Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout

A. del Favero

10

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout

New formulations

Non-steroidal anti-inflammatory drugs (NSAID) that previously had to be given in several daily doses to maintain antiinflammatory serum levels are now being prepared in new sustained- or slow-release formulations (1 R, 2 c, 3 R, 4R). Marketing promotion is focused on two potential advantages: better patient compliance and better gastric tolerability. It is however too early to establish the real merits o f these preparations, and the Osmosin affair (SEDA8, 103) should make the prescriber alert to the risk that new adverse reactions may occur with their use. Two points deserve a short comment: the pharmacokinetics of these drugs and the lack of evidence of a clear advantage over the old preparations. Although little information is available on the relevance of pharmacokinetic characteristics with respect to the efficacy and tolerability of NSAID (5R), it must be stressed that the data available for the new delayed-release formulations are scanty and often inconclusive (1 R, 3 R, 4R). In fact, although slow-release formulation may supply sustained therapeutic activity of the active drug over an extended time period, thus obviating the need for frequent dosing, they do not avoid high drug concentrations in the serum or at specific sites in the gastrointestinal tract. Side effects resulting from high serum or gastrointestinal tract concentrations of drug could thus still occur in Side Effects of Drugs Annual 9 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1985 ISBN 0 444 90394 1 $0.85 per article per page (transactional system) $0.20 per article per page (licensing system)

predisposed patients taking these formulations. Moreover, it is a mistake to assume that frequency of administration should be based on plasma half-life, as even compounds with plasma half-lives o f much less than 12 hours can often be given effectively twice daily (6r). In fact, results o f clinical trials indicate no significant difference between the new and old preparations regarding patient response or preference. In particular, from the point o f view of gastric tolerability and central nervous system side effects, which are still the main reasons for interrupting treatment, comparative clinical trials have failed to demonstrate that the new formulations have any major advantages over the old preparations (1 R, 7 c - 1 1 c ) . In addition, the concern expressed about their potential to irritate the bowel would seem to be justified since absorption of NSAID is usally retarded by delayed-release formulations. The longer-lasting NSAID also raise the issue of flexibility. The usually well-tolerated practice of taking an extra dose of short-acting NSAID, particularly when the relief of pain or stiffness is less than complete, is not feasible with the longer-acting preparations and clinicians are requested to specifically counsel their patients that their new drugs are to be taken only once or twice daily. The usually greater daily cost of these products and the availability of other NSAID which have a similar convenienee of once- or twice-daily dosing must also be taken into consideration. In conclusion, the clinical benefits of these new formulations in relationship to improved patient compliance, control of symptoms and/or fewer side effects need to be further substantiated. This means one should be aware of the problems posed by

84 the new formulations and not be attracted to them simply because they have a 'new look' (12 r, 13).

Nephrotoxicity of NSAID {SEDA-8, 101) While editorials and reviews call attention to the renal side effects of NSAID (14R--16R), a study carried out by the Boston Collaborative Drug Surveillance Program failed to disclose any important renal function effects due to these drugs (17 c). No relationship was found between the use of NSAID and the rate of drugattributable rise in serum urea in a large group of hospitalized patients. In particular, in patients receiving diuretics, among whom this event is common, the rate of rise in serum urea nitrogen levels among diuretic users who also used NSAID was no higher than in those who did not. Moreover, longerterm follow-up in a large group of outpatient users o f NSAID numbering more than 50,000 disclosed that none was hospitalized because of acute kidney disease. These results, related primarily to phenylbutazone, indometacin and ibuprofen, do not mean that NSAID are not nephrotoxic, although they may imply that the incidence of renal toxicity is low with these drugs. However, the report by F o x and Tick (17 c ) has some limitations. The method used of identifying adverse renal effects due to NSAID was necessarily crude and therefore the study may have missed many subjects whose renal function was substantially decreased. Moreover, data on the duration of drug regimes, the exact type of NSAID and the doses are not provided by the survey. Hence, caution and awareness o f this clinical problem with NSAID use are still indicated despite this negative report (18r), particularly in patients at high risk for kidney failure (19cr).

Phototoxicity of NSAID Although a number of NSAID have been reported to induce adverse cutaneous photosensitivity reactions (SEDA-7, 109; SEDA-8, 103, 105), their photosensitizing potential varies greatly. The clinical features of these reactions suggest a p h o t o t o x i c rather than a photoallergic mechanism, since they occur within a short time of taking the drug, resemble severe sunburn, may progress to blistering, but subside fairly quickly

Chapter 10 A. del Favero

when treatment is stopped. A simple mathematical model has been developed to predict the likelihood o f photosensitivity occurring with a given drug by considering the amount of drug normally ingested, its spectral absorption characteristics and the quantity and spectral quality of the radiation the patient may be exposed to (20c); moreover, the photosensitizing potential of different drugs can be investigated in rive with an irradiation monochromator with different exposure doses (21c). When 8 NSAID were examined by these techniques, not only benoxaprofen but also piroxicam, naproxen and tiaprofenic acid were found to have significant capacity to induce photosensitive cutaneous reactions. There was no p h o t o t o x i c response in patients taking indometacin, ketoprofen, benorylate or ibuprofen. Recently the West Midlands Regional Centre for Adverse Drug Reaction Reporting (U.K.) (personal communication) has received 1 report of photosensitivity occurring after 10 days treatment with diclofenac. However, despite the wide prescription of these drugs the incidence o f reported photosensitivity is low with all except benoxaprofen, suggesting that other factors such as difference in skin pigmentation, differences in pharmacokinetics and radiant exposure dose are also important determinants of individual response to phototoxic agents.

PYRAZOLONE DERIVATIVES Agranulocytosis (SED-1 O, 153; SEDA - 7, 10 7) An interim report from a multicenter case-control study still in progress seems to indicate that the annual incidence of agranulocytosis due to pyrazolones is lower than suggested by previous studies (22). However, although this extensive study will eventually provide data that allow the relative risk of bone-marrow damage due to pyrazolones to be assessed, it is doubtful whether it will give a reliable figure for the true incidence of drug-induced agranulocytosis (23).

Hypotension A significant fall (more than 20 mmHg) in systolic blood pressure without any other symptoms or signs of anaphylactic shock has been observed in patients treated parenterally with dipyrone. The fall in blood pressure occurs from within minutes to as much as 6 hours after intra-

Anti-inflammatory analgesics Chapter10

venous administration of the drug and it is usually rapidly and spontaneously reversible. The effect appears to be uncommon as it was found in only 7 (0.34%) of 2053 patients who received intravenous treatment with dipyrone preparations in the two medical divisions participating in the Comprehensive Hospital Drug Monitoring Program-Berne (24 c).

Poisoning (SED-8, 209) According to the Poisons Information Center at Mainz University (F.G.R.), although the signs and symptoms of severe pyrazolone intoxication are similar for all substances in the group, their effect on the target organs differs in intensity. Aminopyrine, propyphenazone and dipyrone affect mainly the central nervous system causing rapid and progressive impairment of consciousness with coma, convulsions and, sometimes, sudden apnea. After a latent period from ingestion o f the drug, liver necrosis sometimes occurs. Liver damage may, instead, be the only manifestation of severe intoxication by oxyphenbutazone and phenylbutazone. Because dipyrone, unlike aminopyrine and propyphenazone, less frequently causes impairment of consciousness (but more frequently abdominal pain, vomiting and vertigo), its degree of acute toxicity is regarded as less severe. Infants apparently have low tolerability to aminopyrine and fatal intoxications have occurred after doses as low as 0.5 g. Forced diuresis and, perhaps, hemoperfusion offer the possibility of lowering the total body load of pyrazolones, but firm data on their usefulness are lacking (25 eR, 26c).

