Inflammopharmacology. 1995; 3: 351-361.

9 1995 Kluwer Academic Publishers. Printed in the Netherlands

C L I N I C A L U P D A T E OF T H E RELATIVE S A F E T Y OF
N A B U M E T O N E IN L O N G - T E R M CLINICAL T R I A L S

J.A. LIPANI and M. POLAND

SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA

ABSTRACT

Lipani JA, Poland M. Clinical update of the relative safety of nabumetone in long-term clinical trials.
Inflammopharmacology. 1995;3:351-361.

Objective: To determine whether the pharmacological profile of nabumetone results in gastric safety,
maintains haemostasis and is renally safe.

Methods: The data from seven double-blind trials and one large randomized clinical trial were pooled
and subjected to Kaplan-Meier life tests to determine the frequency of perforations, ulcers and bleeds
(PUBs). Two studies each examined haemostasis and renal effects in volunteers and patients.

Results
PUBs: The cumulative frequency of PUBs with nabumetone was 0.03% in 4471 patients. The
cumulative frequency with all other NSAIDs comparators ranged from 0.8 to 1.8%.
Haemostasis: The mean impedance increased with nabumetone and decreased following indomethacin
in normal volunteers. In patients, nabumetone was equivalent to placebo in effect on bleeding time, PT
and PPT.
Renal effects: In a triple cross-over study in an at-risk population of elderly hypertensive patients
receiving ACE/diuretic, nabumetone had no effect on GFR or PGE.

Conclusion:The pharmacological profile of nabumetone results in gastric, renal and haemostasis safety.

Keywords: haeanostasis, nabumetone, NSAIDs, renal effects, ulcers

INTRODUCTION

Nabumetone is a non-acidic, non-steroidal, anti-inflammatory drug (NSAID). It is a

prodrug and is rapidly metabolized to 6-methoxy-2-naphthylacetic acid which is a
potent inhibitor of prostaglandin synthesis. Nabumetone has been compared with and
found to be as effective as other NSAIDs in patients with osteoarthritis and
rheumatoid arthritis.
Safety, historically and at the present, has been a major concern with the use of
NSAIDs. Nabumetone, tested in over 48 thousand patients in clinical trials, has
demonstrated a safety profile significant for low gastric toxicity, low hepatic toxicity,
lack of effect on platelet function and low renal toxicity.

351
352 Lipani and Poland

CLINICAL EFFICACY

The efficacy of nabumetone in osteoarthritis (OA) and rheumatoid arthritis (RA) will
not be dealt with here in detail. Suffice to say that in these conditions both patient
global assessments and physician global assessments were comparable to pooled
NSAID comparators. Visual analogue scores for pain were also similar in both RA
and OA [1].

