tisotumab vedotin

tye-SOT-ue-mab ve-DOE-tin

Therapeutic Classification: antineoplastics

Pharmacologic Classification: antimicrotubulars, tissue factor directed antibody drug conjugates

High Alert

Recurrent or metastatic cervical cancer with disease progression during or after chemotherapy.

Acts as an antibody-drug conjugate (ADC) composed of a human IgG1 monoclonal antibody that is directed against tissue factor (located on the cell surface of cancer cells). Monomethyl auristatin E (MMAE) (an agent that disrupts microtubles and subsequently causes apoptosis) is attached to the antibody via a cleavable linker. The ADC binds to tissue factor on the cancer cells; the complex is then internalized, and then the MMAE is cleaved and released inside the cancer cells.

Therapeutic effects:

Reduced progression of recurrent or metastatic cervical cancer.

Absorption: IV administration results in complete bioavailability.

Distribution: Minimally distributed to tissues.

Metabolism/Excretion: Monoclonal antibody component is degraded into smaller peptides via catabolism. MMAE is primarily metabolized in the liver via the CYP3A4 isoenzyme. 17% of MMAE excreted in feces, and 6% excreted in urine, primarily as unchanged drug.

Half-Life: ADC: 4 days; MMAE: 2.5 days.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
IV	unknown	ADC: end of infusion; MMAE: 2–3 days	unknown

Contraindicated in:

Moderate or severe hepatic impairment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: DEEP VEIN THROMBOSIS

Derm: alopecia, pruritus, rash, STEVENS-JOHNSON SYNDROME (SJS)

EENT: conjunctival abrasion/erosion, conjunctival hemorrhage, conjunctival hyperemia, conjunctival scar, conjunctivitis, corneal bleeding, corneal scar, corneal ulceration, dry eye, epistaxis, keratitis, ocular hyperemia, blepharitis

Endo: hypoglycemia

F and E: hypomagnesemia, hyponatremia

GI: ↑liver enzymes, abdominal pain, constipation, diarrhea, hypoalbuminemia, nausea, vomiting, ileus

GU: ↑serum creatinine, urinary tract infection, ↓fertility (males)

Hemat: ↑activated partial thromboplastin time, ↑prothrombin time, anemia, hemorrhage, leukopenia, lymphocytopenia, neutropenia

Metab: ↓appetite, hyperuricemia, weight loss

MS: ↑creatine kinase, arthralgia, myalgia, muscle weakness

Neuro: fatigue, peripheral neuropathy

Resp: pneumonia, PNEUMONITIS, PULMONARY EMBOLISM

Misc: fever

Drug-drug:

Strong CYP3A4 inhibitors, including ketoconazole, may ↑ levels and risk of toxicity of MMAE; monitor closely.

IV (Adults ≥100 kg): 200 mg every 3 wk; continue until disease progression or unacceptable toxicity.
IV (Adults <100 kg): 2 mg/kg every 3 wk; continue until disease progression or unacceptable toxicity.

Lyophilized powder for injection: 40 mg/vial

Obtain ophthalmic exam (visual acuity, slit lamp exam of the anterior segment of the eye), and assess for normal eye movement, ocular signs and symptoms of dry or irritated eyes, secretions, or blurry vision at baseline before every cycle for the 1st 9 cycles and as clinically indicated. If superficial punctate keratitis occurs, monitor patient. For 1st occurrence of confluent superficial keratitis, corneal epithelial defect, or ≥3 line loss in best corrected visual acuity, hold dose until superficial punctate keratitis or normal; then resume therapy at next lower dose. For 2nd occurrence of confluent superficial keratitis, permanently discontinue tisotumab vedotin. If ulcerative keratitis or perforation occurs, permanently discontinue tisotumab vedotin. If conjunctival scarring, corneal scarring, or symblepharon occurs, permanently discontinue tisotumab vedotin. If nonconfluent superficial punctate conjunctival defects with mild vasodilation occur, monitor patient. If confluent superficial punctate conjunctival defects with moderate to severe vasodilation 1st occurrence, hold dose until resolution or improvement; then resume at same dose. If confluent superficial punctate conjunctival defects with moderate to severe vasodilation 2nd occurrence, hold dose until resolution or improvement; then resume at next lower dose level. If no resolution or improvement, permanently discontinue tisotumab vedotin. If confluent superficial punctate conjunctival defects with moderate to severe vasodilation 3rd occurrence, permanently discontinue tisotumab vedotin. If conjunctival ulcer, conjunctival neovascularization, or fibrovascular scarring occurs, permanently discontinue tisotumab vedotin.
Monitor for signs and symptoms of neuropathy (paresthesia, tingling or burning sensation, neuropathic pain, muscle weakness, dysesthesia) during therapy; usually occurs within 1st 2–3 mo of therapy. If Grade 2 peripheral neuropathy occurs, hold dose until Grade ≤1; then resume therapy at next lower dose. If Grade 3 or 4 peripheral neuropathy occurs, permanently discontinue tisotumab vedotin.
Monitor for signs and symptoms of hemorrhage. If pulmonary or CNS hemorrhage occurs, permanently discontinue tisotumab vedotin. For Grade 2 hemorrhage in any other location, hold tisotumab vedotin until bleeding has resolved; then resume at same dose. For 1st occurrence of Grade 3 hemorrhage in any other location, hold tisotumab vedotin until bleeding has resolved; then resume at same dose. For Grade 4 or 2nd occurrence of Grade 3 hemorrhage, permanently discontinue tisotumab vedotin.
Monitor for signs and symptoms of pneumonitis (hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams) during therapy. If Grade 2 pneumonitis occurs, hold dose until Grade ≤1 for persistent or recurrent pneumonitis and consider resuming therapy at next lower dose. If Grade 3 or 4 pneumonitis occurs, permanently discontinue tisotumab vedotin.
Monitor for signs or symptoms of severe cutaneous adverse reactions (target lesions; worsening skin reactions; blistering or peeling of the skin; painful sores in mouth, nose, throat, or genital area; fever or flu-like symptoms; swollen lymph nodes). If signs or symptoms occur, hold tisotumab vedotin until cause has been determined. For confirmed Grade 3 or 4 severe cutaneous adverse reactions, including SJS, permanently discontinue tisotumab vedotin.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
- May cause ↓ hemoglobin, lymphocytes, leukocytes, and neutrophils.
- May cause ↑ serum creatinine, AST, ALT, LDH, uric acid, alkaline phosphatase, and CK.
- May cause ↓ blood glucose, sodium, magnesium, and albumin.
- May cause ↑ PT, INR, and aPTT.

