Enfortumab vedotin interacts in the following cases:
Based on physiologically-based pharmacokinetic (PBPK) modeling, concomitant use of enfortumab vedotin with ketoconazole (a combined P-gp and strong CYP3A inhibitor) is predicted to increase unconjugated MMAE Cmax and AUC exposure to a minor extent, with no change in ADC exposure. Caution is advised in case of concomitant treatment with CYP3A4 inhibitors. Patients receiving concomitant strong CYP3A4 inhibitors (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) should be monitored more closely for signs of toxicities.
Strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort [Hypericum perforatum]) may decrease the exposure of unconjugated MMAE with moderate effect.
Enfortumab vedotin has not been evaluated in patients with end stage renal disease (CrCL <15 mL/min).
Enfortumab vedotin has only been evaluated in a limited number of patients with moderate and severe hepatic impairment. Hepatic impairment is expected to increase the systemic exposure to MMAE (the cytotoxic drug); therefore, patients should be closely monitored for potential adverse events. Due to the sparsity of the data in patients with moderate and severe hepatic impairment, no specific dose recommendation can be given.
In rats, repeat dose administration of enfortumab vedotin, resulted in testicular toxicity and may alter male fertility. Monomethyl auristatin E (MMAE) has been shown to have aneugenic properties. Therefore, men being treated with this medicinal product are advised to have sperm samples frozen and stored before treatment. There are no data on the effect of enfortumab vedotin on human fertility.
Enfortumab vedotin can cause foetal harm when administered to pregnant women based upon findings from animal studies. Embryo-foetal development studies in female rats have shown that intravenous administration of enfortumab vedotin resulted in reduced numbers of viable foetuses, reduced litter size, and increased early resorptions. Enfortumab vedotin is not recommended during pregnancy and in women of childbearing potential not using effective contraception.
It is unknown whether enfortumab vedotin is excreted in human milk. A risk to breast-fed children cannot be excluded. Breastfeeding should be discontinued during enfortumab vedotin treatment and for at least 6 months after the last dose.
Pregnancy testing is recommended for females of reproductive potential within 7 days prior to initiating treatment. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 12 months after stopping treatment. Men being treated with enfortumab vedotin are advised not to father a child during treatment and for up to 9 months following the last dose of enfortumab vedotin.
In rats, repeat dose administration of enfortumab vedotin, resulted in testicular toxicity and may alter male fertility. MMAE has been shown to have aneugenic properties. Therefore, men being treated with this medicinal product are advised to have sperm samples frozen and stored before treatment. There are no data on the effect of enfortumab vedotin on human fertility.
Enfortumab vedotin has no or negligible influence on the ability to drive and use machines.
The safety of enfortumab vedotin was evaluated as monotherapy in 793 patients who received at least one dose of enfortumab vedotin 1.25 mg/kg in two phase 1 studies (EV-101 and EV-102), three phase 2 studies (EV-103, EV-201 and EV-203) and one phase 3 study (EV-301) (see Table 1). Patients were exposed to enfortumab vedotin for a median duration of 4.7 months (range: 0.3 to 55.7 months).
The most common adverse reactions with enfortumab vedotin were alopecia (47.7%), decreased appetite (47.2%), fatigue (46.8%), diarrhoea (39.1%), peripheral sensory neuropathy (38.5%), nausea (37.8%), pruritus (33.4%), dysgeusia (30.4%), anaemia (29.1%), weight decreased (25.2%), rash maculo-papular (23.6%), dry skin (21.8%), vomiting (18.7%), aspartate aminotransferase increased (17%), hyperglycaemia (14.9%), dry eye (12.7%), alanine aminotransferase increased (12.7%) and rash (11.6%).
The most common serious adverse reactions (≥2%) were diarrhoea (2.1%) and hyperglycaemia (2.1%). Twenty-one percent of patients permanently discontinued enfortumab vedotin for adverse reactions; the most common adverse reaction (≥2%) leading to dose discontinuation was peripheral sensory neuropathy (4.8%). Adverse reactions leading to dose interruption occurred in 62% of patients; the most common adverse reactions (≥2%) leading to dose interruption were peripheral sensory neuropathy (14.8%), fatigue (7.4%), rash maculo-papular (4%), aspartate aminotransferase increased (3.4%), alanine aminotransferase increased (3.2%), anaemia (3.2%), hyperglycaemia (3.2%), neutrophil count decreased (3%), diarrhoea (2.8%), rash (2.4%) and peripheral motor neuropathy (2.1%). Thirty-eight percent of patients required a dose reduction due to an adverse reaction; the most common adverse reactions (≥2%) leading to adose reduction were peripheral sensory neuropathy (10.3%), fatigue (5.3%), rash maculo-papular (4.2%) and decreased appetite (2.1%).
