Tivdak Injection, Powder, For Solution
FDA Label NDC 51144-003

• TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. [see Warnings and Precautions (5.1)]
• Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].
• Adhere to premedication and required eye care before, during, and after infusion [see Dosage and Administration (2.2)].
  
• Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].
  

TIVDAK™ is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.1)].
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

The recommended dose of TIVDAK is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Adhere to the following recommendations to reduce the risk of ocular adverse reactions [see Warnings and Precautions (5.1)].

• Ophthalmic exam: Conduct an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated.
  
• Topical corticosteroid eye drops: The initial prescription and all renewals of any corticosteroid medication should be made only after examination with a slit lamp. Administer first drop in each eye prior to each infusion. Instruct patients to continue to administer eye drops in each eye as prescribed for 72 hours after each infusion.
  
• Topical ocular vasoconstrictor drops: Administer in each eye immediately prior to each infusion.
  
• Cold packs: Use cooling eye pads during the infusion of TIVDAK.
  
• Topical lubricating eye drops: Instruct patients to administer for the duration of therapy and for 30 days after the last dose of TIVDAK.
  
• Contact lenses: Advise patients to avoid wearing contact lenses unless advised by their eye care provider for the entire duration of therapy.
  

The recommended TIVDAK dose reduction schedule is provided in Table 1.

The recommended dose modifications for adverse reactions are provided in Table 2. 

• Administer TIVDAK as an intravenous infusion only.
• TIVDAK is a hazardous drug. Follow applicable special handling and disposal procedures¹.
  
• DO NOT mix TIVDAK as an intravenous push or bolus.
  
• DO NOT mix TIVDAK with, or administer as an infusion with, other medicinal products.
  

Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.  Prior to administration, the TIVDAK vial is reconstituted with Sterile Water for Injection, USP. The reconstituted solution is subsequently diluted in an intravenous infusion bag containing one of the following: 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP.

Reconstitution in Single-dose Vial

• Calculate the recommended dose based on the patient’s weight to determine the number of vials needed.
  
• Reconstitute each 40 mg vial with 4 mL of Sterile Water for Injection, USP, resulting in 10 mg/mL TIVDAK.
  
• Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle. DO NOT SHAKE THE VIAL. Do not expose to direct sunlight.
  
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colorless to brownish-yellow and free of visible particles. Discard any vial with visible particles or discoloration.
  
• Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain a preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours in refrigeration at 2°C to 8°C (36 °F to 46 °F) or at room temperature up to 25°C (77°F) for up to a maximum of 8 hours prior to dilution. DO NOT FREEZE. Do not expose to direct sunlight.  Discard unused vials with reconstituted solution beyond the recommended storage time.
  

Dilution in Infusion Bag

• Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.
• Dilute TIVDAK with one of the following: 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP or Lactated Ringer's Injection, USP. The infusion bag size should allow enough diluent to achieve a final concentration of 0.7 mg/mL to 2.4 mg/mL TIVDAK.
• Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG.  Do not expose to direct sunlight.
  
• Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to brownish-yellow and free of visible particles. Discard the infusion bag if particulate matter or discoloration is observed.
  
• Discard any unused portion left in the single-dose vials.
  

Administration

• Confirm administration of steroid and vasoconstrictor eye drops [see Dosage and Administration (2.2)].
• Apply cold packs fully over the eyes following administration of the vasoconstrictor eye drops and leave on during the infusion. Change cold packs as needed throughout infusion to ensure eye area remains cold [see Dosage and Administration (2.2)].
• Immediately administer the infusion over 30 minutes through an intravenous line containing a 0.2 µm in-line filter.
  
• If the infusion is not administered immediately, store the diluted TIVDAK solution in refrigeration as specified in Table 3. Discard if storage time exceeds these limits. DO NOT FREEZE. Once removed from refrigeration, complete administration of the diluted infusion solution of TIVDAK within 4 hours (including infusion time).
  

