Lääkeinformaatiota Lääkelaitokselta

Läkemedelsinformation från Läkemedelsverket, Finland

Drug information from the National Agency for Medicines, Finland

4|2006

LedareLedare

Om biverkningarOm biverkningar

Om läkemedelsanvändningOm läkemedelsanvändning

Om läkemedel för djurOm läkemedel för djur

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Utvecklingen av biologiska läkemedel: innovationeroch övervakningPekka Kurki

Att fela är mänskligt – utredning av felexpediering påapotekenVirpi Savikko | Tuula Teinilä | Marja Airaksinen

Om felmedicinering vid GiftinformationscentralenPia Kuisma | Kalle Hoppu

Telitromycin och ljuseksemLeena SavolainenLamotriginanvändning under graviditeten och risken för kluven gom eller läpp Radhakrishnan Rajaratnam

Biverkningar av antidepressivaAnnikka Kalliokoski | Leena Sommarberg

Användningen av antidepressiva allt almännare blandunga kvinnor Timo Klaukka

Finländarnas användning av blodtrycksläkemedel 2004Terhi Helmiö

CiklosporinTita-Maria Muhonen

Inga fler responsbrev om biverkningar

The development of biological medicinal products:innovations and regulationPekka Kurki

To err is human – a survey of dispensing errors madeby pharmacies in FinlandVirpi Savikko | Tuula Teinilä | Marja Airaksinen

Medication error inquiries in the Poison Information CentrePia Kuisma | Kalle Hoppu

Telithromycin and photodermatitisLeena Savolainen

Adverse reactions due to antidepressantsAnnikka Kalliokoski | Leena Sommarberg

The use of antidepressants in young women has increasedTimo Klaukka

The use of antihypertensives in Finland in 2004Terhi Helmiö

TABU 4.2006

14. vuosikerta14 årgången14th Annual volume

In English

På svenska

EEditorialditorial

ADR NewsADR News

Drug useDrug use

50

51

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55

56

57

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TABU 4.2006 50

Pekka KurkiHead of SectionMarketing AuthorisationNational Agency for Medicines

In English

Biological, especially biotechnology-derived medicinal prod-ucts, have enjoyed very high success during recent years. Sev-eral rare diseases have, for the first time, been managed witheffective therapies, and significant progress has been made inthe treatment of many common diseases. The developmentof gene and cell therapies and tissue engineering productshas reached the stage where therapeutic breakthroughs are tobe expected in the next few years.

The development and introduction into use of therapiesbased on new mechanisms of action and technologies arealways associated with uncertainties. The drug regulatoryauthorities are continuously struggling to find a balancebetween the application of the most recent achievements inscience and technology and ensuring the safety of patients.Excessive boldness may eventually cause safety problems, butthen again excessive cautiousness and an urge towards self-protection will slow down development and delay the intro-duction of new therapies.

The European Medicines Agency (EMEA) and its Com-mittee for Medical Products for Human Use (CHMP) are inthe forefront of regulation of the recent biotechnology-derived medicinal products. The authorities are making aneffort to keep up with ongoing developments in science andtechnology. The experts of EMEA and CHMP, in collabora-tion with the pharmaceutical companies and scientificorganisations, are at present examining ways to facilitate theintroduction of new innovative medicinal products on to themarket (Innovation and Drug Development in Europe,“Innovation Think Tank”). As set out by its strategy, NAMhas been active in this and other development programmesfocusing on the development and regulation of biologicalmedicinal products. The experts of NAM have become res-olutely engaged in solving current topics in their area, suchas similar biological medicinal products, nanoparticles acti-

vated in the cells, and the use of autologous cells for varioustherapeutic purposes.

These complicated issues typically relate to new spheresof science and technology of which the drug regulatoryauthorities have no previous experience, or to areas whichfall in between the different regulatory sectors (e.g. combina-tions of medicines and medical devices). In those sectors ofinfluence within the EU in which it has chosen to be a part,NAM relies heavily on its national networks of experts. Theassignments of expertise within NAM provide an opportuni-ty for university and hospital experts to familiarisethemselves with the technical and clinical applications oftop-level research before they become public. For NAM, thisopens up an opportunity to get a balanced overall view ofthe complicated and novel innovations.

Drug development is able to be tracked down easily fromits very first stages up to the evaluation of the application formarketing authorisation. The risk management of new ther-apies can be developed by making use of and combining var-ious health care registers. In Finland, for example, it is possi-ble to carry out extensive epidemiological studies into theeffects of modern vaccines. Well organised post-marketingsafety surveillance benefit both the patients and the drugdevelopers, allowing safe introduction into use of newbiotechnological medicinal products.

The pharmaceutical industry which develops biologicalmedicinal products is in the forefront of innovations alongthe route staked out by primary research. The risks, bothfinancial and those relating to drug safety, are high. Success-ful outcomes naturally lead to success stories about medicaltherapies and hence to continued investments in research bydrug companies. NAM offers the companies the best possi-ble scientific and administrative advice in support of the suc-cess stories, without haggling over safety.

