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Kwartaalbericht
1e kwartaal 2014
20 februari 2014
Contents
Voorwoord
3 1. Observations
4 1.1. Buprenorphine and inflammation resulting in skin depigmentation
4 1.2. Lamotrigine and nightmares
9 1.3. Mirtazapine and urinary retention
14 1.4. Angiotensin II receptor antagonists and cold hands and feet
19 2. Overviews
2.1. 23 Overview of reports on novel anticoagulants
23 2.2. Update of Overview of Dutch cases of narcolepsy associated with
Pandemic influenza vaccine (Pandemrix®)
3. Publications
27 33 2
Voorwoord
Bij de beoordeling van een melding is het belangrijk dat de bijwerking goed
beschreven en de melding goed gedocumenteerd is. Beoordelaars zien de
patiënt immers niet zelf en kunnen alleen op deze beschrijving en informatie af
gaan.
Het digitale tijdperk is daarbij zeer behulpzaam. Al geruime tijd kan een gescande
ontslagbrief uit het ziekenhuis met een melding worden meegestuurd. Daaruit kan
vaak goede aanvullende informatie worden gehaald.
Het komt ook voor dat er foto’s worden meegestuurd, en ook dat kan soms zeer
informatief zijn. In dit kwartaalbericht ziet u hier een voorbeeld van in het bericht
over buprenorphine en depigmentatie van de huid. In dit geval zijn de foto’s dus
zelfs toegevoegd aan het bericht.
Het digitale tijdperk biedt nog veel meer mogelijkheden om de inhoud van de
meldingen en ook het melden op zich te verbeteren. Kansen die we niet onbenut
mogen laten worden.
Lareb is daarom samen met het NHG in overleg hoe vanuit het huisartseninformatiesysteem via een ‘alert’ er op gewezen kan worden een opgetreden
bijwerking te melden. Vervolgens zal voor de melding noodzakelijke informatie uit
het digitale dossier geautomatiseerd in het meldformulier worden overgenomen.
Ook in een aantal ziekenhuizen zal dit jaar een pilot starten om vanuit bestaande
registraties bijwerkingen door te melden.
Deze ontwikkeling is van belang omdat het aantal meldingen van zorgverleners
stagneert. In 2013 steeg het totaal aantal meldingen met 20%. Maar dat kwam
met name door een forse stijging van het aantal meldingen bij Lareb van
patiënten.
De stagnatie van het aantal meldingen door zorgverleners is zorgelijk. Na de
invoering van de verplichting van het melden van ernstige bijwerkingen in de
Geneesmiddelen hadden we wel een stijging mogen verwachten.
Ik zou Lareb in vele opzichten uiteraard niet willen vergelijken met de
Belastingdienst. Maar één motto wil ik wel overnemen: leuker kunnen we het niet
maken, maar wel makkelijker.
Agnes Kant
3
1. Observations
1.1.
Buprenorphine and inflammation resulting in skin depigmentation
Introduction
Buprenorphine is a mixed agonist-antagonist agent. It exerts analgesic effects by
binding to CNS opiate receptors. It produces partial agonistic effects at the muopioid receptors and antagonistic effects at kappa-opioid receptors.
Buprenorphine has a long duration of action and an analgesic potency 25 to 40
times that of morphine sulfate.
Buprenorphine transdermal is indicated for the management of non-malignant,
moderate chronic pain, for which an opioid is needed in order to reach sufficient
reduction in pain.
Buprenorphine is available as transdermal patches:
BuTrans® 5, 10 or 20 μg / hour, Transtec® 35, 52,5 or 70 μg / hour or generic
Buprenorfine Ranbaxy 35, 52,5 or 70 μg / hour. The active ingredient is
buprenorphine. The inactive excipients ingredients in Butrans® are: levulinic acid,
oleyl oleate, povidone, and polyacrylate cross-linked with aluminum. Butrans® was
granted marketing authorization for the Dutch market in 2008.
Transdermal buprenorphine should be applied to a hairless or nearly hairless
non-irritated skin site on the upper outer arm, upper chest, upper back, or side of
chest. If necessary, the area can be cleansed with water only; it is advised not to
use soaps alcohol, oils, lotions, or abrasive devices on the application site. The
skin at the application site should be allowed to dry completely.
The transdermal buprenorphine patch should be applied immediately after
removal from the protective pouch. Each patch provides analgesia for 7 days.
After removal of the patch, a new patch should be applied to a different skin site
every week making sure that at least 3 weeks pass before the same skin site is
used again. When only 2 weeks had passed between applications on the same
site, a doubling of drug exposition was observed.
In skin depigmentation no pigment in the macules is present, whereas in skin
hypopigmentation macules have retention of some pigment. Skin
hypopigmentation can be caused by systemic conditions, such as cutaneous T
cell lymphoma, leprosy, tinea versicolor, auto-immune related conditions as
sarcoidosis and vitiligo or pityriasis alba, as a result of post-inflammatory reaction
[4].
Reports
Until 17 October 15 2013, the Netherlands Pharmacovigilance Centre Lareb
received 2 reports of skin depigmentation in association with buprenorphine
dermal patches (Butrans®).
Case A (116659)
A specialist doctor (neurologist) reported skin depigmentation is a female aged
61-70 years, who used buprenorphine Butrans® 5 μg / hour for pain. She had
used buprenorphine for 5 months (6 patches) when an inflammatory skin reaction
with pus developed followed by skin depigmentation at the site of the patch.
Buprenorphine was discontinued. The patient had not recovered at the time of
reporting, almost four months later. Follow up information was requested but not
retrieved. Concomitant medication was carbasalate calcium, losartan,
pantoprazole and prednisone.
4
Case B (153414)
A general practitioner reported skin erythema and irritation a female aged 61-70
years, who used buprenorphine Butrans® 5 μg / hour for chronic pain for a
couple of days. After a couple of weeks skin discolouration and vitiligo developed
in the shape of the transdermal patch. Concomitant medication was
acetylsalicylic acid, perindopril, atorvastatin, hydrochlorothiazide, omeprazole and
latanoprost eye drops. Buprenorphine was discontinued. Follow up information
was requested. The patient had not yet recovered six months after
discontinuation. Enclosed pictures show several square-shaped 3x3 cm
depigmented areas on upper chest and back. As also some small depigmented
spots are observed, it cannot not be ruled out that patient is susceptible to vitiligo.
* pictures published with permission of the reporter and patient
5
Other sources of information
SmPC
The most common adverse skin reactions described in the SmPC are pruritus
and erythema (> 10 %), exanthema (1-10%), dry skin and urticaria (0,1 -1 %), and
vesicles and pustules (< 0,01 %). Furthermore an inflammatory reaction is
described at the site of application (0,01-0,1 %). In some cases a delayed allergic
reaction is observed with evident inflammatory aspects. In such cases the
treatment with buprenorphine Butrans® should be discontinued. Skin
depigmentation is not mentioned in the SmPC’s of buprenorphine patches [1-3].
Literature
No reports of skin depigmentation or skin hypopigmentation in association with
buprenorphine could be found.
The US SmPC describes dose- related application site erythema, irritation, rash
and pruritus. Beside this, marked inflammation ( with burning, and vesicles), have
been rarely reported within days to months of initiating buprenorphine transdermal
system [5].
Several topical drug have been related to cause hypopigmentation, including
tretinoine and corticosteroids. Depigmentation is associated primarily with the
application of monobenzyl ether of hydroquinone or exposure to catechols,
phenols or quinones [6]. Use of transdermal patches have been implicated in skin
depigmentation: twice this was observed after transdermal clonidine [7,8] and
chemical leukoderma resulted after the application of a transdermal
methylphenidate patch [9].
Databases
On October 17, 2013, the database of the Netherlands Pharmacovigilance Centre
contained two reports of skin depigmentation in association with buprenorphine
Butrans® 5 μg / hour. No reliable ROR could be calculated because of the low
number of cases.
On October 17, 2013, the WHO database of the Uppsala Monitoring Centre
contained 3 reports of skin depigmentation in association with buprenorphine with
a ROR of 4.0 (1.3-12.3). Two of these originated from the Netherlands, one from
Germany: this concerned a male aged 77 years.
On November 11, 2013, the Eudravigilance database of the EMA contained no
reports of skin depigmentation in association with buprenorphine. It is not clear
why there are no Dutch cases of this association present in Eudravigilance.
Prescription data
The number of patients using buprenorphine in the Netherlands is shown in table
1 [10].
Table 1. Number of patients using buprenorphine in the Netherlands between 2007 and
2011
Drug
®
Buprenorphine (Butrans )
2008
2009
2010
2011
2012
7.822
8.603
25.186
36.095
41.179
6
Mechanism
Melanogenesis is a complex process which includes melanin synthesis, transport
and release to keratinocytes. It is controlled by multiple mediators (growth factors,
cytokines) acting on melanocytes, keratinocytes and fibroblasts.
The suggested aetiopathogenesis behind drug-induced vitiligo is:
(1) activation of cytotoxic T cells directed against melanocyte antigens,
(2) damage to sympathetic nerves that are connected by chemical synapses to
melanocytes with a resultant functional disturbance, and
(3) a direct cytotoxic nature of the drug on melanocytes (apoptosis).
Most of the mechanisms suggested are hypothetical with no direct or scientific
evidence to establish the exact role of the implicated drug [11].
In contact vitiligo following exposure to chemicals, it is suggested that the
instigating factors result in susceptible fragile melanocytes to undergo apoptosis
[12]. There is no indication that above mentioned mechanisms play a role in
buprenorphine induced skin depigmentation.
