- Email: [email protected]
Evaluation of the safety of isoxicam
Evaluation of the Safety of lsoxicam
FRANCIS X. BURCH, M.D. San Antonio.
Data collected from more than 1,800 patients with rheumatoid arthritis or degenerative joint disease in Phase 3 clinical studies of isoxicam (Maxicam) indicated that the drug is well tolerated on both a short-term and a long-term basis. The most common type of adverse reaction to all medications (isoxicam, aspirin, and indomethatin) was gastrointestinal: 22.8 percent with isoxicam, at a dosage greater than 200 mg per day; 14.2 percent with isoxicam at 200 mg per day; 31.6 percent with buffered aspirin at 3,600 to 4,800 mg per day; 24.6 percent with indomethacin at 150 mg per day; and 7.2 percent with placebo. The incidence of tinnitus and deafness was significantly greater with buffered aspirin than with isoxicam, and the number of patients who had at least one episode of dizziness, vertigo, or headache was significantly greater with indomethacin than with isoxicam. In open-label, long-term studies, in which ap proximately 70 percent of the patients participated, the types and frequencies of adverse effects were similar to those observed with isoxicam during the controlled studies. The overall frequency of withdrawal for adverse reactions during the long-term studies was 11.5 percent, similar to that during the controlled studies. At the recommended dosage for isoxicam of 200 mg per day, the incidence of gastrointestinal ulcers was 0.81 percent, well within the range expected among arthritic patients receiving nonsteroidal anti-inflammatory drugs. From the data collected in Phase 3 clinical studies, it may be concluded that isoxicam is better tolerated than either aspirin or indomethacin and should not create unusual problems in the short-term or long-term treatment of rheumatoid arthritis or degenerative joint disease.
Texas
Requests for reprints should be addressed to Dr. Francis X. Burch, 8527 Village Drive, Suite 207, San Antonio, Texas 78212.
28
October
19,1985
The American
Journal
lsoxicam (Maxicam) is a new nonsteroidal anti-inflammatory drug that has shown good activity in both animal [l] and human studies [2]. This report describes the data relating to the safety of isoxicam obtained from Phase 3 clinical studies. Data include the adverse reactions reported by patients and observed by physicians and clinical laboratory values obtained at scheduled intervals. The study populations consisted of more than 900 patients with rheumatoid arthritis and more than 900 with degenerative joint disease. The patients were observed during both shottterm controlled studies and long-term, open-label studies in the United States and Europe. The effects are reported for both the initial studies, in which the dosage ranged from 200 to 400 mg per day, and the long-term studies, in which the dosage was restricted to 200 mg per day. of Medicine
Volume
79
(suppl4B)
ISOXIGAM
TABLE
I
Number
of Patients
Evaluated
Disease Rheumatoid Degenerative Total *Comparison
TABLE
with
II
arthritis joint disease indomethacin
Percentage (Controlled
conducted
for Safety in Phase 3 Studies
lsoxicam
Buffered Aspirin
471 458 929
234 234
in United
of Adverse Studies)
SYMPOSIUM-BURCH
Kingdom
Reactions
lndomethacin 183' 183
Placebo
Total
222 275 497
927 916 1,843
and Europe.
in Patients
with Rheumatoid
Arthritis
or Degenerative
Joint
Disease
lsoxicam Body System
>2Og mglday (n = 535)
200 mg/day (II = 394)
Buffered Aspirin (n = 234)
lndomethacin (II = 133)
Placebo (n = 497)
22.6 4.8 3.0 1.1
14.2 3.6 2.5 0
31.6 6.0 6.4 0.8
24.8 2.2 14.8 0
7.2 1.6 1.0 0
30.5
24.4
53.0
45.9
23.1
19.7
Gastrointestinal Skin and appendages Nervous Hemic/lymphatic Percent of patients with adverse reactions Percent of patients withdrawn for adverse reactions
TABLE
Ill
9.2
9.6
Percentage of More Common Adverse Degenerative Joint Disease (Controlled
Reactions Studies)
in Patients
with Rheumatoid
Arthritis
lb.9 1.6
or
lsoxicam Reaction
200 mg/day (n = 535)
200 mg/day (n = 394)
Buffered Aspirin (n = 234)
lndomethacin (n = 183)
Placebo (It = 497)
7.1 5.0 4.7 4.5 3.6 3.0
4.3 5.8 2.0 3.8 3.6 2.5
12.4
13.1 8.2 0 11.5 3.3 1.6
1.8 1.2 0.8 1.8 1 .o 0.8
Nausea/vomiting Abdominal pain Stomatitis Dyspepsia Diarrhea Rash
MATERIAL
AND METHODS
