WHO Drug Information Vol 20, No

WHO Drug Information Vol 20, No. 4, 2006 World Health Organization

WHO Drug Information

Contents Medicines for Tuberculosis ICH efforts to improve processes 267 Emergence of extensively-resistant Anticounterfeiting Taskforce develops tuberculosis 239 strategy 268 Development of new drugs for tuberculosis 240 Regulatory Action and News Bevacizumab approved for lung cancer 271 Safety and Efficacy Issues Risperidone for irritability associated Teratogenicity of antiepileptic drugs 246 with autism 271 Meningococcal vaccine and Guillain New treatment for chronic hepatitis B 271 Barré syndrome 247 Influenza virus vaccine composition: Panama mystery illness traced to 2007 southern hemisphere 272 diethylene glycol 248 Sitagliptin phosphate for diabetes 272 Imatinib and cardiac dysfunction 248 Dronedarone: marketing application Online reporting of adverse reactions 249 withdrawn 273 SSRI-tricyclic antidepressant interaction 249 Repaglidine marketing authorization Telithromycin: hepatic events and extension request withdrawn 273 myasthenia gravis 250 Abetimus marketing authorization Bioglue¨: chronic inflammation 250 request withdrawn 273 Beware the triple wammy! 251 Imatinab mesilate: revised indications 273 Colchicine: safe use is critical 252 Nitrofurantoin: monitor lung function Recent Publications, in long-term use 252 Proton pump inhibitors and interstitial Information and Events nephritis 253 Vigiflow Online for pharmacovigilance 275 Package insert changes 253 Scientific plant names and synonyms 275 Leflunomide and peripheral neuropathy 256 Pharmaceutical inventory control Exetimibe and depression? 256 software 276 Sirolimus: acute rejection in renal Reporting adverse reactions and transplant patients 257 continuing education 276 Safety update for oseltamivir 257 Good governance in medicines Darifenacin hydrobromide for overactive procurement 276 bladder: what advantage? 258 WHO public hearings on innovation and Tigecycline for serious infections 259 intellectual property 277 Pharmaceutical Forum: better information, access and prices 278 Rational Use of Medicines Pharmacy education symposium: multi- The role of prescribed and defined daily disciplinary practice 278 doses in pharmacoepidemiology 261 Pharmaceutical policy analysis Asthma/COPD drugs: PDDs are critical conference in 2007 279 to determining DDDs 261 Final guidance on quality systems 279 Newly-available guidance documents 280 Topics of Current Interest Development of medicines for neonates 265 Proposed International Plan for paediatric essential medicines 265 Nonproprietary Names: 200 African scientists join forces 266 New strategy to fight tropical diseases 267 List 96 281

237 World Health Organization WHO Drug Information Vol 20, No. 4, 2006

Announcement

The 13th International Conference of Drug Regulatory Authorities (ICDRA) will be hosted by the Swiss Medicines Agency SWISSMEDIC in collaboration with the World Health Organization.

The ICDRA will take place in Berne, Switzerland from 16 to 19 September 2008.

Updated information will be provided regularly at: http://www.icdra.ch

http://www.who.int/medicines/icdra/en/index/html

238 WHO Drug Information Vol 20, No. 4, 2006

Medicines for Tuberculosis

Emergence of extensively drug-resistant tuberculosis

Tuberculosis (TB) is generally treated with a course of four first-line drugs. How- ever, if misused or mismanaged, resistance can develop and multidrug-resistant TB has emerged as a serious threat to the success of treatment programmes. Multidrug-resistant TB requires the use of second-line drugs that are less effective, more toxic, and costlier than the first-line isoniazid- and rifampicin-based regimens. With 425 000 new cases of drug resistant TB globally each year, resistance to drugs is a problem that is growing at a rapid pace. Earlier this year, a WHO/US Centers for Disease Control prevention study was published documenting for the first time cases of tuberculosis that are extensively resistant to current drug treatments. Extensively drug-resistant (XDR)TB was identified in all regions of the world. Results of the survey showed that during the period 2000—2004, 20% of TB isolates were multidrug-resistant and 2% were extensively drug-resistant (XDR). XDR TB could cause a future epidemic of virtually untreatable TB. Concerns about the emergence of XDR-TB have been heightened by reports and studies of high mortality rates in HIV-positive people with XDR-TB. This has led to warnings that XDR-TB could seriously threaten the progress being made in countries on TB control and the scaling up of universal access to HIV treatment and prevention.

