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Kwartaalbericht
3e kwartaal 2014
16 juli 2014
Contents
Voorwoord
3
1. Observations
4
1.1.
Doxycycline and skin discoloration
4
1.2.
Statins and lichenoid drug eruption
10
1.3.
Statins and muscle rupture
16
1.4.
Tamsulosin and urinary incontinence
22
1.5.
Prednisolone and hiccups
27
1.6.
Atovaquone/ proguanil hydrochloride and psychotic disorder
31
1.7.
Ciclosporin and posterior reversible encephalopathy syndrome
36
2. Publications
43
2
Voorwoord
Waakzaamheid
Klaar om op te stijgen van London City airport staan we gereed op de startbaan.
Het toestel maakt snelheid en draait dan plotseling rechts de baan af. Vanuit het
raampje zie ik een ander vliegtuig dezelfde baan naderen. Blijkbaar moest deze
toch nog vrijgemaakt worden voor dit vliegtuig dat de landing al ingezet had. Een
voorbeeld van een noodzakelijke correctie van een procedure die al in gang gezet
was. Niet zozeer een voorbeeld van foutief handelen dus, maar juist van een
normale voor iedereen acceptabele maatregel die de veiligheid vergroot. Een
parallel met de geneesmiddelenbewaking is snel gelegd. Ook hier moeten we
soms veiligheidsmaatregelen nemen die horen bij het continue proces van
afwegen van de balans tussen baten en risico’s van geneesmiddelen en waar
iedereen zijn voordeel mee doet; kleine correcties die erger kunnen voorkomen.
Enkele voorbeelden van zaken die een mogelijke aanpassing in de voorlichting
en waarschuwing van het gebruik van geneesmiddelen behoeven, treft u ook
weer aan in dit kwartaalbericht. Farmacovigilance heeft tot doel het gebruik van
geneesmiddelen veiliger te maken. Correcties en voorzorgsmaatregelen horen
hier bij. “Viglantia” (lat.) betekent dan ook zowel waakzaamheid als zorg. Precies
wat de verkeersleiding in Londen deed, waakzaam zijn en zorgen voor de
veiligheid. Mijn medepassagiers hadden van het voorval niets gemerkt; ze zaten
ontspannen te wachten op het vertrek.
Eugène van Puijenbroek
3
1. Observations
1.1.
Doxycycline and skin discoloration
Introduction
Doxycycline is an antibiotic belonging to the group of tetracyclines. It is active
against gram positive and gram negative bacteria. It has been on the Dutch
market at least since 1973 and the oral preparation is indicated for infections of
the respiratory tract, infections of the urogenital tract, infections of the skin and
soft tissues, Borrelia burgdorfori infections, infections of the gastrointestinal
tract and eye infection in particular trachoma [1-4].
Photodermatitis or photosensitivity is mentioned as an adverse drug reaction in
the SmPC of doxycycline. The SmPC does not mention skin discoloration or skin
hyperpigmentation [1-4].
Melanocytes are derived embryonically from neural crest cells that migrate into
the basal layer of the epidermis. In the skin, melanocytes continuously produce
melanosomes, organelles that are transferred to keratinocytes. The melanosomes
convert tyrosine to melanin, giving skin its color. Under the stimulus of hormones
or irritation, the production of melanosomes increases, leading to
hyperpigmentation. In response to sun exposure or idiopathically in some
disorders, activation of melanocytes occurs and causes hyperpigmentation. The
same melanocyte concentration is present in persons of all races who have
normal skin. However, some races have larger melanosomes, giving their skin a
darker colour [5].
Drug-induced pigmentation represents 10 to 20% of all cases of acquired
hyperpigmentation [6]. Overall, several mechanisms for drug-induced
pigmentation have so far been described [6,7] and these mechanisms are not
mutually exclusive.
Firstly, the accumulation of melanin, either free in the dermis or contained mainly
within cutaneous cells particularly the dermal macrophages rather than in the
basal layer of the epidermis. This melanin accumulation usually results from
either hyperproduction by epidermal melanocytes specifically stimulated by the
medication or in response to a nonspecific cutaneous inflammation linked to the
drug itself. This mechanism is very often worsened by sun exposure.
Secondly, the accumulation of the triggering medication itself, without any
association to melanin, usually appearing as granules freely scattered among
extracellular matrix elements or included within dermal macrophages that are
unable to eliminate these foreign bodies.
Thirdly, the synthesis of special pigments, such as lipofuscin, probably under the
direct influence of the drug.
Lastly, the deposition of iron, usually resulting from drug-induced damage to
dermal vessels with leakage of red blood cells and subsequent lysis throughout
the dermis [6].
Reports
The Netherlands Pharmacovigilance Centre Lareb received 5 reports of skin
discoloration/hyperpigmentation associated with the use of doxycycline in a
period from 01-10-1999 until 21-06-2013. The reports are listed in table 1.
Table 1. Reports of skin and nail discoloration associated with the use of doxycycline
Patient,
Sex, Age
Drug
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
Action with drug
outcome
4
Patient,
Sex, Age
Drug
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
Action with drug
outcome
A 156211
M, 71 years
and older
Specialist
doctor
doxycycline 3 dd 100
mg
Chronic Q-fever and
infected vessel
prothesis
acetylsalicylic
skin
acid,
hyperpigmentation
esomeprazole,
levothyroxine
sodium, nebivolol,
atorvastatin
9 months
discontinued
not recovered
B 156212
M, 71 years
and older
Specialist
doctor
doxycycline, about 4
months 200 mg daily,
the next 6 months 300
mg daily
Chronic Q-fever
acetylsalicylic
hyperpigmentation
acid, omeprazole, skin
ferrous fumarate,
celecoxib,
tamsulosine with
dutasteride,
prednisolone,
azathioprine,
hydroxychloroquine,
simvastatin.
10 months
discontinued
not recovered
C 102886
F, 61-70
years
Pharmacist
doxycycline 100mg
start 2dd, furthermore
once daily 100 mg
Respiratory infection
discoloration skin
2 days
discontinued
recovered
D 51212
F, 31-40
years
General
Practitioner
doxycycline 100mg
perindopril
1dd
Lower respiratory tract
infection
hyperpigmentation
skin
2 weeks
discontinued
unknown
E 60201
M, 61-70
years
Pharmacist
doxycycline 100mg
1dd
Infection
photosensitivity
reaction,
pigmentation
abnormal
9 days after start,
2 days after
cessation
discontinued
not recovered
Additional information about the cases is described below:
Cases A and B were reported by the same Specialist doctor.
In case C it is described that the skin was black as coal and smooth, there was no
itching or any other symptom. The patient has a light tinted skin color. The latency
period described in this case is short, so possibly sun exposure is a causative
factor.
In case D the hyperpigmentation of the skin was located in the face. There were
brown, not sharply defined, maculae on the forehead. The patient does not have
a history of skin disorders or naevi and she is not pregnant.
In case E the patient went on a holiday in the sun two days after doxycycline was
withdrawn. During the course the patient stayed out of the sun but it was unknown
to him that he should do so when the course had ended. He now has severe and
lasting hyperpigmentation on his nose.
In addition, Lareb received three reports of nail discoloration associated with the
use of doxycycline. In two cases the patient also suffered from onycholysis.
These cases are described in Quarterly Report 2013-2 ‘Doxycycline and photoonycholysis – an update’ [8] as Case A (Reportnumber 25961) and case J
(Reportnumber 139748). Additional report 71069 from a pharmacist concerns a
female aged 51-60 years years, with nail discolouration following administration of
doxycycline (dose twice daily 100 mg) for Lyme’s disease with a latency of two
months after start. Doxycycline was withdrawn. The patient outcome is unknown.
5
Because we could not be certain that the nail discoloration is not a result of the
onycholysis in the first two cases, the focus of this signal was placed on
discoloration of the skin and not the nails.
Other sources of information
SmPC
Photodermatitis or photosensitivity is mentioned as an adverse drug reaction in
the SmPC of doxycycline. The SmPC does not mention skin or nail
hyperpigmentation [1-4].
Literature
Hyperpigmentation of the oral cavity (teeth, mucosa, alveolar bone), skin, nails,
eyes, thyroid and even bone has been reported due to minocycline intake [9-11].
Also for other tetracyclines hyperpigmentation of the skin has been described,
albeit to a lesser extent than for minocycline [12-14]. Pichardo et al. [14]
reported on a 44-year old man who had been treated with doxycycline for three
years, 100 mg twice daily for chronic follicular conjunctivitis. For the last six
months he suffered from progressive, symmetric blue-gray periocular
discoloration. A biopsy from lesional skin showed granular deposits of a brown to
black pigment in the superficial dermis. Eight months after cessation of
doxycycline, the patient had almost completely recovered.
Nail discoloration induced by doxycycline has also been described. Akcam et al.
[15] report on an 11-year-old-boy with nail discoloration caused by doxycycline
intake who was referred to their hospital for evaluation. The history revealed that,
in April 2004, the patient had brucellosis that was treated with doxycycline 200 mg
on the first day and 100 mg daily thereafter, combined with gentamicin for 10
days. Doxycycline therapy was stopped because he developed photosensitivity.
The symptoms of brucellosis resolved, but brown discoloration of the nails
developed after 15 days of doxycycline intake. Physical examination revealed
painless brown discoloration of the fingernails. The oral cavity and teeth had no
changes in colour. The laboratory findings revealed normal hematologic and
biochemical results. The nail discoloration disappeared in one month.
Databases
Table 2. Reports of skin discolouration/hyperpigmention with doxycycline in the databases
of the Netherlands Pharmacovigilance Centre Lareb and the WHO- and Eudravigilance
(EMA) database [16,17].
Database
Preferred Terms
Number of reports
ROR (95% CI)
Lareb
Skin hyperpigmentation
3
3.6 (1.1-11.4)
Skin discolouration
1
-
Pigmentation disorder
1
-
Total
5
1.2 (0.5-3.0)
Skin hyperpigmentation
17
3.6 (2.2-5.7)
Skin discolouration
45
1.3 (1.0-1.8)
Pigmentation disorder
14
3.9 (2.3-6.7)
Total
76
1.8 (1.5-2.3)
Skin hyperpigmentation
8
8.5 (4.2 – 17.1)
Skin discolouration
19
3.6 (2.3 – 5.6)
Pigmentation disorder
5
4.4 (1.8 – 10.6)
WHO
Eudravigilance
6
Database
Preferred Terms
Number of reports
ROR (95% CI)
Total
32
4.4 (3.1 – 6.2)
Prescription data
Table 3. Number of patients using doxycycline in the Netherlands between 2009 and 2013
[18].
Drug
2009
2010
2011
2012
2013
Doxycycline
965,820
933,230
878,230
819,780
739,860
Mechanism
Skin hyperpigmentation induced by minocycline is a well-recognized side effect
but has rarely been reported for other tetracyclines. Several types of minocyclineinduced hyperpigmentation of the skin have been distinguished based on distinct
clinical features and their histopathologic correlates. The first type is
characterized by blue-black pigmentation within areas of scars and previously
inflamed skin; in the second type, blue-gray pigment spots develop in normal skin,
especially on the shins and arms; and the third type is characterized
by a muddy-brown generalized pigmentation, mostly accentuated in sun-exposed
areas [6,19]. This third type is likely caused by increased melanin or melanin–
minocycline complexes at the dermal–epidermal interface [9]. Patient E reported
to Lareb the hyperpigmentation occurred after exposure to the sun, which is also
described for the third type of minocycline induced skin discoloration. Based on a
previously reported unusual case of chronic doxycycline abuse of twelve years in
a psychotic patient [13], Böhm et al. [19] have investigated the nature of the
observed pigment changes in the same patient. The histomorphologic and
ultrastructural changes induced by doxycycline shared several features with
cutaneous hyperpigmentation caused by minocycline. The biophysical findings
further suggest a direct deposition of doxycycline, probably chelated with iron
and/or calcium, within the lesional skin. The authors mention that in the present
case a prolonged suprapharmacologic dosage of doxycycline was used, but that
physicians should watch for pigment changes in patients receiving long-term
therapy.
Discussion and conclusion
The association between doxycycline and skin hyperpigmentation has been
reported to Lareb 5 times and is supported by a statistically significant
disproportionality in the WHO- and Eudravigilance database, as well as cases in
the literature [13,14] and a possible pharmacological mechanism [19]. In
addition, Lareb received three reports of nail discoloration associated with
doxycycline use. However, two of these patients also suffered from onycholysis
and it’s unclear if this was also the cause of the discoloration. Nail discoloration
induced by doxycycline has also been described [15].
Risk factors for tetracycline-induce pigmentary changes include the duration of
treatment, the cumulative dose (risk high above 50g) the presence of previous
skin alterations related to inflammation or excessive sun exposure or the
concomitant intake of other pigmentation- inducing medications [6].
Böhm et al. [19] have speculated on the reason for the apparently much higher
incidence of hyperpigmentation caused by minocycline compared with
doxycycline. Minocycline is the classic antibiotic for patients with acne or rosacea
and may be prescribed for several years. Doxycycline is more commonly used for
acute bacterial infections is usually given for shorter periods. However, case A
and B reported to Lareb used doxycycline chronically for months.
7
According to Böhm et al. [19] the apparently higher incidence of pigment
changes in patients taking minocycline may also be the result of differences in the
chemical structures of minocycline and doxycycline. Doxycycline has a hydroxyl
group at position 5 and a methyl group at position 6, whereas minocycline carries
a para-N, N-dimethylamino group at position 7 of the naphthacene carboxamide
ring. These structural differences create a number of changes in the
physicochemical properties of both tetracyclines. For instance, minocycline is
twice as lipophilic as doxycycline and penetrates more easily in tissues.