GASTRIC SAFETY

At the time of the approval of the new drug application (NDA) in the United States in
1991, gastric safety was analysed in 1677 patients. The cumulative frequency of
clinically detected perforations, ulcers and bleeds (PUBs) for nabumetone was 0.3%
(CI: 0.0%, 0.5%) at three months; 0.3% (CI: 0.04%, 0.6%) at six months; 0.5% (CI:
0.1%, 0.9%) at one year; and 0.8% (CI: 0.3%, 1.3%) at two years [2].
The low frequency of PUBs noted in clinical trials is based on the pharmacological
profile of nabumetone. In contrast to most NSAIDs which are acidic, nabumetone is
non-acidic and does not dissociate in the gastric lumen. In addition, nabumetone is
hydrophobic and will not penetrate the mucosal gel layer. If nabumetone does
penetrate the mucosal gel layer and enter the gastric epithelium, it remains inactive
because it is a prodrug and will not affect the prostaglandin synthesis. Therefore, there
is no direct topical effect on the gastric mucosa [3].
The second mechanism by which NSAIDs gain access to the gastric mucosa is via
enterohepatic circulation. This occurs when NSAIDs such as indomethacin,
diclofenac, naproxen, piroxicam, meloxicam, sulindac and etodolac, are absorbed in
the duodenum, processed by the liver and secreted in the bile. Bile will often reflux back
into the stomach, carrying with it the NSAID that has been secreted in the bile. Once
refluxed into the stomach, the NSAID will then be resorbed, resecreted into bile and
re fluxed again into the stomach [3]. Thus, the stomach is constantly bathed with the
NSAID which can indirectly cause topical damage. This recirculation, common to the
NSAIDs noted above, also produces repeated exposure of the NSAID to the hepatic
parenchyma, potentiating hepatotoxicity. Nabumetone, on the other hand, undergoes
extensive first-pass metabolism, i.e. 99~ metabolism in a single pass through the liver.
In the liver, it is converted to 6-MNA, the active metabolite and to several other minor
inactive metabolites. 6-MNA is eliminated by the kidneys as a conjugate or as a
demethylated metabolite. The active metabolite 6-MNA does not undergo
enterohepatic recirculation and therefore is not exposed to the gastric mucosa. As a
result, nabumetone does not cause indirect topical damage [4].
Finally, it is noted in another article in this publication that a second isoform of
prostaglandin synthase has been identified [5]. This isoform, cyclo-oxygenase-2 (COX-
2) or PGHS2, is produced by activated inflammatory cells. Cyclo-oxygenase-1 (COX-l)
is the isoform responsible for the 'housekeeping' function, i.e. it is responsible for the
maintenance of homeostasis in the gut, kidneys and platelets.
Nabumetone Safety 353

C L I N I C A L TRIALS

Since the NDA seven double-blind clinical trials have been conducted by SmithKline
Beecham in both osteoarthritis and rheumatoid arthritis involving diclofenac,
diclofenac-SR, indomethacin, piroxicam and naproxen as comparators [6]. The trials
were numerically matched in populations and lasted from three to six months with
doses ranging from 1-2 g nabumetone. The cumulative frequency of clinically
detectable PUBs in these seven double-blind studies are depicted in Figure 1. In 1184
patients treated with nabumetone, no ulcers were detected. Five comparator NSAIDs
showed ulcer rates ranging from 0.4% to 1.8% based on a Kaplan-Meier life table
analysis.
As elderly patients (greater than 65 years of age) are the subset of patients usually
more susceptible to side-effects due to age, polypharmacy, duration of the disease and
prior exposure to NSAIDs, this patient population was looked at separately in these
studies. In 486 patients over 65 years of age taking nabumetone, no ulcers were
detected. The range of four comparators (diclofenac, diclofenac-SR, piroxicam and
indomethacin) was from 1.1% to 1.7%.
To further query the safety and efficacy of nabumetone, a large multicentre trial was
designed [1,7]. The nabumetone efficacy and safety trial (NEST trial) was an open-
label, randomized, controlled trial that was designed to mimic clinical rheumatological
practice in the United States. It was conducted in over 450 rheumatology offices. It
allowed each physician/investigator to conduct his own two-arm study as he was given
the comparator of his choice from ibuprofen, piroxicam, diclofenac or naproxen. The
patients were randomized as follows: 3315 to nabumetone, 279 to diclofenac, 296 to
naproxen, 235 to ibuprofen, and 286 to piroxicam. Nabumetone, with 3287 patients
with a documented total exposure to treatment, had one clinically detected ulcer. The
remainder of the comparators had a total of six ulcers (Figure 2).
When we combine the data, i.e. the seven double-blind studies and the NEST trial,
the total number of patients who were randomized to nabumetone and had a
documented treatment exposure time was 4471 patients. The cumulative frequency of
clinically detected ulcers and bleeding was 0.03% using the Kaplan-Meier life test
(Figure 3). For the comparator NSAIDs, the cumulative frequencies ranged from 0.8%
to 1.8%.
A total of 6148 patients with osteoarthritis and rheumatoid arthritis treated with
nabumetone in clinical trials had a three-month cumulative incidence of 0.1% and a
six-month incidence of 0.2% which is not clinically different from the 0.3% cumulative
frequency reported for the 1677 patients who were initially analysed for the frequency
of PUBs (Table 1).
The upper limit of the 95% confidence interval with nabumetone was lower than the
lower limit of the 95% confidence interval with the pooled NSAIDs (i.e. no overlap of
cumulative frequencies (Figure 4)).
354 Lipani and Poland