In the controlled phases of the studies, from six weeks to six months in duration, 929 patients received isoxicam, 234 received buffered aspirin, 183 received indomethacin, and 497 received placebo, for a total of 1,843 patients (Table I). All of the patients receiving aspirin had rheumatoid arthritis, and all of the patients receiving indomethacin had degenerative joint disease of either hip pr knee. Initially in the Phase 3 evaluation, isoxicam was administered at dosages from 200 to 400 mg per day. Later, it was decided to establish’ the efficacy and safety of isoxicam at 200 mg per day. Therefore, the incidences of adverse reactions are presented for both dosage groups (Table II). The effect of this dosage reduction in the controlled studies can be seen in the reports of gastrointestinal reactions. At dosages of isoxicam higher than 200 mg per day, the incidence was 22.6 percent; ht 200 mg per day, it was 14.2 percent, both frequencies considerably lower than that with 3,600 to 4,800 mg per day of buffered aspirin (31.6 percent). The inciOctober 18, 1985
9.4 2.1
9.8 4.3 4.7
dence of gastrointestinal reactions with 150 mg per day of indomethacin (24.6 percent) was approximately the same as that with the higher dosage of isoxicam. Generally, the frequencies of skin and nervous system reactions with buffered aspirin were somewhat greater than those with isoxicam. With indomethacin, the incidence of skin reactions was lower, but that of nervous system reactions, 14.6 percent, was considerably higher. The percentages of patients who withdrew because of adverse reactions were also lower with both dosages of isoxicam than with buffered aspirin or indomethacin. RESULTS The more common adverse reactions in the controlled studies were nausea and vomiting, abdominal pain, stomatitis, dyspepsia, diarrhea, and rash (Table Ill). The greatest difference in incidence of adverse effects between the high and low dosages of isoxicam occurred with nausea and/or vomiting, 7.1 percent versus 4.3 percent, and with stomatitis, 4.7 percent versus 2.0 percent. OtherThe American Journal of Medicine
Volume 79 (suppI
29
ISOXICAM
SYMPOSIUM-BUdCH
TABLE
IV
Adverse Reactions in Patients with Rheumatoid (Six-Month, Double-Blind Comparison)
Arthritis
Treated
with lsoxicam
Early Study lsoxicam 300-400 mg/day (n = 127)
Special
i3
senses*
lsoxicam 208 mg/day (n = 106)
6.3
is
22.6
3
of patient reactions
V
72
56.7
80
62.5
25
23.8
23
amblyopia,
taste
Number of Patients
Dizziness Vertigo Headache Total number with at least one reaction
30
41.5
26
24.5
withdrawals
perversion,
lsoxicam 200 m#/day (n = 182)
*Chi-square
44 p < 0.01
18.1
28
21.9
vision
Percent
abnormality,
watery
4 3 3 9 p < 0.001*
2.2 1.6 1.8 4.9
Momethacin 160 mglday (n = 183) Numbjerof Patients 15
ii 16 34
Percent 8.2 6.0 8.7 18.6
test.
October 18, 1985
The American Journal of Medicine
io
9.5
p < 0.01
Adverse Reactions (Special Senses) in Patients with Degenerative Joint Disease Treated with lsoxicam or lndomethacin (12~week, Double-Biind Comparison)
Adierse Reaction
20.8
with
wise, there did not appear to be much difference in the incidence of adverse effects with the two dosage levels. With buffered aspirin, the incidences of nausea and/or vbmiting (12.4 percent), abdominal pain (9.4 percent), and dyspepsia (9.8 percent) were markedly higher than the incidences at either of the dosage levels of isoxicam. For diarrhea and rash, the incidences with buffeied aspirin were slightly greater than those observed with 200 mg per day of isoxicam. With indomethacin, the incidences of abdominal pain (8.2 percent), nausea and/or vomiting (13.1 percent), and dyspepsia (11.5 percent) were also markedly greater than those with either level of isoxicam. At 260 mg per day, isoxicam induces fewer of these common adverse effects than does either buffered aspirin at 3,600 mg per day or indomethacin at 150 mg per day.
TABLE
22 p < 0.0005
NS ‘Tinnitus, deafness, +Chi-square test.
Number of Patients Percent
2.9
NS Total number for adverse
Buffered Aspirin 3,600 m#/day (n = 106)
Number of Number of Patients Percent Patients Percent p < 0.6005’
Total number of patients adverse reactions
Aspirin
Later SluUy Buffered Asp@ 4,600-4,800 mglday (n = 128)
Number of Patients Percent
Body System
or Buffered
eyes.
