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

A. Del Favero

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

COMPARATIVE ADVERSE REACTION RATES In a paper presented at a meeting in Verona in 1982 Weber, of the British Department of Health and Social Security (1) presented an instructive analysis of the relative incidence of adverse reaction reports to a range of non-steroidal anti-inflammatory drugs marketed in the United Kingdom. There is clearly some risk in analyzing material such as this, particularly since, as Weber himself points out, the rate of spontaneous adverse reaction reporting tends to rise after a drug has been on the market for a little while, and then to fall progressively: the incidence o f reports may thus depend in part on the age o f the drug. In addition, there are well-known factors which can distort spontaneous reporting. Nevertheless, the results of the analysis are striking, since they point to a variance in the incidence of some major effects as between different drugs, which is largely in accordance with what individual clinical studies (which all too rarely compare more than two drugs in the same population) would lead one to expect if a broad-ranging comparison between non-steroidal anti-inflammatory drugs were performed. According to Weber's findings, the numbers of prescriptions issued for every adverse reaction report received are approximately as indicated in Table 1 below. Although, when individual reactions are similarly compared, the ranking order can differ somewhat, there is a surprising degree of consistency, with the highest incidence of adverse effects tending to appear with feprazone, fenclofenac and benoxaprofen (the latter having since been withdrawn from sale) and the lowest incidence of various

effects being seen with piroxicam. The full paper, which is not yet in print, deserves careful study. GASTROINTESTINAL COMPLICATIONS OF NON-STEROIDAL ANTIINFLAMMATORY DRUGS (NSAID)

Prevention of gastric complications New data have been published on the mechanisms of gastric toxicity of NSAID and on the possibilities of a pharmacological protection against this side effect (2R). In a double-blind cross-over randomized placebocontrolled study on 1 1 rheumatic patients Kollberg et al. (3 C) confirmed that gastrointestinal bleeding after indomethacin can be reduced by concomitant administration of lower than usual doses of PGE2 (0.33 /ag three times daily) or 15-R-15 MePGEz (40 /zg, three times daily). In this limited study, prostaglandins neither caused side effects nor interfered with the activity of the antiinflammatory drug. However, long-term trials on larger series of patients would be required to evaluate the clinical value of PGE2 in reducing gastric damage. Contrasting opinions have been expressed on the real utility of H2-inhibitors in the control of drug-induced gastric intolerance during anti-inflammatory treatment. Positive results have been reported with eimetidine and ranitidine (4 c, 5c; 6c), but not all investigators have found the same beneficial effects (7c). Recently two cases of perforation have been described in two patients with previous duodenal ulcer who continued to receive indomethacin treatment while on cimetidine, despite the fact that the dyspeptic symptoms were rapidly relieved by

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

Table 1. Total adverse reactions. Ranked com. parisons

Drug

Feprazone Fenclofenac Benoxaprofen Diclofenac Azapropazone Flurbiprofen Sulindac Diflunisal Piroxicam

Ranks

1 2 3 ~ 4 J ~ 5

J

6 7

Approximate number of prescriptions for one ADR report 200 280 400 1200 1700 2300 3000

the anti-ulcer therapy (8c). Physicians must also be aware of the fact that cimetidine may lead to a significant increase in indomethacin absorption and, in consequence, to higher than usual blood levels and, possibly, to more adverse reactions. Experimental studies have also shown that endogenous production of pro-inflammatory endoperoxides may play a role in the mechanism of gastric damage by certain NSAID, and that appropriate doses of antioxidants with radical scavenging properties, such as paracetamol, can reduce NSAIDinduced gastric damage (2R). Sodium salicylate is another hydroxyl radical scavenger, much more potent than benzoic acid, a classical scavenger (9). However, the view that antioxidants may become a useful tool to reduce the gastrotoxicity of some NSAID as exogenously administered prostaglandins apparently do, must be confirmed by further studies. Intestinal disorders Several clinical reports have indicated that orally administered NSAID may cause deterioration or complications in large b o w e l diseases. A relapse was precipitated in patients with ulcerative protocolitis or Crohn's disease, using indomethacin, ibuprofen or flurbiprofen (10 Cr, l lCr). Indomethacin and naproxen induced perforation and/or massive bleeding in patients with diverticular disease of the colon (1 1Cr, 12 C ). Both serious adverse effects may appear as little as four to five days after starting the therapy. The mechanism for the activation of inflammatory disease and the perforation of colonic diverticula could be related to a local prostaglandin deficiency induced by orally

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administered NSAID. This hypothesis is consistent with the knowledge that PGs exert a cytoprotective effect both in the large bowel and the upper gastrointestinal tract (9, 13, 14, 15). However, other mechanisms, such as local action by the unabsorbed drug or accumulation of lipo-oxygenase products, cannot be excluded. Two cases reported by Gustavsson and Nilsson from Sweden suggest that NSAID can cause severe intestinal complications in patients with no clear predisposition (16Or). Two patients, both treated for about three weeks with anti-inflammatory drugs (azapropazone and naproxen + indomethacin, respectively), were admitted to a surgical department because of massive colorectal bleeding. An emergency subtotal colectomy was performed on one patient who succumbed two weeks later after a second laparotomy had revealed an anastomotic leakage. The other patient died of peritonitis following perforation of the sigmoid colon. Both colon specimens showed a similar histological picture with extensive unspecific ulcerations. The connection between the two cases was suggested to be the preceding antiinflammatory treatment. Idiosyncratic reactions to NSAID Anaphylactic or anaphylactic-like reactions to NSAID are probably relatively rare events but they are relatively more frequent with some of these derivatives. Recently cases of anaphylaxis or shock associated with their use and reported to the US FDA's Division of Drug Experience have been reviewed (17CR). 131 notified cases were attributable to these drugs: 36.2% to tolmetin, 13.0% to ibuprofen, 10.7% to zomepirac, 10.0% to indomethacin and 9.1% to sulindac. Aspirin (9.1%), fenopro fen, phenylbutazone, naproxen, sulfinpyrazone, mefenamic acid and meclofenamate were less frequently blamed. Bearing in mind that such figures are always distorted by the fact that some of these drugs are much more widely used than others, it would seem that two structurally related drugs, tolmetin and zomepirac, account for a very high proportion of these effects. In 46% of recorded cases, patients had previously been exposed to the same drug without experiencing any such effect, suggesting a sensitizing mechanism; this percentage rises to 72% for tolmetin. In a smaller n u m b e r of patients, reactions had already occurred with previous

106 exposure to the same as well as to other NSAID. The pathogenic mechanisms responsible for acute idiosyncratic reactions to NSAID are probably various and the clinical picture may vary with the drug used and according to the patient's characteristics, from urticaria and angioedema to serious bronchoconstriction and, in some cases, anaphylactic shock. Subjects with previous reactions to NSAID and with SLE disease are at particular risk (SED 9, 141). Idiosyncratic reactions to pyrazolone drugs can be divided into two groups (18c). The first group includes patients who develop bronchoconstriction when aspirin, noramidopyrine, aminophenazone and other pyrazole drugs are used; the second are those patients who tolerate aspirin and a number of other cyclooxygenase inhibitors well, but present anaphylactic shock and/or urticaria when noramidopyrine or aminophenazone are taken. There is some evidence that the pathogenic mechanisms responsible for these reactions involve inhibition of cyclo-oxygenase in the first group and an allergic reaction in the second. This two-group division is of practical importance because all pyrazolone derivatives, and probably other NSAID, are contraindicated in patients sensitive to aspirin, while in the second group intolerance is restricted to the two closely related drugs amidopyrine and noramidopyrine.

