Tisotumab vedotin-tftv

Tisotumab vedotin-tftv
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra

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Black Box Warning

TITLE See full prescribing information for complete Boxed Warning. Condition Name: (Content)

Overview

Tisotumab vedotin-tftv is a tissue factor-directed antibody and microtubule inhibitor conjugate that is FDA approved for the treatment of recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral neuropathy, alopecia, epistaxis, leukocytes decreased, creatinine increased, dry eye, activated partial thromboplastin time prolonged, hemoglobin decreased, conjunctival adverse reactions, hemorrhage, fatigue, lymphocytes decreased, nausea, prothrombin international normalized ratio increased, rash, and diarrhea..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• 2 mg/kg is the recommended dosage of Tisotumab vedotin-tftv through an intravenous infusion.
• Dosage should be given for 30 minutes every 3 weeks.

Table 1 shows Schedule for Dosage Reductions.

Insert Table 1

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tisotumab vedotin-tftv in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tisotumab vedotin-tftv in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Tisotumab vedotin-tftv FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tisotumab vedotin-tftv in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tisotumab vedotin-tftv in pediatric patients.

Contraindications

There are no contraindications associated with Tisotumab_vedotin-tftv.

Warnings

TITLE See full prescribing information for complete Boxed Warning. Condition Name: (Content)

Ocular Adverse Reactions

• Clinical studies show that 60% of patients with cervical cancer reported ocular adverse reactions when taking Tisotumab vedotin-tftv.
• Of the patients with ocular adverse reactions, patients reported corneal adverse reactions (21%), conjunctival adverse reactions (40%), blepharitis (8%), and dry eye (29%) are the most common.
• 3.8% of patients reported grade 3 ocular adverse reactions.
• Corneal transplantation was required in one patient with signs of ulcerative keratitis with perforation when taking Tisotumab vedotin-tftv.
• 1.2 months was the median time of onset for patients that had first ocular adverse.
• 55% of patients who had ocular events displayed complete resolution.
• 30% of patients who had ocular events showed partial resolution which is defined as a decrease in severity by one or more grades from the worst grade.
• 6% of patients with cervical cancer discontinued use of Tisotumab vedotin-tftv when patients showed signs of ocular adverse reactions.
• Visual acuity changes to 20/50 or worse was seen in 4% of patients in innovaTV 204 where 75% had resolution this issue.
• Visual acuity change to 20/200 was seen in 1% of patients in innovaTV 204 of the patients that had visual acuity changes to 20/50 or worse.
• Advise patients prior to each dose of Tisotumab vedotin-tftv to get an ophthalmic exam.
• Monitor patients slit lamp exam and visual acuity at baseline.
• Advise patients to report any signs and symptoms of new or worsening ocular reactions.
• Advise patients with adverse reactions to permanently discontinue, withhold, or reduce the dose of Tisotumab vedotin-tftv based on the severity.

Peripheral Neuropathy

• 42% of patients with cervical cancer displayed peripheral neuropathy when taking Tisotumab vedotin-tftv.
• 8% of patients with peripheral neuropathy displayed Grade 3 peripheral neuropathy.
• Of the patients with peripheral neuropathy, peripheral sensory neuropathy (11%), motor neuropathy (3%), demyelinating peripheral polyneuropathy (1%), peripheral neuropathy (20%), peripheral sensorimotor neuropathy (5%), and muscular weakness (3%) are the most common adverse reactions reported in patients.
• Guillain-Barre syndrome was reported in one patient with another tumor type when taking Tisotumab vedotin-tftv.
• 2.4 months is the median time to onset in patients that displayed peripheral neuropathy.
• 17% of patients who had peripheral neuropathy displayed complete resolution.
• 17% of patients who had peripheral neuropathy showed partial improvement which is defined as a decrease in severity by one or more grades from the worst grade.
• 8% of patients with cervical cancer discontinued use of Tisotumab vedotin-tftv when patients showed signs of peripheral neuropathy.
• Advise patients about signs and symptoms of peripheral neuropathy such as neuropathic pain, muscle weakness, tingling or a burning sensation, dysesthesia, or paresthesia.
• Advise patients with adverse reactions to permanently discontinue, withhold, or reduce the dose of Tisotumab vedotin-tftv based on the severity.