PHENYLBUTAZONE AND RELATED COMPOUNDS P h e n y l b u t a z o n e and oxyphenbutazone toxicity fSED-10, 153; SED.4-8, 102) Many countries have been reconsidering the use o f butazones since the publication in the lay press o f Ciba-Geigy's own international assessment on Butazolidine {phenylbutazone) and Tanderil {oxyphenbutazone), dated September, 1982, which summarized reports on 1182 deaths associated with the use o f these drugs from their introduction up to 1982 (27, 28 R, 29R). The United

85 Kingdom has withdrawn the licence for oxyphenbutazone and has limited phenylbutazone prescriptions to hospitals for treatment o f patients with ankylosing spondylitis. Both drugs have been banned in Norway, while in other countries only the package insert instructions have been amended to limit phenylbutazone to the treatment o f ankylosing spondylitis, acute gout and psoriatic arthritis patients who fail to respond to other NSAID, and oxyphenbutazone to the treatment o f ankylosing spondylitis only. A petition filed by a health research group for an immediate ban on these two butazones, which is still under consideration by the FDA, indicates that their future in the United States also is in serious doubt. The information relevant to deaths associated with these drugs reported by CibaGeigy is summarized in Table 1. The report confirms the long-known serious risks with the two compounds and gives a clearer and better quantified picture o f probable drug-related death incidence. However, instances o f under- and over-reporting make the true incidence o f serious side effects difficult to estimate. The report shows that the percentage o f serious unwanted effects is high for both phenylbutazone and oxyphenbutazone, and that the most frequent in both cases are dermatological and hematological, closely followed by gastrointestinal. A closer look reveals some differences between the two compounds. Phenylbutazone seems to be responsible for more gastric bleeding and/ or peptic ulcers which tend to occur early in treatment with either drug. On the other hand, in the case o f aplastic anemia or agranulocytosis a difference exists between the two compounds when the duration o f treatment is considered. In fact, the cumulative doses needed to bring about these reactions is lower for oxyphenbutazone than for phenylbutazone. These findings agree with the data from the Committee on Safety o f Medicines [U.K.), which indicates that oxyphenbutazone is more likely to cause death due to bone marrow failure than phenylbutazone (30cR). The Ciba-Geigy report also shows that patients over 61 years o f age, particularly females, are at a higher risk for fatal outcome due to adverse reactions with either o f the two drugs, especially when treatment is long-term. Studies on the relationship between death

86 Table I.

Chapter 10

A. del Favero

Comparison of the majority of the serious unwanted effects with Butazolidine and Tanderil*, **

Major serious unwanted effects

Aplastic anemia or pancytopenia Agranulocytosis Thrombocytopenia Leukemia (hematological malignancies) Gastrointestinal bleeding or peptic ulceration or both Erythema multiforme and variants (Stevens-Johnson and Lyell's syndromes, toxic epidermolysis) and also bullous exanthema Jaundice/hepatitis Hepatic necrosis Anuria, uremia or renal failure Glomerulonephritis, interstitial nephritis, nephrotic syndrome or papillary necrosis Pancreatitis Myocarditis/pericarditis/ vasculitis Anaphylactoid reactions/ asthma tic attacks Totalno. o f / Totalno. of patients /fatalities with all / un wan ted / effects [

Butazolidine (1952-1981)

Tanderil (1960-1982}

Single case-reports + (fatalities)

Health authorities ++ and Ciba-Geigy lists

Single Health case-reports + authorities ++ and (fatalities) Ciba-Geigy lists

141 (74) 122 (53) 5 7 (16) 73 (41)

130 51 24 9

110 (60) 78 (26) 46 (15) 14 (8)

153 55 56

263a(51)

129

62a(15)

36

77 (16)

45

99 (18)

53

92 6 38 23

(21) b (6) (14) e (5)

44 2 13 16

50 2 15 6

(8) b (2) (1) e (0)

40 1 4 3

4 (0) 23 (3) e

2 9

17 (2) 12 (4) c

10 6

24 (6)

5

22 (0)

1485/376 (25%)

1435d/325 unwanted effects

1239/188 (15%)

8

7 1352d/141 unwanted effects

* Modified from Oba-Geigy's Butazolidine, Tanderil, Voltaren. Comparison of Tolerability (February, 1983). ** Except where stated, all numbers in this table refer to number o f patients. + Isolated published case-reports describing patients reporting adverse drug reactions. ++ Duplications to single case-reports cannot be excluded. a Gastrointestinal bleeding secondary to blood disorders excluded. o Fatalities secondary to blood disorders or gastrointestinal bleeding excluded. e Fatalities secondary to liver or blood disorders or gastrointestinal bleeding excluded. cl No. of patients with these unwanted effects not available.

rate per unit o f treatment for the two butazones and other N S A I D in a n u m b e r o f countries have disclosed striking differences (Tables 2 and 3) that can be explained not only by variations in the reliability o f different national systems for reporting adverse reactions and lack o f accurate data on drug consumption, but also by the way the drug is used. For example, a comparison between the United States and the United K i n g d o m reveals that butazones are m o r e f r e q u e n t l y prescribed for the elderly-female highrisk group and for longer term diseases

in the United K i n g d o m , where the mortality rate f o r butazones is considerably higher. In conclusion, the publicity given to the Ciba-Geigy report has at least served as a stimulus to a m o r e wide and careful consideration o f serious risks connected with the use o f butazones and has also p r o m p t e d s o m e regula.tory authorities to intervene with appropriate measures (31). As ample data, other than the Ciba-Geigy report, incriminate butazones in fatal bone-marrow depression and other serious hazards (SED8, 212; SED-9, 145; 30 c R ) and m a n y other

Anti-inflammatory analgesics

Chapter 10

87

Table2. Estimated mortality rate by country for phenylbutazone (Phe) and oxyphenbutazone fOxy) * Country

Worldwide United Kingdom United States Federal Republic o f Germany France Canada Sweden Netherlands Italy

Total reported deaths

Estimated mortality rate per million treatment months

Phe

Oxy

Phe

Oxy

777 442 131 128

405 131 48 16

2.1 1 7. 7 1.4 2.0

2.8 24. 7 3. 6 O.8

22 11 9 9 7

16 5 6 4 1

1.1 1.3 3. 9 4.3 0.3

0.9 1.7 4.6 1.9 0.1

*Modified from Oba Geigy's Re-assessment of Butazofidine and Tanderil {January 20, 1984). Data source specified in the original report. Table 3. Comparison o f NSAID mortality incidence between United Kingdom and United States (per million prescriptions) * Drug

Indoprofen Benoxaprofen Oxyphenbutazone Phenylbutazone Indometacin l~'roxicam Sulindac Naproxen Diclofenac lb uprofen

Accumulated Estimated prescriptions** deaths/million prescriptions U.K.