Non-steroidal anti-inflammatory drugs in pregnancy In an address in Japan, Monma has argued that non-steroidal anti-inflammatory drugs adversely affect the maturation of circulation in the fetus when given to a pregnant woman during the latter part of the pregnancy. The animal studies which he cites would point to particularly strong effects in this respect when using diclofenac, fenbufen, mefenamic acid, ibuprofen, ketoprofen, naproxen, flurbiprofen and tolmetin. There would be less effect with flufenamic acid, indomethacin, sulindac or phenylbutazone. Little effect would be expected with aspirin, dipyrone, acetaminophen, phenacetin, aminopyrine or tiaramide; other NSAID would have no effect (19or). It is difficult to follow the line of proof in this case or to identify any gradation of pharmacological properties which might

A. Del Favero

be expected to run parallel to such a classification; Monma himself suggests that the effect is most marked with those compounds which are acid in nature. Unless further evidence becomes available it would seem wise to regard these statements with much reserve.

NSAID and benign esophageal stricture Heller et al. (20 cR) obtained drug histories from 76 patients undergoing treatment for benign esophageal stricture. Six had consumed drugs known t o c a u s e esophageal ulceration (emepronium bromide or potassium preparations). Of tile remaining 70, 22 had regularly taken a non-steroidal anti-inflammatory drug before the onset of dysphagia, as compared with 10 patients in a healthy control group of the same size. These authors feel that NSAID may have a causative role in the formation of esophageal stricture in patients with gastro-esophageal reflux, for whom they should be prescribed with caution.

NSAID and hepatotoxicity As pointed out in the section of this chapter dealing with benoxaprofen, hepatotoxicity has not generally been regarded as a major problem with NSAID, benoxaprofen apparently being an unfavourable exception to this generalization. It is noteworthy, however, that an influential body such as the US FDA's arthritis advisory committee has recently found it necessary to debate the issue in the light of some recent events. The committee had heard presentations on severe hepatotoxicity problems arising during clinical trials with amfenac sodium, pirprofen and isoxepac. While accepting that potentially serious hepatotoxic effects were an infrequent event, the committee expressed the view that they could occur across nearly the whole class of NSAID, with the possible exception of meclofenamic acid. Special warnings were proposed for the labelling of drugs with which serious hepatotoxicity had been observed (2 l r). In this connection, a very recent report by Sherlock et al. on acute hepatitis apparently resulting from use of diclofenac may be noted (22c); the reaction was apparently compatible with idiosyncratic drug-induced hepatitis of the 'metabolic aberration' type. Another case of 'diclofenac hepatitis' is described elsewhere in this chapter. The

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout reader is referred to the remaining sections dealing with individual drugs (including indomethacin and sulindac) for further cases of apparent liver damage of one type or another. PYRAZOLONE DERIVATIVES Noramidopyrine (SED 9, 840; SEDA-5,

96; SEDA-6, 92) Although the absolute degree of risk connected with the use of noramidopyrine is still hotly debated (23) this drug continues to be widely used. In a survey among general practitioners in Bangladesh, dipyrone was held responsible for 23% of 141 diagnosed agranulocytosis and pancytopenia cases (24c). A case of agranulocytosis associated with rectal necrosis, which required operation, has been described in a 36-year-old woman who was prescribed noramidopyrine for influenza (25Cr). Two hemolytic crises with acute renal failure occurred in a 20year-old hemophilic patient after two single doses of dipyrone (26Cr). The clinical and serological findings suggest that hemolysis resulted from the absorption of drug-antibody immune complexes by the cell membrane.

Propyphenazone A serious case of generalized urticaria with angioneurotic edema, which occurred

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been reported (32 c , 33 C, 34c). Analysis of these reports shows that phenylbutazone can cause three types of hepatic injury, each of which may have a separate pathogenic mechanism: (1) Acute hepatic necrosis is found in poisoning, apparently as the result of a dose-related intrinsic hepatotoxicity of the drug or its metabolites. (2) Mild hepatotoxicity with or without cholestasis, accompanied by granulomas, sometimes also found in extrahepatic sites and varying degrees of steatosis, are the result of a hypersensitivity reaction and, to a lesser extent, also of concurrent hepatotoxic effects. (3) Both factors are probably involved in various types of more severe hepatic cellular damage, generally with cholestasis and without granulomas, but the drug's intrinsic toxic effects play a more important role than does hypersensitivity in these cases. Gastrointestinal Phenylbutazone has been held responsible for a gastric ulcer complicated by a gastrocolic fistula (35c), but such a relationship is difficult to prove in the individual case though it would not be unexpected. Skin It is well known that oxyphenbutazone and phenylbutazone may cross-react. Nevertheless, a case of a patient who exhibited a fixed skin eruption at the same site after the injection of two unrelated drugs, oxyphenbutazone and tetracycline, is worthy of note (36c).

immediately after ingestion of this drug and led to emergency admission to hospital, has been recorded. The patient had a similar reaction on two other occasions as well as during epicutaneous testing with this pyrazole derivative (27c).

Acute poisoning In a patient who ingested 4 g of phenylbutazone, substantial drug removal was achieved by column hemoperfusion without serious complications (34c).

Sulfenazone

Azapropazone

Since the first report appeared in the literature (SEDA-5, 100), other cases of therapy-related benign intracranial hypertension have been described in children on this drug (28 c, 29 c, 30c).

