Bioequivalence Data and Efficacy Data

Bioequivalence Data

The bioequivalence study of EMBEDA

EMBEDA is bioequivalent to a similarly formulated ER morphine sulfate capsules product with regard to rate and extent of plasma morphine absorption1,2

Morphine concentration after administration of a single dose1,2

  • Open-label, randomized, single-dose, 2-sequence, crossover study under fasting conditions in healthy adult volunteers (aged 19-45 years) (N=36).2
  • The primary objective of the study was to evaluate morphine bioequivalence between EMBEDA and morphine sulfate extended-release capsules.2
  • The median time to peak plasma morphine levels (Tmax) was shorter for EMBEDA (7.5 hours) compared with the comparator (10 hours).2
  • Dose-related increase in steady-state predose plasma concentrations of morphine were noted following multiple-dose administration of EMBEDA in patients.1,2
  • There are no adequate, well-controlled studies of the use of EMBEDA longer than 12 weeks.

Study description

  • Open-label, randomized, single-dose, 2-sequence, crossover study under fasting conditions in healthy adult volunteers (aged 19-45 years) (N=36).2
  • The primary objective of the study was to evaluate morphine bioequivalence between EMBEDA and morphine sulfate extended-release capsules.2
  • The primary end point was bioequivalence as established by ln-transformed rations of area under the concentration time curve (AUC) and Cmax falling within the 80% to 125% range with 90% confidence intervals.2
  • After an overnight fast, subjects were randomized to receive a single dose of EMBEDA 100 mg or a single dose of extended-release morphine sulfate 100 mg. Blood samples for serum morphine determination were taken predose and at selected times postdose through 72 hours. After a 14-day washout, subjects returned to the study center and were administered the alternate treatment regimen under the same schedule.2
 
REFERENCES

1. Embeda [prescribing information]. New York, NY: Pfizer Inc; December 2016. 2. Johnson FK, Ciric S, Boudriau S, Kisicki JC, Stauffer J. The relative bioavailability of morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA®) and an extended release morphine sulfate capsule formulation (KADIAN®) in healthy adults under fasting conditions. Am J Ther. 2011;18(1):2-8.

Efficacy Data

Results from the efficacy study of EMBEDA

EMBEDA demonstrated a statistically significant mean change in Brief Pain Inventory (BPI) pain scores versus placebo1,2

Mean change in BPI diary average pain scores1,2

The primary efficacy measure was mean change in BPI diary average pain scores (0-10) scale from baseline (at randomization) to the last 7 days of the maintenance period.2

  • Patients recorded pain intensity daily in an electronic diary using the BPI short-form questionnaire, which assessed pain at its worst and least in past 24 hours, pain on average in past 24 hours, and current level of pain, all assessed on a 0- to 10-point scale (0=no pain and 10=pain as bad as you can imagine).
  • There are no adequate, well-controlled studies of the use of EMBEDA longer than 12 weeks.

Study description

  • This phase 3 study had an enriched enrollment randomized withdrawal (EERW), double-blind, multicenter design. Patients (N=547) with moderate to severe pain due to osteoarthritis (OA) of the hip or knee were titrated to an effective dose of EMBEDA (20-160 mg/day). Responders (n=344) were randomized to 12 weeks of maintenance with an effective EMBEDA dose or tapered to placebo over 2 weeks.1,2
  • Patients recorded pain intensity daily in an electronic diary using the Brief Pain Inventory (BPI) short-form questionnaire, which assessed pain at its worst and least in past 24 hours, pain on average in past 24 hours, and current level of pain, all assessed on a 0- to 10-point scale (0=no pain and 10=pain as bad as you can imagine).1,2
  • In the open-label dose titration phase (up to 45 days; N=547), EMBEDA was initiated at 20 mg QD or 20 mg BID and titrated to a maximum dose of 80 mg BID (160 mg daily).1
  • Following the open-label titration period, patients whose pain responded (BPI score over the last 4 days was ≤4 and declined ≥2 from baseline) were randomized either to continue EMBEDA (n=171) for a 12-week maintenance period or were tapered off EMBEDA and placed on placebo (n=173).1,2
  • Those patients who did not respond to EMBEDA or did not tolerate it were discontinued from the trial.1,2
  • 75.1% of the randomized subjects were opioid-naive and distributed evenly between the 2 groups.1,2
  • The primary efficacy outcome was the change in BPI diary average pain scores from randomization baseline (average of BPI diary 24-hour pain scores over the last 7 days of the titration period) to completion of the maintenance period (for completers, the final 7 days of the 12-week study).1,2
  • Prespecified secondary efficacy outcome measures were: in-clinic pain intensity; weekly diary worst-, least-, current-, and average-pain scores over the past 24 hours; diary average pain scores averaged over the entire maintenance period; and patient-completed assessments on the following instruments: 1) Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, with 3 subscales (pain, stiffness, and physical function) and a composite index score, and 2) Medical Outcomes Study (MOS) Sleep Scale.2
  • Each of the 24 items on the WOMAC Osteoarthritis Index has a score of 0 (none) to 4 (extreme); scores were then standardized on a 0- to 100-point scale.2

Study design

Washout period was 1 to 7 days prior to initiation of titration. During maintenance period, there was a 2-week taper to placebo in double-dummy fashion.

Secondary end point

EMBEDA demonstrated a statistically significant change in WOMAC composite index from baseline to week 12 vs placebo2*

BPI=brief pain inventory; Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index.

*End point presented here was a secondary outcome. End points not shown in chart include BPI Worst Pain, BPI Least Pain, BPI Current Pain, and In-clinic BPI Pain.

REFERENCES

1. Embeda [prescribing information]. New York, NY: Pfizer Inc; December 2016. 2. Katz N, Hale M, Morris D, Stauffer J. Morphine sulfate and naltrexone hydrochloride extended release capsules in patients with chronic osteoarthritis pain. Postgrad Med. 2010;122(4):112-128.