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Kwartaalbericht 1e kwartaal 2003 6 mei 2003 Contents Voorwoord 3 1. Observations 4 1.1. Infliximab and listeria monocytogenes meningitis 4 1.2. Doxycycline and (photo-)onycholysis 6 1.3. Increased use of metformin and lactic acidosis 8 1.4. Cyproterone acetate and osteoporosis 11 1.5. Fluconazole and fixed drug eruption 13 1.6. An overview of reports on tiotropium bromide 15 2. Publications 17 2 Voorwoord Het is mij een genoegen u hierbij het eerste kwartaalbericht van het Nederlands Bijwerkingen Centrum Lareb over 2003 te kunnen aanbieden. Naar mijn mening bevat ook dit bericht een aantal belangwekkende signalen en andere informatie die voor een goede geneesmiddelenbewaking van belang zijn. Het is u ongetwijfeld bekend dat Lareb met ingang van 2 april de mogelijkheid biedt aan patiënten die om welke reden dan ook liever niet via hun behandelend arts of de eigen apotheker willen melden, dat rechtstreeks via de website te doen (www.meldpuntbijwerkingen.nl). Dit initiatief sluit aan bij nationale en internationale ontwikkelingen, zoals beschreven in één van de bijgevoegde publicaties van Lareb. De FDA in de USA en binnenkort ook de MCA in het UK accepteren meldingen van patiënten en ook bij een recente bespreking van het beleid met betrekking tot de organisatie van de geneesmiddelenbewaking in Europa is in het Europees Parlement sterk aangedrongen op deze mogelijkheid. Het Lareb meldpunt is zo ingericht dat alleen serieus te nemen meldingen van bijwerkingen mogelijk zijn. We beschouwen de site als een proef met als doel evidence te krijgen over de bijdrage die patiëntmeldingen kunnen leveren aan het vroeg opsporen van mogelijke bijwerkingen. Ook anderszins spelen Europese ontwikkelingen een rol bij het werk van Lareb. U bent gewend bij een mogelijk nieuw signaal informatie te krijgen over het voorkomen van de betreffende associatie in onze eigen databank en de gegevens wereldwijd, zoals die voorkomen in de WHO databank van het Uppsala Monitoring Centre. Nu in het kader van Eudravigilance de EMEA bezig is een Europese databank op te zetten, is het voor de hand liggend dat ook de Europese gegevens binnenkort meegenomen zullen worden bij de beoordeling van een associatie. Dit is met name relevant als beslissingen over de betreffende associatie op Europees niveau genomen worden. Het spreekt voor zich dat dit alleen mogelijk is als Lareb ook toegang heeft tot deze Europese databank. Kees van Grootheest 3 1. Observations 1.1. Infliximab and listeria monocytogenes meningitis Introduction ® Infliximab (Remicade ) has been approved for marketing on 13-8-1999 in the EU for treatment of rheumatoid arthritis and Crohn’s disease. The therapeutic indication is[1]: Rheumatoid arthritis. The reduction of signs and symptoms as well as the improvement in physical function in patients with active disease when the response to disease-modifying drugs, including methotrexate, has been inadequate. In this patient population, a reduction in the rate of progression of joint damage, as measured by X-ray, has been demonstrated. Efficacy and safety have been demonstrated only in combination with methotrexate. Treatment of severe, active Crohn’s disease, in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. Treatment of fistulising Crohn’s disease, in patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy). Infliximab is a chimeric IgG1 monoclonal antibody against tumour necrosis factor α (TNFα). TNFα, which level is increased in joints of rheumatoid patients and colonic tissue of Crohn’s disease patients, is a cytokine with multiple biologic actions including mediation of inflammatory responses and modulation of the immune system. The most commonly encountered adverse drug reactions during treatment were upper respiratory infections, headache, nausea, sinusitis, rash, cough and acute infusion reactions. Contra-indications include infections and moderate to severe heart failure. Moreover, due to post marketing data, comprehensive precautions were included in the SPC to prevent tuberculosis infections during therapy[1]. Reports A female aged 43 received infliximab for the indication of therapy resistant Crohn's disease. She used azathioprine (125 mg/day) and prednisolone (15 mg/d) as co medication. A fortnight after the first administration of infliximab, a listeria monocytogenes meningitis was diagnosed. She was treated with parenteral antibiotics and recovered. Other sources of information Literature Very recently, FDA affiliated authors published an overview about the association between eternacept, infliximab and listeria infections [2]. This publication reviews literature on this topic [3-6]. The authors discuss 15 patients and mention another 10 cases in association with infliximab in an addendum. All patients