Interactions This drug, which is structurally related to phenylbutazone, exhibits the same pattern of interactions as the parent compound. A serious hypoglycemic reaction in a tolbutamide-treated diabetic patient followed azapropazone administration. The interaction seems to be due to the inhibition of microsomal hepatic metabolism of tolbutamide to hydroxytolbutamide by the drug. Azapropazone should therefore be used with great caution in diabetics treated with tolbutamide and other sulphonylureas (37c). Two cases of phenytoin toxicity also

PHENYLBUTAZONE AND RELATED COMPOUNDS Phenylbutazone (SED 9; 142; SEDA-5, 100;

SEDA-6, 93)

Liver Phenylbutazone hepatotoxicity has been reviewed (31 cR) and new cases have

108 occurred in patients receiving maintenance treatment with this antiepileptic drug when azapropazone was added (38 r 39c). Feprazone (SEDA-4, 64; SEDA-6, 93) A drug-induced immune complex-mediated hemolytic anemia with severe thrombocytopenia has been reported with feprazone (40 C). Six other reports documenting thrombocytopenia associated with the use of this drug have been received by the UK Commission on Safety of Medicines, and two cases were found in a monitored release study on 343 patients with miscellaneous rheumatologieal conditions (41 c). Suxibuzone (SED 9, 145) The Japanese Ministry o f Health and Welfare has ordered that the production o f this drug be suspended, and in Italy its registration has been postponed until its carcinogenic potential can be better evaluated (42).

INDOMETHACIN AND RELATED COMPOUNDS Indomethaein (SED 9, 147; SEDA-5, 101; SEDA-6, 93) Dangers in premature infants with patent ductus arteriosus Conflicting data continue to be presented on the potential toxicity of indomethacin in the treatment of patent ductus arteriosus in infants. Some reports point to a high incidence of serious gastrointestinal central nervous system and ocular complications (43 C, 44c), while others (45 c, 46 c) find no differences in side effects between treated and control groups of patients. A large cooperative study on this problem has recently been completed in the USA, but the results have not yet been published (47). A recent report points to hypoglycemia as a complication (48c). Cardiovascular effects I.e. administration of indomethacin in patients with coronary artery disease caused a significant rise in both mean systemic arterial blood pressure and myocardial oxygen demand, a fall in coronary blood flow and a significant increase in coronary vascular resistance, probably due to coronary vasoconstriction

A. Del Favero (49C). However, despite this impaired coronary blood flow, none of the patients treated had evidence o f myocardial ischemia. The fact that its use is now recommended in the treatment of biliary pain (50), and that it appears to be used on an increasing scale in other conditions in the elderly, means that the results of this study may be of considerable practical importance. However, O'Brien has pointed out that clinical experience and the literature provide little or no evidence that indomethacin is indeed precipitating angina or myocardial infarction, even in the elderly (51 ). Liver A fatal case of acute hepatocellular necrosis, in a 40-year-old patient with Still's disease, probably related to the drug, has been described. However, the patient was also concurrently taking aminophenazone (52C), Kidneys The deleterious effects of the drug on renal function have been used as a therapeutic tool to obtain medical nephrectomy. In one case it caused definitive suppression of renal function with anuria (which required peritoneal dialysis) in a patient with massive proteinuria, refractory edema and renal failure (53e). Indomethacin can significantly increase the urinary excretion of both zinc and calcium, but the clinical relevance of this finding is not known (54, 55). Pregnancy and labor Further reports of serious adverse neonatal effects (pulmonary hypertension with persistence of fetal circulation and ultimately death) following treatment o f preterm labor with this drug, support the contention that the possible hazards associated with the use of indomethacin during pregnancy far outweigh any theoretical advantage it may have (SEDA-5, 101 ; 56c). Skin It has been claimed that indomethacin exacerbates psoriasis when given orally or topically for a short period of time ( 1 - 4 weeks) (57c), but this finding contrasts with other reports which state that indomethacin has no deleterious effects on the course of the disease. Interactions As both indomethacin and other NSAID can cause salt and water retention they may antagonize the effects of diuretics (SEDA-4, 65; 58 c) thereby exacer-

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout bating cardiac failure (59r Some NSAID (i.e. flurbiprofen and sulindac) seem to be less likely to provoke such an interaction (59 e, 60 c, 61e), but these data require confirmation. Clometacin

(SEDA-4, 66; SEDA-5, 102;

SEDA-6, 94) New cases of hepatic damage have been reported from France, where use of this drug is widespread. Nine cases (four of acute and five of chronic active hepatitis, one fatal) were published in 1981; 23 others, some of them already published, have been reported to the Centre Hospitalier de Pharmacovigilance over a period of two years (62CR). Jaundice, hepatomegaly, fever and blood eosinophilia are the most frequent clinical findings, while the histological pattern of lesions varies from acute hepatitis to chronic active hepatitis with or without granulomas and cirrhosis. Evidence is accumulating that an immunoallergic mechanism may be operating in most instances, and that in order to reduce the risk of persistent progressive liver damage, administration of the drug must be interrupted promptly. The risks involved in long-term or repeated use of clometacin should be re-assessed. Oxamethacin (SEDA-4, 66) The side effect profile of this drug is similar to that of iudomethacin. In a multicenter study on 771 patients treated with 2 0 0 - 6 0 0 mg/day for an average of 13 days, side effects were noted in 17% of patients and led to discontinuation of treatment in 8%. 60% of these side effects were gastrointestinal (dyspepsia, gastralgia, nausea, pyrosis, and one case of melena) and 31% central nervous system (particularly headache and dizziness) (63c). Sulindac

Aseptic meningitis Like other NSAID, sulindac can cause aseptic meningitis in patients with SLE (64c). Blood A second case of agranulocytosis, with rapid and complete recovery after drug withdrawal has been described (65c). It may be of interest to note that hematological depression occurred in both patients, neither of whom had previously been ex-

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posed to this drug, after only two weeks of therapy with sulindac. Two new cases of thrombocytopenia were described (66 C, 67c). As in one case mentioned earlier (SEDA-6, 94) the first course of sulindac was completed without any problem but thrombocytopenia and purpura developed shortly after the reinstitution of the drug some weeks later. This and the fact that platelet count increased spontaneously after the drug was discontinued whilst the number of megakaryocytes was normal at marrow biopsy, suggest that platelets are destroyed by an immune mechanism in the presence of sulindac or its metabolite. Liver Abdominal pain, nausea, high temperature with chilis, icterus, raised liver enzymes and tender hepatomegaly developed in a 12-year-old girl after six weeks of treatment with sulindac. Rapid improvement occurred without therapy after discontinuation of the drug. A single 200 mg tablet of sulindac caused recurrence of the same signs and symptoms within 24 hours (68c). The case was presumably a toxic hepatitis. Pancreas (SEDA-5, 102 ; SEDA-6, 95} A n e w case of pancreatitis, which recurred on readministration of the drug, has been described in a patient treated with sulindac for 23 days (69c). Pneumonitis Pulmonary infiltrates have been described as a part of the hypersensitivity reaction during treatment with sulindac (SEDA-6, 94) and a well-documented new case has now been added (70c). Skin A pernio-like reaction (purple discoloration, painful swelling, red papules and desquamation of the distal aspects of several toes) occurred in a patient 10 days after starting sulindac therapy. The lesions resolved over a period of two weeks after drug discontinuation, but recurred after resumption of sulindac (71 c).