New anti-TB drug regimens and better diagnostic tests are urgently needed for effective detection and treatment of drug-resistant TB. Using standard drugs to treat XDR-TB without knowing whether there is drug resistance could effectively condemn a patient to death. The emergence of XDR TB, coupled with increased use of second-line drugs, suggests that urgent measures are needed to establish population-based surveillance for resistance and to plan public health responses.

WHO Global Task Force of XDR-TB will not be possible without on XDR-TB launched close coordination between all those At its first meeting in October 2006, a concerned and, in particular, with HIV WHO Global Task Force outlined a series programmes. The Task Force also of measures that countries must imple- provided recommendations on: ment to effectively combat XDR-TB. The Task Force has acted to establish teams ¥ Drug-resistant TB surveillance methods that can respond to requests for technical and laboratory capacity measures. assistance and be deployed at short notice to risk areas worldwide. ¥ Implementing infection control measures to protect patients, health care Along with a call for countries to strength- workers and visitors (particularly those en TB control, it was agreed that control who are HIV infected).

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¥ Access to second-line anti-TB and 6. Accelerate and widen implementation antiretroviral drugs for countries; com- of recommended infection control meas- munication and information-sharing ures in health care settings and other risk strategies related to XDR-TB preven- areas in order to reduce the ongoing tion, control, and treatment including co- transmission of drug-resistant TB, espe- management with antiretroviral therapy. cially among those who are HIV positive.

¥ Research and development of new TB The laboratory definition of XDR-TB was drugs, vaccines and diagnostic tests. confirmed as: resistance to at least rifampicin and isoniazid from among the ¥ Management of XDR-TB suspects in first line anti-TB drugs in addition to high and low HIV prevalence settings. resistance to any fluoroquinolone, and to at least one of three injectable second- ¥ Accelerating access to rapid tests for line anti-TB drugs used in TB treatment rifampicin resistance, to improve case (capreomycin, kanamycin, and amikacin). detection of all patients suspected of multidrug-resistant TB (MDR-TB) so Future meetings are also planned on that they can be given treatment that is XDR-TB, including development of as effective as possible. Rapid diagno- urgently needed new diagnostics, drugs sis is potentially life saving to those who and vaccines, and implications of antiret- are HIV positive. roviral therapy for HIV patients.

Task Force members contine to coordi- References nate with national and international 1. World Health Organization. Press Release. partners involved in TB and HIV preven- 17 October 2006 http://www.who.int/ tion, care and treatment to take the mediacentre/news/notes/2006/np29 recommendations forward. They have 2. Addressing the threat of tuberculosis. also developed a plan to identify re- Weekly Epidemiological Record, 2006;81:386 sources required to implement outcomes and accelerate the overall emergency 3. Emergence of Mycobacterium tuberculosis response. The Task Force also recom- with extensive resistance to second-line mends that national TB Programme drugs. Mortality and Morbidity Weekly Report, priorities should focus on: 2006, 55(11);301Ð305 1. Adherance to WHO Guidelines for Programmatic Management of Drug Development of new drugs Resistant TB. for tuberculosis

2. Improve MDR-TB management condi- An analysis of the current drug pipeline tions. for tuberculosis drugs has been published in a recent report by Médecins sans 3. Enable access to all MDR-TB second- Frontières (MSF)* in support of its Cam- line drugs, under proper conditions. paign for Access to Essential Medicines. The analysis shows that greater invest- 4. Ensure all patients with HIV are ad- ment is required to respond to extensively equately treated for TB and started on drug-resistant (XDR) TB emergence and appropriate antiretroviral therapy. * The complete report “Development of new 5. Infection control and protection of drugs for TB chemotherapy” is available at http:/ health care workers with emphasis on /www.accessmed-msf.org/documents/ high HIV prevalence settings. TBPipeline.pdf