Hypopigmentation is also observed after various inflammatory skin diseases,
including atopic dermatitis, lichen striatus and pityriasis lichenoides chronica [13].
The variation in individual response to cutaneous inflammation is not well
understood. Ruiz-Maldonado therefore proposed the term ‘individual chromatic
tendency’. The tendency for post inflammatory hypopigmentation might be
genetically determined and inherited in an autosomal dominant pattern. It is
suggested that the hypopigmentation may result from inhibition of melanogenesis
rather than destruction of melanocytes; however severe inflammation may lead to
actual loss of melanocytes ore even melanocyte death and thus permanent
pigmentary changes, resulting in hypopigmentation or depigmentation [14].
Depending on the severity of the hypopigmentation, re-pigmentation can likely
take weeks to years.
Class effects
No cases of skin depigmentation in association with other opioid patches were
reported to Lareb nor was any information found in a literature search.
Discussion
In both reactions reported to Lareb, at first the patients experienced a skin
reaction at the application site of the transdermal patch. Over time, this resulted
in long lasting skin depigmentation. This is in agreement with the mechanism as
observed in post inflammatory hypopigmentation in inflammatory skin diseases. It
is therefore suggested that the observed skin depigmentation in association with
buprenorphine patches is a result of a post inflammatory process.
Skin reactions to transdermal patches, including depigmentation, can be induced
by the active ingredient or other components of the patch. For transdermal
clonidine, most studies have indicated that the skin reactions are related to the
drug itself and not to other factors [8]. For buprenorphine, the severity of the initial
reaction seems to be related to the dose of buprenorphine patches [5]. For this
reason it is suggested that the reaction is caused by the active ingredient
buprenorphine, and not by the adhesion matrix.
Conclusion
Lareb has received two reports of skin depigmentation in association with
buprenorphine Butrans® 5 μg / hour. It is assumed that skin depigmentation
occurred as a post inflammatory reaction after transdermal exposure of
buprenorphine Butrans®. For this reason, it is suggested that buprenorphine
Butrans® might have a causative role in the occurrence of skin depigmentation.
Although only a small number of cases were reported, the specificity of the
reaction warrants the elaboration of a signal.
7

Skin depigmentation, as a result of
inflammation, should be mentioned in the
SmPC of buprenorphine Butrans® .
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
®
Dutch SmPC Butrans . (version date: 18-12-2008, access date: 17-10-2013) http://db.cbgmeb.nl/IB-teksten/h100975.pdf.
®
Dutch SmPC Transtec . (version date: 12-1-2012, access date: 17-10-2013) http://db.cbgmeb.nl/IB-teksten/h32909.pdf.
Dutch SmPC buprenorfine Ranbaxy. (version date: 14-6-2013, access date: 17-10-2013)
http://db.cbg-meb.nl/IB-teksten/h103490.pdf.
®
UpToDate Hypopigmented macules . (version date: 2013, access date: 24-10-2013 BC)
http://www.uptodate.com/contents/approach-to-the-patient-with-macular-skinlesions?source=preview&anchor=H9&selectedTitle=2~54#H9.
®
US SmPC Butrans . (version date: 1-7-2013, access date: 17-10-2013 BC)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021306s016lbl.pdf.
Valeyrie-Allanore L, Sassolas B, Roujeau JC. Drug-induced skin, nail and hair disorders. Drug
Saf 2007;30(11):1011-30.
Doe N, Seth S, Hebert LA. Skin depigmentation related to transdermal clonidine therapy.
Arch.Intern.Med. 1995;155(19):2129
Prisant LM. Transdermal clonidine skin reactions. J.Clin.Hypertens.(Greenwich.) 2002;4(2):1368.
Ghasri P, Gattu S, Saedi N, Ganesan AK. Chemical leukoderma after the application of a
transdermal methylphenidate patch. J.Am.Acad.Dermatol. 2012;66(6):e237-e238
College for Health Insurances GIP database. (version date: 23-6-2013, access date: 24-10-2013)
http://www.gipdatabank.nl/.
Arya V, Bansal M, Girard L, Arya S, Valluri A. Vitiligo at Injection Site of PEG-IFN-alpha 2a in
Two Patients with Chronic Hepatitis C: Case Report and Literature Review. Case.Rep.Dermatol.
2010;2(2):156-64.
Boissy RE, Manga P. On the etiology of contact/occupational vitiligo. Pigment Cell Res.
2004;17(3):208-14.
Vachiramon V, Thadanipon K. Postinflammatory hypopigmentation. Clin.Exp.Dermatol.
2011;36(7):708-14.
Ruiz-Maldonado R, Orozco-Covarrubias ML. Postinflammatory hypopigmentation and
hyperpigmentation. Semin.Cutan.Med.Surg. 1997;16(1):36-43.
8
1.2.
Lamotrigine and nightmares
Introduction
Lamotrigine (Lamictal®) is indicated for people of 13 years and older for the
treatment of epilepsy as adjuvant or monotherapy in partial epilepsy and
generalized epilepsy including tonic-clonic epilepsy, and in epilepsy associated
with Lennox-Gastaut’s syndrome as adjuvant therapy or initial antiepileptic drug.
In people of 2 up to and including 12 years, it is indicated as adjuvant therapy of
partial epilepsy and generalized epilepsy including tonic-clonic attacks, and in
epilepsy associated with Lennox-Gastaut’s syndrome, and as monotherapy in
typical absence epilepsy. Furthermore it is indicated for bipolar disorder. For
people of 18 years and older is it also indicated for prevention of depressive
episodes in patients with a bipolar I disorder who mainly experience depressive
episodes [1].
Lamotrigine is a voltage-dependent blocker of voltage-sensitive sodium channels.
It blocks the constantly repeated firing of neurons and inhibits the release of
glutamate (the neurotransmitter that serves a key role in the onset of epileptic
seizures). These effects probably contribute to the anticonvulsant properties of
lamotrigine. The mechanism of action of lamotrigine in bipolar disorders has not
been established yet, although voltage-sensitive sodium channels probably play
an important role [1].
Lamictal® was granted marketing authorization in the Netherlands on 15 January
1996 [1].
A nightmare is a disturbing dream that awakens the dreamer and is a rapid eye
movement (REM) related parasomnia. In a nightmare disorder there is
exaggeration of the features of REM sleep [2]. Nightmares are defined by The
International Classification of Sleep Disorders II as “recurrent episodes of
awakening from sleep with recall of intensely disturbing dream mentation, usually
involving fear or anxiety, but also anger, sadness, disgust, and other dysphoric
emotions”. Nightmares generally occur in the early hours of the morning because
REM sleep predominates during the final third of the night [3].
The Dutch SmPC of lamotrigine mentions confusion, hallucinations, somnolence,
insomnia and agitation as adverse drug reactions, but does not mention
nightmares or abnormal dreams [1]. This observation describes the association
between nightmares and the use of lamotrigine.
Reports
On 29 October 2013 the database of the Netherlands Pharmacovigilance Centre
Lareb contained three reports concerning nightmares and one of abnormal
dreaming associated with the use of lamotrigine.
Case A (120197)
This well documented non-serious spontaneous report from a consumer concerns
a female aged 51-60 years, with nightmares, headache, diarrhoea, nausea,
blurred vision, pruritus, restlessness and listlessness following administration of
lamotrigine for a bipolar affective disorder with a latency of an unknown number of
weeks after start. The dose of lamotrigine was reduced from 200mg daily to 50mg
daily and the patient recovered from having nightmares. The outcome of the other
symptoms was unknown. Concomitant medications were levothyroxine,
zuclopentixol, pantoprazole, levocetirizine, mirtazapine and diazepam with
unknown start dates.
There was no further reported medical history. The past drug therapy indicated
that the patient used lithiumcarbonate in the past.
9
Case B (126472)
This well documented non-serious spontaneous report from a nurse practitioner
concerns a male aged 31-40 years, with nightmares following administration of
lamotrigine for epilepsy with a latency of about 15 days after start. A short period
after dosage increase from 25 mg daily to 50 mg daily the patient got nightmares.
Using 25 mg daily the patient initially had no complaints, however later the patient
suffered from nightmares even after dosage reduction to 12.5 mg. The drug
lamotrigine was withdrawn, and the patient recovered. Lamotrigine was
reintroduced again because of trembling in the foot, which resulted in the
immediate return of the nightmares (positive rechallenge). Three days after
withdrawal of lamotrigine the nightmares had disappeared again. Concomitant
medications were carbamazepine and valproic acid, both used for many years.
There was no further reported medical history.
Case C (152031)
This well documented non-serious spontaneous report from a specialist doctor
concerns a female aged 31-40 years, with sleep disturbance and nightmares
following administration of lamotrigine for bipolar affective disorder with a latency
of 3 days after start. Lamotrigine was started at a low dose. The complaints
became unbearable, shortly after using a dose of 200 mg daily. Lowering the
dose to 50 mg diminished the complaints, but there were still a few disturbing
dreams present. Concomitant medication was not reported.
The medical history indicated recurrent depressions, and hypomanic episodes
under antidepressant therapy. The patient had no known past drug therapy.
Case D (46158)
This moderately documented non-serious report from a pharmacist concerns a
female aged 41-50 years, with dreams and nightmares and taking lamotrigine 25
mg two times daily with an unknown exact latency of less than a month after start.