For minocycline it has been described that pigmentation of the skin and nails
may require months to years to fade after discontinuation of the drug, and other
sites may remain permanently discoloured [10]. For doxycycline Lareb has also
received cases of patients who had not recovered from the hyperpigmentation at
the moment of reporting.
Based on the available information for this association, skin hyperpigmentation
should be explicitly mentioned in the SmPC of doxycycline in addition to the
photodermatitis/photosensitivity reactions.
 Skin discoloration should be
mentioned in the SmPC of
doxycycline
References
1. Dutch SmPC Doxycycline 100 mg PCH, omhulde tabletten 100 mg. (version date: 12-4-2012,
access date: 16-1-2013) http://db.cbg-meb.nl/IB-teksten/h09519.pdf.
2. Dutch SmPC Doxycycline Actavis Disper 100 mg, tabletten. (version date: 29-11-2006, access
date: 16-1-2013) http://db.cbg-meb.nl/IB-teksten/h12871.pdf.
3. Dutch SmPC Doxycycline dispergeerbaar ratiopharm 100 mg, tabletten. (version date: 21-5-2012,
access date: 16-1-2013) http://db.cbg-meb.nl/IB-teksten/h16491.pdf.
4. Dutch SmPC Efracea, capsules met gereguleerde afgifte, hard 40 mg. (version date: 21-7-0012,
access date: 16-1-2013) http://db.cbg-meb.nl/IB-teksten/h33759.pdf.
5. Stulberg DL, Clark N, Tovey D. Common hyperpigmentation disorders in adults: Part II.
Melanoma, seborrheic keratoses, acanthosis nigricans, melasma, diabetic dermopathy, tinea
versicolor, and postinflammatory hyperpigmentation. Am.Fam.Physician 2003;68(10):1963-8.
6. Dereure O. Drug-induced skin pigmentation. Epidemiology, diagnosis and treatment.
Am.J.Clin.Dermatol. 2001;2(4):253-62.
7. Butler, D. F. Drug-Induced Pigmentation. (version date: 28-9-2012, access date: 15-4-2014)
http://emedicine.medscape.com/article/1069686-overview#a0104.
8. The Netherlands Pharmacovigilance Centre Lareb. Doxycycline and photo-onycholysis – an
update. (version date: 1-6-2013, access date: 15-4-2014)
http://www.lareb.nl/Signalen/KWB_2013_2_doxycycline_photo-onycholysis_WEB.aspx.
9. Tavares J, Leung WW. Discoloration of nail beds and skin from minocycline. CMAJ.
2011;183(2):224
10. Eisen D, Hakim MD. Minocycline-induced pigmentation. Incidence, prevention and management.
Drug Saf 1998;18(6):431-40.
11. Pandit S, Hadden W. Black pigmentation of bone due to long-term minocycline use. Surgeon.
2004;2(4):236-7.
12. Hawfield W, Goodrich R, Warren S, Morrell D. Trauma-induced cutaneous pigmentation from
tetracycline: a case report. Pediatr.Dermatol. 2004;21(2):164-6.
13. Westermann GW, Bohm M, Bonsmann G, Rahn KH, Kisters K. Chronic intoxication by doxycycline
use for more than 12 years. J.Intern.Med. 1999;246(6):591-2.
14. Pichardo RO, Yeatts RP, Sangueza OP. Doxycycline-inducted Cutaneous Hyperpigmentation.
[Abstract] American Journal of Dermatopathology: 2006;28(3):325
15. Akcam M, Artan R, Akcam FZ, Yilmaz A. Nail discoloration induced by doxycycline.
Pediatr.Infect.Dis.J. 2005;24(9):845-6.
16. Uppsala Monitoring Centre. WHO Global Individual Case Safety Reports database (Vigibase).
(version date: 2014, access date: 23-4-2014) https://tools.who-umc.org/webroot/ (access
restricted).
17. European medicines Agency. Eudravigilance database. (version date: 2014, access date: 23-42014) http://bi.eudra.org (access restricted).
8
18. College for Health Insurances. GIP database. (version date: 9-6-2009, access date: 16-3-2011)
http://www.gipdatabank.nl/index.asp?scherm=tabellenFrameSet&infoType=g&tabel=01basis&item=J01FF.
19. Bohm M, Schmidt PF, Lodding B, Uphoff H, Westermann G, Luger TA, Bonsmann G, Metze D.
Cutaneous hyperpigmentation induced by doxycycline: histochemical and ultrastructural
examination, laser microprobe mass analysis, and cathodoluminescence. Am.J.Dermatopathol.
2002;24(4):345-50.
9
1.2.
Statins and lichenoid drug eruption
Introduction
Statins inhibit the enzyme HMG-CoA (3-hydroxy-methylglutaryl-coenzyme Areductase, which plays an important role in the synthesis of cholesterol by
catalysing the conversion from HMG-CoA to mevalonate. Statins are indicated for
hypercholesterolemia. They are effective in both the primary and the secondary
prevention of ischemic heart diseases and stroke prevention. Among the statins
simvastatin (Zocor®) was granted marketing authorization in the eighties,
atorvastatin (Lipitor®), pravastatin (Selektine®) and fluvastatin (Lescol®) in the
nineties, rosuvastatin (Crestor®) in 2002 and pitavastatin (Vezepra®, Livazo®) in
2010. Common adverse skin reactions in this group are urticaria, eczema,
dermatitis, skin eruption, pruritus, alopecia and angioneurotic edema. Beside
these, several serious skin reactions are described [1-7].
Lichen planus (LP) is an inflammatory, pruritic disease of the skin and mucous
membranes, which can be either generalized or localized. It is characterized by
distinctive purplish, flat-topped papules having a predilection for the trunk and
flexor surfaces. On the surface often white stripes (Wickham’s striae) might be
visible. The lesions may be discrete or coalesce to form plaques. Histologically,
there is a "saw-tooth" pattern of epidermal hyperplasia and vacuolar alteration of
the basal layer of the epidermis along with an intense upper dermal inflammatory
infiltrate composed predominantly of T-cells. The etiology is unknown. It occurs in
the general population at a rate of 0.9-1.2 % and oral lesions may be seen in 3070 % of these patients. It affects men and women almost equally and it is likely to
start in middle age. It is diagnosed on clinical symptoms and biopsy can confirm
the diagnosis. It is a self-limiting disease, but recovery might be slow an remission
occurs in 1-2 years; oral lichen seems to follow a more chronic course, with a
mean duration of 4.5 years [8,9].
Drug induced lichenoid eruptions (LDE)* can differ in clinical (and histological)
aspects from lichen planus; next to lichenoid elements, LDE may be accompanied
with papular, scaling and eczematous lesions. The predilection sites are rarely
involved. On the other hand LDE produces lesions that might be clinically and
histologically indistinguishable from idiopathic LP. The two conditions can be
differentiated only by the time course of skin or mucous membrane involvement in
relation to drug administration and by re-challenging with the suspected agent.
Frequently the lichenoid eruptions occur a few months after starting the drug, but
the latency may very between days to several years. Clearance of symptoms can
occur within a few weeks after withdrawal of the drug; in some reports the healing
period stretched from less than a week to many months. In some single case
reports, symptoms cleared without discontinuation of the drug, in another study
with oral LDE patients did not recover after withdrawal of the drug. Similar as in
idiopathic lichen planus LDE results in hyperpigmentation, which regresses slowly
or even can be irreversible. Histologic differences between LP an LDE are often
subtle and not reliable. The dermal infiltrate (as well as peripheral blood) may
contain eosinophils and plasma cells and may sometimes be distinguished from
the infiltrate in LP [8,10].
* A reliable differentiation between lichenoid drug eruption an drug induced lichen
planus cannot be made, therefore the term lichenoid drug eruptions (LDE) is
used [8].
The current observation describes the association between statins and lichenoid
drug eruptions in 13 patients. A previous report regarding this association in 4
patients has been sent to the Medical Evaluation Board in 2004 [11].
10
Reports
Lareb received 13 reports of lichen planus or lichenoid dermatitis associated with
the use of statins, in a period from July 18, 1996 till April 3, 2014. The reports
are listed in Table 1. In one patient (D) biopsy results confirmed the diagnosis. In
four other cases (B,E,I,L) the diagnosis was confirmed by a dermatologist.
Table 1. Reports of lichenoid drug eruptions associated with the use of statins
Patient,
Number,
Sex, Age,
Source
Drug, daily dose
Indication for use
A 14687
F, 51-60
years
Hospital
Pharmacist
simvastatin, 20mg
daily
pure hypercholesterolaemia
B 35066
F, 51-60
years
Pharmacist
atorvastatin 20mg
daily
C 37816
M, 61-70
years
General
Practitioner
Concomitant
Medication
Suspected
adverse drug
reaction
Time to onset,
Action with drug
outcome
dermatitis
lichenoid
unknown (”soon”)
no change
recovering
carbasalate calcium
ibuprofen
lichen planus
12-14 weeks
discontinued
not yet recovered
atorvastatin 20mg
daily
pure hypercholesterolaemia
carbasalate calcium
diclofenac
nitroglycerin
isosorbide dinitrate
metoprolol
dermatitis
lichenoid
2 weeks
no change
unknown
D 43561
M or F
General
Practitioner
simvastatin 10mg daily
diazepam
diclofenac
therapeutic
response
unexpected with
drug
substitution,
dermatitis
lichenoid
unknown
discontinued
recovered
E 48214
F, 51-60
years
Specialist
doctor
simvastatin 20mg daily
pure hypercholesterolaemia
lichen planus
15 years
no change
unknown
F 53337
F, 51-60
years
Pharmacist
atorvastatin 40mg
daily hypercholesterolaemia
ezetimibe 10mg
hypercholesterolaemia
furosemide,
captopril
acetylsalicylic acid
esomeprazole
metoprolol
nitroclycerin transdermal
betahistin
lichen planus
6 years
G 119392
F, 71 years
and older
Pharmacist
simvastatin 20mg daily
hypercholesterolaemia
macrogol/
electrolytes
vitamin B1, B6, B12,
lamotrigine,
miconazole vaginal
oxazepam
omeprazole,
metoprolol
telmisartan/hydrochlorothiazide
sucralfate
lichen planus
2-3 months
no change
not recovered
H 129411
F, 51-60
years
atorvastatin 20mg
daily
hypercholesterolaemia
lichen planus
3 months
discontinued
recovering
4 months
both discontinued
recovering
11
Consumer
I 133942
F, 51-60
years
Consumer
simvastatin 10 mg
daily
hypercholesterolaemia
metformin
irbesartan
lichen planus
< 2 years
discontinued
recovering
J 136378
F, 61-70
years
Pharmacist
simvastatin 20mg daily
hypercholesterolaemia
omeprazole
enalapril
amlodipine
lichen planus on
lower legs and
arms
18 months
discontinued
not yet recovered*
K 146716
M, 61-70
years
Pharmacist
simvastatin 20 mg
daily
hypercholesteraemia
dermatitis
lichenoid
6-7 years
discontinued
unknown**
L 148414
F, 61-70
years
Specialist
doctor
(student)
atorvastatin 20 mg
daily
hypercholesterolaemia
enalapril
triamterene/hydrochl
orothiazide 50/25
metoprolol
dermatitis
lichenoid
1 week
discontinued
recovered
simvastatin 20 mg
daily
hypercholesterolaemia
bisoprolol
fluticasone
carbasalate calcium
ranitidin
lichen planus
1 year
discontinued
recovering
M 172669
F, 51-60
years
Pharmacist
* Report sent at date of discontinuation
**Patient switched to atorvastatin
Other sources of information
SmPC
Lichenoid drug eruptions, including lichen planus, are not mentioned in the
SmPCs of atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin and
pitavastatin [1-7].
Literature
Case reports of lichenoid drug eruptions have been described in association with
simvastatin [12,13] pravastatin [14,15], fluvastatin and lovastatin [16].
Roger et al. described a case of a 57-year-old woman with a pruritic,
erythematous eruption of polygonal papules on her wrists and elbows one month
after starting simvastatin 10 mg once daily. She used no concomitant medication.
Patient did not recover after treatment with a topical corticosteroid. Simvastatin
has been withdrawn and the rash resolved four weeks later. The rash
reassembled a lichenoid drug eruption and histopathology was also compatible
with a lichenoid eruption [12].
Stoebner et al. described a 63-year-old man, who was treated with simvastatin
for hypercholesterolemia. After one month he developed a pruriginous and
bullous lichenoid eruption. Histological and direct immunofluorescent features
were consistent with the diagnosis of lichen planus pemphigoides. After two
months use, simvastatin was discontinued. He was treated with a topical class II
corticosteroid during one week. Four weeks hereafter the itching had vanished
and no new lesions had appeared. Three months later he had recovered with only
some hyperpigmentated sequelae [13].
Pravastatin-induced LDE was first reported in a 75-year-old black patient who
developed a lichenoid rash, on the extensor surfaces of the arms and dorsal
12
aspect of the hands, 3 weeks after starting pravastatin at a dose of 10 mg daily.
Clinical examination revealed multiple scattered, polygonal, erythematous
plaques and papules with a translucent, shiny scale and the diagnosis of a
lichenoid drug eruption was confirmed on histopathological examination of a skin
biopsy. Discontinuation of pravastatin led to resolution with mild postinflammatory
hyperpigmentation in two weeks’ time. Upon re-challenge, the rash reappeared
within 1 week [14].
A case of pravastatin-induced diffuse and numerous pigmented macules on the
face and upper back was described in a 64 year old woman. Histopathological
examination showed a lichenoid dermatitis. Three months before, pravastatin had
been added to her treatment regime, because of an acute coronary syndrome.
