Summary

Drug Investigation 2 (Suppl. 3): 1-6, 1990 0114-2402/90/0300-000 I /$3.00/0 © Adis International Limited All rights reserved. DISUP1856

250 Million Patient-Days with Tenoxicam Results and Perspectives

H. Fenner F. Hoffmann-La Roche Ltd, Basle, Switzerland

Data from patients treated with tenoxicam, a new nonsteroidal anti-inflammatory drug (NSAID), have been collected from patients during the first 2 years of marketing. These data, from 250 mi11ion patient-days of tenoxicam use, have confirmed that the efficacy and safety of the drug compares favourably with that shown by other well es­tablished NSAIDs in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout and soft tissue injury jextra-articular inflammatory disease. The once­daily dose of 20mg established in clinical trials has been shown to control pain and inflammation in short term usage as well as in the long term treatment of chronic rheu­matic disorders. Several studies in elderly patients have shown that tenoxicam can be safely given at this dose for a longer period of time to patients with mild or moderate renal impairment and that a higher frequency of adverse events is not seen in the elderly patient population.

During the preclinical and clinical evaluation of tenoxicam, a new nonsteroidal anti-inflammatory drug (NSAID), efficacy and safety were compared with the efficacy and safety of some major NSAIDs currently used in the treatment of rheumatic dis­eases (piroxicam, diclofenac, naproxen, ibuprofen, ketoprofen). The favourable safety profile of ten­oxicam established in standard animal models was confirmed during more than 250 clinical trials which included more than 9000 patients.

of an NSAID reaches its critical stage. The analysis of postmarketing experience is compared with the previously established profile of the drug. A prog­nosis of the risk: benefit ratio of a new NSAID is based on market experience in all licensed indi­cations and the extension of indications, as well as the introduction of new formulations.

Since early 1987, tenoxicam has been marketed in more than 60 countries. Along with tenoxicam tablets, the use of suppositories has been licensed in some countries. Other formulations {'drinkable' tenoxicam, effervescent tablets} that might be more convenient for some patients have been evaluated in clinical trials. In some clinical conditions, where severe pain and inflammation need rapid control, patients may benefit from parenteral administra-

The most important milestone in the assess­ment of an NSAID, however, is the analysis and review of data collected during the first 2 to 3 years of marketing, representing its use for a significant number of patient-days. After that period of time and the exposure of many patients, the life cycle

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tion of anti-inflammatory/analgesic drugs and ten­oxicam is available as a water-soluble formulation for parenteral use.

1. NSAID Safety Profile 1.1 Gastrointestinal Safety Profile, Renal Effects and Safety in the Elderly

Although NSAIDs are effective in the control of pain and signs of inflammation, most patients have expressed concern about the safety of these drugs. When physicians and patients are questioned on an optimal NSAID safety profile, most are looking for an improved gastrointestinal (GI) safety profile and a low incidence of renal side effects. As many patients are elderly, a clinical programme which considers this age group is important during drug evaluation, and special attention should be paid to these patients in the first years of marketing. The lack of confidence in the safety of NSAIDs is prob­ably due to problems experienced in recent years with some NSAIDs, in particular those which led to the withdrawal of ben ox apr of en, indoprofen and zomepirac, which damaged the relationship be­tween rheumatologists and their patients.

2. NSAID-Induced Gastropathies

Recently, significant progress has been made in understanding the mechanism of NSAID-induced gastroduodenal mucosal damage (Barrier & Hir­schowitz 1989; Fries et al. 1989; Langman 1988). In addition, we have learned from pharmaco­epidemiological studies that 'GI-hospitalizations are more than 6 times more frequent in patients with rheumatoid arthritis who are taking NSAIDs than in those who are not .. .' and 'deaths due to GI causes are roughly twice as frequent in RA patients than in the general population. These findings lend support to the growing consensus that NSAID­associated gastropathy is the most serious medi­cation side effect .. .' (Fries et al. 1989).

Indeed, gastropathy may account for up to 25% of all side effects reported with this class of drugs (Langman 1988).

