SUMMARY

• Alternative Formats of Information
  • A summary of the information provided in this response is provided as a video and infographic that can be accessed by clicking the following links:
    • Video: Mixing ERLEADA 60 mg Tablets with Orange Juice, Applesauce, or Additional Water
    • Infographic: Alternative Method of Administration
• Johnson & Johnson cannot recommend any practices, procedures, or dosage administration techniques that deviate from the approved product labeling.
• ERLEADA is not commercially available as a solution or suspension.
• For patients who cannot swallow tablets whole, the recommended dose of ERLEADA tablets can be dispersed in non-carbonated water and then administered with either orange juice, applesauce, or additional water. Place the entire prescribed dose of ERLEADA tablets in a cup. Do not crush or split the tablets. For 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg): add about 4 teaspoons (20 mL) of non-carbonated water to make sure that the tablets are completely immersed in water. Wait 2 minutes until the tablets are broken up and spread out, then stir the mixture. Add 2 tablespoons (30 mL) of either orange juice, applesauce, or additional water and stir the mixture. Swallow the mixture immediately. Rinse the cup with enough water to make sure the whole dose is taken and drink it immediately. Do not store ERLEADA that is mixed with non-carbonated water, orange juice, or applesauce for later use.¹
• In a phase 1, randomized, open-label, single-center, crossover, relative bioavailability study evaluating ERLEADA 60 mg tablets (4 x 60 mg) administered orally as dispersed tablets mixed in applesauce relative to whole tablets under fasting conditions in healthy male subjects (N=12), the administration of ERLEADA as dispersed tablets demonstrated comparable exposures based on the 90% confidence interval (CI) of the geometric mean ratio for area under the plasma analyte concentration vs time curve from 0 to 168 hours (AUC_0-168h) being contained within the 80%-125% criterion for bioequivalence. Findings from an additional in-vitro compatibility assessment of feasibility, dose accuracy, and in-use stability of apalutamide in different food vehicles showed ERLEADA 60 mg tablets were comparable in purity and dose accuracy when mixed in 50200 g of applesauce or yogurt or 50-200 mL of orange juice or green tea. Additionally, dose accuracy for all food vehicles was found to be within the 85.0%-115.0% criteria with no food vehicles appearing to impact the availability of apalutamide. Across both treatment sequences, 5 subjects (41.7%) reported ≥1 adverse event (AE) and most AEs were grade 1 (33.3%). The most common treatment-emergent adverse event (TEAE) was gynecomastia, reported in 3 subjects (25.0%). No clinically meaningful changes in laboratory parameters, vital signs, or ECG abnormalities were reported.²
• In a clinical trial simulation study to assess the probability of success in demonstrating bioequivalence between ERLEADA 60 mg tablets in applesauce to whole tablets after single and repeat dose administration, >85% of simulated steady state bioequivalence trials with ≥10 subjects comparing daily apalutamide administration in applesauce vs whole tablets met the 80–125% criteria for bioequivalence for both maximum concentration (C_max,ss) and area under the concentration curve at steady state (AUC_0–24h,ss). Simulated pharmacokinetic (PK) profiles for the reference treatment were based on an established population PK model for apalutamide. Simulated profiles for test treatment were based on the same model but with a treatment covariate fitted to the PK observations of the study summarized above.³

ALTERNATE METHOD OF ADMINISTRATION

^aData on File. Apalutamide. Company Core Data Sheet. Janssen Research & Development, LLC. EDMS-ERI-146013831; 2024.¹

^bTablet shown is not actual size.

CLINICAL DATA

Phase 1 Study and Feasibility, Accuracy, and Stability Studies Using ERLEADA
60 mg Tablet Formulation