The development of biological medicinal products:innovations and regulation

Drug treatment has an aim the dis-pense the correct drug in the correctdose to the correct patient via the cor-rect route of administration and at thecorrect time.

The viewpoint traditionally takenin health care is that errors will notoccur and must not occur. The confi-dence in the health care staff ’s faultlessoperation has been high. Nevertheless,the fact that there are deficiencies inthe safety and quality of health care isgradually coming to be understood.

In the United States discussionabout patient safety was triggered by areport by the Institute of Medicine(IOM), ‘To err is human’ (IOM2000). According to the report, anestimate of 44,000–98,000 patients dieand over a million suffer injuries everyyear as a result of a treatment error. Ofthese deaths, 7,000 have been associat-ed with medication errors. Finland hasparticipated in the work of experts inthe Council of Europe with the aim offormulating recommendations in orderto improve the safety of patients andtheir medication.

A medication error is defined as anevent associated with a drug therapywhich can lead to a risk and whichmay be caused by something that hasbeen done, or been ignored, or by safe-ty measures that failed. A medical errorcan occur at any stage of the drugtherapy and treatment, and at anytimebetween the prescribing and dispensingand the administration and follow-up(National Coordinating Council ofMedicat-ion Errors and Prevention,NCC MERP 1998). A dispensingerror is considered to have occurredwhen the strength, dosage, pharmaceu-tical form or a dosage of a medicinalproduct dispensed by a pharmacy dif-

fers from that prescribed by the doctor.A dispensing error has also occurred ifthe drug dispensed is outdated,supplied with inadequate or incorrectinstructions and labelling, or if thedrug is manufactured, packed or storedincorrectly before dispensing from thepharmacy.

The survey was carried out bysending a questionnaire to all privatemain pharmacies in Finland (n=599)in March 2005. The questionnaire wascompleted by over a half (n=340) ofprivate main pharmacies in Finland(response percentage 57%).

Prevalence of dispensingerrors

The pharmacies were requested to statethe number and type or evaluation ofany dispensing errors recorded in 2004(Savikko 2006). Of those completingthe questionnaire, 66% reported thedispensing errors recorded and 31%gave their evaluation of them. Thepharmacies had recorded a total of1,955 dispensing errors, (8.7 errors perpharmacy) during 2004. The estimatednumbers of dispensing errors were alsoclose to the published numbers, anaverage estimate of 8.4 errors per phar-macy. The frequency of errors fromprescriptions was one per 6,000prescriptions. According to the phar-macies, not all errors are recorded andsome pharmacies do not record themat all. The most common dispensingerrors consisted of incorrect strengths,packet sizes and pharmaceutical forms.

Causes and prevention of dispensing errorsDispensing errors are caused by factorsassociated with the working environ-ment, the nature and actions of phar-macists, the prescriptions, the drugsand the patients. The most commonindividual causes were considered to beshortage of time, ambiguous or inaccu-rate prescriptions, carelessness on thepart of the pharmacist, and similaritiesbetween packages. Ambiguous andinaccurate prescriptions were the resultof obscure handwriting, obscure notesincluding e.g. abbreviations andrenewals, and inaccurate notes, forinstance regarding computerised pre-scriptions or therapeutic indications.

The survey participants consideredthat the dispensing errors fromprescriptions could mostly be prevent-ed by carefulness, concentration, accu-racy and attentiveness on the part ofthe staff at all stages of the process,calm and undisturbed workingenvironment, wider introduction ofcomputerised prescriptions, adequatenumbers of staff, and discussing thedispensing errors that have occurredwith the staff.

Handling of dispensing errors

The majority of the survey participants(59%) had written instructions for thehandling of dispensing errors. Most ofthe participants (89%) said their phar-macy would always reimburse theclient for any error, and the rest (11%)also said they would nearly always doso. Dispensing errors are always ornearly always recorded by 76% of thepharmacies in the survey. The record-ing was almost as often made anony-mously. Dispensing error cases are

51 4.2006 TABU

Virpi Savikko Tuula Teinilä Marja AiraksinenM. Sc. (Pharm.) M. Sc. (Pharm.) ProfessorSomeron apteekki Oulunkylän apteekki University of Helsinki

In English

To err is humanA survey of dispensing errors made by pharmacies in Finland

more often discussed with the individ-ual involved rather than jointly withthe staff.

Most of the survey participantsemphasised the importance of record-ing the errors and discussing the casejointly with the staff. According to thesurvey participants, this would make iteasier to follow the possible causes ofthe errors and to discuss openly waysto reduce errors. Suggested ways ofhandling the errors included principal-ly a rectification of the error and reim-bursing the customer, as well as writ-ten instructions for handling of thedispensing errors.

Conclusion

Pharmacies make an effort to take asystematic approach to the handling ofdispensing errors. This is seen, forexample, in the written instructionsavailable in pharmacies and in thereporting practices adopted for errors.In a large number of pharmacies anyerrors that have occurred are recordedand are discussed later jointly by thestaff. The frequency and commonpractice of recording errors could nev-ertheless be improved to achieve amore complete picture of the errorsand near misses that have occurred.The weakness of self-reporting is, infact, under-reporting of dispensingerrors (Ashcroft et al. 2006). A prereq-uisite for reporting errors is being ableto detect them, and preventionrequires identification and recognitionof the errors. Reporting is made easierby an open working community with atendency to discuss rather thanvictimise. Self-reporting has been seento be a cost-effective method for fol-lowing up dispensing errors, and theonly method suitable for continuoususe (Chua et al. 2003).

