Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Ocular adverse reactions occurred in patients treated with tisotumab vedotin across clinical studies in cervical cancer patients (see section 4.8). The most common ocular adverse reactions were conjunctivitis, dry eye, keratitis and blepharitis.
Prior to the first infusion and as clinically indicated, patients should be referred to an eye care professional for a full eye exam (including visual acuity and slit lamp exam). Prior to each infusion, the treating healthcare provider should inspect the patient’s eyes, including control of normal eye movement, and ask about any ocular signs or symptoms. Patients should be monitored for new or worsening ocular signs and symptoms and referred as soon as possible to an eye care professional if warranted. Patients should be instructed to promptly report any new or worsening ocular signs or symptoms. Tivdak should be withheld, dose reduced, or permanently discontinued based on the severity of the adverse reaction (see section 4.2).
Patients should adhere to recommendations in the “Eye care” subsection of section 4.2 to reduce the risk of ocular adverse reactions (see section 4.2).
Peripheral neuropathy has occurred with tisotumab vedotin, including Grade 3 events (see section 4.8). Patients should be monitored for general symptoms of neuropathy, such as paraesthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. Patients experiencing new or worsening peripheral neuropathy may require dose interruption, dose reduction, or permanent discontinuation of Tivdak (see section 4.2).
Severe cutaneous adverse reactions, including events of fatal or life-threatening SJS, can occur in patients treated with tisotumab vedotin. Patients should be monitored for signs or symptoms of severe cutaneous adverse reactions, which include 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, and swollen lymph nodes. If signs or symptoms of severe cutaneous adverse reactions occur, Tivdak should be immediately withheld until the aetiology of the reaction has been determined. Early consultation with a specialist is recommended to ensure greater diagnostic accuracy and appropriate management. Tivdak should be permanently discontinued for confirmed Grade 3 or 4 severe cutaneous adverse reactions, including SJS (see section 4.2).
Based on its mechanism of action and findings from animal studies, tisotumab vedotin can cause foetal harm when administered to a pregnant woman, including embryo-foetal toxicity and structural malformations (see sections 4.6 and 5.3). The pregnancy status of women of childbearing potential should be verified prior to initiating Tivdak treatment. Women of reproductive potential should be advised to use effective contraception during treatment with Tivdak and for 2 months after the last dose (see section 4.6).
Patients with the following conditions were excluded from clinical studies: clinically significant active ocular surface disease, any prior episode of cicatricial conjunctivitis or ocular SJS, Grade ≥ 2 peripheral neuropathy, clinically significant bleeding issues or risks or cardiovascular risks (see section 5.1). In the absence of data, tisotumab vedotin should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Formal drug-drug interaction studies with tisotumab vedotin have not been conducted.
Strong CYP3A4 inhibitors: 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).
Strong CYP3A4 inducers: 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.
Sensitive CYP3A4 substrates: another ADC that contains MMAE co-administered with midazolam (a sensitive CYP3A4 substrate) did not affect the exposure of midazolam. Similarly, tisotumab vedotin is not expected to alter the exposure of drugs that are metabolised by CYP3A4 enzymes.
Transporter systems: MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.
The pregnancy status of women of childbearing potential should be verified prior to initiating Tivdak 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 Tivdak.
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 (see section 5.3).
Tivdak 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 Tivdak and for at least 3 weeks after the last dose.
Based on findings from animal studies, tisotumab vedotin may impair fertility in males and females (see section 5.3).
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 (see sections 4.4 and 4.8), patients should be advised to use caution when driving or operating machines until they are certain that Tivdak 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 3). 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.
Table 3. 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) (see section 4.4).
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) (see section 4.4).
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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