Erleada 60 mg film coated tablets

Formatting error in previous conversion, now updated to correct formatting issue

Updated SmPC Sections:

SmPC Section 3 (Pharmaceutical Form),

Section 4.2 (Posology and method of administration),

Section 4.8 (Undesirable effects) and

Section 6.5 (Nature and contents of container) with minor updates to keep consistency with the SmPC proposed for Erleada 240 mg.

Updated SmPC Sections:

SmPC Section 3 (Pharmaceutical Form),

Section 4.2 (Posology and method of administration),

Section 4.8 (Undesirable effects) and

Section 6.5 (Nature and contents of container) with minor updates to keep consistency with the SmPC proposed for Erleada 240 mg.

SmPC Section 3 (Pharmaceutical Form), Section 4.2 (Posology and method of administration), Section 4.8 (Undesirable effects) and Section 6.5 (Nature and contents of container) with minor updates to keep consistency with the SmPC proposed for Erleada 240 mg.

Section 1 (What Erleada is and what it is used for),

Section 2 (What you need to know before you take Erleada),

Section 3 (How to take Erleada),

Section 4 (Possible Side Effects), and

Section 6 (Contents of the pack and other information) with minor updates to keep consistency with PIL proposed for Erleada 240 mg.

Addition of a ADR (DRESS).

Addition of a new ADR (DRESS).

PIL sections 2 and 4 have been updated to add Stevens-Johnson Syndrome. 

SmPC sections 4.4 and 4.8 has been updated to add Stevens-Johnson Syndorome (SJS) as and ADR with unknown frequency. 

SmPC section 6.3 (Shelf Life) - The Shelf Life for the product has been increased from 2 years to 3 years. 

Section 5.1 (Pharmacodynamic properties) has been updated to include the data from the TITAN Final Analysis. 

Sections 4.6 (fertility, pregnancy and lactation) and  5.3 (Preclinical safety data) have been updated in line with the animal reproductive study data. Some minor changes made to the SmPC.

Section 4.4 - Updated in line with the SPARTAN study data. The ischaemic cerebrovascular disorders added. 

Section 4.8: Updated to add ischaemic cerebrovascular disorders and alopecia.

Section 5.1: Updated to include SPARTAN data.

Section 5.3: Updated to include data from TOX13540 carcinogenicity study.

These sections have been updated to include the SPARTAN study data in relation to ischaemic cerebrovascular disorders. 

Section 4 (Possible side effects) - Toxic epidermal necrolysis and decreased appetite have been added.

Section 4.8 (undesirable effects) - Decreased appetite has been added to this section as and ADR with very common frequency under metabolism and nutition disorders system organ class.

Toxic epidermal necrolysis has been added to this section with unknown frequency under skin and subcutaneous tissue disorders.

4.1     Therapeutic indications

Erleada is indicated:

•  in adult men for the treatment of non‑metastatic castration‑resistant prostate cancer (NM‑nmCRPC) who are at high risk of developing metastatic disease (see section 5.1).
• in adult men for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) (see section 5.1).

4.2     Posology and method of administration

Paediatric population

There is no relevant use of apalutamide in the paediatric population. in the treatment of non-metastatic castration-resistant prostate cancer.

4.4     Special warnings and precautions for use

Seizure

Erleada …………………..the seizure threshold.

In two randomised studies (SPARTAN and TITAN), Sseizure occurred in 0.24% of patients receiving Erleada apalutamide in and in 0.2% of patients treated with placeboclinical studies. These studies excluded patients with a history of seizure or predisposing factors for seizure.

There is no clinical experience in re‑administering Erleada to patients who experienced a seizure.

Falls and fractures

Falls and fractures occurred in patients receiving Erleada apalutamide (see section 4.8). Patients should be evaluated for fractures and fall risk before starting Erleada and should continue to be monitored and managed for fractures according to established treatment guidelines and use of bone-targeted agents should be considered.

Ischaemic heart disease

Ischaemic heart disease, including events leading to death, occurred in patients treated with apalutamide (see section 4.8). The majority of patients had cardiac risk factors. Patients should be monitored for signs and symptoms of ischaemic heart disease and management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidaemia should be optimised as per standard of care.

……………………..