Previous surveys have indicatedpharmaceutical advice as playing a partin the detection and prevention of

errors in dispensing (Abood 1996). Asa last resort, pharmaceutical adviceensures that the correct drug isdispensed to the correct customer.According to one survey, as many as83% of dispensing errors can bedetected and adjusted as a result ofpharmaceutical advice before thewrong medicine reaches the customer(Ukens 1997).

Pharmacies are also carefullypreparing themselves to use a nationalreporting system of dispensing errors.Reporting systems are in use in, forexample, the USA, UK and Denmark.

The experience of pharmacists isthat the dispensing errors are mostlydue to the nature of the individualrather than the operation of the entireworking community. Emphasis amongthe causes and preventive factors forthe errors was laid on the individual’scharacter, such as carefulness and abili-ty to concentrate. There are two differ-ent approaches that can be taken toerrors committed by humans; one ofthem concentrates on the individualand the other on the system (Reason2000). The approach concentrating onthe system emphasises the organisationand the circumstances in which theindividual works (DH 2000). Thisapproach takes into account the factthat humans make mistakes and errorsare possible. They are seen as resultsrather than causes, while their originlies in the system rather than in theindividual.

The collaboration betweenpharmacies and prescribers could befurther improved. Pharmacies shouldavoid excessive interpretation ofprescriptions in ambiguous cases andcontact the doctor to check prescrip-tions and to ensure patient safety.

The customer was also consideredto play an error-promoting role, with ahurried or unusual behaviour and alarge number of prescriptions. Creat-ing undisturbed and calm conditions

for mechanical checking of drug dis-pensing was seen as a solution.

LiteratureAbood R: Errors in Pharmacy practice. USPharm 21 (3), 122-132, 1996

Ashcroft DM, Morecroft C, Parker D,Noyce PR: Likelihood of reporting adverseevents in community pharmacy: an experi-mental study. Qual Saf Health Care 15:48-52, 2006

Chua SS, Wong ICK, Edmondson H, AllenC, Chow J, Peacham J, Hill G, Grantham J:A Feasibility Study for Recording of Dis-pensing Errors and ‘Near Misses’ in FourUK Primary Care Pharmacies. Drug Saf26(11):803-813, 2003

Department of Health (DH): An organisa-tion with a memory. Report of an expertgroup on learning from adverse events in theNHS chaired by the Chief Medical Officer.London 2000. 29.4.2005,www.dh.gov.uk/assetRoot/04/06/50/86/04065086.pdf

Institute of Medicine (IOM): To Err Is Hu-man: Building a Safer Health System. Toim.Kohn L.,Carrigan J., Donaldson M, Nation-al Academy Press Washington DC 2000

National Coordinating Council of Medica-tion Errors and Prevention (NCC MERP).Taxonomy of Medication Errors, 1998.15.9.2004, http://www.nccmerp.org/pdf/taxo2001-07-31.pdf

Reason J: Human error: models and man-agement. Brit Med J 320: 768-770, 2000

Savikko V: Oikea lääke oikealle asiakkaalle -apteekkien toimitusturvallisuus. Pro gradu-tutkielma, sosiaalifarmasian osasto, far-maseuttinen tiedekunta, University of Helsin-ki, 2006

Ukens C: Deadly dispensing: an exclusivesurvey of Rx errors by pharmacists. DrugTopics March 100-11, 1997

TABU 4.2006 52

In English

The Poison Information Centrereceives 40,000 telephone inquiriesevery year, 30,000 of which concernacute poisoning in humans. An averageof 200 of these telephone inquiriesrelate to medication errors that haveoccurred in health care.

A survey was carried out of thetelephone inquiries received by thePoison Information Centre betweenJune 2000 and December 2005 inwhich the cause was either a medica-tion error or a suspected medicationerror in humans. The use of an incor-rect drug, dose or route of administra-tion by a health care professional wasconsidered a medication error.

Findings

There were a total of 150,036 inquiriesabout acute poisoning during the sur-vey period, 852 (0.6 %) of which wereabout medication errors. Fifty percentof those in whom medication errorhad occurred were women and 37%were men. The sex was not reported in12% of the cases and 1% of theinquiries concerned more than onepatient. There were three main types oferrors (Figure).

The majority of the medicationerrors reported occurred in the medica-tion of children under 10 years of ageand the elderly between 80 and 89years of age. The youngest patient wasone day old and the oldest 99 years ofage. The majority of calls were fromthe Province of Southern Finland(56%). The location where the medi-cation error had taken place was usual-ly registered when the call was madefrom a health care unit. It was never-theless not known in many cases,

because the patient had already beenmoved to a health centre or hospital,and contact was made from there.