Topical corticosteroid ophthalmic drops: After examination with a slit lamp, administer one drop in each eye before each infusion. Continue administration in each eye 3 times a day for 72 hr after each infusion.
Topical vasoconstrictor ophthalmic drops: Administer in each eye immediately before each infusion.
Cooling packs: Use cooling eye packs during each infusion. Be sure to fully cover eyes, and change packs to ensure the eyes remain cold throughout the infusion.
Topical lubricating ophthalmic drops: Administer during treatment and for 30 days after last dose.
Contact lenses: Avoid wearing contact lenses for the entire duration of treatment unless advised by a health care professional.
Administer prophylactic antiemetics if needed. Consider a scalp cooling system per guidelines to prevent alopecia.
Recommended Dose Reductions: Starting dose: 2 mg/kg. First dose reduction: 1.3 mg/kg. Second dose reduction: 0.9 mg/kg. Permanently discontinue tisotumab vedotin if unable to tolerate 0.9 mg/kg.

IV Administration:

IV: Wear gloves, gown, and mask while handling medication. If powder or solution comes in contact with skin or mucosa, wash thoroughly with soap and water. Discard equipment in specially designated containers.
Intermittent Infusion: Reconstitution: Reconstitute each 40 mg vial with 4 mL of sterile water for injection. Slowly swirl each vial until contents are completely dissolved; do not shake. Allow reconstituted vial(s) to settle. Do not expose to direct sunlight. Reconstituted solution is clear to slightly opalescent, colorless to brownish-yellow; do not administer solutions that are cloudy, discolored, or contain particulate matter. Reconstituted solution is stable for 8 hr at room temperature or 24 hr if refrigerated; do not freeze. Concentration: 10 mg/mL. Diluent: Dilute further with D5W, 0.9% NaCl, or LR. Mix by gentle inversion. 0.7–2.4 mg/mL. Diluted solution is clear to slightly opalescent, colorless to brownish-yellow; do not administer solutions that are cloudy, discolored, or contain particulate matter. If diluted with 0.9% NaCl, solution is stable up to 18 hr if refrigerated. If diluted with D5W, solution is stable up to 24 hr if refrigerated. If diluted with LR, solution is stable up to 12 hr if refrigerated. Do not freeze. Once removed from refrigerator, complete infusion within 4 hr.
Rate: Infuse over 30 min through an IV line containing a 0.2-micron in-line filter. Do not administer as IV push or bolus.
Y-Site Incompatibility: Do not administer other drugs through same IV line.

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy and periodically during therapy in case of changes.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Inform patient about the eye exams they will receive before starting therapy, before each of the first 9 cycles, and as clinically indicated.
Advise patient about ocular adverse reactions and to contact a health care professional if any occur.
Instruct patient to bring their eye drops to each infusion, and advise on how to administer the eye drops throughout treatment.
Advise patients to avoid wearing contact lenses, unless advised by their eye care provider, for the entire duration of therapy.
Advise patient to notify health care professional immediately if signs and symptoms of bleeding (blood in stools or black stools, blood in urine, cough up or vomit blood, unusual vaginal bleeding, any unusual or heavy bleeding), lung problems (trouble breathing, shortness of breath, cough), severe skin reactions (skin reactions that look like rings [target lesions]; worsening rash or itching; blistering or peeling of skin; painful sores or ulcers in mouth, nose, throat, or genital area; fever or flu-like symptoms; swollen lymph nodes), or peripheral neuropathy (numbness in hands or feet, muscle weakness) occur.
Discuss with patient the possibility of hair loss. Explore methods of coping. May also cause darkening of skin and fingernails.
Rep: May cause fetal harm. Advise women of reproductive potential to use effective contraception during and for 2 mo after last dose and to avoid breastfeeding during therapy and for 3 wk after last dose. Advise men with female partners of reproductive potential to use effective contraception during and for 4 mo after last dose. May impair male fertility.

Reduced progression of recurrent or metastatic cervical cancer.

Tivdak

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Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