for whom information was reported were receiving immunosuppressant drugs. From these 25 patients, eight died, two patients had not recovered at the moment of notification, six patients had recovered including one with persisting neurological damage. From the other patients, the outcome remained unknown. An annual reporting rate of 43 : 1,000,000 for all patients treated with infliximab could be calculated; 29 : 1,000,000 for users with Crohn's disease and 61 : 1,000,000 for users with rheumatoid arthritis. The background incidence of listeria infections is 3 : 1,000,000/year for all ages with a mortality of 21%. In the elderly (≥ 60 y), the incidence is higher; 13 : 4 1,000,000/year [7]. Background incidences in populations with rheumatoid arthritis or Crohn's disease are unknown. Databases The reported case is the first in the Lareb database. The WHO database does not allow a specific search for listeria infections. Mechanism Tumour necrosis factor alpha is substantially involved in defence mechanisms. A pharmacological blockade of TNFα will decrease the defensive mechanism, which is especially relevant for intracellular micro organisms like listeria monocytogenes and tuberculosis. Conclusion The report associates the infection with listeria monocytogenes with the use of infliximab. This association is supported by literature, including an article on the FDA database. The mortality of a listeria infection is above 20% in the general population, and may be even higher in patients with rheumatoid arthritis or Crohn's disease. As with tuberculosis, preventive strategies might be able to reduce listeria infections. Avoidance of non-pasteurised milk or cheese consumption, as recommended during pregnancy, are examples [8]. References 1. European Public Assessment Report of Remicade® (revision 4; 25-7-2002) http://www.eudra.org/humandocs/PDFs/EPAR/Remicade/190199en4.pdf (accessed 18-4-2003). 2. Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum. 2003;48(2):319-24. 3. Stephens MC, Shepanski MA, Mamula P, Markowitz JE, Brown KA, Baldassano RN. Safety and steroid-sparing experience using infliximab for Crohn's disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol. 2003;98(1):104-11. 4. Gluck T, Linde HJ, Scholmerich J, Muller-Ladner U, Fiehn C, Bohland P. Anti-tumor necrosis factor therapy and Listeria monocytogenes infection: report of two cases. Arthritis Rheum. 2002;46(8):2255-7; author reply 2257. 5. Kamath BM, Mamula P, Baldassano RN, Markowitz JE. Listeria meningitis after treatment with infliximab. J Pediatr Gastroenterol Nutr. 2002;34(4):410-2. 6. Morelli J, Wilson FA. Does administration of infliximab increase susceptibility to listeriosis? Am J Gastroenterol. 2000;95(3):841-2. 7. URL: http://www.cdc.gov/foodnet/annual.htm (accessed 12 March 2003). 8. Zwangerschap (voeding, medicijnen, drugs). http://www.ziekenhuis.nl/ziektebeelden/206.html Listeria infection is associated with use of TNFα blockers Use of TNF-α blockers justifies preventive strategies against listeria infection 5 1.2. Doxycycline and (photo-)onycholysis Introduction Doxycycline is a tetracycline antibiotic with a broad spectrum of activity. It is produced by several manufacturers and has been on the international market since 1966 [1]. It is indicated for infections caused by doxycycline sensitive bacteria: infections of the respiratory tract (including ear nose and throat infections), infections of the urogenital tract (including uncomplicated gonorrhoea, non-gonococcal-urethritis, syphilis), infections of skin and connective tissue, infections of the gastro-intestinal tract, infections with borrelia burgdorferi and eye infections (especially trachoma) [2]. Adverse drug reactions mentioned in the SPC with respect to skin and allergic reactions are: maculopapular and erythematous rash, exfoliative dermatitis, urticaria, angioneurotic oedema, anaphylaxis, anaphylactoid purpura, pericarditis, excacerbation of systemic lupus erythematosus and photodermatitis. The SPC does not mention (photo-)onycholysis [2]. Photo-onycholysis refers to separation of the nail plate from the nail bed after exposure to ultraviolet light. Although the complication is not dangerous, it is painful in the early stages of the process [3]. Reports Up to March 2003, the Lareb database contains a total of 8 reports of onycholysis as a suspected adverse drug reaction. Three reports refer to (photo-)onycholysis associated with the use of doxycyclin. The first case concerns a 12-year old boy. Twelve days after starting doxycyclin, he developed a photosensitivity reaction in his face upon sunbathing: swelling and redness of his face, ears, lips and nose. Also white spots arose on his cheeks, ears, nose and upper lip. The doxycyclin course was finished 2 days later. The patient developed onycholysis 3 