U.S.A.

U.K.

U.S.A.

0.1 1.8 10.2 58.2 57.8 5.6 2.0 12.0 3.2 33. 0

15.0 60.0 51.3 6.1 20.6 23.6 52.3

59.3 33.9 12.8 7.6 4.9 4.3 4.0 3.9 1.9 1.8

5.5 3.8 2.2 5.1 3.8 2.4 1.3

* Modified from C-Yba-Geigy's Re-assessment of Butazolidine and Tanderil (January 20, 1984). Data source specified in the original report. **Accumulated prescriptions since 1964 (U.K.) or 1969 (U.S.A.) or date o f introduction. equally e f f e c t i v e a n d safer N S A I D are available, there is no j u s t i f i c a t i o n f o r still w i d e l y prescribing p h e n y l b u t a z o n e a n d o x y p h e n b u t a z o n e , a n d it also s e e m s wise to suggest a careful re-evaluation o f the r i s k / b e n e f i t ratio o f o t h e r b u t a z o n e derivatives still in use.

Azapropazone ( S E D - I O, 156; S E D A - 8 , 102) A single case of hematuria, which may have resulted from uric acid crystal precipitation within the renal tract, and a generalized significant fall in hemoglobin, without evidence o f gastrointestinal bleeding was found in 22 hyperuricemic gout patients treated with the drug for 3 months. Evidence o f r e d u c e d g l o m e r u l a r f u n c t i o n during azapropazone therapy has been confirmed (SEDA-8, 102; 32C).

Feprazone In the United Kingdom, marketing of feprazone has been discontinued since last March following concern from the Committee on Safety of Medicines about its risk/benefit ratio (33). As pointed out before (SEDA-3, 91; SEDA-4, 64; SEDA7, 104; SED-9, 145), the adverse reactions to feprazone resemble those of phenylbutazone and, taking into account its prescription rates, are particularly frequent. Weber (34 R) of the British Department of Health and Social Security, presented data which show that when comparing the number of adverse drug reactions reported to NSAID in proportion to the number of prescriptions issued, feprazone was proportionately the most frequently reported as suspected of producing the following adverse reactions: gastrointestinal hemorrhage, liver damage (including hepatitis), blood dyscrasias (mainly thrombocytopenia), nephropathy, and severe bullous dermatosis. Skin reactions are particularly frequent and serious enough to force a high percentage of affected patients to interrupt treatment. The above data contrast with the results of two large short-term multicenter studies involving a total of 11,000 patients, specifically performed to test the efficacy and tolerance of the drug as regards its future extensive use (35 r, 36 r) and with a manufacturer's own internal assessment o f Phase III and Phase IV studies in Italy. In these studies the frequency of side effects was very low (1.2-9.8%) a n d no serious reactions were observed (37). This striking discrepancy cannot be due entirely to differences in the duration of treatment or diseases treated, and it casts serious doubts on the reliability of the results of this s o r t of large, uncontrolled general practice study.

88 INDOMETACIN AND RELATED COMPOUNDS Indometaein (SED-I O, 158; SEDA-8, 102)

Intravenous administration of indometacin for the treatment of ureteral colic has been found to be both efficacious and usually well tolerated (SEDA-8, 102). However, in a recent clinical trial (38C), 90% of patients treated with slow (at least 5 min) intravenous indometacin injection suffered side effects which, in order of frequency, were: significant (more than 20 mmHg) increases in blood pressure, nausea, vertigo, vomiting, and reactivation of symptoms of peptic ulcer (1 patient). The severity of the adverse reactions encountered prompted the authors of this study to suggest that intravenous indometacin, although efficacious, should not be considered as first-line therapy in ureteral colic and should be used only in closely monitored hospitalized patients. The differences in the tolerability found by the above-mentioned studies may perhaps be explained by differences in the formulation or in the rate of i.v. infusion adopted, and it is possible that a very slow rate (more than 5 min for 50 mg of indometacin) might decrease the incidence of side effects. Cardiovascular effects Intravenous administration of indometacin may result in dangerous cardiovascular effects by increasing mean arterial blood pressure, diminishing coronary flow in patients with angina and, experimentally, attenuating the coronary dilator and venodilator effects of nitroglycerin (SED-10, 158; 39R). Despite this, indometacin has not been shown to adversely affect either exercise capacity or the response o f patients with stable angina of effort to nitroglycerin (40). Moreover, the inconsistency of the effect indometacin exerts on blood pressure makes predicting its effects in individual patients difficult. The mechanism of indometacin action on blood pressure is poorly understood and, probably, complex. However, there is some evidence that a high intravenous infusion rate causes hypertension in normal subjects more frequently than a slow infusion, and that indometacin and other NSAID have an adverse effect on the blood pressure control of patients with volume-sensitive hypertension, but they are antihypertensive in patients with prostaglandin
Chapter 10 A. del Favero Intravenous administration of indometacin in patients with heart failure may cause deleterious effects and should be avoided. Not only does it inhibit the sodium excretion mechanisms of the renal medulla and the natriuretic effects of diuretics, but it m a y also reduce the vasodilator action o f circulating prostaglandins E2 and I2 which are increased in patients with severe congestive heart failure. Patients with hyponatremia depend on this compensatory mechanism to maintain circulatory h o m e o s t a s i s and administration of indometacin can result in a significant deterioration of circulatory hemodynamics (43Cr).

Pregnancy Fetal anuria resulting from longterm intrauterine exposure to indometacin has been shown to be responsible for severe oligohydramnios seen in pregnant women taking this drug (44 C , 45 C). Interaction A 78-year-old patient with diabetes and moderate renal insufficiency developed hyperkalemia only when simultaneously treated with indometacin and Moduretic (amiloride + hydrochlorothiazide). This increase in plasma potassium could not be attributed to either a reduction in glomerular filtration rate or hypoaldosteronism (46 c). Although there are experimental data showing t h a t gastrointestinal toxicity of indometacin can be decreased significantly when combining it with sodium salicylate, no significant improvement of subjective tolerability was found in patients treated with this combination (47c). Poisoning Data on 31 indometacin overdoses reported to the National Poisons Information Service, London, U.K. show that up to 2500 mg was said to have been ingested by adults without any adverse sequelae. The only symptoms described were nausea, abdominal pain, drowsiness, headache and tinnitus, with 61% of patients remaining asymptomatic (48 CR). This experience is in accord with a previously published report (49 C). Glucametaein (SED-9, 149; SEDA-5, 102) Despite claims o f better gastric tolerability, the most frequently reported side effects with this indometacin derivative

Anti-inflammatory analgesics Chapter10 remain nausea and heartburn. Gastrointestinal bleeding has also been documented (50e). Sulindac (SED-9, .149; SEDA-8, 105) Kidney Sulindac has recently been confirmed as a suitable substitute for other NSAID in patients with slightly impaired kidney function who are experiencing, or at risk for, adverse renal effects (SEDA-8, 101; 51c).

Hypersensitivity Both sulindac and other NSAID can cause aseptic meningitis in patients with systemic lupus erythematosus or mixed connective tissue disease (SEDA-7, 109). A case of recurrent (3 episodes) aseptic meningitis caused by this drug has been described in a woman who had no demonstrable systemic collagen disease (52 C).

