Tisotumab vedotin-tftv
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
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TITLE
See full prescribing information for complete Boxed Warning.
Condition Name: (Content)
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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
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See full prescribing information for complete Boxed Warning.
Condition Name: (Content)
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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
There is limited information regarding Tisotumab vedotin-tftv Mechanism of Action in the drug label.
Structure
There is limited information regarding Tisotumab vedotin-tftv Structure in the drug label.
Pharmacodynamics
There is limited information regarding Tisotumab vedotin-tftv Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Tisotumab vedotin-tftv Pharmacokinetics in the drug label.
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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Package and Label Display Panel
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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.