Naprelan
Россия
  • Россия
  • Украина

Naprelan - Scientific Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Osteoarthritis, Rheumatoid Arthritis
Class: Nonsteroidal anti-inflammatory agents
Form: Tablets
Ingredients: naproxen sodium, ammonio methacrylate copolymer Type A, ammonio methacrylate copolymer Type B, citric acid, crospovidone, magnesium stearate, methacrylic acid copolymer Type A, microcrystalline cellulose, povidone, and talc.

Pharmaceutical Information

Drug Substance

Proper name: Naproxen sodium
Chemical name: 2-naphthaleneacetic acid, 6-methoxy-α-methyl-sodium salt, (s)-
Molecular formula and molecular mass: C14H13NaO3; 252.24
Structural formula:



Physicochemical properties: Naproxen sodium is an odorless crystalline powder, white to
creamy in color. It is soluble in methanol and water.
Solubility: 250 mg/mL in water; 200 mg/mL in methanol;
14 mg/mL in ethanol; 0.102 mg/mL in acetone;
0.04 mg/mL chloroform; 0.014 mg/mL in
toluene; and 0.001 mg/mL in benzene
pKa: The pKa of naproxen (free acid) is:
4.39 at an ionic strength of 0.01
4.50 at an ionic strength of 0.1
pH: The pH of a 1 in 20 solution of naproxen sodium in
water is between 7.5 and 9.0.
Melting Point: Naproxen sodium melts at about 255°C with
decomposition

Clinical Trials

Randomized clinical trials with NAPRELAN have NOT been designed to detect differences in cardiovascular adverse events in a chronic setting.

Rheumatoid Arthritis

Study Demographics and Trial design

The use of NAPRELAN for the management of the signs and symptoms of rheumatoid arthritis (RA) was assessed in a 12 week double blind, randomized placebo and active-controlled, parallel group comparison study in patients with RA. In the double blind phase of this study, efficacy of NAPRELAN 1000 mg once daily was compared with Naprosyn 500 mg twice daily and placebo. A total of 348 patients were randomized to treatment, 116 in each group (NAPRELAN, Naprosyn and placebo). 246 patients completed the double blind phase of the RA study (84 NAPRELAN, 89 Naprosyn and 73 placebo). All patients received at least one dose of study medication and thus were included in the intent-to-treat analysis. Patients were male and female patients 18 to 75 years of age with a diagnosis of rheumatoid arthritis for at least six months prior to screening. Brief study demographics and trial design for the double blind phase is provided below (Table 1). The primary objective of the double blind study phase was to compare the safety and efficacy of NAPRELAN 1000 mg once daily, Naprosyn 500 mg twice daily, and placebo given for 12 weeks in patients with rheumatoid arthritis (RA). A secondary objective was to establish equivalent efficacy of controlled-release NAPRELAN 1000 mg once daily and Naprosyn 500 mg twice daily. Efficacy was evaluated at baseline, then at weeks 1, 2, 4, 8, and 12 (visits 3 through 7).

For the double blind phase of the RA study, efficacy was evaluated and compared among the three treatment groups using the following primary efficacy variables.

  • Physician’s Global Assessment on the Visit Day (PhyGA)
  • Patient’s Global Assessment of Condition Since Previous Visit (PtGA)
  • Number of Painful Joints (NPJ)-Assessed as pain on palpation and/or motion for all 68 diarthrodial joints, except hips
  • Number of Swollen Joints (NSJ)-Assessed as synovial fluid and/or soft tissue swelling, but not bony overgrowth

In the double blind phase of the RA study, analysis was made from the intent-to-treat population. The intent-to-treat analysis compared the mean reductions in each efficacy variable from baseline (visit 2), at 12 weeks (visit 7) and at the last visit before stopping treatment. A summary of the mean changes from baseline for visit 7 (week 12) is provided (Table 2).

The double blind phase of the RA study was followed by a NAPRELAN open label phase. Patients who completed twelve weeks of double blind therapy were eligible for open label therapy with NAPRELAN 1000 mg once per day and were to continue the open label phase for an additional nine months. A total of 240 patients chose to enroll in the open label phase. Brief study demographics and trial design for the open label phase also provided below (Table 1).