GnRH Analog

In mHSPC subjects receiving leuprolide acetate (a GnRH analog), co-administration with apalutamide had no apparent effect on the steady-state exposure of leuprolide.

4.8     Undesirable effects

Summary of the safety profile

The most common adverse reactions are fatigue (3026%), skin rash (2426% of any grade and 56% Grade 3 or 4), hypertension (22%), hot flush (18%), weight decreased (16%), arthralgia (1617%), diarrhoea (16%), and fall (136%), and weight decreased (13%). Other important adverse reactions include fractures (121%) and hypothyroidism (8%).

Description of selected adverse reactions

Skin rash

Skin rash associated with Erleada apalutamide was most commonly described as macular or maculo‑papular. Skin rash included rash, rash maculo‑papular, rash generalised, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, dermatitis, and rash vesicular. Adverse reactions of skin rash were reported for 2426% of patients treated with Erleadaapalutamide. Grade 3 skin rashes (defined as covering > 30% body surface area [BSA]) were reported with Erleada apalutamide treatment in 5.26% of patients.

The median days to onset of skin rash was 82 83 days with a range of 1 to 994 days. Eighty-oneSeventy-eight percent of patients had resolution of rash with a median of 60 78 days to resolution.  Medicinal products utilised included topical corticosteroids, oral anti-histamines, and 19% of patients received systemic corticosteroids and oral anti‑histamines. Among patients with skin rash, dose interruption occurred in 28% and dose reduction occurred in 1214% (see section 4.2). Skin rash recurred in 59% of patients who had dose interruption.approximately half of patients who were re‑challenged. Skin rash led to Erleada apalutamide treatment discontinuation in 97% of patients who experienced skin rash.

Falls and fractures

In Study ARN‑509‑003, fracture was reported for 11.7% of patients treated with Erleada apalutamide and 6.5% of patients treated with placebo. Half of the patients experienced a fall within 7 days before the fracture event in both treatment groups. Falls were reported for 15.6% of patients treated with Erleada apalutamide versus 9.0% of patients treated with placebo (see section 4.4).

Ischaemic heart disease

In a randomised study (SPARTAN) of patients with nmCRPC, ischaemic heart disease occurred in 4% of patients treated with apalutamide and 3% of patients treated with placebo. In a randomised study (TITAN) in patients with mHSPC, ischaemic heart disease occurred in 4% of patients treated with apalutamide and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with apalutamide and 2 patients (0.2%) treated with placebo died from an ischaemic heart disease (see section 4.4).

5.1     Pharmacodynamic properties

…..

Clinical efficacy and safety

The efficacy and safety of apalutamide has been established in two Phase 3 randomised, placebo-controlled studies, Study ARN-509-003 (nmCRPC) and 56021927PCR3002 (mHSPC).

TITAN: Metastatic Hormone-sensitive Prostate Cancer (mHSPC)

TITAN was a randomised, double-blind, placebo-controlled, multinational, multicenter clinical trial in which 1052 patients with mHSPC were randomised (1:1) to receive either apalutamide orally at a dose of 240 mg once daily (N = 525) or placebo once daily (N = 527). All patients were required to have at least one bone metastasis on Technetium ^99m bone scan. Patients were excluded if the site of metastases was limited to either the lymph nodes or viscera (e.g., liver or lung). All patients in the TITAN trial received concomitant GnRH analog or had prior bilateral orchiectomy. Around 11% of patients received prior treatment with docetaxel (maximum of 6 cycles, last dose ≤2 months prior to randomisation and maintained response prior to randomisation). The exclusion criteria included known brain metastases; prior treatment with other next generation anti-androgens (eg, enzalutamide), CYP17 inhibitors (eg, abiraterone acetate), immunotherapy (eg, sipuleucel-T), radiopharmaceutical agents or other treatments for prostate cancer; or history of seizure or condition that may predispose to seizure. Patients were stratified by Gleason score at diagnosis, prior docetaxel use, and region of the world. Patients with both high- and low-volume mHSPC were eligible for the study. High-volume disease was defined as either visceral metastases and at least 1 bone lesion or at least 4 bone lesions, with at least 1 bone lesion outside of the vertebral column or pelvis. Low-volume disease was defined as the presence of bone lesion(s) not meeting the definition of high-volume.