In direct six-month, double-blind comparisons of isoxicam with buffered aspirin, the major differences in frequencies of adverse reactions were in the special senses. In both an early study, in which isoxicam and aspirin were administered in higher dosages,, and a later study, in which isoxicam was administered at the recommended dosage of 200 mg per day and aspirin at 3,600 mg per day, the frequency of adverse reactions of the special senses was sjgnificantiy lower with isoxicam than with aspirin (Table IV). In the earlier study, the overall proportion of patients with adverse reactions and the proportion who withdrew for adverse reactions were higher with aspirin than with isoxicam, but the differences were not statistically significant. In the later study, however, both the proportion of patients with adverse reactiohs and the proportion who withdrew because of them were significantly higher with aspirin than with isoxicam. The most common adverse, reaction of the special senses was tinnltus. In the earlier study, it occurred in 23 of 128 (18.0 percent) patients treated with aspirin and in four of 127 (3.1 percent) patients treated with isoxicam. In the later study, it occurred in 20 of 106 (18.9 percent) patients treated with aspirin and in three of 105 (2.9 percent) patients treated with isoxicam. Because headache, dizziness, and vertigo are common reactions with indomethacin [3], their frequencies, were compared in an international study of patients with degenerative joint disease receiving 200 mg per day of isoxicam or 150 mg per day of indomethacin, The number of patients in whom, at least one of these symptoms developed was significantly greater with indomethacin than with isoxicam (Table V). Table VI lists the incidences of the common adverse
Volume 79 (suppl 48)
ISOXICAM
reactions observed during the open-label studies when patients received isoxicam for periods of up to three years, 740 patients at dosages greater than 200 mg per day and 1,084 patients at 200 mg per day. The total of 1,824 patients is more than entered the open-label phase from the controlled phase and the reason for this apparent discrepancy is that many of the 740 patients who received more than 200 mg per day are also included in the patients who received 200 mg per day because they were in the long-term phase when the dosage was reduced. The effect of dosage reduction is clearly evident in these data. Except for abdominal pain and diarrhea, the incidences of adverse reactions with the higher dosage are at least twice those reported with the lower dosage. Table VII presents the number of patients in the openlabel studies who withdrew from the study because of adverse reactions. Among the patients with rheumatoid arthritis receiving isoxicam in the open-label studies, 44.8 percent had adverse effects and 12.8 percent withdrew from the study because of them. Of the 501 patients with degenerative joint disease who received isoxicam during the open-label studies, 27.1 percent had adverse effects and 9.4 percent withdrew because of them. This table does not separate the patients into groups at the two dosage levels of isoxicam. Therefore, 1,318 is the actual number of patients who received isoxicam at any dosage during the long-term, open-label studies. The incidence of withdrawals before dosage reduction (13.2 percent) is markedly higher than either that after dosage reduction (4.4 percent) or that at only 200 mg (5.6 percent) (Table
TABLE
Number and Percentage Label Studies)
of Patients
TABLE
VII
Disease
Rheumatoid arthritis Degenerative joint disease Total
516
82
224 740
16 98
6.5 11.4 0.8 8.8 3.5 6.1
2.4 6.2 2.4 3.1 2.2 2.4
Total Number of Patients
817 501 1,318
Patients with Adverse Reactions Number
Percent
Number
Percent
366
44.8
105
12.8
136
27.1
502
38.1
47 152
11.5
Withdrawn
from lsoxicam
Because
of Adverse
After Dosage Reduction
Reactions
Number
15.9
321
9
7.1 13.2
264 585
17 26
October 18, 1985
9.4
(Open-
At 200 mg/day from Beginning
Withdrawn Number of Patients
Percent
Patients Withdrawn for Adverse Reactions
controlled phases (9.3 and 8.4 percent versus 3.2 and 2.0 percent), but otherwise the abnormal values during the long-term phase were similar to those during the controlled phases. Changes in the results of liver function tests occurred in 6.8 percent of the patients, but careful evaluation of the results showed that only one, among patients receiving 200 mg per day, was greater than the levels specified in the Food and Drug Administration hepatotoxicity guidelines [4]. The results indicate that, at the
Withdrawn Number
200 mg/day (n = 1,084)
Number and Percentage of Adverse Reactions and Drug Withdrawals in Patients Treated with lsoxicam (OpenLabel Studies)
Rheumatoid arthritis Degenerative joint disease Total
Before Dosage Reduction Number of Patients
>200 mg/day (II = 740)
Nauseaivomiting Abdominalpain Stomatitis Dyspepsia Diarrhea Rash
The vast majority of laboratory values remained within normal ranges in both the controlled and long-term phases of the studies (Table IX). During the open-label phases, in which patients received isoxicam for periods of more than two years, the percent of patients who had decreases in hemoglobin or hematocrit values of at least 1.5 percent (none had decreases of as much as 25 percent) was notably larger at both dosage levels than during the
VIII
Percentage of Patients with More Common Adverse Reactions (Open-Label Studies)
Adverse Reactions
VIII).