Cessation of pravastatin resulted in gradual fading of pigmentation over a 9
months period. All other chronic medications, including furosemide and
candesartan – which both can cause also LDE- had been continued [15].
Sebök described a case of a 59-year old woman with bilateral pruritic, papulous
eruption on the dorsal side of her forearms, hands and on the volar surfaces of
her wrists, on the soles and to a lesser extent on her trunk and thighs four weeks
after starting fluvastatin. Topical steroids had only a temporary effect. The
antihypertensive treatment, perindopril, was continued. After discontinuation of
fluvastatin and treatment with mometason-furoate, the lesions cleared after three
weeks. Two weeks later, lovastatin was introduced, because of an increase in
cholesterol levels. The eruption recurred. Biopsy showed a lichenoid dermatitis.
After stopping lovastatin, recovery was observed within three weeks, leaving postinflammatory hyperpigmented macules [16].
Databases
Table 2. Reports of lichen planus/lichenoid dermatitis with statins in the databases of the
Netherlands Pharmacovigilance Centre Lareb, the WHO- and Eudravigilance (EMA)
database [17,18].
Database
Preferred Terms
Number of reports
ROR (95% CI)
Lareb
Lichen planus
8
4.3 (2.3-10.4)
Lichenoid dermatitis*
5
5.7 (2.2-15.1)
WHO
Lichen planus
91
5.3 (4.3-6.6)
Eudravigilance
Lichen planus
31
3.2 (2.3 -4.7)
*Lichenoid dermatitis is the Lower Level Term; the corresponding MedDRA Preferred Term Lichenoid
keratosis is not appropriate
Prescription data
Table 3. Number of patients using statins in the Netherlands between 2009 and
2013 [19].
Drug
2009
2010
2011
2012
2013
simvastatin
826,190
930,700
980,250
pravastatin
164,470
170,080
169,640
170,760
171,410
fluvastatin
23,113
22,181
21,667
21,474
20,937
1,044,000 1,084,000
13
Drug
2009
2010
2011
atorvastatin
394,750
375,810
rosuvastatin
179,010
Total
2012
2013
364,900
383,670
412,580
181,230
191,890
209,550
221,690
1.507.000 1.594.000
1.662.000
1.751.000 1.827.000
Mechanism
The pathogenic mechanism of LDE is not well understood, a type IV allergy is
sometimes involved. A dose dependency is suggested. Some drugs change
surface antigens, whereas other drugs change enzyme systems. These
aberrations may precipitate an immune response, in which cytotoxic CD8+ T cells
are activated, which then cause epidermal damage [8,10]. For statins no specific
mechanism is described.
Discussion and conclusion
Lareb has received 13 reports of lichen planus and lichenoid dermatitis in
association with statins; in one case a lichenoid dermatitis occurred after drug
substitution of simvastatin and in one case also ezetimibe was reported as
suspected drug.
In one patient (D) biopsy results confirmed the diagnosis. In four other cases
(B,E,I,L) reporting was done by a dermatologist or patients had been referred to a
dermatologist, therefore a reliable diagnosis was assumed.
As is described by Ellgehausen it is difficult to distinguish LDE form idiopathic
lichen planus, clinically as well as histologically [8]. The time course in relation to
drug administration of the suspected agent might be of help, but may also vary
between days and years. In the reported cases to Lareb, the latency in most
patients was several weeks.
According to Ellgehausen, the clearance of symptoms in LDE might vary from a
week to many months or can be irreversible. Therefore idiopathic lichen planus
cannot be ruled out easily. Of the thirteen cases reported to Lareb, five had
recovered or were recovering after discontinuation of the statins at the moment of
reporting; in one case also the suspected ezetimibe was discontinued. Four of
these patients had also been treated with either topical corticosteroids, light
treatment or acupuncture. Recovery took weeks to several months. In three of
these patients several concomitant medications were used, which are known to
be associated with lichenenoid eruptions as well, including bisoprolol, metoprolol,
hydrochlorothiazide and/or enalapril/captopril. These medications were however
continued during the recovering phase, which strengthens an association with
the statin.
The association was supported by the WHO- and Eudravigilance data and by
several publications; in one of these even a positive re-challenge was observed
after re-introduction of a statin.
It is of importance to acknowledge the possible role of statins in a patient with
lichenoid eruption, which might have a major influence on well-being.
Discontinuation of these statins might result in a substantial improvement in
symptoms.
For this reason, it is suggested statins might have a causative role in the
occurrence of lichenoid drug eruption.
14

Lichenoid drug eruptions should be mentioned
in the SmPC of statins
References
1. Dutch SmPC Lescol®. (version date: 1-11-2013, access date: 3-4-2014) http://db.cbg-meb.nl/IBteksten/h18719.pdf.
2. Dutch SmPC Zocor®. (version date: 31-12-2013, access date: 3-4-2014) http://db.cbg-meb.nl/IBteksten/h13193.pdf.
3. Dutch SmPC Lipitor®. (version date: 2-1-2014, access date: 3-4-2014) http://db.cbg-meb.nl/IBteksten/h21081.pdf.
4. Dutch SmPC Selektine®. (version date: 30-4-2013, access date: 3-4-2014) http://db.cbgmeb.nl/IB-teksten/h13755.pdf.
5. Dutch SmPC Crestor®. (version date: 23-12-2013, access date: 3-4-2014) http://db.cbg-meb.nl/IBteksten/h26872.pdf.
6. Dutch SmPC Vezepra®. (version date: 19-8-2012, access date: 22-4-2014) http://db.cbgmeb.nl/IB-teksten/h103422.pdf.
7. Dutch SmPC Livazo®. (version date: 19-8-2012, access date: 22-4-2014) http://db.cbg-meb.nl/IBteksten/h103768.pdf.
8. Ellgehausen P, Elsner P, Burg G. Drug-induced lichen planus. Clin.Dermatol. 1998;16(3):325-32.
9. Thompson DF, Skaehill PA. Drug-induced lichen planus. Pharmacotherapy 1994;14(5):561-71.
10. Mulder WMC, editor. Side effects in dermatology. Naarden: IMP; 2009.
11. Netherlands Pharmacovigilance Centre Lareb. HMG-CoA-reductase inhibitors and lichenoid
eruption. (version date: 2004, access date: 22-4-2014)
http://www.lareb.nl/Signalen/kwb_2004_2_stati2.
12. Roger D, Rolle F, Labrousse F, Brosset A, Bonnetblanc JM. Simvastatin-induced lichenoid drug
eruption. Clin.Exp.Dermatol. 1994;19(1):88-9.
13. Stoebner PE, Michot C, Ligeron C, Durand L, Meynadier J, Meunier L. [Simvastatin-induced lichen
planus pemphigoides]. Ann.Dermatol.Venereol. 2003;130(2 Pt 1):187-90.
14. Keough GC, Richardson TT, Grabski WJ. Pravastatin-induced lichenoid drug eruption. Cutis
1998;61(2):98-100.
15. Pua VS, Scolyer RA, Barnetson RS. Pravastatin-induced lichenoid drug eruption.
Australas.J.Dermatol. 2006;47(1):57-9.
16. Sebok B, Toth M, Anga B, Harangi F, Schneider I. Lichenoid drug eruption with HMG-CoA
reductase inhibitors (fluvastatin and lovastatin). Acta Derm.Venereol. 2004;84(3):229-30.
17. WHO Global Individual Case Safety Reports database (Vigibase). (version date: 2014, access
date: 23-4-2014) https://tools.who-umc.org/webroot/ (access restricted).
18. Eudravigilance database. (version date: 2014, access date: 23-4-2014) http://bi.eudra.org (access
restricted).
19. College for health insurances. GIP database. (version date: 7-3-2014, access date: 15-4-2014)
http://www.gipdatabank.nl/.
15
1.3.
Statins and muscle rupture
Introduction
Statins inhibit the enzyme 3-hydroxy-methylglutaryl-co-enzyme A-reductase
(HMG-CoA-reductase), which plays an essential role in the synthesis of
cholesterol by catalysing the conversion from HMG-CoA to mevalonate [1].
Statins are indicated for hypercholesterolemia. They are effective in both the
primary and the secondary prevention of ischemic heart diseases and stroke
prevention [2-4]. Over the past decades, several statins have been granted
marketing authorization in the Netherlands, including simvastatin (Zocor®),
pravastatin (Selektine®), fluvastatin (Lescol®), atorvastatin (Lipitor®), rosuvastatin
(Crestor®) and more recently pitavastatin (Vezepra®, Livazo®) [1].
One of the most important and well-known ADRs of statins are the
musculoskeletal ADRs; including myalgia, muscle cramp, myopathy, myositis
and rhabdomyolysis [1,5-11]. It is important to differentiate myalgia from
myopathy and myositis. Although myopathy and myositis may cause myalgia,
most individuals with myalgia have neither [12]. The risk for myopathy is
increased by higher doses, predisposing factors (renal failure,
hypothyroidism, personal or family history of hereditary muscular disorders,
history of muscular toxicity caused by a statin or fibrate, history of liver
disease and/or alcohol abuse, female sex, and age >65 years) and in
combination with other drugs, in particular fibrates [1].
A muscle rupture is a contraction-induced injury in which muscle fibres tear. It
mostly occurs as a result of a powerful eccentric contraction or overstretching
of the muscle and is therefore a typical injury during explosive movements,
such as sprinting, lunging or jumping [13]. Historically, acute muscle injuries
have been classified as strains (grade I), partial tears (grade II) and complete
tears (grade III) [14]. Spontaneous muscle ruptures that occur without intense
muscle contraction are very rare.
Reports
The Netherlands Pharmacovigilance Centre Lareb received 11 reports on muscle
rupture associated with the use of statins, in the period from 22 February 2006
until 12 January 2014. The reports are listed in Table 1.
Table 1. Reports of muscle rupture associated with the use of statins.
Patient,
Number,
Sex, Age,
Source
Drug, daily dose
Indication for use
Concomitant
Medication
Suspected adverse
drug reaction
Time to onset,
Action with
drug,
outcome
A, 166606,
M, 61-70
years,
physician
simvastatin, 1dd
40mg, secondary
prevention CVA
baclofen,
clopidogrel,
lisinopril,
valsartan,
tamsulosin,
hydrochlorothiazide,
venlafaxine,
nifedipine
muscle rupture
15 month,
withdrawn,
recovering
B, 158137,
F, 61-70
years,
physician
simvastatin, 1dd
40mg,
hypercholesterola
emia
salmeterol/fluticas
one, calcium
carbonate/colecalc
iferol, fluticasone,
zolpidem,
pramipexole,
muscle rupture
8 months,
withdrawn,
unknown
16
omeprazole,
oxazepam,
ibuprofen
C, 154672,
F, 51-60
years,
physician
rosuvastatin, 1dd
10mg,
hypercholesterola
emia
pramipexole
muscle rupture
7 months,
withdrawn,
recovering
D, 152410,
M, 41-50
years,
consumer
atorvastatin, 1dd
20mg,
cardiovascular
disorder
metoprolol
muscle rupture, back
pain, myalgia, liver
enzyme abnormal,
stools abnormal
1 month,
withdrawn,
recovered
E, 115957,
M, 61-70
years,
pharmacist
atorvastatin, 1dd
10mg, cardiac
arrhythmia
phenprocoumon,
digoxin, metoprolol
muscle rupture
5 years,
continued,
recovered
F, 128372,
F, 71 years
and older,
consumer
pravastatin, 1dd
20mg,
hypertension
ezetimib
muscle rupture,
myalgia
4 months,
withdrawn,
unknown
G, 86755,
M, 51-60
years,
nurse
pravastatin, 1dd
10mg,
hypercholesterola
emia
muscle rupture,
tendon rupture
within 1 month,
withdrawn,
recovered with
sequel
H, 83259,
M, 61-70
years,
physician
rosuvastatin, 1dd
10mg,
hypercholesterola
emia
ofloxacine, 1dd
400mg, prostatitis
muscle rupture, drug
interaction
2 years / 3 days,
continued /
withdrawn,
unknown
I, 70663, M,
physician
fluvastatin 20mg
muscle rupture
7 years,
withdrawn,
unknown
J, 58917, M,
41-50
years,
specialist
doctor
rosuvastatin 1dd
40mg,
hypercholesterola
emia
muscle rupture
months,
withdrawn,
recovered
K, 55786,
M, 61-70
years,
specialist
doctor
fluvastatin,
hypercholesterola
emia, diltiazem,
coronary artery
disease
muscle rupture,
tendon rupture
5 years,
withdrawn,
unknown
omeprazole,
metoprolol,
ramipril,
lercanidipine,
hydrochlorothiazide/valsartan,
povidone
acetylsalicylic
acid, quinapril
Case A describes a patient with first a rupture of his left biceps and second a
rupture of his right biceps. The patient was a highly trained athlete in the period
before the ruptures occurred.
Case B describes a partial rupture of the biceps muscle.
Case C describes a rupture of the calf muscle. Within several months the patient
experienced three spontaneous muscle ruptures of the calf in both legs. The
muscle rupture did not occur during exercise or lunging, but during normal daily
activities. The earlier muscle ruptures were misdiagnosed as thrombophlebitis.
This report involves the third rupture, which was a rupture of the medial head of
the gastrocnemius muscle. This was confirmed by a physiotherapist. In the period
of the occurrence of the first muscle rupture, creatine kinase (CK) level was 123
U/L. Four months later the CK level was 190 U/L. Again one month later, at the
17
moment of the third muscle rupture, CK level was 156 U/L. CK levels after the
withdrawal of rosuvastatin were unknown.