When enfortumab vedotin is administered in combination with pembrolizumab, refer to the SmPC for pembrolizumab prior to initiation of treatment.
The safety of enfortumab vedotin was evaluated in combination with pembrolizumab in 564 patients who received at least one dose of enfortumab vedotin 1.25 mg/kg in combination with pembrolizumab in one phase 2 study (EV-103) and one phase 3 study (EV-302) (see Table 1). Patients were exposed to enfortumab vedotin in combination with pembrolizumab for a median duration of 9.4 months (range: 0.3 to 34.4 months).
The most common adverse reactions with enfortumab vedotin in combination with pembrolizumab were peripheral sensory neuropathy (53.4%), pruritus (41.1%), fatigue (40.4%), diarrhoea (39.2%), alopecia (38.5%), rash maculo-papular (36%), weight decreased (36%), decreased appetite (33.9%), nausea (28.4%), anaemia (25.7%), dysgeusia (24.3%), dry skin (18.1%), alanine aminotransferase increased (16.8%), hyperglycaemia (16.7%), aspartate aminotransferase increased (15.4%), dry eye (14.4%), vomiting (13.3%), rash macular (11.3%), hypothyroidism (10.5%) and neutropenia (10.1%).
The most common serious adverse reactions (≥2%) were diarrhoea (3%) and pneumonitis (2.3%). Thirty-six percent of patients permanently discontinued enfortumab vedotin for adverse reactions; the most common adverse reactions (≥2%) leading to discontinuation were peripheral sensory neuropathy (12.2%) and rash maculo-papular (2%).
Adverse reactions leading to dose interruption of enfortumab vedotin occurred in 72% of patients. The most common adverse reactions (≥2%) leading to dose interruption were peripheral sensory neuropathy (17%), rash maculo-papular (6.9%), diarrhoea (4.8%), fatigue (3.7%), pneumonitis (3.7%), hyperglycaemia (3.4%), neutropenia (3.2%), alanine aminotransferase increased (3%), pruritus (2.3%) and anaemia (2%).
Adverse reactions leading to dose reduction of enfortumab vedotin occurred in 42.4% of patients. The most common adverse reactions (≥2%) leading to dose reduction were peripheral sensory neuropathy (9.9%), rash maculo-papular (6.4%), fatigue (3.2%), diarrhoea (2.3%) and neutropenia (2.1%).
Adverse reactions observed during clinical studies of enfortumab vedotin as monotherapy or in combination with pembrolizumab, or reported from post-marketing use of enfortumab vedotin are listed in this section by frequency category. Frequency categories are defined as follows: 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 order of decreasing seriousness.
