Glafenine-associated anaphylaxis as a cause of hospital admission in the Netherlands

Summary In 1981 generalized anaphylaxis was registered on 166 occasions in Dutch general and academic hospitals. Clinical details of 120 of those patients revealed that in 107 anaphylaxis was either probable (n=90) or possible (n=17), whereas in 13 cases some other reaction than anaphylaxis had occurred. The series of confirmed cases contained 46 men and 61 women, with mean ages of 47 y and 48 y, respectively.There was a complete recovery in 102 patients and two patients died. Hypotension was present in 79 cases (74%), dyspnoea in 34 cases (32%) and a skin reaction, mainly urticaria, erythema or angioedema, was mentioned in 62 cases (58%). Most cases of anaphylaxis were drug-induced (76%), the main causes being the analgesic glafenine and contrast media. Glafenine was mentioned as the cause in 36% of all admissions for drug-induced anaphylaxis. Only 3.7% of cases had been reported to the voluntary reporting scheme of the Netherlands Centre for Monitoring of Adverse Reactions to Drugs.On the basis of reimbursement data, the risk of developing severe anaphylaxis to glafenine was estimated at 11.7–19.3-fold relative to indomethacin, and 13.4–20.2-fold relative to oral penicillins.     

Glafenine-associated hepatic injury

ABSTRACT— Glafenine was associated with hepatic injury in 38 cases. The causal relationship was assessed on the basis of the temporal relationship with drug use, course and exclusion of other causes. In 27 cases a causal relationship was considered likely, i.e. ‘probable’ (12 cases) or ‘possible’ (15 cases), whereas in 11 cases it was either unlikely or unclassifiable. In both the ‘probable’ and ‘possible’ groups 60–70% of individuals were women. Jaundice was present in three-quarters of cases in both groups. Eosinophilia was more frequent in the group of ‘probable’ cases, and this group had the highest case-fatality rate (42%). Onset varied from 2 days (after a rechallenge) to 8 months, but most cases appeared between 2 weeks and 4 months after starting therapy. Histology in 22 cases showed a predominantly hepatocellular pattern, varying from spotty panlobular necrosis, centrilobular and (sub)massive necrosis (acute pattern) to fibrosis and cirrhosis (chronic pattern). The chemical structure of glafenine and the clinicopathological pattern it induces resemble that of cinchophen. The incidence is unknown. Either metabolic idiosyncrasy or an immunoallergic mechanism seems to be responsible.     

Drug-associated anaphylaxis: 20 years of reporting in the Netherlands (1974–1994) and review of the literature

Background Since 1963, the Drug Safety Unit of the Dutch Inspectorate for Health Care (DSU) holds a voluntary reporting system. Objective To analyse all reports received in the years 1974 to 1994, registered as anaphylaxis or as a diagnosis that could contain cases of anaphylaxis. Methods All reports were classified as probable or possible anaphylaxis according to previously described criteria and the causal relationship between exposure and anaphylaxis was assessed. Results Nine hundred and ninety-two reports possibly concerning anaphylaxis were received between 1974 and 1994. Fifty-six were unclassifiable. The remaining 936 reports concerned 326 men and 610 women. Three hundred and forty-five reports were classified as anaphylaxis probable, 485 as anaphylaxis possible, and 106 as anaphylaxis unlikely by previously specified criteria. Drugs frequently associated with anaphylaxis (causal relationship certain or probable) were: glafenine (326 reports classified as anaphylaxis probable or possible), combination preparations with (propy)phenazone or propyphenazone/phenacetine (39), diclofenac (30), dextran (20), ibuprofen (14), floctafenine (12), allergen extracts (12), sulfamethoxazole with trimethoprim (12), and trimethoprim (11). There is probably substantial under-reporting as well as reporting bias in these data. Furthermore, many reports were classified as possible and not as probable anaphylaxis because the temporal relationship was unknown or not reported. Conclusion Drugs that caused anaphylaxis most frequently were glafenine, NSAID and certain antibiotics. Data from a voluntary reporting system such as the DSU are valuable as an early warning system for drugs that may induce anaphylactic reactions.     

Double blind study of the effect of glafenine (Glifanan®) on oral anticoagulant therapy with phenprocoumon (Marcumar®)

Summary The interaction between phenprocoumon (Marcumar^®) and glafenine (Glifanan^®) was investigated in a double blind study of twenty patients receiving long term treatment with phenprocoumon. Thrombotesttime (TT) values had been stable for more than three months before the study. Patients taking glafenine showed a significant increase in TT during the second and third week of the trial (P<0.05) compared with the placebo group. The increase in TT was not significant in the fourth week. The average concentrations of phenprocoumon were similar in both groups, which suggests that displacement of the drug from binding was not important. Concentrations of clotting factors II, VII and X showed a decrease in all patients at the time of the maximum TT values. A possible explanation for this interaction is discussed, but the mechanism remains uncertain.     

Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers

Pharmacokinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid chromatographic method. Glafenine absorption was significantly delayed in cirrhotic patients (CP) (Tmax = 2.8 +/- 1.3 hvs 1.5 +/- 0.4 h, p less than 0.01) and was dramatically reduced in 3 patients. The large hepatic 'first pass' effect observed in healthy volunteers was markedly reduced in CP (ratio Cmax GA/Cmax G = 3.6 +/- 2.9 vs 18.9 +/- 9.8, p less than 0.001; ratio areas under the curves AUC GA/AUC G = 2.3 +/- 2.3 vs 18.2 +/- 11.2, p less than 0.001). The elimination half-life of G was prolonged in the CP (13.0 +/- 13.1 h vs 1.5 +/- 0.5 h, p less than 0.01). In CP, GA elimination half-life was increased (12.0 +/- 13.4 h vs 4.3 +/- 1.3 h, NS) but the difference did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (Cmax = 2.2 +/- 2.1 mg/L vs 0.7 +/- 0.2 mg/L, p less than 0.05) and its longer half-life would lead to an accumulation if the usual dosage regimen was prescribed for CP and could result in nephrotoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephrotoxic. Hence, G should be given with great caution to CP.     