The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 68 years (range 43-94) and 23% of patients were 75 years of age or older. The racial distribution was 68% Caucasian, 22% Asian, and 2% Black. Sixty-three percent (63%) of patients had high-volume disease and 37% had low-volume disease. Sixteen percent (16%) of patients had prior surgery, radiotherapy of the prostate or both. A majority of patients had a Gleason score of 7 or higher (92%). Sixty-eight percent (68%) of patients received prior treatment with a first-generation anti-androgen in the non-metastatic setting. Although criteria for castration resistance were not determined at baseline, 94% of patients demonstrated a decrease in prostate specific antigen (PSA) from initiation of androgen deprivation therapy (ADT) to first dose of apalutamide or placebo. All patients except one in the placebo group, had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. Among the patients who discontinued study treatment (N = 271 for placebo and N = 170 for Erleada), the most common reason for discontinuation in both arms was disease progression. A greater proportion (73%) of patients treated with placebo received subsequent anti-cancer therapy compared to patients treated with Erleada (54%).

The major efficacy outcome measures of the study were overall survival (OS) and radiographic progression-free survival (rPFS). Efficacy results of TITAN are summarised in Table 2 and Figures 1 and 2.

A statistically significant improvement in OS and rPFS was demonstrated in patients randomised to receive Erleada compared with patients randomised to receive placebo. Consistent improvement in rPFS was observed across patient subgroups including high- or low-volume disease, prior docetaxel use (yes or no), age (< 65, ≥65, or ≥75 years old), baseline PSA above median (yes or no), and number of bone lesions (≤10 or >10).

Figure 1:    Kaplan-Meier Plot of Overall Survival (OS); Intent-to-treat mHSPC Population (TITAN)

Figure 2:    Kaplan-Meier Plot of Radiographic Progression-Free Survival (rPFS); Intent-to-treat mHSPC Population (TITAN)

​

Treatment with Erleada statistically significantly delayed the initiation of cytotoxic chemotherapy (HR = 0.391, CI = 0.274, 0.558; p < 0.0001), resulting in a 61% reduction of risk for subjects in the treatment arm compared to the placebo arm.

For health-related quality of life or patient reported outcomes, no statistically significant differences were observed favoring one treatment over the other (apalutamide + ADT versus ADT) in the FACT-P or the EQ5D-5L scores, which suggests maintenance of effect and no deterioriation.

SPARTAN: Non-Metastatic Castration Resistant Prostate Cancer (nmCRPC)

A total of 1207 subjects with NM‑CRPC were randomised 2:1 to receive either apalutamide orally at a dose of 240 mg once daily in combination with androgen deprivation therapy (ADT) (medical castration or prior surgical castration) or placebo with ADT in a multicenter, double‑blind, clinical study (Study ARN‑509‑003). Subjects enrolled had a Prostate Specific Antigen (PSA) Doubling Time (PSADT) ≤ 10 months, considered to be at high risk of imminent metastatic disease and prostate cancer‑specific death. All subjects who were not surgically castrated received ADT continuously throughout the study. PSA results were blinded and were not used for treatment discontinuation. Subjects randomised to either arm were to continue treatment until disease progression defined by blinded central imaging review (BICR), initiation of new treatment, unacceptable toxicity or withdrawal

5.2     Pharmacokinetic properties

….

The apparent oral clearance (CL/F) of apalutamide is 1.3 L/h after single dosing and increases to 2.0 L/h at steady‑state after once‑daily dosing. The mean effective half‑life for apalutamide in patients is about 3 days at steady‑state.

4.1     Therapeutic indications

Erleada is indicated:

•  in adult men for the treatment of non‑metastatic castration‑resistant prostate cancer (NM‑nmCRPC) who are at high risk of developing metastatic disease (see section 5.1).
• in adult men for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) (see section 5.1).

4.2     Posology and method of administration

Paediatric population

There is no relevant use of apalutamide in the paediatric population. in the treatment of non-metastatic castration-resistant prostate cancer.

4.4     Special warnings and precautions for use

Seizure

Erleada …………………..the seizure threshold.

In two randomised studies (SPARTAN and TITAN), Sseizure occurred in 0.24% of patients receiving Erleada apalutamide in and in 0.2% of patients treated with placeboclinical studies. These studies excluded patients with a history of seizure or predisposing factors for seizure.