Drug Invest. 2 (Suppl. 3) 1990

INSAIDs l lIOrganic acidsl/

Primary insult Secondary Insult

Direct Prostaglandin acid damage Inhibition

·1 Dual insult 1 ...

I Gastric damage I Fig. 1. Mechanisms of NSAID-induced gastric damage: the dual-insult hypothesis (after Schoen & Vender 1989).

The following are important questions concern­ing NSAID usage and peptic ulceration: • How frequently do NSAIDs induce peptic ulcers? • How frequently do ulcers present without pain or dyspeptic symptoms? • Which risk factors predispose to peptic ulcers? • Are certain NSAIDs less ulcerogenic?

For many years pharmaceutical firms have tried to improve the gastrointestinal tolerability of NSAIDs. Unfortunately, changes in formulation, the introduction of controlled release drugs and the design of prodrugs have not significantly altered the frequency of adverse events in controlled clinical trials. 'Although theoretically attractive, prodrugs, suppositories, enteric coated or con­trolled release formulations afford no significant clinical advantage - systemic rather than local ef­fects remain important.' (Doherty 1989).

A recently published review on the mechanism of NSAID-induced gastric damage advocates a 'dual-injury hypothesis' (Schoen & Vender 1989); in addition to acid-induced mucosal damage, the role of prostaglandin (PG) inhibition is emphasised (fig. 1).

Thus, a strategy to avoid potential gastroduo­denal mucosal injury would suggest the use of NSAIDs that are weak acids in low daily doses and with a low PG inhibitory activity.

Patient-Days with Tenoxicam

3. Factors Influencing the GI Tolerability 0/ Acidic PG Inhibitors

GI tolerability of acidic PG inhibitors can be influenced by the following: Mode of administration: • NSAIDs are better tolerated if they are given with a meal, or with plenty of fluid after a meal. Drug properties: • NSAIDs with a low acidity (pKa > 5) admini­stered at a low single dose once or twice daily have a low potential to interact with the mucosal barrier. • NSAIDs with low PG inhibitory activity will interact to a lesser degree with prostanoid-me­diated mucosal function and integrity compared with potent PG inhibitors. • Rapid absorption of an NSAID results in a smaller area of mucosa being exposed during the absorption process for a shorter period of time. It has been postulated that drugs excreted in bile as unchanged cyclo-oxygenase inhibitors or as con­jugates metabolised to a cyclo-oxygenase inhibitor in the gut may have a greater potential to cause mucosal injury in the duodenum. • Tenoxicam is only weakly acidic, has low PG inhibitory activity and is rapidly absorbed. This drug is, therefore, according to new insights into the mechanism of GI mucosal damage, classified as an NSAID with a lowered risk of causing GI problems.

4. Clinical Studies Investigating Tenoxicam GI Tolerability

Endoscopic studies on gastroduodenal mucosal injury after short term NSAID administration may indicate the relative frequency of differences in mucosal damage between individual drugs and their pharmacological properties, but these need to be confirmed by longer term clinical trials.

Recently, the comparative effects of tenoxicam and diclofenac on gastric and duodenal mucosa have been evaluated using endoscopy (Muller et al. 1989). The results of a parallel group, double-blind, randomised comparison between diclofenac in a

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Table I. Endoscopic scores of subjects receiving diclofenac in a controlled release formulation (100 mg/day) or tenoxicam (20 mg/day)

Tenoxicam (n = 19)

Baseline endoscopy 1.0 (0.8 ± 0.4) After 2 weeks 1.0 (1.3 ± 0.7) Control endoscopy 1.0 (0.8 ± 0.4)

after 2 weeks

* p = 0.01; n = number of volunteers.

Diclofenac (n = 17)

1.0 (0.9 ± 0.2) 2.0 (2.2 ± 1.1*) 1.0 (0.9 ± 0.3)

controlled release formulation (100 mg/day) and tenoxicam (20 mg/day) demonstrate a statistically significant difference in the effects of the 2 drugs on the GI mucosa (table I).

All 36 volunteers included in this 2-week trial had similar endoscopic scores at baseline (fig. 2).

