Tivdak 40 mg powder for concentrate for solution for infusion

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).

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

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

*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.

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

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.

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.

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).

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.

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

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.

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.

Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody-drug conjugates, ATC code: L01FX23

Mechanism of action

Tisotumab vedotin is an antibody-drug conjugate (ADC) directed to tissue factor (TF), a cell surface protein expressed at elevated levels on a variety of solid tumours relative to normal tissue. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Tisotumab vedotin binds to TF-expressing tumour cells, the ADC-TF complex is internalised, and local release of MMAE occurs via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death.

Direct cytotoxicity in TF-expressing cells, bystander cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and immunogenic cell death has been demonstrated in vitro with tisotumab and/or tisotumab vedotin.

Immunogenicity

Anti-drug antibodies (ADA) were commonly detected (5% across clinical studies). No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.

Cardiac electrophysiology

The effect of tisotumab vedotin (2 mg/kg every 3 weeks) on the QTc interval was evaluated in 153 patients. At the dose of 2 mg/kg every 3 weeks, tisotumab vedotin had no clinically meaningful effect on QTc prolongation.

Clinical efficacy and safety

Cervical cancer

SGNTV-003

The efficacy of tisotumab vedotin was evaluated in an open-label, multicentre, randomised phase 3 study (SGNTV-003) in 502 patients with recurrent or metastatic cervical cancer who had received one or two prior systemic therapy regimens that included doublet chemotherapy (patients without prior exposure to platinum were allowed) with or without bevacizumab and an anti-PD-1/PD-L1 agent if eligible and available. Patients were randomised 1:1 to receive either tisotumab vedotin 2 mg/kg intravenously every 3 weeks or investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) until disease progression or unacceptable toxicity.

Randomisation was stratified by ECOG performance status (0 vs 1), prior bevacizumab administration (yes vs no), region (US, EU, Other), and prior anti-PD-1 or anti-PD-L1 administration (yes vs no). Tumour response assessments were performed every 6 weeks for the first 30 weeks and every 12 weeks thereafter.

Patients were excluded from the study if they had primary neuroendocrine, lymphoid, or sarcomatoid histologies, 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, including known coagulation defects, diffuse alveolar haemorrhage from vasculitis and known bleeding diathesis, or significant cardiovascular issues or risks.

The primary endpoint of the study was overall survival (OS). Key secondary endpoints were progression free survival (PFS) and confirmed objective response rate (ORR) as assessed by investigator using RECIST v1.1.

Of the 502 patients randomised, the median age was 50 years (range: 26 to 80); 49% were White, 36% were Asian, and 2% were Black. Seventeen percent of patients were ≥ 65 years. Twenty percent of patients were Hispanic or Latino. Sixty-three percent of patients had squamous cell carcinoma, 32% had adenocarcinoma, and 5% had adenosquamous histology. ECOG performance status was 0 (54%) or 1 (46%). Sixty-one percent of patients had received 1 prior line of systemic therapy, and 38% had 2 prior lines of systemic therapy. Six patients (1.2%) had not received and 496 patients (99%) had received prior treatment with platinum-containing chemotherapy in the recurrent or metastatic setting. Sixty-four percent of patients had received bevacizumab and 27% of patients had received an anti-PD-1 or anti‑PD‑L1 as part of their prior systemic therapy.

At a median duration of follow-up of 10.8 months (95% CI: 10.3 to 11.6), SGNTV-003 demonstrated statistically significant improvement in OS, PFS and ORR for patients treated with tisotumab vedotin compared to chemotherapy. Efficacy results are summarised in Table 4 and Figures 1 and 2.

Table 4: Efficacy Results in SGNTV-003

CI=confidence interval; CR=complete response; NR=not reached; ORR=objective response rate; PR=partial response.

¹The threshold for statistical significance is 0.0226 (2-sided)

²evaluated by investigator assessment using RECIST v1.1

³The threshold for statistical significance is 0.0453 (2-sided)

⁴Based on patients with a best objective response as confirmed complete or partial response (n=45 for tisotumab vedotin, n=13 for chemotherapy)

Figure 1: Kaplan Meier Plot of Overall Survival

Figure 2: Kaplan Meier Plot of Progression Free Survival

Efficacy results for OS and PFS were generally consistent across prespecified patient subgroups.