Hemorrhage

• 62% of patients with cervical cancer reported Hemorrhage when taking Tisotumab vedotin-tftv.
• Of the patients that reported signs of Hemorrhage, hematuria (10%), epistaxis (44%), and vaginal hemorrhage (10%).
• Of the patients that reported signs of Hemorrhage, 5% of patients displayed signs and symptoms of Grade 3 hemorrhage.
• 0.3 months is the median time to onset in patients with hemorrhage taking Tisotumab vedotin-tftv.
• 71% of patients who had hemorrhage displayed complete resolution.
• 11% of patients who had hemorrhage events showed partial resolution which is defined as a decrease in severity by one or more grades from the worst grade.
• Monitor patients that display any signs and symptoms of hemorrhage.
• Permanently discontinue the use of Tisotumab vedotin-tftv when experiencing pulmonary or CNS hemorrhage.
• Withhold treatment or permanently discontinue the use of Tisotumab vedotin-tftv based on the severity of grade ≥2 hemorrhage.

Pneumonitis

• Signs of Severe, life-threatening, or fatal pneumonitis has been reported in patients when using antibody drug conjugates containing vedotin including Tisotumab vedotin-tftv.
• Clinical studies showed 1.3% patients displayed signs of pneumonitis where one patient in the study had a fatal outcome of pneumonitis.
• Monitor patients for signs of pneumonitis such as dyspnea, cough, interstitial infiltrates on radiologic exam, or hypoxia.
• Dose reductions of Tisotumab vedotin-tftv may occur if patients display persistent or recurrent Grade 2 pneumonitis.
• Patients that display Grade 3 or 4 pneumonitis should permanently discontinue the use of Tisotumab vedotin-tftv.

Embryo-Fetal Toxicity

• Fetal harm may occur in pregnant women taking Tisotumab vedotin-tftv based on animal studies.
• MMAE caused structural abnormalities and embryo-fetal mortality in rats.
• Advise females about potential risks to a fetus when taking Tisotumab vedotin-tftv.
• Advise females of reproductive potential to use effective contraception during treatment with Tisotumab vedotin-tftv and for at least 2 months after the last dose.
• Advise males of reproductive potential to use effective contraception during treatment with Tisotumab vedotin-tftv and for at least 4 months after the last dose.

Adverse Reactions

Clinical Trials Experience

Clinical Trial Experiance

• Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions of Tisotumab vedotin-tftv was looked into 158 patients with recurrent or metastatic cervical cancer. These patients all received at least one dose of Tisotumab vedotin-tftv at 2 mg/kg intravenously every 3 weeks in innovaTV 201 (NCT02001623), innovaTV 203 (NCT03245736), innovaTV 202 (NCT02552121), and innovaTV 204 (NCT03438396).

InnovaTV 204 Study

• 43% of patients displayed serious adverse reactions from the innovaTV 204. Of the patients that displayed serious adverse reactions included pneumonia (4%), ileus (6%), peripheral neuropathy (3%), pyrexia (3%), hemorrhage (5%), sepsis (3%), and constipation (3%) were the most common.
• 4% of patients taking Tisotumab vedotin-tftv displayed fatal adverse reactions. Some of the fatal adverse reactions included pneumonitis (1%), multisystem organ failure (1%), sudden death (1%), and septic shock (1%).
• 13% of patients had to permanently discontinue Tisotumab vedotin-tftv treatment when experiencing adverse reactions. Corneal adverse reactions (4%) and peripheral neuropathy (5%) were the most common adverse reactions in patients who had to discontinue Tisotumab vedotin-tftv treatment.
• 47% of patients had dose interruption with Tisotumab vedotin-tftv treatment when experiencing adverse reactions. Hemorrhage (4%), peripheral neuropathy (8%), and conjunctival adverse reactions (4%) were the most common adverse reactions in patients who had dose interruption with Tisotumab_vedotin-tftv treatment.
• 23% of patients had dose reduction with Tisotumab vedotin-tftv treatment when experiencing adverse reactions. Corneal adverse reactions (9%) and conjunctival adverse reactions (8%) were the most common adverse reactions in patients who had dose reduction with Tisotumab vedotin-tftv treatment.
• In laboratory abnormalities, nausea, peripheral neuropathy, alopecia, epistaxis, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, hemoglobin decreased, fatigue, lymphocytes decreased, conjunctival adverse reactions, diarrhea, and rash were the most common adverse reactions (≥25%) when taking Tisotumab vedotin-tftv.