weeks afterwards (5 weeks after starting doxycyclin). The second case describes a 38-year-old woman who developed onycholysis 3 days after starting a doxycyclin course. At first, one nail came off; 2 weeks later two other nails followed. The patient was on holidays and had been sunbathing. She did not develop any other adverse skin reactions. As concomitant medication she used citalopram. Two months later (one month after finishing the doxycyclin course), she was recovering. A third patient, also a 38-year-old female, developed severe pain in the nails several hours after starting doxycyclin for Lyme disease. She was on holidays and was exposed to sunlight. During the continued doxycyclin course (14 days) her nails became less painful, but the middle parts of the nails became disconnected from the skin. All finger nails were involved, plus 4 of the toenails. Onycholysis occurred in this patient as single adverse skin reaction. It took 5 months for her nails to recover. Other sources of information Literature Several case reports of onycholysis upon use of doxycyclin are described in literature. In all cases the combination with sunlight exposure is described as an important condition, pointing to a phototoxic reaction[3-7]. Databases The database of the WHO Monitoring Centre contains 6973 possible ADRs during the use of doxycycline, and 141 reports of onycholysis as an adverse drug reaction to drugs in general. An association between doxycyclin and onycholysis 6 was suggested in 15 reports. The Reporting Odds Ratio of this combination is 48.3 (95% CI 28.7-82.6). Associations between onycholysis, minocycline, tetracycline were not statistically significant disproportionally present in the WHO database. Mechanism Tetracycline induced phototoxic skin reactions, including onycholysis, are well known ADRs. Due to the fact that the nailbed is relatively unprotected from sunlight, onycholysis may be the sole expression of a phototoxic reaction [8]. The nail contains less melanin, therefore offering less ultraviolet protection to the nailbeds. This is supported by the observation that local application of chemical sunscreen may be protective [3,6]. The phototoxic reaction may be mediated by excited-state singlet oxygen and free radicals, which arise upon irradiation with UV-A and cause selective injury to mitochondria, within which doxycyclin is localised [3]. Conclusion Three cases in the database of the Netherlands Pharmacovigilance Centre Lareb show an association between doxycyclin and photo-onycholysis. Due to the absence of melatonin in the nail, onycholysis may occur even without other phototoxic skin reactions. These findings are supported by data from the WHO-database. In addition, the WHO-database suggests that this association is limited to doxycylcin. Literature supports this association as well. (Photo-)onycholysis is not mentioned in the Summary of Product Characteristics of doxycyclin. References 1. Informatorium Medicamentorum 2003. 2. Dutch Summary of Product Characteristics of Dumex®. version 3-12-1999. http://www.cbgmeb.nl/IB-teksten/08299.pdf (accessed 17-4-2003). 3. Yong CK, Prendiville J, Peacock DL, Wong LT, Davidson AG. An unusual presentation of doxycyclin-induced photosensitivity. Pediatrics 2000:106;E13 4. Frank SB, Choen HJ & Minkin W: Photo-onycholysis due to tetracycline hydrochloride and doxycycline. Arch Dermatol 1971; 103:520-521. 5. Ramelli G et al: Photo-onycholysis following doxycycline hyclate. Cutis 1972; 10:155-156. 6. Baran R. Juhlin L. Drug-induced photo-onycholysis. Three subtypes identified in a study of 15 cases. J. Am. Acad. Dermatol. 1987:17:1012-16. 7. Cavens TR. Onycholysis of the thumbs probably due to a phototoxic reaction from doxycyclin. Cutis 1981:27:53-4. 8. Bruinsma W. A guide to drug eruptions. 2000, page 26. Onycholysis as phototoxic reaction is associated with doxycycline and not with other tetracyclines Onycholysis may occur as single adverse skin reaction The available data may justify mentioning of preventive strategies in the SPC 7 1.3. Increased use of metformin and lactic acidosis Introduction ® Metformin (e.g. Glucophage ) is a biguanide used in the treatment of diabetes mellitus. Since February 1999 according to the practice guidelines of the Dutch College of General Practitioners [1], metformin is the drug of first choice for the treatment of obese patients with diabetes mellitus. This was based on the results of the UKPDS study[2]. Since then there is a gradual increase in the number of dispensed Defined Daily Dosages (DDD=2g) of metformin in the Netherlands (Figure 1) [3]. Metformin causes lowering of the blood glucose and improve blood lipids in the diabetic by inhibition of the active transport of glucose in the intestinal mucosa, an absent activation of glucose transporters, inhibition