TABLE
VI
SYMPOSIUM-BURCH
Withdrawn Number of Patients
Number
Percent -
2.8
296
14
4.7
6.4 4.4
203 499
14 28
6.9 5.6
Percent
The American Journal of Medicine
Volume 79 (suppl 46)
31
ISOXICAM
TABLE
SYMPOSIUM-BURCH
IX
Percentage lsoxicam
of Patients
with Clinically
Significant
Controlled
Laboratory
Measure
X
> 200 mg/day (n = 819)
200 mglday (n = 1,054)
3.2 3.0 0.6
2.0 3.3 3.6 5.6
9.3 2.6 0.9 6.0 2.6 0.2
2.0 1.1 4.5 1.2 2.1
1.4
1.3
4.8 2.8
5.8 1.8 0.8
0.2 0.7
2 65 years (n = 970)
Abdominal pain Nausea/vomiting Dyspepsia Stomatitis Diarrhea Gastrointestinal disorder
10.1 6.7 7.0 4.3 3.9 2.2
7.6 6.2 4.8
3.1 2.5 1.8
REFERENCES 1. 2.
3.
CONCLUSIONS
lsoxicam at 200 mg per day was better tolerated than buffered aspirin at 3,600 mg per day in the Phase 3 studies. Gastrointestinal adverse reactions, the most common with
American
Journal
of Medicine
a.4
both drugs, were much less frequent with isoxicam than with aspirin. Adverse reactions of the special senses, particularly tinnitus and hearing loss, were significantly more frequent with aspirin than with isoxicam. The proportion of patients who had headache, dizziness, and/or vertigo was significantly greater with indomethacin than with isoxicam. In long-term use, adverse reactions with isoxicam were of the same kinds and frequencies as in the short-term controlled studies. Clinical laboratory assessments did not reveal any signs of systemic toxicity. The percentage of patients who had reductions in hematocrit or hemoglobin values of 15 percent or more (none was more than 25 percent) was greater in the long-term studies than in the short-term studies, but for all other clinical laboratory values there were no differences between the short- and long-term studies. Hepatic function tests showed occasional abnormal results, but among those from patients receiving the recommended 200 mg per day, only one result was abnormal enough to be classified as toxic under the guidelines for toxicity of the Food and Drug Administration. On the basis of the studies described in this report, isoxicam is a well-tolerated drug and offers no unusual problems in the short-term or long-term treatment of rheumatoid arthritis or degenerative joint disease.
recommended 200 mg per day dosage of isoxicam, no clear pattern of drug-related hematopoietic, hepatic, or renal toxicity was observed. Among 3,217 patients who received isoxicam for any indication during the domestic and international clinical studies, there were 55 gastrointestinal ulcers, an incidence of 1.7 percent. However, among the 2,343 patients receiving 200 mg per day of isoxicam, there were 19 ulcers, an incidence of 0.81 percent. This is well within the range that might be expected in arthritic patients receiving nonsteroidal anti-inflammatory drugs. Frequencies of the more common adverse reactions were analyzed for patients younger than 65 years old, and for those 65 years old and older (Table X), including patients with either rheumatoid arthritis or degenerative joint disease. The incidences were nearly the same in both age groups. Thus, it appears that age does not increase the risk of adverse reactions with isoxicam. There were 14 deaths among the patients who received isoxicam in the course of these studies. None of these deaths was believed to be drug-related.
The
with
Open Label
Percentage of Patients with More Frequent Gastrointestinal Reactions Associated with lsoxicam
l&1985
after Treatment
200 mg/day (n = 394)
< 65 years (n = 1,708)
October
Values
Studies
Reaction
32
Laboratory
>200 mg/day (II = 535)
Hemoglobinlhematocrit White blood cell count Platelet Alkaline phosphatase SGOTISGPT Bilirubin Creatinine
TABLE
Abnormal
4.
Volume
Yakatan GJ: Pharmacology and pharmacokinetics of isoxicam. Semin Arthritis Rheum 1962; 12(suppl 2): 154-159. Fogari R, Bonebrake RA: Aspirin- and placebo-controlled study of isoxicam in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1962; 12(suppl 2): 165-169. Flower RJ, Mancada S, Vane JR: Analgesic-antipyretics and antiinflammatory agents; drugs employed in the treatment of gout. In: Gilman AG, Goodman LS, Gilman A, eds. Goodman and Gilman’s the pharmacological basis of therapeutics, ed 6. New York: MacMillan, 1980; 682-728. Guidelines for detection of hepatotoxicity due to drugs and chemicals. Washington: US Department of Health, Education, and Welfare, Health Service, National Institutes of Health.