Hepatitis Has been reported previously (SEDA-5, 101). In the following case it was associated with toxic epidermal necrolysis. A 52-year-old woman was prescribed sulindac 200 mg twice daily for low back pain. Fourteen days later she developed fever, malaise and subsequently noted mouth ulcers, facial erythema and dysuria. Two days later she was admitted to hospital with fever, conjunctivitis, keratitis, a generalized maculoerythematous rash with scattered vesicobuUous lesions and ulceration of the buccal mucosa and external genitalia. A skin biopsy revealed findings consistent with toxic epidermal necrolysis. Laboratory investigation showed f'mdings indicative of acute hepatitis (increased bilirubin, LDH, APh, SGOT and prothrombin time). Despite vigorous treatment the patient died 22 days after she started taking sulindac (53C).

Interaction Two cases of peripheral neuropathy after combined treatment with oral sulindac and topical dimethylsulfoxide, that were clearly n o t due to sulindac alone, have been described (54 c , 55c). After 3 - 4 months of concomitant therapy b o t h patients developed serious sensirnotor deficits in the extremities in direct contact with dimethyisulfoxide. When the topical therapy was discontinued, b o t h patients slowly recovered, despite the fact that one continued to take sulindac. The mechanism by which concomitant administration of these two drugs causes neurotoxicity

89 is unknown, but an interaction or dimethylsulfoxide itself may be responsible. However, although high doses of dimethylsulfoxide inhibit nerve conduction in animals, neuropathy has never been reported in man. Indometacin, which is related to sulindac can cause peripheral neuropathy (SED-10, 158). Poisoning F e w cases of overdose are known to the National Poisons Information Service (U.K.) for sulindac (8 reports, 3 in young children) and all subjects remained asymptomatic (48CR). No dose range was reported.

Etodolac (SEDA-8, 11 O) A review of the side effects encountered in 6 clinical studies involving 298 patients showed this drug to have the same sideeffect pattern, as other NSAID, notably gastrointestinal and central nervous system. Apart from a few cases of raised hepatic enzyme levels, which p r o m p t e d the interruption of treatment, there were no consistent abnormal laboratory findings (56 C R).

ARYLALKANOIC ACID DERIVATIVES AND RELATED COMPOUNDS

Benoxaprofen {SEDA-4, 68; SEDA-8, 105) A serious hypersensitivity reaction characterized by a general vasculitis has been described (57c). Seven reports o f overdose (dose range ingested 1 . 2 - 1 2 g) with this drug have been received by the National Poisons Information Service (U.K.). Symptoms following benoxaprofen overdose included vomiting, dizziness, drowsiness and restlessness (48CR). Benoxaprofen was withdrawn from the world market in 1982 due to serious side effects. The decision reawakened doubts about the efficacy of existing adverse reactions monitoring systems and the wisdom of the current marketing policy of the pharmaceutical industry (SEDA-8, 105). In the United States, a report based on hearings held by the House Government Operations Subcommittee on Intergovernmental Relations charged Eli Lilly, the benoxaprofen manufacturer, with having improperly withheld information from the F D A

90 on side effects associated with the use of benoxaprofen overseas prior to its approval in that country. The manufacturer's reply to these charges has recently been published (58). After attempting to minimize the authority of the report ('a subcommittee staff report') and to deny its legitimacy to pass judgment on pharmaceutical companies or their products ('the report ranged far beyond the subject matter of the hearing; i.e. the manner in which FDA was administering the law'), the company rebutted all the charges. Reading the report, however, one gets the impression that the rebuttal is based more on proving the formal respect by the company of the existing regulations than on showing an appropriate handling of available information. Moreover, the coneluding statement in Lilly's letter, that the company acted responsibly in the Oraflex matter, does not look credible if one takes into account that the company has been charged by the FDA with misbranding the drug in a press kit and associated materials which contained a false and misleading headline implying that the drug was harmless, despite the fact that a report of fatal cases related to benoxaprofen use was already known to the company. The company's intense marketing campaign has been heavily criticized (31) and the recommendation of the WHO that drugs likely to be used in the elderly should be investigated in the elderly at an early stage has been disregarded.

Clozic Clozic (2- [ 4'-(p-chiorophenyl)b enzyloxyl] 2-methylpropionic acid) while under investigation was thought to have a penicillaminelike action. However, after clozic had been given to 1800 patients, the manufacturer withdrew the drug from the market because of the development of Stevens-Johnson syndrome in 4 patients, 1 of whom died (59r). Dielofenac (SED-I O, 164; SED-8, 105) Gastrointestinal A young woman developed

esophageal ulceration after taking a tablet of diclofenac without water just before going to sleep (60c). Hatelets Spontaneous- in vitro platelet aggregation after diclofenac treatment has been described in 1 patient. As the drug

Chapter 10 A. del Favero has been documented as having an inhibitory action on collagen-induced platelet aggregation, the finding requires confirmation (61c).

Fenbufen (SED-1 O, 166; SEDA-8, 106) The pathogenesis of the rashes which seem to be relatively frequent in fenbufentreated patients is unclear. The clinical findings and the presence of circulating immune complexes in 3 cases of generalized skin reactions argue in favor of an immunemediated mechanism (62 C).

Fenclofenac (SED-I O, 165) Drug withdrawal Fenclofenac has been withdrawn from the United Kingdom market after the Medicines Commission's refusal to relicense it because of the unsatisfactory adverse drug reaction prof'fle (63). The withdrawal applies to all other countries where the drug is marketed (Ireland, Pakistan, South Africa, the Gulf states and the Latin America market). The U.S. NDA filing has also been withdrawn (64). The Committee on Safety of Medicines' adverse drug reaction data have recorded 7 deaths and 895 side effects in patients taking Flenac. The majority of the unwanted effects were skin-related. According to Weber (34R), when comparing the number of reports on adverse reactions to NSAID in proportion to the number of prescriptions issued, fenclofenac has the second highest incidence of reported side effects and ranks first for the number and severity of dermatological reactions. Thyroid The suppression of TSH responsiveness to TRH induced by fenclofenac is not mediated by its direct effect on the pituitary gland, but is secondary to a rise in the free thyroid hormones displaced from their serum protein binding sites by the drug (65c).

Fenoprofen (SED-1 O, 163; SEDA-8, 100) Kidney The confirmed importance of immune-mediated mechanisms in the pathogenesis of fenoprofen nephropathy (interstitial nephritis and minimal-change glomerulopathy) suggests the need for immunosuppressive (steroid) therapy in patients with severe uremia, when drug withdrawal alone fails to improve renal function (66c). Blood Fenoprofen can cause blood dyscrasias (SEDA-3, 94; SEDA-4, 67; SEDA-5,

Anti-inflammatory analgesics Chapter10 104; SEDA-7, 112) but pure red cell aplasia (PRCA) has not been previously described. A 69-year-old man, while being treated with fenoprofen, developed PRCA which was fully reversed after the drug was discontinued. The patient had an epidermoid carcinoma, however, and PRCA has also been described with malignancies (67Cr). Poisoning A total of 17 reports are known for fenoprofen to the National Poisons Information Service (U.K.). The majority of patients who were said to have ingested less than 15 g of fenoprofen were asymptomatic or had mild symptoms including drowsiness, ataxia, tinnitus, nausea, hypotension, tachycardia and dyspnea. But fenoprofen can also cause serious toxicity (1 fatal case) in overdose, and reversible non-oliguric renal failure, hypothermia, coma and respiratory depression have been described (48 c R).