After 2 weeks ofNSAID administration, 3 of 19 subjects in the tenoxicam group had erosions in the stomach or duodenum while 16 of 19 patients had no change in their endoscopic score (0 to I).

In the diclofenac group only 6 of 17 subjects still had no sign of erosion (score 0 to I). Two had ero­sions and/or invasive ulcerations in the stomach and duodenum (score 4), 6 had erosions in the stomach or the duodenum (score 3) and 3 had pe­techiae in the stomach or duodenum (score 2). The authors conclude: 'If the low incidence of gastric mucosal damage were to be confirmed in further controlled clinical trials, tenoxicam should be re­garded as a real advantage in the treatment ofrheu­matic diseases.'

Conclusions drawn from these studies need to take into consideration the differences in the half­lives of the drugs under investigation, which result in different drug distributions in the short term. Small differences identified in this type of study between a drug with a short half-life and one with a long half-life should not be regarded as relevant if they are merely the result of an open 2-week study.

A recent study (Moser et al. 1989) compared the efficacy and tolerability of tenoxicam (20 mg/day; 805 patients) with that of controlled release diclo-

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16 a 14

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10

B

6

4

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., C 0 G> +~ 0 2 3 4 a. "0 0 16 z b

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Fig. 2. Endoscopic scores of 36 subjects at baseline (1iiJl) and after 2 weeks' treatment (_) with (a) tenoxicam 20 mg/day and (b) controlled release diclofenac 100 mg/day. The endo­scopic scale used was 0 = no visible lesion; I = erythema (gastritis-duodenitis); 2 = petechiae in stomach or duo­denum; 3 = erosions in stomach or duodenum; 4 = erosions and/or invasive ulcerations in stomach and duodenum.

fenac (100 mg/day; 473 patients) in patients with either osteoarthritis or soft tissue injury/extra­articular inflammation. In both patient groups ten­oxicam was demonstrated to have a favourable GI tolerability profile. The frequency of GI tract dis­orders in patients receiving tenoxicam was 16.6% compared with 24.1 % of those receiving controlled release diclofenac; 3.6% compared with 7% of patients withdrew from treatment with tenoxicam and controlled release diclofenac, respectively, be­cause of GI adverse effects.

In short term double-blind trials (data on file, F. Hoffmann-La Roche) including 1908 patients with rheumatoid arthritis, osteoarthritis and soft tissue injury, 76 of 955 (7.9%) patients receiving tenoxicam (20 mg/day) had GI disorders com-

Drug Invest. 2 (Suppl. 3) 1990

pared with 120 of 953 (12.6%) patients in the pi­roxicam group (20 mg/day).

In a long term double-blind study (data on file, F. Hoffmann-La Roche) of 6 months' duration in patients with rheumatoid arthritis, osteoarthritis or ankylosing spondylitis, 22 of 192 (11.5%) patients receiving tenoxicam had GI disorders compared with 34 of 192 (17.7%) in the piroxicam group.

With reference to the 'dual-injury hypothesis', these differences between 2 NSAIDs of the same chemical class, acidity and daily dose could be ex­plained by their different inhibitory activity on the PG synthesis: in in vitro systems tenoxicam has been demonstrated to have a IO-fold lower PG in­hibitory activity than piroxicam.

These results confirm animal data on the ul­cerogenic dose for tenoxicam and piroxicam in rats; tenoxicam showed a more favourable ratio of the dose required to prevent the development of adjuvant-induced arthritis to the gastric ulcero­genic dose when compared with this ratio for piroxicam (Pradshaw et al. 1984).

5. Tenoxicam Tolerability in the Elderly 5.1 Renal Effects of Tenoxicam

As PGs maintain renal blood flow and contrib­ute significantly to normal kidney function, their inhibition may adversely influence renal function. Studies on the renal effects of NSAIDs need to in­clude patients with moderate or severe renal insufficiency. As many patients are treated with NSAIDs for periods from months to years, they therefore need to be monitored carefully for pos­sible renal impairment. Many of the patients are elderly and may have an age-related decrease in renal function. In the interpretation of results from studies of NSAIDs on kidney function, it should be considered that rheumatic disease itself may be associated with a greater degree of renal impairment.