TABLE 1: Summary of patient demographics in patients diagnosed with RA
Trial Design Dosage Route of
administration
and duration
Study
subjects
n=number
Mean
age
Gender
(Double Blind
Phase)
NAPRELAN 1000
mg once daily
compared with that
of placebo and
Naprosyn 500mg
bid
Oral
12 wks
n=348 55 years 263 females
85 males
(Open Label
Phase)
NAPRELAN 1000
mg once daily
Oral
9 months
n=240 55 years 180 females
60 males
TABLE 2: Summary of Primary Efficacy Variables at Visit 7 (Week 12), for the 12-week, Double Blind Phase, in the Intent-to-Treat Population
Variable1 Visit 7 (twelve weeks of treatment)
Mean Change ± SEM (standard
error of the mean) from Baseline
p-Value
NAPRELAN
(N = 84)
Naprosyn
(N = 89)
Placebo
(N = 73)
NAPRELAN
vs.
Placebo
Naprosyn
vs.
Placebo
NAPRELAN
vs.
Naprosyn
PhyGA 3.3 ± 0.2 3.1 ± 0.2 3.0 ± 0.2 0.1386 0.9753 0.1265
PtGA 3.3 ± 0.2 3.4 ± 0.2 2.6 ± 0.3 0.0141 * 0.0125 * 0.9926
NPJ 16.1 ± 1.4 14.2 ± 1.4 15.3 ±1.5 0.0846 0.8499 0.1057
NSJ 8.3 ± 0.9 9.4 ± 0.9 8.9 ± 1.0 0.5511 0.9881 0.5417

1 PhyGA=Physician's Global Assessment: PtGA=Patient's Global Assessment: NPJ=Number of Painful Joints: NSJ=Number of Swollen Joints

* statistically significant (p ≤ 0.05), using ANCOVA. The between treatment comparisons favor either the relevant active drug or NAPRELAN for comparison between active drugs.

Rheumatoid Arthritis, Study Results (Double Blind and Open Label RA Studies)

For the double blind treatment phase of the RA study, the NAPRELAN and Naprosyn groups were more effective than the placebo group for the Patient’s Global Assessment (PtGA) at both visit 7 (week 12) and Endpoint (endpoint data from last available visit for patients failing to complete the full 12 week double blind phase). In addition, at visit 7 (week 12), the NAPRELAN group was better than placebo in the Physician’s Global Assessment on the Visit Day (PhyGA). The results from the efficacy variable analysis demonstrated NAPRELAN 1000 mg once daily in the treatment of RA as superior to placebo and at least equivalent to Naprosyn 500 mg twice daily in PtGA.

For the open label treatment phase of the RA study, those patients initially treated with active drug, either NAPRELAN or Naprosyn maintained the improvement that they achieved during the double blind phase. For the open label phase, efficacy was limited to the Physicians Global Assessment (PhyGA) and the Patient’s Global Assessment (PtGA) with the evaluations performed at Months 4 and 12 (visits 8 and 11). Patients initially treated with placebo showed improvement in PhyGA and PtGA after the first month of NAPRELAN treatment.

Osteoarthritis

Study Demographics and Trial design

The use of NAPRELAN for the management of the signs and symptoms of osteoarthritis (OA) was assessed in a 12 week double blind, placebo and active-controlled study in patients with OA. In the double blind phase of this study, efficacy of NAPRELAN 1000 mg once daily was compared with Naprosyn 500 mg twice daily and placebo. A total of 347 patients were randomized to treatment, (116 in the NAPRELAN group, 115 in the Naprosyn group and 116 in the placebo group. 245 patients completed the double blind phase of the OA study. Patients were male and female patients 18 to 80 years of age and a diagnosis of osteoarthritis of the knee for at least six months prior to screening. Brief study demographics and trial design for the double blind phase is provided below (Table 3). The primary objective of the double blind study phase was to compare the safety and efficacy of NAPRELAN 1000 mg once daily, Naprosyn 500 mg twice daily, and placebo given for 12 weeks in patients with osteoarthritis (OA) of the knee. A secondary objective was to establish equivalent efficacy of controlled-release NAPRELAN 1000 mg once daily and Naprosyn 500 mg twice daily.

For the double blind phase of the OA study, efficacy was evaluated at baseline, then at weeks 1, 2, 4, 8 and 12 (visits 3 through 7) and compared among the three treatment groups using the following primary efficacy variables.

