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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 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Netherlands Pharmacovigilance Centre Lareb. Overview of Dutch cases of narcolepsy ® associated with Pandemic influenza vaccine (Pandemrix ). Kwartaalbericht 2011-3. www.lareb.nl Sweden. Läkemedelsverket - Medical Products Agency. Occurrence of narcolepsy with cataplexy among children and adolescents in relation to the H1N1 pandemic and Pandemrix vaccinations Results of a case inventory study by the MPA in Sweden during 2009-2010. MPA, Sweden, June 30, 2011. 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