79 (suppl
4B)
FRANCIS X. BURCH, M.D. San Antonio.
Data collected from more than 1,800 patients with rheumatoid arthritis or degenerative joint disease in Phase 3 clinical studies of isoxicam (Maxicam) indicated that the drug is well tolerated on both a short-term and a long-term basis. The most common type of adverse reaction to all medications (isoxicam, aspirin, and indomethatin) was gastrointestinal: 22.8 percent with isoxicam, at a dosage greater than 200 mg per day; 14.2 percent with isoxicam at 200 mg per day; 31.6 percent with buffered aspirin at 3,600 to 4,800 mg per day; 24.6 percent with indomethacin at 150 mg per day; and 7.2 percent with placebo. The incidence of tinnitus and deafness was significantly greater with buffered aspirin than with isoxicam, and the number of patients who had at least one episode of dizziness, vertigo, or headache was significantly greater with indomethacin than with isoxicam. In open-label, long-term studies, in which ap proximately 70 percent of the patients participated, the types and frequencies of adverse effects were similar to those observed with isoxicam during the controlled studies. The overall frequency of withdrawal for adverse reactions during the long-term studies was 11.5 percent, similar to that during the controlled studies. At the recommended dosage for isoxicam of 200 mg per day, the incidence of gastrointestinal ulcers was 0.81 percent, well within the range expected among arthritic patients receiving nonsteroidal anti-inflammatory drugs. From the data collected in Phase 3 clinical studies, it may be concluded that isoxicam is better tolerated than either aspirin or indomethacin and should not create unusual problems in the short-term or long-term treatment of rheumatoid arthritis or degenerative joint disease.
Texas
Requests for reprints should be addressed to Dr. Francis X. Burch, 8527 Village Drive, Suite 207, San Antonio, Texas 78212.
28
October
19,1985
The American
Journal
lsoxicam (Maxicam) is a new nonsteroidal anti-inflammatory drug that has shown good activity in both animal [l] and human studies [2]. This report describes the data relating to the safety of isoxicam obtained from Phase 3 clinical studies. Data include the adverse reactions reported by patients and observed by physicians and clinical laboratory values obtained at scheduled intervals. The study populations consisted of more than 900 patients with rheumatoid arthritis and more than 900 with degenerative joint disease. The patients were observed during both shottterm controlled studies and long-term, open-label studies in the United States and Europe. The effects are reported for both the initial studies, in which the dosage ranged from 200 to 400 mg per day, and the long-term studies, in which the dosage was restricted to 200 mg per day. of Medicine
Volume
79
(suppl4B)
ISOXIGAM
TABLE
I
Number
of Patients
Evaluated
Disease Rheumatoid Degenerative Total *Comparison
TABLE
with
II
arthritis joint disease indomethacin
Percentage (Controlled
conducted
for Safety in Phase 3 Studies
lsoxicam
Buffered Aspirin
471 458 929
234 234
in United
of Adverse Studies)
SYMPOSIUM-BURCH
Kingdom
Reactions
lndomethacin 183' 183
Placebo
Total
222 275 497
927 916 1,843
and Europe.
in Patients
with Rheumatoid
Arthritis
or Degenerative
Joint
Disease
lsoxicam Body System
>2Og mglday (n = 535)
200 mg/day (II = 394)
Buffered Aspirin (n = 234)
lndomethacin (II = 133)
Placebo (n = 497)
22.6 4.8 3.0 1.1
14.2 3.6 2.5 0
31.6 6.0 6.4 0.8
24.8 2.2 14.8 0
7.2 1.6 1.0 0
30.5
24.4
53.0
45.9
23.1
19.7
Gastrointestinal Skin and appendages Nervous Hemic/lymphatic Percent of patients with adverse reactions Percent of patients withdrawn for adverse reactions
TABLE
Ill
9.2
9.6
Percentage of More Common Adverse Degenerative Joint Disease (Controlled
Reactions Studies)
in Patients
with Rheumatoid
Arthritis
lb.9 1.6
or
lsoxicam Reaction
200 mg/day (n = 535)
200 mg/day (n = 394)
Buffered Aspirin (n = 234)
lndomethacin (n = 183)
Placebo (It = 497)
7.1 5.0 4.7 4.5 3.6 3.0
4.3 5.8 2.0 3.8 3.6 2.5
12.4
13.1 8.2 0 11.5 3.3 1.6
1.8 1.2 0.8 1.8 1 .o 0.8
Nausea/vomiting Abdominal pain Stomatitis Dyspepsia Diarrhea Rash
MATERIAL
AND METHODS