of gluconeogenesis, inhibition of fatty acid oxidation and of lipid synthesis which [4]. Metformin is approved in the Netherlands since 1967 for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), especially in obese patients, when the blood glucose cannot be regulated by dietary measurements or sufficient physical exercise alone[5]. The most frequent adverse events include gastrointestinal complaints (15-25%) like nausea, vomiting, diarrhea, abdominal pain and anorexia. More rarely, dysgeusia may occur[4]. Early symptoms of lactic acidosis, generally defined as an accumulation of lactic acid more rapidly than it can be metabolised, include nausea, vomiting and diarrhea. Since these adverse events may also occur as such, differential diagnosis with the initial stages of lactic acidosis may be bothersome. Reports The Netherlands Pharmacovigilance Centre Lareb has received seven reports concerning lactic acidosis associated with the use of metformin (table 1). The reports concerned three females and four males. The mean age was 61.3 years (range 50-77). Four patients died. Five reports were submitted by specialist doctors. One report has been submitted to Lareb before adaptation of the referred guidelines, and six reports have been received afterwards. The relative number of reports of lactic acidosis in respect to reports on other ADRs associated with metformin is not statistically significant higher after adaptation of this guidelines (odds ratio 6.4 (95% confidence interval 0.8-54.6). However, the increase in the use of metformin will also cause an increase in the number of cases of lactic acidosis. Other sources of information Literature Other biguanides like phenformin and buphormin, have been withdrawn from the market in the 1970s in many countries because of the risk of lactic acidosis[4]. Lactic acidosis, associated with the use of metformin, however, is a rare event and may occur with an average incidence rate of 3 per 100,000 patient-years [68] Lactic acid accumulations, may especially occur in the presence of predisposing conditions like superimposed shock, renal insufficiency, concurrent heart failure, liver disease or alcohol abuse. A study by Horlen showed that 22 percent of the patients did have one or more contraindications[9]. Also in all patients, reported to Lareb, there were known risk factors for developing a lactic acidosis. 8 Table 1. Reports of lactic acidosis in suspected association with metformin Patient, Sex, age A M, 77 Dose Source Concomitant medication 850 mg 1dd1 pharmacist B M, 51 500 mg 2dd1 specialist furosemide triamterene verapamil digoxin bisacodyl amitryptiyline bromhexine susp insulin nadroparin C M, 50 850 mg 3dd1 specialist D F, 52 850 mg 3dd hospital pharmacist E M, 75 500mg, 2dd specialist F M, 65 500mg 2dd2 specialist G, F, 59 850 mg 2dd specialist adverse Additional drug risk factors reaction lactic acidosis chronic heart failure Time to onset; outcome; remarks lactic acidois hepatic insufficiency 2 weeks recovered Not clear if hepatic insufficiency is cause or result of lactic acidosis. unknown hepatic insufficiency? acenocoumarol digoxin benzbromarone furosemide enalapril tolbutamide venlafaxin acamprosaat lactic acidosis chronic heart multiple failure? organ failure morphine acarbose atenolol Ferro sulfate amlodipine atenolol enalapril/ hydrochlorothiaz. glimepiride simvastatin glimepiride chlortalidone atenolol irbesartan domperidone lactic acidosis renal insufficiency, lactic acidosis alcohol abuse, hepatic cirrhosis. time to onset unknown recovered time to onset unknown Patient died Case report published[10] time to onset unknown patient died lactic acidosis Pyelonephritis, septic shock time to onset unknown patient died lactic acidosis renal insufficiency five years after start patient died 90 80 70 60 50 40 30 20 10 0 1996 1997 1998 1999 2000 2001 Figure 1. The number of dispensed Defined Daily Dosages (DDD=2g) for metformin from 1996 till 2001[3]. 9 Databases The WHO database contains over 2251 reports on lactic acidosis associated with the use of metformin which makes this association is exceptionally disproportional present in the database (ROR 572 (95% CI 524-624)). There is no clear relationship between the annual number of reports submitted to the WHO and the publication of the UKPDS study. Mechanism Serum lactate concentrations are usually not clinically important and less then 2 meq/L with metformin therapy[6]. Additional factors may cause an accumulation of lactic acid, like renal insufficiency leading to high plasma levels of metformin or diseases associated with an impaired tissue perfusion, like concurrent heart failure. Finally, a liver disorder or alcohol abuse may cause increase lactic acid plasma levels due to a decrease in the lactate utilization. Conclusion Lareb