Kwartaalbericht 1e kwartaal 2005
11 maart 2005
Contents
1. Safety concern
4 ®
1.1. Aripiprazole (Abilify ) and suicide
4
2. Observations
7
2.1.
Overview of reports on oral and sublingual allergen-specific immunotherapy 7
2.2.
A combination of metoclopramide and selective serotonin reuptake inhibitors: additional extrapyramidal effects? 11
2.3.
Mumps, measles and rubella (MMR) vaccine and idiopathic thrombocytopenic purpura (ITP) 13
2.4.
Itraconazole and paresthesias
15
3. Short notes 3.1. Contra-indications of ceftriaxone
18 18
3.2. Amoxicillin and black tongue / tooth discolouration
18
3.3. Chlorhexidine and anaphylaxis 19 4. Appendix Omzettingsproblemen bij carbamazepine CR
20 20
5. Publications
23
6. Enclosure
24
2
Voorwoord
Lareb is voortdurend bezig te bezien hoe ze het College beter van dienst kan zijn in haar taak met betrekking tot geneesmiddelenbewaking. Het kwartaalbericht heeft een belangrijke rol bij de informatieverstrekking van Lareb naar het College. In dit kwartaalbericht zijn een aantal veranderingen doorgevoerd. e
Dit is het kwartaalbericht over het 1 kwartaal 2005. Het kwartaalbericht heet dus vanaf nu naar het kwartaal waarin het verschenen is. Er komt dus geen e
kwartaalbericht over het 4 kwartaal 2004. De indeling van het kwartaalbericht is gewijzigd. De opbouw is nu als volgt: -
Eerst, indien van toepassing, de safety concerns. Dit zijn belangrijke signalen, waarover soms het College al tussentijds is ingelicht.
-
Daarna de observations. Dit zijn de kwartaalberichten zoals u die gewend bent. Wel streven we ernaar ze korter te houden en makkelijker leesbaar te maken.
-
Een nieuwe rubriek vormen de short notes. Dit zijn korte berichten, die als regel voorstellen voor wijzigingen van de SPC-tekst betreffen.
Als appendix is dit maal ter informatie een notitie over carbamazepine opgenomen, waarover eerder contact geweest is op bureauniveau. Tenslotte is als bijlage een artikel over neonatale ontrekkingsverschijnselen bij gebruik door de moeder van SSRI‟s. Het artikel is mede gebaseerd op Nederlandse meldingen. Hierover is uw College eerder geïnformeerd in de kwartaalberichten 1999/4 en 2001/3. Mocht u het met ons eens zijn dat de bovengenoemde veranderingen ook inderdaad verbeteringen zijn, dan zullen we trachten ook de uiterlijke vormgeving plezieriger en dus makkelijker leesbaar te maken. We hopen dat u met ons van mening bent dat de inhoud onveranderd en goed is.
Kees van Grootheest directeur Lareb
3
1. Safety concern 1.1.
®
Aripiprazole (Abilify ) and suicide Introduction Aripiprazole is a new atypical antipsychotic drug, which has been available in de USA, Argentina, Brazil and Australia since 2003 [1]. On June, 6 2004 it has been approved for the European market. It is indicated for the treatment of schizophrenia. The recommended dose is 15 mg once daily, the maximum dose is 30 mg. Special warnings and considerations are: “…it may take days to weeks before clinical improvement occurs, patients have to be followed closely in this period…” ADRs reported in the SPC occurring more often than with placebo, (≥1:100), or symptoms that were identified as possibly medically relevant unwanted drug reactions are: lightheadedness, insomnia, akathisia, sleepiness, tremor, blurred vision, tachycardia, orthostatic hypotension, nausea, vomiting, dyspepsia, constipation, headache, asthenia. Other ADRs that are known to occur with the use of antipsychotics and that have been reported in association with the use of aripiprazole are: malign neuroleptic syndrome, tardive dyskinesia and convulsions. For the effects of overdose, a study in a limited number of patients is mentioned in which doses up to 140 mg in one day did not show any unexpected adverse effects. A clinical study with up to 90 mg daily during 15 days showed no unexpected ADRs [2]. Reports Up to February 17, 2005 Lareb received 18 reports from health professionals and consumers on ADRs in association with the use of aripiprazole. Six of these reports concern suicide attempts including 2 fatal outcomes (Table 1). In 5 patients, aripiprazole treatment was preceded by other antipsychotic therapy. In patient C, participating in a clinical study, such information was not reported. Of the 4 non-fatal suicide attempts, 3 were reported by medical specialists from the same hospital. The other 12 reports contained amongst others: insomnia, aggravated psychotic disorder, depression, sleep disturbance, suicidal ideation, wandering (possibly caused by aggravated psychosis), restlessness, and feeling uncomfortable. These ADRs may precede a suicide attempt. Table 1: reports of (attempted) suicide associated with the use of aripiprazole Patient, Sex, age
Drug Indication for use
Concomitant medication not reported, risperidone was recently tapered
ADR
A M, 25
aripiprazole 15mg recurring psychotic episodes
B M, 55
aripiprazole 15mg levo-/carbidopa schizophrenia, paranoid temazepam type acenocoumarol fraxiparine lorazepam; olanzapine was recently tapered
1. anxiety 1,2: days-weeks 2. insomnia 3: 4 months, 3. suicide attempt with recovered promethazine
C M, 32
aripiprazole 25 mg schizophrenia
suicide attempt
not reported
1: suicide attempt 2: suicide
Time to onset, outcome 1: 10 days 2: 5 weeks, fatal
5 weeks, recovered
4
Patient, Sex, age
Drug Indication for use
Concomitant medication
ADR
Time to onset, outcome
D F, 30
aripiprazole 15mg none; olanzapine 30mg (last 6 days was recently before withdrawal) tapered schizophrenia, paranoid type
1. anxiety 2. insomnia 3. suicide attempt with olanzapine and oxazepam
1,2: unknown 3: 7 weeks after start, 10 days after withdrawal, recovered
E F,41
aripiprazole 15mg citalopram schizophrenia, paranoid lormetazepam; type risperidone was recently tapered
1. insomnia 2. aggravated depression 3. suicide attempt with risperidone
1: 12 days 2: 2 months 3: 9 weeks, recovered
F F, 62
aripiprazole 15mg psychosis, depressive type
1. suicidal tendency 2. withdrawal from treatment 3. suicide
weeks, fatal
oxazepam temazepam promethazine; haloperidol was recently tapered