In the controlled phases of the studies, from six weeks to six months in duration, 929 patients received isoxicam, 234 received buffered aspirin, 183 received indomethacin, and 497 received placebo, for a total of 1,843 patients (Table I). All of the patients receiving aspirin had rheumatoid arthritis, and all of the patients receiving indomethacin had degenerative joint disease of either hip pr knee. Initially in the Phase 3 evaluation, isoxicam was administered at dosages from 200 to 400 mg per day. Later, it was decided to establish’ the efficacy and safety of isoxicam at 200 mg per day. Therefore, the incidences of adverse reactions are presented for both dosage groups (Table II). The effect of this dosage reduction in the controlled studies can be seen in the reports of gastrointestinal reactions. At dosages of isoxicam higher than 200 mg per day, the incidence was 22.6 percent; ht 200 mg per day, it was 14.2 percent, both frequencies considerably lower than that with 3,600 to 4,800 mg per day of buffered aspirin (31.6 percent). The inciOctober 18, 1985
9.4 2.1
9.8 4.3 4.7
dence of gastrointestinal reactions with 150 mg per day of indomethacin (24.6 percent) was approximately the same as that with the higher dosage of isoxicam. Generally, the frequencies of skin and nervous system reactions with buffered aspirin were somewhat greater than those with isoxicam. With indomethacin, the incidence of skin reactions was lower, but that of nervous system reactions, 14.6 percent, was considerably higher. The percentages of patients who withdrew because of adverse reactions were also lower with both dosages of isoxicam than with buffered aspirin or indomethacin. RESULTS The more common adverse reactions in the controlled studies were nausea and vomiting, abdominal pain, stomatitis, dyspepsia, diarrhea, and rash (Table Ill). The greatest difference in incidence of adverse effects between the high and low dosages of isoxicam occurred with nausea and/or vomiting, 7.1 percent versus 4.3 percent, and with stomatitis, 4.7 percent versus 2.0 percent. OtherThe American Journal of Medicine
Volume 79 (suppI
29
ISOXICAM
SYMPOSIUM-BUdCH
TABLE
IV
Adverse Reactions in Patients with Rheumatoid (Six-Month, Double-Blind Comparison)
Arthritis
Treated
with lsoxicam
Early Study lsoxicam 300-400 mg/day (n = 127)
Special
i3
senses*
lsoxicam 208 mg/day (n = 106)
6.3
is
22.6
3
of patient reactions
V
72
56.7
80
62.5
25
23.8
23
amblyopia,
taste
Number of Patients
Dizziness Vertigo Headache Total number with at least one reaction
30
41.5
26
24.5
withdrawals
perversion,
lsoxicam 200 m#/day (n = 182)
*Chi-square
44 p < 0.01
18.1
28
21.9
vision
Percent
abnormality,
watery
4 3 3 9 p < 0.001*
2.2 1.6 1.8 4.9
Momethacin 160 mglday (n = 183) Numbjerof Patients 15
ii 16 34
Percent 8.2 6.0 8.7 18.6
test.
October 18, 1985
The American Journal of Medicine
io
9.5
p < 0.01
Adverse Reactions (Special Senses) in Patients with Degenerative Joint Disease Treated with lsoxicam or lndomethacin (12~week, Double-Biind Comparison)
Adierse Reaction
20.8
with
wise, there did not appear to be much difference in the incidence of adverse effects with the two dosage levels. With buffered aspirin, the incidences of nausea and/or vbmiting (12.4 percent), abdominal pain (9.4 percent), and dyspepsia (9.8 percent) were markedly higher than the incidences at either of the dosage levels of isoxicam. For diarrhea and rash, the incidences with buffeied aspirin were slightly greater than those observed with 200 mg per day of isoxicam. With indomethacin, the incidences of abdominal pain (8.2 percent), nausea and/or vomiting (13.1 percent), and dyspepsia (11.5 percent) were also markedly greater than those with either level of isoxicam. At 260 mg per day, isoxicam induces fewer of these common adverse effects than does either buffered aspirin at 3,600 mg per day or indomethacin at 150 mg per day.
TABLE
22 p < 0.0005
NS ‘Tinnitus, deafness, +Chi-square test.
Number of Patients Percent
2.9
NS Total number for adverse
Buffered Aspirin 3,600 m#/day (n = 106)
Number of Number of Patients Percent Patients Percent p < 0.6005’
Total number of patients adverse reactions
Aspirin
Later SluUy Buffered Asp@ 4,600-4,800 mglday (n = 128)
Number of Patients Percent
Body System
or Buffered
eyes.