Fentiazac (SED-I O, 166; SEDA-8, 106j Rectal administration of fentiazac may give rise to various side effects, both local (rectal tenesmus, diarrhea, local intolerance and burning), and systemic (68c). Most NSAID can cause local effects when given rectally, but the generally high incidence of adverse reactions to this drug must be remembered. Flurbiprofen (SED-1 O, 163; SEDA-8, 106) After 2 - 6 weeks' administration, even low doses (50 mg/d) of the flurbiprofen can significantly reduce urinary calcium excretion in patients with idiopathic hypercalciuria (69r This effect is rapidly reversible after stopping the treatment and may be shared with other NSAID (70r).

91 be protean and difficult to interpret. A case has been reported of a woman who experienced a severe reaction to ibuprofen on 2 separate occasions (73c). Fouprofen was prescribed to a 62-yeax-old woman for gum swelling, and the patient completed the full course of therapy without problems. Two weeks later she took 2 tablets of 400 mg ibuprofen and several hours later she presented with nausea, vomiting, joint and muscle pains, a sensation of skin burning and tightness, and fainting on standing. She improved gradually with bed rest. Three days later she took another 2 tablets of ibuprofen and within minutes she developed the same symptoms again and collapsed. She was brought to hospital where she was found to be hypotonsive, with fever, generalized erythematous rash and serious hypoxemic respiratory failure. A chest X-ray film revealed bilateral alveolar infiltrates. Laboratory investigations revealed elevated levels of creatinine phosphokinase and mildly elevated levels of LDH, slightly decreased levels of factors C1 and C3 of complement and moderately positive results of tests for circulating immune complexes. With vigorous treatment, including assisted mechanical ventilation, steroids and continued infusion of dopamine, she gradually improved. Poisoning In spite of the large n u m b e r of prescriptions, acute intoxication with ibuprofen appears to be rare and not serious. The alleged dose of ibuprofen ingested in cases in which full details of outcome are available varied from 4 to more than 20 g. Many patients were asymptomatic and the most commonly reported symptoms are nausea and vomiting. There have been very occasional reports of more serious symptoms (transient renal insufficiency, hypotension and coma), but they involved simultaneous ingestion of other drugs. Treatment should be supportive only (74c).

Indoprofen fSED-IO, 166; SEDA-8, 106) Ibuprofen (SED-1 O, 162; SEDA -8, 106) Hypersensitivity Ibuprofen-induced aseptic meningitis is a well-known side effect in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (SEDA-3, 93; SEDA-4, 67; SEDA-5, 105). A similar reaction now has been described in 2 patients, apparently without SLE (71 c , 72c). Generalized hypersensitivity reactions to NSAID may be more common than previously realized and the manifestations may

Worldwide withdrawal of the drug The U.K. Licensing Authority suspended the product license for this drug on the grounds of safety on December 13, 1983, and, in the middle of July, 1984, the Italian manufacturer, Farmitalia-Carlo Erba decided to withdraw it from the world market. The decision of the U.K. Licensing Authority was taken after the discovery of a high level of adverse drug reactions both by a voluntary U.K. post-marketing surveillance study and an analysis of Committee on Safety of

92 Medicines yellow-card reports, which revealed 217 serious adverse effects, mainly gastrointestinal (bleeding and perforation), including 8 deaths (see also Table 3) (75, 76). According to the manufacturer, the side effect profile seen in the United Kingdom has not emerged in other countries (77 c) and has not even been suspected in previous evaluations (78 R, 79R). A survey of adverse reactions encountered in Phase II, III and .IV studies, involving 6764 patients (most having been treated for 1 month or less), showed that life-threatening events were rare, including overall 16 instances of clinically overt gastrointestinal bleeding and 2 anaphylactic reactions. In a post-marketing surveillance study on 3823 osteoarthritic patients, serious adverse reactions occurred with even less frequency (80r). Data presented by the manufacturer at the 'Flosin' hearing held by the Federal German Health Authorities on March 16, 1984, confirmed the apparently good tolerability of indoprofen, although data were subjected to detailed criticism by the BGA representatives. According to these data, deaths reported in association with indoprofen treatment in 3 countries were 46 (5 in Federal Republic of Germany, 34 in United Kingdom and 7 in Italy), but only 11 were judged as probably or possibly drug-related. The majority (9) o f these indoprofen-related deaths were caused by gastrointestinal reactions. The BGA eventually decided to temporarily withdraw the drug from the German market and the controversies ended on July 13 when the manufacturer decided to stop marketing the drug worldwide giving the reason that indoprofen has been found to be carcinogenic during long-term animal toxicological studies. To what extent the clinical events played a role in the decision is not clear. Kidney Treatment with indoprofen was discontinued in 3 children with juvenile rheumatoid arthritis due to the appearance of microhematuria. No renal function deterioration was, however, documented during this 12-week study involving 24 patients (81c).

Chapter 10 A. del Favero ently for 7 years has been attributed to ketoprofen. The patient was also taking triamterene and this may have enhanced the drug's nephrotoxicity since it is well-known to reduce renal function (82c).

Nabumetone (SEDA-8, 11 O) This compound is a naphthyl derivative of naproxen with a long half-life, which is completely metabolized in vivo to the major derivative 6-methoxy-2-naphthylacetic acid, which itself has anti-inflammatory activity. The pattern of its side effects is almost completely unknown, but from the few published studies it would seem to be comparable to that of other NSAID (83c).

Naproxen (SED-I O, 164; SEDA-8, 107) Lung Another 4 well-documented cases of

pulmonary infiltrates associated with naproxen have been published. In all cases, clinical findings were similar to those already described in the first published case-report (SEDA-8, 107), except for the radii~logical features which were variable and non-specific (84 c , 85c). In these cases, too, the process was spontaneously reversible and rechallenge in 2 patients caused recurrence of symptoms. Kidney A 31-year-old man with rheumatoid arthritis, who had previously been treated with sulindac, fenoprofen, salicylates and gold salts, developed renal papillary necrosis (RPN) 4 months after institution of naproxen therapy. No other factors predisposing to the development o f RPN were present. The patient subsequently tolerated therapy with sulindac (86 c). Poisoning A patient who ingested 25 g of naproxen suffered only transient nausea and indigestion ( 8 7 c ) , but a man who ingested 35 g was found having what was described as an epileptic fit (48cR). Oxaprozin (SED-I O, 168; SEDA-8, 107)

Diarrhea may be frequent in patients treated with this drug (88c).

Ketoprofen {SED-I O, 163; SEDA-8, 106) Pirprofen (SED-1 O, 164; SEDA-8, 10 7) Kidney A case of irreversible acute renal insufficiency in a patient with a transplanted kidney that had functioned effici-

In an open, non-comparative field trial on 1506 patients the reported side effects

Anti-inflammatory analgesics Chapter10 were essentially related to the gastrointestinal tract and consisted mostly of epigastric pain. As one might expect, the frequency of unwanted effects causing patients to interrupt treatment was less in the patients receiving 800 mg than in those receiving 1200 mg daily throughout the trial. There was 1 case each o f asthmatic attack, iron deficiency anemia, leukopenia and elevation o f transaminase levels (more than 10 times normal values) (89c).