To study the influence of tenoxicam (20 mg/ day) on renal function, creatinine clearance was monitored in 58 rheumatic patients with renal im­pairment (mean age 69 years) during a period of 3 months' treatment after withdrawal of any previ-

Patient-Days with Tenoxicam

ously administered NSAIDs (Bird et aI., data on file, F. Hoffmann-la Roche). Renal function was measured before and after a brief run-in period. The mean initial creatinine clearance before the in­troduction of tenoxicam was 52.1 ml/min. 54% of patients were analysed after completion of the study; the others were withdrawn for various rea­sons. The decrease in creatinine clearance was 6.8 ml/min after 12 weeks' treatment. The authors concluded that tenoxicam in a daily dose of 20mg can be safely given for a longer period in patients with mild or moderate renal impairment.

Only a few clinical studies with a comparable study design have been published. No data are available from crossover studies using different types of NSAIDs. A relationship between the po­tential renal effects of NSAIDs and their phar­macological properties (half-life, drug disposition, PG inhibitory activity) has not been reported.

A recent study (Hale et ai. 1989) looked at the renal effects of ibuprofen, indomethacin, na­proxen, piroxicam, sulindac and tolmetin. The change in estimated creatinine clearance (ECC) for elderly patients beginning a treatment with these NSAIDs was compared with a control group of subjects who did not use NSAIDs, aspirin or para­cetamol (acetaminophen). There was a significant difference between male and female patients in the influence of NSAIDs on creatinine clearance. ibu­profen and indomethacin were associated with a significant decrease in ECC, whereas other NSAIDs studied had no significant effect. In the indometh­acin group (9 male patients, 18 female patients), a highly significant reduction in ECC (12.2%) was seen only in men. 44 women treated with ibupro­fen showed a mean fall in ECC of 8.3%, whereas 15 male patients showed a reduction of 6.8%.

The results of this study in elderly rheumatic patients treated with different NSAIDs do not pro­vide evidence to show that drugs with a short half­life (ibuprofen, indomethacin) have a lower risk of renal effects than drugs with a longer half-life (naproxen, piroxicam). It is interesting to note that a weak inhibitor of PG synthesis (ibuprofen) had a weaker effect on the ECC than a very potent PG inhibitor (indomethacin).

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5.2 Adverse Events

Elderly rheumatic patients are more frequently exposed to antirheumatic drugs than younger patients. Some NSAIDs have been withdrawn in recent years because of a higher frequency of ad­verse effects in this population.

A double-blind study (data on file, F. Hoff­mann-la-Roche) was conducted to evaluate the in­fluence of sex and age on the frequency of adverse events in 955 patients treated with tenoxicam and 953 treated with piroxicam. The results of this study are summarised in table II and indicate that no age-related increase in adverse events occurred in these patient groups, although a slightly higher in­cidence of adverse events was reported for patients being treated with piroxicam compared with those treated with tenoxicam.

6. Tenoxicam Safety Profile

All data from clinical trials where tenoxicam was used at a dose of 20mg daily have been entered in a computerised clinical trial safety data base to give an overall safety profile from about 5000 patients.

All patient data were analysed according to the following criteria: 1. Frequency of discontinuation due to adverse re­actions/events. 2. Frequency of specific adverse reactions/events:

• GI disorders • CNS reactions • skin reactions • others.

3. Frequency of serious reactions/events. 4. Comparative analysis of tenoxicam safety pro­file ('safety data base'):

• demographic data • indication • duration of treatment.

