4.1. Therapeutic indications

Tivdak as monotherapy is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy (see section 5.1).

4.2. Posology and method of administration

Treatment with Tivdak should be initiated and supervised by a physician experienced in the use of anti-cancer therapies. Prior to the first infusion and as clinically indicated, an eye care professional should conduct an ophthalmic exam, including visual acuity and slit lamp exam (see “Eye care” at the end of this section and section 4.4).

Posology

The recommended dose of Tivdak is 2 mg/kg (up to a maximum of 200 mg for patients ≥ 100 kg) every 3 weeks until disease progression or unacceptable toxicity.

Dose modifications

The recommended Tivdak dose reduction schedule is provided in Table 1. Tivdak should be permanently discontinued in patients who cannot tolerate 0.9 mg/kg.

Table 1: Dose reduction schedule

Dose level

Starting dose

2 mg/kg (up to maximum of 200 mg)

First dose reduction

1.3 mg/kg (up to maximum of 130 mg)

Second dose reduction

0.9 mg/kg (up to maximum of 90 mg)

The recommended dose modifications for adverse reactions are provided in Table 2. Patients should be referred to an eye care professional as soon as possible for an assessment of new or worsening ocular symptoms (see section 4.4).

Table 2: Dose modifications

Adverse reaction

Severity*

Occurrence

Dose modification

Keratitis

Grade 1

Any

Withhold dose until clinically stable, then resume treatment at the same dose.

Grade 2

First occurrence

Withhold dose until Grade ≤ 1, then resume treatment at the next lower dose level.

Second occurrence

Withhold dose until Grade ≤ 1, then resume treatment at the next lower dose level. If no resolution to Grade ≤ 1, permanently discontinue.

Third occurrence

Permanently discontinue.

Grade 3 or 4

Any

Permanently discontinue.

Conjunctival ulceration

Grade 1 or 2

First occurrence

Withhold dose until clinically stable, then resume treatment at the next lower dose level.

Second occurrence or more

Withhold dose until clinically stable, then resume treatment at the next lower dose level.

If no stabilisation or improvement, permanently discontinue.

Grade 3 or 4

Any

Permanently discontinue.

Conjunctival or corneal scarring or symblepharon

Any grade

Any

Permanently discontinue.

Conjunctivitis and other ocular reactions

Grade 1

Any

Withhold dose until clinically stable, then resume treatment at the same dose.

Grade 2

First occurrence

Withhold dose until Grade ≤ 1, then resume treatment at the same dose.

Second occurrence

Withhold dose until Grade ≤ 1, then resume treatment at the next lower dose level. If no resolution to Grade ≤ 1, permanently discontinue.

Third occurrence

Permanently discontinue.

Grade 3 or 4

Any

Permanently discontinue.

Peripheral neuropathy

Grade 2 or 3

Any (initial or worsening of pre‑existing condition)

Withhold dose until Grade ≤ 1, then resume treatment at the next lower dose level.

Grade 4

Any

Permanently discontinue.

Severe cutaneous adverse reactions (including Stevens‑Johnson syndrome (SJS))

Suspected (any grade)

Any

Immediately withhold dose and consult a specialist to confirm the diagnosis.

Confirmed Grade 3 or 4

Any

Permanently discontinue.

*Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) where Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening

Missed doses

If a planned dose of Tivdak is missed, it should be administered as soon as possible. The scheduling of administration should be adjusted to maintain the appropriate interval between doses.

Eye care

Patients should adhere to the following recommendations to reduce the risk of ocular adverse reactions (see section 4.4).

Ocular evaluation by treating healthcare provider

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. The patient should be referred to an eye care professional for any ocular signs or symptoms (see section 4.4).

Topical preservative-free corticosteroid eye drops (e.g., dexamethasone 0.1% 3 times a day or the equivalent as prescribed)

Patients should be instructed to administer 1 drop in each eye 3 times daily starting 1 day prior to each infusion and to continue to administer as prescribed for 3 days after each infusion.

Topical preservative-free ocular vasoconstrictor drops (e.g., brimonidine tartrate 0.2% 3 drops per eye or the equivalent as prescribed)

Drops should be administered in each eye immediately prior to each infusion.

Cold packs

Following administration of eye drops, cooling eye pads should be applied prior to the start of the infusion and used during and for 30 minutes after the infusion.

Topical preservative-free lubricating eye drops

Patients should be instructed to administer lubricating eye drops multiple times every day throughout treatment and for 30 days after the last dose of Tivdak.

Contact lenses

Patients should be advised to avoid wearing contact lenses for the entire duration of therapy unless advised by their eye care professional.

Special populations

Elderly

No dose adjustment is required in patients aged ≥ 65 years (see section 5.2).

Renal impairment

No dose adjustment is required in patients with mild renal impairment [creatinine clearance (CrCL) > 60-90 mL/min], moderate (CrCL 30-60 mL/min). 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) (see section 5.2).

Hepatic impairment

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 (see section 5.2).

Paediatric population

The safety and efficacy of Tivdak in children and adolescents below the age of 18 years have not been established. No data are available.

Method of administration

Tivdak is for intravenous use. The recommended dose must be administered by intravenous infusion over 30 minutes. Tisotumab vedotin must not be administered as an intravenous push or bolus injection.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

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

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

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

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).

Embryo-foetal toxicity

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 excluded from clinical studies

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.

4.5. Interaction with other medicinal products and other forms of interaction

Formal drug-drug interaction studies with tisotumab vedotin have not been conducted.

CYP3A4 inhibitors, substrates, and inducers

Drug interaction studies

Clinical studies

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.

In vitro studies

Transporter systems: MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P‑gp.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females and males

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.

Pregnancy

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.

Breast-feeding

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.

Fertility

Based on findings from animal studies, tisotumab vedotin may impair fertility in males and females (see section 5.3).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

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%).

Tabulated list of adverse reactions

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

1Peripheral 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

2Dry eye includes dry eye and lacrimation increased

3Eye irritation includes eye discharge, eye pain, eye irritation, and eye oedema

4Nausea includes nausea and retching

5Diarrhoea includes diarrhoea and gastroenteritis

6Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and abdominal tenderness

7Rash includes rash, rash maculo-papular, erythema, eczema, rash macular, dermatitis acneiform, rash pustular, urticaria, dermatitis, dermatitis allergic, rash erythematous, skin irritation and skin toxicity

Description of selected adverse reactions

Ocular adverse reactions

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

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

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).

Gastrointestinal adverse reactions

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.

Special populations

Elderly

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 of suspected adverse reactions

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no known antidote for overdose with tisotumab vedotin. In case of overdose, the patient should be closely monitored for adverse reactions and supportive treatment should be administered.