Table 4 summarizes InnovaTV 204 Adverse Reactions.

Insert Table 4

Table 5 summarizes InnovaTV 204 Laboratory Abnormalities.

Insert Table 5

Immunogenicity

• Tisotumab vedotin-tftv may have an immune response. Specificity and sensitivity of the assay play a role in the formation of antibodies against Tisotumab vedotin-tftv. Assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease are factors that influence the positivity of antibody incidence.
• Immunogenicity of Tisotumab vedotin-tftv was tested in 93 patients in the InnovaTV 204 study. Anti-Tisotumab vedotin-tftv antibodies were found in 5% of patients. 2 patients showed signs of neutralizing anti-Tisotumab vedotin-tftv antibodies. 5.5% patients with cervical cancer from all the studies displayed anti-Tisotumab vedotin-tftv antibodies. The studies did not indicate a conclusion on the potential effect of immunogenicity on safety or efficacy.

Postmarketing Experience

There is limited information about "Postmarketing Experiance" in the drug label.

Drug Interactions

Strong CYP3A4 Inhibitors

• A substrate of CYP3A4 is MMAE.
• Increase in unconjugated MMAE exposure may occur in patients with concomitant use of strong CYP3A4 inhibitors and Tisotumab vedotin-tftv.
• Increase in adverse reactions may also occur in patients with concomitant use of strong CYP3A4 inhibitors and Tisotumab vedotin-tftv.
• Monitor patients for any adverse reactions that may occur with concomitant use of strong CYP3A4 inhibitors and Tisotumab vedotin-tftv.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Reproduction studies done on pregnant rats has shown that fetal harm can be associated with Tisotumab vedotin-tftv treatment. Structural abnormalities and embryo-fetal mortality was seen in pregnant rats during the period of organogenesis when receiving MMAE (small molecule component of Tisotumab vedotin-tftv. Structural abnormalities seen in pregnant rats are malrotated limbs, gastroschisis, protruding tongue, and agnathia when given 0.2 mg/kg of Tisotumab vedotin-tftv. Advise female patients about risks associated to the fetus when taking Tisotumab vedotin-tftv.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tisotumab vedotin-tftv in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Tisotumab vedotin-tftv during labor and delivery.

Nursing Mothers

No data is present on the effects on the breastfed child and the effects on milk production when treated with Tisotumab vedotin-tftv. Advise female patients to not nurse when taking Tisotumab vedotin-tftv and for 3 weeks after the last dose due to the serious adverse reactions reported in studies.

Pediatric Use

There is no FDA guidance on the use of Tisotumab vedotin-tftv in pediatric settings.

Geriatic Use

13% of patients in the innovaTV 204 study treated with Tisotumab vedotin-tftv were greater than 65 years of age. 69% of patients greater than 65 years of age showed signs of grade ≥3 adverse reactions. 59% of patients under 65 years of age also showed signs of grade ≥3 adverse reactions. 54% of patients greater than 65 years of age showed signs of serious adverse reactions. 41% of patients under 65 years of age also showed signs of serious adverse reactions.

Gender

There is no FDA guidance on the use of Tisotumab vedotin-tftv with respect to specific gender populations.

Race

There is no FDA guidance on the use of Tisotumab vedotin-tftv with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Tisotumab vedotin-tftv in patients with renal impairment.

Hepatic Impairment

Patients with moderate and severe hepatic impairment should avoid Tisotumab vedotin-tftv treatment. Monitor for adverse reactions in patients with mild hepatic impairment. Altering starting dosage of Tisotumab vedotin-tftv is not recommended in patients with mild hepatic impairment.

Females of Reproductive Potential and Males

Fetal harm can be associated with Tisotumab vedotin-tftv treatment in pregnant women. Verify the pregnancy status of the female patient before starting Tisotumab vedotin-tftv. Advise females of reproductive potential to use effective contraception during treatment with Tisotumab vedotin-tftv and for at least 2 months after the last dose. Advise male patients with females of reproductive potential to use effective contraception during treatment with Tisotumab vedotin-tftv and for at least 4 months after the last dose. Infertility may occur in male patients taking Tisotumab vedotin-tftv.

