metamizol

The Journal of International Medical Research2010; 38: 1374 – 1380

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Update on the Incidence of MetamizoleSodium-induced Blood Dyscrasias in

Poland

GW BASAK, J DROZD-SOKOŁOWSKA AND W WIKTOR-JEDRZEJCZAK

Department of Haematology, Oncology and Internal Diseases, The Medical University ofWarsaw, Warsaw, Poland

Metamizole sodium (metamizole) is apopular non-opioid analgesic and acommon non-prescription product inPoland. Controversy exists regarding thelevel of risk of agranulocytosis or aplasticanaemia associated with its use. Twoprevious pharmacovigilance studiesconducted in Poland found the risk waslow. Twenty-four of the 25 haematologycentres that provide specialist care for the30 million adults in Poland participated inthis prospective 12-month study. Twenty-one cases of agranulocytosis, 48 of aplastic

anaemia, 15 of neutropenia and 11 ofpancytopenia were reported. Of these cases,three (two agranulocytosis; one aplasticanaemia) were judged as being possiblyrelated to metamizole. Crude estimates ofthe rate of agranulocytosis and aplasticanaemia associated with metamizole were0.16 and 0.08 cases/million person-days ofuse, respectively. Ongoing national safetysurveillance in Poland shows that, despitethe possibility of drug-induced blooddyscrasias with metamizole, the risk is verylow.

KEY WORDS: METAMIZOLE SODIUM; ANALGESIC; AGRANULOCYTOSIS; APLASTIC ANAEMIA;BLOOD DYSCRASIAS; PROSPECTIVE PHARMACOVIGILANCE

IntroductionAgranulocytosis and other blood dyscrasias,such as aplastic anaemia, are rare butpotentially life-threatening adverse reactionsto many drugs.1,2 Over 100 drugs have beenimplicated in the development of blooddyscrasias, including some antithyroid drugs(e.g. carbimazole and methimazole),antibiotics (e.g. β-lactam and cotrimoxazole),antiplatelet agents (e.g. ticlodipine),antipsychotics (e.g. clozapine), antiepileptics(e.g. carbamazepine) and non-steroidal anti-inflammatory drugs (e.g. indomethacin,phenylbutazone and metamizole sodium

[metamizole]).1 The observed reactions areidiosyncratic and are not dose-dependent.1,2

Metamizole is an effective antipyretic andanalgesic drug3,4 but there is controversyregarding the exact level of risk ofhaematological toxicity associated with itsuse.5 – 7 This is reflected in the notabledifferences in regulatory policies of differentcountries. While metamizole is prohibited inthe USA, UK, Denmark and Sweden, it iswidely available in Spain, Africa, Poland,Bulgaria, Russia, India and Latin and SouthAmerica.3,5 Differences in the methods usedin the various pharmacovigilance studies

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TABLE 1:Diagnostic criteria for blood dyscrasias defined by the National Consultant inHaematology, Poland, for a prospective safety surveillance study of metamizole sodiumuse performed between 1 April 2006 and 31 March 2007

Blood dyscrasia Definition

Agranulocytosis Granulocyte count < 0.5 × 109/la

Patient does not meet the criteria for aplastic anaemiaAplastic anaemia Granulocyte count < 1.5 × 109/l, platelets < 100 g/l, reticulocytes < 0.5%a

Bone marrow biopsy: fat-rich with haematopoietic cells occupying < 25% ofthe marrow space

Neutropenia Granulocyte count < 1.5 × 109/la

Patient does not meet the criteria for aplastic anaemiaPancytopenia Granulocyte count < 1.5 × 109/l, platelets < 100 g/l, haemoglobin level

< 90 g/la

Patient does not meet the criteria for aplastic anaemiaaTwo measurements from separate blood samples.

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GW Basak, J Drozd-Sokołowska, W Wiktor-JedrzejczakPolish data on metamizole-induced blood dyscrasias

and concurrent drug use probably accountfor the widely differing estimates of the riskof blood dyscrasias associated withmetamizole.6 – 9

Although a process for spontaneousreporting exists, the culture of adverse-eventreporting is not well established in Poland.Consequently, little information is availableon the safety of medicinal products used inthe general population. Active safetysurveillance on metamizole was, however,initiated in Poland in 1997, followingdivergent reports on its safety and itswidespread use. Previous studies, coveringthe periods 1997 – 2001 and 2002 – 2003,examined the frequency of metamizole-induced blood dyscrasias, specificallyagranulocytosis and aplastic anaemia, thatoccurred at six haematology centres acrossPoland.4,8 The purpose of the present studywas to confirm previous surveillancefindings and provide more comprehensivedata on the possible association betweenmetamizole use and the occurrence of blooddyscrasias from almost the entire adultpopulation of Poland.