Case D describes a muscle rupture during exercise. During earlier treatment with
simvastatin the patient was suffering from musculoskeletal pain and had
increased liver enzymes.
Case E describes a rupture of the hamstring. The patient twice experienced a
hamstring injury in the past. It is unknown if the patient was treated with statins
during the occurrence of the previous hamstring injuries.
Case F describes a spontaneous rupture of the right biceps and rupture of a knee
ligament.
Case G describes a patient who was treated with atorvastatin prior to the
treatment with pravastatin. Case H describes a rupture of the right calf muscle
that occurred spontaneously while standing. In this case it cannot ruled out that
the muscle rupture is caused by the treatment with ofloxacine.
Case I describes that the deterioration continued after withdrawal of fluvastatin.
Later the situation stabilised.
Case J describes an obese patient (BMI: 32.8 kg/m 2) who experienced three
muscle ruptures during treatment with rosuvastatin. The patient suffered from
myalgia during earlier treatment with atorvastatin. The patient was physically
active. At the moment atorvastatin was withdrawn and rosuvastatin was started
CK levels were 212 U/L. At the moment of the first muscle rupture the CK level
was 310 U/L. In the month that rosuvastatin was withdrawn the CK level was 121
U/L.
Case K describes a patient with a rupture of muscles and tendons of both biceps
and both quadriceps. CK levels were 88 U/L, which is within the normal range of
20-200 U/L for men, nine months after the withdrawal of fluvastatin.
In 2 cases (B and C) the reporter explicitly stated that the rupture was not a
rupture of the tendon. In two cases (D and J) exercise could have played a role in
the occurrence of the muscle rupture. In five cases (B, E, G, I and K) it was
unknown if the muscle rupture occurred during exercise or during normal daily
activities. In four cases (A, C, F and H) it was mentioned that the muscle rupture
occurred spontaneously during normal daily activities. It is remarkable that only
two reports (D and F) mentioned myalgia as an ADR.
Other sources of information
SmPC
The SmPCs of statins available on the Dutch market do not mention muscle
rupture as an ADR [5-9]. However they do mention, except for fluvastatin [7] and
pitavastatin [10,11], tendon rupture as a possible ADR [5,6,8,9].
The US SPCs of statins available on the US market do not mention muscle
rupture as a possible ADR [15-21]. Only the US SmPC of atorvastatin mentions
tendon rupture as a possible ADR [16].
Literature
Myotoxicity can occur during treatment with statins. Possible ADRs that are
described in literature are myalgia, muscle cramps, myositis, rhabdomyolysis and
increased serum levels of creatine kinase. Tendon ruptures are also described
[22,23].
Mansi et al. reported for the first time that statin use was associated with
increased risk of dislocation/strain/sprain and maybe osteoarthritis [22]. An
association between treatment with statins and muscle rupture has not been
described in literature.
18
Databases
Table 2. Total reports of muscle rupture associated with statins in the databases of Lareb
[24], WHO [25] and EMA [26].
Drug
Number of reports
Combined ROR (95% CI)
statins
Lareb: 11
WHO: 107
Eudravigilance: 118
24.1 (10.6 – 54.6)
11.7 (9.5 – 14.4)
13.1 (10.7 – 16.0)
Prescription data
Table 3. Total number of patients using statins in the Netherlands between 2009 and 2013
[27].
statines
2009
1,507,000
2010
1,594,000
2011
1,662,000
2012
1,751,000
2013
1,827,000
Mechanism
It is plausible that myotoxicity can predispose muscles to tear. Many hypothesis
have been proposed to explain the myotoxicity caused by statin use. Statins can
weaken the integrity of skeletal muscles by reducing the cholesterol content in cell
membranes. Another theory explains the myotoxicity by a reduction in the
availability of the isoprenoid cometabolites farnesyl pyrophosphate (FPP) and
geranylgeranyl pyrophosphate (G-PP), causing a reduction in the prenylation of
small guanosine triphosphate-binding proteins, such as Rac, Rho, and Ras, which
is thought to result in apoptosis of muscle cells. Statins catalyzes the synthesis of
mevalonate. Mevalonate is an important precursor of cholesterol, but also of
ubiquinone (coenzyme Q), dolichol, and isopentenyl adenosine. Deficiencies in
these products may affect the membrane of the myocyte adversely, predisposing
the cell to myotoxic consequences. In addition, statins induce a sustained
increase in cytosolic Ca2+ levels, which could lead to muscle dysfunction and
dysregulation. Statin use can also lead to secondary carnitine deficiency that
clinically may manifest as myositis and/or myalgia. Some evidence suggests that
statins can inhibit lactic acid efflux from myocytes and thereby induce damage to
muscle cells. Alterations of protein synthesis and protein degradation have also
been implicated in statin-induced myotoxicity [28].
Draeger et al. performed a study to further investigate the mechanism that
mediated statin-induced skeletal muscle damage. Skeletal muscle biopsies from
statin users who were asymptomatic were examined and compared with skeletal
muscle biopsies from non-statin-users, using both electron microscopy and
biochemical approaches. The study shows a clear evidence of skeletal muscle
damage in statin-users, with a characteristic pattern that includes breakdown of
the T-tubular system and subsarcolemmal rupture. These characteristic structural
abnormalities were reproduced by extraction of cholesterol from skeletal muscle
fibers in vitro. The authors hypothesize that statin-induced cholesterol lowering
contributes to myocyte damage, regardless of whether the patient is symptomatic.
This could explain why only two casus describe myalgia as an ADR. The
sophisticated membrane architecture with its unique lipid/protein segregation of
the skeletal muscle accounts for the vulnerability of skeletal muscle sarcolemma
[29].
Discussion and conclusion
Lareb received 11 reports of muscle rupture associated with the use of statins.
The association showed strong significant disproportionality in the Lareb, WHO
and Eudravigilance database. Despite that the association has not been
19
described in literature, it is plausible that statin-induced myotoxicity can
predispose muscles to tear. Myotoxicity is a well-known ADR of statins [22]. Our
data suggests that statin-induced muscle rupture can occur without intense
muscle contraction and without the presence of myalgia. The association of
muscle rupture with the use of statins is a new signal.

Further investigation of the
marketing authorization holder and
other national centres is needed to
evaluate the signal
References
1. KNMP. Informatorium Medicamentorum. (version date: 2014, access date: 14-4-2014)
http://kennisbank.knmp.nl/index.asp#IMG1030.
2. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey SG, Ward K, Ebrahim S. Statins
for the primary prevention of cardiovascular disease. Cochrane.Database.Syst.Rev.
2013;1:CD004816
3. Ward S, Lloyd JM, Pandor A, Holmes M, Ara R, Ryan A, Yeo W, Payne N. A systematic review
and economic evaluation of statins for the prevention of coronary events. Health Technol.Assess.
2007;11(14):1-iv
4. Elley CR. ACP Journal Club. Review: Statins reduce mortality and major vascular events in
patients with no history of CV disease. Ann.Intern.Med. 2013;159(2):JC2
5. SPC Zocor®. (version date: 31-12-2013, access date: 14-4-2014) http://db.cbg-meb.nl/IBteksten/h13194.pdf.
6. SPC Lipitor®. (version date: 2-1-2014, access date: 14-4-2014) http://db.cbg-meb.nl/IBteksten/h21082.pdf.
7. SPC Lescol®. (version date: 1-11-2013, access date: 14-4-2014) http://db.cbg-meb.nl/IBteksten/h18720.pdf.
8. SPC Selektine®. (version date: 30-4-2013, access date: 14-4-2014) http://db.cbg-meb.nl/IBteksten/h20665.pdf.
9. SPC Crestor®. (version date: 23-12-2013, access date: 14-4-2014) http://db.cbg-meb.nl/IBteksten/h26873.pdf.
10. SPC Livazo®. (version date: 19-8-2012, access date: 16-4-2014) http://db.cbg-meb.nl/IBteksten/h103768.pdf.
11. SPC Vezepra®. (version date: 19-8-2012, access date: 16-4-2014) http://db.cbg-meb.nl/IBteksten/h103447.pdf.
12. Shmerling, R. H. Approach to the patient with myalgia. (version date: 22-1-2014, access date: 155-2014) http://www.uptodate.com/contents/approach-to-the-patient-with-myalgia.
13. Garrett WE, Jr. Muscle strain injuries. Am.J.Sports Med. 1996;24(6 Suppl):S2-S8
14. Chan O, Del BA, Best TM, Maffulli N. Acute muscle strain injuries: a proposed new classification
system. Knee.Surg.Sports Traumatol.Arthrosc. 2012;20(11):2356-62.
15. US SPC Zocor®. (version date: 2014, access date: 16-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019766s091lbl.pdf.
16. US SPC Lipitor®. (version date: 2012, access date: 16-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020702s062s063lbl.pdf.
17. US SPC Lescol®. (version date: 2012, access date: 16-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020261s048,021192s021lbl.pdf.
18. US SPC Crestor®. (version date: 2013, access date: 16-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021366s028s029lbl.pdf.
19. US SPC Pravachol®. (version date: 2012, access date: 16-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019898s063s064lbl.pdf.
20. US SPC Livalo®. (version date: 2013, access date: 16-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022363s012lbl.pdf.
21. US SPC Altoprev®. (version date: 2012, access date: 16-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021316s028lbl.pdf.
22. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions,
arthropathies, and injuries. JAMA Intern.Med. 2013;173(14):1-10.
23. Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:a2286
24. Lareb database. (version date: 2014, access date: 22-4-2014)
http://www.lareb.nl/Bijwerkingen/Zoek-op-geneesmiddel.
25. WHO Database. (version date: 2014, access date: 22-4-2014) https://tools.who-umc.org/webroot/
(access restricted).
20
26. Eudravigilance database. (version date: 2014, access date: 23-4-2014) http://bi.eudra.org (access
restricted).
27. GIP database – Drug Information System of the Dutch Health Care insurance Board. (version date: 7-32014, access date: 18-4-2014) http://www.gipdatabank.nl/databank.asp?tabel=01basis&geg=gebr&item=C10A.
28. Taha DA, De Moor CH, Barrett DA, Gershkovich P. Translational insight into statin-induced
muscle toxicity: from cell culture to clinical studies. Transl.Res. 2014;
29. Draeger A, Monastyrskaya K, Mohaupt M, Hoppeler H, Savolainen H, Allemann C, Babiychuk EB.
Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia.
J.Pathol. 2006;210(1):94-102.
21
1.4.
Tamsulosin and urinary incontinence
Introduction
Tamsulosin hydrochloride (Omnic®) is an antagonist of α1-adrenoceptors in the
prostate. Tamsulosin is indicated for the treatment of the signs and symptoms of
benign prostatic hyperplasia (BPH). It is also used off-label for the treatment of
nephrolithiasis in women [1]. Tamsulosin has been approved for the Dutch market
since April 1995 [2].
The symptoms associated with benign prostatic hyperplasia (BPH) are related to
bladder outlet obstruction, which is comprised of two underlying components:
static and dynamic. The static component is related to an increase in prostate
size caused, in part, by a proliferation of smooth muscle cells in the prostatic
stroma. The dynamic component is a function of an increase in smooth muscle
tone in the prostate and bladder neck leading to constriction of the bladder outlet.
Smooth muscle tone is mediated by the sympathetic nervous stimulation of
alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule,
prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause
smooth muscles in the bladder neck and prostate to relax, resulting in an
improvement in urine flow rate and a reduction in symptoms of BPH. In clinical
practice tamsulosin is also used off-label for the treatment of nephrolithiasis.
Tamsulosin exhibits selectivity for α1-receptors in the human prostate. At least
three discrete α1-adrenoceptor subtypes have been identified: α1A, α1B, and α1D;
their distribution differs between human organs and tissue. Approximately 70% of
the α1-adrenoreceptors in the human prostate are of the α1A subtype [3].
Other selective α1-antagonists for the treatment of BPH on the Dutch market are
alfuzosin (Xatral®), doxazosin (Cardura®), silodosin (Silodyx®) and terazosin
(Hytrin®).
Urinary incontinence often has an identifiable cause in younger persons. In older
persons a multifactorial syndrome is more likely. Neuro-urinary pathology, agerelated factors, comorbid conditions, medications, and functional and cognitive
impairments may play a role in the older population [4].
The current observation describes the association between tamsulosin and
urinary incontinence. No reports for incontinence associated with other α1adrenoceptor antagonists were received by Lareb. Therefore, a possible class
effect was not investigated.
Reports
On April 11th 2014, the database of the Netherlands
Pharmacovigilance Centre Lareb contained eleven reports of incontinence
associated with the use of tamsulosin. The reports are listed in table 1.