Immunocompromised Patients

There is no FDA guidance one the use of Tisotumab vedotin-tftv in patients who are immunocompromised.

Administration and Monitoring

Administration

• Patients should only administer Tisotumab vedotin-tftv treatment as an intravenous infusion.
• Advise patients about the disposal procedures and special handling of Tisotumab vedotin-tftv.
• Advise patients to not mix Tisotumab vedotin-tftv as an intravenous bolus or push.
• Advise patients to not mix an infusion of other medicinal products and Tisotumab vedotin-tftv.
• Vial should be reconstituted with sterile water before Tisotumab vedotin-tftv administration.
• Dilute reconstituted solution with an intravenous infusion bag containing either Lactated Ringer’s Injection USP, 5% Dextrose Injection USP, or 0.9% Sodium Chloride Injection USP.

Reconstitution in Single-dose Vial

• Patient's weight is the determinant of the number of needed vials.
• Reconstitute each 40 mg vial with 4 mL of sterile water which leads to 10 mg/mL of Tisotumab vedotin-tftv.
• Swirl the vial slowly until all components dissolve completely and allow it to settle.
• Vial should not be shaken or exposed to direct sunlight.
• The vial should be be clear to slightly opalescent, colorless to brownish-yellow and free of visible particles.
• Reconstituted solution from the vial should be immediately added to the infusion bag based on the calculated dose amount.
• Reconstituted vials may be stored in refrigeration at 2°C to 8°C for up to 24 hours.
• Reconstituted vials may be stored at room temperature up to 25°C for up to 8 hours.

Dilution in Infusion Bag

• Withdraw reconstituted solution that will be transferred to the infusion bag.
• Dilute reconstituted solution with an intravenous infusion bag containing either Lactated Ringer’s Injection USP, 5% Dextrose Injection USP, or 0.9% Sodium Chloride Injection USP.
• 0.7 mg/mL to 2.4 mg/mL should be the final concentration of Tisotumab vedotin-tftv.
• Gently invert the diluted solution.
• Solution should not be shaken or exposed to direct sunlight.
• The solution should be be clear to slightly opalescent, colorless to brownish-yellow and free of visible particles.
• Unused portion from the single dose vials should be discarded appropriately.

Administration of Solution

• During infusion, leave ice packs fully over the eyes.
• Ice packs can be changed during infusion, make sure they stay cold.
• Immediately administer the infusion over 30 minutes through an intravenous line containing a 0.2 µm in-line filter.

Table 3 shows the Conditions for Refrigeration Storage of Diluted Tisotumab vedotin-tftv.

Insert Table 3

Monitoring

Table 2 shows the Modifications necessary for any displayed Adverse Reactions.

Insert Table 2

IV Compatibility

There is limited information regarding the compatibility of Tisotumab vedotin-tftv and IV administrations.

Overdosage

There is limited information regarding Tisotumab vedotin-tftv overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Tisotumab vedotin-tftv Pharmacology in the drug label.

Mechanism of Action

• Tisotumab vedotin-tftv is a tissue factor (TF)-directed antibody drug conjugate. Human IgG1 directed against cell surface TF is the antibody. Extrinsic blood coagulation cascade is primarily initiated by TF. A protease-cleavable linker is used to attach the antibody to a microtubule-disrupting agent called MMAE.
• The mechanism seen in nonclinical studies show TF expressing cancer cells binds to ADC of Tisotumab vedotin-tftv which is followed by ADC-TF complex internalization, and the release though proteolytic cleavage of MMAE. Apoptotic cell death and cell cycle arrest occurs with the disruption of microtubule networks of actively dividing cells by MMAE.
• In vitro, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis are mediated by Tisotumab vedotin-tftv treatment.

Structure

• Tisotumab vedotin-tftv is a tissue factor (TF)-directed antibody drug conjugate for Oral Administration. It has a molecular weight of 153 kDa.

Pharmacodynamics

Cardiac Electrophysiology

• There was no large mean effect on QTc prolongation when given Tisotumab vedotin-tftv at the recommended dosage.