The medication error was usuallydetected quickly, and calls to the Poi-son Information Centre regardingseverity and necessary measures weremade rather soon after the incident. Atotal of 562 (66%) of the inquirieswere received within less than onehour from the incident. Incorrectdoses were repeatedly administered to61 patients (7%). Every year the num-ber of inquiries has peaked in the sum-mer months and in December, whenthe number of permanent staff is lowerand the number of temporary replace-ments higher than usual.

Incorrect drug

A total of 507 calls concerned theadministration of an incorrect medica-

tion, where it was usually a question ofadministering a drug to the wrongpatient.

The majority of cases of an incor-rect drug having been administeredoccurred in nursing homes or responsi-ble care units for the elderly, for thementally retarded and for dementiapatients. The largest age group was the80- to 89-year-olds, who made up19% (94 patients) of the total.

The majority of the inquiries wereabout drugs with a central nervous sys-tem effect (61%), drugs with an effecton the cardiovascular system (15%),and drugs with an effect on thealimentary tract and the metabolism(6%). The most common medicinalsubstances concerned included carba-mazepine, sodium valproate, clozapine,risperidone and lorazepam. Sixty-sevenpercent of the calls concerned medica-tion errors involving 1–3 drugs at the

53 4.2006 TABU

In English

Pia KuismaB. Sc. (Pharm.)

Kalle HoppuChief Physician

Poison Information Centre

Medication error inquiries in the Poison Information Centre

Väärä lääke

59 %

Väärä annos

35 %

Väärä antoreitti

6 %

Incorrect route of administration, 6%

Incorrect dose,35%

Incorrect drug,59%

Types of medication errors (n=855)

In English

same time; in 33% of the cases thenumber of drugs erroneously used wasbetween 4 and 13.

Incorrect dose

Enquiries were made in 299 callsabout the administration of an incor-rect dose or a dose with an incorrectstrength. The majority of these alsooccurred in nursing homes or responsi-ble care units for the elderly, for thementally retarded and for dementiapatients.

The incorrect dosages administeredwere mostly to patients under 10 yearsof age (24%), usually in hospital, atthe pharmacy, or in association withvaccination. There were 8 newborns,all of whom were incorrectly dosed inhospital. Five of these infants hadreceived an overdose which was 10times the required dose.

The groups of therapy mostfrequently enquired about includeddrugs with a CNS effect (71%),systemic anti-infectives (19%), andcardiovascular drugs (17%). The mostcommon drugs included vaccines,sodium valproate, carbamazepine,paracetamol and lamotrigine. Almost80% of the inquiries concerned incor-rect dosage of one medicinal substance.

Incorrect route of administration

Forty-nine of the calls concerned caseswhere an incorrect route of administra-tion had been used. The calls wereusually made from hospitals, with themajority of them concerning adults.The largest age groups were the 80- to89-year-olds (11 calls out of 49) andunder 10-year-olds (8 calls out of 49).

The groups of drugs about whichqueries were most frequently raisedincluded systemic anti-infectives

(30%), drugs with a CNS effect (22%)and drugs used to treat respiratory dis-eases (8%). In most cases the drug hadbeen inadvertently administered viathe intravascular (38%), oral (10%) orintramuscular route (8%). The mostcommon incorrect routes of adminis-tration included the intravascularadministration of drugs intended forintramuscular or oral administration.

Inquiries concerning pharmacies

Seventeen (2%) of the 852 calls intotal were cases where a prescriptionerror was suspected of having occurredin the pharmacy. The ages of thepatients varied between 6 months and90 years: the under 16-year-olds num-bered 11, the 16- to 75-year-olds 3,and the over 75-year-olds 2 (in onecase, the age was unknown). Calls werereceived from the public (10), thepharmacy (6) and the physician (1).

The patient instructions suppliedwith the drugs included 7 cases ofincorrect dosage instructions, and anincorrect strength of the drug was sup-plied by the pharmacy on 10 occa-sions. In one case medicine was dis-pensed incorrectly in the drug dis-penser, and in the other case bothincorrect strength and dosage instruc-tions were supplied. The majority ofinquiries made were about antimicro-bials, cough medicine and antihista-mines.

Even though errors of this type canin the worst scenario have severe con-sequences, the medicines about whichqueries were made were nevertheless ina large number of cases fairly risk-free.The Poison Information Centrerecommended follow-up at home for15 patients, and two patients wereconsidered to need treatment by aphysician.

Symptoms and treatment

Of the total of 852 patients in the sur-vey 77% were symptom-free at thetime of the call, probably owing to thefact that the call was made not longafter the erroneous administration andbefore any symptoms had developed.No information is available about thesymptoms the patients possibly mani-fested later and the treatment they mayhave required. The longer the timethat had passed since the incident, thehigher the number of inquiriesconcerning patients with symptoms.About 75% of the patients couldremain in follow-up treatment athome, and 25% were recommendedfor treatment at a health centre or hos-pitalisation.

Conclusions

The statistics of the Poison Inform-ation Centre include telephone inquir-ies spontaneously received about casesof medication error or poisoning.