Study Design/Methods

• Phase 1 study:² randomized, open-label, single-center, crossover study (NCT03802682)⁴ to determine the relative bioavailability of ERLEADA administered as a mixture with applesauce vs whole tablets in healthy fasted male subjects (N=12).
  • Subjects were randomized 1:1 in a crossover manner, separated by a washout period of 42-56 days between the two periods (or the reverse sequence), and administered a single dose of ERLEADA 240 mg orally under fasted conditions (≥10 hours with noncarbonated water allowed up to 1 hour before study drug administration), either as:
    • Whole tablets (4 x 60 mg) swallowed whole
    • Dispersed tablets (4 x 60 mg) mixed in applesauce
• All study drugs were taken in the morning on day 1 of each treatment period, with 240 mL of noncarbonated water accompanying the whole tablets or with a 120-mL container rinse of noncarbonated water accompanying the 120 mL of applesauce mixed with ERLEADA tablets. An additional 50 mL of water for either treatment was allowed if necessary. The ERLEADA-applesauce mixture had to be ingested within 5 minutes and was prepared only by trained pharmacists or pharmaceutical technicians. Subjects continued fasting until 4 hours postdose, drinking 1 glass of water approximately 1 hour postdose with water allowed from then onwards.
• Serial PK samples were collected predose and at various timepoints postdose up to day 8 (168-hours postdose).
• Palatability was assessed via a taste questionnaire that consisted of a visual analog scale to rate sweetness, bitterness, and smell as well as overall acceptability, performed within 30 minutes of administration of the ERLEADA-applesauce mixture.
• AEs were either reported voluntarily or obtained via interview in a nondirected manner at study visits. ECGs were recorded at screening or at admission and at study completion, including the end-of-study visit. Clinical laboratory tests and vital signs were evaluated at screening, on day -1, on day 2, and at study completion, including the end-of-study visit.
• Select inclusion criteria: Healthy men aged 18-55 years, body mass index (BMI) 18-30 kg/m² with body weight ≥50 kg, normal blood pressure and a 12-lead ECG consistent with normal cardiac function at screening.
• Select exclusion criteria: Subjects with clinically significant abnormal values for hematology, clinical chemistry, serum testosterone <200 ng/dL, and thyroid stimulating hormone level greater than the upper limit of normal at screening.
• Feasibility, accuracy, and stability studies:² in vitro compatibility studies that evaluated dose accuracy, in-use stability, and purity of ERLEADA tablets mixed in commonly available aqueous food products (applesauce, yogurt, orange juice, and green tea).
  • Triplicate dose accuracy, in-use stability testing, and chromatographic purity assessments were conducted. For in-use stability testing, sample mixtures were tested over a period (after 3 and 6 hours) at room temperature to verify the chemical stability of the product in contact with food vehicle and evaluate situations in which a dose was prepared far in advance of administration.
  • ERLEADA tablets were dispersed in a specified amount of food vehicle (i.e. 50 g or 200 g applesauce, 50 g or 200 g yogurt, 50 mL or 200 mL orange juice, 200 mL green tea extract) and uniform mixture was formed by gently mixing the contents with a spatula for about 10 seconds, repeated after 15 minutes, and subsequently after an additional 15 minutes.

Results

Subject Characteristics

• All subjects were white males, mean age was 45.3 years, and mean BMI was 25.1 kg/m².
• Of the 12 subjects randomized, 2 subjects discontinued from the study (one due to personal reasons after receiving the whole tablets and one due to grade 1 gynecomastia after receiving the applesauce mixture).

Pharmacokinetics

• On average, apalutamide plasma levels were higher with the applesauce mixture compared to whole tablets until about 4 hours postdose. Thereafter, the plasma concentrations were comparable in both treatments. Apalutamide plasma concentrations decreased in a multiphasic manner and were quantifiable at the last PK sample (168 hours postdose) for both treatments and for all subjects. See results in Table: Pharmacokinetic Parameters of Apalutamide After Whole Tablets or Applesauce Mixture Administration.
• Administration of ERLEADA as either an applesauce mixture or whole tablets demonstrated comparable exposures based on the 90% CI of the geometric mean ratio for AUC_0168h being contained within the 80%-125% criterion for bioequivalence. The maximum observed plasma analyte concentration (C_max) was increased by 27.6% for the ERLEADA-applesauce mixture compared to whole tablets. See results in Table: Statistical Analysis of Pharmacokinetic Parameters of Apalutamide.
• Different amounts of the food vehicles as well as durations (up to 6 hours) did not affect the total apalutamide content available.
• Dose-accuracy testing found results for all food vehicles to be within the 85.0% to 115.0% criterion (applesauce, 98.3% to 104.5%; yogurt, 95.1% to 101.3%; orange juice, 97.5% to 102.0%; green tea, 99.7% to 101.5%). As such, the tested food vehicles do not appear to impact the availability of apalutamide.
• No significant changes in purity were observed during the in-use study of the food vehicle mixtures and all samples met the specification limit of 85%-115%.  