5. Special studies: • elderly patients • patients with impaired renal function • long term tolerability. The most common adverse events recorded were

headache and dizziness, which occurred in ap-

6 Drug Invest. 2 (Suppl. 3) 1990

Table II. Adverse events and withdrawals in relation to sex and age (number of patients in parentheses)

Age and sex Frequency of adverse events ("!o) Withdrawals due to adverse events ("!o)

tenoxicam 20mg piroxicam 20mg tenoxicam 20mg piroxicam 20mg

Male < 60 years 10.9 19.5 (386) (400)

Female < 60 years 13.9 17.6 (390) (370)

Male > 60 years 9.1 10.3 (55) (58)

Female> 60 years 11.3 16.0 (124) (125)

proximately 1 % of patients; exanthema was re­corded for 0.3% and erythema for 0.1 %. Gastroin­testinal ulcers occurred in 0.1% of patients and GI bleeding in 0.04%, confirming the relative safety of tenoxicam with respect to the occurrence ofGI ad­verse events.

Phototoxicity has been demonstrated to be an additional risk factor for NSAIDs, so the potential phototoxicity of tenoxicam has been evaluated in animal and human studies. No phototoxic poten­tial was demonstrated in these studies and these results are supported by photosensitivity being re­corded for only 0.01% of the patients included in the tenoxicam safety data base.

In recent years, the discussion of cartilage dam­age as a result of NSAID usage has attracted in­terest. In a study using chondrocytes from human cartilage, no influence of tenoxicam on the meta­bolic turnover could be demonstrated (Bassleer & Franchimont 1988).

7. Conclusion

Data collected from 250 million patient-days of tenoxicam use have confirmed that the efficacy and safety of the drug compares favourably with that shown by other well-established NSAIDs in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis and soft tis­sue injury/extra-articular inflammatory disease. The once-daily dose of 20mg established in clinical trials has been shown to control pain and inflammation

2.6 3.5

1.0 3.0

1.7

3.2 4.8

in short term usage as well as in the long term treatment of chronic rheumatic disorders.

References

Barrier CH, Hirschowitz BI. Controversies in the detection and management of non-steroidal anti-inflammatory drug-induced side effects of the upper gastrointestinal tract. Arthritis and Rheumatism 32: 926, 1989

Bassleer C, Franchimont P. Effects of non-steroidal anti-inflam­matory drugs on the anabolism of differentiated human chon­drocytes cultivated in clusters. The 6th SEPAL Congress of Rheumatology, Tokyo, 5-9 Sep, 1988

Doherty M. Non-steroidal anti-inflammatory drugs in patients with peptic ulcer disease: to be considered in certain circumstances. British Medical Journal 298: 176, 1989

Fries JF, Miller SR, Spitz PW, Williams CA, Hubert HB, et al. Toward an epidemiology of gastropathy associated with non­steroidal anti-inflammatory drugs use. Gastroenterology 96: 647-655, 1989

Hale WE, May FE, Marks RG, Moore MT, Stewart RB. Renal effects of nonsteroidal anti-inflammatory drugs in the elderly. Current Therapeutic Research 46: 173-179, 1989

Langman MJS. Ulcer complications and non-steroidal anti­inflammatory drugs. American Journal of Medicine 84: 15-19, 1988

Moser U, Waldburger M, Schwartz HA, Gobelet CA. A double­blind randomized muIticentre study with tenoxicam, piroxi­cam and diclofenac-sodium retard in the treatment of ambu­lant patients with osteoarthritis and extraarticular rheuma­tism. Schweizerische Rundschau fUr Medizin 78 (10): 263-269, 1989

Muller P, Dammann HG, Leucht U, Simon B. Comparison of the gastroduodenal tolerance of tenoxicam and diclofenac Na. European Journal of Clinical Pharmacology 36: 419-421, 1989

Pradshaw D, Cashin CH, Kennedy AJ, Roberts NA. Pharmaco­logical and biochemical activities of tenoxicam (Ro-I2-0068), a new non-steroidal antiinflammatory drug. Agents and Ac­tions 15: 569-577, 1984

Schoen TR, Vender RJ. Mechanisms of nonsteroidal anti-inflam­matory drug-induced gastric damage. American" Journal of Medicine 86: 449-458, 1989

Author's address: Prof. H. Fenner, F. Hoffmann-La Roche Ltd, Aktiengesellschaft, 4002 Basle, Switzerland.