ARYL ALKANOIC ACID DERIVATIVES AND RELATED COMPOUNDS

Benoxaprofen (SED 9,

149; SEDA-4, 68; SEDA-5, 103; SEDA-6, 95} A t the beginning of August, 1982, The British Committee on Safety o f Medicines

110 announced that the Licensing Authority had suspended with immediate e f f e c t the product licences for compounds containing benoxaprofen on grounds o f safety. The suspension was initially in force f o r a period o f three months. Similar measures were taken simultaneously in Denmark and the manufacturer decided to withdraw the drug worldwide. The British suspension was issued on the basis o f over 3500 reports o f adverse reactions associated with this drug. Sixty-one cases were fatal, predominantly in the elderly. Serious adverse effects o f the drug affected various organ systems, particularly the gastrointestinal tract, the liver and bone marrow, skin, eyes and nails (72). It must be noted, however, that the data on the incidence o f adverse reactions attributable to this drug vary greatly (73 C, 74 c - 76c). In fact, while in two large comparative studies the side effects profile o f benoxaprofen was at least as favorable as those o f comparative drugs (73C), recently published reports pointed to the high incidence and seriousness o f its side effects (77 C, 78 c, 79C-83C).

Integumentary system Skin rashes, phototoxicity and onycholysis were noted in early trials (SEDA-4, 68; SEDA-5, 103) and soon it became clear that cutaneous reactions represented a serious problem (SEDA-6, 95). Halsey et al. (77 C} treated 300 patients with daily doses o f 600 mg f o r an average o f 6.4 months and found that 196 patients (65.3%) reported one or more side effects f o r a total o f 259 adverse reactions, o f which 180 (69.5%) were cutaneous, the commonest being photosensitivity (86 patients) which led to withdrawal o f benoxaprofen in 26 (30.2%} cases. Onycholysis was observed in 38 patients (12.6%), while multiple subepidermal cysts (milia) were noted in 16. The wide spectrum o f cutaneous side effects is now better understood and is here reviewed. Phototoxic reactions Benoxaprofen is a potent photosensitizer. Photosensitization is due to a phototoxic reaction and some evidence suggests that the photoreactive molecule is the drug itself rather than a metabolite (84). The reaction is due to both ultraviolet A and B rays, wavelengths between 3 1 0 - 3 3 0 nm being the most likely to produce this effect (78, 85). Reaction is dominated by a reddening o f the skin accompanied by a sensation o f severe burning and itching and, sometimes, the for-

A. Del Favero mation o f weals. Only on rare occasions does severe bullous dermatitis occur (86c}. Photoreactions are related to the intensity o f sunlight and may appear after short exposure to sunlight or to outdoor daylight, within two days o f taking the drug. The reaction, which is transient and dose related, can be minimized by the use o f protective clothing and/or sunscreen lotions, but in some patients therapy has to be withdrawn. Rashes As f o r other N S A I D this type o f reaction is often mild a n d transient and unaffected by exposure to the sun. Nail dystrophies Different types o f nail changes have been described, all o f which suggest that benoxaprofen, or one o f its metabolites, can cause more widespread disruption o f nail growth than previously thought. Onycholysis appears as a pale area where the nail is normally pink and it is due to a gradual separation o f the nail from the nail bed. Normally it does not affect more than half o f the nail, finger nails being more often affected than toe nails, and may be only in part related to exposure to ultraviolet light. Onycholysis is usually painless and only becomes evident after weeks or months o f therapy, so that it often goes unnoticed by patients. It disappears slowly when the drug is stopped. Increased nail growth, warping and increased ridging o f the nail plate and koilonychia complete the spectrum o f described nail changes (77 C, 8 7 c - 9 2 c ) , although these are much less frequent reactions with respect to onycholysis. Hypertrichosis has only occasionally been reported (77 C, 89c). It is generally preceded by photosensitivity and new hairs grow on sites exposed to sun. Reversal o f malepattern baldness has been noted in two patients (89c). Milia Multiple subepidermal cysts on sun-exposed skin (face and limbs) were observed in 5.3% o f Halsey's patients (77 C} and others have reported the same reaction (78 c, 88 c, 93c). The cysts develop gradually after 3 - 1 8 months o f benoxaprofen therapy before they become noticeable and they tend to resolve slowly after discontinuation o f the drug. There is a frequent association with photosensitivity and cysts seem more florid in patients on corticosteroid treatment (77 C, 88e). Four cases each o f erythema multiforme and Stevens-Johnson syndrome (SEDA-6, 95; 78 e) have been reported. In some cases

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout benoxaprofen was the sole treatment given and the reactions appeared after a variable time lag o f a f e w days to several weeks after the start o f therapy. All patients recovered uneventfully. Two lethal cases o f toxic epidermal neerolysis, with pancytopenia in one patient (78c), have also been reported (94c). Finally it may be o f interest to note that benoxapro.fen has been found to be apparently useful in treating certain dermatological problems, such as nodular acne, prurigo (78 c, 95 c) and intractable psoriasis (96c).

Gastrointestinal When benoxaprofen was first marketed there was some hope, due to its weaker inhibitory activity on prostaglandin biosynthesis, that it would be less likely to cause serious gastric disturbances than other NSAID. This view was supported by the results o f studies which showed that the amount o f gastrointestinal microbleeding, as measured by 51Cr-labeled erythrocytes technique, induced by benoxaprofen was much less pronounced than with more potent prostaglandin-synthetase inhibitors (7, 97). However, in clinical trials, benoxapro fen was no better tolerated than other N S A I D (SEDA-6, 95) and the gastrointestinal side effects were the most frequently reported, although drug-related peptic ulcer was rare, the incidence being calculated at one per 200 patient-years (75~. The elderly are more susceptible to gastrointestinal complications, and, in fact, daily doses o f 600 mg are associated with an unacceptab~ high incidence o f gastric side effects (77 ~, 9 7aC). Cases o f serious gastrointestinal bleeding, peptic ulceration and perforation have been reported (98c). Liver Liver damage is an uncommon finding with NSAID in general and therefore it is surprising to see that 14 cases o f cholestatic jaundice, most o f them with fatal outcome, were described in British patients taking benoxaprofen during the first half o f 1982 (79-83C), the number apparently increasing to more than 60 by the time the license was suspended. However, according to Inman's statement (72), jaundice was identified as a problem in a pilot study ofpostmarketing surveillance and reported as an 'event' in eight out o f the 6000 patients in the study, but a subsequent follow-up, by eliminating patients who had not taken the drug or where there were other obvious reasons for

