Worldwide clinical safety experience with diclofenac

Worldwide Clinical Safety Experience With Diclofenac By Robert F. WiIlkens

ELECTION of a nonsteroidal anti-inflammatory drug (NSAID) is today being made more and more on the basis of its relative safety. This presentation reviews the safety data accumulated over ten years of experience with diclofenac, now prescribed for the treatment of rheumatic disease in 94 countries. These data are derived from clinical use in more than 18,000 patients in controlled clinical trials and in over 85,000 patients in open-label studies performed in 21 countries:

S

UNITED STATES CLINICAL TRIALS

A total of 1,786 patients treated with diclofenac in U.S. trials were analyzed for safety; 1,227 received diclofenac in short-term controlled trials, and 559 additional patients were treated for the first time with diclofenac in long-term trials lasting up to 58 weeks (including the double-blind phase).2 Of the patients already in the short-term trials, 614 continued to receive diclofenac in the long-term trials. Patients ranged in age from 18 to 77 years and were treated at doses varying from 75 mg to 200 mg/day, with ISO mg/day the most commonly used dosage. The proportion of patients reporting one or more adverse experiences in the long-term trials, 27.1 %, was slightly lower than that in the shortterm trials, which was 31.2%. These rates of adverse experiences for diclofenac must be viewed in light of the relatively high rate of such reactions reported in short-term trials for the placebo group, 23.1 %. When adverse experience rates in short-term trials for the diclofenac treatment group were compared with those for control agents, they were found to be lower (31.2%) than all others with the exception of naproxen, 500 mg/day (26.1 %) (Table I). However, diclofenac was given at doses up to 200 mg while the 500 mg dose of naproxen is lower than the currently recommended dose in rheumatoid arthritis. In diclofenac-treated patients, the commonest adverse experiences were diarrhea (4.1 %) and nausea (3.7%). Two-thirds of all adverse reactions were gastrointestinal in nature. Adverse reactions were reported by the inves-

tigators as mild, moderate, or severe. "Severe" was a judgment regarding the intensity, not the seriousness, of the reaction. A review of the incidence of severe adverse reactions in the shortterm controlled trials (Table 2) gives an indication of the comparative safety of diclofenac. Severe adverse experiences occurred in 4.6% of diclofenac-treated patients, in 9.2% treated with aspirin, 10.0% with indomethacin, 5.4% with ibuprofen, 4.5% with placebo, and 3.3% with 500 mg of naproxen. Differences in numbers of treated patients and in dosage ranges may have influenced these results. The frequency of severe adverse reactions to diclofenac was similar in short-term (4:6%; n = 1,227) and long-term trials (4.9%; n = 1,173). Older and younger patients did not differ substantially in the frequency of adverse experiences. Rates of premature discontinuation for unsatisfactory therapeutic response and for adverse reactions have customarily been considered indirect measures of efficacy and tolerability, respectively. These rates have been compiled for rheumatoid arthritis and osteoarthritis. 2 Withdrawals due to unsatisfactory treatment response were most frequent among patients treated with placebo (Figs. 1 and 2). In the rheumatoid arthritis studies, drop-outs due to adverse effects were most frequent among patients treated with aspirin; in the osteoarthritis studies, they were similar for all groups. Among patients with rheumatoid arthritis who dropped out of the studies for treatment-related reasons, the drop-out rate was lower for patients treated with diclofenac (25%) than for patients treated with any of the other agents (Fig. 3). For osteoarthritis patients, the drop-out rate for unsatisfactory response and

From the University of Washington School of Medicine. Seattle. Washington Robert F. Wi//kens. MD: Department of Medicine. Division of Rheumatology. University of Washington School of Medicine. Seattle. Washington Address reprint requests to Robert F. Wi/lkens. MD. Harborview Medical Center. 325 Ninth Avenue. Seattle. Washington 98104 © 1985 by Grune & Stratton. Inc. 0049...{)172/85/1502-1122$5.00/0

Ssminars in Arthritis and Rheumatism. Vol 15. No 2. Suppl 1 (November). 1985: pp 105-110

105

ROBERT F. WILLKENS

106

Table 1. United States Short-Term- Controlled Trials: Pooled Data OlClofenllC 175-200 mg/d) NI'l(,) No of pat,ents No wIth effects per body systems: D,gesllV8

1,227

Placebo

Ibuprofen (2.4l//dl

Neproxen (5OOmll!d)

IndomelhllCtn (75-125 mll!d)

N(%)

N(%)

N(%)

N(%)

74 29 (39) 21 (28) 6 (8)

92 24 (26) 15 (16)

130 54(42) 35 (27)

4(5) 2 (3)

7 (8) 3 (3) 6 (7)

28 (21) 1(1)

4(5)

0

N(%)

721

359 83 (23) 43 (12)

383131lt 258 (21)