Table 1. Adverse reactions in patients treated with enfortumab vedotin:
| Monotherapy | In combination with pembrolizumab | |
|---|---|---|
| Blood and lymphatic system disorders | ||
| Very common | Anaemia | Anaemia |
| Not known1 | Neutropenia, febrile neutropenia, neutrophil count decreased | Neutropenia, febrile neutropenia, neutrophil count decreased |
| Endocrine disorders | ||
| Very common | Hypothyroidism | |
| Metabolism and nutrition disorders | ||
| Very common | Hyperglycaemia, decreased appetite | Hyperglycaemia, decreased appetite |
| Nervous system disorders | ||
| Very common | Peripheral sensory neuropathy, dysgeusia | Peripheral sensory neuropathy, dysgeusia |
| Common | Neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paraesthesia, hypoaesthesia, gait disturbance, muscular weakness | Peripheral motor neuropathy, peripheral sensorimotor neuropathy, paraesthesia, hypoaesthesia, gait disturbance, muscular weakness |
| Uncommon | Demyelinating polyneuropathy, polyneuropathy, neurotoxicity, motor dysfunction, dysaesthesia, muscle atrophy, neuralgia, peroneal nerve palsy, sensory loss, skin burning sensation, burning sensation | Neurotoxicity, dysaesthesia, myasthenia gravis, neuralgia, peroneal nerve palsy, skin burning sensation |
| Eye disorders | ||
| Very common | Dry eye | Dry eye |
| Respiratory, thoracic, and mediastinal disorders | ||
| Very common | Pneumonitis/ILD2 | |
| Common | Pneumonitis/ILD2 | |
| Gastrointestinal disorders | ||
| Very common | Diarrhoea, vomiting, nausea | Diarrhoea, vomiting, nausea |
| Skin and subcutaneous tissue disorders | ||
| Very common | Alopecia, pruritus, rash, rash maculo-papular, dry skin | Alopecia, pruritus, rash maculo-papular, dry skin, rash macular |
| Common | Drug eruption, skin exfoliation, conjunctivitis, dermatitis bullous, blister, stomatitis, palmar-plantar erythrodysesthesia syndrome, eczema, erythaema, rash erythaematous, rash macular, rash papular, rash pruritic, rash vesicular | Rash, skin exfoliation, conjunctivitis, dermatitis bullous, blister, stomatitis, palmar-plantar erythrodysesthesia syndrome, eczema, erythaema, rash erythaematous, rash papular, rash pruritic, rash vesicular, erythaema multiforme, dermatitis |
| Uncommon | Dermatitis exfoliative generalised, erythaema multiforme, exfoliative rash, pemphigoid, rash maculovesicular, dermatitis, dermatitis allergic, dermatitis contact, intertrigo, skin irritation, stasis dermatitis, blood blister | Drug eruption, dermatitis exfoliative generalised, exfoliative rash, pemphigoid, dermatitis contact, intertrigo, skin irritation, stasis dermatitis |
| Not known1 | Toxic epidermal necrolysis, Stevens-Johnson syndrome, epidermal necrosis, symmetrical drug-related intertriginous and flexural exanthaema | Toxic epidermal necrolysis, Stevens-Johnson syndrome, epidermal necrosis, symmetrical drug-related intertriginous and flexural exanthaema |
| Musculoskeletal and connective tissue disorders | ||
| Common | Myositis | |
| General disorders and administration site conditions | ||
| Very common | Fatigue | Fatigue |
| Common | Infusion site extravasation | Infusion site extravasation |
| Investigations | ||
| Very common | Alanine aminotransferase increased, aspartate aminotransferase increased, weight decreased | Alanine aminotransferase increased, aspartate aminotransferase increased, weight decreased |
| Common | Lipase increased | |
1 Based on global post-marketing experience.
2 Includes: acute respiratory distress syndrome, autoimmune lung disease, immune-mediated lung disease, interstitial lung disease, lung opacity, organising pneumonia, pneumonitis, pulmonary fibrosis, pulmonary toxicity and sarcoidosis.
A total of 697 patients were tested for immunogenicity to enfortumab vedotin 1.25 mg/kg as monotherapy; 16 patients were confirmed to be positive at baseline for anti-drug antibody (ADA), and in patients that were negative at baseline (N=681), a total of 24 (3.5%) were positive post baseline.
A total of 490 patients were tested for immunogenicity against enfortumab vedotin following enfortumab vedotin in combination with pembrolizumab; 24 patients were confirmed to be positive at baseline for ADA, and in patients that were negative at baseline (N=466), a total of 14 (3%) were positive post baseline. The incidence of treatment-emergent anti-enfortumab vedotin antibody formation was consistent when assessed following enfortumab vedotin administration as monotherapy and in combination with pembrolizumab.
Due to the limited number of patients with antibodies against enfortumab vedotin, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy, safety or pharmacokinetics.
In clinical studies of enfortumab vedotin as monotherapy, skin reactions occurred in 57% (452) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Severe (Grade 3 or 4) skin reactions occurred in 14% (108) of patients and a majority of these reactions included rash maculo-papular, stomatitis, rash erythematous, rash or drug eruption. The median time to onset of severe skin reactions was 0.7 months (range: 0.1 to 8.2 months). Serious skin reactions occurred in 4.3% (34) of patients. Of the patients who experienced skin reactions and had data regarding resolution (N=366), 61% had complete resolution, 24% had partial improvement, and 15% had no improvement at the time of their last evaluation. Of the 39% of patients with residual skin reactions at last evaluation, 38% had Grade ≥2 events.