Suprofen (sutoprofen) (SEDA-8, 107) (90 r) This is a benzene acetic acid derivative which, although developed primarily as an analgesic, shares the properties of other NSAID. It has a terminal plasma half-life of about 2 - 4 hours, and is rapidly metabolized in the liver and predominantly eliminated in the urine. The major metabolite in the urine is an ester glucuronide conjugate of suprofen (90r). Very few data are available for properly evaluating the incidence and t y p e o f side effects and, as usual, the drug is presented as being at least as safe and as well tolerated as reference drugs (aspirin, ibuprofen, propoxyphene alone or in combination) (91R). As may be expected, gastrointestinal side effects are those most frequently reported, and peptic ulcer has been observed (9 lC-94c). Although toxicological data and the resuits of studies on gastrointestinal blood loss in volunteers appear favorable (95), the propensity of the drug to provoke damage and bleeding in the gastrointestinal tract should be considered the same as for other NSAID. The number of patients who drop out from multiple dose trials due to unwanted effects varies from 0% to 39% (92% 93 c) and, once again, gastrointestinal upset is the most often cited reason. Central nervous system side effects responsible for withdrawal from the drug were more frequent in the older age groups. Occasionally elevated liver enzyme levels and a few cases o f mild leukopenia o f dubious significance have also been observed. Interference with platelet function should be anticipated.

93 trolled trials, has shown that the overall pattern of tolmetin sodium side effects in geriatric patients is similar to that known for the general population studied. The most significant side effects are gastrointestinal (43.6% of patients). The percentage of peptic ulcer (3.2%) and gastrointestinal bleeding (1.3%) is somewhat higher than for patients under 65 (1.9% and 0.4%, respectively). The dropout rate due to adverse reactions is 15.5% of patients, a figure higher than that for patients younger than 65, but not significantly so. Zomepirac (SED-I O, 167; SEDA-8, 108) Blood A case of reversible agranulocytosis, possibly related to this drug, has been documented (97 c ) . Hypersensitivity A combination o f acute hepatitis with serious liver failure, acute renal failure consistent with acute tubular necrosis and Coombs' positive hemolytic anemia suddenly followed the ingestion of 1 tablet each of naproxen and zomepirac sodium. Six months previously the patient had become 'deadly ill' after taking zomepirac (98 C). It is interesting to note that even a large multicenter study on 15,484 patients treated with zomepirac for 7 days (99 c) and a long-term (more than 1 year) multicenter study on 405 patients (100 c) failed to disclose any of the serious allergic reactions that led to the drug being withdrawn from the world market. A prescription eventmonitoring study, which followed the suspension of zomepirac license, also suggests that severe sensitivity reactions are rare (101c).

ANTHRANILIC ACID DERIVATIVES Glafenine (SED-1 O, 169; SEDA-8, 109) Allergy An unusual association of hemolysis, acute anuric renal insufficiency and cholestatic hepatitis has been reported in a patient who had previously taken glafenine without ill-effects.

Tolmetin (SED-I O, 165) Use in the elderly A retrospective analysis (96 R) on 847 patients 65 years of age or older, who participated in long-term con-

A 73-year-old woman, a few minutes ingesting 400 mg of glafenine for back presented with malaise, vomiting, lumbar and passing dark urine, followed by anuria.

after pain, pain, Two

94

Chapter 10 A. del Favero

days later she was hospitalized and the physical yokes enteritis and colitis in patients with examination showed fever (38~ and jaundice. no obvious predispositions ( 105 C, 106 c ). Laboratory investigations showed mild anemia with leukocytosis and eosinophilia, hyperbili- Menstrual disorders Mefenamic acid sigrubinemia (50% conjugated) and increased cre- nificantly relieves dysmenorrhea, but it can atinine, liver enzymes and prothrombin time. Circulating immune complexes and decreased C4 delay menstruation by several days. The were also found. The patient was treated with menstrual cycle returns to normal when it dialysis and supportive measures and improved is withdrawn. Other NSAID might also be expected to cause this side effect (107 C). gradually (102C). Since effective, less dangerous alternative anMgesic drugs are available, the wisdom of allowing the use of this compound with its record o f hypersensitivity reactions and liver and kidney toxicity to continue must yet again be questioned. Kidney Five cases of glafenine stones have been examined (103t;). Two different mechanisms could have been responsible for the glafenine in the stones. The first could be precipitation of free metabolites on a preexisting stone of different origin; the second, precipitation of glafenic acid and hydroxyglafenic acids excreted in excess amount due to an unidentified metabolic defect. Antrafenine This drug is structurally related to glafenine and the same adverse reaction profile should be expected (SED-10, 170). The French marketing authorization has been suspended for 1 year, apparently to allow the manufacturer to complete further toxicological studies and evaluate the relevance of colonic lesions found in longterm toxicology studies conducted on mice (104). Mefenamic acid (SED-I O, 168; SEDA-8, 109} Bowel Diarrhea, steatorrhea and loss of weight are well-recognized long-term mefenamic acid administration side effects (SEDA-1, 90;SEDA-2, 97). When properly investigated, patients suffering from these complaints may prove to have enteritis and/or colitis characterized by non-specific inflammatory alterations in the mucosa. A number of reports have claimed that many NSAID can cause worsening of, or complications in, large bowel diseases (SEDA-7, 105), but mefenamic acid apparently pro-

OXICAMS Piroxieam (SED-I O, 170; SEDA-8, 110J Fatalities and gastrointestinal reactions Concerns about the reported deaths of patients taking piroxicam and the pattern of adverse drug reactions reported, prompted the Federal German Health Authorities to hold a special hearing on oxicams in Berlin in September, 1983 (108r). The Authorities had reports on 102 deaths worldwide, 45 of them, according to the manufacturer, possibly related to piroxicam (109r). The pattern of drug-related deaths was as follows: gastrointestinal 61 (32 possibly drug-related), blood 14 (6), cardiovascular 8 (none), dermatological 6 (4), hepatic 4 (1), others 9 (none). The relative frequency of piroxicam adverse reactions from the main national monitoring centers has also been presented (Table 4) and, not surprisingly, (SEDA-6, 100) gastrointestinal side effects were generally the most frequently reported. However, at the hearing the main concern was related not to the frequency of unwanted gastrointestinal reactions as much as to their severity. In fact, a closer look at only the severe side effects shows an even more uniform pattern among countries, as data indicate that severe gastrointestinal reactions due to piroxicam are significantly more common than severe cutaneous reactions (110 r, 111 cR, 112 c, 113e), making the drug (where roughly comparable data exist, as in the United Kingdom) one of the NSAID which most frequently causes gastrointestinal bleeding and perforation (34 cR). As concomitant therapy (often gastrotoxic drugs) and excessive doses seem to be frequently involved in these reactions, they could probably be significantly reduced by taking more care to avoid potentially harmful interactions, and to use the lowest effective dose (no more than 20 mg/d).