There is no clinical experience in re‑administering Erleada to patients who experienced a seizure.

Falls and fractures

Falls and fractures occurred in patients receiving Erleada apalutamide (see section 4.8). Patients should be evaluated for fractures and fall risk before starting Erleada and should continue to be monitored and managed for fractures according to established treatment guidelines and use of bone-targeted agents should be considered.

Ischaemic heart disease

Ischaemic heart disease, including events leading to death, occurred in patients treated with apalutamide (see section 4.8). The majority of patients had cardiac risk factors. Patients should be monitored for signs and symptoms of ischaemic heart disease and management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidaemia should be optimised as per standard of care.

……………………..

GnRH Analog

In mHSPC subjects receiving leuprolide acetate (a GnRH analog), co-administration with apalutamide had no apparent effect on the steady-state exposure of leuprolide.

4.8     Undesirable effects

Summary of the safety profile

The most common adverse reactions are fatigue (3026%), skin rash (2426% of any grade and 56% Grade 3 or 4), hypertension (22%), hot flush (18%), weight decreased (16%), arthralgia (1617%), diarrhoea (16%), and fall (136%), and weight decreased (13%). Other important adverse reactions include fractures (121%) and hypothyroidism (8%).

Description of selected adverse reactions

Skin rash

Skin rash associated with Erleada apalutamide was most commonly described as macular or maculo‑papular. Skin rash included rash, rash maculo‑papular, rash generalised, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, dermatitis, and rash vesicular. Adverse reactions of skin rash were reported for 2426% of patients treated with Erleadaapalutamide. Grade 3 skin rashes (defined as covering > 30% body surface area [BSA]) were reported with Erleada apalutamide treatment in 5.26% of patients.

The median days to onset of skin rash was 82 83 days with a range of 1 to 994 days. Eighty-oneSeventy-eight percent of patients had resolution of rash with a median of 60 78 days to resolution.  Medicinal products utilised included topical corticosteroids, oral anti-histamines, and 19% of patients received systemic corticosteroids and oral anti‑histamines. Among patients with skin rash, dose interruption occurred in 28% and dose reduction occurred in 1214% (see section 4.2). Skin rash recurred in 59% of patients who had dose interruption.approximately half of patients who were re‑challenged. Skin rash led to Erleada apalutamide treatment discontinuation in 97% of patients who experienced skin rash.

Falls and fractures

In Study ARN‑509‑003, fracture was reported for 11.7% of patients treated with Erleada apalutamide and 6.5% of patients treated with placebo. Half of the patients experienced a fall within 7 days before the fracture event in both treatment groups. Falls were reported for 15.6% of patients treated with Erleada apalutamide versus 9.0% of patients treated with placebo (see section 4.4).

Ischaemic heart disease

In a randomised study (SPARTAN) of patients with nmCRPC, ischaemic heart disease occurred in 4% of patients treated with apalutamide and 3% of patients treated with placebo. In a randomised study (TITAN) in patients with mHSPC, ischaemic heart disease occurred in 4% of patients treated with apalutamide and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with apalutamide and 2 patients (0.2%) treated with placebo died from an ischaemic heart disease (see section 4.4).

5.1     Pharmacodynamic properties

…..

Clinical efficacy and safety

The efficacy and safety of apalutamide has been established in two Phase 3 randomised, placebo-controlled studies, Study ARN-509-003 (nmCRPC) and 56021927PCR3002 (mHSPC).

TITAN: Metastatic Hormone-sensitive Prostate Cancer (mHSPC)