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the event, left only three rather doubtful cases where the drug might have been responsible. All but three patients were elderly (over 70 years old) and took benoxaprofen for a mean o f 489 months before symptoms o f hepatic dysfunction appeared. Clinical findings are similar, jaundice, associated with raised transaminase and alkaline phosphatase being the common finding, while renal insufficiency is present in most patients. Pathological findings are characterized by centrilobular or canalicular type o f intrahepatic cholestasis, without extensive liver cell necrosis (except in two cases; 98C), sometimes associated with mild inflammatory reaction and acute tubular necrosis o f the kidneys, which, in two cases, was judged secondary to the liver dysfunction. Although the pathological and biochemical findings in most o f these patients were not consistent with major hepatocellular damage, the outcome was fatal in 11 subjects, in two o f which for reasons unrelated to the drug therapy. Therefore the mechanism by which benoxaprofen induced liver and renal damage and so serious outcome is not clear. It should be remembered, however, that benoxaprofen has a very long plasma half-life ( 3 0 - 3 5 hr} especially in the elderly, where it exceeds 100 hours, and that is partly excreted in the bile and partly in the urine as the glycuronide conjugate. I f an accumulation occurs in certain patients (e.g. elderly) the drug may directly damage the liver and the kidneys and thereby lead to further accumulation and eventually fatal toxicity (79C). Unfortunately there are no data on plasma levels o f benoxaprofen in these patients to support this view.

Kidney lsolated cases o f transitory reduction o f glomerular filtration rate (99c), reversible renal insufficiency (lOOC), associated with multisystem disease and LE cells in the peripheral circulation, nephrotic syndrome without renal failure (1016') and renal papillary necrosis (102 C) have been reported. Other adverse reactions (SEDA-6, 95) including isolated thrombocytopenia (103 c) and photophobia (104 c) have also been described, but none was so unusual or troublesome as those already described. In conclusion, the side effect profile o f benoxapro fen is characterized by the cutaneous and hepatic reactions, and there seems to be no doubt that the elderly are at higher risk for

112 serious complications. In this respect it is unique among the NSAID. The decision o f the UK Committee on the Safety o f Medicine to suspend the produce license has been criticized both as a tardy initiative as well as an over-zealous reaction to a cluster o f adverse reactions recently reported, which has deprived patients o f a useful drug. It is premature to say where the truth lies but it can be said that the decision seems, on the basis o f present evidence, well founded, since a great number o f alternative N S A I D are available for therapy, and only i f benoxapro fen could be shown to have unique compensating benefits (e.g. disease-modifying properties in rheumatoid arthritis, as has been suggested) would its re-introduction, for the treatment o f selected patients, seem justified. There are various lessons to be learnt from the benoxaprofen experiences (105R). One is, perhaps, that where a drug is likely to be used largely in the elderly it should be most carefully studied with respect to kinetics and safety in that group before being widely used, a point which has been made earlier by the World Health Organization (106R ). Diclofenae (SED 9, 152; SEDA-5, 103; SEDA-6, 96) Intramuscular injection o f diclofenac was significantly more effective and had fewer side effects than administration of a narcotic ('Spasmofen') in the treatment of renal colic (107c). Rectal administration of 1 0 0 - 2 0 0 mg/day for 5 - 1 5 days in a multicenter open study on 1003 patients with various rheumatic disorders, caused side effects in 15.6% of them. Gastrointestinal adverse reactions were the most frequent (13.5% of patients), while skin rashes, edema and central nervous system disorders were each reported by less than 1% of patients. Treatment had to be discontinued due to side effects, most of them gastrointestinal, in 0.8% of patients (108c). Liver Abnormalities in serum fiver function tests of unknown significance m a y develop during treatment with this drug (SEDA-5, 103; 109 c, 110e), but liver damage has only recently been described. A case of bioptieally proven acute ieteric hepatitis, which occurred after five months of

A. Del Favero theravv with diclofenac and recurred on rechallenge with the drug has been reported (11 lC). Recovery was prompt and complete after drug withdrawal. Skin A serious buUous dermatosis, which recurred after reintroduction of the drug, with linear IgA deposits along the basal membrane in both lesional and perilesional skin, occurred in a rheumatoid patient treated with diclofenac for one year (112c). Interaction Diclofenac significantly decreases the renal clearance of lithium, possibly by a prostaglandin-dependent mechanism, and increases its plasma levels. The risk of lithium intoxication for patients concurrently treated with this drug (or other NSAID) and lithium must therefore be borne in mind (113). Fenbufen (SED 9, 149; SEDA-5, 104; SEDA-6, 96) Skin Itching and/or maculopapular rashes, which seem to be more frequent in patients treated with large single daily doses, and can be serious enough to require drug discontinuation, occur in about 5% of patients treated with this drug (114 r, 115c). Fenclofenac (SEDA-5, 104; SEDA-6, 9 7) In a large multicenter study involving 1631 patients, 25% presented unwanted effects, including skin rash (6.9%), gastrointestinal (4.8%) and central nervous system effects (1.3%) and 14.2% withdrew because of these effects; this confirms the previous data on the frequency o f skin reactions with the use of this drug (I 16c). Fenoprofen (SED 9, 151; SEDA-5, 104; SEDA-6, 97) Blood Two cases of aplastic anemia, one fatal, have been reported. The clinical findings suggest that fenoprofen was probably responsible for the blood dyserasia. Other cases have been reported to the UK Committee on Safety of Medicines (117c). Flurbiprofen (SEDA-5, 93, 104) Systemic and local tolerance o f flurbiprofen suppository was good in a 4-week trial on 20 patients. Local effects were mild and transient and included local discomfort

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout or irritation, tenesmus and diarrhea (118c). Like other NSAID flurbiprofen may interfere with the diuretic action of frusemide (119c). Two reports received by the Netherlands Center for Adverse Reaction Monitoring point to the fact that flurbiprofen can potentiate the effect of the anticoagulant acenocoumarol. In both the cases, the effect was sufficient to result in hematoma and bleeding into the urinary or gastrointestinal tract. Discussing the cases, Stricker has suggested that the interference might involve several mechanisms (gastrointestinal erosions, interference with t h r o m b o c y t e function, prolongation of the prothrombin time or thrombocytopenia) (120 cR).