  • Physician’s Global Assessment on the Visit Day (PhyGA)
  • Patient’s Global Assessment of Condition Since Previous Visit (PtGA)
  • Severity of Pain Aggravated by Movement (PAM)-Assessed as knee pain on movement measured weight-bearing pain and pain on active/passive movement.
  • Severity of Pain on Palpation (POP)-Assessed as severity of knee pain when the investigator palpated the joint.

In the double blind phase of the OA study, analysis was made from the intent-to-treat population. The intent-to-treat analysis compared the mean reductions in each efficacy variable from baseline (visit 2), at 12 weeks (visit 7) and at the last visit before stopping treatment. An assessment of efficacy of all treatment groups was performed after all patients had either completed visit 7 (twelve weeks of treatment) or discontinued the study prior to visit 7 (the last available visit, Endpoint). A summary of the mean changes from baseline for visit 7 (week 12) is provided (Table 4).

The double blind phase of the OA study was followed by a NAPRELAN open label phase. Patients who completed twelve weeks of double blind therapy were eligible for open label therapy with NAPRELAN 1000 mg once per day and were to continue the open label phase for an additional nine months. A total of 228 patients chose to enroll in the open label phase. Brief study demographics and trial design for the open label phase also provided below (Table 3).

TABLE 3: Summary of patient demographics in patients diagnosed with osteoarthritis of the knee
Trial Design Dosage Route of
administration
and duration
Study
subjects
n=number
Mean
age
Gender
(Double
Blind Phase)
NAPRELAN
1000 mg od
compared with
that of placebo
and
Naprosyn
500 mg bid
Oral
12 wks
n=347 63.8 years 238 females
109 males
(Open Label
Phase)
NAPRELAN
1000 mg once
daily
Oral
9 months
n=228 63.7 years 159 females
69 males
TABLE 4: Summary of Primary Efficacy at Visit 7 (Week 12), for the 12-week, Double Blind Phase, in the Intent-to-Treat Population
Variable1 Visit 7 (twelve weeks of treatment)
Mean Change ± SEM (standard
error of the mean) from Baseline
p-Value
NAPRELAN
(N = 84)
Naprosyn
(N = 84)
Placebo
(N = 77)
NAPRELAN
vs.
Placebo
Naprosyn
vs.
Placebo
NAPRELAN
vs.
Naprosyn
PhyGA 3.6 ± 0.2 3.6 ± 0.3 2.9 ± 0.3 0.0116 * 0.0310 * 0.6863
PtGA 3.8 ± 0.3 3.9 ± 0.3 2.1 ± 0.3 0.0000 * 0.0000 * 0.8495
PAM 3.6 ± 0.3 3.7 ± 0.3 2.6 ±0.3 0.0154 * 0.0123 * 0.9512
POP 3.2 ± 0.3 3.2 ± 0.3 2.8 ± 0.3 0.1667 0.1475 0.9554

1 PhyGA=Physician's Global Assessment; PtGA=Patient's Global Assessment; PAM=Pain Aggravated by Movement; POP=Pain on Palpation.

* statistically significant difference (p ≤ 0.05) using ANOVA.

Osteoarthritis, Study Results (Double Blind and Open Label OA Studies)

For the double blind treatment phase of the OA of the knee study, at the end of 12 weeks of treatment, three of the four primary efficacy variables favored NAPRELAN over placebo. Mean scores in the active-control (naproxen 500 mg bid) treated group were also significantly greater than those in the placebo treated group. NAPRELAN and the active control were equally effective. Thus, NAPRELAN 1000mg once daily and naproxen 500mg tablets twice daily were more effective than placebo. Clinical effectiveness was demonstrated at one week and continued for the duration of the study. In the double blind treatment phase, NAPRELAN and Naprosyn demonstrated comparable efficacy with no significant differences in the mean efficacy scores. After 12-weeks, three of the four primary efficacy variables (PhyGA, PtGA and PAM) favored NAPRELAN and Naprosyn when compared with placebo.

For the open label treatment phase of the OA of the knee study, evaluation of efficacy was limited to the Physicians Global Assessment (PhyGA) and the Patient’s Global Assessment (PtGA) with the evaluations performed at Months 4 and 12 (visits 8 and 11). Patients who initially received either NAPRELAN or Naprosyn maintained their improvement achieved in the double blind phase. By contrast, patients who initially received placebo showed improvement in PhyGA and PtGA after the first month of NAPRELAN treatment.