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newer drugs will need to be available to trant nature of persistent infections pose patients as soon as possible, with accel- additional challenges to treatment with erated development of those already in currently available anti-TB drugs. The clinical trials. situation is exacerbated by the increasing emergence of extensively drug-resistant Drugs making up the standard TB treat- (XDR) TB. ment regimen were developed in the 1950s and 1960s and the most commonly The Global Alliance for TB Drug Develop- used TB test was developed over a ment (TB Alliance)* has played a critical century ago — it manages to detect TB in role in changing the TB research and only about half of cases. In addition, development landscape and is associated existing TB drugs and tests are even less with approximately half of all compounds adapted for use in people who also have or projects aimed to identify candidate HIV/AIDS. compounds in development. The main MSF considers that to respond to XDR- criteria established by the TB Alliance to TB emergence, WHO will need to get select drug candidates for further devel- newer drugs to patients as soon as opment are: shortening of the current possible by working with regulatory treatment regimen, activity against MDR- agencies and pharmaceutical companies TB, and lack of interactions with anti- to ensure fast-track clinical development retroviral drugs. and availability of new drugs under compassionate use. WHO will also need Among the major advances in basic to promote development of more easy-to- research, molecular and genetic tools use tests and urge major investment into have become available for Mycobacte- research and development to ensure the rium tuberculosis and include targeted availability of newer drugs that can mutagenesis, array-based analysis of shorten and improve treatment. mutant libraries, techniques for conditional gene silencing, and global gene expression profiling. This has led to Current drug pipeline for impressive improvements in the knowl- tuberculosis chemotherapy edge and understanding of the basic With approximately 9 million people biology and physiology of M. tuberculosis. developing active tuberculosis (TB) every year and 1.7 million deaths annually, TB Despite these positive changes there are is far from under control. Human immuno- still problems that need to be tackled. A deficiency virus infection dramatically critical question today is whether increases the risk of developing active progress is sufficient to bring improved tuberculosis and is driving the TB epi- treatment to patients in the next few demic in Africa. HIV renders tuberculosis years. Most importantly, financial support more difficult to diagnose due to higher will need to increase to ensure that any incidence of sputum negative disease, promising new compounds reach clinical and to treat due to interactions and side- development and trial. There will also effects. need to be a sufficient number of promising compounds in the TB pipeline for a The increasing spread of multidrug- broadly effective new treatment combina- resistant TB (MDR-TB) and the recalci- tion to be developed. Many of the com-

* The non-profit Global Alliance for TB Drug Development comprises representatives of governments, nongovernmental organizations, professional organizations, acadaemia, foundations, and industry. http://tballiance.org

241 Medicines for Tuberculosis WHO Drug Information Vol 20, No. 4, 2006 pounds currently in the pipeline are either Novel chemical entities derivatives of existing compounds or they target the same cellular processes as Diarylquinoline TMC207 drugs currently in use. Whilst analogues (Johnson & Johnson) and derivatives are far quicker to develop, Diarylquinoline TMC207 is a promising they may be subject to cross-resistance, member of a new class of anti-mycobac- as has been the case with the new terial agents. The target and mechanism rifamycins and quinolones. of action is different from those of other anti-TB agents implying low probability of Modern technologies and rational ap- cross-resistance with existing TB drugs. proaches to drug design such as creation This is further suggested by the fact that of genomic libraries of M. tuberculosis diarylquinoline TMC207 is able to inhibit conditional knock-out mutants for bacterial growth when tested on MDR-TB comprehensive target identification and isolates. validation, target-based drug discovery, or determination of three dimensional crystal This compound has potent early bacteri- structure of molecular targets, are still cidal activity in the nonestablished infec- weakly implemented. tion murine mouse model, matching or exceeding that of isoniazid. Substitution Even the more promising candidate of rifampicin, isoniazid or pyrazinamide compounds currently in clinical develop- with diarylquinoline TMC207, accelerated ment were identified serendipitously. activity leading to complete culture There is also an urgent need for rational conversion after 2 months of treatment in approaches aimed at tackling the prob- some combinations. In particular, diaryl- lem of mycobacterial persistence. The quinoline /isoniazid/pyrazinamide and adaptations that allow M. tuberculosis to diaryl-quinoline/rifampicin/pyrazinamide persist in the host despite a vigorous combinations cleared the lungs of TB in adaptive immune response likely contrib- mice after 2 months. Diarylquinoline ute to the difficulty in curing TB with TMC207 is currently in phase IIa clinical current chemotherapy. trials.