Paediatric population

The Licensing Authority has waived the obligation to submit the results of studies with Tivdak in all subsets of the paediatric population in cervical cancer (see section 4.2 for information on paediatric use).

Distribution

Based on population pharmacokinetic analysis tisotumab vedotin central volume of distribution was estimated to be 3.10 L.

In vitro, the binding of MMAE to human plasma proteins ranged from 68–82%.

Biotransformation

Tisotumab vedotin catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related metabolites. Tisotumab vedotin releases MMAE via proteolytic cleavage, and MMAE is primarily metabolised by CYP3A4 in vitro. In vivo data in animals and humans suggest that only a small fraction of MMAE released from tisotumab vedotin is metabolised. The levels of MMAE metabolites have not been measured in human plasma.

Elimination

Based on population pharmacokinetic analysis, the median terminal half-life of tisotumab vedotin is approximately 4.04 days and the terminal half-life of MMAE is approximately 2.56 days. The linear clearance of tisotumab vedotin was estimated to be 1.42 L/day and following a 2 mg/kg dose approximately 60% of the dose was estimated to be eliminated by linear clearance (CL). Clearance of unconjugated MMAE was estimated to be 42.8 L/day. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin.

Excretion

The excretion of tisotumab vedotin is not fully characterised. Following a single dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in faeces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin administration.

Specific populations

Elderly

Based on population pharmacokinetic analysis, age (21 to 81 years) does not have a clinically meaningful effect on the pharmacokinetics of tisotumab vedotin.

Gender

Based on population pharmacokinetic analysis, gender does not have a clinically meaningful effect on the pharmacokinetics of tisotumab vedotin.

Renal impairment

Based on population pharmacokinetic analysis, no clinically meaningful differences in exposures of tisotumab vedotin and MMAE were observed in patients with mild (creatinine clearance; CrCL > 60-90 mL/min, n=142) or moderate (CrCL 30-60 mL/min, n=42) renal impairment compared to patients with normal renal function. The effect of severe renal impairment or end-stage renal disease with or without dialysis on tisotumab vedotin and unconjugated MMAE pharmacokinetics is unknown.

Hepatic impairment

Based on population pharmacokinetic analysis, no clinically meaningful differences in exposures of tisotumab vedotin were observed in patients with mild hepatic impairment (total bilirubin > 1 to 1.5 × ULN and any AST, or total bilirubin ≤ ULN and AST > ULN, n=58) compared to patients with normal hepatic function, while MMAE exposures were 37% higher in mild hepatic impairment as compared to normal hepatic function. The effect of moderate or severe hepatic impairment or liver transplantation on the pharmacokinetics of tisotumab vedotin or unconjugated MMAE is unknown.

Pharmacokinetic/pharmacodynamic relationships

In an exposure-response analysis at 2 mg/kg every 3 weeks, a higher tisotumab vedotin exposure was associated with higher incidence of some adverse reactions (e.g., Grade ≥ 2 ocular adverse reactions) and a lower exposure was associated with lower efficacy.

Repeat-dose toxicity

Repeat-dose toxicity studies were performed with tisotumab vedotin at approximately 2.3‑4.3 times the human area under the curve (AUC) at the recommended clinical dose. Skin lesions were noted in a repeat-dose study at ≥ 3 mg/kg in monkeys (13 weeks). The skin changes were fully reversible by the end of a 6-week recovery period. In both rats and cynomolgus monkeys, administration of MMAE and tisotumab vedotin (only monkeys dosed at ≥ 3 mg/kg) led to reversible bone marrow toxicity and associated peripheral blood cell effects. Reddened or swollen eyes and conjunctiva (with or without discharge), and/or conjunctivitis was observed following tisotumab vedotin treatment in monkeys at 5 mg/kg (13 weeks). These findings reversed following a 6-week recovery period.

Carcinogenicity

Carcinogenicity studies in animals have not been performed with tisotumab vedotin or MMAE.

Genotoxicity

MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism.

Reproductive and developmental toxicity

Dedicated fertility studies in animals have not been performed with tisotumab vedotin or MMAE. However, results of repeat-dose toxicity studies indicate the potential for tisotumab vedotin to impair male and female fertility.