Ibuprofen (SED 9, 150; SEDA-5, 105; SEDA-6, 9 7) Side effects of a sustained release formulation of ibuprofen are very similar to those found with the standard drug (121c). Kidney Patients with SLE are apparently at risk of developing acute renal impairment when treated with ibuprofen (SEDA-5, 90) and two new cases of acute renal failure due to acute tubular necrosis have been reported (122c). The possible implications o f ibuprofen and other NSAID in inducing renal papillary necrosis have recently been reviewed (123Rc). A patient developed bilateral papillary necrosis three weeks after initiation of ibuprofen, but it is unlikely that the therapy was responsible (124 c). Skin Bullous pemphigoid occurred following a six-month course of ibuprofen; the patient improved after two months of oral corticosteroid therapy (125 C). Indoprofen (SEDA-4, 68; SEDA-5, 95; 105) Recently published comparative studies show a spectrum of adverse reactions similar to those found with other NSAID. In these trials indoprofen ( 2 0 0 - 1 0 0 0 mg/day) induced fewer side effects than acetylsalicylic acid (126 c - 129 c) but caused about the same incidence and t y p e o f adverse reactions as naproxen (130 c, 131 c) and ibuprofen (132c). The data on comparative studies with indomethacin are more conflicting, as some trials show the side effects as being less frequent and less severe with indoprofen (133 c, 134e), while other

113

studies do not show such a difference, especially when high doses are given and gastrointestinal side effects are considered (135 c, 136c).

Interactions Although

no interactions between indoprofen and hypoglycemic sulfonylureas or warfarin have been traced in specific studies in which they were looked for, it should be remembered that indoprofen prolongs bleeding time and reduces platelet aggregation (137, 138, 127e).

Naproxen (SED 9, 152; SEDA-5, 106; SEDA-6, 97) Ototoxicity In rare instances naproxen may cause hearing loss or tinnitus. One patient suffered sudden and permanent bilateral hearing loss and acute rens] failure, both attributed to the drug (139Cr). Oxaprozin (SEDA-4, 68) This drug is responsible for significantly less gastroscopic gastric mucosa changes than comparable doses of aspirin (140c). Pirprofen The withdrawal rate for side effects was calculated as being 8% in 700 patients participating in long-term studies, and 3% in short-term trials. Cutaneous allergic symptoms were the most frequent side effects in over 1000 patients treated in France (141r). Tiaprofenic acid (SEDA-5, 106) Experience with this drug is still limited, but gastrointestinal side effects appear to be the most frequent (142 c, 143 c, 144e), especially at the highest dosage (145c). In a study involving 244 patients 14.7% presented gastric unwanted effects, which led to interruption of therapy in 8.2% of subjects (146c). Tiaprofenic acid was not found to interact with phenprocoumon in a study on healthy volunteers (147). Tolmetin (SED 9, 152; SEDA-5, 106; SEDA-6, 98) Incidence of side effects In a postmarketing survey on 32,207 patients with various rheumatic disorders treated with 2 0 0 - 1 2 0 0 mg

114 tolmetin daily for an average period o f 1 - 4 weeks, side effects, mostly gastrointestinal, were noted in 12.3% and led to withdrawal of treatment in 3.6%. Only three allergic reactions were observed (Quincke's edema, bronchospasms and anaphylaxis) (148c). Tolerance was comparable to that reported for naproxen and indomethacin in two studies (149, 150). Allergy As pointed out earlier in this chapter, tolmetin, for unknown reasons, seems to cause more anaphylactic or anaphylactoid reactions than do other congeners (SEDA-5, 106; SEDA-6, 98; 17 r 151 C) and it would seem that a sensitizing mechanism operates in most of these cases. Blood Acute reversible thrombocytopenic purpura (platelet count 12,000/mm a) traceable to tolmetin-related antibodies, has been described in a patient with a history of multiple allergies, who was treated f o r four weeks with the drug. Thrombocytopenia recurred after a single 400 mg dose of the drug (platelet count 10,000/mm 3) and subcutaneous administration o f a drop of 2% tolmetin sodium solution caused recurrence within 60 minutes (platelet count 43,600/ mma). Other cases o f t h r o m b o c y t o p e n i a are stated to have been reported to the US FDA (152c). Kidney A nephrotic syndrome associated with tolmetin sodium has been described but the causal relationship to the drug is not convincing (153c).

Zornepirac Zomepirac is a pyrrole-acetic acid, structurally related to tolmetin sodium, recently marketed in various coun tries as an analgesic. Numerous reviews have been published on its properties (154 R, 155 R, 156 R, 157, 158R). Its exact mechanism o f action remains unknown; presumably its activity may be due to inhibition o f prostaglandin synthesis. Oral zomepirac is rapidly and completely absorbed, as it is highly bound to plasma proteins and rapidly excreted in the urine, mainly as glucuronide (159). No data have been published on placental transfer, excretion in breast milk or disposition in patients with renal or hepatic dysfunction. A pharmacokinetic study in rhesus monkeys showed zomepirac elimination to be dose-

A. Del Favero dependent and the picture may be the same in man (160). Well-conducted trials have clearly demonstrated that zomepirac is an effective analgesic, but up to now there is insufficient information on its side effects. Sixteen clinical trials comparing zomepirac with other NSAID or placebo were performed during the last 2 - 3 years ( 1 6 1 176). A n analysis o f available data suggests that the same adverse reaction pattern is found in zomepirac- as in other NSAID-treated patients. The incidence o f such reactions is also similar after zomepirac and after other NSAID treatments. Data based on 496 patients indicate that after a single dose o f zomepirac 179 (36%) o f the patients had some side effects, mostly mild CNS disturbances (drowsiness, dizziness, headache) and/or minimal gastrointestinal symptoms, most frequently nausea. No withdrawal for side effects was reported. In short-term therapy (lasting no longer than two weeks) 458 out o f 1079 patients (42.5%) suffered from adverse reactions which in 38 (3.5%) led to therapy discontinuation. When zomepirac was administered for a longer period o f time ( 3 - 1 2 weeks) 290 (65%} out o f 448 patients had side effects and 51 (11.4%) had to stop therapy. The discontinuation rate because o f side effects was generally lower for zomepirac than for comparative drugs; in the only long-term study {one year) published to date, the withdrawal rate (unspecified) was similar to that o f ASA (1 77). Gastrointestinal symptoms are not only the most commonly encountered side effects but also the most frequent reason for interrupting treatment (178). They appear to be dose-related and their incidence is higher in long-term studies. The most common o f them are nausea, dyspepsia, gastrointestinal distress, abdominal pain, diarrhea, constipation and vomiting, lntense erythematous stomatitis with tongue pain, which recurred on rechallenge, was one o f these {179~). Fecal blood loss was found to be significantly increased during zomepirac treatment with respect to the control period. 300 rag/day was better tolerated and caused less fecal blood loss than 3.9 g/day o f ASA, but there were no differences at 600 mg/day (180). Central nervous system symptoms are generally the second worse adverse reaction