If faster progress is to be achieved, then Nitroimidazole PA-824 knowledge about M. tuberculosis metabo- (Chiron Corp.-TB Alliance) lism and physiology needs to be trans- Nitroimidazole PA-824 is a new nitro- lated into validated targets that can be imidazole derivative currently being used for screening of new lead com- developed by the TB Alliance. After pounds. The TB Alliance is associated activation by a mechanism dependent on with approximately half of all compounds M. tuberculosis F420 factor, PA-824 acts or projects aimed to identify candidate mainly by inhibiting the synthesis of cell compounds currently being developed. In wall components through molecular order to analyse the pipeline, it is useful targets that are yet to be identified. In to group drug candidates currently in two vitro, PA-824 showed high activity against main categories: drug-sensitive and drug-resistant M. tuberculosis strains, indicating that there ¥ Novel chemical entities. is no cross-resistance with current TB drugs. Moreover, PA-824 exhibited ¥ Compounds originating from existing bactericidal activity against both replicat- families of drugs, where innovative ing and static bacteria in vitro. Although chemistry is used to optimise the PA-824 was significantly more efficient compounds.

242 WHO Drug Information Vol 20, No. 4, 2006 Medicines for Tuberculosis

than isoniazid or moxifloxacin in clearing Pleuromutilins (GlaxoSmithKlineÐ the infection during the continuation TB Alliance Partnership) phase, it was not better than that of a The pleuromutilins represent a novel rifampicin+isoniazid combination. How- class of antibiotics derived from a natural ever, when a 6-month treatment regimen product. They interfere with protein containing PA- 824 in combination with synthesis by binding to the 23S rRNA. rifampicin, isoniazid and pyrazinamide Despite the novelty of this class of com- was tested in mice, the PA-824 containing pounds, recent studies have shown that regimens were superior to the standard cross-resistance might occur among first line regimen in terms of more rapid pleuromutilins and oxazolidinones. reductions of the bacterial burden during treatment and lower rates of relapse after Pleuromutilins have been shown to inhibit treatment. PA-824 entered phase I clinical the growth of M. tuberculosis in vitro. The trials in June 2005. goal of this project is the identification of a pleuromutilin derivative that is active Nitroimidazole OPC-67683 against MDR-TB and allows shortening of (Otsuka Pharmaceuticals, Japan) the treatment schedule. Little information about this compound is publicly available. It belongs to a subclass Dipiperidine SQ-609 (Sequella Inc.) of mycolic acid inhibitors. In vitro, OPC- Dipiperidine SQ-609 is a novel compound 67683 showed high activity against drug- structurally unrelated to existing anti-TB sensitive as well drug-resistant strains. drugs. It kills M. tuberculosis by interfer- No cross-resistance with any of the ing with cell wall biosynthesis (precise current first-line drugs was observed. mechanism unknown). Antimicrobial activity has been demonstrated in vivo in Moreover, OPC-67683 showed strong mouse models. intracellular activity against H37Rv strain of M. tuberculosis residing within human ATP Synthase Inhibitor FAS20013 macrophages and type II pneumocytes. (FASgene) When tested in mouse models for chronic FAS20013 is a novel compound belong- tuberculosis, OPC-67683 showed a 6Ð7 ing to the class of §-sulphonylcarbox- fold higher activity compared to first line amides. The compound is very effective drugs isoniazid and rifampicin. No an- in killing MDR-TB organisms that are tagonist activity could be observed when resistant to multiple drugs currently in OPC-67683 was used in combination with use. A series of recent laboratory experi- currently used anti-TB drugs in vivo. ments indicates the superior effect of FAS20013 compared to current drugs in Pyrrole LL- 3858 (Lupin Limited, India) terms of its ability to “sterilize” TB lesions Very limited information on the develop- and kill latent TB. Therapeutic evaluation ment of pyrroles as antimycobacterial of FAS20013 has repeatedly shown its agents is currently available. Pyrrole effectiveness in mice, and it appears to derivatives were found to be active have no serious side effects. against standard and drug-sensitive M. tuberculosis strains in vitro. Pyrrole Translocase I Inhibitor (Sequella Inc.) derivative LL-3858 showed higher bacte- Translocase inhibitors specifically inhibit ricidal activity than isoniazid when admin- mycobacterial translocase I, an enzyme istered as monotherapy to infected mice. required for bacterial cell wall synthesis. Pyrrole LL3858 is currently in Phase I Preclinical evaluation of the compounds clinical trials. is planned.