The action taken for lamotrigine was unknown. The patient outcome was
unknown. The patient described the severity of the complaints as a 4 on a scale
from 1 to 5. Concomitant medication was alprazolam, used chronically for at least
a year with an unknown start date. The past drug therapy indicated gabapentin.
Other sources of information
SmPC
The Dutch SmPC of lamotrigine mentions confusion, hallucinations, somnolence,
insomnia and agitation as adverse drug reactions, but does not mention
nightmares or abnormal dreams [1]. The US SmPC of the FDA mentions dream
abnormality as an adverse event of lamotrigine in 6% of patients with the use of
lamotrigine as monotherapy (100 to 400 mg/day) in bipolar disorder in two
double-blind, placebo-controlled trials of 18 months’ duration, and greater than
1% and less than 5% in all studies [4].
Literature
Uher et al [5,6] described a case of a 42-year-old woman with dose-related visual
hallucinations and sleep disturbances within 4 weeks of starting lamotrigine. This
patient had a history of depression and alcohol abuse, but not of hallucinations.
Because of depression and hypomania this patient started lamotrigine. After four
weeks in which the dose of lamotrigine was gradually increased to 100 mg/day,
she experienced disturbed sleep with frequent wakening and vivid dream-like
experiences without being completely asleep. Later she also experienced
hallucinations. The dose of lamotrigine was reduced to 50 mg/day. After a dose
increase to 75 mg/day two months later, sleep disturbances and nightmares
returned within one week. Further increase to 100 mg/day resulted in
10
hallucinations, both during the day and during the night. After decrease to 75
mg/day the hallucinations disappeared and the hallucinations and nightmares
have not recurred despite continued treatment on lamotrigine 75 mg/day.
Concomitant medication was citalopram.
The book Meyler’s Side Effects of Drugs describes two boys aged 6 and 8 years
with sleep difficulties, one case associated with scary dreams, after being
stabilized on lamotrigine, 8 mg/kg. After dose reduction the disturbances
improved [7,8].
On the other hand an article bij Economou et al [9], describes a case of a 68year-old man already suffering from a Rapid eye movement (REM) behavior
disorder (RBD). RBD is a parasomnia that is manifested by vivid, often frightening
dreams associated with simple or complex motor behavior during REM sleep [10].
In the article of Economou et al [9], a patient started using lamotrigine because of
a diagnosis of epilepsy. This patient started lamotrigine at 25 mg/day, reached a
maximum of 100 mg/day after 2 months and was retained at this dose for 1 more
month. During treatment there were no appreciable changes in the frequency and
intensity of RBD symptomatology. But, after abrupt discontinuation of lamotrigine
immediately RBD symptomatology was severely aggravated, with dreams
becoming more vivid and frightening and occurring almost every night. Over two
months RBD symptomatology gradually subsided, reaching levels comparable to
those before lamotrigine.
Databases
On 30 October 2013 the database of the Netherlands Pharmacovigilance Centre
Lareb contained three reports of the MedDRA® Preferred Term (PT) Nightmare en
one report of Abnormal dreams associated with the use of lamotrigine. The
reporting odds ratio (ROR) was 1.6 (95% CI 0.5 – 5.1) for nightmare. The
combined ROR of nightmare and abnormal dreams was 1.3 (95% CI 0.5 – 3.5).
These were not disproportional.
The WHO database of the Uppsala Monitoring contained 107 reports of
Nightmare and 75 reports of Abnormal dreams with the use of lamotrigine (see
table 1).
Table 1. Reports of nightmares and abnormal dreams associated with lamotrigine in the
WHO database
Drug
MedDRA PT
Number of
reports
ROR (95% CI)
Lamotrigine
Nightmare
107
1.4 (1.2 - 1.7)
Abnormal dreams
75
1.2 (0.9 - 1.5)
Combined
182
1.3 (1.1 - 1.5)
The reports of nightmares and abnormal dreams for lamotrigine in the
Eudravigilance database are given in table 2.
Table 2. Reports of nightmares and abnormal dreams associated with lamotrigine in the
Eudravigilance database
Drug
MedDRA PT
Number of
reports
ROR (95% CI)
Lamotrigine
Nightmare
35
1.6 (1.1 – 2.2)
Abnormal dreams
13
1.0 (0.6 – 1.7)
Combined
48
1.35 (1.02 – 1.80)
11
Prescription data
The number of patients using lamotrigine in The Netherlands is shown in Table 3.
Table 3. Number of patients using lamotrigine in the Netherlands between 2008 and 2012
[11].
Drug
lamotrigine
2008
2009
2010
2011
2012
16,433
16,720
17,237
17,753
18,517
Mechanism
An article by Foldvary et al [12] describes a study where ten adults with focal
epilepsy taking or carbamazepine or phenytoin were titrated to a lamotrigine dose
of 400 mg/day to study the effect of lamotrigine on sleep. Treatment with
lamotrigine was associated, although not reaching statistical significance, with a
reduction in arousals and stage shifts and an increase in REM periods. Maybe,
because a nightmare is a REM related parasomnia, the increase of REM periods
might play a role in the occurrence of nightmares while using lamotrigine. In the
article by Foldvary et al increase in dreaming was reported by one subject.
Insomnia or restlessness were not reported with treatment in the article by
Foldvary et al. The article did also not mention the occurrence of nightmares.
Discussion and conclusion
The Netherlands Pharmacovigilance Centre Lareb received three reports of
nightmares and one of abnormal dreams associated with the use of lamotrigine.
In the WHO database there are 107 cases present of nightmares and 75 cases of
abnormal dreams associated with lamotrigine. In the Lareb database the
associations are not disproportionally present. In the WHO- and Eudravigilance
database the association between nightmares and lamotrigine, and the
combination of nightmares and abnormal dreams and lamotrigine are
disproportionally present.
The US SmPC of the FDA mentions dream abnormality as an adverse event of
lamotrigine [4].
In the three cases of nightmares from Lareb there were positive dechallenges,
after lowering the dose or withdrawal of the drug, the nightmares diminished or
disappeared. In one case (case B) it is known that three days after withdrawal of
the lamotrigine, the nightmares had disappeared. In case B there was also a clear
rechallenge. Case D contained no information on de- and rechallenge.
In case A, B and C a relation is described between the dosage and the severity of
the nightmares, what could fit in a type A adverse drug reaction.
Weak aspects of the associations were the differences in latencies of three days
to a number of weeks, and an unknown exact latency of less than a month in
case D.
In case A and D concomitant medications could play a role. In case A the patient
used zuclopentixol, mirtazapine and diazepam as concomitant medication with
unknown start dates. The Dutch SmPC of zuclopentixol describes nightmare as a
uncommon (≥ 1/1,000, <1/100) occurring adverse reaction [13]. Nightmares are
described as an uncommon (≥ 1/1,000, <1/100) occurring adverse reaction in the
Dutch SmPC of mirtazapine [14]. The Dutch SmPC of diazepam mentions that
nightmares were described in the use of benzodiazepines [15]. Whether action
was taken for the concomitant medication in case A was unknown. In case D the
patient also used alprazolam. Similar to the SmPC of diazepam, the Dutch SmPC
of alprazolam also mentions that nightmares were described in the use of
benzodiazepines [16].
12
Although confounding by concomitant medication could not be ruled out, and
although there was a variety in latencies, and the association was only slightly
disproportionally present in the WHO database, it is supported by the FDA SmPC,
literature and positive dechallenges in three cases and in one case also a clear
rechallenge. For these reasons, it is suggested that lamotrigine might have a
causative role in the occurrence of nightmares.

Nightmares should be mentioned in the SmPC
of lamotrigine
References
®
1. Dutch SmPC Lamictal 2/5/25/50/100/200 mg, dispergeerbare/kauwtabletten. (version date: 26-62013, access date: 29-10-2013). http://db.cbg-meb.nl/IB-teksten/h19115.pdf
2. UpToDate. (version date: 2012, access date: 29-10-2013).
http://www.uptodate.com/contents/classification-of-sleepdisorders?detectedLanguage=en&source=search_result&search=nightmares&selectedTitle=4%7
E150&provider=noProvider
3. UpToDate. (version date: 2012, access date: 29-10-2013).
http://www.uptodate.com/contents/sleepwalking-and-other-parasomnias-inchildren?detectedLanguage=en&source=search_result&search=nightmares&selectedTitle=1%7E
150&provider=noProvider
®
4. FDA SmPC of lamotrigine Lamictal . (access date: 29-10-2013).
http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s1
4s18s19s20lbl.pdf
5. Uher R, Jones HM. Hallucinations during lamotrigine treatment of bipolar disorder. Am J
Psychiatry. 2006 Apr;163(4):749-50.
®
6. Micromedex Healthcare Series, (electronic version). Thomson Micromedex, Greenwood Village,
Colorado, USA. (access date: 29-10-2013)
7. Aronson J.K. [Edit.], Meyler's Side effects of Drugs, 15thedition 2006, Elsevier
8. Champagne J, Whiting SE. Sleep disturbance on lamotrigine. Epilepsia 1999;40(Suppl 7):118-19.
9. Economou NT, Bonakis A, Ghika A, Ferini-Strambi L, Vassilopoulos D, Kyrozis A. Lamotrigine
withdrawal may worsen RBD symptoms. Neurologist. 2011 Sep;17(5):279-81.
10. Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep
behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and
future directions. Ann N Y Acad Sci. 2010 Jan;1184:15-54.