Special Studies

Endoscopic Effects

Study 1: A double blind, randomized, parallel group study, male subjects received either two NAPRELAN 500 mg tablets (1000 mg) once daily or naproxen 500 mg tablets twice daily (1000 mg) for 7 days. 19 subjects completed the study; 10 evaluable subjects took NAPRELAN and 9 evaluable subjects took naproxen. Following treatment the subjects underwent an endoscopic examination to evaluate the gastroduodenal mucosa for damage. The endoscopic examination was assessed visually and scored using the Euler and Lanza visual analog scales. Mucosal biopsies were taken at endoscopy and mucosal damage was evaluated histologically. Following 7 days of treatment with either NAPRELAN 1000 mg once daily or naproxen 500 mg twice daily, results indicate both products caused significant (p<0.05) mucosal change from baseline.

Study 2: A double blind, randomized crossover comparison of NAPRELAN (1000 mg once daily), naproxen (500 mg twice daily) and aspirin (650 mg four times daily). Each of the three administration periods lasted for 7 days, with a washout period of 21 days between administration. Twenty-three (23) subjects (12 males, 11 females) completed the study. The study drugs were administered in random order. Prior to receiving and following dosing of the study drugs, each subject underwent gastroduodenal endoscopy to evaluate the mucosa. The primary objective was to compare levels of mucosal damage to the stomach and duodenum for each of the drug regimens. The primary end points were the total number of erosions in the stomach and the total number in the duodenum. In the stomach the mean number of erosions was 18.32 for ASA, 5.00 for naproxen, and 4.57 for NAPRELAN. The difference between ASA and the other two formulations was significant (p<0.001) but there was no significant difference between NAPRELAN and naproxen. In the duodenum the mean number of erosions was 5.91 for ASA, 4.57 for naproxen and 1.83 for NAPRELAN. Mucosal damage in the duodenum was significant for NAPRELAN vs. naproxen (p=0.024) and for NAPRELAN vs. ASA (p=0.009), but there was no significant difference between naproxen vs. ASA. The clinical significance of these findings is unknown.

Detailed Pharmacology

Pharmacokinetics

NAPRELAN Tablet Matrix Disintegration and Bead Dispersion Characteristics

An in vivo imaging study was performed to validate the tablet matrix disintegration and bead dispersion characteristics of NAPRELAN under both fasted and fed conditions. This study used a gamma scintigraphy camera and a radioisotope distributed in the controlled release beads. The integrity, distribution and transit characteristics of 1) the intact matrix tablet, 2) the disintegrated tablet and 3) the delayed release beads, plotted under both fasting and fed conditions, also matched the pharmacokinetic profile of the product in a group of healthy volunteers. This technique provides an in vivo verification of the rapid disintegration of the tablet, and the subsequent distribution and dispersion of the delayed release beads in the upper and lower small intestine.

Based on the pharmacokinetic profile, it is clear that the absorption phase of NAPRELAN, limited to primarily the first four to six hours after administration, coincides with the disintegration of the tablet in the stomach and the transit of the controlled released beads through the small intestine and into the proximal large intestine. The absorption phase is consistent with a control of the peak plasma concentrations following NAPRELAN administration, rather than being associated with a greatly extended absorption phase, which is unnecessary given the long inherent half life of naproxen. The presence of food did not significantly affect the disintegration or dispersion characteristics of the dosage form in the gastrointestinal tract, nor were the pharmacokinetic characteristics of the product significantly affected.

Food Effect

In addition to the imaging study described above, another study was conducted with NAPRELAN under fasted and fed conditions to determine if the consumption of food had any impact on the pharmacokinetic profile of NAPRELAN.

In a randomized crossover fashion, 24 male volunteers received a single dose of NAPRELAN 500 mg in a fasted state and 30 minutes following a heavy breakfast. Plasma sampling for 48 hours post-dose was conducted. Food was found to have little effect on the in vivo pharmacokinetics of NAPRELAN. The rate and extent of absorption, as estimated by AUC0-4 and Cmax was unaffected by food [90% Confidence Interval for NAPRELAN (fed)/NAPRELAN (fasted): log10 AUC0-4 = 95.50% - 100.00%; log10 Cmax = 85.11% - 97.73%]. Administration of NAPRELAN with food resulted in a slight delay in Tmax [fed Tmax: 7.42±4.94 hours; fasted Tmax: 4.13±1.48 hours (p<0.01)].