Appearance of Mixture

• No notable changes in the appearance of mixture were observed during the in-use period of the food vehicles. The colors of the applesauce, orange juice, and green tea were found to be lighter for the mixtures, changing from orange for the applesauce and orange juice and yellowish-brown for the green tea (placebo) to yellowish (mixture). The yogurt appearance changed from white (placebo) to slightly yellowish (mixture).

Palatability

• The overall acceptability of the applesauce mixture ranged from “maybe bad, maybe good” in 1 subject (9.1%) to “supergood” in 3 subjects (27.3%).
• Most subjects (90.9%) did not find it annoying to swallow the applesauce mixture and the taste was reported to be “sweet” or “pleasant.”
• Bitterness and smell ranged from “good” to “supergood.” Most subjects did not experience bitterness (81.8%); the remaining subjects experienced bitterness 1 or 2 minutes postdose. Bitterness did not last for >5 minutes in any of the subjects. All subjects reported that it was acceptable for long-term use.

Safety

• Across both treatment sequences, 5 subjects (41.7%) reported ≥1 AE and most AEs were grade 1 (33.3%). Additional safety data is reported in Table: Treatment-Emergent Adverse Events.
• One subject experienced grade 2 bursitis, which was not considered drug related by the investigator. Two subjects spontaneously reported gynecomastia after study completion and both cases were considered drug related by the investigator. Additionally, one subject receiving the ERLEADA-applesauce mixture reported drug-related gynecomastia. The gynecomastia cases were resolved 90-125 days postevent.
• No clinically meaningful changes in laboratory parameters, vital signs, or ECG abnormalities were reported.

Bioequivalence Clinical Trial Simulation Study of ERLEADA 60 mg Tablet Formulation Administered in Applesauce vs Whole Tablets

Study Design/Methods

• Clinical trial simulation study³ to assess the probability of success in demonstrating bioequivalence between ERLEADA 60 mg tablets in applesauce to whole tablets after repeat dose and single dose administration.
• Simulated PK profiles for the reference treatment were based on an established population PK model for apalutamide and simulated profiles for test treatment were based on the same model but with a treatment covariate fitted to the PK observations of the phase 1 study described above.
• A simulated population of 10,000 individuals with their associated PK parameters was used as a source for the 2 simulation scenarios for bioequivalence trials (n=1000). In the single dose scenario, bioequivalence of the 2 administration methods was assessed using randomly sampled PK parameters (C_max and AUC_0–168h) for the test and reference treatments. In the scenario representing steady state (SS), bioequivalence between the 2 administration methods was assessed using randomly sampled PK parameters (C_max,ss and AUC_0–24h,ss) for the test and reference treatments.
• All plasma samples with quantifiable apalutamide concentrations with available date, time, and dose administration data were included in the population PK analysis. Blood samples to determine apalutamide plasma concentrations were collected through a 168-hour PK sampling period, including 11 samples on day 1 (pre-dose, every 30 minutes until 2 hours, followed by every hour until 6 hours, and at 8 and 12 hours), 2 samples on day 2 (at 24 and 26 hours), and single samples on days 3-8 (at 48 hours and every 24 hours thereafter).

Results

Pharmacokinetics

• Following an increase in concentration, a biphasic decline in apalutamide concentrations was observed when concentrations were studied on a linear scale as a function of time following single dose administration.
• Parameter estimates for the covariates of formulation on the model parameters from the final model are summarized in Table: Population Pharmacokinetic Parameter Estimates for Applesauce Covariates Added.
• Model-derived PK parameters of apalutamide per empirical Bayseian estimates are summarized in Table: Statistical Analysis of Pharmacokinetic Parameters of Apalutamide per Empirical Bayesian Estimates. The geometric mean ratio was slightly higher with 90% CI overlap compared with the observed phase 1 study data described above.
• In summary statistics of geometric mean ratios for C_max and AUC derived from analysis of variance of simulated data, AUC_0-24h,ss was comparable with AUC_0-168h at steady state and C_max decreased by ~19% compared to a single dose.
• The probability of success in demonstrating bioequivalence are summarized in Table: Simulation of 1000 Bioequivalence Trials.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 28 May 2024.