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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