2.0%- 1.8% 1.8%

z
1.4%
..~ 1.5%-

0.9%
1.0% -

0.4% /
,, 0.5%-

0.0%-
Nabumetone Naproxen Indomethacin Diclofenac DiclofenacSR Piroxicam
(n=1184) (n=317) (n=164) (n=168) (n=388) (n=147)

Kaplan-MeierLife Test

Figure l. Cumulative frequency of clinically detected PUBs in seven double-blind studies post-
NDA

2.0%.1111
i

I
1.3%
t- 1.5%
1.1%
O..

1.0%

E I
|

0.5%- '
rl

0,0%
Nabumetone Diclofenac Piroxicam Ibuprofen Naproxen
(n=3287) (n=291) (n=284) (n=229) (n=273)

Kaplan-Meier Life Test

Figure 2. Cumulative frequency of clinically detected PUBs in the NEST trial

Nabumetone Safety 355

2.0% - / 1.8%

E 1.5%
1.1%
0.

i
"6 0.9 % 0.9 % 0.9%
A
1.0%

0.5%

0.0%
o~
Nabunret~)ne
tn=4471~

Kaplan-Meier Life Test

Diclr
(n=459) (n=l(~l) In=431 )
J
lnd,n~ethacin Pirc~xlcam Napr{~xen tbuprofen Did{)fenacSR
(n=5(XI) (n=229) (n=.~)

Figure 3. Comparison of cumulative frequency of clinically detected PUBs pre- and post-NDA

TABLE 1
The cumulative frequency of PUBs with the 95% confidence intervals (CI)

Cumulative frequency of PUBs (95% CI)

Treatment NDA current label Post-NDA studies NDA+post-NDA studies

duration (n = 1677) (n = 4471) (n = 6148)

3 months
(up to 90 days) 0.3% (0.0%, 0.5%) 0.03% (0.0%, 0.08%) 0.1% (0.01%, 0.2%)

6 months
(up to 180 days) 0.3% (0.04%, 0.6%) 0.03% (0.0%, 0.08%) 0.2% (0.01%, 0.3%)

1 year
(up to 365 days) 0.5% (0.]%, 0.95/0)

2 years
(up to 730 days) 0.8% (0.3%, 1.3%)

Kaplan-Meier life test

356 Lipani and Poland
0.03%
Nabumetone
Post NDA
n=4471 0.0% 0.08%

0.2%
Nabumetone
Pre/Post NDA
n=6148 0.01% 0.3%

1.4%
Pooled NSA IDs
Post-NDA
n=2261 0.5% 2.4%
I
Figure 4. Cumulative frequencies of PUBs with 95% confidence intervals: nabumetone versus
pooled NSAIDs using the Kaplan-Meier life test

