treatment at the same dose. Grade 3 in any other location (second occurrence): permanently discontinue. Grade 4 in any other location (any occurrence): permanently discontinue
Pneumonitis	Grade 2 (any occurrence): withhold dose until grade ≤1 for persistent or recurrent pneumonitis, consider resuming treatment at next lower dose level. Grade 3 or 4 (any occurrence): permanently discontinue.
Severe cutaneous adverse reactions (including Stevens-Johnson syndrome [SJS])	Suspected, any grade (any occurrence): immediately withhold dose and consult a specialist to confirm the diagnosis. Confirmed grade 3 or 4: permanently discontinue.

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment to initial dosage recommended.

Moderate or severe hepatic impairment (AST> 3 times ULN or total bilirubin >1.5 times ULN): Avoid use.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Tisotumab Vedotin-tftv

Contraindications

None.

Warnings/Precautions

Ocular Toxicity

Risk of severe ocular toxicity, potentially causing vision changes or loss (see Boxed Warning). Severe ocular adverse reactions reported include conjunctivitis, keratopathy (keratitis, punctate keratitis, and ulcerative keratitis), and dry eye (increased lacrimation, eye pain, eye discharge, pruritus, irritation, and foreign body sensation); may lead to changes in vision and/or corneal ulceration.

Conduct ophthalmic exams before starting treatment, before each cycle for the first 9 cycles, and as clinically indicated. Follow strict premedication eye protocols. Withhold treatment if toxicity occurs; resume, reduce, or discontinue therapy based on severity.

Other Warnings and Precautions

Peripheral Neuropathy

Peripheral neuropathy, mainly sensory neuropathy, paresthesia and muscular weakness, occurs commonly; median time to onset 2.4 months.

Monitor patients for paresthesia, tingling or a burning sensation,neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, withhold dose, then reduce dose or permanently discontinue based on the severity of peripheral neuropathy.

Hemorrhage

Hemorrhage commonly occurs with a median time of onset of 0.3 months.

Monitor patients for signs and symptoms of hemorrhage.

For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue drug. For grade ≥2 hemorrhage in any other location, withhold therapy 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.

Pneumonitis

Pneumonitis that is severe, potentially life-threatening, or fatal can occur with vedotin-containing antibody-drug conjugates.

For patients who develop persistent or recurrent grade 2 pneumonitis, withhold and consider dose reduction; for grade 3 or 4, permanently discontinue.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions including life-threatening or fatal Stevens-Johnson syndrome (SJS) may occur.

Withhold therapy if a severe skin reaction occurs until diagnosis is confirmed. Consult a specialist early. Discontinue permanently for confirmed grade 3 or 4 reactions, including SJS.

Fetal/Neonatal Morbidity and Mortality

Based on mechanism of action and findings in animals, tisotumab vedotin can cause fetal harm when administered to a pregnant woman. MMAE caused adverse developmental outcomes, including embryofetal mortality and structural abnormalities, in rats at exposures below those occurring clinically at the recommended dose.

Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with tisotumab vedotin and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with the drug and for 4 months after the last dose.

Specific Populations

Pregnancy

May cause fetal harm based on mechanism of action and findings from animal studies.

Lactation

No data available on whether tisotumab vedotin is present in human milk or if the drug has any effects on a breastfed child or on milk production. Avoid breastfeeding during treatment and for 3 weeks after the final dose.

Females and Males of Reproductive Potential

May cause fetal harm. Confirm pregnancy status before initiating treatment.

Advise females to use contraception during treatment and for 2 months after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

May impair fertility in both females and males, although the effect is reversible in females, based on findings from animal studies with MMAE-containing antibody-drug conjugates.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Clinical studies did not include enough patients ≥65 years of age to determine if they respond differently from younger adults.

Hepatic Impairment

Avoid use in patients with moderate or severe hepatic impairment (AST >3 times ULN or bilirubin >1.5 times ULN). For patients with mild impairment, monitor closely; no dosage adjustment needed.

Renal Impairment

No significant exposure differences between patients with mild to moderate renal impairment and those with normal function. Effects in severe renal impairment or end-stage renal disease unknown.

Common Adverse Effects

Most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, peripheral neuropathy, conjunctival adverse reactions, nausea, fatigue, increased AST, epistaxis, alopecia, increased ALT, hemorrhage.

Drug Interactions

No drug-drug interaction studies conducted. To characterize the drug interaction potential of unconjugated MMAE, clinical studies with another antibody drug conjugate (ADC) that contains MMAE are described.