Table 1. Reports of urinary incontinence associated with the use of tamsulosin
Patient,
Number,
Sex, Age,
Source
Drug, daily dose
Indication for use
A 24881
M, 61-70
years
Pharmacist
B 41722
M, 61-70
years
General
Concomitant
Medication
Suspected
adverse
drug
reaction
Time to
onset,
Action with
drug
outcome
tamsulosin 0.4mg 1dd
hyperplasia of
prostate
urinary
incontinence,
rash
not reported
unknown
not reported
tamsulosin 0.4mg 1dd
not reported
urinary
incontinence
3 days
discontinued
recovered
positive
22
Practitioner
rechallenge
C 44261
M, 61-70
years
Consumer
tamsulosin 0.4mg 1dd
hyperplasia of
prostate
allopurinol
urinary
incontinence
not reported
unknown
not recovered
D 52650
M, 71
years and
older
Pharmacist
tamsulosin 0.4mg 1dd
hydrochlorothiazide
with quinapril
pyridoxine
calcium
levothyroxine
carbasalate
calcium
folic acid
dihydrotachysterol
urinary
incontinence,
therapeutic
response
unexpected
with drug
substitution
not reported
no change
unknown
E 72129
F, 51-60
years
Pharmacist
tamsulosin 0.4mg 1dd
kidney stone
diclofenac
allopurinol
zopiclone
incontinence
3 days
no change
recovered
positive
rechallenge
F 107476
M, 51-60
years
Pharmacist
tamsulosin 0.4mg 1dd
benign prostatic
hyperplasia
incontinence
of urine
2 months
discontinued
not recovered
G 129137
M, 51-60
years
Consumer
dutasteride/tamsulosin
0,5/0,4mg 1dd
benign prostatic
hyperplasia
Incontinence,
ejaculation
failure
2 months
no change
not recovered
H 145200
F, 51-60
years
Specialist
doctor
tamsulosin 0.4mg 1dd
stone urinary bladder
hydrochlorothiazide
incontinence
of urine
several days
discontinued
recovered
I 147585
M, 61-70
years
Pharmacist
tamsulosin 0.4mg 1dd
benign neoplasm of
prostate
losartan
incontinence,
headache,
tremor,
urticaria,
hot flush,
palpitations,
rhinorrhea
1 day
discontinued
recovered
J 160773
M, 61-70
years
Pharmacist
tamsulosin 0.4mg 1dd
lower abdominal pain
leuprorelin
urinary
incontinence
5 days
discontinued
recovered
K 168760
M, 71
years and
older
Pharmacist
tamsulosin 0.4mg 1dd
benign prostatic
hyperplasia
colecalciferol
urea
mometasone
urinary
incontinence,
fecal
incontinence,
therapeutic
response
unexpected
with drug
substitution
4.5 years
discontinued
recovered
Additional information about the cases is described below:
In case A, the complaints were reported as urge incontinence.
In case B, both a positive de- and rechallenge were reported. Additionally, the
patient ceased his excessive consumption of alcohol (gamma-GT value of 280
U/l) after starting tamsulosin.
23
In case C, the patient experienced the complaints related to stress incontinence
(blowing his nose).
In case D, the complaints arose when the patient was switched from capsules to
tablets.
In case E, the patient experienced similar problems in the past.
In case F, the patient had not recovered at the time of reporting, which was 6
days after withdrawal of tamsulosin.
In case G, the patient switched to separate preparations of dutasteride and
alfuzosin and experienced the same complaints. The patient previously used
tamsulosin without dutasteride and experienced the ejaculation disorder.
Incontinence was not reported for this episode of tamsulosin use.
In case I, the patient was treated with cetirizine for his urticaria, and recovered
from all complaints two days after withdrawal of tamsulosin.
In case J, the patient had a history of prostate cancer for which he underwent
surgery. He previously used tamsulosin without experiencing any complaints.
In case K, the patients switched from the Ranbaxy brand (which he had been
using for approximately 2 years) to the Mylan brand and his complaints
disappeared quickly.
Other sources of information
SmPC
Urinary incontinence is not mentioned in the SmPC of tamsulosin [2].
Literature
Urinary incontinence has been described as an adverse effect in women using
tamsulosin. In a prospective study with 106 patients with voiding dysfunction,
three patients developed de novo stress incontinence and one patient
experienced an aggravation of an existing stress incontinence [5]. Furthermore, a
study with α1-adrenoceptors other than tamsulosin (prazosin, terazosin and
doxazosin) showed a statistically significant higher percentage of urinary
incontinence in patients using α1-adrenoceptors compared to matched controls
[6]. Studies investigating this association in male patients could not be found.
Databases
Table 2. Reports of (urinary) incontinence with tamsulosin (with or without dutasteride) in
the databases of the Netherlands Pharmacovigilance Centre Lareb and the WHO [7] and
Eudravigilance (EMA) database [8].
Database
Preferred Terms
Number of reports
ROR (95% CI)
Lareb
Urinary incontinence
8
7.2 (3.5 – 14.6)
Incontinence
3
18.3 (5.6 – 59.3)
Total
11
8.7 (4.7 – 15.9)
Urinary incontinence
103
5.1 (4.2 – 6.1)
Incontinence
30
9.3 (6.5 – 13.3)
Total
133
5.7 (4.8 – 6.7)
Urinary incontinence
31
3.5 (2.5 – 5.0)
Incontinence
12
4.5 (2.6 – 8.0)
Total
43
3.8 (2.8 – 5.1)
WHO
Eudravigilance
24
Prescription data
Table 3. Number of patients using tamsulosin in the Netherlands between 2009 and 2013
[9].
Drug
2009
2010
2011
2012
2013
Tamsulosin
172,950
186,450
194,660
199,250
205,890
Tamsulosine /
dutasteride
-
5,723
19,438
28,787
34,019
Mechanism
Tamsulosin binds selectively and competitively to the postsynaptic α1adrenoreceptors, in particular to the subtype α1A and α1D [2]. It is known that α1adrenergic receptors are present in both the detrusor muscle [10] and the bladder
sphincter [11]. The antagonistic effect of tamsulosin on the α1-adrenergic
receptors of the bladder could therefore theoretically result in both urinary
retention and incontinence, depending on the exact affinity of the drug for each
receptor subtype and their ratios in sphincter and detrusor. A functional
urodynamic study however, showed that tamsulosin had a significant relaxing
effect on the resting urethral tone, suggesting a pharmacological treatment for
urinary retention [12]. Urinary incontinence could therefore be seen as a possible
detrimental effect of this pharmacological mechanism.
Discussion and conclusion
Lareb received eleven cases of urinary incontinence associated with the use of
tamsulosin. The reports concern nine males and two females. In five cases a
positive dechallenge was reported and in two cases a positive rechallenge, which
support the causality of this association. However, there was also one negative
dechallenge. In one case the complaints arose after switching to another brand
and in one case after switching to another formulation (tablets to capsules of the
same brand). This association was disproportionality present in the Lareb, WHO
and Eudravigilance databases, has been described in literature and seems
pharmacologically plausible. In addition to the previously described literature, a
case report of a woman experiencing stress urinary incontinence after starting
doxazosin was found [13]. This case shows similarities with our case C who also
experienced stress incontinence, indicating that the complaints are possibly not
due to confounding by indication (BPH). Although the articles found in the
literature are limited to studies in female patients, our data suggest that male
patients could also experience these symptoms.
Although BPH could be considered as a possible confounder, these patients often
experience overflow incontinence. This is however not mentioned in any of the
described cases. Moreover, in two cases (E,H) this can be ruled out since the
patients are female, whereas two other cases (A,C) specifically mention urge and
stress incontinence respectively. Age however, could be a possible confounding
factor in this association.
 Urinary incontinence should be
mentioned in the SmPC of
tamsulosin
References
25
1. van LJ, van Koningsbruggen PJ, Boukes FS, Goudswaard AN. [Summary of the practice guideline
'Urolithiasis' (first revision) from the Dutch College of General Practitioners].
Ned.Tijdschr.Geneeskd. 2008;152(45):2448-51.
2. Dutch SPC Omnic®. (version date: 2014, access date: 11-4-2014) http://db.cbg-meb.nl/IBteksten/h17931.pdf.
3. US SPC Flomax®. (version date: 2011, access date: 11-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020579s027lbl.pdf.
4. UpToDate. UpToDate. (version date: 2012, access date: 11-4-2014) http://www.uptodate.com/.
5. Lee KS, Han DH, Lee YS, Choo MS, Yoo TK, Park HJ, Yoon H, Jeong H, Lee SJ, Kim H, et al.
Efficacy and safety of tamsulosin for the treatment of non-neurogenic voiding dysfunction in
females: a 8-week prospective study. J.Korean Med.Sci. 2010;25(1):117-22.
6. Marshall HJ, Beevers DG. Alpha-adrenoceptor blocking drugs and female urinary incontinence:
prevalence and reversibility. Br.J.Clin.Pharmacol. 1996;42(4):507-9.
7. WHO Global Individual Case Safety Reports database (Vigibase). (version date: 2014, access
date: 23-4-2014) https://tools.who-umc.org/webroot/ (access restricted).
8. Eudravigilance database. (version date: 2014, access date: 23-4-2014) http://bi.eudra.org (access
restricted).
9. College for Health Insurances. GIP database. (version date: 9-6-2009, access date: 16-3-2011)
http://www.gipdatabank.nl/index.asp?scherm=tabellenFrameSet&infoType=g&tabel=01basis&item=J01FF.
10. Malloy BJ, Price DT, Price RR, Bienstock AM, Dole MK, Funk BL, Rudner XL, Richardson CD,
Donatucci CF, Schwinn DA. Alpha1-adrenergic receptor subtypes in human detrusor. J.Urol.
1998;160(3 Pt 1):937-43.
11. KNMP kennisbank. (version date: 2014, access date: 11-4-2014)
http://www.kennisbank.knmp.nl/index.asp#home.
12. Reitz A, Haferkamp A, Kyburz T, Knapp PA, Wefer B, Schurch B. The effect of tamsulosin on the
resting tone and the contractile behaviour of the female urethra: a functional urodynamic study in
healthy women. Eur.Urol. 2004;46(2):235-40.
13. Menefee SA, Chesson R, Wall LL. Stress urinary incontinence due to prescription medications:
alpha-blockers and angiotensin converting enzyme inhibitors. Obstet.Gynecol. 1998;91(5 Pt
2):853-4.
The Marketing Authorization Holder of tamsulosin (Astellas)
has informed Lareb on 07-10-2014 of the following: After
careful evaluation of the signal report tamsulosin and urinary
incontinence, the Marketing Authorization Holder, is of the
opinion that there is no sufficient evidence to support a
causal relationship between tamsulosin and urinary
incontinence. An addition of a warning for urinary
incontinence to the SmPC is therefore not warranted,
according to Astellas.
26
1.5.
Prednisolone and hiccups
Introduction
Prednisolone is a corticosteroid drug with predominant glucocorticoid and low
mineralocorticoid activity which is used to treat a variety of inflammatory and autoimmune condition [1]. Prednisolone has been marketed internationally since
1955. Prednisolone is the active metabolite of the drug prednisone and is
preferred especially in patients with hepatic failure, as these individuals are
unable to metabolise prednisone into prednisolone [2].
Prednisolone irreversibly binds with glucocorticoid receptors (GR) alpha and beta
for which they have a high affinity. AlphaGR and BetaGR are found in virtually all
tissues with variable numbers between 3000 and 10000 per cell, depending on
the tissue involved. Prednisolone can activate and influence biochemical
behaviour of most cells. The steroid/receptor complexes dimerise and interact
with cellular DNA in the nucleus, binding to steroid-response elements and
modifying gene transcription. They induce synthesis of some proteins, and inhibit
synthesis of others [3].
A hiccup is an involuntary, intermittent, spasmodic contraction of the diaphragm
and intercostal muscles. There are numerous causes of hiccups. Hiccups are
usually caused by gastric distention from overeating or carbonated beverages.
Other causes include gastrointestinal disorders, thoracic disorders or cardiac
disorders. Hiccups may also be drug-related. In rare cases, hiccups can be a
manifestation of severe underlying disease (eg, malignancy, multiple sclerosis)
[4].
Reports
The Netherlands Pharmacovigilance Centre Lareb received 3 reports of hiccups
associated with the use of prednisolone, in a period from July 11th 2013 to
November 1st 2013.
Case A (157126)
This non-serious spontaneous report from a pharmacist concerns a male aged 71
years and older, with hiccups following administration of prednisolone tablets 20
mg twice daily for asthma with a latency of 1 day after start. The hiccups lasted
for 4 days. Prednisolone was withdrawn. The patient recovered. Concomitant
medications were levothyroxine sodium, salbutamol/ipratropium,
salmeterol/fluticasone, alfacalcidol, fenoterol/ipratropium, tiotropium bromide,
formoterol/beclometasone, indacaterol, montelukast, pravastatin, candesartan,
diltiazem, carbasalate calcium, pantoprazole, lercanidipine. Start- and stopdates
of the concomitant medications were not reported, follow-up questions did not
lead to more information.
Case B (160866)
This report from a pharmacist concerns a male aged 61-70 years years, with
hiccups following administration of prednisolone capsules 30 mg once daily for
exacerbation of a lung disease and pregabaline 150 mg twice daily for
neuropathic pain with a latency of 2 days after start of prednisolone and 1 year
after start of pregabaline. The dose for prednisolone and pregabaline was not
changed. The patient recovered after 5 days. Concomitant medications were
formoterol/budesonide, alfuzosin, amlodipine, metformin, omeprazole and
allopurinol.
Follow-up questions about the duration of treatment with prednisolone did not
lead to more information.
27
Case C (162118)
This non-serious spontaneous report from a specialist doctor concerns a male of
unknown age, with hiccups following oral administration of prednisolone (dose
unknown) for Bechterew's disease with a latency of 1 day after start. The drug
prednisolone was withdrawn. The patient recovered almost immediately. After
restart of intramuscular prednisolone some time later, the hiccups appeared again
within 24 hours. After withdrawal the patient recovered. Concomitant medication
was not reported.
Other sources of information
SmPC
Hiccups are not mentioned in the SmPC of prednisolone [5], however the SmPC’s
of dexamethasone [6], betamethasone [7] and methylprednisolone [8] do mention
hiccups.