Anti-inflammatory analgesics Chapter i 0

95

Table 4. Incidence of adverse reactions to piroxicam (in % of all reports) reported to some national monitoring eenters

Source

No. of adverse reactions

GI

Skin

B l o o d Renal

Hepatic

Edema

CNS Other

United Kingdom (CSM) Sweden (SLA) Norway (SLK) United States(FDA) WHO (Uppsala)

891 56 118 593 1626

41.2 28.6 86.4 22.5 39.1

13.9 39.3 7.6 46.2 20.7

1.8 . 3.9 1.9

1.8 . 5.7 0.7

5.7 14.3

13.4 7.1

.

. 4.0 1.0

. 5.7

15.8 7.2 5.9 17.7 14.1 16.8

*Modified from Ref. 108.

It is worth remembering the dose-related ulcerogenic potential and the extremely wide range of reported half-life of piroxicam. Kidney Chemotherapy-induced uric acid nephropathy was apparently precipitated in an elderly patient when piroxicam was added to his chemotherapeutic treatment. NSAID-provoked alterations in renal hemodynamics may have lead to a decrease in urate clearance at a time when there was elevated urate release due to the chemotherapy and so predisposing the patient to kidney failure ( 114 C).

Colon A possible piroxicam-induced ulcer in the ascending colon, which perforated and required hemicolectomy, has been described in a young female diagnosed as also having an acute duodenal ulcer (115c). Similar cases have been described with other NSAID (SEDA-7, 105).

Cardiovascular Fluid retention with resistance to diuretic treatment is a well-documented complication of all NSAID and piroxicam is no exception. It has been claimed to be an even more likely cause of fluid retention in the elderly and in patients with healthy hearts than other NSAID (110 c, 116c). However, the incidence of edema in large open studies varies greatly from 0.3% (117 c) to 8.2% (118c).

Hypersensitivity Serious allergic reactions seem to be rare with piroxicam but shock has been described in a patient on a second administration of the drug (119c).

Exacerbation of systemic lupus erythematosus In 2 patients an exacerbation of col-

lagen disease has been suspected, but the report requires confirmation (110c). Poisoning The main signs of intoxication after ingestion of 560 mg of piroxicam were altered consciousness, muscle twitchings and slight abnormality of liver function tests (120e).

Isoxicam This oxicam derivative, with a shorter half-life (30 h) than piroxicam, seems to have a similar pattern of toxicity to that of the parent compound, but clinical experience is very limited. The percentage of patients suffering from side effects varies in controlled trials from 7% to 30%; an analysis of their relative incidence indicates that gastrointestinal adverse reactions are the most frequently reported ( 6 4 - 7 9 % ) followed by skin reactions ( 5 - 1 1 % ) and central nervous system symptoms ( 9 - 1 1 % ) . Spontaneous reports to the Federal German Health Authorities seem to indicate a high percentage of skin reactions (51.2% of 84 reports) ( I 0 8 r, 109r). MISCELLANEOUS DRUGS

Orgotein Intra-articular injections of this enzyme preparation caused transient adverse reactions such as temperature rise and swelling, redness, heat and pain at the injection site in some patients (121e). The side effect was attributed to some impurity of the particular batch of orgotein preparation used, but similar subcutaneous reactions have been described before (SEDA-6, 100).

96

Chapter 10 A. del Favero

Phenazopyridine (SED-1 O, 154, 171,558) Suffhemoglobinemia Despite the fact that Van den Bergh and Reeves (122 c ) reported that phenazopyridine could cause a mild degree o f sulfhemoglobinemia as long ago as 1931, its propensity to provoke this condition, unlike methemoglobinemia, is not generally recognized. A new case of sulfhemoglobinemia and cyanosis following 26day administration of phenazopyridine to a 76-year-old patient and 2 further dubious cases can be traced in the literature (123 CR, 124 C, 125c). It is unlikely that phenazopyridine administration causes sufficient sulfhemoglobin production to endanger a patient's life, but once sulfhemoglobin has been formed it cannot, like methemoglobin, be converted to normal hemoglobin b y the administration o f methylene blue or any other known substance.

Timegadine Timegadine is a guanidine derivative which under experimental conditions inhibits the cyclo-oxygenase pathway o f arachidonic acid metabolism and also moderately inhibits lipoxygenase and phospholipase activity. Only a few clinical studies have been published and the side-effect profile of this drug is still largely unknown. Side effects reported by patients taking this drug are

skin rashes, epigastralgia, nausea, oral aphthous lesions, dizziness, vertigo, dysuria and sleep disturbances (126 c - 128c). Side effects attributed to the drug which most often lead to interruption of therapy are skin eruptions and abnormalities in liver enzymes. An acute interstitial pneumonitis with eosinophilia, 2 months after the beginning of treatment, has also been described (128c).

DRUGS USED IN THE TREATMENT O F GOUT Allopurinol (SED-I O, 1 72; SEDA-8, 111) Hypersensitivity Allopurinol can cause a life-threatening syndrome consistent with a diffuse vasculitis (SED-10, 172). Such reactions are almost exclusively found in patients with renal insufficiency and in patients receiving thiazide diuretics (SED-9, 155; SEDA-3, 96; SEDA-5, 108). The mechanism of this toxicity syndrome is not known, but an immune hypersensitivity reaction to allopurinol, or one of its metabolites, has been suggested. In fact, elevated serum concentrations of oxipurinol appear to correlate with the development of this toxicity syndrome (130CR). Oxipurinol is the main metabolite of allopurinol, has a long half-life, and accumulates in the b o d y when renal function is impaired. If allopurinol therapy is considered essential in a patient with renal insufficiency, the doses should be modified on the basis of the creatinine clearance, so as to maintain optimal therapeutic non-toxic concentrations of oxipurinol in the serum.

Eye A number of clinical observations have indicated a possible relationship between aUopurinol therapy and human cataracts. Experimental data show that allopurinol is capable of being p h o t o b o u n d to human lens proteins, suggesting a cataractogenic potential for this drug in some patients. A comb ination of long-term allopurinol therapy and exposure to high levels of ultraviolet radiation seem to be a prerequisite for allopurinol cataractogenesis ( 131CR). Colchicine {SED-I O, 174; SEDA-8, 111J

Pyritinol (pyrithioxine) (SED-9, 1 72, 416; SEDA-8, 111) The second case has been described of

hepatitis, this time cholestatic in nature, attributed to the use of pyrithioxine (129 c). The patient died of the sequelae of operation for supposed (but subsequently disproven) extrahepatic cholestasis.

Poisoning A study on hemodynamic changes induced by acute colchicine poisoning revealed complex features. As the outcome of colchicine poisoning largely depends on the occurrence o f shock (septic or cardiogenic), early monitoring of heinedynamics during acute colchicine poisoning is mandatory (132c).