11. College for Health Insurances. GIP database. (version date: 9-6-2009, actualized 23-6-2013,
access date: 30-10-2013). http://www.gipdatabank.nl/
12. Foldvary N, Perry M, Lee J, Dinner D, Morris HH. The effects of lamotrigine on sleep in patients
with epilepsy. Epilepsia. 2001 Dec;42(12):1569-73.
®
13. Dutch SmPC Cisordinol 2/10/25 mg filmomhulde tabletten. (version date: 29 november 2012,
access date: 30-10-2013). http://db.cbg-meb.nl/IB-teksten/h04294.pdf
®
14. Dutch SmPC Remeron 15 mg tabletten. (version date: 15-2-2011 met laatste herziening 12 maart
2011, access date: 6-11-2013). http://db.cbg-meb.nl/IB-teksten/h16685.pdf
15. Dutch SmPC diazepam ratiopharm 2/5/10 mg tabletten. (version date: 05 december 2012, access
date: 6-11-2013). http://db.cbg-meb.nl/IB-teksten/h52640.pdf
®
16. Dutch SmPC Xanax 0,25/0,5 mg tabletten, 0,5/1/2 mg tabletten met gereguleerde afgifte.
(version date: Jan 2013, laatste wijziging op 25 maart 2013, access date: 30-10-2013).
http://db.cbg-meb.nl/IB-teksten/h14409.pdf
13
1.3.
Mirtazapine and urinary retention
Introduction
Mirtazapine is an antidepressant that has been approved for the Dutch market
since March 1994. It is indicated for the treatment of episodes of major
depression[1]. By blocking the presynaptic α2 receptors, mirtazapine increases the
noradrenergic and serotonergic (5-HT) neurotransmission. The enhancement of
5-HT neurotransmission is specifically mediated via 5-HT1 receptors, since 5-HT2
and 5-HT3 receptors are blocked by mirtazapine. The sedative effect of
mirtazapine is explained by the strong blockage of the histamine H1 receptor.
According to the SmPC of mirtazapine, the drug has practically no anticholinergic
activity [1].
The current observation describes the possible association between mirtazapine
and urinary retention. Urinary retention is a condition in which impaired emptying
of the bladder results the retention of residual urine. It can be categorized into
‘chronic’ or ‘acute’. Chronic urinary retention develops over a long period with
development of a painless, palpable bladder. Risk factors are detrusor
hypocontractility, chronic bladder outlet obstruction or neurological bladder
dysfunction. In acute urinary retention, the symptoms develop acute and the
retention itself is often painful and requires treatment by urinary catheterization.
It occurs most frequently in men over age 60 and is often the result of BPH
[10,19].
Reports
Until October 10th 2013, the Netherlands Pharmacovigilance Centre Lareb had
received 6 reports concerning urinary retention associated with the use of
mirtazapine, see Table 1. Additionally, Lareb received 2 reports of “micturition
disorder” associated with the use of mirtazapine, see Table 2. One patient had a
dropwise micturition (G) and the other H had the urgency to urinate but there was
no micturition (H).
All reports were made by healthcare professionals. The age of the patients varied
from 24 to 90 years with an median of 56 years. A positive dechallenge was
reported 4 times (A, B, D, F). With the exception of patient C, the time to onset
varied from 8 hours till 7 days after start of mirtazapine with a median of 1 day.
In two patients (C, E) besides mirtazapine, another suspected drug was reported:
for patient C venlafaxine and patient E carbidopa/levodopa. For both of these
drugs urinary retention is mentioned in the SmPC [3,4].
Table 1. Reports of urinary retention associated with the use of mirtazapine
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 30234
M, 51-60
years
General
Practitioner
mirtazapine tablet 30mg
acetylsalicylic acid,
diltiazem
urinary retention
not reported
discontinued
recovering
B 38053
M, 41-50
years
Specialist
doctor
mirtazapine tablet 30mg
depressive episode
urinary retention
2 days
discontinued
recovered
C 48575
mirtazapine tablet 30mg
urinary retention
mirtazapine:
oxazepam,
14
M, 70 years
and older
Specialist
doctor
depression,
venlafaxine tablet 75mg
neurotic depression
D 108030
M, 51-60
years
Specialist
doctor
mirtazapine tablet 15mg
depression
clemastine,
venlafaxine ,
bisoprolol ,
simvastatin,
gabapentin,
paracetamol/codeine
urinary retention
8 hours after
increase of the
dosage
discontinued
recovered
E 142843
M, 70 years
and older
Specialist
doctor
carbidopa/levodopa
tablet 100/25mg
parkinson's disease,
mirtazapine tablet 15mg
mood swings
tamsulosine
bladder retention
mirtazapine:
7 days
no change
F 154911
M, 70 years
and older
General
Practitioner
Mirtazapine tablet 15 mg
depression
flurazepam
1 year
no change
venlafaxine:
1 day
discontinued
recovered
carbidopa/
levodopa:
6 years
no change
unknown
urinary retention
1 day
discontinued
recovered
Patient A used paroxetine in the past and developed urinary retention. For this
drug this is a known ADR [18]. Mirtazapine was prescribed because urinary
retention was not a known ADR for this drug.
Patients B is known with micturition difficulties and patient D and E are known
with BPH. For patient D it was reported that he never experienced urinary
retention until increase of the dosage of mirtazapine of 7,5 mg to 15 mg once a
day. In patient E the urinary retention is treated with catheterization. For the other
reports no information about treatment was given.
For patient C the urinary retention started 1 day after start of venlafaxine and
recovered after withdrawal of venlafaxine. In patient D venlafaxine is reported as
concomitant medication. In this patient the urinary retention started 8 hours after
increase of the dosage of mirtazapine and recovered after withdrawal of
mirtazapine.
Table 2. Reports of micturition disorder associated with the use of mirtazapine
Patient,
Number,
Sex, Age,
Source
Drug, daily dose
Indication for use
Concomitant
Medication
Suspected
adverse drug
reaction
Time to onset,
Action with
drug
outcome
G 15706
F, 21-30
years
General
Practitioner
mirtazapine tablet 15 mg
depression
ethinylestradiol/
desogestrel,
clobetason
micturition
disorder
12 hours
dose reduced
unknown
H 38053
M, 41-50
years
General
practitioner
mirtazapine tablet 30mg
micturition
disorder,
leg pain
1 day
no change
unknown
15
Other sources of information
SmPC
Urinary retention is not mentioned in section 4.8 of the SmPC of mirtazapine. In
section 4.4 (special warnings and precautions before use) of the SmPC is
mentioned that mirtazapine should be used with caution in patients with
micturition disorders (although there is little chance of problems with mirtazapine
because of the very weak anticholinergic activity) [1].
Literature
Oulis et al. described a 85-year-old male who experienced urinary retention within
24 hours of initiating treatment with mirtazapine 15 mg/day for depression. Within
24 hours of starting mirtazapine he developed acute urinary retention requiring
catheterization. Mirtazapine was discontinued and within 24 hours his urinary
retention subsided. One week late, a rechallenge demonstrated the same pattern
of urinary retention [5].
In contrast to this case report, Lenze et al. described a case of reversal of SSRIassociated urinary retention with mirtazapine augmentation. This case concerns a
30-year-old female who developed urinary retention after administration of
citalopram. After mirtazapine augmentation the urinary retention recovered. The
authors state that because the variable affinity of mirtazapine for 5-HT receptors,
it may reverse SSRI-associated urinary retention [6].
Databases
On October 11th 2013, the database of Lareb, the WHO and Eudravigilance
contained respectively 6, 118 and 88 reports of urinary retention associated with
the use of mirtazapine. The reporting odd ratio (ROR) for all these databases is
disproportional, see Table 3.
Table 3. Number of reported cases of urinary retention associated with the use of
mirtazapine in the dataset of Lareb, the WHO and Eudravigilance
Drug
Number of reports
ROR (95% CI)
mirtazapine
Lareb: 6
3.6 (1.6-8.0)
WHO: 118
4.9 (4.1-5.9)
Eudravigilance: 88
4.3 (3.5- 5.3)
Prescription data
The number of mirtazapine users in the Netherlands is shown in table 4.
Table 4. Number of patients using mirtazapine in the Netherlands between 2008 and 2012
[7]
Mirtazapine
2008
2009
2010
2011
2012
92,152
93,596
98,289
102,940
105,890
Mechanism
The act of micturition follows a very complex mechanism. There are two
sphincters (the internal and external urethral sphincters) in the urethral wall that
prevent urine loss as the bladder fills. The storage function of the bladder is
controlled by the sympathetic nervous system including bladder relaxation by the
16
binding of noradrenaline to the β3-adrenergic receptors on the detrusor smooth
muscle cells and internal sphincter contraction by stimulating α1 receptors on the
internal sphincter. The external sphincter is under control of the Onuf’s nucleus.
Both α and 5-TH2 receptors are located in the Onuf’s nucleus and they facilitate
the storage reflex. The serotonergic activity facilitates urine storage by enhancing
the sympathetic reflex pathway and inhibiting the parasympathetic voiding
pathway.
When the bladder volume reaches a certain capacity a trigger signal is sent to the
cerebral cortex and the desire to micturate is perceived. With the decision to void,
both the internal and the external sphincter relax and the bladder detrusor muscle
contracts. Bladder contraction is a result of the binding of acetylcholine to
muscarinic M3 receptors on the detrusor smooth muscle cell [2].