RENAL AND HAEMOSTASIS EFFECTS

NSAIDs affect the kidney by inhibiting renal prostaglandin formation potentially

causing vasoconstriction, interference with potassium excretion and enhanced sodium
resorption. These effects can lead to a variety of syndromes associated with NSAID
treatment, specifically, salt retention and oedema, hyperkalaemia, acute renal failure,
and rarely, nephrotic syndrome, interstitial nephritis and papillary necrosis.
Clinical trials were designed to show the renal effects of treatment with nabumetone.
The first, conducted by Freed et al. [8] studied 12 healthy, non-smoking females who
abstained from sexual intercourse to avoid contamination of urine specimens with
seminal prostaglandins. They were aged 21 to 43 with a mean age of 26.1 and a mean
weight of 61.3 kg. The trial utilized a cross-over design with indomethacin 100 mg,
nabumetone 1 g, and sulindac 400 mg. Urinary prostaglandin E2 was analysed at day 1
and day 7 for each of the arms of the protocol. A summary of the prostaglandin E2
values is seen in Figure 5. Prostaglandin E2 was decreased after treatment with
indomethacin and increased after treatment with both nabumetone and sulindac.
Whole blood platelet aggregation test via platelet aggregometry using impedance
versus collagen concentration was also part of the study [8]. Figure 6 shows graphically
the increase in impedance with both nabumetone and sulindac but inhibition of
platelet aggregation with indomethacin.
The effects of nabumetone on haemostasis were demonstrated in patients
undergoing arthroscopy for internal derangement of the knee. In 101 patients
randomized to placebo or nabumetone 2 g, no difference was found in the treatment
groups for bleeding time, prothrombin time and partial thromboplastin time [9]
(Figure 7).
Nabumetone Safety 357

30

20
Mean
Impedance
(ohms)
10 T ~ O ]ndomethacln

y
'~ [
-

I I
D) NalbUd::~

I
1 2 3 4
CollagenConcentration(Fg/mL)

Figure 5. Urinary prostaglandin E2: adjusted mean (+ SEM) change from baseline

150 ~t

100

A 50
PGE2
(pg/min)
o

-50

-100
Day1 Day7 Day1 Day7 Day1 Day7
Indomethacin Nabumetone Sullndac
* vs I n d o m e t h a c i n p < O . 0 5

Figure 6. Whole blood platelet aggregation; impedance (+ SEM) versus collagen concentration
on day 1 at 4 h
358 Lipani and Poland

50

40

[] Nabumetone (n = 52) 30.6 30.1

30
[] Placebo (n = 49)

20
12.8 12.9 12.8 12.8

10

0
IW Beedng "lTme(mitt) Prothom~n Time (sec.) Partial "lT~rri0o~astin "Time(sec.)

Figure 7. Haemostasis tests pre- and post-arthroscopic surgery in patients with osteoarthritis

1.7
2
I Sulindac lbuprofen
0
-2 Nabumelone
E
-4
-6
-8
-10 -8.5

Figure 8. Mean change in GFR (inulin clearance)

Nabumetone Safety 359

500 PGE2 6-Keto-PGFla Thromboxane B2

400 363.4

300
223.5
200 159

100

0
-16
-100 -68.1
-105.2 -122
-200
-213.3
-300

-400

Nabumetone ~ Sullndac I l Ibuprofen

Figure 9. Changes in renal prostaglandins, ng/min (n = 17)

9 mGFR mPGE2 O6.Keio .... OTB2

75%
49%
50%

25%
LU
(3 4%
Z 0%
'1-
-25% -17%
-21%F -29% l~dRI-29O/o
-50% -43%
-51% ~o
-63%
-75%
-73% -68%
-100%
Patient 6 Patient 108 Patient 11 Patient 14

Figure 10. Patients with acute renal failure after one month of ibuprofen treatment
360 Lipani and Poland

