tissue factor directed antibody drug conjugates
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.
Reduced progression of recurrent or metastatic cervical cancer.
Absorption: IV administration results in complete bioavailability.
Distribution: Minimally distributed to tissues.
Metabolism and 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.
TIME/ACTION PROFILE (plasma concentrations)
|IV||unknown||ADC: end of infusion; MMAE: 2–3 days||unknown|
- 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.
Adverse Reactions/Side Effects
CV: DEEP VEIN THROMBOSIS
Derm: alopecia, pruritus, rash, STEVENS-JOHNSON SYNDROME (SJS)
EENT: blepharitis, conjunctival abrasion/erosion, conjunctival hemorrhage, conjunctival hyperemia, conjunctival scar, conjunctivitis, corneal bleeding, corneal erosion, corneal scar, dry eye, epistaxis, keratitis, ocular hyperemia, blepharitis
F and E: hypomagnesemia, hyponatremia
GI: ↓ appetite, ↓ weight, ↑ 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
MS: ↑creatine kinase, arthralgia, myalgia, muscle weakness
Neuro: fatigue, peripheral neuropathy
Resp: pneumonia, PNEUMONITIS, PULMONARY EMBOLISM
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
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
- May cause changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration; usually begin within first 1–2 mo of therapy. 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. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. If superficial punctate keratitis occurs, monitor patient. For first occurrence of confluent superficial keratitis, hold tisotumab dose until superficial punctate keratitis or normal, then resume therapy at next lower dose. For second occurrence of confluent superficial keratitis, permanently discontinue tisotumab. For first occurrence of conjunctival ulceration, hold dose until complete conjunctival re-epithelialization, then resume therapy at next lower dose. For second occurrence of conjunctival ulceration, permanently discontinue tisotumab. If conjunctival or corneal scarring or symblepharon occur, permanently discontinue tisotumab. If Grade 1 conjunctivitis and other ocular adverse reactions occur, monitor patient. For first occurrence of Grade 2 conjunctivitis and other ocular adverse reactions, hold dose until Grade ≤1, then resume therapy at same dose. For second occurrence, hold dose until Grade ≤1, then resume therapy at next lower dose level. If no resolution to Grade ≤1, permanently discontinue. For third occurrence of Grade 3 or 4 conjunctivitis, permanently discontinue tisotumab.
- Monitor for signs and symptoms of neuropathy, (paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, dysesthesia) during therapy; usually occurs within first 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
Monitor for signs and symptoms of hemorrhage. If pulmonary or CNS hemorrhage occurs, permanently discontinue tisotumab. For Grade 2 hemorrhage in any other location, hold tisotumab until bleeding has resolved then resume at same dose. For first occurrence of Grade 3 hemorrhage in any other location, hold tisotumab until bleeding has resolved then resume at same dose. For second occurrence of Grade 3 or Grade 4 hemorrhage, permanently discontinue tisotumab.
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, consider resuming therapy at next lower dose. If Grade 3 or 4 pneumonitis occurs, discontinue tisotumab permanently.
- 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 Tivdak until cause has been determined. Permanently discontinue Tivdak for confirmed Grade 3 or 4 severe cutaneous adverse reactions, including SJS.
Lab Test Considerations:
Verify negative pregnancy test before starting therapy.
- May cause ↓ hemoglobin, ↓ lymphocytes, ↓ leukocytes, and ↓ neutrophils.
- May cause ↑ serum creatinine, AST, ALT, LDH, urate, alkaline phosphatase, and CK levels.
- May cause ↓ blood glucose, sodium, magnesium, and albumin.
- May cause ↑ PT, INR, and aPTT.
- After examination with a slit lamp, administer first drop of topical corticosteroid eye drops in each eye prior to each infusion. Instruct patient to continue to administer eye drops in each eye for 72 hr after each infusion.
- Administer topical ocular vasoconstrictor drops in each eye immediately prior to each infusion. Change cold packs as needed during infusion to ensure eye area remains cold.
- Use cooling eye pads during the infusion.
- Recommended Dose Reductions: Starting dose: 2 mg/kg. First dose reduction: 1.3 mg/kg. Second dose reduction: 0.9 mg/kg
- IV Solution should be prepared in a biologic cabinet. 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. Add to diluent immediately. Reconstituted solution is stable for 8 hr at room temperature or 24 hr if refrigerated; do not freeze. Concentration: 10 mg/mL. Dilution: Dilute further with D5W, 0.9% NaCl, or LR. Mix by gentle inversion. Concentration: 0.7 mg/mL to 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 mix with or administer with other medications.
- Explain purpose of tisotumab to patient. Advise patient to read Medication Guide before starting and periodically during therapy in case of changes.
- Inform patient of potential eye problems and eye drop regimen. Instruct patient to use steroid eye drops before each infusion and as prescribed for 72 hr after each infusion. Instruct patient to use vasoconstrictor eye drops right before each infusion. Instruct patient to administer topical lubricating eye drops for duration of therapy and for 30 days after last dose of tisotumab. Advise patient to notify health care professional if new or worsening vision changes or eye problems develop during therapy.
- 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]; rash or itching that continues to get worse; 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.
- 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.
- Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 2 mo after last dose and to avoid breastfeeding during and for 3 wk after last dose. Advise males 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.