In direct six-month, double-blind comparisons of isoxicam with buffered aspirin, the major differences in frequencies of adverse reactions were in the special senses. In both an early study, in which isoxicam and aspirin were administered in higher dosages,, and a later study, in which isoxicam was administered at the recommended dosage of 200 mg per day and aspirin at 3,600 mg per day, the frequency of adverse reactions of the special senses was sjgnificantiy lower with isoxicam than with aspirin (Table IV). In the earlier study, the overall proportion of patients with adverse reactions and the proportion who withdrew for adverse reactions were higher with aspirin than with isoxicam, but the differences were not statistically significant. In the later study, however, both the proportion of patients with adverse reactiohs and the proportion who withdrew because of them were significantly higher with aspirin than with isoxicam. The most common adverse, reaction of the special senses was tinnltus. In the earlier study, it occurred in 23 of 128 (18.0 percent) patients treated with aspirin and in four of 127 (3.1 percent) patients treated with isoxicam. In the later study, it occurred in 20 of 106 (18.9 percent) patients treated with aspirin and in three of 105 (2.9 percent) patients treated with isoxicam. Because headache, dizziness, and vertigo are common reactions with indomethacin [3], their frequencies, were compared in an international study of patients with degenerative joint disease receiving 200 mg per day of isoxicam or 150 mg per day of indomethacin, The number of patients in whom, at least one of these symptoms developed was significantly greater with indomethacin than with isoxicam (Table V). Table VI lists the incidences of the common adverse
Volume 79 (suppl 48)
ISOXICAM
reactions observed during the open-label studies when patients received isoxicam for periods of up to three years, 740 patients at dosages greater than 200 mg per day and 1,084 patients at 200 mg per day. The total of 1,824 patients is more than entered the open-label phase from the controlled phase and the reason for this apparent discrepancy is that many of the 740 patients who received more than 200 mg per day are also included in the patients who received 200 mg per day because they were in the long-term phase when the dosage was reduced. The effect of dosage reduction is clearly evident in these data. Except for abdominal pain and diarrhea, the incidences of adverse reactions with the higher dosage are at least twice those reported with the lower dosage. Table VII presents the number of patients in the openlabel studies who withdrew from the study because of adverse reactions. Among the patients with rheumatoid arthritis receiving isoxicam in the open-label studies, 44.8 percent had adverse effects and 12.8 percent withdrew from the study because of them. Of the 501 patients with degenerative joint disease who received isoxicam during the open-label studies, 27.1 percent had adverse effects and 9.4 percent withdrew because of them. This table does not separate the patients into groups at the two dosage levels of isoxicam. Therefore, 1,318 is the actual number of patients who received isoxicam at any dosage during the long-term, open-label studies. The incidence of withdrawals before dosage reduction (13.2 percent) is markedly higher than either that after dosage reduction (4.4 percent) or that at only 200 mg (5.6 percent) (Table
TABLE
Number and Percentage Label Studies)
of Patients
TABLE
VII
Disease
Rheumatoid arthritis Degenerative joint disease Total
516
82
224 740
16 98
6.5 11.4 0.8 8.8 3.5 6.1
2.4 6.2 2.4 3.1 2.2 2.4
Total Number of Patients
817 501 1,318
Patients with Adverse Reactions Number
Percent
Number
Percent
366
44.8
105
12.8
136
27.1
502
38.1
47 152
11.5
Withdrawn
from lsoxicam
Because
of Adverse
After Dosage Reduction
Reactions
Number
15.9
321
9
7.1 13.2
264 585
17 26
October 18, 1985
9.4
(Open-
At 200 mg/day from Beginning
Withdrawn Number of Patients
Percent
Patients Withdrawn for Adverse Reactions
controlled phases (9.3 and 8.4 percent versus 3.2 and 2.0 percent), but otherwise the abnormal values during the long-term phase were similar to those during the controlled phases. Changes in the results of liver function tests occurred in 6.8 percent of the patients, but careful evaluation of the results showed that only one, among patients receiving 200 mg per day, was greater than the levels specified in the Food and Drug Administration hepatotoxicity guidelines [4]. The results indicate that, at the
Withdrawn Number
200 mg/day (n = 1,084)
Number and Percentage of Adverse Reactions and Drug Withdrawals in Patients Treated with lsoxicam (OpenLabel Studies)
Rheumatoid arthritis Degenerative joint disease Total
Before Dosage Reduction Number of Patients
>200 mg/day (II = 740)
Nauseaivomiting Abdominalpain Stomatitis Dyspepsia Diarrhea Rash
The vast majority of laboratory values remained within normal ranges in both the controlled and long-term phases of the studies (Table IX). During the open-label phases, in which patients received isoxicam for periods of more than two years, the percent of patients who had decreases in hemoglobin or hematocrit values of at least 1.5 percent (none had decreases of as much as 25 percent) was notably larger at both dosage levels than during the
VIII
Percentage of Patients with More Common Adverse Reactions (Open-Label Studies)
Adverse Reactions
VIII).