Other sources of information Literature An increased risk of suicide is not mentioned in the literature on aripiprazole; a Medline search did not reveal any article. In our recent overview on aripiprazole, the mechanism of its action on the different (dopamine and serotonin) receptors and the expected ADRs of aripiprazole are summarized [1]. An increased suicide risk was not anticipated. An overview on aripiprazole by Swainston mentions that aripiprazole was generally well tolerated [3]. The most frequent treatment-emerged ADR included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52 week trial). Reeves describes a case report of a man with a bipolar type schizo-affective disorder. His symptoms of grandiose delusions and responses to internal stimuli worsened during aripiprazole treatment. After increasing the dose he became agitated, began threatening others and spent hours wandering in the streets. He had been treated with quietiapine before. There was a positive dechallenge, rechallenge and again dechallenge [4]. Databases On February, 21 2005 the WHO Vigibase has 33 reports of suicide attempt in association with aripiprazole. Mechanism Aripiprazole acts as a D2 antagonist in regions of the brain with excess of dopamine activity, just like all antipsychotics. But in regions of the brain with diminished dopamine activity it acts as a dopamine agonist. Therefore aripiprazole is expected not only to diminish positive symptoms of schizophrenia (like agitation and psychosis, due to excess of dopamine activity) but also the negative symptoms (like apathy, emotional bluntness, due to diminished dopamine activity) and to show less ADRs like extrapyramidal symptoms and hyperprolactinaemia. A remarkable feature of the reports with suicide attempt is that in five patients treatment with aripiprazole immediately followed previous antipsychotic treatment. This previous antipsychotic treatment may have induced a diminished dopamine activity and upregulation of D2-receptors, thereby causing aripiprazole to act firmly
5
as a D2 agonist with reduction of negative symptoms, which may facilitate suicide ideations. The Scientific Discussion in the EPAR does not clarify whether aripiprazole treatment in the included patients was preceded by antipsychotic treatment [2]. If the included patients were not using antipsychotic treatment just before starting aripiprazole therapy, this may imply that the dopamine antagonistic effects of preceding antipsychotic treatment have not been studied before approval. Conclusion The Netherlands Pharmacovigilance Centre Lareb received 18 reports on aripiprazole, of which 6 refer to suicide (4 attempts and 2 fatal). The other reports include increased physical and psychological activity. Taking into account the pharmacological effect of previous antipsychotic treatment and the occurrence of most suicidal and negative symptom reduction events within weeks to months after switch to aripiprazole, a relation with previous antipsychotic treatment is suggested. The Scientific Discussion in the EPAR does not clarify whether a switch from an antipsychotic treatment to aripiprazole has been studied in the phase III trials. References 1. De Langen-Wouterse JJ, Van Grootheest AC, Van Puijenbroek EP. Anticiperen op bijwerkingen aripiprazol. Pharmacetisch Weekblad 2004;139(16):550-4. 2. European public assessment Report of Abilify® http://www.emea.eu.int/humandocs/Humans/EPAR/abilify/abilify.htm, version 04/06/04 Abilify-H471-00-00-PI. Accessed 21-2-2005 3. Swainston Harrison T, Perry CM. Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs 2004;64(15)1715-36. 4. Reeves RR and Mack JE. Worsening schizoaffective disorder with aripiprazole. Am J Psychiatry 2004;161(7):1308
Lareb expresses serious concern on the number of reports on suicidal events in association with aripiprazole Reports suggest that preceding antipsychotic therapy might be involved in suicidal behaviour during use of aripiprazole
6
2. Observations 2.1.
Overview of reports on oral and sublingual allergen-specific immunotherapy Introduction Allergen-specific immunotherapy is, together with avoidance of allergens, the only specific treatment of allergic disorders. Traditionally, the route of administration of allergen-specific immunotherapy was subcutaneous. Adverse reactions of subcutaneous allergen-specific immunotherapy can be divided into two categories: local reactions at the injection site and systemic reactions. Systemic reactions mentioned in the available SPCs are conjunctivitis, rhinitis, urticaria, angioneurotic oedema, bronchoconstriction, fatigue, larynx oedema and anafylactic reactions [1]. Because of the potential serious systemic ADRs of subcutaneous administration, other application routes, such as oral, intranasal, and sublingual administration [2,3] have been investigated. Several products are available for oral or sublingual ® ® allergen-specific immunotherapy in the Netherlands. Novo-Helisen , ALK oral , ® ® Oralgen Pollen and Oralgen Mite are products for oral allergen-specific ® ® immunotherapy and Sublivac B.E.S.T and SLITone are administered sublingual [4,5]. Information about ADRs of products for oral and sublingual allergen-specific ® ® immunotherapy is limited. Sublivac B.E.S.T and SLITone are only available on named patient basis. For ALK oral there is no information available on the ® ® registration status. Oralgen Pollen and Oralgen Mite , which previously were not on prescription, are approved for marketing by virtue of a temporary provision and in the mean time there are no SPCs of these products available yet. We consider it important to give an overview of all reports concerning the oral and sublingual use of allergen-specific immunotherapy to illustrate the need for SPCs. Reports Until Februari 8, 2005, 41 reports concerning the use of allergen-specific immunotherapy were submitted to the Netherlands Pharmacovigilance Centre Lareb. Of these reports, 17 concern oral or sublingual allergen-specific immunotherapy (Table 1). Cutaneous and gastrointestinal symptoms are the most frequently reported ADRs. Three patients suffered from serious generalised systemic hypersensitivity reactions, being two patients with systemic allergic reactions and one with an anaphylactic reaction. Ten patients recovered after discontinuation of allergen-specific immunotherapy, which supports a causal relationship.