Pharmacokinetics

Exposure Parameters

• Near the end of infusion, Tisotumab vedotin-tftv showed a peak in concentrations after patients received one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg.
• 2 to 3 days after patients received their Tisotumab vedotin-tftv dose, concentrations of un-conjugated MMAE peaked.
• After patients received a single dosage (0.3–2.2 mg/kg) of Tisotumab vedotin-tftv, the AUC0-last of Tisotumab_vedotin-tftv increased in a more than dose-proportional manner while the Cmax of Tisotumab_vedotin-tftv increased proportionally.
• Un-conjugated MMAE and Tisotumab vedotin-tftv had no accumulation.
• After 1 treatment cycle, un-conjugated MMAE and tisotumab vedotin-tftv reached their steady-state concentrations.

Table 6 shows the Parameters of Exposure found in Un-conjugated MMAE and Tisotumab Vedotin-tftv.

Insert Table 6

Distribution

• 7.83 L is the steady state volume of distribution found in Tisotumab vedotin-tftv.
• In vitro, MMAE has a 68% to 82% plasma protein binding percentage.

Elimination

• 4.04 days is the median terminal half-life found in Tisotumab vedotin-tftv.
• 2.56 days is the median terminal half-life found in un-conjugated MMAE.
• 1.54 L/day is the linear clearance found in Tisotumab vedotin-tftv.
• 45.9 L/day is the linear clearance found in un-conjugated MMAE.

Metabolism

• Amino acids, un-conjugated MMAE-related catabolites, small peptides, and un-conjugated MMAE are catabolized by Tisotumab vedotin-tftv.
• In vitro, un-conjugated MMAE is released during proteolytic cleavage by Tisotumab vedotin-tftv.
• In vitro, CYP3A4 primarily metabolizes a un-conjugated MMAE.

Excretion

• In feces after a single dosage of an ADC that contains MMAE over the span of 1 week, 17% of MMAE was found in which most was found unchanged.
• In urine after a single dosage of an ADC that contains MMAE over the span of 1 week, 6% of MMAE was found in which most was found unchanged.
• Excretion patterns of MMAE should be similar when patient are given Tisotumab vedotin-tftv to when patients are given a single dosage of an ADC that contains MMAE.

Specific Populations

• Sex, age (21 to 81 years), ethnicity, and race showed no clinically significant differences in Tisotumab vedotin-tftv pharmacokinetics.
• Patients with mild to moderate renal impairment showed no clinically significant differences in exposures to patients with normal renal function when given Tisotumab vedotin-tftv.

Patients with Hepatic Impairment

• Patients with mild hepatic impairment showed a 37% increase in exposures of un-conjugated MMAE compared to patients with normal hepatic function.

Drug Interaction Studies Clinical Studies:

• Strong CYP3A4 Inhibitors: The C­max of un-conjugated MMAE increased by 25% with concomitant use an ADC that contains MMAE and Ketoconazole (strong CYP3A4 inhibitor). The AUC of un-conjugated MMAE increased by 34% with concomitant use an ADC that contains MMAE and Ketoconazole. No changes to exposure were detected in ADC with concomitant use an ADC that contains MMAE and Ketoconazole.
• Strong CYP3A4 Inducers: The C­max of un-conjugated MMAE decreased by 44% with concomitant use an ADC that contains MMAE and Rifampin (strong CYP3A4 inducer). The AUC of un-conjugated MMAE decreased by 46% with concomitant use an ADC that contains MMAE and Rifampin. No changes to exposure were detected in ADC with concomitant use an ADC that contains MMAE and Rifampin.

In Vitro Studies:

• Cytochrome P450 (CYP) Enzymes: CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP1A2, or CYP2C19 are not inhibited by MMAE. In human hepatocytes, major CYP450 enzymes are not induced by MMAE.
• Transporter Systems: A substrate of P-gp is MMAE. P-gp is not inhibited by MMAE.

Nonclinical Toxicology

There is limited information regarding Tisotumab vedotin-tftv Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Tisotumab vedotin-tftv Clinical Studies in the drug label.

How Supplied

There is limited information regarding Tisotumab vedotin-tftv How Supplied in the drug label.

Storage

There is limited information regarding Tisotumab vedotin-tftv Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Tisotumab vedotin-tftv Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Tisotumab vedotin-tftv interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Tisotumab vedotin-tftv Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Tisotumab vedotin-tftv Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.