MMAE is a CYP3A4 substrate.

MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

MMAE does not induce any major CYP isoenzymes in human hepatocytes.

MMAE is a P-gp substrate, but not a P-gp inhibitor.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors: May increase MMAE exposure and risk of adverse reactions. Monitor patients closely.

Specific Drugs

Drug	Interaction	Comments
Ketoconazole	When ketoconazole (strong CYP3A4 inhibitor) was used concomitantly with another ADC that contains MMAE, increased peak plasma concentration and AUC of unconjugated MMAE observed with no change in ADC exposure	May increase risk of adverse effects; monitor closely
Midazolam	No clinically significant differences in midazolam (sensitive CYP3A4 substrate) pharmacokinetics when used concomitantly with another ADC that contains MMAE
Rifampin	When rifampin (strong CYP3A4 inducer) was used concomitantly with another ADC that contains MMAE, decreased peak plasma concentration and AUC of unconjugated MMAE observed with no change in ADC exposure

Tisotumab Vedotin-tftv Pharmacokinetics

Absorption

Plasma Concentrations

Peak plasma concentrations of tisotumab vedotin are achieved near the end of the infusion; concentrations of unconjugated MMAE peaked approximately 2 to 3 days later.

Distribution

Extent

Distribution of tisotumab vedotin is moderate.

Plasma Protein Binding

MMAE has a significant level of plasma protein binding.

Elimination

Metabolism

Tisotumab vedotin breaks down into smaller components including MMAE, which is mainly metabolized by CYP3A4.

Elimination Route

MMAE is expected to be excreted primarily through feces and urine.

Half-life

Median elimination half-lives for tisotumab vedotin and MMAE were 4.04 and 2.56 days, respectively, with different rates of clearance.

Stability

Storage

Parenteral

Powder for Injection

Store vials at 2–8°C in the original carton to protect from light; do not freeze or shake.

Reconstituted vials: if not used immediately, may store up to 24 hours in the refrigerator at 2–8°C or at room temperature up to 25°C for a maximum of 8 hours prior to dilution; do not freeze or expose to direct sunlight.

Diluted solution: if not used immediately, may store in refrigerator (2–8°C) for up to 24 hours if prepared with 5% dextrose injection, up to 18 hours if prepared with 0.9% sodium chloride injection, or up to 12 hours if prepared with lactated Ringer’s injection. Discard if storage time exceeds these limits; do not freeze. Once removed from refrigeration, complete administration of diluted solution within 4 hours (including infusion time).

Actions

A tissue factor (TF)-directed antibody drug conjugate (ADC); contains a human anti-TF IgG₁ kappa antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). Each monoclonal antibody molecule carries an average of 4 MMAE molecules.
Delivers MMAE, the cytotoxic component, directly to cancer cells through the monoclonal antibody that binds to TF on surface of these cells.
TF initiates the extrinsic blood coagulation cascade and is elevated in several solid tumors, including recurrent cervical cancer.. Based on nonclinical data, anticancer effects arise from binding of the ADC to TF-expressing cancer cells, subsequent internalization of the ADC-TF complex, and MMAE release via proteolytic cleavage; MMAE disrupts microtubules of actively dividing cells, leading to cell cycle arrest and apoptosis.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (medication guide).
Inform patients about the eye exam they will receive before treatment, before each of the first nine cycles, and as clinically indicated.
Inform patients that ocular adverse reactions may occur during treatment and to contact their healthcare provider if they experience new or worsening ocular signs and symptoms.
Inform patients to bring their eye drops to each infusion and advise on how to administer the eye drops throughout treatment.
Inform patients to avoid wearing contact lenses during treatment unless directed by an eye care provider.
Advise patients to report to their healthcare provider any numbness and tingling of the hands or feet or muscle weakness.
Inform patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage.
Inform patients to immediately report new or worsening respiratory symptoms.
Inform patients about the signs of severe skin reactions, including life-threatening SJS, such as target lesions, worsening skin reactions, blistering or peeling skin, painful sores, fever, flu-like symptoms, and swollen lymph nodes. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of severe cutaneous adverse reactions, including SJS.
Advise pregnant women and females of reproductive potential of the potential risk to the fetus and to inform their healthcare providers of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.
Inform female patients not to breastfeed during treatment and for 3 weeks after the last dose.
Inform healthcare provider of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.