received seven reports of lactic acidosis in association with metformin, including six cases reported since metformin is the first choice of treatment and increased dispension. Four patients died. Our reports suggest that, possibly neglected risk factors contribute to this adverse drug reaction. Moreover, risk factors may evolve or aggravate during therapy. Lareb is concerned about the increasing lactic-acidosis-associated morbidity and mortality due to increased prescription, despite proper recommendations in the SPC. Lareb is preparing a publication on this subject. References 1. Rutten GEHM, Verhoeven S, Heine RJ, De Grauw WJC, Cromme PVM, Reenders K, Van Ballegooie E, Wiersma Tj. NHG-Standaard Diabetes Mellitus Type 2 (eerste herziening). Huisarts en Wetenschap 1999;42(2):67-84. 2. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):854-65. 3. Genees- en hulpmiddelen Informatie Project van het College voor Zorgverzekeringen 2003 Mar 1; Number of DDDs of metformin 1996-2002. 4. Krans HMJ. Dukes MNG, Aronson JK, editors.Meyler's side effects of drugs. Amsterdam: Elsevier; 2000; 42, Insulin, glucagon and oral hypoglycemic drugs. p. 1512-5. 5. Dutch Summary of Product Characteristics of Glucophage 2003 http://www.cbgmeb.nl/nl/prodinfo/index.htm (accessed 3 March 2003) 6. Bailey CJ. Biguanides and NIDDM. Diabetes Care 1992;15(6):755-72. 7. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes 1974;23(2):105-11. 8. Bailey CJ, Turner RC. Metformin. N.Engl.J Med. 1996;334(9):574-9. 9. Horlen C, Malone R, Bryant B, Dennis B, Carey T, Pignone M, Rothman R. Frequency of inappropriate metformin prescriptions. JAMA 2002;287(19):2504-5. Lareb is concerned about the increasing lacticacidosis-associated morbidity and mortality due to increased prescription, despite proper recommendations in the SPC 10 1.4. Cyproterone acetate and osteoporosis Introduction Cyproterone acetate (Androcur) is an antiandrogen with progestogenic activity and was granted a marketing authorisation for the Dutch market in 1973. According to the Dutch SPC cyproterone acetate is indicated: in males for the treatment of advanced prostatic carcinoma, hypersexual behaviour disorders and hot flushes associated with orchiectomy or LHRH agonist therapy in males and for the treatment of idiopathic hirsutism and androgenic induced acne and alopecia in females [1]. Adverse effects of cyproterone acetate include impotence, inhibition of spermatogenesis, headache, lassitude, menstrual irregularities, gynecomastia, galactorrhea, weight gain, lipid abnormalities, gastrointestinal disturbances, and anemia; several cases of hepatotoxicity (some fatal) have been reported in the literature. Long-term treatment with androgen-depleting drugs is associated with osteoporosis. Hypogonadism, chronic alcoholism and chronic glucocorticoid therapy are the major cause of osteoporosis in men and account for approximately one-half of all cases of male osteoporosis [2]. Osteoporosis in men seems to occur rarely. Reports The Netherlands Pharmacovigilance Centre Lareb received two reports of osteoporosis in men taking cyproteron acetate (table 1). Patient A, a male aged 39, was reported to have osteoporosis 18 months after start of cyproterone acetate to treat exhibitionism. The therapy was successful but caused gynaecomastia and symptoms of cyproterone acetate induced hypogonadism: reduced frequency of erections, loss of ejaculation and diminished beard growth. A control duplex radiographic absorptiometry (DXA) scan showed a significant reduction of bone mineral density (BMD) at the lumbar region of the spine (L2-L4 T-score –3.3, Z-score -4.0; femoral neck T-score –1.6, Zscore –0.9) indicating osteoporosis [3]. The patient however did not experience any musculosceletal complaints. Physical examination revealed a normal male hair pattern, adiposity (133kg weight and 1.89m height). Both testicles were normal on palpation. Laboratory results: testosterone 4.1 [normal range 14 – 42 nmol/L] was reduced. All other laboratory results (SHBG, TSH, FreeT4, LH, FSH, cortisol, Hb, glucose, kreatinine, calcium, phosphate, AF) were within the normal range indicating absence of hormonal disturbances. Treatment of ® osteoporosis with risedronate (Actonel ) and calcium suppletion was initiated. Patient B, a man aged 52, had been treated for a sexual deviation with cyproterone acetate for ten years. Then, osteoporosis was diagnosed (BMD: T-score –3.4 and Z-score –2.8) [4]. Table 1. Lareb reports of osteoporosis or fractures in males associated with the use of cyproterone acetate (patient B also published as a case report [4]) Patient, Drug age Indication for use A, 39 cyproterone acetate tabl Concomitant medication none reported Suspected adverse drug reaction osteoporosis Time to onset captopril, hydrochlothiazide osteoporosis, hip