TITAN was a randomised, double-blind, placebo-controlled, multinational, multicenter clinical trial in which 1052 patients with mHSPC were randomised (1:1) to receive either apalutamide orally at a dose of 240 mg once daily (N = 525) or placebo once daily (N = 527). All patients were required to have at least one bone metastasis on Technetium ^99m bone scan. Patients were excluded if the site of metastases was limited to either the lymph nodes or viscera (e.g., liver or lung). All patients in the TITAN trial received concomitant GnRH analog or had prior bilateral orchiectomy. Around 11% of patients received prior treatment with docetaxel (maximum of 6 cycles, last dose ≤2 months prior to randomisation and maintained response prior to randomisation). The exclusion criteria included known brain metastases; prior treatment with other next generation anti-androgens (eg, enzalutamide), CYP17 inhibitors (eg, abiraterone acetate), immunotherapy (eg, sipuleucel-T), radiopharmaceutical agents or other treatments for prostate cancer; or history of seizure or condition that may predispose to seizure. Patients were stratified by Gleason score at diagnosis, prior docetaxel use, and region of the world. Patients with both high- and low-volume mHSPC were eligible for the study. High-volume disease was defined as either visceral metastases and at least 1 bone lesion or at least 4 bone lesions, with at least 1 bone lesion outside of the vertebral column or pelvis. Low-volume disease was defined as the presence of bone lesion(s) not meeting the definition of high-volume.

The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 68 years (range 43-94) and 23% of patients were 75 years of age or older. The racial distribution was 68% Caucasian, 22% Asian, and 2% Black. Sixty-three percent (63%) of patients had high-volume disease and 37% had low-volume disease. Sixteen percent (16%) of patients had prior surgery, radiotherapy of the prostate or both. A majority of patients had a Gleason score of 7 or higher (92%). Sixty-eight percent (68%) of patients received prior treatment with a first-generation anti-androgen in the non-metastatic setting. Although criteria for castration resistance were not determined at baseline, 94% of patients demonstrated a decrease in prostate specific antigen (PSA) from initiation of androgen deprivation therapy (ADT) to first dose of apalutamide or placebo. All patients except one in the placebo group, had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. Among the patients who discontinued study treatment (N = 271 for placebo and N = 170 for Erleada), the most common reason for discontinuation in both arms was disease progression. A greater proportion (73%) of patients treated with placebo received subsequent anti-cancer therapy compared to patients treated with Erleada (54%).

The major efficacy outcome measures of the study were overall survival (OS) and radiographic progression-free survival (rPFS). Efficacy results of TITAN are summarised in Table 2 and Figures 1 and 2.

A statistically significant improvement in OS and rPFS was demonstrated in patients randomised to receive Erleada compared with patients randomised to receive placebo. Consistent improvement in rPFS was observed across patient subgroups including high- or low-volume disease, prior docetaxel use (yes or no), age (< 65, ≥65, or ≥75 years old), baseline PSA above median (yes or no), and number of bone lesions (≤10 or >10).

Figure 1:    Kaplan-Meier Plot of Overall Survival (OS); Intent-to-treat mHSPC Population (TITAN)

Figure 2:    Kaplan-Meier Plot of Radiographic Progression-Free Survival (rPFS); Intent-to-treat mHSPC Population (TITAN)

​

Treatment with Erleada statistically significantly delayed the initiation of cytotoxic chemotherapy (HR = 0.391, CI = 0.274, 0.558; p < 0.0001), resulting in a 61% reduction of risk for subjects in the treatment arm compared to the placebo arm.

For health-related quality of life or patient reported outcomes, no statistically significant differences were observed favoring one treatment over the other (apalutamide + ADT versus ADT) in the FACT-P or the EQ5D-5L scores, which suggests maintenance of effect and no deterioriation.

SPARTAN: Non-Metastatic Castration Resistant Prostate Cancer (nmCRPC)

A total of 1207 subjects with NM‑CRPC were randomised 2:1 to receive either apalutamide orally at a dose of 240 mg once daily in combination with androgen deprivation therapy (ADT) (medical castration or prior surgical castration) or placebo with ADT in a multicenter, double‑blind, clinical study (Study ARN‑509‑003). Subjects enrolled had a Prostate Specific Antigen (PSA) Doubling Time (PSADT) ≤ 10 months, considered to be at high risk of imminent metastatic disease and prostate cancer‑specific death. All subjects who were not surgically castrated received ADT continuously throughout the study. PSA results were blinded and were not used for treatment discontinuation. Subjects randomised to either arm were to continue treatment until disease progression defined by blinded central imaging review (BICR), initiation of new treatment, unacceptable toxicity or withdrawal

5.2     Pharmacokinetic properties

….

The apparent oral clearance (CL/F) of apalutamide is 1.3 L/h after single dosing and increases to 2.0 L/h at steady‑state after once‑daily dosing. The mean effective half‑life for apalutamide in patients is about 3 days at steady‑state.