Tivdak (tisotumab vedotin-tftv)

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.

The manufacturer's recommended dosage reduction schedule and dosing modifications for adverse reactions are provided in 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 Schedule

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 Reactions

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 nonco nfluent 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. Ulcerat ive keratitis or perforation (any occurrence): permanently discontinue. Conjunctival or corneal scarring or Any scarring or symblepharon (any symblepharon occurrence): permanently discontinue. Conjunctivitis and other ocular Nonconfluent superficial punctate adverse reactions 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 conjunctival defects, mild vasodilation, per manently discontinue. Confluent superficial punctate conjunctival defects, moderate to severe vasodilation (third occurrence): permanently discontinue. Conjunctival ulcer, conjunctival neovascularization, or fibrovascular scarring (any occurrence): perman ently 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 do se 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 Suspected, any grade (any (including Stevens-Johnson syndrome occurrence): immediately withhold (SJS)) dose and consult a specialist to confirm the diagnosis Confirmed grade 3 or 4: permanently discontinue

Tisotumab vedotin-tftv is administered by IV infusion only; do not administer as an IV push or bolus. The drug is commercially available as a lyophilized powder that must be reconstituted and diluted prior to administration.

Tisotumab vedotin infusion is administered over 30 minutes through an IV line containing a 0.2 mcm inline filter.

Because the drug can cause severe ocular toxicities, clinicians must adhere to the required premedication and eye care recommendations before, during, and after infusion.

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

No dosing information is available for this tab.

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

The small molecule component of tisotumab vedotin, MMAE, is a cytochrome P-450 (CYP) 3A4 substrate.

In vitro studies indicate that MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6, nor does it induce any major CYP isoenzymes in human hepatocytes.

MMAE is a substrate of P-glycoprotein (P-gp), but does not inhibit P-gp.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Igg Antibodies And Derivatives/Efgartigimod-Alfa

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Efgartigimod-alfa binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of efgartigimod-alfa states that efgartigimod-alfa should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, efgartigimod-alfa should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with efgartigimod-alfa have not been performed. Efgartigimod-alfa may decrease concentrations of compounds that bind to the human FcRn.(3)

Igg Antibodies And Derivatives/Nipocalimab-Aahu

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Nipocalimab-aahu binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nipocalimab-aahu states that nipocalimab-aahu should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, nipocalimab-aahu should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with nipocalimab-aahu have not been performed. Nipocalimab-aahu may decrease concentrations of compounds that bind to the human FcRn.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Igg Antibodies And Derivatives/Rozanolixizumab-Noli

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Rozanolixizumab-noli binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medications that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of rozanolixizumab-noli states that concurrent use with medications that bind to the human neonatal Fc receptor (FcRn) should be closely monitored for reduced effectiveness of these medications. If long-term use of such medications is essential for the patient, consider discontinuing rozanolixizumab-noli and use alternative therapies.(3)

DISCUSSION: Clinical drug interaction studies with rozanolixizumab-noli have not been performed. Rozanolixizumab-noli may decrease concentrations of compounds that bind to the human FcRn.(3)

Immunosuppressives; Immunomodulators/Covid-19 Vaccines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)

CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.

DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)

Tisotumab/Anticoagulants; Antiplatelets

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding, including hemorrhage, has been reported with the use of tisotumab.(1)

CLINICAL EFFECTS: Concurrent use of tisotumab with either anticoagulants, antiplatelets, or NSAIDs may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with tisotumab and anticoagulants, antiplatelets, and/or NSAIDs should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR). For patients experiencing pulmonary or central nervous system (CNS) hemorrhage, permanently discontinue tisotumab. For grade 2 or greater 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. After resolution, either resume treatment or permanently discontinue tisotumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Hemorrhage occurred in 62% of patients with cervical cancer treated with tisotumab 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.(1)

*None.

• Lactation

• Hemorrhage
• Peripheral neuropathy
• Pregnancy

• Child-pugh class A hepatic impairment

The most common (>=25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, peripheral neuropathy, conjunctival adverse reactions, nausea, fatigue, increased AST, epistaxis, alopecia, increased ALT, and hemorrhage.

More Frequent

• Hemorrhage
• Leukopenia
• Lymphopenia
• Prolonged activated partial thromboplastin time

Less Frequent

• Conjunctival hemorrhage
• Corneal erosion
• Corneal ulcer
• Hypomagnesemia
• Ileus
• Interstitial pneumonitis
• Keratitis
• Multiple organ failure
• Neutropenic disorder
• Pneumonia
• Pulmonary thromboembolism
• Venous thrombosis

Rare or Very Rare

• Blistering skin
• Maculopapular rash
• Stevens-johnson syndrome
• Vision impairment

More Frequent

• Alopecia
• Blepharitis
• Conjunctivitis
• Diarrhea
• Dry eye
• Epistaxis
• Fatigue
• Nausea
• Peripheral sensory neuropathy
• Skin rash
• Visual changes

Less Frequent

• Acute abdominal pain
• Anorexia
• Arthralgia
• Constipation
• Fever
• Foreign body sensation of eye
• Myalgia
• Ocular itching
• Pain in extremities
• Peripheral motor neuropathy
• Pruritus of skin
• Urinary tract infection
• Vomiting
• Weight loss

Rare or Very Rare

• Skin lesion
• Stomatitis

No enhanced messaging available.

Safety and effectiveness of tisotumab vedotin-tftv in pediatric patients have not been established.

Tisotumab vedotin may cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings from animal studies. Human data are not available to assess the drug-associated risk in pregnant women. In animal studies, the small molecule component of tisotumab vedotin (MMAE) caused embryofetal death and structural abnormalities in pregnant rats at exposure levels lower than those used clinically. MMAE is a synthetic antineoplastic agent that disrupts the microtubule network in cells, leading to cell cycle arrest and apoptosis. Patients should be informed of the potential risk to a fetus.

No data are available on whether tisotumab vedotin is present in human milk or whether the drug has any effects on a breastfed child or on milk production. Due to the potential for serious adverse reactions in a breastfed child, lactating women should be advised not to breastfeed during treatment and for 3 weeks after the final dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Among the 425 patients with cervical cancer treated with tisotumab vedotin-tftv in clinical trials, 14% were 65 years of age and older, and 2.4% were older than 75 years of age. Grade 3 or higher adverse reactions occurred in 60% of patients 65 years of age and older, compared to 55% of those younger than 65 years of age. The drug was discontinued due to adverse reactions in 25% of patients 65 years of age and older, versus 13% of those younger than 65 years. The clinical studies did not include enough patients 65 years of age and older to determine if they respond differently from those younger than 65 years of age.