Tisotumab vedotin interacts in the following cases:
No dose adjustment is required in patients with mild hepatic impairment (total bilirubin of >1 to 1.5 × upper limit of normal (ULN) and any aspartate aminotransferase (AST), or total bilirubin ≤ ULN and AST > ULN, as defined using the National Cancer Institute criteria for hepatic impairment). However, as the exposure is expected to increase in patients with mild hepatic impairment, caution is advised when treating patients with mild hepatic impairment. Tisotumab vedotin has not been studied in patients with moderate or severe hepatic impairment.
Ketoconazole (a strong CYP3A4 inhibitor) co-administered with another antibody-drug conjugate (ADC) that contains MMAE increased MMAE exposure, with no change in ADC exposure. The concomitant use of strong inhibitors of CYP3A4 with tisotumab vedotin would likely result in similar effects on unconjugated MMAE and ADC. Caution is advised in case of treatment with strong CYP3A4 inhibitors. Patients should be closely monitored for adverse reactions when tisotumab vedotin is given concomitantly with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole).
Rifampicin (a strong CYP3A4 inducer) co-administered with another ADC that contains MMAE decreased MMAE exposure, with no change in ADC exposure. The concomitant use of strong inducers of CYP3A4 with tisotumab vedotin would likely result in similar effects on unconjugated MMAE and ADC.
Tisotumab vedotin has not been studied in patients with severe renal impairment (CrCL 15 - <30 mL/min) or end-stage renal disease (CrCL <15 mL/min).
Based on findings from animal studies, tisotumab vedotin may impair fertility in males and females.
There are no available data from the use of tisotumab vedotin in pregnant women.
Based on its mechanism of action and findings from animal studies, tisotumab vedotin could cause embryo-foetal harm when administered to a pregnant woman, including embryo-foetal toxicity and structural malformations.
Tisotumab vedotin should not be used during pregnancy unless the clinical condition of the woman requires treatment with tisotumab vedotin.
It is unknown whether tisotumab vedotin is excreted in human milk. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with tisotumab vedotin and for at least 3 weeks after the last dose.
The pregnancy status of women of childbearing potential should be verified prior to initiating tisotumab vedotin treatment. Females of childbearing potential should be advised to use effective contraception during treatment and for at least 2 months after stopping treatment.
Males with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 4 months after the last dose of tisotumab vedotin.
Based on findings from animal studies, tisotumab vedotin may impair fertility in males and females.
Tisotumab vedotin has moderate influence on the ability to drive and use machines. Because of potential adverse reactions such as ocular adverse reactions and peripheral neuropathy, patients should be advised to use caution when driving or operating machines until they are certain that tisotumab vedotin does not adversely affect them. The clinical status of the patient should be considered when assessing the patient’s ability to perform tasks that require judgement, motor, or cognitive skills.
Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 425 patients exposed to at least one dose of tisotumab vedotin 2 mg/kg intravenously during a median duration of 3.7 months in clinical studies.
The most common adverse reactions (≥25%) were peripheral neuropathy (39%), nausea (37%), epistaxis (33%), conjunctivitis (32%), alopecia (31%), anaemia (27%) and diarrhoea (25%).
Severe (Grade ≥3) adverse reactions occurred in 56% of patients. The most common severe adverse reactions (≥2%) were anaemia (10%), peripheral neuropathy (6%), fatigue (5%), abdominal pain (3%), neutropenia (3%), vomiting (2%), asthenia (2%) and diarrhoea (2%).
Serious adverse reactions occurred in 37% of patients. The most common serious adverse reactions (≥2%) were abdominal pain (2%), constipation (2%), pyrexia (2%), peripheral neuropathy (2%) and vomiting (2%). Fatal adverse reactions occurred in 2% of patients.
Adverse reactions leading to treatment discontinuation occurred in 15% of patients receiving tisotumab vedotin; the most common adverse reactions leading to treatment discontinuation (≥2%) were peripheral neuropathy (7%), conjunctivitis (2%) and keratitis (2%).
Adverse reactions leading to dose interruption occurred in 37% of patients; the most common adverse reactions leading to dose interruption (≥2%) were conjunctivitis (6%), peripheral neuropathy (6%) and keratitis (3%).
Adverse reactions leading to dose reduction occurred in 25% of patients; the most common adverse reactions leading to dose reduction (≥2%) were peripheral neuropathy (6%), conjunctivitis (5%) and keratitis (3%).
Adverse reactions observed during clinical studies for tisotumab vedotin are listed by MedDRA System Organ Class and Preferred Term (see table). Within each System Organ Class, adverse reactions are listed under frequency categories of: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1 000 to <1/100); Rare (≥1/10 000 to <1/1 000); Very rare (<1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing frequency.