Patients and methodsSTUDY DESIGN AND CENTRESHaematology centres in Poland receiveprimary and secondary referrals for seriousblood dyscrasias from their surroundingregions. This prospective safety surveillancestudy was performed between 1 April 2006and 31 March 2007, and collectedinformation from 24 of the 25 centres thatprovide haematology care for the entirePolish adult population (approximately 30million people; adults defined as ≥ 16 yearsold for the purposes of this study). Six ofthese centres had previously participated insimilar studies evaluating the frequencies ofagranulocytosis and aplastic anaemiafollowing metamizole use.4,8 One smallcentre based in Gorzów Wielkopolski did notparticipate because of insufficient staff.

PATIENTSPrior to the start of the study, the diagnosticcriteria for different blood dyscrasias weredefined by the National Consultant inHaematology (Table 1) and a physician wasassigned in each participating centre to



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collect and report data. Irrespective ofprevious therapy, all patients were screenedfor agranulocytosis, aplastic anaemia,neutropenia and pancytopenia. Those oncancer chemotherapy, radiation therapy orimmunosuppressive drugs, and those withdiseases that may have caused blooddyscrasias (e.g. tumour infiltration of thebone marrow) were excluded from theanalysis. At diagnosis of the blood dyscrasia,demography and medical history includingany medication taken in the previous 3months were obtained, including the use ofmetamizole in the 8 weeks prior to diagnosis.All cases in which metamizole had been usedwere reported within 15 days to the Centrefor the Monitoring of Drug Side-effects of thePharmaceutical Institute, in Warsaw.

ASSESSMENTSThe frequency of each of the blood dyscrasiaspotentially judged to be associated with theuse of metamizole was calculated bydividing the total adult population(approximately 30 million people) by thenumber of reports of each disorder.Polpharma company internal sales data ontablets sold during the study period and thedefined daily dose of 3 g (i.e. 6 × 500 mgtablets) were used to calculate the number ofperson-days of use, on the assumption thatthe entire adult population had beenexposed to the tablet formulation.

ResultsDuring the 12 months of the study, 21 casesof agranulocytosis were reported and theincidence was calculated to be 0.7 cases permillion adults per year. Metamizole hadbeen used in the previous 8 weeks in onlytwo cases. Among the 48 cases of aplasticanaemia (1.6 cases per million adults peryear), metamizole had been previously usedin only one case. Among the 15 cases of

neutropenia (0.5 cases per million adults peryear) and 11 cases of pancytopenia (0.37cases per million adults per year)metamizole had been used in one case ofneutropenia and one case of pancytopenia.

Of the five cases of blood dyscrasiaidentified in which metamizole had beenused, two were in male and three were infemale patients. Their ages ranged from 16to 82 years, and all had been receivingconcurrent medication at the time of thereports. Four of the patients recovered fullybut one patient with agranulocytosis died. Inthree of the five cases (two cases ofagranulocytosis and one of aplasticanaemia), metamizole causality wascategorized as ‘possibly related to therapy’.The two patients with agranulocytosis werealso receiving long-term therapy withcarbamazepine (an agent that has also beenreported to be associated with blooddyscrasias1) and the patient with aplasticanaemia was a chronic glue-sniffer. The tworemaining reports were categorized as‘unrelated to metamizole therapy’.

The five cases of blood dyscrasia identifiedin which metamizole had been used are nowdiscussed.

CASE 1: AGRANULOCYTOSISAn 82-year old man with trigeminalneuralgia was admitted to hospital withfever and dysphagia resulting from fungalmucositis. He had previously takencarbamazepine chronically (300 mg/day),ketoprofen, diclofenac and a few tablets ofmetamizole during the previous 8 weeks. Thepatient died of septic shock 5 weeks afteradmission to hospital and the event wasjudged by the reporting physician to bepossibly related to metamizole.

CASE 2: AGRANULOCYTOSISA 62-year old woman with cervical spinal



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neuralgia was admitted to hospital becauseof pharyngitis and fever. She had takencarbamazepine (800 mg/day) for 24 daysand metamizole for several preceding days(15 × 500 mg tablets in total). Normalizationof her peripheral blood cell count wasachieved following antibacterial, antifungaland haematopoietic therapy. Heragranulocytosis was judged to be possiblyrelated to metamizole.