Literature
Although not widely reported, several articles associate hiccups with
corticosteroid treatment, however not specifically with prednisolone. Peacock [9]
describes a patient who was given preoperative dexamethasone and developed
hiccups before anaesthesia and surgery commenced. He at no time was in
distress, and the surgical procedure was completed without complication. By the
second postsurgical day his hiccups were resolved completely. Other authors
report annoying hiccups following intra-articular corticosteroid injection of
betamethasone acetate/betamethasone sodium phosphate at the knee joint [10].
A case series presents five patients who developed hiccups after receiving
dexamethasone for chemotherapy-induced nausea and vomiting. However,
switching dexamethasone to an equipotent dosage of either methylprednisolone
or prednisolone resolved the hiccups [11]. This was also seen in a study of 40
cancer patients. Dexamethasone-induced hiccups in these patients could be
controlled by replacing dexamethasone with methylprednisolone. After
readministration of dexamethasone 74% had recurrence of hiccups [12].
Databases
On April 4th 2014, the database of the Netherlands Pharmacovigilance Centre
Lareb contained 3 reports of hiccups associated with the use of prednisolone.
Hiccups might possibly be a class-effect of corticosteroids, therefore other
corticosteroids were taken into account as well.
Table 1. Reports of hiccups associated with the use of glucocorticoids in the Lareb, WHO
and Eudravigilance database [13,14].
Database
Drug
Number of reports
ROR (95% CI)
Lareb
Prednisolone
3
5.9 (1.9-18.7)
Betamethasone
1
N.A.
Dexamethasone
10
42.9 (22.2-82.8)
Methylprednisolone
2
N.A.
Prednisolone
27
3.0 (2.0-4.3)
Betamethasone
50
26.1 (19.7-34.6)
Cortisone
2
N.A.
Dexamethasone
268
30.5 (27.0-34.6)
Hydrocortisone
7
2.8 (1.4-6.0)
Methylprednisolone
48
6.2 (4.6-8.2)
WHO
28
Database
Drug
Number of reports
ROR (95% CI)
Prednisone
17
1.4 (0.9-2.3)
Triamcinolone
12
3.3 (1.9-5.8)
7
1.3 (0.6 – 2.6)
Betamethasone
10
12.1 (6.5 – 22.6)
Cortisone
2
N.A.
Dexamethasone
38
11.2 (8.1 – 15.4)
Hydrocortisone
1
N.A.
Methylprednisolone
11
3.5 (1.9 – 6.4)
Prednisone
4
0.8 (0.3 – 2.2)
Triamcinolone
2
N.A.
Eudravigilance Prednisolone
Prescription data
Table 3. Number of patients using glucocorticoids (with ATC code H) in the Netherlands
between 2009 and 2013 [15].
Drug
2009
2010
2011
2012
2013
412,080
427,550
452,730
472,340
488,330
31,541
34,069
18,280
20,007
23,803
2,269
2,181
1,787
1,475
1,385
Dexamethasone
34,918
35,015
46,520
42,169
44,692
Hydrocortisone
6,502
7,235
8,024
7,984
8,611
Methylprednisolone
11,615
11,831
11,913
11,589
11,832
Prednisone
39,707
34,979
33,030
29,778
25,635
170,910
173,930
179,380
182,940
190,310
Prednisolone
Betamethasone
Cortisone
Triamcinolone
Mechanism
The mechanism by which corticosteroids induce hiccups has not been fully
elucidated yet. Hiccups have been classified as a neurologic reaction triggered by
a multitude of factors. However, it has been proposed that corticosteroids lower
the threshold for synaptic transmission in the midbrain and directly stimulate the
hiccup reflex arc [16].
Discussion and conclusion
The Netherlands Pharmacovigilance Centre Lareb received 3 reports of hiccups
associated with the use of prednisolone. Two positive dechallenges and one
positive rechallenge were reported.
The association of prednisolone and hiccups is supported by a statistically
significant disproportionality in the database of Lareb and the WHO. This is also
the case for other glucocorticoids. The literature mentions hiccups predominantly
with the use of dexamethasone and corticosteroid rotation with
(methyl)prednisolone is thought to reduce the hiccups. The mechanism behind
this is not clear. Other glucocorticoids such as betamethasone are also described
to induce hiccups. Therefore, the more potent corticosteroids are reported in the
literature to induce hiccups. Possibly the relatively high doses of prednisolone
administered in the patients described in the cases reported to Lareb contribute to
29
the occurrence of the hiccups. Several SmPCs of glucocorticoids already mention
hiccups as an adverse event, however the SmPC of prednisolone does not.
 Hiccups should be mentioned in
the SmPC of prednisolone
References
1. Dutch SmPC Di-Adreson-F®. (version date: 2011, access date: 4-4-2014) http://db.cbg-meb.nl/IBteksten/h00093.pdf.
2. KNMP/Winap. Informatorium Medicamentorum. (version date: 1-10-2012, access date: 4-4-0014)
http://kennisbank.knmp.nl/index.asp#IMS324.
3. Rang HP, Dale MM, Ritter JM, et al. Hunter I, editors.5 ed. 2003;The pituitary and the adrenal
cortex. p. 413-5.
4. Lembo, A. J. Overview of hiccups. (version date: 7-11-2013, access date: Up to Date®.
5. Dutch SmPC prednisolon. (version date: 2012, access date: 4-4-2014) http://db.cbg-meb.nl/IBteksten/h50969.pdf.
6. Dutch SmPC Oradexon®. (version date: 2014, access date: 4-4-2014) http://db.cbg-meb.nl/IBteksten/h00113.pdf.
7. Dutch SmPC Celestone®. (version date: 2010, access date: 4-4-2014) http://db.cbg-meb.nl/IBteksten/h01834.pdf.
8. Dutch SmPC Depo-Medrol®. (version date: 2013, access date: 4-4-2014) http://db.cbg-meb.nl/IBteksten/h00605.pdf.
9. Peacock ME. Transient hiccups associated with oral dexamethasone. Case.Rep.Dent.
2013;2013:426178
10. Habib G, Artul S, Hakim G. Annoying Hiccups following Intra-Articular Corticosteroid Injection of
Betamethasone Acetate/Betamethasone Sodium Phosphate at the Knee Joint.
Case.Rep.Rheumatol. 2013;2013:829620
11. Kang JH, Hui D, Kim MJ, Kim HG, Kang MH, Lee GW, Bruera E. Corticosteroid rotation to
alleviate dexamethasone-induced hiccup: a case series at a single institution. J.Pain
Symptom.Manage. 2012;43(3):625-30.
12. Lee GW, Oh SY, Kang MH, Kang JH, Park SH, Hwang IG, Yi SY, Choi YJ, Ji JH, Lee HY, et al.
Treatment of dexamethasone-induced hiccup in chemotherapy patients by methylprednisolone
rotation. Oncologist. 2013;18(11):1229-34.
13. WHO database Vigimine. (version date: 2014, access date: 4-4-2014) https://tools.whoumc.org/webroot/ (access restricted).
14. Eudravigilance database. (version date: 2014, access date: 23-4-2014) http://bi.eudra.org (access
restricted).
15. GIPdatabase - Drug Information System of the Dutch Health Care Insurance Board. (version date:
2013, access date: 4-4-2014) http://www.gipdatabank.nl.
16. Dickerman RD, Jaikumar S. The hiccup reflex arc and persistent hiccups with high-dose anabolic
steroids: is the brainstem the steroid-responsive locus? Clin.Neuropharmacol. 2001;24(1):62-4.
30
1.6.
Atovaquone/ proguanil hydrochloride and psychotic disorder
Introduction
Atovaquone/ proguanil hydrochloride (generic, Malarone® and Malarone® junior)
is indicated for the prophylaxis of Plasmodium falciparum malaria in travelers
(Malarone® junior: 11-40 kg) and for the treatment of acute and uncomplicated
Plasmodium falciparum malaria (Malarone® junior: 5-11 kg) [1-7]. It is
recommended for the prophylaxis and the treatment of Plasmodium falciparum in
the area where the pathogen is resistant to other antimalarials [1-7].
Atovaquone/ proguanil interferes with two different pathways, both are involved in
the biosynthesis of pyrimidines required for the nucleic acid replication of the
malaria parasite. Atovaquone inhibits the mitochondrial electron transport and
disrupts the mitochondrial membrane potential. The active metabolite of
proguanil, cycloguanil, inhibits dihydrofolate reductase and enhances the effect of
atovaquone on the mitochondrial membrane potential [1,2].
Atovaquone/ proguanil hydrochloride was granted marketing authorization in the
Netherlands on 25 July 2000 (Malarone®) [1] and on 3 March 2003 (Malarone
junior®) [2].
The term psychotic disorder has historically received a number of different
definitions, none of which has achieved universal acceptance. The narrowest
definition of psychotic disorder is restricted to symptoms like delusions or
prominent hallucinations. A broader definition concerns a mental disorder that
resulted in “impairment that grossly interferes with the capacity to meet ordinary
demands of life”. The term has been defined as a loss of ego boundaries or a
gross impairment in reality testing [8].
Reports
The Netherlands Pharmacovigilance Centre Lareb received four reports of
psychotic disorder associated with atovaquone/ proguanil, in a period from June
1st 1995 to April 22th 2014, see Table 1. Additional information regarding the
cases is described below.
Table 1. Reports of psychotic disorder associated with the use of atovaquone/ proguanil.
Patient,
Sex, Age,
source
Drug
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
Action with drug
outcome
A 153871
M, 21-70
years
Psychiatrist
Atovaquone/ proguanil
tablet
Malaria prophylaxis
Short psychotic
disorder
2 days
discontinued
recovered in 3
months
B 36146
M, 41-50
years
Community
health
professional
Atovaquone/ proguanil
tablet
Malaria prophylaxis
C 56444
F 41-50
years
Community
health
professional
Atovaquone/ proguanil
tablet
Malaria prophylaxis
Auditory
hallucinations that
ultimately resulted in
a psychosis
12 days
Discontinued
Unknown
D 54661
F, unknown
Physician
Atovaquone/ proguanil
tablet
Drug use for unknown
indication
Psychosis
Unknown
Unknown
Recovered
Chlorthalidone 25 Strong psychosis with
mg and cetirizine severe suicidal
10 mg.
characteristics,
irritability, ulcer
hands, and
paraesthesia of the
mouth
1 day
discontinued
recovered in 2
days
31
In all four cases, it is unknown when the consumers started the use of
atovaquone/ proguanil at home or abroad.
Casus A: The patient was hospitalized in the psychiatric ward and treated with
olanzapine. Another influencing factor mentioned was sleep deprivation. The
destination for holiday and medical history were unknown.
Casus B: The community health professional reported about himself. The patient
was not able to continue atovaquone/ proguanil therapy and evacuation from
Tanzania was necessary. Cetirizine was started 1 month before the start of
atovaquone/ proguanil and withdrawn on the same date as atovaquone/
proguanil. There was no psychiatric history and he had never had atovaquone/
proguanil therapy before.
Casus C: The destination was unknown. The patient was admitted at a psychiatric
hospital and diagnosed with Schizophrenia. There is no information on further
treatment. Other influencing factor was a stressful period before administration of
atovaquone/ proguanil.
Casus D: Due to psychosis the patient had returned back home from Africa.
Other sources of information
SmPC
All the SmPCs of atovaquone/ proguanil mention abnormal dreams, depression,
anxiety, hallucinations, panic attack and nightmares as possible adverse drug
reactions (ADRs) [1-4,6,7,9]. The SmPCs of brand Malarone® and Malarone®
junior also mention psychiatric disorders [1,2]. Psychotic disorder is not explicitly
mentioned in the SmPCs of atovaquone/ proguanil [1-4,6,7,9].
The US SmPC of the FDA mentions that psychotic events (such as
hallucinations) have been identified during postmarketing use of atovaquone/
proguanil. However, a causal relationship has not been established [10].
Literature
A search on Pubmed revealed no specific information of atovaquone/ proguanil
induced psychotic disorder or hallucinations. One systematic review and metaanalysis, written by Halima Nakato et al. [11], described the occurrence of
neuropsychiatric ADRs of atovaquone/ proguanil compared to chloroquine/
proguanil or mefloquine. Ten randomized controlled trials were included. Of these
trials, three meta-analysis were included in which patients could report ADRs. No
significant difference was found (RR = 0.74; 95% CI = 0.5 - 1.1; I2 = 86.7%) in the
reporting of neuropsychiatric ADRs. One of the included trials [12] described the
neuropsychiatric ADRs of atovaquone/ proguanil compared to mefloquine in a
randomized double blind study. The atovaquone/ proguanil group (n=493)
experienced lower neuropsychiatric ADRs than the mefloquine group (n=483)
(14% versus 29%, P = 0.001). Among the neuropsychiatric ADRs reported were
dreaming, insomnia, anxiety and depression. No hallucination or psychotic
disorder were reported. The study was funded by Glaxo Smith Kline.
Databases
Table 2. Number of reported cases of psychotic disorder associated with the use of
atovaquone/ proguanil in the database of Lareb, the WHO and Eudravigilance on April 23rd
[13-15].
Drug
Number of
reports
ROR (95% CI)
Atovaquone/ proguanil
Lareb: 4
4.4 (95% CI 1.6 – 12.0)
WHO: 27
6.0 (95% CI 4.1 – 8.8)
32
Drug
Number of
reports
ROR (95% CI)
Eudravigilance: 29 9.0 (95% CI; 6.2 – 12.9)
Prescription data
Prescription data are retrieved from the GIP database [16], were most of the
reimbursed prescriptions are stored. Because atovaquone/ proguanil is not
covered by most of the basic insurance, the numbers of patients in the GIP
database are not a real reflection of the users of atovaquone/ proguanil.
Therefore, prescription data are unknown.