The majority of inquiries receivedby the Centre concerning erroneousmedication relate to a normal dose ofmedicine being given to the wrongpatient. The error usually occurs in anursing home for the elderly to apatient with several primary diseasesand on several drug therapies. Even ifit is a drug dose intended for a patient,it may in another patient cause unex-pectedly strong symptoms and even befatal.

When an accident occurs it isimportant to act immediately andestablish whether the situation requiresany treatment measures. Informationabout risks involved with medicinesand their dispensing should also beincreased, especially among staff work-ing in in-patient wards, nursing homesor responsible units.

TABU 4.2006 54

55 4.2006 TABU

My patient is a 54-year-old officeworker, with asthma as her primarydisease since 1987. For the treatmentof her asthma the patient has for yearsused Seretide 25/250 mg 2 x 2, theo-phylline prolonged-release tablet 200mg in the evening, tiotropium inhala-tion powder 18 microg 1 x 1 and, asnecessary, salbutamol inhalation 100microg. On diagnosing asthma in1995, prick tests showed positive reac-tions to epithelia from cats and guineapigs. The patient had suffered fromatopic dermatitis in childhood.

During her working life the patientsuffered from recurrent bronchitis andsinusitis, which were often treated withcourses of antibiotics. These usuallyincluded doxicycline and cefalexin, afew times also azithromycin and onceroxithromycin and a course of cefurox-ime. In November 1998, after a courseof azithromycin, the patient experi-enced a short-term facial rash of theurticaria type. The course was givenduring a dark season. But a course ofazithromycin given later on did notcause a rash.

A 7-day course of telithromycin forthe treatment of bronchitis was startedat the beginning of April. On the sec-ond day of the course, an itching, ery-thematous, small papular rash develop-ed on the light-exposed areas of theface, neck and upper chest, and theback of the metacarpal area and thearms. The itch was intense, even dis-turbing night-time sleep. The patientcontinued using telithromycin for aperiod of 5 days. She did not use othermedicines, except for her anti-asthmat-ic agents.

I met my patient at the beginningof May and prescribed hydrocortisone-17-butyrate cream, saline baths andcetirizine 10 mg 1 x 1 for thetreatment of the rash. A week later thepatient told me that the rash had abat-ed, there was no itching or redness,but that some scaling remained.

Certain cosmetic preparations havecaused irritation of the skin, but noepicutaneus tests have been carriedout. From then on, the patient onlyused the basic ointments which usuallydid not cause a problem.

My observation of an adverse drug reaction

Telithromycin and photodermatitis

In English

Leena SavolainenDermatologist ADR NewsItä-Suomen Lääkärikeskus

Since 1973, the adverse drug reac-tion register of NAM in Finlandhas received 107 reports of photo-sensitivity cases. There are no fur-ther reports associated with theuse of telithromycin; andazithromycin, one of theantibiotics of the macrolide group,has been reported on twice.Azithromycin is the onlymacrolide, the SPC of whichmentions photosensitivity as anadverse reaction (albeit rare).

The majority of reports onphotosensitivity have concernedproducts containing a thiazidediuretic (14 reports) and tetracy-clines (13 reports, 7 of which wereon doxicycline). Products contain-ing ketoprofen have been reportedon 8 times in total (7 of whichconcerned the topicalpreparation), and piroxicam 6times (all of them concerning theoral preparation). Preparationscontaining sulpha have beenreported on 6 times (on 4 ofwhich the trimethoprim combina-tion product was concerned), andamiodarone has been reported on4 times. These reports serve as agood account of the spectrum ofdrugs known to cause photosensi-tivity.

Annikka Kalliokoski

TABU 4.2006 56

From 1998 to 2005 the adverse reac-tion register of NAM in Finlandreceived a total of 396 reports ofadverse reactions associated with anti-depressants. Of these, 268 concernedwomen and 126 men. Two reports didnot mention the sex. The Figure repre-sents the number of reports categorisedinto age groups.

The number of reports accordingto the category of the active ingredientare presented in the Table. The reportmay involve more than one suspecteddrug, and therefore the number of sus-pected drugs is higher than that of thereports. Equally, one report mayinclude one or more symptoms.

A total of 170 reports were receivedon the selective serotonin re-uptakeinhibitors (SSRIs), the majority ofwhich were on sertraline (51), citalo-pram (44) and paroxetine (27). Abouta third of the cases related to variousadverse reactions involving the nervoussystem (including headache, dizziness,tics, seizures, dysaesthesia, sleep distur-bances, hallucinations, confusion).Adverse reactions relating to the skinand the digestive organs (nausea,abdominal pain, diarrhoea) and oede-

ma were also common. Intentionaloverdose was reported on 8 cases. Sero-tonin syndrome was mentioned in fourreports, two of which were in associa-tion with an interaction and one withan overdose. There were also 11reports about withdrawal symptoms.

Also most of the adverse reactionsassociated with the use of mirtazapine,venlafaxine and reboxetine involvedthe nervous system. Adverse reactionsassociated with the use of mirtazapineincluded seizures (12 reports) and rest-less legs (6 reports); others were e.g.dizziness, tremor and headache. Vari-ous adverse reactions associated withthe skin were also reported, besidesedema; a total of 12 reports werereceived on various degrees of leucope-nia. Oral adverse reactions were report-ed on 12 times, four of whichconcerned stomatitis.