Table 3: Diluted TIVDAK Solution Refrigeration Storage Conditions

Diluent Used to Prepare Solution for Infusion	Diluted TIVDAK Solution Storage Conditions (Including Infusion Time)
0.9% Sodium Chloride Injection, USP	Up to 18 hours at 2°C to 8°C (36°F to 46°F)
5% Dextrose Injection, USP	Up to 24 hours at 2°C to 8°C (36°F to 46°F)
Lactated Ringer’s Injection, USP	Up to 12 hours at 2°C to 8°C (36°F to 46°F)

For Injection: 40 mg of tisotumab vedotin-tftv as a white to off-white lyophilized cake or powder in a single-dose vial for reconstitution.

None.

Ocular adverse reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common ocular adverse reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose.

The median time to onset of the first ocular adverse reaction was 1.2 months (range, 0 – 6.5). Of the patients who experienced ocular events, 55% had complete resolution and 30% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Ocular adverse reactions led to discontinuation of TIVDAK in 6% of patients with cervical cancer.

In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions [see Dosage and Administration (2.2)].
Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms.

Withhold, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction [see Dosage and Administration (2.3)].

Peripheral neuropathy occurred in 42% of patients with cervical cancer treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain-Barre syndrome.

The median time to onset of peripheral neuropathy was 2.4 months (range, 0-11.3). Of the patients who experienced peripheral neuropathy, 17% had complete resolution and 17% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Peripheral neuropathy led to discontinuation of TIVDAK in 8% of patients with cervical cancer.

Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, withhold dose, then dose reduce, or permanently discontinue TIVDAK based on the severity of peripheral neuropathy [see Dosage and Administration (2.3)].

Hemorrhage occurred in 62% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.

The median time to onset of hemorrhage was 0.3 months (range, 0-6.5). Of the patients who experienced hemorrhage, 71% had complete resolution and 11% had partial resolution (defined as a decrease in severity by one or more grades from the worst grade) at last follow-up.

Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For grade ≥2 hemorrhage in any other location, withhold 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. After resolution, either resume treatment or permanently discontinue TIVDAK [see Dosage and Administration (2.3)].

Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody drug conjugates containing vedotin including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms indicative of pneumonitis. Symptoms may include hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations.

Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis [see Dosage and Administration (2.3)].

Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman. The small molecule component of TIVDAK, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, 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 TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3), and Clinical Pharmacology (12.1)].

The following serious adverse reactions are described elsewhere in the labeling:

• Ocular Adverse Reactions [see Boxed Warning, Warnings and Precautions (5.1)]
• Peripheral Neuropathy [see Warnings and Precautions (5.2)]
• Hemorrhage [see Warnings and Precautions (5.3)]
  
• Pneumonitis [see Warnings and Precautions (5.4)]
  

Because clinical trials are conducted under widely varying conditions, 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 data in the WARNINGS AND PRECAUTIONS section reflect exposure to TIVDAK in 158 patients with recurrent or metastatic cervical cancer who received at least one dose of TIVDAK at 2 mg/kg intravenously every 3 weeks in innovaTV 204 (NCT03438396), innovaTV 201 (NCT02001623), innovaTV 202 (NCT02552121) and innovaTV 203 (NCT03245736).

The data described in this section reflect exposure to TIVDAK from innovaTV 204 (NCT0348396), a single arm study in patients (n=101) with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Patients received TIVDAK 2.0 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7-16).

Serious adverse reactions occurred in 43% of patients. The most common (≥3%) serious adverse reactions were ileus (6%), hemorrhage (5%), pneumonia (4%), peripheral neuropathy, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock (1%), pneumonitis (1%), sudden death (1%), and multisystem organ failure (1%).

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to permanent discontinuation were peripheral neuropathy (5%) and corneal adverse reactions (4%).

Adverse reactions leading to dose interruption occurred in 47% of patients; the most (≥3%) common adverse reactions leading to dose interruption were peripheral neuropathy (8%), conjunctival adverse reactions (4%), and hemorrhage (4%).

Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) adverse reactions leading to dose reduction were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash.

Table 4 summarizes the all grade and Grade 3-4 adverse reactions from innovaTV 204.

Clinically relevant adverse reactions in <10% of patients who received TIVDAK in innovaTV 204 included venous thrombosis (3%), pulmonary embolism (3%), and pneumonitis (2%).

Table 5 summarizes the laboratory abnormalities in innovaTV 204.

As with all therapeutic proteins, there is potential for an immune response to TIVDAK. The detection of antibody formation against tisotumab vedotin-tftv is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tisotumab vedotin-tftv in other studies or to other products may be misleading.

In innovaTV 204, a total of 93 patients were tested for immunogenicity to TIVDAK; 5 patients (5%) developed treatment-emergent anti-tisotumab vedotin-tftv antibodies. Neutralizing anti-tisotumab vedotin-tftv antibodies were detected in 2 patients in Study innovaTV 204. Across all studies, 8 cervical cancer patients (5.5%) out of 145 evaluable patients developed treatment-emergent anti-tisotumab vedotin-tftv antibodies. Given the low number of patients who developed anti-tisotumab vedotin-tftv antibodies, no conclusions can be drawn concerning a potential effect of immunogenicity on PK, efficacy or safety.

Strong CYP3A4 Inhibitors
MMAE is a CYP3A4 substrate. Concomitant use of TIVDAK with strong CYP3A4 inhibitors may increase unconjugated MMAE exposure [see Clinical Pharmacology (12.3)], which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for adverse reactions of TIVDAK when used concomitantly with strong CYP3A4 inhibitors.

Risk Summary

Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on TIVDAK use in pregnant women to inform a drug-associated risk.  In an animal reproduction study, administration of the small molecule component of TIVDAK, MMAE, to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at exposures below the clinical exposure at the recommended dose (see Data). Advise patients of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data
Animal Data

No embryo-fetal development studies in animals have been performed with tisotumab vedotin-tftv. In an embryo-fetal development study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of TIVDAK, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose).

Risk Summary

There are no data on the presence of tisotumab vedotin-tftv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with TIVDAK and for 3 weeks after the last dose.

TIVDAK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy testing

Verify pregnancy status in females of reproductive potential prior to initiating TIVDAK treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose.

Males

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

Infertility

Males

Based on findings from animal studies, TIVDAK may impair male fertility [see Nonclinical Toxicology (13.1)].

Safety and effectiveness of TIVDAK in pediatric patients have not been established.

Of the 101 patients treated with TIVDAK in innovaTV 204, 13% were ≥65 years of age. Grade ≥3 adverse reactions occurred in 69% patients ≥65 years and in 59% patients <65 years. Serious adverse reactions occurred in 54% patients ≥65 years and in 41% patients <65 years.  No patients aged ≥65 years treated with TIVDAK in innovaTV 204 experienced a tumor response.

Avoid use of TIVDAK in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN) [see Clinical Pharmacology (12.3)].

In patients with mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin > 1 to 1.5 × ULN and any AST), closely monitor patients for adverse reactions of TIVDAK, but no dosage adjustment in the starting dose of TIVDAK is recommended.

Tisotumab vedotin-tftv is a Tissue Factor (TF) directed antibody drug conjugate (ADC) comprised of a human anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable vc (valine-citrulline) linker. The monoclonal antibody is produced in a mammalian cell cline (Chinese hamster ovary). MMAE and the linker are produced by chemical synthesis. Each monoclonal antibody molecule carries an average of 4 MMAE molecules. Tisotumab vedotin-tftv has an approximate molecular weight of 153 kDa. The chemical structure is as follows:

                                                                                      Figure 1. Structural Formula

Structural Formula (Structure)

TIVDAK (tisotumab vedotin-tftv) for injection, is provided as a sterile, preservative-free, white to off-white lyophilized cake or powder in a single-dose vial for infusion after dilution. Following reconstitution with 4 mL of Sterile Water for Injection, a clear to slightly opalescent, colorless to brownish-yellow solution containing 10 mg/mL tisotumab vedotin-tftv is produced [see Dosage and Administration (2.3)]. Each mL of reconstituted solution contains 10 mg of tisotumab vedotin-tftv, d-mannitol (30 mg), l-histidine (2.11 mg), l-histidine monohydrochloride (3.44 mg), and sucrose (30 mg), at pH 6.0.