7
Table 1. Overview of reports on products for oral and sublingual allergen-specific immunotherapy Patient, Sex, age
Drug Indication for use
Concomitant medication
Adverse drug reaction
Time to onset, outcome
A F, 35
Novo-Helisen® allergy
not specified
abdominal pain
6 weeks, not reported
B F, 50
ALK oral SQ combi®
not specified
throat pain and swelling
1 hour, recovered after discontinuation
C F, 34
Oralgen Pollen® 1 ml once daily allergy
not specified
painful burning sensation of the oesophagus
5 days, recovered after discontinuation
D M, 70
Oralgen Pollen/house-dust mite® 10 gtt once daily allergy
none
depressive symptoms, agitation, anhedonia
3 years, recovered after discontinuation
E M, 32
Oralgen Pollen® allergy for grassand treepollen
not specified
abdominal cramps
unknown, recovered after discontinuation
F F, 21
ALK oral SQ grass & tree pollen combi® rhinoconjunctivitis and asthma
Diversity of oral antihistamines, continued
angioedema of tongue, lips and throat; stridor
15 minutes, recovered with antihistamines and corticosteroids. discontinuation
G F, 36
Oralgen Pollen® allergic rhinitis/conjunctivitis
sodiumcromoglic ate, triamcinolon and budesonide
urticaria
unknown, recovered after discontinuation
H F, 41
Sublivac Best®
rofecoxib, acetaminophen, magnesium, metoprolol, hydrochlorothiazidum, nifedipin, clonazepaml, temazepam, sodiumcromoglicate, flixotide
allergic reaction: oedema, erythema, burning skin, pruritus, swollen throat, dyspnoea
unknown, recovered after treatment with levocetirizine
I M, 36
Oralgen Pollen® hay fever
not specified
allergic reaction: swollen throat, pruritus, erythema, breathing difficulties
immediately after intake, recovered after discontinuation
J* M, 30
Sublivac Best®
venlafaxin
flatulent distension of the belly
10 days, not recovered 3.5 months after the event
K F, 31
SLITone® grassen
none
oedema oral cavity
3 weeks, not reported
L F, 16
Oralgen Pollen® hay fever
ethinylestradiol/ levonorgestrel, cremor lanette
eczema
19 days, treated with prednisolon and levocetirizine whereafter the complaints temporarily improved.
8
Patient, Sex, age
Drug Indication for use
Concomitant medication
Adverse drug reaction
Time to onset, outcome
M F, 47
SLITone® bomen SLITone® grassen
Not specified
Itching/heavy feeling of oesophagus (no pyrosis)
4 weeks after change from ALK oral to SLIT positive dechallenge and rechallenge
N M, 37
Oralgen Pollen® hay fever
not specified
eczema
several days, recovered after discontinuation
O* M, 37
Oralgen Mite® house dust-mite
pantoprazole, salmeterol/fluticasone, fexofenadine
fatigue
1 day, recovered with continuation of allergen immunotherapy
P M,28
Oralgen Pollen® hyposensibilisation
none
anaphylactic reaction: exanthema, dizziness, itching of the mouth, hypotension
4 days, recovered after discontinuation
Q F, 14
Oralgen Pollen® grass & tree
1. generalized pruritus; 2. weakness; throat swelling
1. after 1 hour 2. after 2 hours, recovered with levocetirizine, continuation not reported.
* Lareb considers causality unlikely in cases J and O.
Other sources of information Literature A Medline search yielded 23 hits. Most of these articles present results of efficacy studies, rather than results of safety studies. ADRs mentioned in these studies are local reactions in the buccal cavity, rhinitis, gastrointestinal reactions, such as abdominal pain, and skin reactions, such as urticaria and pruritus. No systemic allergic reactions or anaphylactic reactions have been reported in those studies. Databases The database of the Uppsala Monitoring Centre (WHO) does not contain any ® other report, beside the Dutch cases, concerning the oral use of Oralgen Pollen ® ® and Oralgen Mite or the sublingual use of Sublivac B.E.S.T . The database ® contains four reports concerning the oral use of Novo Helisen , in two of these causality was considered unlikely, one was hyperactive behaviour and aggressive reaction, the other concerned Stevens Johnson syndrome in a patient also using carbamazepine. Prescription data Total number of prescriptions of insect allergens and allergen specific immunotherapy are shown in table 2.
9
Table 2. Total number of prescriptions of insect allergens and allergen specific immunotherapy per year since 1999 (Source: GIP College voor Zorgverzekeringen, Diemen). 1999
2000
2001
2002
2003
allergen specific immunotherapy
29.200
28.800
31.800
40.000
48.700
Insect allergens
3.000
2.800
3.000
2.900
3.200
Total
32.200
31.600
34.800
42.900
51.900
Conclusion Seventeen reports concerning the use of oral and sublingual allergen-specific immunotherapy are submitted to the Netherlands Pharmacovigilance Centre Lareb. Gastrointestinal symptoms and skin reactions are the most reported ADRs. Three patients suffered from serious generalised hypersensitivity reactions, such as systemic allergic reactions and anaphylactic reactions on oral or sublingual allergen-specific immunotherapy.
References 1. Dutch SPC Pollinex®. (version date 16-5-2003) http://www.cbg-meb.nl/IB-teksten/16288.pdf. 2. Khinchi MS, Poulsen LK, Carat F, André C, Hansen AB, Malling HJ. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebocontrolled, double-blind, double-dummy study. Allergy 2004;59(45):53 3. Passalacqua G, Fumagalli F, Guerra L, Canocica GW. Safety of allergen-specific sublingual immunotherapy and nasal immunotherapy. Chem Immunol Allergy 2003;82:109-18. 4. Winap, editor. Informatorium Medicamentorum 2005. Den Haag: 2005. 5. Di Rienzo V, Marcucci F, Puccinelli P, Parmiani S, Frati F, Sensi L, Canonica GW, Passalacqua G. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin Exp Allergy 2003;33:206-210
Serious generalised hypersensitivity reactions also occur during oral or sublingual allergen specific immunotherapy
It is recommended to include serious allergic and anaphylactic reactions in the available SPCs of products for oral or sublingual allergen-specific immunotherapy
Products for oral or sublingual allergen-specific immunotherapy without SPC should be accompanied by proper information on serious generalised hypersensitivity reactions
10
2.2.