In clinical studies of enfortumab vedotin in combination with pembrolizumab, skin reactions occurred in 70% (392) of the 564 patients and a majority of these skin reactions included rash maculo-papular, rash macular and rash papular. Severe (Grade 3 or 4) skin reactions occurred in 17% (97) of patients (Grade 3: 16%, Grade 4: 1%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Of the patients who experienced skin reactions and had data regarding resolution (N=391), 59% had complete resolution, 30% had partial improvement, and 10% had no improvement at the time of their last evaluation. Of the 41% of patients with residual skin reactions at last evaluation, 27% had Grade ≥2 events.
In clinical studies of enfortumab vedotin as monotherapy, pneumonitis/ILD occurred in 26 (3.3%) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Less than 1% of patients experienced severe (Grade 3 or 4) pneumonitis/ILD (Grade 3: 0.5%, Grade 4: 0.3%). Pneumonitis/ILD led to discontinuation of enfortumab vedotin in 0.5% of patients. There were no deaths from pneumonitis/ILD. The median time to onset of any grade pneumonitis/ILD was 2.7 months (range: 0.6 to 6.0 months) and the median duration for pneumonitis/ILD was 1.6 months (range: 0.1 to 43.0 months). Of the 26 patients who experienced pneumonitis/ILD, 8 (30.8%) had resolution of symptoms.
In clinical studies of enfortumab vedotin in combination with pembrolizumab, pneumonitis/ILD occurred in 58 (10.3%) of the 564 patients. Severe (Grade 3 or 4) pneumonitis/ILD occurred in 20 patients (Grade 3: 3.0%, Grade 4: 0.5%). Pneumonitis/ILD led to discontinuation of enfortumab vedotin in 2.1% of patients. Two patients experienced a fatal event of pneumonitis/ILD. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26.2 months).
In clinical studies of enfortumab vedotin as monotherapy, hyperglycaemia (blood glucose >13.9 mmol/L) occurred in 17% (133) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Serious events of hyperglycaemia occurred in 2.5% of patients, 7% of patients developed severe (Grade 3 or 4) hyperglycaemia and 0.3% of patients experienced fatal events, one event each of hyperglycaemia and diabetic ketoacidosis. The incidence of Grade 3-4 hyperglycaemia increased consistently in patients with higher body mass index and in patients with higher baseline haemoglobin A1C (HbA1c). The median time to onset of hyperglycaemia was 0.5 months (range: 0 to 20.3). Of the patients who experienced hyperglycaemia and had data regarding resolution (N=106), 66% had complete resolution, 19% had partial improvement, and 15% had no improvement at the time of their last evaluation. Of the 34% of patients with residual hyperglycaemia at last evaluation, 64% had Grade ≥2 events.
In clinical studies of enfortumab vedotin as monotherapy, peripheral neuropathy occurred in 53% (422) of the 793 patients treated with enfortumab vedotin 1.25 mg/kg. Five percent of patients experienced severe (Grade 3 or 4) peripheral neuropathy including sensory and motor events. The median time to onset of Grade ≥2 peripheral neuropathy was 5months (range: 0.1 to 20.2). Of the patients who experienced neuropathy and had data regarding resolution (N=340), 14% had complete resolution, 46% had partial improvement, and 41% had no improvement at the time of their last evaluation. Of the 86% of patients with residual neuropathy at last evaluation, 51% had Grade ≥2 events.
In clinical studies of enfortumab vedotin as monotherapy, 30% of patients experienced dry eye during treatment with enfortumab vedotin 1.25 mg/kg. Treatment was interrupted in 1.5% of patients and 0.1% of patients permanently discontinued treatment due to dry eye. Severe (Grade 3) dry eye only occurred in 3 patients (0.4%). The median time to onset of dry eye was 1.7 months (range: 0 to 30.6 months).
Enfortumab vedotin in combination with pembrolizumab has been studied in 173 patients <65 years and 391 patients ≥65 years. Generally, adverse event frequencies were higher in patients ≥65 years of age compared to <65 years of age, particularly for serious adverse events (56.3%, and 35.3%, respectively) and Grade ≥3 events (80.3% and 64.2%, respectively), similar to observations with the chemotherapy comparator.
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