Toxicology

Three preclinical toxicology studies were conducted with NAPRELAN, as described below. These studies focused on naproxen’s effects on the most sensitive organ system, the gastrointestinal tract.

Acute Toxicity

24 hour GI Toxicity Study of NAPRELAN in Dogs

A 24-hour gastrointestinal toxicity study in dogs was undertaken to assess the local irritancy in nine males and nine females. The doses administered were NAPRELAN 1500 mg (equivalent to 500 mg x 3), Naprosyn 1500 mg (500 mg x 3) for the active control, and preformulated placebo tablets. In each case, intact 500 mg tablets were placed in ligated sections of the duodenum, ileum and colon. The tissue was necropsied 24 hours later and macroscopic and microscopic effects in the mucosa were observed.

There were no clinical signs of toxicity observed upon gross examination or histopathology that could be attributed to the test or control articles. No clinical chemistry data indicated the presence of any abnormalities related to treatment. The only laboratory changes were small increases in BUN and serum creatinine levels in the dogs dosed with NAPRELAN and Naprosyn when compared to the vehicle controls.

The gross effects were less in the NAPRELAN and Naprosyn groups than in the placebo group. This was probably due to a reduction of the inflammatory effects by the surgical procedure. There were no signs of chemical irritation. No histological damage could be attributed to the test drugs or control article.

Long-Term Toxicity

Two long term toxicity gastrointestinal studies were conducted with NAPRELAN, similar to each other in design but involving two different species, micro-swine and monkeys. NAPRELAN tablets were administered daily at two dose levels to correspond with the minimum and maximum clinical dose range. The Naprosyn dose was chosen to mimic low to average clinical dose levels for this product, and provide a relevant baseline for comparison with NAPRELAN.

Repeated Dose Oral Toxicity Study of NAPRELAN in Micro-swine

This study examined the gastrointestinal effects of NAPRELAN through a repeat dose oral toxicity study in micro-swine. The effects of seven days dosing with NAPRELAN daily at two dose levels (500 mg qd or 1500 qd), Naprosyn (375 mg bid), and placebo on eight males and eight female swine were assessed.

No clinical signs of toxicity were observed. There were small erosions in the mucosa of 2- Naprosyn, 1-500 mg NAPRELAN, and 2-1500 mg NAPRELAN and 0-placebo treated swine. In general, the erosions with Naprosyn were deeper and included submucosal inflammation. No abnormal findings were noted during the ophthalmic examinations. No trends in the hematologic or clinical chemistry data suggest the presence of any treatment effects.

Repeated Dose Oral Toxicity Study in NAPRELAN in Rhesus Monkeys

An additional study was conducted in monkeys to confirm the gastrointestinal tolerability of NAPRELAN. This study was very similar in design to that conducted with the micro-swine. Eight male and eight female monkeys were dosed for seven days with either 500 mg or 1500 mg NAPRELAN, 375 mg Naprosyn bid or placebo.

In contrast to the micro-swine, the monkeys exhibited vomiting with the 1500 mg dose of NAPRELAN. In addition, there was a possible effect on BUN and creatinine in all monkeys who received naproxen. The gastrointestinal mucosa of the fundus and pyloric area exhibited small erosions in the animals that received Naprosyn. Histopathological examination showed erosions in three monkeys in the 1500 mg group, two in the Naprosyn group, and none in the other two groups. Only one animal in the 1500 mg NAPRELAN group exhibited reddish streaks in the fundus.

The 500 mg NAPRELAN group demonstrated substantially less gastrointestinal irritation than the other treated animals. The toxicity of NAPRELAN and Naprosyn was limited to superficial gastric erosions that were associated with local inflammation and occasionally with minute gastric hemorrhage or edema. No abnormal findings were noted during the ophthalmic examinations.

NAPRELAN at 1500 mg dosing was of similar overall toxicity as Naprosyn dosing at 750 mg.

NAPRELAN dosing at 500 mg appeared to be substantially less toxic than either the 1500 mg dose of NAPRELAN or the 750 mg dose of Naprosyn. Additionally, an observed toxic effect of treatment with 1500 mg NAPRELAN was vomiting.

Reproductive and Developmental Toxicity

Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure) and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug.

There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Naproxen readily crosses the placental barrier.