Metabolic/nutrition

79 (6) 37 (3) 31 (3)

26 (7) 15 (4) 4(1)

SpecIal senses

33 (3)

6 (2)

Nervous SkIn and appendages

Aspwln (2.4-4.8 l//d)

313 (43) 194 (27) 57 (8) 19 (3) 11 (2) 147 (20)

2 (2) 2(2)

• Most tnals up to 12 weeks ,n duration. tF,gures ,n parentheses are percentages. Numbers are rounded to the neareSI whole number.

adverse reactions combined was lower for diclofenac patients (17%) than for the other treatment groups (Fig. 4). These data are pooled across the studies. Laboratory profiles were done on all patients to assess the comparative safety of diclofenac. Most patients had no clinically significant laboratory findings. I n the evaluation of hepatic tolerability, approximately 1% of all patients treated with diclofenac in the long- and shortterm trials had serum glutamic oxaloacetic transaminase (SGOT) elevations of ~ 120 I U fl. which may have been related to the therapy. Hyperbilirubinemia and clinical jaundice were not observed. There were no significant differences in hepatic tolerability between diclofenac and aspirin. ibuprofen, naproxen, or indomethacin. Four deaths occurred in the United States trials. none of which appeared to have been directly related to the drug. Three patients had cerebrovascular or cardiovascular disease. and in one the cause of death was poorly defined. INTERNATIONAL CLINICAL TRIALS

Diclofenac was first marketed in Japan. in 1974. Since its introduction, it has been used in 94 countries for an estimated 115 million patient-months of therapy. Approximately 18,000 patients have participated in controlled trials and over 85,000 received open-label didofenac treatment in 21 countries. One would

expect that with this large network of reporting, and after 12 years of use worldwide, a clear picture of any toxicity associated with the use of diclofenac would emerge. Several studies have shown that nondrug factors (nature and phase of the underlying disease, concomitant illness. etc.) have an important influence on the incidence of side effects reported. H The incidence of side effects in noncomparative studies of diclofenac, ranging from 5% to 27%, differs considerably from place to place and from one indication to another. The incidence of adverse reactions is not higher with 150 mg/day than with 75 mg/day.s

Controlled Clinical Trials Extensive double-blind trials have been conducted comparing diclofenac with other nonsteroidal anti-inAammatory drugs. Diclofenac and Aspirin. The results of four trials summarize the non- U.S. controlled trials of diclofenac versus aspirin. These trials involved 286 patients treated with 75 mg or 150 mg daily of diclofenac and 142 patients treated with aspirin in a dosage of 1.8 to 5.0 g daily.6 Significantly fewer patients complained of side effects during medication with diclofenac than during treatment with aspirin (P
Table 2. Frequency of Severe Adverse Reactions: United States Short-Term Trials OlClofenac (75-200 mg/dl No. of patients No. of patients (%) with severe reactIon

1.227 5714.6)

Placebo 359 1614.5)

Aepr,n (2.4-4.8 g/dl

721 66 (9.2)

Ibuprofen (2.4ll!d) 74 4 (5.4)

NaproKlln (500 mll!d) 92 3 (3.3)

Indometh8CIn (75-125 mll!d) 130 13110.0)

107

WORLDWIDE CLINICAL SAFETY

50

o o

30

-

40

Aspirin

36%

Ibuprofen

30

26%

~

cf

48%

I}~:~;~:~:::~J Placebo

40

c:Ql

50 -

~ Diclofenac

44%

25%

22% 20

~

10

10 l-

Adverse Effects

Unsatisfactory Treatment Response

30%

-

Dlclofenac

..

Ibuprofen Aspirin Treatment Agent

Placebo

Fig. 1. Treatment-relatad reasons for drop-outs among patients with rheumatoid arthritis (short-term studiesl.

Fig. 3. Treatment-related drop-outs emong patients with rheumatoid arthritis (short-term studies).

28% of those receiving aspirin. No cases of ulcers or of gross bleeding were observed in these trials with either agent. Only one patient complained of tinnitus during treatment with diclofenac, although this was the most frequent side effect reported in response to aspirin, occurring in 18% of patients. Diclofenac and Ibuprofen. Data on the incidence of unwanted effects that occurred in the international controlled studies of diclofenac versus ibuprofen were reviewed and summarized by Ciccolunghi and associates. 6 The daily dosage for

diclofenac ranged from 75 mg to 150 mg/day (usual dose, ISO mg), and from 600 mg to 1200 mg/day for ibuprofen. No significant difference was observed in tolerability between the two drugs. A total of 13% of the 161 patients receiving diclofenac complained of unwanted effects during treatment; the figure for ibuprofen was 17% of 175 patients. Gastrointestinal symptoms occurred in about 10% of cases in each treatment group, and central nervous system disturbances in 5%. The 4.5% discontinuation rate was the same in both groups.