The most common nervous systemadverse reaction associated withvenlafaxine was dizziness. A total of 4reports were received on the serotoninsyndrome, and 5 on withdrawal symp-toms. There were also 4 reports on theprolongation of the QT interval. Ofthe 15 reports on mianserin, 8 ment-

ioned agranulocytosis/granulocytope-nia.

There were a total of 21 adversereactions involving 15–19-year-oldadolescents (16 women and 5 men).The adverse reactions manifested inthis age group were of the same type asthose in older age groups. Intentionaloverdosing was reported on three occa-sions. Reports on complicationsinvolving the newborn totalled 7, all ofthem on the SSRI drugs. Some of thecomplications involving the newbornhave been recorded in the mother’sreport. Symptoms in the newbornincluded, for example, somnolence,seizures, breathing and eating difficul-ties.

Adverse reactions due to antidepressants

In English

Annikka Kalliokoski ADR NewsSenior Medical Officer

Leena SommarbergResearcher

PharmacovigilanceNational Agency for Medicines

Adverse reactions due to antidepressants from 1998 to 2005

Number of reports

Tricyclic antidepressants (e.g. amitriptyline) 7

Selective serotonin re-uptake inhibitors (SSRIs), total 170sertraline 51citalopram 44paroxetine 27fluoxetine 22escitalopram 18fluvoxamine 8

Others, total 227mirtazapine 106venlafaxine 53reboxetine 20milnacipran 15mianserin 15moclobemide 9duloxetine 5trazodone 4

0

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10

15

20

25

30

35

40

0-4yrs

5-9yrs

10-14yrs

15-19yrs

20-24yrs

25-29yrs

30-34yrs

35-39yrs

40-44yrs

45-49yrs

50-54yrs

55-59yrs

60-64yrs

65-69yrs

70-74yrs

75-79yrs

80-84yrs

85-89yrs

90-94yrs

Ikä

Number

Women Men

57 4.2006 TABU

In English

Timo KlaukkaResearch ProfessorSocial Insurance Institution

The use of antidepressants in young women has increased

The consumption of antidepressantstook an upward turn in Finland andother Western countries at the end ofthe 1980s, i.e. after the introduction ofgroup SSRI drugs with a new mecha-nism of action. According to the salesrecords of medicinal products of NAMin Finland, the consumption hadincreased seven-fold in 2005 comparedwith the year 1990. The Social Insur-ance Institution statistics for refundsshow that 328,000 individuals, or6.3% of the population, werereimbursed for these drugs last year.The proportion of women was 7.8%and of men 4.6%.

In 2005, a great regional variationin the use was seen (See map on page18). The use was most common inPohjois-Savo, where the proportion ofthe population using these drugs

reached over 7%. The next largest pro-portions were found in Pohjois-Karjalaand Varsinais-Suomi. The consump-tion was smallest in the hospitaldistricts of Länsi-Pohja and Lappi,where it was about 5%. The highestfigure for consumption in the health-care centre districts was found atHyrynsalmi, 9.2%, while Heinävesiand Rautavaara also nearly reached thelevel of 9%.

Citalopram is the mostcommonly used

The antidepressant most commonlyused in Finland ever since the firstyears of the 1990s has been citalo-pram. The number of people receivinga refund for it in 2005 was 99,000.Mirtazapine was the next most

commonly used, with 64,000 peoplereceiving a refund, and escitalopramcame in third place with 49,000 recipi-ents of a refund. Among the old anti-depressants, amitriptyline was the mostfrequently used with 19,500 recipientsof a refund, while 11,500 people hadused doxepin. A proportion of theconsumption of amitriptyline mayhave been for the treatment of chronicpain.

Prices reduced through generic substitution

The end of patent protection hasintroduced several importantantidepressants into the generic substi-tution sector. This is shown in thestrong decrease in their consumer spe-cific costs (Fig. 1). Among the drugs

0

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IV/02 I/03 II/03 III/03 IV/03 I/04 II/04 III/04 IV/04 I/05 II/05 III/05 IV/05

Euroa

VenlafaksiiniEssitalopraamiMirtatsapiiniSertraliiniParoksetiiniSitalopraamiFluoksetiiniAmitriptyliini

Venlafaxine

Escitalopram

Mirtazapine

Sertraline

Paroxetine

Citalopram

Fluoxetine

Amitriptyline

Fig. 1. The costs of antidepressants per user during three months between October 2002 – December 2005

Euros

TABU 4.2006 58

mostly used, only venlafaxin and esci-talopram have retained a relatively sta-ble cost level. Citalopram, paroxetineand fluoxetin in particular have beenat the centre of tough price competi-tion, and certraline was targeted byprice competition during 2005. Mir-tazapine is already also available as anumber of generic products, and itsaverage cost level has started on adownward trend. Calculated per con-sumer, the cost of the most commonlyused antidepressant, citalopram, wasless than a fifth of that of the mostexpensive one, venlafaxine.