A combination of metoclopramide and selective serotonin reuptake inhibitors: additional extrapyramidal effects? Introduction ® Metoclopramide (Primperan ) is a prokinetic agent, which increases gastrointestinal motility. It was approved in the Netherlands in 1968. Metoclopramide possesses central and peripheral dopamine antagonistic properties and it acts on the peripheral 5HT 4-receptors, which results in acetylcholine release from the myenteric plexus [1]. The serotonin reuptake inhibitors (SSRIs) are widely used as antidepressants. SSRIs inhibit the presynaptic reuptake of serotonin. Some of the SSRIs have some acetylcholine antagonistic properties [1]. Extrapyramidal reactions occur during metoclopramide therapy due to the dopamine antagonism of metoclopramide. Extrapyramidal reactions have also been reported during the use of SSRIs. These reactions are probably caused by a serotonergic inhibition of the dopamine neurotransmission in the striatum [2,3]. The SPCs of metoclopramide and most of the SSRIs [4-11] do mention extrapyramidal symptoms as adverse drug reaction. However an additive effect or an interaction between metoclopramide and SSRIs is not mentioned in the SPC of either metoclopramide or the SSRIs [4-10]. Reports Lareb received 6 reports of extrapyramidal symptoms during combined use of metoclopramide and SSRI‟s (table 1). All cases were reported by a health professional. In cases A and B the reporting health professional recognized the interaction between the SSRI and metoclopramide, in cases C, D and E the SSRI was mentioned as concomitant medication and in case F metoclopramide was considered as concomitant medication. The symptoms started within a few hours after metoclopramide was administered in cases A,B,C,D and E. In case B and case E the patient was admitted to the hospital because of the extrapyramidal reaction. Table 1. reports of extrapyramidal reactions with metoclopramide and a SSRIs Patient, Existing therapy/ Sex, age time to onset
Additional therapy/ time to onset
Adverse drug reaction
Action taken, outcome
A, F, 32
fluvoxamine 50mg*/ metoclopramide 3 days 10mg*/ hours
akathisia
both drugs withdrawn, recovered
B, F, 35
fluvoxamine 50mg*/ metoclopramide days 10mg*/ hours
tardive dyskinesia, trismus
hospitalisation, both drugs withdrawn, recovered
C, F, 38
fluoxetine 20mg/ concomitant
metoclopramide 10mg*/ 1 day
dyskinesia
?, recovered
D, F, 44
paroxetine 20mg/ concomitant
metoclopramide 20mg*/ 6 hours
akathisia, dystonia
?, ?
E, F, 38
paroxetine 20mg/ concomitant
metoclopramide 20mg*/6 hours
extrapyramidal reaction
metoclopramide withdrawn, biperidene, recovered
F, F, 49
metoclopramide sertraline 50mg*/ 3 dystonia, tinnitus 10mg/ concomitant days *suspected medication according to health professional
sertraline withdrawn, recovered
11
Other sources of information Literature In the Dutch interaction-reference-works the interaction between metoclopramide and SSRIs is not mentioned [13,14]. According to Stockley the additive effect of fluoxetine, fluvoxamine and sertraline and metoclopramide was reported in a few isolated case reports [15]. Fisher and Davis published two cases of a serotonin syndrome with serious extrapyramidal movement disorders. The symptoms appeared in two patients on chronical treatment with sertraline or venlafaxine after a single dose metoclopramide [16]. Mechanism An explanation for these extrapyramidal symptoms is a pharmacodynamic interaction. SSRIs increase the serotonin activity, which inhibits the dopaminergic system, leading to severe extrapyramidal symptoms in combination with the antidopaminergic activity of metoclopramide. In addition, a pharmacokinetic interaction should be taken into account. Metoclopramide is a known substrate for cytochrome P450 2D6. Citalopram, fluoxetine, paroxetine and sertraline are (weak) inhibitors of this enzyme [1,12]. A decreased metabolism of metoclopramide could enhance the interaction between metoclopramide and SSRI‟s. Conclusion Lareb received 6 reports of a possible interaction of metoclopramide and a SSRI shortly after start of the second drug. SSRIs and metoclopramide both have the potential to cause extrapyramidal reactions by itself. It is conceivable that the combination increases the risk for extrapyramidal symptoms. References 1. KNMP; 2004 Informatorium medicamentorum 2004 2 . Caley CF. Extrapyramidal reactions and selective serotonin-reuptake inhibitors. The annals of pharmacotherapy 1997;31:1481-7 3. Schillevoort I, van Puijenbroek EP, de Boer A, Roos RA, Jansen PA, Leufkens HG. Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors: a case control study using spontaneous reports. Int Clin Psychopharmacolol 2002;17(2):75-9 4. Dutch SPC Primperan (13-03-2003) http://www.cbg-meb.nl 5. Dutch SPC Seroxat (12-04-2002) http://www.cbg-meb.nl 6. Dutch SPC Prozac(19-08-2003) http://www.cbg-meb.nl 7. Dutch SPC Fevarin (29-03-2004) http://www.cbg-meb.nl 8. Dutch SPC Efexor (16-06-2004) http://www.cbg-meb.nl 9. Dutch SPC Zoloft (05-07-2004) http://www.cbg-meb.nl 10. Dutch SPC Cipramil (05-2003) http://www.cbg-meb.nl 11. Kwartaalbericht 2004-2 12. Flockhart http://medicine.iupui.edu/flockhart/Januari 2004 13. Pharmacom/medicom Commentaren medicatiebewaking 2004-2005, Houten healthbase 14. Winap interacties via Kombirom januari 2004 15. Stockley IH. Ed. Stockley‟s drug interactions, 6th ed. 2003 16. Fisher A David M. Serotonin syndrome caused by selective serotonin reuptake inhibitors metoclopramide interaction. Ann Pharmacother 2002;36:67-71.
In the SPCs of metoclopramide and SSRIs a warning for an interaction between both drugs, resulting in extrapyramidal symptoms, should be added.
12
2.3.