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout reported with zomepirac, but their frequency varies greatly in different studies. Other reactions were much less frequent and the relationship between some o f them (Le. respiratory tract infections, sinusitis) and drug administration is dubious. It is not surprising to find that zomepirac, in common with certain other NSAID, was responsible for sweating, itching, urticaria, weight gain, edema and hypertension; zomepirac is a sodium salt which contains 0.34 mEq o f sodium every 100 mg and this could be problematical in the long-term treatment o f certain patients. In animals, the prolonged administration o f high doses o f zomepirac can induce renal damage (renal papillary necrosis and chronic interstitial nephritis) (149), which is also a common finding with other NSAID, but acute Lv. administration has little effect on renal blood flow, inulin clearance or urinary excretion o f Na and K (181, 182). Nevertheless BUN and creatinine values, without changes in urinalysis, which returned to baseline following drug discontinuation, have also been noted (1 74 c, 177 c} and acute non-oliguric renal failure has been reported in a patient (who had previously received a cadaver renal transplant) after three days o f higher than usual doses o f zomepirac (600 rag~day); renal function returned to normal within four days after the drug was withdrawn (183C). Some urinary symptoms not usually associated with other NSAID (i.e. urinary frequency, dysuria, cystitis, hematuria and pyuria) have also been reported with zomepirac, but their causal relationship to the drug cannot be adequately sustained (177c). Zomepirac should therefore be used with great caution in patients with impaired renal function and dosage should be reduced. Although only recently marketed, zomepirac has been held responsible for a number o f anaphylactic or anaphylactoid reactions. 10% o f such reactions reported to the DDE (USA} were attributed to this drug, which is second only to tolmetin in this respect, and it is noteworthy that tolmetin is structurally very similar to zomepirac (17CR). These reactions can be serious, as is illustrated by various recent case reports (184 c, 185 C, 186r Zomepirac must be avoided in aspirin-sensitive asthmatics and in patients with a history o f previous reaction to tolmetin or other NSAID. No clinically important changes were revealed in the few long-term studies per-

115

formed to detect the possible opthalmological, audiometric, immunological or ECG effects (1 74, 177, 187). Likewise, with few exceptions, routine laboratory values were not significantly affected. Elevated liver enzyme values (SGOT and SGPT values o f 135 and 201 IU/l), anemia and w.b.c. decrease attributable to zomepirac were a reason for discontinuing treatment in three patients {174c); however, the relationship to drug administration was not proven. Zomepirac can prolong template bleeding time and decrease platelet adhesiveness, release o f serotonin and aggregation. However, these effects are transitory and there is a return to pretreatment values within 1 2 - 2 4 hours (188). Postoperative bleeding was not increased by the drug, but zomepirac should be used with the same caution as other NSAID in patients with known coagulation or platelet function defects. Interactions Zomepirac is highly proteinbound and therefore could either displace other protein-bound drugs from binding sites or be displaced by them. Zomepirac does not, however, affect the binding o f warfarin, nor does it have any effect on hypoprothrombinemia when concomitantly administered (189). No interaction with antacids has been noted at the absorption level (1 77).

Overdosage Limited information is available on acute overdose toxicity. One recently reported case (190 c} is consistent with the findings from other cases o f acute NSAID toxicity. 3 - 4 g o f the drug caused drowsiness, lethargy and mild elevation in serum creatinine when taken by an apparently healthy woman. Recovery was uneventful and without sequelae. Unpublished data from the manufacturer shows mild nausea and gastrointestinal distress as the only symptoms which occurred in 12 patients following the ingestion o f up to 2.1 g o f zomepirac (155 R ). Addiction Shortly after the introduction o f zomepirac in the USA, the FDA "s 'Division o f Drug Experience' was struck by what appeared to be a cluster o f overdosage reports. This led the Division to compile and issue a comprehensive review o f the whole question o f 'abuse potential associated with N S A I D ' (191R}. There were indeed a number o f cases o f depression associated with zomepirac abuse, but the authors

116 o f the review conclude that the drug's abuse potential is probably no greater than that o f any other NSAID. The cluster o f problems reported may reflect the very intensive marketing o f the drug at the time o f its introduction and the characteristics o f some o f the patients who would be prone to misuse any drug, perhaps alongside alcohol, in the hope o f experiencing exotic sensations. Most NSAID have at some time been the subject o f this type o f fashion-dictated abuse.

ANTHRANILIC ACID DERIVATIVES

Antrafenine (SEDA-4, 69; SEDA-5, 93) This drug causes less gastrointestinal bleeding than equianalgesic doses of aspirin (192 c) but, as with related agents, there is occasional nephrotoxicity (SEDA-4, 69) as another recent case shows. Abdominal pain, vomiting and acute oliguric renal failure, due to a tubulo-interstitial nephritis, which required hemodialytic treatment, appeared after four days of treatment (total dose 2.4 g) with antrafenine in a young apparently healthy patient with no history of previous exposure to this drug (193C).

A. Del Favero gastrointestinal side effects. Diarrhea, reported by 1 1 - 4 6 % of subjects, is the main problem, especially in long-term trials. Despite the fact that the amount of gastrointestinal bleeding, as determined by fecal blood loss, has been reported to be less for 300 mg of meclofenamic acid daily than for 3.6 g of aspirin daily, significant decreases in hematocrit values, ranging from 15 to 25% or even over 25% below initial values, have been found in about 15% of patients in some studies (198 e, 201 e, 202c). Other unwanted effects include abdominal pain, nausea, anorexia, vomiting, heartburn, flatulence, peptic ulcer and rectal bleeding (198 c 202c). A serious thrombocytopenia, which recurred on reinstitution of the drug, has been described in an 81-year-old female with mild renal failure (203C). Three cases of acute thrombotic events (two myocardial infarctions and one superficial venous thrombosis) were recorded in patients with past clinical conditions predisposing to these events during drug therapy in two of the above mentioned trials (200 e, 202e), but a link with meclofenamate treatment seems unlikely. Rashes are also relatively common ( 8 - 9 % patients), and the withdrawal rate for side effects ranged from 7 - 3 1 % , reaching its maximum in long-term studies.

Floctafenine Mefenamic acid (SEDA-5, 93; SEDA-6, 99) Coma, possibly related to floctafenine administration occurred in a cirrhotic patient who had also been treated with diuretics and cimetidine (194c). As interactions between coumarin derivatives and floctafenine have been demonstrated, patients taking both medications should be subjected to appropriate checks (195c).

Glafenine (SED 9, 153; SEDA-5, 106; SEDA-6, 98) Recurrent acute renal failure in a child due to glafenine intoxication, as a consequence of abuse, has been clearly described (196c). The mechanisms of glafenine intolerance have been reviewed (197er).