Tisotumab vedotin-tftv is a tissue factor (TF)-directed antibody drug conjugate (ADC). The antibody is a human IgG1 directed against cell surface TF. TF is the primary initiator of the extrinsic blood coagulation cascade. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggests that the anticancer activity of tisotumab vedotin-tftv is due to the binding of the ADC 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 apoptotic cell death. In vitro, tisotumab vedotin-tftv also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

Tisotumab vedotin-tftv exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

Cardiac Electrophysiology

At the recommended dose, tisotumab vedotin-tftv had no large mean effect on QTc prolongation (>20 msec).

Table 6 summarizes the exposure parameters of tisotumab vedotin-tftv and unconjugated MMAE (the cytotoxic component of tisotumab vedotin-tftv) following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg to patients. Tisotumab vedotin-tftv concentrations peaked near the end of the infusion, while unconjugated MMAE concentrations peaked approximately 2 to 3 days after tisotumab vedotin-tftv dosing. Tisotumab vedotin-tftv Cmax increased proportionally, while AUC0-last increased in a more than dose-proportional manner, after a single dose ranging from 0.3–2.2 mg/kg (0.15 to 1.1 times the approved recommended dose). There was no accumulation of tisotumab vedotin-tftv and unconjugated MMAE. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after 1 treatment cycle.

Distribution

The tisotumab vedotin-tftv steady state volume of distribution is 7.83 (%CV: 19.1) L. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.

Elimination

The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively. The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv. 

Metabolism

Tisotumab vedotin-tftv is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Tisotumab vedotin-tftv releases unconjugated MMAE via proteolytic cleavage, and unconjugated MMAE is primarily metabolized by CYP3A4 in vitro.

Excretion

The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv administration.

Specific Populations

No clinically significant differences in the pharmacokinetics of tisotumab vedotin-tftv were observed based on age (21 to 81 years), sex, race (white vs non-white) or ethnicity (Hispanic or Latino vs non-Hispanic or non-Latino). No clinically significant differences in exposures of tisotumab vedotin-tftv and unconjugated MMAE were observed in patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min using the Cockcroft-Gault equation) compared to patients with normal renal function. The effect of severe renal impairment (CLcr 15 to < 30 mL/min) or end-stage renal disease with or without dialysis on pharmacokinetics of tisotumab vedotin-tftv and unconjugated MMAE is unknown.

Patients with Hepatic Impairment

Unconjugated MMAE exposures were 37% higher, but there were no clinically significant differences in exposures of tisotumab vedotin-tftv in patients with mild hepatic impairment (bilirubin of 1 to 1.5 X ULN and AST < ULN, or bilirubin ≤ ULN and AST > ULN) compared to patients with normal hepatic function. The effect of moderate or severe hepatic impairment (AST > 3 x ULN or total bilirubin > 1.5 x ULN) or liver transplantation on the pharmacokinetics of tisotumab vedotin-tftv or unconjugated MMAE is unknown.

Drug Interaction Studies

Clinical Studies

No clinical studies evaluating the drug-drug interaction potential of tisotumab vedotin-tftv have been conducted. To characterize the drug-drug interaction potential of unconjugated MMAE, clinical studies with another ADC that contains MMAE are described below, and similar effects on tisotumab vedotin-tftv and unconjugated MMAE exposures are expected with concomitant use of TIVDAK.