50

50 r-

~ Diclofenac

tJ::~~:J Placebo

D

40

o

34%

c:CIl

cf

Naproxen

30

~

20

10

c:

1,6% 11%1 .....

39%

40 I-

Aspirin

30 I25%

~

23%

(lJ

ll.

17%

-

17%

5%

- , - - - ' - _........

Unsalisfaclory Treatment Response

-

10 -

9% 6%

20

Adverse Effects

Fig. 2. Treatment-related reasons for drop-outs among patients with osteoarthritis (short-term studies).

Dlclofenac

Naproxen

Aspirin

Placebo

Treatment Agent

Fig. 4. Treatment-related drop-outs emong patients with osteoarthritis (short-term studies).

108

ROBERT F. WILLKENS

Diclofenac and Naproxen. The proportion of patients complaining of unwanted effects was virtually the same with diclofenac, 50 mg bid (16%), as with naproxen 250 mg bid (15%). 7 The unwanted effects were primarily mild gastrointestinal disturbances. Treatment was discontinued in four of 205 patients taking diclofenac and in five of 187 patients taking naproxen. These results are from five published studies7- 1l and from unpublished data (Alvarez 1976, Sheard 1976, Ganna and Rachid 1978: reported in ref. 6). Other studies comparing diclofenac with naproxen include a double-blind trial of 120 patients with soft-tissue rheumatism who were given either 75 mg of diclofenac or 500 mg of naproxen daily for two weeks. 12 Fifteen patients of 60 receiving diclofenac and 14 of 60 receiving naproxen complained of unwanted effects. These clinical trials failed to show any appreciable difference between naproxen and diclofenac with respect to gastrointestinal tolerability. Nevertheless, using special methods (gastroscopic studies and studies measuring gastrointestinal blood losses), naproxen has been shown to be more irritating to the gastric mucosa than diclofenac. 8- 15

One hundred and sixty-two clinical studies of diclofenac appeared in the world literature from 1972 to 1982. A total of 10,075 adverse reactions were reported among 85,361 patients (12%) who received diclofenac; most complications were not serious. A total of 1,604 patients discontinued the drug, which was 1.9% of the entire patient sample, and represented 16% of those who experienced an adverse reaction. Table 3 summarizes these findings. '6 Gastrointestinal symptoms were the most common side effects encountered, totalling 6,503 Table 3. Adverse Reactions with Diclofenac: Open Clinical Studies (Foreign Trials)

Gastrointestinal eNS 6"ergiC or local ther Total Adverse Reactions

Table 4. Summary of Adverse Reactions: Open Studies in UK. France. and Japan Adverse Reaction Gastrointestinal Nausea/vomiting Gastric upset/discomfort Poor appetite Ulcers Hematemesls Unspecified

Open Studies

Ad_se Reaction

cases and representing 7.6% of the patients treated. The major symptoms were dyspepsia or gastric upset. There were eight reports of ulcers (0.009%), three of colitis and two of gastric erosion. Fifty-eight studies comprising 3,760 patients provided laboratory data. Of these, 3,639 patients (96.8%) had normal laboratory values. Occasional hematologic abnormalities such as fluctuations in hemoglobin, white blood cell count, and eosinophilia, were observed. Abnormal findings on liver function tests were rare; only five patients had trace amounts of proteinuria, and tests for occult blood were negative. The results of six studies summarize postmarketing experience with dic10fenac in the United Kingdom, France, and Japan: 6 Four were included in the review of open studies above. A

No. of Patients (%1

6.503 (7.6) 632 (0.71 354 (0.4) 2.586 10.075 (11.71

No. Discontinued

998 53 79 474 1.604 (1.9)

No. Reported

467 3.223 339 3 636 4.668 (10.2%)

eNS symptoms Headache DiZZiness DrOWSiness Insomnia Excitement UnspecifIed

No. Discontinued

1 158 159

11 55 30 2 5 20 123 (0.3%)

AllergiC or local Rash Unspecified

184 11 19510.4%)

Other Visual disturbances Hearing disturbances Edema Unspecified

Overall totals Adverse reactions Total no. of patients Overall mean Incidence

3 4 162 608

523

777 (1.6%)

523

5.763 45.932 12.5%

682 1.5%

WORLDWIDE CLINICAL SAFETY

109

Table 6. Adverse Reactions from Diclofenac and Piroxicam Reported to UK Committee on Safety of Medicine (1978) No. of

Drug Diclofenac Porox,cam

Years of

Total

Dateo! F~.t ADR

Commercoal

Patient

Dlstnbutlon

Vears

6/78 8/78

4.5 3.0

213.6 179.1

Totel No. of Reports GI ReportS

681 1.211

220 490

Abbreviations: ADR - adverse drug react,on: GI - gastrointestonal.