Mechanism
No possible mechanism explaining this association could be found in the
literature.
Atovaquone is a highly lipophilic compound. Intake with fat can increase the Area
Under the Curve (AUC) by a factor 2 to 3 and the maximum concentration
(Cmax) by a factor 5 compared to fasting. The bioavailability of atovaquone
shows considerable interindividual variability of 45%. It is advised to administrate
atovaquone/ proguanil with food or a dairy drink to increase the degree of
absorption [1]. Proguanil is not dependent on the food intake [1].
Theoretically, the possible high fat content of a travelers diet in addition to the
variable interindividual availability makes specific travelers group at risk to a
higher concentration of atovaquone. It is plausible that a higher blood
concentration increases the risk of ADRs. However, in susceptible air travel
passengers, a jet lag may be sufficient to exacerbate affective illness and result in
psychiatric morbidity [17].
No information could be found in literature about the passage of the drug through
the blood-brain barrier.
Discussion and conclusion
The Netherlands Pharmacovigilance Centre Lareb received four reports of
psychotic disorder associated with the use of atovaquone/ proguanil. All reports
were assessed as serious. In case A and C, the consumer was hospitalized in the
psychiatric ward. Patient C was diagnosed with Schizophrenia at the age of 44.
The onset of Schizophrenia typically occurs between the late teens and the mid30s, but a late-onset (e.g., after age 45 years) may also occur. Woman are more
likely to have a later-onset [8].
In case B and D, evacuation to home country was necessary. The latency period
ranged from 1 day to 12 days. Patient B had no psychiatric history before and had
a positive dechallenge. The patient recovered 2 days after atovaquone/ proguanil
and cetirizine were withdrawn. The SmPC of cetirizine describes also
hallucinations and confusion with an incidence of 0.001-0.01% [18]. However,
because cetirizine started a month earlier than atovaquone/ proguanil and the
psychotic disorder occurred 1 day after the start of atovaquone/ proguanil, it is
more likely that the patient recovered due to the withdrawal of atovaquone/
proguanil. In reports A and C, sleep deprivation and stress were mentioned as a
possible influencing factor. Most travellers experience sleep deprivation, stress,
jet lag, circadian rhythm disruptions, dietary changes, alcohol consumption, or
illicit drug use while traveling, which can contribute to a psychosic disorder [19].
In cases A and B, the psychotic symptoms started within 2 days. In case C, the
psychotic symptoms started after 12 days and in case D the latency time is
unknown. Because malaria incubation period is about 8 to 25 days [20], and
none of the reported cases report fever or other malaria related symptoms, it is
unlikely that malaria infection induced the psychotic symptoms.
33
The lifetime prevalence for any psychotic disorder is 3% [21] Psychotic disorder
with the use of atovaquone/ proguanil is not widely described in literature. Halima
Nakato et al [11] found neuropsychiatric ADRs with the use of atovaquone/
proguanil, however this difference was not significant compared to mefloquine.
The US SmPC of the FDA mentions that psychotic events have been identified
during postmarketing use of atovaquone/ proguanil [10].
Lareb received four reports of psychotic disorder with the use of atovaquone/
proguanil. Although the definition for psychotic disorder is broad and there is a
high background incidence, literature is available which describes the occurrence
of neuropsychiatric disorder with the use of atovaquone/ proguanil. This
association is further strengthened by the disproportional RORs in the Lareb
database, Eudravigilance database and WHO database. Because
atovaquone/ proguanil is an alternative drug therapy especially when mefloquine
is contraindicated in patients with a recent history psychiatric disorders [1], it is
important to further investigate if atovaquone/ proguanil can also cause psychotic
disorder.
 Further investigation of the
information of the marketing
authorization holders and other
national centers is needed to
evaluate the signal
References
1. Dutch SmPC Malarone® 250 mg /100 mg Filmomhulde Tabletten. (version date: 1-10-2013,
access date: 18-4-2014) http://db.cbg-meb.nl/IB-teksten/h25386.pdf.
2. Dutch SmPC Malarone Junior® 62,5 mg /25 mg Filmomhulde Tabletten . (version date: 18-102013, access date: 18-4-2014) http://db.cbg-meb.nl/IB-teksten/h28319.pdf.
3. Dutch SmPC Atovaquon/Proguanilhydrochloride Glenmark 250 mg /100 mg Filmomhulde
Tabletten. (version date: 7-3-2011, access date: 18-4-2014) http://db.cbg-meb.nl/IBteksten/h105808.pdf.
4. Dutch SmPC Atovaquon/Proguanil HCL Mylan 250 mg /100 mg Filmomhulde Tabletten. (version
date: 30-8-2014, access date: 18-4-2014) http://db.cbg-meb.nl/IB-teksten/h109086.pdf.
5. Dutch SmPC Atovaquon/Proguanil HCL Teva 250 mg/100 mg, filmomhulde tabletten. (version
date: 23-9-2013, access date: 18-4-2014) http://db.cbg-meb.nl/IB-teksten/h111742.pdf.
6. Dutch SmPC Atovaquon/Proguanil HCL Ratiopharm 250 mg/100 mg, filmomhulde tabletten.
(version date: 23-9-2013, access date: 18-4-2014) http://db.cbg-meb.nl/IB-teksten/h111747.pdf.
7. Dutch SmPC Atovaquon/Proguanil HCL Sandoz 250 mg/100 mg, filmomhulde tabletten. (version
date: 28-6-2013, access date: 18-4-2014) http://db.cbg-meb.nl/IB-teksten/h111785.pdf.
8. American Psychiatric Association. DSM-IV. 4 ed. 1994. 273p.
9. Dutch SmPC Atovaquon/Proguanil HCL Teva 250 mg/100 mg, filmomhulde tabletten. (version
date: 23-9-2013, access date: 18-4-2014) http://db.cbg-meb.nl/IB-teksten/h111742.pdf.
10. FDA SmPC Malarone®. (version date: 7-2-2013, access date: 18-4-2014)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021078s022lbl.pdf.
11. Nakato H, Vivancos R, Hunter PR. A systematic review and meta-analysis of the effectiveness
and safety of atovaquone proguanil (Malarone) for chemoprophylaxis against malaria.
J.Antimicrob.Chemother. 2007;60(5):929-36.
12. Overbosch D, Schilthuis H, Bienzle U, Behrens RH, Kain KC, Clarke PD, Toovey S, Knobloch J,
Nothdurft HD, Shaw D, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in
nonimmune travelers: results from a randomized, double-blind study. Clin.Infect.Dis.
2001;33(7):1015-21.
13. WHO database . (version date: 2014, access date: 23-4-2014) https://tools.who-umc.org/webroot/.
14. Eudravigilance database . (version date: 2014, access date: 23-4-2014) http://bi.eudra.org.
15. Netherlands Pharmacovigilance Centrum Lareb Database. (version date: 2014, access date: 23-42014) http://www.lareb.nl/Bijwerkingen/Zoek-op-geneesmiddel.
16. College for Health Insurances. GIP-database. (version date: 7-3-2014, access date: 18-4-2014)
http://www.gipdatabank.nl/.
17. Srinivasan V, Singh J, Pandi-Perumal SR, Brown GM, Spence DW, Cardinali DP. Jet lag,
circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs.
Adv.Ther. 2010;27(11):796-813.
34
18. Dutch SmPC Zyrtec® 10 mg filmomhulde tabletten . (version date: 3-10-2012, access date: 18-42014) http://db.cbg-meb.nl/IB-teksten/h13010.pdf.
19. Meier CR, Wilcock K, Jick SS. The risk of severe depression, psychosis or panic attacks with
prophylactic antimalarials. Drug Saf 2004;27(3):203-13.
20. Mandell. Gerald L, editor. Principles and practice of infectious diseases. 7 ed. 2010. 3447p.
21. Perala J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsa E, Pirkola S, Partonen T, TuulioHenriksson A, Hintikka J, Kieseppa T, et al. Lifetime prevalence of psychotic and bipolar I
disorders in a general population. Arch.Gen.Psychiatry 2007;64(1):19-28.
35
1.7.
Ciclosporin and posterior reversible encephalopathy syndrome
Introduction
Ciclosporin (Neoral®) is indicated after organ transplantation to prevent the
rejection of a transplanted solid organ, where ciclosporin can be used as
monotherapy or in combination with low doses of corticosteroids or other
immunosuppressive medication. Furthermore ciclosporin is indicated after bone
marrow transplantation for the prophylaxis of graft rejection, and for the
prophylaxis or treatment of "graft-versus-host" (GVH) reaction. In addition
ciclosporin is indicated for very severe psoriasis when other therapies had not
been effective, very severe therapy-resistant atopical dermatitis in adults, steroidresistant nephrotic syndrome as a result of glomerular pathology, and very severe
rheumatoid arthritis in adults when other therapies had not been effective [1].
Ciclosporin is a cyclic polypeptide consisting of 11 amino acids. It is a potent
immunosuppressive agent. Preclinical studies showed that ciclosporin inhibits the
development of cell responses, including the rejection of allogenic grafts, skin
hypersensitivity of the delayed type, " graft versus host " reactions and T celldependent antibody formation. At cellular level, ciclosporin inhibits the production
and release of lymphokine, including interleukin-2. It appears that ciclosporin
blocks the resting lymphocytes in the G0 or G1 phase of the cell cycle and inhibits
the antigen induced release of lymphokines from activated T-cells.
The available data suggest that ciclosporin has a specific and reversible effect on
lymphocytes. In contrast to cytotoxic drugs, ciclosporin has no clinically relevant
effect on hematopoiesis [1].
Ciclosporin was granted marketing authorization in the Netherlands in 1983 [2].
Posterior reversible encephalopathy syndrome (PRES), also referred to as
reversible posterior leukoencephalopathy syndrome (RPLS), is a clinical
radiographic syndrome of heterogeneous etiologies that are grouped together
because of similar findings on neuroimaging studies. The clinical syndrome is
characterized by headaches, altered consciousness, visual disturbances and
seizures.
The syndrome is not always reversible, and it is often not confined to either the
white matter or the posterior regions of the brain [3].
The incidence of PRES is unknown and all age groups appear susceptible. PRES
has been described in a number of medical conditions, with hypertensive
encephalopathy, eclampsia, and the use of cytotoxic and immunosuppressant
drugs being the most common. Another risk factor is renal disease [3].
It is important to recognize and treat this condition promptly, in preventing the
permanent damage that can occur in this otherwise typically reversible condition
[3].
Reports
From 1 August 2013 1999 until 20 February 2014 the Netherlands
Pharmacovigilance Centre Lareb received two reports of PRES as the reported
reaction, associated with ciclosporin.
Of encephalopathy as the reported reaction, associated with ciclosporin, Lareb
received six reports in the period from 29 April 1999 until 6 December 2012.
The two reports with PRES as the coded reaction, are described here:
Case A (158347)
This serious spontaneous report from a specialist doctor concerns a male aged
71 years and older, with progressive renal failure following administration of
36
ciclosporin for nephrotic syndrome with a latency of 1 month after start. The dose
for ciclosporin was reduced, followed by improved renal function. About 1 year
and 3 months after start of ciclosporin the patient was hospitalized because of
atrial fibrillation which spontaneously converted to sinusrithm after rate control.
During this hospitalization the patient experienced progressive hypertension,
despite elevation of the antihypertensive medication. Then the patient
experienced unwellness and a convulsion wherefore admission to the intensive
care unit, eventually designated or as occipital ischaemic CVA, or as PRES
(differential diagnosis: caused by moxifloxacin/ciclosporin or hypertension). The
drug ciclosporin was withdrawn. The patient recovered. Concomitant medications
were prednisolone, moxifloxacin, rifampicin.
The medical history indicates renal failure due to focal segmental
glomerulosclerosis. Furthermore the medical history indicates total hip
replacement. For wound infection the patient used moxifloxacin and rifampicin.
The past drug therapy indicates risedronic acid with aggravated hip pain and
alendronic acid with back pain.
Case B (168399)
This serious (hospitalisation) spontaneous report from a pharmacist concerns a
female aged 51-60 years, with reversible posterior leukoencephalopathy
syndrome (RPLS/PRES) resulting in seizures, following oral administration of
ciclosporin, in a dosage of twice a day 275 mg, for immunosuppression in graft
versus host disease after donor lymphocyte infusion, with a latency of 12 days
after start. The patient was hospitalized for graft versus host disease after donor
lymphocyte infusion. The patient was hospitalized for 5 weeks. CT en MRI 11
days after start of ciclosporin indicated RPLS. The CT scan 19 days after start of
ciclosporin showed subarachnoidal bleedings and diffuse white matter
abnormalities, and the patient had seizures. The drug ciclosporin was withdrawn
and replaced by sirolimus. The seizures were treated with levatiracetam. The
patient was recovering at the time the report was submitted to Lareb.
Concomitant medications were pantoprazole, alendronic acid, posaconazole,
levofloxacin, valaciclovir, calcium / colecalciferol, prednisone, levothyroxine
sodium.
The medical history indicates multiple myeloma stage IIIa, allogeneic stem cell
transplantation, donor lymphocyte infusion in the month before start of the
reaction. The patient used ciclosporin in the past without a similar reaction.
In Case A the diagnosis PRES was considered possible, since the differential
diagnosis also comprised ischaemic CVA. In addition, the patient also
experienced hypertension, which made have played a role in the possible PRES.
The report did not contain information whether a cerebral imaging was performed.
In Case B the symptomatology of the patient and the image of PRES on the
scans, were described. In this case a change in blood pressure was not
described. The latencies of the two cases were very different: about 1 year and 3
months, and 12 days respectively. One patient recovered and the other patient
was recovering at the time the report was submitted to Lareb, after withdrawal of
ciclosporin.