By its noradrenergic activity mirtazapine can theoretically increase bladder
relaxation by the binding of noradrenaline to the β3-adrenergic receptors. Further,
anticholinergic activity can reduce bladder contraction by preventing acetylcholine
to bind to muscarinic M3 receptors. The SmPC of mirtazapine describes that the
drug has practically no anticholinergic activity. The database of the Psychoactive
Drug Screening Program demonstrates some anticholinergic M3 receptor activity
[8].
Another possible mechanism involves glutamate. Glutamate functions as a
excitatory transmitter in the micturition reflex pathway in the brain [10]. 5-HT
receptors have an effect on the glutamate release: 5-HT2A receptors stimulate the
glutamate release while 5-HT1A receptors inhibit the glutamate release [9].
Mirtazapine specifically acts on the 5-HT1 receptors and blocks 5-HT2 receptors.
This would theoretically result in inhibition of glutamate release which may
subsequently lead to loss of micturition reflex.
Class effect
Mirtazapine belong to the group of ‘other’ antidepressants. Within this group, the
drugs mianserin and trazodone have similar actions. Both drugs block α1 and 5HT2 receptors. Urinary retention is not described in the SmPC of mianserin or
trazodone [20,21]. The SmPC of mianserin describes micturition disorders [20].
Lareb received no reports of urinary retention associated with the use of
mianserin or trazodone. The database of the WHO contains 29 reports of urinary
retention associated with the use mianserin and 50 associated with the use of
trazodone resulting in a ROR of respectively 3.1 (95%CI 2.1-4.4) and 2.8 (95% CI
2.1-3.7). Furthermore, urinary retention is described associated with these drugs
in literature [23]. A possible class effect cannot be excluded.
Discussion and conclusion
Lareb received 6 reports of urinary retention and 2 reports of micturition disorder
associated with the use of mirtazapine. One case (C) is strongly confounded by
the use of venlafaxine. In another case (D) venlafaxine was reported as
concomitant medication. In this patient the urinary retention started 8 hours after
increase of the dosage of mirtazapine and recovered after withdrawal of
mirtazapine. This makes a causal relationship with mirtazapine likely.
Most reports concern older men in which you would expect urinary retention to
occur more frequently. For three patients micturition difficulties or BPH was
reported as a comorbidity. Although urinary retention may occur spontaneously in
patients with micturition difficulties, a positive dechallenge for two of these
patients points towards a causal relation with the use of mirtazapine. Overall, a
positive dechallenge was reported 4 times. With exception of patient C, the time
to onset corresponds between the several reports.
This association is disproportionately present in the database of Lareb, the WHO
and Eudravigilance. There are several possible mechanism of how mirtazapine
17
could cause urinary retention. Mirtazapine its noradrenergic and anticholinergic
activity as well as its possible effect on the glutamate release may all contribute to
the occurrence of the urinary retention.

Urinary retention should be mentioned in
the SmPC of mirtazapine.
References
®
Dutch SmPC Remeron . (version date: 15-2-2011, access date: 11-10-2013) http://db.cbgmeb.nl/IB-teksten/h16685.pdf.
2. Verhamme KM, Sturkenboom MC, Stricker BH, Bosch R. Drug-induced urinary retention:
incidence, management and prevention. Drug Saf 2008;31(5):373-88.
®
3. Dutch SmPC Sinemat . (version date: 11-11-2012, access date: 11-10-2013) http://db.cbgmeb.nl/IB-teksten/h06706.pdf.
®
4. Dutch SmPC Efexor . (version date: 22-1-2012, access date: 11-10-2013) http://db.cbgmeb.nl/IB-teksten/h20862.pdf.
5. Oulis P, Leonardos A, Koulouris GC, Konstantakopoulos G. Mirtazapine-associated urinary
retention. J.Neuropsychiatry Clin.Neurosci. 2010;22(3):352o-352.
6. Lenze EJ. Reversal of SSRI-associated urinary retention with mirtazapine augmentation.
J.Clin.Psychopharmacol. 2012;32(3):434
7. College for health insurances. Drug Information System. (version date: 2012, access date: 18-72012) .
8. Verkes RJ; Ruhé HG. Keuzecriteria voor antidepressiva. van Zuiden Communications B.V.;
2010. 87p.
9. Stahl SM. Third ed. 2008;Stahl's Essential Psychopharmacology: Neuroscientific Basic and
Practical Applications. p. 361
10. de Groat WC, Yoshimura N. Pharmacology of the Lower Uniary Tract. Annu Rev Pharmacol
toxicol 2001;41:691-721.
1.
18
1.4.
Angiotensin II receptor antagonists and cold hands and feet
Introduction
Angiotensin II receptor (type AT1) antagonists are available on the Dutch market
since 1995 and are indicated for the treatment of hypertension. In addition other
indications are mentioned in the various SmPC’s such as treatment of cardiac
failure and a decreased systolic left ventricular function in addition to therapy with
ACE inhibitors or when ACE inhibitors are contraindicated and treatment of
diabetic nephropathy [1-8].
The following angiotensin II receptor antagonists are registered in the
Netherlands: azilsartan (Edarbi®), candesartan (Atacand®), eprosartan
(Teveten®), irbesartan (Aprovel®), losartan (Cozaar®), olmesartan (Olmetec®),
telmisartan (Micardis®) and valsartan (Diovan®). Most angiotensin II receptor
antagonists are also registered in combination with other antihypertensive drugs.
Angiotensin II receptor antagonists block the vasoconstrictor and aldosteronesecreting effects of angiotensin II by selectively blocking the binding of
angiotensin II to the AT1 receptor found in many tissues (e.g. vascular smooth
muscle, adrenal gland).
The current observation describes the association between peripheral coldness
(cold hands and/or feet) and Raynaud’s phenomenon associated with the use of
angiotensin II receptor antagonists. The Raynaud phenomenon is an exaggerated
vascular response to cold temperature or emotional stress. This phenomenon is
manifested clinically by sharply demarcated colour changes of the skin of the
digits. Abnormal vasoconstriction of digital arteries and cutaneous arterioles due
to a local defect in normal vascular responses is thought to underlie the disorder
[9].
Reports
On October 14th 2013, the database of the Netherlands Pharmacovigilance
Centre Lareb contained 22 reports of peripheral coldness (irbesartan (n=8),
losartan (n=6), candesartan (n=3), olmesartan (n=2), eprosartan (n=1),
telmisartan (n=1) and valsartan (n=1) and eight reports of Raynaud’s
phenomenon (losartan (n=3), candesartan (n=3), irbesartan (n=1) and valsartan
(n=1) associated with the use of angiotensin II receptor antagonists. There is no
clear distinction between peripheral coldness and Raynaud’s phenomenon in the
reports. Some reporters use the term peripheral coldness, while others use the
term Raynaud’s phenomenon for the same symptoms. Most reports were
reported by general practitioners (n=15) and pharmacists (n=10). There were
three reports from consumers, one report from a specialist doctor and one report
from a specialist nurse. Peripheral coldness was reported in 12 men (age 42-84)
and ten women (age 41-87). Raynaud’s phenomenon was reported in five men
(age 45-77) and three women (age 65-84).
All patients used the angiotensin II receptor antagonist for hypertension except for
one patient who used it for cardiac failure. The median age was 59 years and
ranged from 41 to 84 years. Time to onset of peripheral coldness varied from an
acute effect to years but was mostly present after several days use. Time to onset
of Raynaud’s phenomenon varied from 1 day to 6 months. Nine patients
recovered after stopping treatment with the angiotensin II receptor antagonist.
Two patients reported the same problems after restart (positive rechallenge).
Three patients discontinued the use of the angiotensin II receptor antagonist but
did not recover, two patients did not change the medication and recovered and 16
patients did not report the action with the drug or the outcome. Two patients
reported comedication known to cause Raynaud’s phenomenon (atomoxetine [10]
and propranolol [11]), however, they both started these drugs years before the
start of the angiotensin II receptor antagonist and did not experience any adverse
19
events then. One patient reported cold feet only when using irbesartan
Aurobondo pharma. He did not have this complaint when using irbesartan Teva.
None of the reports mention anything about smoking habits, known to trigger
Raynaud’s phenomenon [12].
Other sources of information
SmPC
None of the SmPC’s of the various angiotensin II receptor antagonists mention
peripheral coldness or Raynaud’s phenomenon [1-8].
Literature
No publications could be found that describe peripheral coldness, peripheral
vasoconstriction or Raynaud’s phenomenon caused by angiotensin II receptor
antagonists.
However, a review is published which described the use of angiotensin-converting
enzyme inhibitors and angiotensin II receptor antagonists in the treatment of
Raynaud's phenomenon. It was concluded that angiotensin-converting enzyme
inhibitors and angiotensin II receptor antagonists may provide some minor
benefits in the relief of Raynaud's phenomenon, although no definite evidence
exists to suggest that they are superior to traditionally used treatments such as
calcium-channel blockers [13].
Databases
On October 14th 2013, the database of the Netherlands Pharmacovigilance
Centre Lareb contained 22 reports of peripheral coldness and eight reports of
Raynaud’s phenomenon associated with the use of angiotensin II receptor
antagonists. The reporting odds ratios were disproportional (see table 1).
Table 1. Reports of peripheral coldness and Raynaud’s phenomenon for the angiotensin II
receptor antagonists in the Lareb database.
Drug
Preferred term
Number of reports
ROR (95% CI)
Angiotensin II receptor antagonists
Peripheral
coldness
22
5.8 (3.7-8.9)
Angiotensin II receptor antagonists
Raynaud’s
phenomenon
8
6.9 (3.4-14.4)
The WHO database of the Uppsala Monitoring Centre contained 84 reports of
peripheral coldness associated with the use of angiotensin II receptor antagonists
and 49 reports of Raynaud’s phenomenon. These associations are
disproportionally reported.