Mumps, measles and rubella (MMR) vaccine and idiopathic thrombocytopenic purpura (ITP) Introduction Mumps, measles and rubella (MMR) vaccine has been included in the Netherlands Childhood Immunization Programme (Rijksvaccinatieprogamma, RVP) since 1987. It is a combination vaccine which contains live attenuated viruses and is administered by subcutaneous injection at the ages of 14 months and 9 years. It is indicated: for active immunization against mumps, measles and rubella. In the Netherlands several MMR vaccines have been granted a marketing authorisation but only the MMR vaccine produced by the Nederlands Vaccin Instituut (NVI) is used in the RVP. Adverse drug reactions listed in the SPC of „Bof-, Mazelen-, Rubellavaccin‟ (NVI-MMR) include: injection site pain, erythema, fever, fever convulsions, encephalitis, cervical and occipital lymphadenopathy, arthralgia and arthritis in adult females and allergic reactions [1]. Although the term „idiopathic‟ trombocytopenic purpura is linguistically not correct in case of infection or vaccination induced cases, this report follows common clinical terminology. Reports Until January 2005 Lareb received 4 reports of ITP associated with the use of the NVI-MMR vaccine in the RVP. Three of these 4 ITP cases were notified in 2004. All reports were forwarded from the RIVM-Libris database. In 2002 the RIVM considered 6 out of 7 reports of ITP possibly related to the MMR vaccine [2]. Table 1. ITP associated with the use of the NVI-MMR vaccine in the RVP. All infants recovered Lareb Sex, age nr. [months]
Time to onset
Platelet count Concomitant medication
Treatment
remarks
41175 F, 15
17 days
3 * 109/L
None reported
prednisolone
Recurring ITP, EBV infection
43578 F, 14
21 days
1* 109/L
NeisVac® vaccine Miconazole cream
prednisone ferrous fumarate
-
46364 M, 16
23 days
9 * 109/L
NeisVac® vaccine
not reported
-
46365 F, 14
28 days
5* 109/L
NeisVac® vaccine
not reported
-
Other sources of information Literature Information from the literature indicates that a causal relationship between MMR vaccine and ITP is generally accepted, both abroad [3,4,5] and in the Netherlands ® [6]. Two other MMR vaccines are licensed in the Netherlands: M-M-R II and ® ® Priorix . Thrombocytopenia and purpura are listed in the Dutch SPC of M-M-R II vaccine [7]. Thrombocytopenia and purpura are not listed in the Dutch SPC of ® ® Priorix [8] but they are listed in the UK SPC of Priorix [9]. Moreover, in the year 2001 the Committee on Safety of Medicines in the UK issued a recommendation on how to proceed with the second MMR immunisation in children who developed ITP within 6 weeks of the first dose of MMR. This recommendation has been included in the MMR vaccine product information [10].
13
Databases At the end of the second quarter of 2004 the reporting odds ratio of the association between MMR vaccine and thrombocytopenia in the database of the Uppsala Monitoring Centre of the WHO was 0.98 (95% CI 0.97–1.0). For purpura and thrombocytopenic purpura the RORs were 1.6 (95% CI 1.5–1.8) and 8.4 (95% CI 7.0–10.0), indicating that the two latter associations are more often reported to the WHO collaborating centre than other associations. Mechanism ITP is an uncommon disorder but it is one of the most frequently diagnosed hematological disorders among young children [4]. Over 70% of ITP cases are caused by a viral infection which includes natural infections with measles (common), rubella (1 in 3000 infections) and mumps (rare) viruses. The attenuated measles and rubella viruses are the most likely components of the MMR vaccines to cause ITP [5]. Conclusion The Lareb and WHO reports and literature data indicate that MMR vaccine is associated with the rare occurrence of ITP. The absence of this adverse drug reaction in the SPC of NVI- MMR suggests a more favourable safety profile as compared to other MMR vaccines with a marketing authorization in the Netherlands where this ITP is listed in the SPC. Nevertheless, it should be reminded that the incidence of vaccine induced ITP is lower than ITP caused by viral infections. References 1. Dutch SPC Mumps, measles and rubella vaccine. NVI (version date 02-07-1997) http://www.cbgmeb.nl/IB-teksten/17654.pdf 2. RIVM Rapport 000001009: Adverse Events Following Immunisation under the National Vaccination Programme of The Netherlands Number IX - Reports in 2002 http://www.rivm.nl/bibliotheek/rapporten/000001009.html 3. Jefferson T, Price D, Demichelli V, Bianco E. EUSEFAFEVAC project. Unintended events following immunization with MMR: a systematic review. Vaccine 2003;21(25-26):3954-60. 4. Black C, Kaye JA, Jick H. MMR vaccine and idiopathic thrombocytopenic purpura.. Br J Clin Pharmacol. 2003;55(1):107-11. 5. Miller E, Waight P, Farrington CP, Andrews N, Stowe J, Yaylor B. vaccine and idiopathic thrombocytopenic purpura and MMR. Arch Dis Child 2001 ;84(3):227-9. 6. Rumke HC, Visser HK. Vaccinaties op de kinderleeftijd anno 2004.II. Echte en vermeende bijwerkingen. Ned Tijdschr Geneesk 2004 ;148(8):364-71. 7. Dutch SPC M-M-R II (version date 16-09-1997)http://www.cbg-meb.nl/IB-teksten/17672.pdf 8. Dutch SPC Priorix (version date 17-12-2002 ) http://www.cbg-meb.nl/IB-teksten/22052.pdf 9. UK SPC Priorix (version date 03-10-2004 ) http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=2054 10. MMR vaccine and and idiopathic thrombocytopenic purpura. Current problems in Pharmacovigilance 2001;27:15.
Lareb advises to include ITP in the SPC of NVI-MMR
14
2.4.