There were no clinically significant differences in midazolam (sensitive CYP3A4 substrate) pharmacokinetics when used concomitantly with another ADC that contains MMAE. 

Strong CYP3A4 Inhibitors: Ketoconazole (strong CYP3A4 inhibitor) used concomitantly with another ADC that contains MMAE increased unconjugated MMAE C­_max by 25% and AUC by 34%, with no change in ADC exposure.

Strong CYP3A4 Inducers: Rifampin (strong CYP3A4 inducer) used concomitantly with another ADC that contains MMAE decreased unconjugated MMAE C_max by 44% and AUC by 46%, with no change in ADC exposure.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.  MMAE did not induce any major CYP450 enzymes in human hepatocytes.

Transporter Systems: MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.

Carcinogenicity studies in animals have not been performed with tisotumab vedotin-tftv or MMAE.

MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism. MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178 TK^+/- mouse lymphoma forward mutation assay.

Fertility studies with tisotumab vedotin-tftv or MMAE have not been conducted. However, results of a repeat-dose toxicity study in monkeys indicate the potential for tisotumab vedotin-tftv to impair male reproductive function and fertility.  

In a repeat-dose toxicology study conducted in monkeys for 13 weeks, doses ≥1 mg/kg tisotumab vedotin-tftv (≥0.6 times the human exposure [AUC] at the recommended dose) resulted in decreased testicular size and seminiferous tubule atrophy, reduction or absence in sperm count, and decreased sperm motility. Findings of sperm absence and decreased motility did not reverse by the end of the recovery period at doses ≥3 mg/kg (≥1.7 times the human exposure [AUC] at the recommended dose).

The efficacy of TIVDAK was evaluated in innovaTV 204 (NCT03438396), an open-label, multicenter, single-arm trial that treated 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Patients were excluded if they had active ocular surface disease, any prior episode of cicatricial conjunctivitis or Stevens Johnson syndrome, Grade ≥2 peripheral neuropathy or known coagulation defects leading to an increased risk of bleeding.

Patients received TIVDAK 2 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks for the first 30 weeks and every 12 weeks thereafter.

The median age was 50 years (range: 31 to 78); 95% were White, 2% were Asian, and 1% were Black. Six percent of patients were Hispanic or Latino. Sixty-eight percent of patients had squamous cell carcinoma, 27% had adenocarcinoma, and 5% had adenosquamous histology. ECOG performance status was 0 (58%) or 1 (42%). Seventy percent of patients had received 1 prior line of systemic therapy, and 30% had 2 prior lines of systemic therapy. Sixty-nine percent of patients previously received bevacizumab as part of their prior systemic therapy. Sixty-three percent received bevacizumab in combination with chemotherapy (paclitaxel and cisplatin or carboplatin, or paclitaxel and topotecan) as first-line therapy.

The major efficacy outcome measures were confirmed objective response rate (ORR) as assessed by an independent review committee (IRC) using RECIST v1.1 criteria and duration of response (DOR). 

Efficacy results are presented in Table 7.

• OHSA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index/html
  

How Supplied

TIVDAK (tisotumab vedotin-tftv) is supplied as a white to off-white lyophilized cake or powder in a 40 mg single-dose vial for reconstitution. TIVDAK vials are available in the following packages:

• Carton of one 40 mg single-dose vial [NDC 51144-003-01]

Storage
Store TIVDAK vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.

Special Handling

TIVDAK is a hazardous drug. Follow special handling and disposal procedures.¹

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Ocular Adverse Reactions

• Inform patients about the eye exam they will receive before treatment and prior to each dose.
• Inform patients that ocular adverse reactions may occur during treatment with TIVDAK and to contact their healthcare provider if they experience new or worsening ocular signs and symptoms [see Warnings and Precautions (5.1)].
• Instruct patients to bring their eye drops to each infusion and advise on how to administer the eye drops throughout treatment [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].
  
• Inform patients to avoid wearing contact lenses during treatment unless directed by an eye care provider [see Dosage and Administration (2.2)].
  