Table 2 shows the number of reports of peripheral coldness and Raynaud’s
phenomenon associated with the use of angiotensin II receptor antagonists in the
WHO database. Data for the Eudravigilance database are given in Table 3.
Table 2. Reports of peripheral coldness and Raynaud’s phenomenon for the angiotensin II
receptor antagonists in the WHO database.
Drug
Preferred term
Number of reports
ROR (95% CI)
Angiotensin II receptor antagonists
Peripheral
coldness
84
3.4 (2.7-4.2)
Angiotensin II receptor antagonists
Raynaud’s
phenomenon
49
5.4 (4.1-7.2)
20
Table 3. Reports of peripheral coldness and Raynaud’s phenomenon for the angiotensin II
receptor antagonists in the Eudravigilance database.
Drug
Preferred term
Angiotensin II receptor antagonists Peripheral coldness
Number of reports ROR (95% CI)
52
2.2 (1.6 – 2.8)
Angiotensin II receptor antagonists Raynaud’s phenomenon 26
2.5 (1.7 – 3.6)
Prescription data
The number of patients using angiotensin II receptor antagonists in the
Netherlands is shown in Table 4.
Table 4. Number of patients using angiotensin II receptor antagonists in the Netherlands
between 2008 and 2012 [14].
Drug
2008
2009
2010
2011
2012
-
-
-
-
-
61,122
65,793
67,500
69,818
71,651
6,394
5,601
5,149
4,648
4,201
irbesartan
121,460
126,040
130,200
132,160
133,710
losartan
195.690
199.310
205.130
209.730
217.550
olmesartan
15,652
16,460
16,856
17,284
17,755
telmisartan
37,275
40,822
45,206
47,605
48,483
129,130
132,300
139,780
145,760
154,040
azilsartan
candesartan
eprosartan
valsartan
Mechanism
No possible mechanism explaining this association could be found in the
literature. It is contrary to what is expected since angiotensin II receptor
antagonists block the vasoconstrictor effects of angiotensin II by selectively
blocking the binding of angiotensin II to the AT1 receptor. Peripheral coldness
and Raynaud’s phenomenon are caused by vasoconstriction.
A proposed hypothesis is that due to the blood pressure lowering effect of the
angiotensin II receptor antagonist the already critical perfusion of the vascular bed
is reduced even further, resulting in peripheral coldness.
Discussion and conclusion
The Netherlands Pharmacovigilance Centre Lareb received 30 reports of
peripheral coldness and Raynaud’s phenomenon associated with the use of
angiotensin II receptor antagonists. Peripheral coldness was mostly present after
several days use of the angiotensin II receptor antagonist and time to onset of
Raynaud’s phenomenon varied from 1 day to 6 months. There were nine positive
dechallenges and two positive rechallenges. Almost all reports were reported by
medically qualified persons. No information was reported about possible
confounders such as smoking habits. Two patients reported comedication known
to cause Raynaud’s phenomenon but these patients started these drugs years
earlier without any adverse events.
The association of angiotensin II receptor antagonists with peripheral coldness
and Raynaud’s phenomenon is supported by a statistically significant
disproportionality in the database of Lareb, Eudravigilance and the WHO.
This association is not supported by studies described in the literature or a known
mechanism.
21
 New signal of cold hands and feet
associated with angiotensin II
receptor antagonists
References
1. Dutch SmPC Edarbi®. (version date: 11-6-2012, access date: 14-10-2013)
http://www.ema.europa.eu/docs/nl_NL/document_library/EPAR__Product_Information/human/002293/WC500119204.pdf.
2. Dutch SmPC Atacand®. (version date: 13-12-2011, access date: 14-10-2013) http://db.cbgmeb.nl/IB-teksten/h21704.pdf.
3. Dutch SmPC Teveten®. (version date: 13-6-2013, access date: 14-10-2013) http://db.cbgmeb.nl/IB-teksten/h22260.pdf.
4. Dutch SmPC Aprovel®. (version date: 23-9-2013, access date: 14-10-2013)
http://www.ema.europa.eu/docs/nl_NL/document_library/EPAR__Product_Information/human/000141/WC500025752.pdf.
5. Dutch SmPC Cozaar®. (version date: 23-8-2013, access date: 14-10-2013) http://db.cbgmeb.nl/IB-teksten/h17617.pdf.
6. Dutch SmPC Olmetec®. (version date: 18-4-2013, access date: 14-10-2013) http://db.cbgmeb.nl/IB-teksten/h28782.pdf.
7. Dutch SmPC Micardis®. (version date: 27-3-2013, access date: 14-10-2013)
http://www.ema.europa.eu/docs/nl_NL/document_library/EPAR__Product_Information/human/000209/WC500027641.pdf.
8. Dutch SmPC Diovan®. (version date: 20-6-2013, access date: 14-10-2013) http://db.cbgmeb.nl/IB-teksten/h26939.pdf.
9. Wigley FM. Clinical practice. Raynaud's Phenomenon. N.Engl.J.Med. 2002;347(13):1001-8.
10. Dutch SmPC Strattera®. (version date: 7-3-2013, access date: 14-10-2013) http://db.cbgmeb.nl/IB-teksten/h31494.pdf.
11. Dutch SmPC propranolol. (version date: 12-6-1998, access date: 14-10-2013) http://db.cbgmeb.nl/IB-teksten/h10216.pdf.
12. Middelen bij het fenomeen van Raynaud. (version date: 1-10-2013, access date: 14-10-2013)
http://www.fk.cvz.nl/inleidendeteksten/i/inl%20middelen%20bij%20het%20fenomeen%20van%20r
aynaud.asp.
13. Wood HM, Ernst ME. Renin-angiotensin system mediators and Raynaud's phenomenon.
Ann.Pharmacother. 2006;40(11):1998-2002.
14. GIPdatabase - Drug Information System of the Dutch Health Care Insurance Board. (version date:
15-5-2012, access date: 19-10-2012) http://www.gipdatabank.nl.
22
2. Overviews
2.1.
Overview of reports on novel anticoagulants
Introduction
The group of novel anticoagulants consists of the oral anticoagulants apixaban,
(Eliquis®) argatroban (Arganova®), dabigatran (Pradaxa®), rivaroxaban (Xarelto®)
ximelagatran (Exanta®) and the non-oral anticoagulants bivalirudine (Angiox®)
and fondaparinux (Arixtra®). The introduction of these drugs as a replacement for
low molecular weight heparins (LMWH) and vitamin K antagonists (VKA) has
raised questions regarding their safety [1,2]. Recently, Lareb published an
overview of reports concerning novel anticoagulants in Quarterly Reports 2013-3,
and since then, new reports have been received. On request of the Medicines
Evaluation Board (MEB), Lareb provides a short update of the reports received on
the novel anticoagulants for the current Quarterly Report.
For this overview, data from both the spontaneous reporting system and the
Lareb Intensive Monitoring System (LIM) were used. Dabigatran, rivaroxaban and
apixaban have been monitored with the LIM methodology since September 2012.
Reports
On October 21, 2013 the Netherlands Pharmacovigilance Centre Lareb had
received 492 reports associated with the use of novel anticoagulants. Of these,
396 were received through the spontaneous reporting system and 96 through the
LIM system. The reports contained a total of 709 possible adverse drug reactions.
Of these 492 reports, 264 were reported as serious according to the CIOMS
criteria. In 27 reports a fatal outcome was reported. Additional information is
provided in table 1 and 2.
Table 1. Numbers of reports received by Lareb
Quarterly report
2014-1
492
396 (80%)
96 (20%)
Number of reports
Spontaneous (%)
LIM (%)
Serious reports (%)
264 (54%)
Fatal reports (%)
27 (5.5%)
Table 2. Characteristics of reports received in association with novel anticoagulants
Active
substance
Number of reports
Reports with
fatal outcome
Total
Serious (%)
Non-serious (%)
Dabigatran
249
115 (46%)
134 (54%)
15
Rivaroxaban
161
81 (50%)
80 (50%)
6
Fondaparinux
67
55 (82%)
12 (18%)
0
Bivalirudine
11
11 (100%)
0 (0%)
6
Argatroban
1
0 (0%)
1 (100%)
0
Apixaban
2
0 (0%)
2 (100%
0
Ximelagatran*
1
1 (100%)
0 (0%)
0
* The application for a marketing authorization for ximelagatran was withdrawn by AstraZeneca prior to
a recommendation by the CHMP
In order to provide more insight into the spectrum of ADRs reported to Lareb, the
ADRs were grouped into MedDRA® System Organ Classes (SOCs). Grouping
23
was done on the basis of the pharmacokinetic profile. Since direct thrombin
inhibitors (e.g. dabigatran) are mainly excreted unchanged by the kidney whereas
factor Xa inhibitors (e.g. rivaroxaban) are metabolized by the liver, differences in
ADR profiles could be observed. In order to determine if this is the case, the
SOCs of the ADRs reported for each drug are displayed in table 3. Only
dabigatran and rivaroxaban were selected since the other anticoagulants had an
insufficient number of reports (argotraban, apixaban, ximelagatran) or belong to
the non-oral anticoagulants (which can influence the results).