As a result of the price competit-ion, the cost of antidepressants in out-patient care has decreased in the lastcouple of years. In 2002, i.e. before thegeneric substitution, the total costs ofthis drug group amounted to 80 mil-lion euros, whereas the correspondingfigure last year was 65 million.

The use is most frequentamong the elderly, while adolescent use has beenincreasing

Last year the frequency of use variedgreatly by age group. The consumptioncurves had two peaks, i.e. 50 to 59-year-old patients used these drugsmore commonly than the nextyounger and older age groups. The sec-ond, and at the same time higher, peakwas found among the over 85-year-

olds. Among the female patients thefrequency of use was 1.7 fold that ofthe 70 to 74-year-olds. On anotherstudy, the consumption was found tobecome frequent up until the age ofabout 90 years.

Special attention has recently beenfocused on the use of antidepressantsby children and adolescents, becausethis is considered to be associated withself-destruction. From 1998 to 2005the proportion of 15 to 19-year-oldwomen receiving refunds for anti-depressants has nearly trebled, and inmen in that age group it has doubled(Fig. 2). Consumption in the groupsyounger than this has clearly beenrarer, nor has it become generalised.The difference between the sexes in thefrequency of use in 15 to 19-year-oldshas been relatively wide for the wholeperiod reviewed, and men have onlynow reached the level at which youngwomen already were in 1998.

Review

The use of antidepressants has beenunder lively discussion for as long astwo decades. Concern has beenexpressed about the rapid increase intheir use, while it is also consideredthat prevanlence of depression hasincreased and a proportion of thedepressed has been left without med-ical treatment. According to a Health2000 study in Finland, about 7% of

adults aged 30 years and over sufferedfrom a severe state of depression. Theproportion of antidepressant users inthe population shown in the statisticsis therefore of the same magnitude asthe prevalence of severe depression.This, however, does not reveal whetherthere are any false positives among theusers, or how many of those in need oftreatment have been left without it.The number of elderly among theusers in particular is essentially higherthan the prevalence of severedepression in the group would necessi-tate.

The use of antidepressants hasincreased in recent years relativelyrapidly among the 15 to 19-year-olds,and among women of the age group inparticular. Reports of self-destructionassociated with the use of antidepres-sants in this age group have beenreceived recently to such a degree thatwarnings about it have been added inthe patient information leaflets of sev-eral drugs. Careful monitoring of theeffect of these warnings on thetreatment practices during the currentyear is recommended.

In English

0

5

10

15

20

25

30

1998 1999 2000 2001 2002 2003 2004 2005

Women aged 15-19 years Men aged 15-19 years

Fig. 2. The frequence of the use of antidepressants among 15–19 year old women and men in Finland1998–2005

59 4.2006 TABU

In 2004, 499,658 people with chronichypertension, 194,369 with coronaryartery disease and 64,135 with cardiacinsufficiency were entitled to a specialrefund of the price of their medication.Some of these people enjoyed severalentitlements to a refund (1).

The main group of drugs used inthe treatment of hypertension includesdiuretics, beta-blockers, calcium chan-nel blockers, ACE inhibitors andangiotensin receptor antagonists,which all have an approximately equalhypotensive effect (2). A combinationof two or more drugs is needed in overhalf of the patients to achieve the treat-ment target (3). Beta-blockers were themost commonly used antihypertensives(either alone or in combination) in thestudy by Rantanen et al. (4). The useof diuretics in Finland is too low inrelation to the efficacy proven and theassociated benefits (4, 5).

The consumption of antihyperten-sives has increased in all the Nordiccountries during 1999–2003. Diureticswere the treatment of choice duringthis period in Denmark and Swedenmore often than in the other Nordiccountries. The use of beta-blockers wasbecoming more common in all theNordic countries, but their consump-tion (DDD/1,000 inh./day) in Den-mark was half that in Finland or Swe-den. In relation to population, theconsumption of combination productsof ACE inhibitors and diuretics washighest in Finland, and the consump-tion of combination products ofangiotensin receptor antagonists anddiuretics highest in Norway (6).

The aim of the study was to estab-lish which antihypertensives were inuse, and how the consumption andcosts of drugs were distributed in Fin-land with regard to income level, edu-

cational level, age, sex, mother tongueand employment status in 2004. Drugtherapies were also reviewed from theviewpoint of the recommended treat-ment in hypertension and some associ-ated diseases (2, 3).

The study was carried out as a reg-ister review based on the data of theSocial Insurance Institution and theStatistical Finland. The study subjectswere randomly chosen among peoplewith special refund entitlement fromthe Social Insurance Institution for thedrugs they used for chronic hyperten-sion (205) and/or chronic coronaryheart disease (206) and/or chronic car-diac insufficiency (201). Theirprescription data were checked and alldrugs classified as antihypertensiveswere included in the study irrespectiveof which of these three special refundentitlements the drugs were assignedto. The study included potassium(A12B), antihypertensives (C02),diuretics (C03), beta-blockers (C07),calcium channel blockers (C08), ACEinhibitors (C09A/C09B) andangiotensin receptor antagonists(C09C/C09D) (7).