Peripheral Neuropathy

• Advise patients to report to their healthcare provider any numbness and tingling of the hands or feet or muscle weakness [see Warnings and Precautions (5.2)].

Hemorrhage

• Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage [see Warnings and Precautions (5.3)].
  

Pneumonitis

• Advise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise patients to inform their healthcare providers of a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].
• 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 [see Use in Specific Populations (8.1, 8.3)].
  

Lactation

• Advise women not to breastfeed during treatment with TIVDAK and for 3 weeks after the last dose [see Use in Specific Populations (8.2)].

Manufactured by:
Seagen Inc.
Bothell, WA 98021
1-855-4SEAGEN

Marketed by:
Seagen Inc.
Bothell, WA 98021
and
Genmab US, Inc.
Plainsboro, NJ 08536

U.S. License 2257
TIVDAK^TM is a trademark owned by Seagen Inc.
©2021 Seagen Inc. and Genmab US, Inc.

                                                                                                                                           MEDICATION GUIDE
                                                                                                                                             TIVDAK (TIV-dack)
                                                                                                                                          (tisotumab vedotin-tftv)
                                                                                                                                   for injection, for intravenous use

What is the most important information I should know about TIVDAK?
TIVDAK can cause serious side effects, including:

• Eye problems.  Eye problems are common with TIVDAK, and can also be serious. TIVDAK can cause changes to the surface of your eye that can lead to dry eyes, eye redness, eye irritation, corneal ulcers, blurred vision, and severe vision loss. Tell your healthcare provider if you develop new or worsening vision changes or eye problems during treatment with TIVDAK.
  • Your healthcare provider will send you to an eye specialist to check your eyes before you start treatment with TIVDAK, before each dose of TIVDAK, and as needed for any new or worsening signs and symptoms of eye problems.
  • Your healthcare provider will prescribe 3 different types of eye drops before you start treatment with TIVDAK.
    Bring the eye drops with you to each infusion and use them as directed by your healthcare provider to reduce your risk of eye problems:
    • You should use steroid eye drops before each infusion and as prescribed for 72 hours after each infusion.
    • You should use vasoconstrictor eye drops right before each infusion.
      
    • You should use lubricating eye drops throughout treatment and for 30 days after your last dose of TIVDAK.
    • Do not wear contact lenses throughout your treatment with TIVDAK unless you are told to use them by your eye specialist.
      

    See “What are the possible side effects of TIVDAK? for more information about side effects.

    What is TIVDAK?

    TIVDAK is a prescription medicine used to treat adults with cervical cancer:

    • that has returned or has spread to other parts of the body, and
    • who have received chemotherapy that did not work or is no longer working.

    It is not known if TIVDAK is safe and effective in children.

    Before receiving TIVDAK, tell your healthcare provider about all of your medical conditions, including if you:

    • have a history of vision or eye problems
    • have numbness or tingling in your hands or feet
    • have bleeding problems
      
    • have liver problems
      
    • are pregnant or plan to become pregnant. TIVDAK can harm your unborn baby.  Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TIVDAK.
      

          Females who are able to become pregnant:
    

    • Your healthcare provider should do a pregnancy test before you start treatment with TIVDAK.
    • You should use an effective birth control during treatment and for 2 months after your last dose of TIVDAK.

          Males with female partners who are able to become pregnant:

    • You should use an effective birth control during treatment and for 4 months after your last dose of TIVDAK.
    • are breastfeeding or plan to breastfeed. It is not known if TIVDAK passes into your breast milk. Do not breastfeed during treatment and for 3 weeks after your last dose of TIVDAK.

    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking TIVDAK with certain other medicines may cause side effects.

    How will I receive TIVDAK?

    • TIVDAK will be given to you by intravenous (IV) infusion into your vein over 30 minutes.
    • TIVDAK is usually given every 3 weeks.
    • Your healthcare provider will decide how many infusions you need.
      