fracture 10 years after start 1 dd 50mg B, 52 Sexual deviation cyproterone acetate injection 300 mg every 2 weeks Sexual deviation 18 months after start 11 Other sources of information Literature Gooren et al. presented patient B as a case-report in the Lancet [4]. Vasireddy and Swinson published another case report concerning a 58 year-old male with a sexual deviation who had been treated with cyproterone acetate from 1976 –1979. After complaints of pain in the back he was diagnosed to have osteoporotic wedge fractures of dorsal vertebrae in 1987. A DXA-scan in 1992 confirmed a significant reduction in BMD at the spine (L2-L4 T-score –2.46, Zscore –1.96) [5]. Databases In February 2003 the Lareb database contained a grand total of 4 ADR reports with event code osteoporosis. Apart from patient A and patient B listed in the table, osteoporosis was also reported in a female aged 35 - suspected drug oxcarbazepine and in a male aged 51 - suspected drug gosereline. At the end of th the 4 quarter of 2002 the WHO combination database contained 6 reports, ROR 19.2 (8.6-42.9) of osteoporosis in association with cyproterone acetate. Mechanism The underlying mechanism of osteoporosis is the same in men and women: an absolute or relative (to bone formation) increase in osteoclast mediated bone resorption leading to progressive bone loss [5]. Estrogen playes a major role in regulating male bone metabolism: both estrogen and testosterone are important in maintaining bone formation and estrogen regulates bone resorption partly through its action on estrogen-receptor alpha. In the male estrogen is produced by conversion of androgen precursors, mediated by the enzyme aromatase [5]. Therapy with anti-androgens influences bone homeostasis because it interferes with this conversion of androgens into estrogens [5]. Conclusion The Netherlands Pharmacovigilance Centre Lareb received two reports of osteoporosis in men taking cyproteron acetate for a period of months to years for treatment of sexual deviant behaviour. This association is supported by data from the database of the WHO and the literature. Pharmacological plausibility also supports this association. Osteoporosis is not listed as a potential side effect in the Dutch summary of product characteristics of cyproterone acetate (Androcur). References 1. Dutch Summary of Product Characteristics of Androcur (version 20-07-1991) http://www.cbgmeb.nl 2. Smith MR. Osteoporosis and other adverse bodycomposition changes during androgen deprivation therapy for prostate cancer. Cancer Met Rev 2002; 21: 159–66. 3. How does it work? Bone mineral density scans. BMJ 2002; 325: 31 4. Gooren LJG, Lips P, Gijs L. Osteoporosis and androgen-depleting drugs in sexoffenders. Lancet 2001;357:1208-09. 5. Vasireddy S, Swinson DR. Male osteoporosis associated with longterm cyproterone treatment. J. Rheumatology 2001;28:1702-03. Long term use of cyproterone acetate (Androcur) is associated with osteoporosis which is not listed as an adverse drug reaction in the SPC 12 1.5. Fluconazole and fixed drug eruption Introduction Fluconazole (Diflucan) is a triazole antifungal agent. The mechanism of action of fluconazole is similar to that of other imidazole and triazole antifungal agents, specifically, inhibition of fungal cytochrome P-450-dependent ergosterol synthesis and thereby inhibition of cell membrane formation. It appears to have a greater selectivity for fungal as compared to human P-450- enzymes. It was approved for the Dutch Market in 1990 for the following indications: Vaginal candidiasis, (prophylaxis of) oropharyngeal candidiasis, esophageal candidiasis, deep systemic candidiasis, cryptococcal meningitis and as maintenance treatment in patients with AIDS as prevention of a relapse of cryptococcal meningitis [1]. Fluconazole has a long half life, which permits once daily dosing. In vaginal candidiasis single doses of 150 mg have been effective. Commonly observed adverse events are nausea, vomiting and elevations in liver function tests. Observed hypersensitivity reactions are anaphylactic reactions, angioedema and facial oedema, pruritus, urticaria, erythemateous –or maculopapular rash and exfoliative skin reactions, including Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)[1,2]. Reports Lareb received five reports of fixed drug eruption (FDE) on fluconazole capsules between 1996 and 2002 from various healthcare professionals. Fixed drug eruption is a sharply demarcated erythema, oval or circular in shape, which recurs in exactly the same place after following exposure to a specific drug. Usually there is only one lesion, but two or more may be present. The size varies from a few millimetres to 10-20 cm in diameter. Initially it is a dusky red lesion with oedema, followed by development of vesiculae or bullae. Healing