Itraconazole and paresthesias Introduction ® Itraconazole (Trisporal ) is a triazole antifungal agent which has been approved for the Dutch market in 1988. The gastro-intestinal and hepatobiliary adverse drug reactions are the most common. With long term use, also peripheral neuropathy has been described [1]. However, short term use appears to be associated with paresthesia. It is unclear whether this paresthesisia with such remarkable short latency time is a first sign of peripheral neuropathy. Itraconazole induced paresthesia with such short latency time is not mentioned in the SPC [2]. Reports On February 8, 2004 the database of the Netherlands Pharmacovigilance Centre contained 18 reports concerning paresthesias associated with the use of itraconazole. The latency period for these reports was in most cases short, only one to several days (table 1). In addition Lareb received 12 reports (not listed in table 1) concerning (poly)neuropathy, but only in three of these cases neural damage was confirmed by a neurologist. First symptoms in these confirmed reports have been tingling sensations and numbness in feet, legs, hands and arms. Latency time varied from a few weeks to 8 months. No cases of paresthesias or neuropathy on other triazole derivatives (voriconazole, fluconazole, terconazole) are present in the database. Table 1. paresthesias in combination with itraconazole reported to Lareb patient
sex, age
concomitant medication
symptoms
dosage (mg)
time to onset
remarks
A
F, 77
tingling sensation hands and feet
none
2dd100
8 days
B
F, 49
tingling sensation
mometasone cream
unknown 1 day
C
M, 59
tingling sensation arm and hands
none
1dd100
1 week
pos. dechallenge
D
F, 31
paresthesia arms, legs and feet, polyneuropathy
none
2dd100
2 hours
pos. dechallenge
E
M, 32
tingling pain in fingers
none
2dd100
same day
F
F, 44
tingling sensation
none
1dd100
1 day
G
M, 35
tingling sensation fingers and axilla
none
1dd100
1 day
H
F, 59
paresthesias fingers, feet and wrist
homeopathics (2), albuterol/ipratropium inhalation
1dd100
10 months
I
M, 52
numbness arms and hands
ranitidine
1dd100
10 days
J
F, 31
tingling sensation facial skin
none
1dd100
same day
pos. dechallenge
K
M, 44
tingling sensation left hand and arm
carbasalate calcium, metoprolol, isosorbidemononitrate
1dd100
5 hours
pos. dechallenge
L
M, 61
nocturnal none paraesthesias arms
2dd200
1 day
pos. dechallenge, pos. rechallenge
pos. dechallenge
15
sex, age
patient
concomitant medication
symptoms
dosage (mg)
time to onset
remarks
M
F, 36
generalized tingling nebivolol sensation
2dd100
2 days
N
F, 32
tingling sensation arms and legs
oral contraceptive
1dd200
7 weeks
3 months after withdrawal, not yet recovered
O
F, 65
tingling sensation arm, asthenia legs
flecainide, enalapril, triamterene/epitizide
2dd200
13 days
pos. dechallenge
P
F, 32
tingling sensation arms
miconazole cream, diclofenac, sumatriptan, oral contraceptive
1dd100
same day
Q
F, 33
tingling sensation hands
miconazole cream, oral contraceptive
1dd200
few days
R
F, 40
tingling sensation jaws and legs
oral contraceptive
2dd200
5 days
pos. dechallenge
Other sources of information Literature A literature search reveals no relevant publications of paresthesias or peripheral neuropathy in combination with the use of itraconazole or other triazoles. In the general population, peripheral neuropathy is quite common with a prevalence of 2.4% [3]. Because it can be disabling or fatal, early diagnosis is important. The most common causes of acute generalized peripheral neuropathy are vasculitis, diabetes mellitus, critical illness or drugs. First symptoms of neuropathy are (distal) paresthesias, altered sensation and weakness. Most peripheral neuropathies are chronic and usually develop over several months [3]. Databases The association itraconazole and paresthesias is disproportionally present in both the Lareb and the database of the WHO Uppsala monitoring centre (table 2). Table 2. Overview of data of case/non-case approach of Lareb and WHO database Database
itraconazole and paresthesias
itraconazole total
ROR (95% CI)
Lareb WHO
18 119
282 5667
4.2 (2.6 – 6.9) 1.4 (1.1 – 1.6)
Mechanism The mechanism of itraconazole induced paresthesias is unknown. Taking into account the short latency time, we presume a direct neurotoxic mechanism. However no data could be found to support this hypothesis. Prescription data Total number of prescriptions of itraconazole are shown in table 3.
16
Table 3. Total number of prescriptions of itraconazole per year since 1999 (Source: GIP College voor Zorgverzekeringen, Diemen). 1999 J02AC02 Itraconazol
177.000
2000
2001
2002
187.000 173.000 157.000
2003 151.000
Conclusion Lareb received 18 reports of paresthesias in association with itraconazole. Most cases have a remarkable short latency of a few days after start. Paresthesias are disproportionally associated with itraconazole in both the WHO and Lareb databases. Paresthesias are not mentioned in the SPCs of itraconazole.
References 1. KNMP; 2004; Informatorium Medicamentorum 2004 2. Dutch SPC Trisporal®. (version date 06-08-2002) http://www.cbg-meb.nl/IB-teksten/13224.pdf 3. Hughes RAC. Clinical review: Peripheral neuropathy. BMJ 2002; 324:466-469
Itraconazole is associated with paresthesias with remarkable short latency time Paresthesias, especially with short latency time, should be included in the SPC of itraconazole
17
3. Short notes 3.1.
Contra-indications of ceftriaxone The Netherlands Pharmacovigilance Centre Lareb received a report of a threemonth-old boy with tonic-clonic convulsions after intramuscular injection of ceftriaxone. While assessing this report we noticed discrepancies between the SPCs of several ceftriaxone brands and formulations with regard to lower limits of age as contra-indication lidocain containing formulations and contra-indicated intravenous administration
The SPCs of the ceftriaxones should be harmonised.
3.2.
Amoxicillin and black tongue / tooth discolouration The Netherlands Pharmacovigilance Centre Lareb received several reports of black tongue (19 reports) and tooth discolouration (25 reports) associated with use of amoxicillin. These associations are disproportionally reported in both the Lareb and the database of the Uppsala Monitoring Centre of the WHO. Though, well-known and supported by literature, black tongue is not mentioned in most SPCs of amoxicillin, with some exceptions (e.g. RVG 29702). The same ® applies for tooth discolouration, which is mentioned e.g. in the SPC of Clamoxyl , but not in the majority of other SPCs of amoxicillin. Black tongue and tooth discolouration should be included in all SPCs of amoxicillin. References 1. Meyboom RHB et al. Reversibele tandverkleuring tijdens oraal gebruik van antibiotica. NTvG 1996;140(4):207-9 2. Bouvy M. Haartong bij het gebruik van antibiotica. Pharm Weekbl 1996;131: 628 3. de Leest K. Zwarte harige tong. Pharm Weekbl 2002;137 (36):1285 4. Dutch SPC Clamoxyl®. (version date 25-10-1999) http://www.cbg-meb.nl/IB-teksten/06495.PDF. 5. Dutch SPC amoxicilline®. (version date 30-02-2004) http://www.cbg-meb.nl/IB-teksten/57640.PDF 6. Dutch SPC amoxicilline®. (version date 28-01-2004) http://www.cbg-meb.nl/IB-teksten/29702.PDF 7. KNMP;2004;Informatorium Medicamentorum 2004 8. College voor Zorgverzekeringen. Farmacotherapeutisch Kompas 2004.