    • Your healthcare provider will put cold packs on your eyes during each infusion. Your healthcare provider may decrease your dose, temporarily stop, or completely stop treatment with TIVDAK if you have side effects.
      

    What are the possible side effects of TIVDAK?
    TIVDAK can cause serious side effects, including:

    • See “What is the most important information I should know about TIVDAK?"
    • Peripheral neuropathy. Nerve problems called peripheral neuropathy are common with TIVDAK, and can also be serious. Tell your healthcare provider right away if you get numbness or tingling in your hands or feet or muscle weakness.
    • Bleeding (hemorrhage). Bleeding problems are common with TIVDAK, and can also be serious. Tell your healthcare provider right away if you get signs or symptoms of bleeding during treatment with TIVDAK, including:

    blood in your stools or black stools (looks like tar)  blood in your urine  cough up or vomit blood

    unusual vaginal bleeding  any unusual or heavy bleeding

    • Lung problems. TIVDAK may cause severe or life-threatening inflammation of the lungs that can lead to death. Tell your healthcare provider right away if you get new or worsening symptoms, including trouble breathing, shortness of breath, or cough.

    The most common side effects of TIVDAK include:

    decreased red blood cell and white blood cell counts  tiredness nausea

    hair loss (alopecia)  nosebleed  changes in kidney function blood tests  dry eye

    abnormal blood clotting test results  diarrhea  rash

    TIVDAK may cause fertility problems in males, which may affect your ability to father children. Talk to your healthcare provider if this is a concern for you.
    These are not all the possible side effects of TIVDAK.
    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    General information about the safe and effective use of TIVDAK.
    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about TIVDAK, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TIVDAK that is written for healthcare professionals.

    What are the ingredients in TIVDAK?
    Active ingredient: tisotumab vedotin-tftv
    Inactive ingredients: d-mannitol, l-histidine, l-histidine monohydrochloride, and sucrose.
    
    Manufactured by: Seagen Inc., Bothell, WA 98021, 1-855-4SEAGEN
    Marketed by: Seagen Inc., Bothell, WA 98021 and Genmab US, Inc., Plainsboro, NJ 08536
    U.S. License 2257
    TIVDAK^TM is a trademark owned by Seagen Inc.
    ©2021 Seagen Inc. and Genmab US, Inc.
    For more information, go to www.tivdak.com or call 1-855-4SEAGEN

    This Medication Guide has been approved by the U.S. Food and Drug Administration.                                                                                                                      Issued: September 2021                                             

Rx Only

NDC 51144-003-01

tivdak_™

(tisotumab vedotin-tftv)
for injection

40 mg/vial

CAUTION: Hazardous Agent

For intravenous infusion only

Must reconstitute and dilute before use

One single-dose vial.
Discard unused portion.

Provide the enclosed 
Medication Guide to each patient

Seagen^®

Genmab

Dosage:
See Prescribing Information.

Storage:
Store vial refrigerated at 
2°C to 8°C (36°F to 46°F) in 
original carton to protect from
light. DO NOT FREEZE.
DO NOT SHAKE.

No U.S. Standard of Potency

U.S. License 2257

TIVDAK and the TIVDAK logo 
are trademarks owned by
Seagen Inc.

Logo (Smalllogo)

Carton (Carton)

Rx Only

NDC 51144-003-01

tivdak_™

(tisotumab vedotin-tftv)
for injection

40 mg/vial

For intravenous infusion only

Must reconstitute and dilute before use

Single-dose vial.

Discard unused portion.

CAUTION: Hazardous Agent

Store at 2°C to 8°C (36°F to 46°F)

Protect from light.
DO NOT FREEZE. DO NOT SHAKE.

Dosage: See Prescribing Information

Provide the enclosed Medication Guide to each patient

Mfg by: Seagen Inc. US. License 2257
PRODUCT OF SWITZERLAND

Seagen^® Genmab

Label (Label)