Results

The subjects of the study were335,879 individuals on antihyperten-sive therapy. The data were collectedfrom 53% of those with special refundentitlement for antihypertensives,59% of those with special refund enti-tlement for cardiac insufficiency and31% for coronary heart disease during2004.

The use of antihypertensives wasrelatively more common in women, inolder people, in those of Finnishmother tongue, in those with a lowerlevel of education, and in those living

in eastern Finland and small munici-palities, rather than in men, inyounger people, in those of Swedish orother mother tongue, those with ahigher level of education, or those liv-ing in either southern or south-westernFinland and/or in large municipalities.

The most common antihyperten-sive therapies consisted of either abeta-blocker alone and/or a combina-tion product containing it (19%), anACE inhibitor alone and/or a combi-nation product containing it (8%), abeta-blocker together with an ACEinhibitor and/or a combination prod-uct containing it (7%) and a beta-blocker together with a calcium chan-nel blocker and/or a combinationproduct containing it (7%). The use ofACE inhibitors in men under the ageof 65 was slightly more common thanthe use of beta-blockers, whereas thesituation in women was the reverse.The use of calcium channel blockers inmen older than this was relativelymore common, whereas in women theuse of diuretics became more commonwith age.

The groups of antihypertensivesmost commonly used and number ofusers are presented in the Table. Thesubjects had an average of 2 antihyper-tensives in use during the year: 38%were using one, 33% two and 18%three antihypertensives.

The Finnish Treatment recommen-dations for hypertension were fairlywell adhered to in respect of peoplesuffering from coronary heart disease,cardiac insufficiency and diabetes. Ofthe patients who had asthma in addi-tion to cardiovascukar disease 23%used beta-blockers and/or combinationproducts containing them, whereas thepercentage for all the study patientswas 59%. One and a half percent of

In English

Terhi Helmiö Drug useD.Sc. (Tech.), Senior ResearcherPlanning for Pharmaceutical PoliciesNational Agency for Medicines

The use of antihypertensives in Finland in 2004

TABU 4.2006 60

Translation Mervi Moisander

the asthma patients were using a non-selective beta-blocker. According to thetreatment recommendation, however,beta-blockers are usually contraindicat-ed in asthma patients. In compellingcircumstances (such as coronary heartdisease), either as potent a beta-1-selec-tive blocker as possible or a blockerwith an additional beta-2-agonist effectmay be used (2).

The cost of antihypertensives perperson Finland in 2004 was on averageEUR 301. The cost of drugs increasedwith age up to the age of 55–59 years,after which it diminished again. Inrelation to other socio-economic vari-ables, there were no significant differ-ences in the cost of drugs. The annualcosts for individuals using one drugonly were on average EUR 157, forthose using two drugs EUR 313, andfor those using three drugs EUR 430.The costs for antihypertensive drugs indiabetics were higher than in others,an average of EUR 366, owing to thestricter target level of blood pressure in

diabetics and, consequently, theincreased medication.

Conclusion

The use of antihypertensivescorresponded fairly well with the treat-ment recommendations. Beta-blockersand diuretics and/or combinationscontaining them remained the mostcommon antihypertensives. Over a halfof the study subjects used more thanone antihypertensive. Almost one inevery four asthma patients used beta-blockers, which did not comply withthe Finnish Treatment recommenda-tions except under compelling circum-stances (such as if the patient was suf-fering from a coronary heart disease).The prevalence of use differed by sexand age group.

The differences in drug costsbetween individuals were relativelyspeaking highest among those on oneantihypertensive alone. The leastexpensive drugs were the diuretics and

the most expensive ones the angio-tensin receptor antagonists. When sev-eral drugs were used, the costsincreased almost linearly with thenumber of drugs. The annual costs ofantihypertensives for diabetics werehigher than those for others.

Literature

(1) Läkemedelsverket och FPA. Finlandsläkemedelsstatistik 2004. Helsingfors, 2005.(2) Suomen verenpaineyhdistys ry:n asettamatyöryhmä. Kohonneen verenpaineen hoito.Gängse Vård-rekommendationen. Duodecim,2002;118:110-26.(3) Ruskoaho, H. Verenpainelääkkeet –lääkeyhdistelmien käytön perusteet. Duodec-im, 2000;116:2826-30.(4) Rantanen K, Strandberg T, Vanhanen H.Aivohalvausriski verenpainelääkityillä avo-hoitopotilailla. Finlands Läkartidning2005;60:2445-2450.(5) Neuvonen PJ, Tilvis R. Diureetit ovateturivin verenpainelääkkeitä. Finlands Läkar-tidning 2005; 60:2348-2351.(6) NOMESCO, 2004. Medical Consump-tion in the Nordic Countries 1999-2003.Nordic Medico-Statistical Committee72:2004.(7) Läkemedelsverket. Klassificering avläkemedel (ATC) och definierade dygnsdoser(DDD). 2004.

In English

The antihypertensives most commonly used and number of users

Antihypertensive and/or Number of users a combination product

Beta-blocker 197,000

Diuretic 171,000

ACE inhibitor 120,000

Calcium channel blocker 113,000

Angiotensin receptor antagonist 72,000