Although this drug has not previously been implicated as a cause of pancreatitis, a case suggestive of this has been reported (204c). Mefenamic acid overdosage (discussed in a paper by Balai-Mood and others which was referred to in SEDA-6, p. 99) cart occasionally lead to coma. Such an instance has now been described by G6ssinger et al. from Germany (205e). The patient here was a girl of 13 who had ingested 5 - 1 0 g, and who became unconscious within the next I~A hours; some time later, in full coma, grand mal convulsions occurred. The patient had fully recovered within 12 hours.

Tolfenamic acid (SEDA-4, 68; SEDA-5, 93) Meclofenamate (SEDA-6, 99) 3 4 - 6 0 % of patients treated with meclofenamate in various clinical trials experience

A non-specific reaction, possibly druginduced hepatitis, which recurred on rechallenge, has been reported (206 C).

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

Fluproquazone This drug (300 mg daily for seven days) causes far less gastric lesions and fecal blood loss, as respectively assessed by gastroscopy and s 1Cr.labelled erythrocytes technique, than does acetylsaiicylic acid (207c). In the present state of knowledge of NSAID such a finding does not, however, mean very much; much more experience (and comparisons with a range of NSAID) is needed before the gastrointestinal tolerance of a drug can be described in meaningful terms.

Nimesulide Gastric complaints (heartburn, pain and nausea), rash with itching, nervousness and vertigo have been observed in a study on 70 patients treated for an average of 25 days with 2 0 0 - 6 0 0 mg/day (208c).

Piroxicam (209 R) (SED 9, 154; SEDA-5,

117

tress, pyrosis, nausea and two endoscopically proven gastric ulcers of recent onset attributable to the drug were recorded (214c). As the bioavailability of the suppositories is similar to that of the oral formulation (214) and as gastrotoxicity is dose-related (SEDA6, 100) the dosage employed in this study may have been excessive. Kidney Nephropathy and Sch6nlein-Henoch purpura occurred in two patients with rheumatoid arthritis. A 51-year-old woman took piroxicam with excellent clinical response but, shortly after beginning therapy, she observed painless macroscopic hematuria and complained of rash and abdominal discomfort and so was admitted to hospital. Clinical examination showed purpuric rash, peripheral edema, gastro-intestinal hemorrhage and hematuria with reduced glomerular filtration rate. Concentrations of circulating IgA immune complexes were raised. Her condition improved rapidly and completely after piroxicam was stopped but the adverse reaction recurred when the drug was readministered (215c).

107; SEDA-6, 100) In 18,888 German patients treated with this drug for a mean period of 4 - 5 weeks, adverse reactions were found in 2574 (13.6%) and led to interruption of treatment in 594 (3.1%). 2927 side effects were reported: 73.5% gastrointestinal, 13.9% central nervous system, 6.1% water retention, 4.2% cardiovascular and 2.4% other disorders. Five cases of melena and one of peptic ulcer were reported (210 c). Blood Aplastic anemia has been attributed to piroxicam but the link with drug therapy seems dubious (211 c). Gastrointestinal Despite the fact that piroxicam is a potent inhibitor of prostaglandin synthetase and can cause peptic ulceration (SEDA-6,100) it is one of the few NSAID in widespread use that authorities of some countries do not regard as contraindicated in patients with peptic ulcer. Unfortunately, however, new cases of serious gastrointestinal complications such as hematemesis or frequently symptomless melena underline its gastrotoxicity (212 c, 213c). Even rectal administration can cause serious side effects, as is shown by a study in 33 patients given piroxicarn suppositories ( 3 0 - 4 0 rag, once daily for two weeks). Epigastric pain or dis-

Skin Lyell's syndrome, complicated with renal insufficiency, serious leukopenia and sepsis, occurred in a 39-year-old woman after 18 days of treatment, and caused death on the 1 l t h day after the appearance of the first symptoms (216 C).

Phenazopyridine [SEDA-4, 70; SEDA-5, 108) This drug can induce methemoglobinemia after overdose and in patients with decreased renal function. However, methemoglobinemia and hemolytic anemia have now also been reported in two patients with apparently normal renal function who took normal doses (217 c).

Pyritinol [SEDA-5, 108; SEDA-6, 13, 100, 147, 234) Lichenoid eruption and loss of taste can occur in patients treated with this drug (218c). As pointed out by Lopatin et al. in SEDA-6 (p. 13), a cross-allergic reaction with penicillamine could be involved in such cases.

Rimazolium Nausea, vertigo and drowsiness have been reported (219c), but clinical experience

A. Del Favero

118 with this drug is very limited, though it has been known for many years.

ology, gastrointestinal, hematological and neurological reactions being the most frequent (223 cR).

DRUGS USED IN THE TREATMENT OF GOUT

Sulfinpyrazone (SED 9, 15 7; SEDA-5,

Allopurinol (SED 9, 155; SEDA-5, 108; SEDA-6, 104)

Sulfinpyrazone can cause acute renal failure by different pathogenic mechanisms; immunoallergic induced acute interstitial nephritis (224c), acute renal failure due to the inhibition of renal prostaglandin synthesis (225 C, 226 C) and acute renal impairment due to precipitation of uric acid stones (227 C) have all been reported. The incidence of renal complications was, however, apparently low in two trials on prevention of postmyocardial infarction sudden death. One out of 813 patients suffered acute renal dysfunction, probably due to interstitial nephritis, and three out of 365 patients presented renal colic without impairment of renal function (228 e, 229c). Patients at risk should have their renal function closely monitored.

6.2% of 29,524 hospitalized medical patients received allopurinol. After skin reactions had been excluded, 33 patients (1.8%) suffered adverse reactions attributable to this drug. Hematological abnormalities (leukopenia and/or thrombocytopenia, 11 patients, 0.6%), diarrhea and drug fever (5 patients each, 0.3%) were the most frequent. Adverse effects were dose-related but unrelated to age, reason for therapy, admission blood urea, albumin concentration or previous aUopurinol use (220e).

Bone marrow toxicity There is some evidence that neoplastic patients on chemotherapy who also receive aUopurinol are more susceptible to bone marrow depression than the same patients who do not (SED-9, 155; 221). However, recent data suggest that allopurinol does not increase the toxic reactions of some widely used chemotherapeutic agents (222c). Colchicine {SED 9, 156; SEDA-5, 109) Acute intoxications with colchicine are characterized by proteiform symptomat-

109, 328; SEDA-6, 104, 309)

Interactions Sulfinpyrazone increases the hypoprothrombinemia of racemic warfarin stereoselectivelv by reducin~ the metabolic clearance of S-warfarin enantiomorph (230). This problem was discussed by Loeliger in SEDA-6 (p. 309). In order to avoid an exaggerated anticoagulant effect and serious bleeding (231 c, 232 r careful monitoring of prothrombin time is imperative when either drug is added to a stabilized regimen of the other.

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