total of 5,763 adverse reactions were reported among 45,932 patients treated with diclofenac, representing an incidence of 13% of the patient population (Table 4). Patients discontinuing the drug because of adverse reactions numbered 682, approximately 1.5% of the patient population. Gastrointestinal symptoms (typically gastric upset/discomfort) were the most common adverse effects reported in the open studies. There were 4,668 such reactions, representing a frequency of approximately 10%. There were three reports of ulceration in 45,932 patients. Comparison of the safety profile of diclofenac with that of piroxicam, a drug introduced in the United Kingdom at approximately the same time, gives some perspective of the safety of diclofenac (Table 5). The denominator, patient exposure, is calculated by converting commercial distribution of the drug into patient-years of experience, based on days of treatment at the average daily recommended dose. Although piroxicam was available one and a half years after diclofenac, the first adverse reactions for both drugs were reported to the Committee on Safety of Medicine at approximately the same time. There were 681 adverse reactions reported

for diclofenac out of 213,600 years of exposure, compared with 1,211 adverse reactions for piroxicam out of 179, I00 years of exposure. Thus, the number of reported adverse reactions per year of exposure for piroxicam (0.7%) was more than twice that for diclofenac (0.3%). In view of the fact that more adverse reactions are reported during the first years of introduction than during subsequent years, the safety profile of diclofenac is good. SUMMARY

Data from more than 100,000 patients in foreign and United States trials provide substantial evidence of diclofenac's safety and tolerability. Adverse experiences were infrequent and generally mild or transient. In United States short-term trials, the frequency and severity of side effects compared favorably with rates for placebo, aspirin, and other NSAIDs. The drop-out rate for therapeutic reasons (adverse effects or lack of efficacy) was lower for diclofenac than for any of the comparative treatments. In long-term trials, dicIofenac has been taken safely for a year or more. The incidence of adverse experiences reported for older patients (~ 65 years) treated with dicIofenac did not generally differ from that reported for younger patients. No significant differences in the incidence of hepatic problems were detected between diclofenac and other active treatments in U.S. trials. Finally, foreign post-marketing data on adverse experiences show that dicIofenac is one of the safest agents of its kind for the treatment of a broad range of rheumatic conditions.

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large-scale, multicenter clinical trials. J Clin Pharmacol 1979; 19:303-312 5. Ciccolonghi SN, Chaudri, HA: Results of worldwide clinical trials with Voltaren. In: Wagenhauser FJ, ed. Chronic Forms of Polyarthritis. International Symposium, Torremolinos, 1975. Berne: Hans Huber, 1976, p 345-358 6. Ciccolunghi SN. Schubiger BI, Reddrop R: Comparison of tolerability findings in international clinical trials. In: Haslock I, et ai, eds. Diclofenac (Voltarol~) in the Treatment of Rheumatic Diseases: A Conspectus of International Experience. International Symposium, Tangier, 1978. Rheumatol Rehabil1979; 17 (SuppI2):122-l34 7. Bach GL: Klinische Priifung von Diclofenac Na (Voltaren) bei Arthrosen. Therapiewoche 1976;26:2958-2965

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8. Siraux P: Diclofenac (Voltaren) for the treatment of osteoarthrosis: A double-blind comparison with naproxen. J Int Med Res 1977:5:169-174 9. Clinical Report (1975): Quoted in Ciccolunghi SN. Schubiger BI, Reddrop R: Comparison of tolerability findings in international clincial trials. In: Haslock I, et ai, eds: Diclofenac (VoltaroI S ) in the Treatment of Rheumatic Diseases: A Conspectus of International Experience. International Symposium, Tangier, 1978. Rheumatol Rehabil 1979: 17:122-134 10. Car A, Jajic I, Krampac I, et al: A double-blind multicenter comparison of diclofenac sodium and naproxen in osteoarthrosis of the hip. Scand J Rheumatol 1978:22:6368 I\. Kajander A, Martio J: Diclofenac sodium (Voltaren) and naproxen in the treatment of rheumatoid arthritis: A

ROBERT F. WILLKENS

comparative double-blind study. Scand J Rheumatol 1978;22:57-62 12. Valtonen EJ: A comparative short-term trial with Voltaren (diclofenac sodium) and naproxen in soft-tissue rheumatism. Scand J Rheumatol 1978; suppl 22:69-73 13. Uthgenannt H. Timm H: On the effect of Voltaren on gastrointestinal excretion of blood. MMW 1975; 117: 19871990 14. Uthgenannt H: Gastrointestinal blood losses while taking feprazone, naproxen and diclofenac. Med Welt 1977;28:989-992 15. Lehtola J. Sipponen P: A gastroscopic and histological double-blind study of the effects of diclofenac sodium and naproxen on the human gastric mucosa. Scand J Rheumatol 1977:6:97-102 16. CIBA-GEIGY Corporation: Data-on-file: NDA Foreign Safety Report