The six reports received by Lareb, with encephalopathy as the reported reaction
are listed in Table 1.
In three of these cases other possible causes of encephopathy were described:
Case 34796 concerned progressive multifocal leukoencephalopathy. Case 64031
concerned hyperammonemia in a mycobacterium genavense infection, where the
patient experienced septic shock, ARDS, hepatic failure and encephalopathy
among other symptoms. Case 159238 concerned encephalopathy, hyponatremia,
hyperammonemia, and fever, and lumbar puncture revealed infection.
37
Table 1. Reports of encephalopathy associated with the use of ciclosporin
Patient,
Number,
Sex, Age,
Source
Drug, daily dose
Indication for use
Concomitant
Medication
Suspected
adverse drug
reaction
Time to
onset,
Action with
drug
outcome
A 46582
F, 21-30 years
Pharmaceutical
Company
tacrolimus 4mg per day
lung transplant,
ciclosporin 100mg 2dd
lung transplant
mycophenolate mofetil,
prednisone,
levonorgestrel/ethinyle
stradiol
headache,
vision blurred,
encephalopathy,
somnolence,
hemianopia,
blood pressure
increased,
nausea
not reported
discontinued
recovered
B 24478
M, 61-70 years
Specialist doctor
ciclosporin 2dd 175 mg
kidney transplant
amitriptyline,
acetylsalic acid,
omeprazole,
isradipine,
prednisone,
furosemide
encephalopathy
2 years
discontinued
recovering
C 34796
M,
Pharmaceutical
Company
ciclosporin dose
unknown
lung transplant
cataract,
encephalopathy,
death nos
not reported
unknown
fatal
D 64031
F, 61-70 years
ciclosporin dose
unknown
renal transplant
prednisolone,
mycophenolate mofetil
disseminated
intravascular
coagulation,
renal failure,
body temperature
increased,
lymphopenia,
glasgow coma
scale abnormal,
septic shock,
diarrhea,
encephalopathy,
normocytic anemia,
acute respiratory
distress syndrome,
hyperammonemia,
neutrophilia,
hemoglobin low,
palpitations,
tachycardia,
mycobacterial
infection,
consciousness
decreased,
spleen enlarged,
myocardial
infarction,
hepatic failure,
abdominal
tenderness,
lymphadenopathy
214 days
unknown
fatal
E 159238
F,
non specified blood stem
cell transplant
chronic lymphocytic
leukaemia,
ciclosporin dose
unknown,
fludarabine dose
unknown
chronic lymphocytic
mycophenolic acid
encephalopathy
38 days
no change
recovered
38
leukaemia,
non specified drug
prophylaxis,
mycophenolate mofetil
dose unknown
chronic lymphocytic
leukemia
F 84712
M, 2-4 years
Specialist doctor
ciclosporin 2 dd 90 mg
graft versus host disease
co-trimoxazole
encephalopathy
18 months
discontinued
recovered
with
sequelae
Other sources of information
SmPC
There is a variation between SmPCs of ciclosporin within The Netherlands
concerning the way this adverse drug reaction is mentioned.
The Dutch SmPC of generic ciclosporin mentions as an uncommon (between
1/100 and 1/1,000) occurring adverse drug reaction: "Signs of encephalopathy
such as convulsions, confusion, disorientation, decreased reactivity, irritability,
insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar
ataxia". Furthermore the Dutch SmPC of ciclosporin mentiones that with JCvirus
associated progressive multifocal leukoencephalopathy (PML), has been
observed in patients treated with cyclosporine. PRES is not specifically mentioned
in the The Dutch SmPC of generic ciclosporin [4].
The SmPC of ciclosporin Neoral® mentiones as an uncommon (between 1/100
and 1/1,000) occurring adverse drug reaction: “Encephalopathy including
Posterior Reversible Encefalopathiesyndrome (PRES), signs and symptoms such
as convulsions, confusion, disorientation, decreased responsiveness, agitation,
insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar
ataxia” [1].
The US SmPC of the FDA mentions that encephalopathy, including Posterior
Reversible Encephalopathy Syndrome (PRES), has been described both in postmarketing reports and in the literature. It is mentioned that manifestations include
impaired consciousness, convulsions, visual disturbances (including blindness),
loss of motor function, movement disorders and psychiatric disturbances.
Furthermore it is describes that in many cases, changes in the white matter have
been detected using imaging techniques and pathologic specimens. The US
SmPC also describes that predisposing factors such as hypertension,
hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high
ciclosporin blood concentrations, and graft-versushost disease have been noted
in many but not all of the reported cases. The SmPC mentions that the changes
in most cases have been reversible upon discontinuation of ciclosporin, and in
some cases improvement was noted after reduction of dose. Furthermore the
SmPC adds that it appears that patients receiving liver transplant are more
susceptible to encephalopathy than those receiving kidney transplant [5].
Literature
In 1996 PRES was first described as an entity. It was described that PRES has
diverse causes, immunosuppressive drugs being one of the common precipitants.
In four of the cases the use of cyclosporine was described [6].
Afterwards many more cases have been published reporting PRES associated
with the use of cyclosporine.
39
An article by Teive et al described eight patients who received ciclosporin A after
allogeneic bone marrow transplantation or as treatment for severe aplastic
anemia who developed PRES. In six of these patients neurological dysfunction
occurred preceded by or concomitant with high blood pressure and some degree
of acute renal failure. When lowering the dose or withdrawal of ciclosporin the
symptoms and neuroimaging abnormalities improved [7].
Two patients after pulmonary transplantation for cystic fibrosis, developed arterial
hypertension, headache, visual trouble and generalized seizures with diffuse
cortical and subcortical lesions predominantly in posterior regions. Disappearance
of the symptoms after withdrawal of ciclosporin confirmed the diagnosis of
cyclosporine-related PRES [8].
A 27-year old patient with collapsing focal glomerulosclerosis developed abrupt
elevation of blood pressure and neurological symptoms 3 weeks after start of
ciclosporin. An MRI showed scan lesions suggestive of PRES. Two months after
withdrawal of ciclosporin the MRI had normalized [9].
PRES related to ciclosporin has also been described in two cases after heart
transplantation. A 68-year old woman developed arterial hypertension, headache,
visual disturbances, and generalized seizures at day 14 after start of ciclosporin
and mycophenolate mofetil and prednisone, and lesions on MRI were visible. A
19-year old man developed acute headache and generalized seizures on day 44
after start of ciclosporin and prednisone, with lesions on MRI. Ciclosporin
concentrations were therapeutic. Both patients recovered. In the first case
ciclosporin had to be withdrawn to reverse the symptoms [10].
A 35-year old woman with SLE was described who developed PRES during
ciclosporin use. Althought this patient also had transient elevated blood pressure
3 days before development of the neurological symptoms, the authors estimated
that ciclosporin had a causative role in the development of PRES, based on
elevated serum ciclosporin level and dramatic neurologic recovery after
withdrawal of ciclosporin [11].
In a study of 660 renal pediatric patients 11 patients (8 males, 3 females, age 315 years) experienced PRES, in which in one patient high trough level of
ciclosporin was measured and ciclosporin toxicity was considered a contributory
factor [12].
Databases
Table 2. Reports of posterior reversible encephalopathy syndrome associated with
ciclosporine in the Lareb, WHO and Eudravigilance database
Database
MedDRA PT
Number of
reports
ROR (95% CI)
Lareb
Posterior reversible
encephalopathy
syndrome
2
-
WHO
“
158
68.1 (57.5 - 80.7)
Eudravigilance
“
279
32.4 (28.4 – 36.8)
Prescription data
Table 3. Number of patients using ciclosporin in The Netherlands between 2009 and 2013
[13].
Drug
2009
2010
2011
2012
2013
Ciclosporin
7,629
7,407
7,055
6,826
6,737
Mechanism
40
The pathogenesis of PRES remains unclear, but it appears to be related to
disordered cerebral autoregulation and endothelial dysfunction. Different
mechanisms might be etiologically important in different clinical situations.
Ciclosporin is associated with the neurologic deficits of PRES. After renal toxicity,
neurotoxicity is the most serious side effect with ciclosporin, which affects 25
percent to 59 percent of transplant patients. Hypomagnesemia,
hypocholesterolemia, the vasoactive agent endothelin and hypertension have
been implicated in facilitating ciclosporin neurotoxicity. Ciclosporin may
exacerbate hypertension by inhibiting nitric oxide production. The symptoms of
ciclosporin neurotoxicity resemble mitochondrial encephalopathy indicating an
underlying mechanism of mitochondrial dysfunction [3]. In a previous study [14] in
sixteen patients with neurologic injury attributed to cyclosporine therapy, the
clinical and radiologic findings in patients showing the neurotoxic effects of
ciclosporin appeared to be identical to those with hypertensive encephalopathy. In
this study the only major factor associated with the neurotoxic effects of
ciclosporin in all patients was systemic hypertension, although microangiopathic
hemolytic anemia, thrombocytopenia, and hypoalbuminemia were common.
Discussion and conclusion
The Netherlands Pharmacovigilance Centre Lareb received a report of possible
PRES and one of PRES, associated with the use of ciclosporin. Lareb also
received three reports of encephalopathy in which no other causes of
encephalopathy were described, so which might have indicated PRES. In the
WHO database there are 158 cases present of PRES associated with
ciclosporine, with a ROR of 68.1 (95% CI 57.5 - 80.7). In the Eudravigilance
database there is the large number of 279 cases of PRES associated with
cyclosporine present, with a ROR of 32.4 (95% CI 28.4 - 36.8). The FDA SmPC of
ciclosporine also mentiones PRES in ciclosporin and provides an extensive
explanation. The FDA SmPC mentions that encephalopathy, including PRES, has
been described both in post-marketing reports and in the literature and it
describes it’s manifestations. The FDA SmPC also describes that changes in
most cases have been reversible upon discontinuation of ciclosporin, and in some
cases improvement was noted after reduction of dose [5].
Also in the literature many cases of PRES in ciclosporin have been described.
In the Dutch SmPCs there is a variation on mentioning PRES between different
ciclosporin products.
Because of the possible reversibility of the serious condition of PRES, it is
important that PRES is specifically mentioned in the SmPCs of ciclosporin.
As reported on the website of the European Medicines Agency (EMA), the EMA
completed a review of Sandimmun and Sandimmun Neoral on 27 June 2013, and
the Agency’s Committee for Medicinal Products for Human Use (CHMP)
concluded that there was a need to harmonise the prescribing information for
Sandimmun® and Sandimmun Neoral® in the European Union (EU) [15]. In the
Sandimmun Article-30 referral-Annex III PRES is specifically mentioned [16].

Posterior Reversible Encephalopathy
Syndrome (PRES), should be mentioned in
the SmPC of all ciclosporin products
41
References
1. Dutch SmPC Neoral® 25 mg capsules, 100 mg capsules. (version date: 4-11-2013, access date:
22-4-2014) http://db.cbg-meb.nl/IB-teksten/h17496.pdf.
2. Dutch SmPC Sandimmune® concentraat voor oplossing voor intraveneuze infusie 50 mg/ml.
(version date: 4-11-2013, access date: 29-4-2014) http://db.cbg-meb.nl/IB-teksten/h09846.pdf.
3. UpToDate. (version date: 2012, access date: 3-4-2014)
http://www.uptodate.com/contents/reversible-posterior-leukoencephalopathysyndrome?source=search_result&search=reversible+posterior+leukoencephalopathy+syndrome&
selectedTitle=1%7E150.
4. Dutch SmPC ciclosporine Actavis 25 mg capsules, 50 mg capsules, 100 mg capsules. (version
date: 30-5-2013, access date: 22-4-2014) http://db.cbg-meb.nl/IB-teksten/h34434.pdf.
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http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050715s033,050716s034lbl.pdf.
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bone marrow transplantation. Arq Neuropsiquiatr. 2001;59(3-B):784-9.
8. Lepoivre T, Treilhaud M, Auffray-Calvier E, Rigal JC, Blanloeil Y. [Posterior reversible
encephalopathy syndrome: about 2 cases related to the cyclosporine]. Ann Fr Anesth Reanim.
2003;22(5):466-9.
9. de Oliveira RA, Fechine LM, Neto FC, Nicodemus JM, Silva GBJr, Silva LS. Posterior reversible
encephalopathy syndrome (PRES) induced by cyclosporine use in a patient with collapsing focal
glomeruloesclerosis. Int Urol Nephrol. 2008;40(4):1095-8.
10. Dzudie A, Boissonnat P, Roussoulieres A, Cakmak, Mosbah K, Bejui FT, Obadia JF, Sebbaq L.
Cyclosporine-related posterior reversible encephalopathy syndrome after heart transplantation:
should we withdraw or reduce cyclosporine?: case reports. Transplant Proc. 2009;41(2):716-20.
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should not be forgotten: cyclosporine-induced posterior reversible encephalopathy syndrome.
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encephalopathy syndrome in children with kidney disease. Indian J Nephrol. 2014;24(1):28-34.
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http://www.gipdatabank.nl/.
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neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16
cases. AJR Am J Roentgenol. 1995;165(3):627
15. European Medicines Agency. Referrals. Sandimmun and associated names. (version date: 20-122013, access date: 10-7-2014)
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Sandimmun_and
_associated_names/human_referral_000346.jsp&mid=WC0b01ac05805c516f.
16. Annex III . Summary of product characteristics, labelling and package leaflet. Sandimmun and
associated names. (version date: 20-12-2013, access date: 10-7-2014)
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Sandimmun_30/W
C500144898.pdf.
42
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43