Anti-inflammatory analgesics Chapter10 S u l f i n p y r a z o n e (SED-1 O, 1 74; SEDA-8, 111) K i d n e y T h e r e have b e e n m o r e r e p o r t s o f significant, b u t t r a n s i e n t , increases in s e r u m

97 c r e a t i n i n e levels in p a t i e n t s s u l f i n p y r a z o n e a few days ary bypass surgery ( 1 3 3 c ) .

treated with after coron-

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Anti-inflammatory analgesics

Chapter 10

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99

2 7, Suppl 1, 55. 93. Denis FR, De Beer JMM (1983) Clinical evaluation of suprofen in the treatment of elderly patients with pain of diverse etiology. Pharmacology, 27, Suppl 1, 81. 94. Honig WJ, Van Ochten J (1983) Eine klinisch kontrollierte Einzeldosis-Vergleichsstudie yon Suprofen und Diflunisal. Arzneim.-Forsch./ Drug Research, 33, 1331. 95. Arnold JD, Berger AE (1983) Comparison of fecal blood loss after use of aspirin and suprofen. Pharmacology, 27, Suppl 1, 14. 96. O'Brien WM (1983) Long-term efficacy and safety of tolmetin sodium in treatment of geriatric patients with rheumatoid arthritis and osteoarthritis: a retrospective study. J. Clin. Pharmacol., 23, 309. 97. Olsen KM, Thompson GD, Sullivan MD (1984) Possible agranulocytosis secondary to zomepirac. Clin. Pharmacol., 3, 85. 98. Patmas MA, Wilborn SL, Sbankel SW (1984) Acute multisystem toxicity associated with the use of nonsteroidal anti-inflammatory drugs. Arch. Intern. Med., 144, 519. 99. Steele CE, Jefferson WL (1983) A multicentre study of zomepirac in painful conditions: an analysis of clinical data for 15,484 patients. Curt. Med. Res. Opin., 8, 382. 100. Honig S (1983) Long-term therapy for the pain of osteoarthritis: a comparison of zomepirac sodium and aspirin. J. Clin. PharmacoL, 23, 494. 101. Inman WHW, Rawson NSB (1983) Zomepirac and cardiovascular deaths. Lancet, 2, 908. 102. Pinta P, Offenstadt G, Barbare JC et al (1983) H~molyse anurie et h~patite apr~s prise de glaf~nine. Th~rapie, 38, 701. 103. Daudon M, Protat MF, Reveillaud RJ (1983) Toxicit~ r~nale de la glaf~nine chez l'homme: calculs r~naux et insuffisance r~nale aigu~. Ann. Biol. Clin., 41,105. 104. Anonymous (1984) Stakane suspended in France. Scrip, 919, 15. 105. Hall RI, Petty AH, Cobden I e t al (1983) Enteritis and colitis associated with mefenamic acid. Br. Med. J., 287, 1182. 106. Phillips MS, Fehilly B, Stewart S et al (1983) Enteritis and colitis associated with mefenamic acid. Br. Med. J., 287, 1626. 107. Halbert DR (1983) Menstrual delay and dysfunctional uterine bleeding associated with antiprostaglandin therapy for dysmenorrhea. J. Reprod. Med., 28, 592. 108. Anonymous (1983) Oxicam hearing in FRG. Scrip, 836, 1. 109. Anonymous (1983) Gute Medikamente unsachgem/isser Gebrauch? Mi~nch. Med. Wochenschr., 125, 18. 110. Anonymous (1982) Piroxicam ADRs in Sweden analysed. Scrip, 742, 4. 111. Laake K, Kjeldaas L, Borchgrevink CF (1984) Side-effects of piroxicam (Feldene~). Acta Med. Scand., 215, 81.

100

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112. Phelip X (1984) La tol&ance du Feld~ne | pyridine (Pyridium | administration. Ohio State (piroxicam): bilan de trois 6tudes coop6ratives Med. J., 79, 796. concernant 48353 observations. Gaz. M~d., 91, 124. Lim TP, Lower D (1970) 'Enterogenous' 93: cyanosis. Am. Rev. Resp. Dis., 101,419. 113. Marty C (1984) Feld~ne et rhumatismes 125. Gabor EP, Lowenstein L, De Leeuw NK extra-articulaires: r6sultats d'une 6tude multi(1964) Hemolytic anemia induced by phenylazocentrique sur 5402 malades. Gaz. M~d., 91, 91. diamino-pyridine (pyridium). Can. Med. Assoc. 114. Pulliam JP, Mundis RJ, Muther RS (1984) J., 91,756. Piroxicam (Feldene) predisposes to chemother- 126. Caruso I, Fumagalli M, Montrone F et al apy-induced acute uric acid nephropathy. (1983) Timegadine: long-term open study in Arthritis Rheum., 27, 116. rheumatoid arthritis. Clin. Rheumatol., 2, 363. 115. Irving AD, Sadek SA (1983) Major gastro- 127. Berry H, Bloom B, Fernandes L e t al (1983) intestinal ulceration in association with piroxComparison of timegadine and naproxen in icam therapy. J. R. CoIL Surg. Edinburgh, 28, rheumatoid arthritis: a placebo controlled 121. trial. Clin. Rheumatol., 2, 357. 116. Fowler RN, Arnold KG (1983) Non-steroi- 128. Mbuyi-Muamba JM, Dequeker J (1983) dal analgesic and anti-inflammatory agents. A comparative trial of timegadine and d-penicilBr. Med. J., 287, 835. lamine in rheumatoid arthritis. Clin. RheumatoL, 117. Alvart R (1983) Multicentre trial of piroxi2, 369. cam in ambulant rheumatology. Eur. J. Rheuma. 129. Gouet D, Alcalay M, Briaud M e t al (1983) tol. lnflam., 6, 99. H6patite induite par la pyrithioxine: toxicit~ 118. Langloh N (1983) Experience with piroxidirecte ou idiosyncrasie? Rev. Rhum.. 50, 167. cam in general practice; results of a German mul- 130. Hande KR, Noone RM, Stone WJ (1984) ticenter study on 18,888 patients. Eur. J. RheuSevere allopurinol toxicity. Am. J. Med., 76, matol. Inflam., 6, 84. 47. 119. Commandre F (1983) Double blind com- 131. Lerman S, Megaw J, Fraunfelder FT (1984) parative study of piroxicam and indomethacin Further studies on allopurinol therapy and in acute locomotor affections linked with sports human cataractogenesis. Am. J. Ophthalmol., activity. Eur. J. Rheumatol. lnflarrt, 6, 113. 97, 205. 120. Lo GCC, Chan JYW (1983) Piroxicam pois- 132. Sauder P, Kopferschmitt J, Jaeger A et al oning. Br. Med. J., 287, 7~8. (1983) Haemodynamic studies in eight cases 121. Lund-Olesen K, Menander-Huber KB (1983) of acute cholchicine poisoning. Hum. Toxicol., Intra-articular orgotein therapy in osteoarthritis 2, 169. of the knee. Arzneim.-Forsch./Drug Res., 33, [133. Boelaert J, Robbens E, Lijnen P (1983) 1199. Renal dysfunction due to sulphinpyrazone after 122. Van den Bergh AAH, Revers FE (1931) coronary bypass surgery: a prospective doubleSulfh/imoglobinamie nach Gebrauch yon Pyriblind study. In: Proceedings, Symposium on dium. Dtsch. Med. Ir 57, 706. 'Myocardial Revascularizalion in Acute Condi123. Smith PF, Palermo GA, Vester JW (1983) tions ', Brussels, 1983. Sulfhemoglobinemia associated with phenazo-