18
3.3.
Chlorhexidine and anaphylaxis Recently, the Netherlands Pharmacovigilance Centre Lareb has received two reports of anaphylaxis in patients upon application of chlorhexidine used as a bactericide lubricant on catheters. Anaphylaxis on the bactericide chlorhexidine both on topical and oral applications is well known and extensively described in literature [1,2]. Anaphylactic shock and anaphylactic reactions are disproportionally associated with use of chlorhexidine in the WHO database. While assessing these reports a discrepancy between the various SPCs of the 36 chlorhexidine containing products available in the Netherlands was noticed [3]. Anaphylactic reactions are mentioned in only four SPCs as ADR. In 19 SPCs hypersensitivity is listed as a contraindication. Other SPCs do not mention hypersensitivity reactions at all. Conclusion The SPCs of the 36 chlorhexidine containing products are inconsistent with respect to anaphylaxis and hypersensitivity reactions. Over the counter availability and the potential seriousness of (unexpected) anaphylaxis deserves adaptation of the SPCs. References 1. Beaudouin E, Kanny G, Morisset M, Renaudin JM, Mertes M, Laxenaire MC, Mouton C, Jacson F, Moneret-Vautrin DA. Immediate hypersensitivity to chlorhexidine: literature review. Allerg.Immunol.(Paris) 2004;36(4):123-6. 2. Stephens R, Mythen M, Kallis P, Davies DW, Egner W, Rickards A. Two episodes of lifethreatening anaphylaxis in the same patient to a chlorhexidine-sulphadiazine-coated central venous catheter. Br J Anaesth. 2001;87(2):306-8. 3. Dutch SPCs of chlorhexidine containing products. http://www.cbg-meb.nl (assessed December 2004).
19
4. Appendix Omzettingsproblemen bij carbamazepine CR Introductie In de tachtiger en begin negentiger jaren van de vorige eeuw zijn enkele controlled release (CR) preparaten van carbamazepine in de handel gekomen. ® De eerste vorm was het specialité Tegretol CR van destijds Ciba-Geigy, thans ® Novartis. Later is Carbymal retard van de firma Katwijk in de handel gekomen, gevolgd door varianten van generieke firma‟s. De controlled release preparaten carbamazepine zijn terug te voeren op twee varianten: de bruine, vaste “Novartis” variant, en de witte, zachtere “Katwijk” variant. Beide tabletvormen hebben vergelijkbare farmacologische profielen. Eén van de grotere generiek firma‟s (Alpharma) heeft tot begin 2004 de bruine “Novartis” variant van carbamazepine-CR geleverd (Carbamazepine Dumex ® Retard ). Ongeveer 1 januari 2004 is deze firma overgeschakeld op de witte “Katwijk” variant (tabel 1) met behoud van dezelfde merknaam. Patiënten die ® Carbamazepine Dumex Retard van Alpharma gebruikten kregen na januari 2004 de nieuwe witte variant in plaats van de vroegere bruine variant mee van de apotheek. Tabel 1. RVG nummers van Carbamazepine Dumex Retard tabletten (Alpharma) vóór 1-1-04 sterkte, vorm RVG
essential similarity
na 1-1-04 uiterlijk RVG
essential similarity
uiterlijk
Carbamazepine RVG 25643 =24401 lichtoranje RVG 28995 =21169 Dumex Retard Tegretol CR® 200 ovaal, iets bol Carbama200 mg zepine 200 mg retard Katwijk
wit rond
Carbamazepine RVG 25644 = 24402 bruinoranje RVG 28996 =16869 Dumex Retard Tegretol CR® 400 ovaal, iets bol Carbama400 mg zepine 400 mg retard Katwijk
wit langwerpig
Rapporten In de eerste maanden van 2004 zijn zeven meldingen ontvangen van verhoogde frequentie en/of ernstiger vorm van epilepsieaanvallen bij patiënten die ® overgegaan waren van de bruine Carbamazepine Dumex Retard naar de witte ® variant van Carbamazepine Dumex Retard (Tabel 2, patiënt A-G). Al deze patiënten hadden een lokalisatiegebonden epilepsie met (complex) partiele aanvallen. Bij patiënt D, F en G trad hierbij secondaire generalisatie op, leidend tot tonisch-clonische insulten. Bij patiënt F leidde dit tot een ziekenhuisopname. Vijf van de zeven patiënten herstelden na overgezet te zijn van Carbamazepine ® ® Dumex Retard op Tegretol CR . Patiënt B herstelde uiteindelijk tijdens ® continuering van de witte Carbamazepine Dumex Retard . Patiënt E ondervond ® nog een aanval nadat hij was overgezet op Tegretol CR . Bij patiënt F werd na het incident een proef gestart, waarbij serumconcentraties werden gemeten bij gebruik ® van 3 weken bruine Carbamazepine Dumex Retard , gevolgd door 3 weken witte ® Carbamazepine Dumex Retard beide in een dagdosering van 1200 mg. Gedurende 3 dagen werden nuchtere serumconcentraties bepaald, waarbij de ® gemiddelde serumconcentratie van de witte Carbamazepine Dumex Retard 15 % 20
lager lag dan van de bruine variant. Bij twee andere patiënten werden spiegels gemeten; bij patiënt B werden adequate spiegels gevonden bij de witte ® Carbamazepine Dumex Retard , bij patiënt C werd geen verschil tussen de witte ® en de bruine Carbamazepine Dumex Retard gevonden. Tevens is nog een melding gedaan van een 43 jarige vrouw, bij wie een daling van 15 % in de (tweevoudig bepaalde) dalspiegel gevonden werd na overgang ® van de bruine naar de witte Carbamazepine Dumex Retard , overigens zonder verandering in het aanvalsbeeld (Tabel 2, patiënt H). Conclusie ® Begin januari 2004 werd het product Carbamazepine Dumex Retard van ® Alpharma gewijzigd: aanvankelijk was het product identiek aan Tegretol CR (bruine variant), sinds de wijziging is het product identiek aan Carbamazepine ® retard Katwijk (witte variant). Ondanks deze wijzigingen is de naam van de ® Alpharma producten - Carbamazepine Dumex Retard -ongewijzigd gebleven. De casus geven aan dat deze wijziging gepaard is gegaan met meldingen van verhoogde aanvalsfrequentie; in sommige casus konden verlaagde serum concentraties worden gevonden. Hoewel alle carbamazepine CR formuleringen ® bioaequivalent zijn met Tegretol CR , illustreren deze casus dat bioaequivalentie niet betekent dat formuleringen volledig uitwisselbaar zijn. De wijziging van de formulering met behoud van dezelfde merknaam blijkt klinisch significante bijwerkingen te hebben, ondanks de bioaequivalentie. Dit rechtvaardigt dat voorschrijvers, apothekers en patiënten op korte termijn hierover worden geïnformeerd.