System Organ Class (SOC)
Blood and lymphatic system disorders
DABIGATRAN
N
%
7
1.9
RIVAROXABAN
N
%
7
2.7
Cardiac disorders
14
3.7
8
3.1
Congenital, familial and genetic disorders
1
0.3
0
0.0
Ear and labyrinth disorders
1
0.3
1
0.4
Eye disorders
5
1.3
2
0.8
Gastrointestinal disorders
92
24.6
39
15.0
General disorders and administration site conditions
37
9.9
30
11.5
Hepatobiliary disorders
2
0.5
0
0.0
Infections and infestations
5
1.3
1
0.4
Injury, poisoning and procedural complications
8
2.1
17
6.5
Investigations
5
1.3
6
2.3
Metabolism and nutrition disorders
10
2.7
2
0.8
Musculoskeletal and connective tissue disorders
5
1.3
10
3.8
Neoplasms benign. malignant and unspecified (incl cysts
and polyps)
Nervous system disorders
6
1.6
0
0.0
49
13.1
36
13.8
Psychiatric disorders
10
2.7
9
3.5
Renal and urinary disorders
20
5.3
10
3.8
Reproductive system and breast disorders
5
1.3
6
2.3
Respiratory. thoracic and mediastinal disorders
21
5.6
20
7.7
Skin and subcutaneous tissue disorders
19
5.1
17
6.5
Surgical and medical procedures
6
1.6
1
0.4
Vascular disorders
46
12.3
38
14.6
TOTAL
374
100
260
100
Gastrointestinal ADRs
The results in table 3 show that the spectrum of ADRs is similar between
dabigatran and rivaroxaban, except for gastrointestinal disorders, which were
reported significantly more often in dabigatran users than in rivaroxaban users
(24.6% vs. 15.0% respectively: p<0.001).
Analysis of these data reveals that the main difference in ADR pattern within the
gastrointestinal subset of ADRs relates to a difference hemorrhagic events versus
non-hemorrhagic events. The percentages of hemorrhagic events were 23% for
dabigatran and 41% for rivaroxaban (see also table 4).
24
Table 4. Numbers of hemorrhagic versus non-hemorrhagic gastrointestinal ADRs
Dabigatran
Hemorrhagic*
#
Non-hemorrhagic
TOTAL
21 (23%)
71 (73%)
92 (100%)
Rivaroxaban
16 (41%)
23 (59%)
39 (100%)
* Hemorrhagic ADRs were gastrointestinal bleedings including hematemesis,
hematochezia and melaena
#
The most frequently reported non-hemorrhagic ADRs were gastrointestinal pain /
discomfort, diarrhoea, nausea
Renal ADRs
Although the percentage of reported renal ADRs seems similar between
dabigatran and rivaroxaban (5.3% and 3.8% respectively), the types of ADRs that
were reported within this SOC were different for dabigatran and rivaroxaban.
Although the numbers are small, bleedings (including hematuria) seem to occur
more in rivaroxaban users whereas renal impairment and renal failure occur more
in dabigatran users (see also table 5). Further analysis showed a difference in
prescription indication between dabigatran users (mainly atrial fibrillation) and
rivaroxaban users (mainly thromboprophylaxis). Based on this, a difference in
mean age between dabigatran and rivaroxaban users could be expected.
However, the small difference that was found does not seem relevant (dabigatran
74.5 years; rivaroxaban 72 years).
Table 5. Numbers of renal ADRs
Dabigatran
Hemorrhagic (including
hematuria)
Renal impairment (including
failure)
Other
TOTAL
Rivaroxaban
3 (15%)
6 (60%)
6 (30%)
2 (20%)
11 (55%)
20 (100%)
2 (20%)
10 (100%)
Other sources of information
Prescription data
The number of patients using novel anticoagulants in the Netherlands [3] is
shown in table 6.
Table 6. Number of patients using novel anticoagulants in the Netherlands between 2007
and 2012 [3].
Drug
Dabigatran
2007
-
2008
29
2009
1,026
2010
1,048
2011
2,064
2012
4,648
Rivaroxaban
-
-
1,960
6,244
7,037
9,843
Fondaparinux
5,837
6,966
8,592
6,864
5,842
5,441
Prescription data were not available for bivalirudine, argatroban and apixaban
Discussion and conclusion
Recently, Lareb published an overview of the novel anticoagulants in their
quarterly report (2013-3). The aim of this report was to give an update on the
number of the ADRs associated with the use of novel anticoagulants. Additionally,
possible differences in ADR pattern due to pharmacokinetic differences between
direct thrombin inhibitors and factor Xa inhibitors were investigated.
25
Since the previous quarterly report, the number of reports sent to Lareb regarding
novel anticoagulants has increased with 53%. Although the percentage of serious
reports has decreased (from 61% to 54%) a small increase in the number of
reports with a fatal outcome was observed (from 4.7% to 5.5%). It should be
noted however, the latter is based on a small number of reports. In general, the
distribution of ADRs over the different SOCs is rather similar between both
groups, with the exception of gastrointestinal ADRs, which seem to occur more
frequently in patients using dabigatran. Further analysis revealed that the ratio of
reported hemorrhagic versus non-hemorrhagic ADRs was higher in rivaroxaban
users than in dabigatran users for gastrointestinal ADRs. The same was observed
for renal ADRs, although it should be mentioned that this applies to a small
number of reports and the difference was not tested for statistical significance.
The current overview did not give rise to a new signal of adverse drug reactions
related to the use of novel anticoagulants.
References
1. Bijl D. Publiciteit nieuwe orale antistollingsmiddelen. Geneesmiddelenbulletin 2013;47(3):37-8.
2. Bijl D. Nieuwe orale anticoagulantia: niet vergoed. wel voorgeschreven. Geneesmiddelenbulletin
2012;46(5):58-60.
3. College voor Zorgverzekeringen. GIP Databank. College voor Zorgverzekeringen. GIP Databank.
(version date: 22-3-2011. access date: http://www.gipdatabank.nl/).
26
2.2.
Update of Overview of Dutch cases of narcolepsy associated with Pandemic
influenza vaccine (Pandemrix®)
Introduction
In august 2010, within a year after the vaccination campaign against H1N1, the
EMA acknowledged the existence of a possible signal concerning the association
between vaccination with Pandemrix® and the occurrence of cases of narcolepsy
and studies were initiated to confirm and quantify this association. There were
differences in the age groups that were vaccinated with Pandemrix® between
European countries. In the Netherlands this vaccination campaign especially
included younger children from 6 months to 5 years old, as well as the risk
populations that are usually indicated for seasonal influenza vaccination. In
addition, pregnant women in 2nd and 3rd trimester were offered vaccine. The
children received Pandmrix®, offered in group sessions, while the risk groups
received Focetria®, mainly given by their GP’s. In 2011, Lareb presented reports
of 3 patients with narcolepsy after administration of pandemic influenza vaccines
[1]. Until February 2014, 4 more cases have been reported. All 7 cases have
been reported after concerns about a possible association between pandemic
influenza vaccine and narcolepsy were reported in the media. The reported
patients are summarized in more detail below. Because of the additional reports,
and new literature on an association of pandemic influenza vaccines and
narcolepsy an update of the previous overview is presented [2-9].
Reports
Case definitions to classify patients with narcolepsy have been developed by the
Brighton Collaboration [10]. Except for one, all reported cases can now be
classified accordingly.
Table 1. Reports of narcolepsy associated with the use of Pandemrix®
Patient,
Number,
Sex, Age,
Source
Drug, daily dose
Indication for use
A 112011
M, 2-4
years
RIVM
pandemic influenza
vaccine (Pandemrix)
prophylaxis
B 111048 pandemic influenza
M, 2-4
vaccine (Pandemrix)
years
prophylaxis
RIVM/pare
nts
Concomitant
Medication
Suspected adverse
drug reaction
Brighton
Collaboration case
level
Time to onset,
Outcome,
causality
narcolepsy
BC level 1
2 days
not recovered
unlikely
DTPP vaccination narcolepsy
BC level
unclassifiable
Started before
Pandemrix, and 4
months after
DPTP
not recovered
unlikely
C 117581
F, 11-20
years
parents
pandemic influenza
vaccine (Pandemrix)
prophylaxis
narcolepsy
BC level 1
2 months
not recovered,
possible
D 137759
M, 2-4
years
parents
pandemic influenza
vaccine (Pandemrix)
prophylaxis
narcolepsy
BC level 3
> 6 months
not recovered
unlikely
E 156002
F, 2-4
years
parents
pandemic influenza
vaccine (Pandemrix)
prophylaxis
narcolepsy
BC level 1
few weeks ?
not recovered
possible
27
Patient,
Number,
Sex, Age,
Source
Drug, daily dose
Indication for use
F 156062
F, 2-4
years
parents
G 160436
F, 2-4
years
parents
Concomitant
Medication
Suspected adverse
drug reaction
Brighton
Collaboration case
level
Time to onset,
Outcome,
causality
pandemic influenza
vaccine (Pandemrix)
prophylaxis
narcolepsy
BC level 1
5-6 months
not recovered
possible
pandemic influenza
vaccine (Pandemrix)
prophylaxis
narcolepsy
BC level 2 or 3
3 years
not recovered
unlikely
Summaries of cases:
Case A
This serious report from a physician concerns a male aged 2-4 years HLADQB1*0602 positive, with confirmed (observation and hypocretin) narcolepsy
(sleep attacks, weight gain, no hypnagogic hallucination nor sleep paralysis)
following two-times administration of pandemic influenza vaccine (Pandemrix®,
batch number A81CA160A) with an unknown latency, however a few days at
most. The patient has not recovered. Concomitant medication was not reported.