takes place with pigmentation. The FDE may be localized on skin and mucous membranes. The first report concerned a 20-year-old woman, known with manifestations of herpes simplex and nickel allergy. She had used fluconazole 200 mg capsules once monthly for vaginal candidiasis for 2 years, when the first episode of FDE appeared. On the day of exposure she experienced redness and swelling on the left side of the lower lip. Afterwards the lesion became pigmented. Each month, after intake of a tablet fluconazole, the lesion recurred. As co medication she used ethinylestradiol/cyproteronacetate. Eight months later fluconazole was discontinued. A post-inflammation hyperpigmentation remained. Lareb received four other reports of FDE in association with use of fluconazole. Twice the inner part of the hand was affected, with formation of blisters. Another report showed a sharp circumscribed flaming red swelling on the right side of the tongue within hours after intake of fluconazole 50 mg. In the last case symptoms existed of redness, itching and vesicles on the right forearm, which occurred four times after intake of fluconazole 150 mg in a 31-year-old woman. Biopsy revealed a superficial and deep perivascular and interstitial inflammation with many leucocytes and violation of the epidermis/dermis boundary. After discontinuation of fluconazole this patient recovered. Other sources of information Literature. Three publications of fixed drug eruption have been published [3,4,5]. In the first publication a 27-year-old man suffered from 15 episodes of FDE on the extensor surfaces of his elbows, each lasting three days and resolving spontaneously to leave residual bluish-gray macules. Biopsy showed spongiosis, hydropic degeneration of the basal layer, a predominantly lymphocytic perivascular 13 infiltrate and dermal melanophages. Each time he had used fluconazole 150 mg for candidal balanitis within hours before symptoms appeared [3]. In another case a local provocation test with 10 % fluconazole in petrolatum applied at the previous lesion of FDE reproduced the eruption clinically and histopathologically [4]. Databases The WHO combinations database contains 17 reports of FDE disproportionally associated with the use of fluconazole (Odds ratio 4.55, 95% CI 2.82 – 7.33). Mechanism The pathogenic mechanism is unknown. In FDE vesiculae or bullae may follow the initial lesion. A re-administration of the suspected drug may result in extensive bullous lesions, which is occasionally so extensive as to mimic TEN [6]. Conclusion Lareb has received five reports of fixed drug eruption on fluconazole. The association between fixed drug eruption and fluconazole is supported by the publications in the literature and findings in the WHO database. Fixed drug eruption is not mentioned as adverse drug reaction in the Dutch SPC of fluconazole. References 1. Dutch summary of product characteristics of Diflucanl (version 11-7-2001) http:/www.cbgmeb.nl/1B-teksten/13038-14767-13039-14768-14769-15757-15758.PDF (accessed 17 Dec 2002) 2. Micromedex Health Base Series, database on line 1974-2002 3. Morgan JM, Carmichael AJ. Fixed drug eruption with fluconazole. BMJ 1994; 308 (6926):454 4. Heikkila H, Timonen K, Stubb S. Fixed drug eruption due to fluconazole. J Am Acad Dermatol. 2000 May:42 (5Pt 2):883-4 5. Ghislain PD, Ghislain E. Fixed drug eruption due to fluconazole: a third case. J Am Acad Dermatol. 2002 Mar;46 (3):467 6. Bruinsma W. A guide to drug eruptions. Side effects in dermatology. 7th edtion 2000. IMP, Amsterdam. Fluconazole is associated with fixed drug eruption Fixed drug eruption is not mentioned as adverse drug reaction in the Dutch SPC of fluconazole 14 1.6. An overview of reports on tiotropium bromide Introduction ® Tiotropium bromide (Spiriva ) is a once-daily long-acting anticholinergic bronchodilator. It was granted a marketing authorisation on 9 October 2001 as bronchodilator for maintenance treatment of chronic obstructive pulmonary disease[1]. The Netherlands act as RMS. Tiotropium is considered a new chemical entity that exerts its action by competitive binding to all three muscarinic receptor sub-types that control smooth muscle function in human airways [2]. Tiotropium exhibits a kinetic receptor subtype selectivity, dissociating rapidly from M2 receptors but slowly from M1 and M3 receptor subtypes hence preventing stimulation of acetylcholine release by negative feedback modulation [3,4]. Tiotropium bromide differs from ipratropium bromide in its longer duration of action and its more rapid M2 receptor dissociation. Like ipratropium bromide it has a quaternary structure which limits absorption and hence systemic bioavailability. Therefore adverse drug reactions based on local anticholinergic reactions will prevail above systemic effects. Adverse drug