21
Tabel 2. rapporten van bijwerkingen na de overgang van de bruine naar de witte Carbamazepine Dumex Retard
®
patiënt geslacht leeftijd
dagdosering witte Carbamazepine Dumex Retard®
co-medicatie
bijwerking
latentietijd, herstel (*)
A F,37
800 mg
topiramaat 300 mg
aanvalsfrequentie hoger dagen, hersteld na overgang op Tegretol CR®
50 % gedaald (dal of piekspiegels?)
B M, 52
1200 mg
levetiracetam 2000 mg clobazam 15 mg
aanvalsfrequentie verzesvoudigd
dagen, hersteld bij continueren witte Carbamazepine Dumex Retard®
adequaat (10.1-11.2 mcg/ml)
C M, 51
1600 mg
geen
toename in aanvallen, was hiervoor 8 jaar aanvalsvrij
dagen – weken, hersteld na overgang op Tegretol CR®
geen daling
D F, 43
800 mg
valproaat
zwaardere aanvallen dan voorheen
1 week, hersteld na overgang op Tegretol CR®
nvt
E M, 37
1000 mg
geen
aanvalsfrequentie hoger 1 week, nvt (voorheen 2-3 aanvallen nogmaals aanval na overgang op Tegretol ® per jaar) CR
F M, 19
1200 mg
methylfenidaat 30 mg
status epilepticus partialis leidend tot ziekenhuisopname
G M,6
500 mg
geen
aanvalsfrequentie hoger dagen - 1 week, nvt hersteld na overgang op Tegretol CR® 600 mg
H, F, 43
800 mg
geen
daling spiegel; geen toename in aanvallen
1 week, hersteld na overgang op Tegretol CR®
dagen, nvt (continuering van witte Carbamazepine Dumex Retard®)
(*) herstel tot uitgangsniveau (#) nuchtere serumconcentraties dmv bloedspot methode: gemiddelde van 3 metingen ($) gemiddelde van 2 metingen
spiegel
daling met 15 % (#) (6.03 naar 5.13 mcg/l)
daling met 15 % ($) (6.8 naar 5.8 mcg/l)
5. Publications
1. Diemont WL and de Groot MCH. Weet wat u voorschrijft. Waar vindt u informatie over geneesmiddelen? Ned Tijdschr Reumatol 2004;7(4):60-2. 2. Dodoo ANO, Labadie J, Renner L, Addison J, Pappoe V, Haybor S, AntwiAgyei KO, and van Grootheest AC. Safety monitoring of a new pentavalent vaccine (DPT+HepB+HIB) in Ghana's expanded programme on immunisation (EPI). Pharmacoepidemiol Drug Saf 2004;27(12):927 3. Waller P, Van Puijenbroek EP, Egberts ACG, Evans S. The reporting odds ratio versus the proportional reporting ratio: 'deuce'. Pharmacoepidemiol Drug Saf 2004;13(8):525-6. 4. Van Puijenbroek EP, Diemont WL, and van Grootheest AC. Time required for follow up information on spontaneous reports. Drug Saf 2004;27(12):956-7. 5. Kabel JS, Van Puijenbroek EP, and Bouwes Bavinck JN. Cooperation between the national pharmacovigilance centre and regiscar in the Netherlands: mutual profitable. Drug Saf 2004;27(12):938-9. 6. Bijl AMH and Van Puijenbroek EP. Anaphylactic reactions to OTC analgesics, particularly propyphenazone-combinations. Drug Saf 2004;27(12):921-2. 7. Kaouass EG, Kustura A, Hoebe DM, Labadie J, and Schellens JHM. Angineuze klachten bij het gebruik van 5-fluorouracil en capecitabine; Pijn op de borst kan een stopteken zijn. Pharm Weekbl 2004;139(48):1604-7. 8. Passier JLM, Van Puijenbroek EP, and van Grootheest AC. Meldingen bij het Nederlands Bijwerkingen Centrum Lareb van expulsie van een vaginaleanticonceptie-ring (NuvaRing) en van zwangerschap tijdens het gebruik ervan (ingezonden brief). Ned Tijdschr Geneeskd 2004;148(42):2096-67. 9. Passier JLM, Van Puijenbroek EP, and van Grootheest AC. Meldingen bij het Nederlands Bijwerkingen Centrum Lareb van expulsie van een vaginaleanticonceptie-ring (NuvaRing) en van zwangerschap tijdens het gebruik ervan. Ned Tijdschr Geneeskd 2004;148(41):2033-5. 10. Denissen J and de Langen-Wouterse JJ. Amoxicilline/clavulaanzuur (Augmentin®) en leverfunctiestoornissen. Geneesmiddelenbulletin 2004;38(10):79 11. Passier JLM. Pijn activering door sumatriptan. Geneesmiddelenbulletin 2004;38(10):79-80.
6. Enclosure
Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Emilio J Sanz, Carlos De-las-Cuevas, Anne Kiuru, Andrew Bate, Ralph Edwards. 2005 Lancet 365:482-487
24