Comparative analgesic efficacy and tolerability of ketorolac tromethamine and glafenine in patients with post-operative pain

Summary

In a randomized, single-dose, double-blind, parallel comparative trial of analgesic efficacy, 96 adult patients received either 10?mg ketorolac tromethamine or 400?mg glafenine orally the morning after surgery if they requested pain relief medication. Each patient provided a baseline pain assessment and then received the assigned medication. Patients assessed pain intensity and pain relief and reported any adverse events in interviews held 30 minutes after drug administration and then hourly for 6 hours. The demographic characteristics, baseline pain intensity, and surgical categories of the 47 patients who received ketorolac tromethamine and the 49 who received glafenine were similar. Both drugs provided prompt, sustained pain relief throughout the 6-hour observation period, and there were no statistically significant differences between the two groups in any of the efficacy measures analyzed. The global assessment recorded by patients suggested a slight clinical advantage for ketorolac tromethamine (32.6% of ‘excellent’ responses) as compared to glafenine (12.5% ‘excellent’). The differences in overall response were statistically significant (p = 0.017). Fourteen (30%) patients who received ketorolac tromethamine and 17 (35%) who received glafenine reported adverse experiences that began or seemed to worsen after administration of the study drugs. The most prominent were drowsiness and sleeping, both of which are common in post-surgical patients.     

Tiapride versus glafenine: a double-blind comparative study in the management of acute rheumatic pain

Summary

A double-blind study was carried out in 42 patients suffering from acute rheumatic pain to compare the analgesic effectiveness and tolerance of tiapride with that of glafenine, a widely used analgesic in Europe. Patients were allocated at random to receive either 100?mg tiapride or 200?mg glafenine 3-times daily over a period of 14 days. Pain intensity was rated daily by the patients using a visual analogue scale and an overall assessment of response to treatment was made by both patients and physician at the end of the study. The results showed that. whilst both treatments resulted in a marked reduction in mean pain scores, pain disappeared completely in 16 (76%) of the 21 patients treated with tiapride compared with 9 (43%) of the 21 receiving glafenine. There was also a signqicant difference in favour of tiapride in the physician's overall assessment of response which was considered as excellent in 71% of the patients on tiapride compared with 31% receiving glafenine. Both treatments were well tolerated and few side-effects were reported. Drowsiness occurred in 6 patients on tiapride but this was only mild in 5 and moderate in the other patient.     

Investigating the TNP-OVA and direct popliteal lymph node assays for the detection of immunostimulation by drugs associated with anaphylaxis in humans

Using current animal models, it is not possible to identify low-molecular-weight compounds (LMWCs) that are likely to be associated with anaphylaxis. It is generally accepted that the ultimate effector mechanism involves drug-induced IgE antibody. The objective of the present study was to determine if diclofenac, zomepirac and glafenine, which are associated with anaphylaxis in humans, have immunostimulating potential in the murine TNP-OVA (trinitrophenyl-ovalbumin) popliteal lymph node assay (PLNA), and more specifically to determine if the immunostimulation caused by these LMWCs results in IgE antibody production. These LMWCs were chosen because both zomepirac and glafenine were removed from the market due to high association with anaphylaxis, and diclofenac, which remains on the market, is frequently associated with anaphylaxis. In addition to conducting a TNP-OVA PLNA, the immunostimulating potential of these compounds was examined in the direct PLNA. When co-administered with TNP-OVA, all three LMWCs caused dose-dependent (0.25, 0.50, 1.00 and 1.25 mg) increases in popliteal lymph node (PLN) weight and cellularity that were observed beginning with the 0.25-mg dose. In addition, beginning with the 0.25-mg dose, all three compounds caused dose-dependent increases in TNP-OVA specific IgM and IgG(1) antibody-forming cells (AFCs). Diclofenac induced an isotype switch and caused a dose-dependent increase in the number of IgE AFCs with no detectable IgG(2a) AFCs and minimal high-dose-only IgG(2b) AFCs. Zomepirac induced IgE, IgG(2a) and IgG(2b) AFCs following the injection of 0.50 mg only, and glafenine induced IgE, IgG(2a) and IgG(2b) AFCs following the injection of 0.50-1.00 mg. In the direct PLNA, diclofenac caused dose-dependent increases in PLN weight and cellularity that were observed beginning with dose of 0.50 mg, whereas zomepirac failed to increase any PLN parameter and glafenine only increased the PLN weight. These results suggest that diclofenac, zomepirac and glafenine are immunostimulating LMWCs in the TNP-OVA PLNA with the potential to induce IgE antibody against a co-administered hapten-conjugate. Furthermore, these results suggest that the TNP-OVA PLNA offered significant advantages over the direct PLNA. Although it is not realistic to suggest that a single assay, based on a low number of test compounds, can identify all LMWCs with the potential to cause anaphylaxis in humans, these observations do demonstrate the potential utility of the PLNAs in examining LMWC-induced immunomodulation and support further development and investigation of the assays.