TABLE
VI
SYMPOSIUM-BURCH
Withdrawn Number of Patients
Number
Percent -
2.8
296
14
4.7
6.4 4.4
203 499
14 28
6.9 5.6
Percent
The American Journal of Medicine
Volume 79 (suppl 46)
31
ISOXICAM
TABLE
SYMPOSIUM-BURCH
IX
Percentage lsoxicam
of Patients
with Clinically
Significant
Controlled
Laboratory
Measure
X
> 200 mg/day (n = 819)
200 mglday (n = 1,054)
3.2 3.0 0.6
2.0 3.3 3.6 5.6
9.3 2.6 0.9 6.0 2.6 0.2
2.0 1.1 4.5 1.2 2.1
1.4
1.3
4.8 2.8
5.8 1.8 0.8
0.2 0.7
2 65 years (n = 970)
Abdominal pain Nausea/vomiting Dyspepsia Stomatitis Diarrhea Gastrointestinal disorder
10.1 6.7 7.0 4.3 3.9 2.2
7.6 6.2 4.8
3.1 2.5 1.8
REFERENCES 1. 2.
3.
CONCLUSIONS
lsoxicam at 200 mg per day was better tolerated than buffered aspirin at 3,600 mg per day in the Phase 3 studies. Gastrointestinal adverse reactions, the most common with
American
Journal
of Medicine
a.4
both drugs, were much less frequent with isoxicam than with aspirin. Adverse reactions of the special senses, particularly tinnitus and hearing loss, were significantly more frequent with aspirin than with isoxicam. The proportion of patients who had headache, dizziness, and/or vertigo was significantly greater with indomethacin than with isoxicam. In long-term use, adverse reactions with isoxicam were of the same kinds and frequencies as in the short-term controlled studies. Clinical laboratory assessments did not reveal any signs of systemic toxicity. The percentage of patients who had reductions in hematocrit or hemoglobin values of 15 percent or more (none was more than 25 percent) was greater in the long-term studies than in the short-term studies, but for all other clinical laboratory values there were no differences between the short- and long-term studies. Hepatic function tests showed occasional abnormal results, but among those from patients receiving the recommended 200 mg per day, only one result was abnormal enough to be classified as toxic under the guidelines for toxicity of the Food and Drug Administration. On the basis of the studies described in this report, isoxicam is a well-tolerated drug and offers no unusual problems in the short-term or long-term treatment of rheumatoid arthritis or degenerative joint disease.
recommended 200 mg per day dosage of isoxicam, no clear pattern of drug-related hematopoietic, hepatic, or renal toxicity was observed. Among 3,217 patients who received isoxicam for any indication during the domestic and international clinical studies, there were 55 gastrointestinal ulcers, an incidence of 1.7 percent. However, among the 2,343 patients receiving 200 mg per day of isoxicam, there were 19 ulcers, an incidence of 0.81 percent. This is well within the range that might be expected in arthritic patients receiving nonsteroidal anti-inflammatory drugs. Frequencies of the more common adverse reactions were analyzed for patients younger than 65 years old, and for those 65 years old and older (Table X), including patients with either rheumatoid arthritis or degenerative joint disease. The incidences were nearly the same in both age groups. Thus, it appears that age does not increase the risk of adverse reactions with isoxicam. There were 14 deaths among the patients who received isoxicam in the course of these studies. None of these deaths was believed to be drug-related.
The
with
Open Label
Percentage of Patients with More Frequent Gastrointestinal Reactions Associated with lsoxicam
l&1985
after Treatment
200 mg/day (n = 394)
< 65 years (n = 1,708)
October
Values
Studies
Reaction
32
Laboratory
>200 mg/day (II = 535)
Hemoglobinlhematocrit White blood cell count Platelet Alkaline phosphatase SGOTISGPT Bilirubin Creatinine
TABLE
Abnormal
4.
Volume
Yakatan GJ: Pharmacology and pharmacokinetics of isoxicam. Semin Arthritis Rheum 1962; 12(suppl 2): 154-159. Fogari R, Bonebrake RA: Aspirin- and placebo-controlled study of isoxicam in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1962; 12(suppl 2): 165-169. Flower RJ, Mancada S, Vane JR: Analgesic-antipyretics and antiinflammatory agents; drugs employed in the treatment of gout. In: Gilman AG, Goodman LS, Gilman A, eds. Goodman and Gilman’s the pharmacological basis of therapeutics, ed 6. New York: MacMillan, 1980; 682-728. Guidelines for detection of hepatotoxicity due to drugs and chemicals. Washington: US Department of Health, Education, and Welfare, Health Service, National Institutes of Health.
79 (suppl
4B)