The Freed study in normals was complemented by a trial utilizing at-risk patients
[10]. This trial involved 17 females with a diagnosis of hypertension controlled with an
ACE inhibitor and a diuretic as well as osteoarthritis according to the American
College of Rheumatology criteria.
The study design was a triple cross-over, observer blind trial, involving nabumetone
2 g, sulindac 400 mg, and ibuprofen 2400 mg. Each NSAID treatment was preceeded
by and concluded by baseline renal function studies (glomerular filtration rate (GFR)
by inulin clearance, renal prostaglandin assays) and rheumatology assessments. The
patients were screened, taken off their NSAIDs for two weeks, then treated for one
month followed by a two-week interval offNSAIDs. This process was repeated until all
three NSAIDs had been used by each patient.
The patients, age range 56-74 years, were all black, hypertensive females with
osteoarthritis of the hips and knees. Previous NSAIDs had been used by all but six
patients in the three months prior to entry into the trial.
The mean change in GFR by inulin clearance showed an increase in inulin clearance
in the nabumetone group, a maintenance of baseline in the sulindac group and a
decrease in the ibuprofen group (Figure 8).
Renal prostaglandins assayed were prostaglandin E2 (PGE2), 6-keto-prostaglandin
F1~, (6-keto-PGFl~) and thromboxane B2. Figure 9 shows the changes in renal
prostaglandins in nanograms per minute. Nabumetone either maintained or
increased the vasodilatory prostaglandins assayed in this study [10].
Four patients in this study had a 20% or greater decrease in GFR on the ibuprofen
arm of the triple cross-over study. In all of these patients, coincident with the decrease
in GFR, was a decrease in PGE2, 6-keto-PGFla and thromboxane B2 (Figure 10).
This renal function study in an at-risk population showed that nabumetone had no
clinically meaningful effect on renal function or vasodilating renal prostaglandins. The
reference standard, ibuprofen, did result in a decrease in renal function due to a
decrease in renal prostaglandins.

CONCLUSIONS

Nabumetone, 1-2 g per day, in over six thousand patients treated for 3-6 months in
clinical trials had a cumulative incidence of PUBs of 0.1% at three months and 0.2% at
six months.
In normals and in patients at risk for renal impairment, nabumetone maintains renal
function and does not inhibit the vasodilatory renal prostaglandins.
There is no significant effect on platelet function in normal subjects and patients
given nabumetone 1-2 g/day. Haemostasis is unaffected.

ACKNOWLEDGEMENTS

The authors wish to express their gratitude to Agnes McCoy for her invaluable
expertise in the preparation of this manuscript.
Nabumetone Safety 361

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1. Lister BJ, Poland M, DeLapp RE. Efficacy of nabumetone versus diclofenac, naproxen, ibuprofen, and
piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med. 1993;95(suppi 2A):2S-9S.
2. Relafen (nabumetone) tablets. In: Physicians' Desk Reference, 49th edn. Medical Economics Data
Production Co., Montvale, NJ. 1995:2395-7.
3. Blower PR. The unique pharmacologic profile ofnabumetone. J Rheumatol. 1992;19(suppl 36):13-9.
4. Brett MA, Buscher G, Ellrich E et al. Lack of enterohepatic circulation of the active metabolite of
nabumetone in humans. J Rheumatol. 1992;19(suppl 36):81-2.
5. Laneuville O, Breuer DK, DeWitt DL, Hla T, Funk CD, Smith WL. Differential inhibition of human
prostaglandin endoperoxide H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs. J
Pharmacol Exp Ther. 1994;271:927-34.
6. Bellamy N, Bensen WG, Beaulieu A et al. A multicenter study of nabumetone and diclofenac SR in
patients with osteoarthritis. J Rheumatol. 1995;22(S):915-20.
7. Eversmeyer W, Poland M, DeLapp RE, Jensen CP. Safety experience with nabumetone versus
diclofenac, naproxen, ibuprofen and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med.
1993;95(suppl 12):10S-18S.
8. Freed MI, Audet PR, Zariffa N et al. Comparative effects of nabumetone, sulindac, and indomethacin
on urinary prostaglandin excretion and platelet function in volunteers. J Clin Pharmacol.
1994;34:1098-108.
9. Data on file at SmithKline Beecham.
10. Wallin JD, Cook ME, Thakur VD et al. Comparative effects of nabumetone, sulindae and ibuprofen on
renal function. [submitted].

Manuscript received 3 Sept. 95.

Accepted for publication 20 Sept. 95.