Adverse reactions:
| System organ class | Frequency category | Adverse reaction |
|---|---|---|
| Blood and lymphatic system disorders | Very common | anaemia |
| Common | neutropenia | |
| Uncommon | febrile neutropenia | |
| Metabolism and nutrition disorders | Very common | decreased appetite |
| Nervous system disorders | Very common | peripheral neuropathy1 |
| Eye disorders | Very common | conjunctivitis, dry eye2, keratitis |
| Common | eye irritation3, blepharitis, punctate keratitis, ulcerative keratitis, eye pruritus, ocular hyperaemia, conjunctival ulcer, entropion, conjunctival hyperaemia, episcleritis, meibomianitis | |
| Uncommon | corneal erosion, trichiasis, vital dye staining cornea present, conjunctival scar, keratopathy, conjunctival disorder, conjunctival erosion, eyelid oedema, madarosis, meibomian gland dysfunction, periorbital oedema, symblepharon, chalazion, conjunctival abrasion, conjunctival oedema, corneal degeneration, corneal irritation, corneal opacity, corneal scar, corneal thinning, erythema of eyelid, eyelid margin crusting, noninfective conjunctivitis, swelling of eyelid | |
| Respiratory, thoracic and mediastinal disorders | Very common | epistaxis |
| Gastrointestinal disorders | Very common | nausea4, diarrhoea5, constipation, abdominal pain6, vomiting |
| Skin and subcutaneous tissue disorders | Very common | alopecia, rash7, pruritus |
| Uncommon | erythema multiforme, dermatitis bullous, Stevens-Johnson syndrome | |
| General disorders and administration site conditions | Very common | fatigue, pyrexia, asthenia |
1 Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, paraesthesia, peripheral sensorimotor neuropathy, muscular weakness, peripheral motor neuropathy, hypoesthesia, gait disturbance, neuralgia, burning sensation, demyelinating polyneuropathy, neurotoxicity, polyneuropathy, sensory loss, and skin burning sensation.
2 Dry eye includes dry eye and lacrimation increased.
3 Eye irritation includes eye discharge, eye pain, eye irritation, and eye oedema.
4 Nausea includes nausea and retching.
5 Diarrhoea includes diarrhoea and gastroenteritis.
6 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and abdominal tenderness.
7 Rash includes rash, rash maculo-papular, erythema, eczema, rash macular, dermatitis acneiform, rash pustular, urticaria, dermatitis, dermatitis allergic, rash erythematous, skin irritation and skin toxicity.
Ocular adverse reactions occurred in 55% of the 425 patients with cervical cancer treated with tisotumab vedotin across clinical studies. The most common ocular adverse reactions were conjunctivitis (32%), dry eye (17%), keratitis (12%), and blepharitis (5%). Grade 3 ocular adverse reactions occurred in 3% of patients. Cases of Grade 3 ulcerative keratitis were reported in 1.2% of patients. Grade 4 ocular adverse reactions occurred in 0.2% of patients, including ulcerative keratitis.
The median time to onset for the first event of any grade ocular adverse reaction was 1.2 months (range: 0 to 17.1). Ocular adverse reactions led to treatment discontinuation in 6%, dose interruption in 13% and dose reduction in 12% of patients. Of the patients who experienced ocular adverse reactions, 59% had complete resolution and 31% had partial improvement at last follow-up. Of the patients with ongoing ocular adverse reactions at last follow-up, 28% of patients had maximum Grade 1, 10% had maximum Grade 2, and 3% had maximum Grade 3. For patients in whom events resolved, the median time to resolution was 0.59 months (range: 0 to 12.6).
Peripheral neuropathy occurred in 39% of the 425 patients with cervical cancer treated with tisotumab vedotin across clinical trials; 6% were Grade 3. The most common all grade peripheral neuropathy events were peripheral sensory neuropathy (23%), neuropathy peripheral (5%), paraesthesia (4%), peripheral sensorimotor neuropathy (3%) and muscular weakness (3%).
The median time to onset of the first event of any grade peripheral neuropathy was 2.4 months (range: 0 to 11.3). Of the patients who experienced peripheral neuropathy, 18% had complete resolution and 21% had partial improvement at last follow-up. Of the patients with ongoing peripheral neuropathy at last follow-up, 45% of patients had maximum Grade 1, 27% had maximum Grade 2, and 10% had maximum Grade 3. For patients in whom events resolved, the median time to resolution was 0.72 months (range: 0 to 20.7).
Severe cutaneous adverse reactions occurred in 1.6% of the 425 patients with cervical cancer treated with tisotumab vedotin across clinical studies, including erythema multiforme (0.7%), bullous dermatitis (0.5%) and SJS (0.5%). Grade ≥3 severe cutaneous adverse reactions occurred in 0.5% of patients, including 1 patient who had a fatal outcome.
The median time to onset of the first event of severe cutaneous adverse reactions was 0.2 months (range: 0.1 to 0.9). Of the patients who experienced severe cutaneous adverse reactions, 43% had complete resolution at last follow-up. For patients in whom events resolved, the median time to resolution was 0.79 months (range: 0.5 to 2.3).
Nausea, diarrhoea, constipation, abdominal pain, and vomiting were the most common all grade gastrointestinal disorders reported in the 425 patients with cervical cancer treated with tisotumab vedotin. Nausea occurred in 37% of patients and was Grade ≥3 in 1% patients. Diarrhoea occurred in 25% of patients and was Grade ≥3 in 2% of patients. Constipation occurred in 24% of patients and was Grade ≥3 in 1% of patients. Abdominal pain occurred in 22% of patients and was Grade ≥3 in 3% of patients. Vomiting occurred in 20% of patients and was Grade ≥3 in 2% of patients.
Among 425 patients with cervical cancer treated with tisotumab vedotin across clinical studies, 60 (14%) were ≥65 years of age. Grade ≥3 adverse reactions occurred in 60% of patients ≥65 years and in 55% of patients <65 years. Serious adverse reactions occurred in 35% patients ≥65 years and in 38% of patients <65 years.
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