Results of a 13-week repeat-dose toxicity study in cynomolgus monkeys administered tisotumab vedotin demonstrated seminiferous tubular atrophy of the testes and absence of sperm, decreased sperm content, and epithelial vacuolation in the epididymides. The changes were associated with decreased testicular size, and reduced or total absence of sperm counts and sperm motility was observed at doses of 1, 3, and 5 mg/kg corresponding to approximately 0.5- to 4-fold the human systemic exposure (based on AUC) at the clinically recommended dose. There was partial recovery of the testes and epididymides findings at 3 and 5 mg/kg; and full recovery at 1 mg/kg after a 6-week postdose period.

Ovarian effects were observed in repeat-dose toxicity studies of other MMAE-containing ADCs. A mild to moderate decrease in, or absence of, secondary and tertiary ovarian follicles was observed in young female cynomolgus monkeys at doses ≥ 3 mg/kg weekly for 4 weeks. These effects showed evidence of recovery 6 weeks after the end of dosing and no changes were observed in primordial follicles.

Animal reproduction studies have not been conducted with tisotumab vedotin to evaluate its effect on reproduction and foetal development. Based on its mechanism of action and findings from animal studies, tisotumab vedotin could cause embryo-foetal harm when administered to a pregnant woman. Intravenous administration of MMAE to pregnant rats during organogenesis (gestational Days 6 and 13) resulted in increased total resorptions, post implantation loss, early delivery, loss of viable foetuses, and teratogenic embryo-foetal toxicity at a dose of 0.2 mg/kg (approximately 0.5 times the human AUC at the recommended dose).

L-histidine

L-histidine hydrochloride monohydrate

Sucrose

D-mannitol

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened vial

5 years

Reconstituted solution in the vial

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to 24 hours at 2 °C to 8 °C or for up to 8 hours at 9 °C to 25 °C.

From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Diluted solution in the infusion bag

Chemical and physical in-use stability of the diluted solution has been demonstrated for the durations listed in Table 5.

From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the diluted solution should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Table 5: Diluted Tivdak solution refrigeration storage conditions

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

10mL Type I glass vial with grey butyl rubber stopper, plug and top, 20 mm seal with silver coloured aluminium cap and red disc. Each carton contains 1 vial.

Reconstitution in single-dose vial

1. Follow procedures for proper handling and disposal of cytotoxic medicinal products.

2. Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.

3. Calculate the recommended dose based on the patient's actual body weight to determine the number of vials needed.

4. Reconstitute each 40 mg vial with 4 mL of sterile water for injection, resulting in 10 mg/mL Tivdak.

5. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle. Do not shake the vial. Do not expose to direct sunlight.

6. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colourless to brownish‑yellow and free of visible particles. Discard any vial with visible particles or discolouration.

7. Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain a preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours refrigerated at 2 °C to 8 °C or at room temperature (9 °C to 25 °C) up to a maximum of 8 hours prior to dilution. Do not freeze. Discard unused vials with reconstituted solution beyond the recommended storage time.

Dilution in infusion bag

8. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.

9. Dilute Tivdak with one of the following: dextrose 50 mg/mL (5%), sodium chloride 9 mg/mL (0.9%), or Lactated Ringer's solution for injection. The infusion bag size should allow enough diluent to achieve a final concentration of 0.7 mg/mL to 2.4 mg/mL Tivdak.

10. Mix diluted solution by gentle inversion. Do not shake the bag. Do not expose to direct sunlight.

11. Visually inspect the infusion bag for any particulate matter or discolouration prior to use. The reconstituted solution should be clear to slightly opalescent, colourless to brownish-yellow and free of visible particles. Do not use the infusion bag if particulate matter or discolouration is observed.

12. Discard any unused portion left in the single-dose vials.

Administration

13. Confirm administration of steroid and vasoconstrictor eye drops (see section 4.2).

14. Apply cold packs fully over the eyes following administration of the vasoconstrictor eye drops, leave on during infusion and until 30 minutes after infusion. Change cold packs as needed throughout infusion to ensure eye area remains cold (see section 4.2).

15. Immediately administer the infusion over 30 minutes through an intravenous line containing a 0.2 µm in-line filter.

16. If the infusion is not administered immediately, store the diluted Tivdak solution in refrigeration as specified in Table 5 (see section 6.3). Discard if storage time exceeds these limits. Do not freeze. Once removed from refrigeration, complete administration of the diluted infusion solution of Tivdak within 4 hours (including infusion time).

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.