Prior to influenza vaccination the patient suffered from infections which were not
responsive to multiple courses of antibiotic therapy. Fatigue was at latest
mentioned by his GP two days following the first pandemic vaccine
administration. Behavioural symptoms existed since April 2009. Laboratory
testing revealed mild hypothyroidism. Diagnostic testing for Niemann Pick C was
planned but results remained unknown. Causality: (due to maximal two days
latency) unlikely.
Case B
This serious report concerns a male aged 2-4 years with sleepiness and fatigue,
diagnosed as narcolepsy with cataplexia following administration of Infanrix IPV, a
Diphtheria, Tetanus, acellular Pertussis, Poliomyelitis (inactivated) (DTaPP)
vaccine (Batch AC20B123AM) and Pandemrix® (A81CA049D), (November 2009
and December 2009). The DTaPP vaccine was given in April 2010 and the first
signs of fatigue occurred in the end of April. In July the patient was hospitalised in
Italy because of somnolence, decreased muscle strength, dysarthria and
decreased balance. Days later admission in a tertiary centre followed due to
worsening of his condition. Initially, ataxia was diagnosed due to a suspected viral
infection for which acyclovir was started. In July the patient was examined in the
Netherlands with partial improvement however, later, narcolepsy with cataplexia
was diagnosed. Behavioural changes were also reported, starting in the autumn
of 2009. Hypocretin levels in CSF, HLA typing and sleep test results were not
reported. The diagnosis can therefore not be classified according to the criteria of
the Brighton Collaboration. From the history it is concluded that symptoms
associated with narcolepsy already were present before the pandemic influenza
vaccination. Causality for this vaccine is therefore unlikely. However, although
DTaPP vaccine was not reported as a suspect drug, causality for this vaccine is
cannot be excluded.
Case C
This serious report from a consumer concerns a female aged 11-20 years, with
narcolepsy with cataplexia and deficient hypocretin following administration of
pandemic influenza vaccine (Pandemrix®, batch A81CA136A) for prophylaxis with
a latency of 2 months before onset of symptoms. The clinical picture worsened
28
gradually with manifestation of excessive daytime sleepiness and sleep attacks,
however absent sleep paralysis and hypnopompic hallucinations with a
progressively increased impact on daily life. Symptoms were treated with
modafinil. Following treatment the symptoms were alleviated. Concomitant
medication was not reported. The patient has no known medical history and no
known past drug therapy. The vaccine was administered outside the Netherlands
in an EU country with a general vaccination policy prior to the 2009 type A H1N1
pandemic. Causality: possible
Case D
This serious report from a consumer concerns a male aged 2-4 years, with
narcolepsy following administration of pandemic influenza vaccine (Pandemrix®,
batch A81CA143A, and A81CA160A) for prophylaxis with a latency of more than
6 months before onset of the symptoms.
The clinical picture worsened gradually with manifestation of excessive daytime
sleepiness without cataplexy which was first medically documented at least 6
months after the second vaccination. Narcolepsy was further evidenced by a
sleep test. Results of CSF test for hypocretin level are unknown. Concomitant
medication was not reported. Causality: (due to long latency) unlikely.
Case E
This serious report from a consumer concerns a female aged 2-4 years, with
narcolepsy following administration of Pandemrix® (2 doses November and
December 2009, batch numbers A81CA159A and A81CA143A) for prophylaxis
with a latency of a few weeks after vaccinations when the girl developed fatigue. It
is not certain if the fatigue should be considered as an early symptom of
narcolepsy. The clinical picture worsened gradually with manifestation of
excessive daytime sleepiness. Narcolepsy was confirmed 15 months after
vaccination, by a conclusive sleep test and low levels of hypocretin in CSF.
Concomitant medication was not reported. Causality: possible.
Case F
This serious report from a consumer concerns a female aged 2-4 years, with
narcolepsy following administration of pandemic influenza vaccine (Pandemrix®, 2
doses November and December 2009, batch numbers both AC81CA069B) for
prophylaxis with a latency of 5-6 months after vaccinations when the girl
developed excessive daytime sleeping. The clinical picture worsened gradually
and was associated with increased eating and weight gain. Narcolepsy was
confirmed by low levels of hypocretin in CSF. Concomitant medication was not
reported. Causality: possible.
Case G
This serious report from a consumer concerns a female aged 2-4 years, with
narcolepsy following administration of pandemic influenza vaccine (Pandemrix®,
November and December 2009; batch numbers both dose 1 and 2: A81CA069B)
for prophylaxis with a latency of 39 months after vaccinations. The first year in
primary school (age 4 years) she needed more sleep than other children. The
next year she went to school all day. At age 6 she had to stay home and sleep in
the afternoons, leading to pediatric referral. From age 2 there were mild tantrums,
which aggravated suddenly at age 6. From then also there are night terrors, and
unexplained weight gain. There is no cataplexy. Diagnosis of narcolepsy was
based on clinical history, supported by compatible polysomnography. Levels of
hypocretin in CSF and HLA typing are unknown. Concomitant medication was not
reported. Causality: (due to long latency) unlikely.
29
Other sources of information
Literature
Since 2011 several studies have been published on narcolepsy in association
with pandemic influenza vaccination [2-9]. In the first signaling country Finland, an
excess of cases (with an age range 5 to 19 years) after vaccination were seen
compared to unvaccinated individuals, the majority of excess cases with onset of
symptoms between a few weeks and 6 months after vaccination [4,5]. The signal
was confirmed in Sweden [2], Ireland [3] and the United Kingdom [8]. The
European VAESCO study linking hospital registrations with vaccination registers
gives a scattered pattern of countries with increased incidences and other
countries in which the signal is not confirmed [6,7]. Incidence rates were higher in
Finland and Sweden, and lower in The Netherlands. The VAESCO study includes
data from 21 patients (age 0-18 years) from the Netherlands, but only 4 below 5
years of age [6]. The VAESCO investigators concluded that the data from The
Netherlands did not confirm a higher risk for pandemic influenza vaccination and
narcolepsy [6,7]. According to the article of Barker et al. [9] in The Lancet
Infectious Diseases, the association described so far is of an epidemiological
nature, and not confirmed in all countries where pandemic influenza vaccines
have been used.
Prescription data
A total of 588 750 children received the first dosage and 490 584 children
received a second dosage. Of the relatives of the children involved, 124 096
received one dosage and 101 765 received the recommended two dosages.
Lareb did not receive reports of narcolepsia from these relatives [11].
Mechanism
A causative mechanism on which an increased risk is based, is unknown. Current
theories favour an autoimmune mechanism, possibly with genetic factors that
together lead to the development of narcolepsy. Epitopes on H1N1 proteins
closely resemble parts of the hypocretin molecule. Immunization with H1N1
epitopes presented by a particular HLA molecule (HLA-DQB1*0602), may lead to
destruction of hypocretin-producing cells, mediated by T-lymphocytes [12]. The
findings may point to a unique combination of a genetic factor, epitopes on the
influenza A/H1N1 virus with specific cross-reaction with hypocretin-producing
cells, possibly magnified by the AS03 adjuvant.
The role of circulating pandemic influenza A/H1N1 virus as an inducer of autoimmunity cannot be excluded either. Over a period of 12 years, an investigation in
China demonstrated that the onset of narcolepsy (629 patients; 86% children)
was seasonal, and increased after the H1N1 pandemic [12]. Of the new cases
identified after the pandemic started, 8 of 142 (6%) patients received a H1N1
vaccination [13], suggesting a minor contribution of the vaccination. In The
Netherlands, we may have a similar situation, because circulation of influenza
A/H1N1 virus was increased in the months preceding the vaccination campaigns
in 2009,
If an auto-immune reaction induced by the vaccine is a cause of narcolepsy, a
compatible latency time would be in the order of weeks for the first symptoms to
start after vaccination (few weeks if the auto-immune destruction is mediated by
T-cells, later if mediated by IgG-antibodies). Dauvilliers et al report that acute
onset of cataplexy occurred between 2-8 weeks after vaccination [14], but also
suggest that a slower onset may occur later [14]. We consider an onset of
symptoms later than 6 months after vaccination less compatible with an autoimmune cause of narcolepsy.
30
Discussion and conclusion
Lareb received 7 reports of narcolepsy after pandemic influenza vaccination. All
cases have been confirmed by neurologists specialised in sleep disorders. In all
seven cases reported to Lareb, Pandemrix® was the suspected vaccine. In 3 of
these 7 reports the onset of narcolepsy was considered compatible with a
causative auto-immune mechanism and thereby it is considered possible that
there is a relation with the Pandemrix® vaccination. More research is needed to
firmly establish the causal association between narcolepsy and vaccination with
this brand of pandemic influenza vaccine, including the role of the AS03 adjuvant.
At present, Pandemrix® and Focetria® are no longer marketed. November 2013,
the US FDA approved a potential future pandemic monovalent influenza A/H5N1
(Q-Pan) vaccine, again with the AS03 adjuvant [15].
Six out of the seven cases were children below 5 years of age. The 7th patient
was an adolescent, vaccinated in another country. In countries where an
increased incidence was found, vaccinations were given at an older age than in
The Netherlands, while in The Netherlands this vaccination campaign especially
included younger children to 5 years old. Usually, narcolepsy starts to occur in
adolescence, and not at the age at which 6 of our cases occurred. The
unexpected young age of our cases is remarkable, whether there is a causal
relationship with Pandemrix® or not.
31
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32
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