reactions listed in the SPC include: dry mouth, constipation, moniliasis, sinusitis and faryngitis [1]. The Netherlands Pharmacovigilance Centre provides an overview of the reports it received during the first 1.5 year after approval. Reports Until 1 March 2003 the Netherlands Pharmacovigilance Centre Lareb received 41 reports concerning 66 adverse drug reactions (table 1.). Four of these reports originated from the marketing authorisation holder. Two cases of death were reported. One 66-year-old female patient with chronic heart failure and an ejection fraction of 20%, died 10 days after start of tiotropium bromide. The reporting general practitioner considered causality unlikely. In the same week Lareb received a report from the marketing authorisation holder describing a patient of unknown age and sex with cardiac complaints who died while taking tiotropium bromide in the Netherlands. Follow up information was never received. It cannot be excluded that these 2 reports refer to the same patient. The 4 additional reports that were classified serious included urinary tract infection and sepsis in a patient with prostatitis, urinary retention, chest pain and headache, and a patient with vomiting, dizziness, diarrhoea, and nausea. Other sources of information Literature Most studies describe a dry mouth as the most common adverse drug reaction occurring in 6 to 15% of the patients[2-5]. A search in literature reveals no other adverse drug reactions as mentioned in the SPC. Databases The WHO adverse drug reactions database contains no information on tiotropium. Mechanism The pharmacological mechanism by which tiotropium bromide perceives its effectiveness in the human airways may facilitate anticholinergic adverse drug reactions. It is suggested that structural features limit absorption into the circulation and that the rapid dissociation of the M2 receptor reduces these anticholinergic adverse drug reactions[5]. 15 Table 1. Adverse drug reactions on tiotropium use reported to Lareb per MedDRA system organ class S&O class ADR n S&O class ADR n Card Angina pectoris 1 Inv Weight increase 1 Palpitation 1 Metab Anorexia 2 Dry eyes 1 Nerv Burning sensation 1 Vision abnormal 1 Dizziness 4 Vision blurred 3 Drop attacks 1 Visual disturbance 1 Headache 3 Abdominal discomfort 1 Migraine aggravated 1 Constipation 1 Somnolence 1 Diarrhoea 1 Agitation 1 Gingivitis 1 Paroniria 1 Mouth dry 2 Renal Urinary retention 2 Nausea 1 Resp Asthma aggravated 1 Oedema mouth 1 Dyspnoea 3 Throat sore 1 Hoarseness 1 Vomiting 2 Hyperpigment. skin 1 Chest pain 3 Itching 1 Chest pressure 1 Pruritus 2 Death NOS 2 Rash 3 Feeling strange 1 Rash psoriaform 1 Malaise 3 Sweating increased 1 Mucosal swelling 1 Vesicular eruption 1 Sepsis 1 Vesicular rash 1 Urinary tract infection 1 Eye Gastr Genrl Infec Psych Skin Total 66 Conclusion During the first 1.5 year after granting a marketing authorisation in the Netherlands, 41 reports on tiotropium were received, including 6 serious reports. The pattern of reported adverse drug reactions on tiotropium bromide reflect described adverse drug reactions in SPC and literature. Many of them can be classified as an anticholinergic reaction. However little information from literature is available until now. References 1. Summary of Product Characteristics Spiriva® (version 19-8-2002) http://www.cbg-meb.nl/IBteksten/26191.pdf (accessed 5-3-2003). 2. Hvizdos KM, Goa KL. Tiotropium bromide. Drugs 2002;62(8):1195-203. 3. Disse B, Reichl R, Speck G, Traunecker W, Ludwig Rominger KL, Hammer R. Ba 679 BR, a novel long-acting anticholinergic bronchodilator. Life Sci. 1993;52(5-6):537-44. 4. Barnes PJ, Belvisi MG, Mak JC, Haddad EB, O'Connor B. Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci. 1995;56(11-12):853-9. 5. Casaburi R, Briggs DD, Jr., Donohue JF, Serby CW, Menjoge SS, Witek TJ, Jr. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. Chest 2000;118(5):1294-302. The adverse drug reactions on tiotropium bromide reported to Lareb reflect the SPC 16 2. Publications 1. van Grootheest AC, Vrieling T. Thromboembolism associated with the new contraceptive Yasmin. BMJ 2003;326(7383):257. 2. ten Tusscher MP, Jacobs PJ, Busch MJ, de Graaf L, Diemont WL. Bilateral anterior toxic optic neuropathy and the use of infliximab. BMJ 2003;326(7389):579. 3. van Grootheest AC. Melden nodig voor bewaken veiligheid geneesmiddelen. Geneesmiddelenbulletin 2003;37(1):9. 4. van Puijenbroek EP, van Grootheest AC. Bijwerkingen van geneesmiddelen in de huisartspraktijk. Tijdschr v Huisartsgeneeskunde 2003;20(1):35-8. 5. van Grootheest AC. Bijwerkingen van geneesmiddelen: ervaringen in de praktijk zijn erg belangrijk. NVDA Nieuws 2003;31(2):18-9. 6. de Graaf L, Admiraal P, Van Puijenbroek EP. Ballism associated with bupropion use. Ann.Pharmacother. 2003;37(2):303-4. 17