CASE 3: APLASTIC ANAEMIAA 21-year old man was admitted to hospitalbecause of fatigue lasting > 1 month. Fourweeks before admission he had an upperrespiratory tract infection, and as asymptomatic treatment took metamizole(two tablets, 500 mg each) and paracetamol(two tablets, 500 mg each). He was a chronicglue-sniffer, therefore exposure to toxicsubstances could not be ruled out as themain cause of the blood dyscrasia. Whilehighly unlikely, the blood dyscrasia wasjudged to be possibly related to metamizole.

CASE 4: NEUTROPENIANeutropenia and vitamin B12 deficiency werereported in a 25-year old woman admitted tohospital with fever, headaches, malaise andfatigue. Within the previous 4 days she hadtaken two tablets of metamizole (500 mgeach), three tablets of ibuprofen (200 mgeach) and three tablets of paracetamol (500mg each). Following vitamin B12

supplementation, her blood count returnedto within normal values. The neutropeniawas judged to be unrelated to metamizole.

CASE 5: PANCYTOPENIAPancytopenia was reported in a 16-year oldfemale with gluten intolerance. Three weeksbefore admission to hospital she had takenmetamizole (two 500 mg tablets), ibuprofen(five 200 mg tablets) and paracetamol (two

500 mg tablets) because of gastrointestinaltract infection, headache and fever.Investigations led to a diagnosis of coeliacdisease. After administration of folic acidand vitamin B12, her blood count returned towithin normal values. Pancytopenia wasjudged to be unrelated to metamizole in thispatient.

OVERALL FREQUENCY OFMETAMIZOLE-RELATED BLOODDYSCRASIASA total of 75 475 180 tablets of 500 mgmetamizole were sold during the studyperiod, equivalent to 12 579 196 person-daysof use. Thus, assuming that the studyinvolved almost 100% of the adultpopulation of Poland, the three reports ofpossible metamizole-related blood dyscrasiasresulted in a crude estimate of 0.16 cases ofagranulocytosis per million person-days ofuse and of 0.08 cases of aplastic anaemia permillion person-days of use.

DiscussionThe observed overall frequency of aplasticanaemia (1.6 cases per million adults peryear) was similar to that reported in aprevious Polish study (1.8 per million adultsper year) and within internationallyaccepted values (0.7 – 4.1 per million adultsper year).2,4 The frequency ofagranulocytosis (0.7 cases per million adultsper year) was lower than in a previousprospective study from Poland (1.07 permillion adults per year)4 and lower thandata from several international studies (1.1 –4.9 per million individuals per year).2 It wassimilar to data from Thailand (0.7 permillion individuals per year)9 and from LatinAmerica (0.4 per million individuals peryear).7 Although one of the 25 Polishhaematology centres did not wish tocontribute to the study, its exclusion is



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unlikely to have affected the overall findingssince it was a small centre covering a smallcatchment area.

None of the reports of neutropenia orpancytopenia following the use ofmetamizole was judged to be treatment-related. Two cases of agranulocytosis inpatients also receiving regularcarbamazepine therapy were, however,judged to be possibly related to metamizole.

Relating these reports to drugconsumption data over the same period, acrude estimate of the incidence ofagranulocytosis associated with the use ofmetamizole in Poland was calculated as 0.16cases per million person-days of use. Thisvalue is similar to data from a previous studyconducted in Poland (0.2 cases per millionperson-days of use)8 and data from severalinternational studies (0.3 – 4.0 per millionpersons-days of use),6,10 but much lower thandata from Sweden (one case in 1400individuals).11 The one case of aplasticanaemia in the present study that wasjudged possibly related to metamizole wasreported in a patient with chronic substanceabuse (glue-sniffing). As a crude estimate,this equates to 0.08 cases per million person-days of use, a value lower than observedpreviously in data from Poland (0.25 casesper million persons-days of use).4

Poland is one of several countries wheremetamizole is frequently used (over 75million tablets per year). In Latin America,metamizole one of the most widely useddrugs7 and in this region its association withagranulocytosis appears to be minimal.7

Although differences in the methods used inthe various pharmacovigilance studies – aswell as differences in age range, gender,underlying conditions and concurrent druguse of the patients – may be responsible forsome of the disparity, some authors havesuggested that genetic polymorphisms may

be more prevalent in some ethnic groupsthan in others.7 For example, data from aBulgarian study have suggested that thehistocompatibility antigen (humanlymphocyte antigen [HLA]) A24 is involvedin the predisposition to metamizole-inducedagranulocytosis.12 An association betweenHLA-B27 and HLA-B38 and increased risk ofagranulocytosis with clozapine has also beenreported.13 Patients who receive clozapineneed to have their full blood countsmonitored regularly and, if the total whitecell and/or neutrophil counts indicateagranulocytosis, clozapine must beterminated.14 Testing the involvement of agenetic link to this, however, would requireDNA sampling and assessment of eachpatient. While further study into ethnicgroup differences and concomitant drug useis warranted, a pragmatic solution is tomaintain pharmacovigilance.

In conclusion, these data show that,despite the possibility of drug-induced blooddyscrasias with the use of metamizole, theseblood disorders are rare events and the drugmay be considered relatively safe. Untiladverse event reporting in Poland becomes amore reliable source of safety data, however,metamizole pharmacovigilance should becontinued. Consideration should also begiven to introducing similarpharmacovigilance programmes forcarbamazepine and other agents potentiallyassociated with blood dyscrasias.

AcknowledgementsThe authors wish to thank the followingindividuals for their participation in thisstudy (all based in Poland): PiotrCentkowski, Institute of Haematology andTransfusion Medicine, Warsaw; WaldemarTomczak, Department of Haematooncologyand Bone Marrow Transplantation, MedicalUniversity of Lublin, Lublin; Anna



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• Received for publication 17 February 2010 • Accepted subject to revision 4 March 2010• Revised accepted 8 June 2010

Copyright © 2010 Field House Publishing LLP

Szmigielska-Kaplon, Department ofHaematology, Medical University of Lodz,Lodz; Malgorzata Pawlowska, Department ofHaematology, Medical University ofBialystok, Bialystok; Teresa Borysewicz-Czajka, Department of Internal Diseases andHaematology, Military Institute of Medicine,Warsaw; Mariusz Janczarski, Department ofHaematology and Oncology, CentralHospital of the Ministry of Internal Affairs,Warsaw; Malgorzata Wojciechowska,Haematology Ward, Voivodship SpecializedHospital, Olsztyn; Malgorzata Calbecka,Haematology Ward, Specialized Hospital,Torun; Jolanta Starzak-Gwozdz,Haematology Ward, Voivodship SpecializedHospital, Rzeszow; Dorota Krochmalczyk,Department of Haematology, CollegiumMedicum, Jagiellonian University, Cracow;Andrzej Zdunczyk, Haematology Ward,Ludwik Rydygier Voivodship SpecializedHospital, Cracow; Marek Kielbinski,Department of Haematology, MedicalUniversity of Wroclaw, Wroclaw; AleksandraHolowiecka-Goral, Department ofHaematology, Silesian Medical University,Katowice; Marcin Wojtowicz, HaematologyWard, Voivodship Hospital, Opole; Maria

Bieniaszewska, Department of HaematologyMedical University of Gdansk, Gdansk;Wojciech Pietras, Department of PaediatricHaematology, Medical University of Wroclaw,Wroclaw; Joanna Rupa, Department ofHaematology, Medical University of Poznan,Poznan; Agnieszka Kasprzyk, HaematologyWard, J. Strus Hospital, Poznan; MariaNowakowska-Domagala, HaematologyWard, Swietokrzyskie Oncology Centre,Kielce; Grazyna Gadomska, HaematologyWard, Jan Biziel Voivodship Hospital,Bydgoszcz; Piotr Adamek, Ward of InternalDiseases, Military Hospital, Szczecin; BarbaraZdziarska, Department of Haematology,Pomeranian Medical University, Szczecin;Andrzej Lange, Low-Silesian Centre forCellular Transplantation, Wroclaw. Theauthors also wish to acknowledge theeditorial help provided by Dr Sue Daly andDr Yvonne Lis during the preparation of themanuscript. The study was supported byPolpharma Pharmaceuticals, StarogardGdansk, Poland

Conflicts of interestThe authors had no conflicts of interest todeclare in relation to this article.

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Author’s address for correspondenceDr Wieslaw Wiktor-Jedrzejczak

Department of Haematology, Oncology and Internal Diseases, The Medical University ofWarsaw, 1A Banacha Str., 02-097 Warsaw, Poland.

E-mail: [email protected]

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