243 Medicines for Tuberculosis WHO Drug Information Vol 20, No. 4, 2006

InhA Inhibitors (GlaxoSmithKlineÐ ferase Inhibitors, Methyltransferas inhibi- TB Alliance) tors, and Quinolones. InhA, the enoyl reductase enzyme from M. tuberculosis catalyses the last step in Timeline for development the fatty acid biosynthesis pathway (FAS of candidate drugs II). Frontline anti-tuberculosis drugs such as isoniazid (INH) target this enzyme. Clinical trials to register a TB drug repre- Drug resistance to INH results primarily sent a lengthy and expensive process from mutations in KatG, the enzyme that that can take a minimum of six years, activates INH. Consequently, InhA inhibi- generally longer than for other infectious tors that do not require activation by KatG diseases. The greatest challenge in the are attractive candidates for drug discov- design of TB clinical trials is in Phase III ery. The main purpose for this screen is Trials. These trials are usually large therefore to bypass the activation step scale, randomized clinical trials designed and directly inhibit InhA. A possible to show improvement or equivalent limitation is that cross-resistance with efficacy compared to the standard isoniazid may occur. regimen among diseased patients.

Isocitrate Lyase Inhibitors Efficacy evaluation requires measure- (GlaxoSmithKlineÐTB Alliance) ments of relapse rate during a 1Ð2 year The isocitrate lyase (ICL) enzyme has follow-up after completion of the already been shown to be essential for long-term lengthy 6-month treatment regimen. persistence of M. tuberculosis in mice, Relapse rate after chemotherapy is but not required for bacilli viability in commonly accepted as the endpoint to normal culture or hypoxic conditions. determine the efficacy of a new therapy Inhibition of the two isoforms of isocytrate and to assess whether a new drug lyase present in M. tuberculosis blocks can improve sterilizing activity. Since growth and survival of M. tuberculosis relapse rates under random clinical trial bacteria. conditions are often 3% or less, large numbers of patients are needed to The absence of ICL orthologs in mam- demonstrate an improvement in relapse mals should facilitate the development of rate. This results in high drug develop- glyoxylate cycle inhibitors as new drugs ment costs and long delays in introducing for the treatment for tuberculosis. Such a new medicines. new drug is expected to be able to kill persistent bacteria and therefore have Regulatory agencies require that efficacy sterilizing activity and shorten treatment is demonstrated during phase III trials time. However, the structure of ICL active involving a combination of traditional and site is making the screening for inhibitors surrogate markers for activity. Since the particularly lengthy and laborious. identification of biomarkers could significantly streamline and accelerate clinical Compounds originating from development, the TB Alliance has re- existing families of drugs cently established a collaboration with BG Medicine Inc. to identify biomarkers for Other promising candidate anti-TB drugs drug efficacy in TB treatment. Validated include: Gatifloxacin, Moxifloxacin, surrogate markers of relapse could Diamine SQ-109, Non-Fluorinated provide evidence on the efficacy and the Quinolones, Nitrofuranylamides, Pico- sterilising activity of a drug/regimen linamide Imidazoles, Thiolactomycin without requiring large numbers of pa- Analogs, Dihydrolipoamide Acyltrans- tients.

244 WHO Drug Information Vol 20, No. 4, 2006 Medicines for Tuberculosis

Expected timelines towards approval for new candidate TB drugs

Moxifloxacin

Gatifloxacin

PA-824

Diarylquinoline TMC 207 Pyrrole LL3858

Otsuka-OPC 67683

New drug approvals (NDA)

The current need for large number of References patients recruited for Phase III clinical trials implies the need to conduct trials in 1. Médecins sans Frontières. Development of new drugs for TB chemotherapy: analysis of countries with high TB incidence rates in the current drug pipeline. http://www.access order to ensure that a sufficient study med-msf.org population can be obtained. Phase III infrastructure is, in particular, poorly 2. Gloal Alliance for TB Drug Development. developed and might require additional http://www.tballiance.org coordination, regulatory support and specific funding to overcome gaps.

245 WHO Drug Information Vol 20, No. 4, 2006

Safety and Efficacy Issues

Teratogenicity The North American Pregnancy Registry of antiepileptic drugs found that valproate monotherapy was associated with a 10.7% frequency of Prescribing for women with epilepsy is major congenital malformation. This complicated by the potential terato- represents an increased relative risk of genicity of antiepileptic drugs. Current 7.3 compared with a control group from guidelines recommend that the most one US teaching hospital’s malformation effective drug should be chosen before surveillance programme (6). The US conception and prescribed at its lowest registry had previously reported an effective dose, ideally as monotherapy increased risk of malformation in babies (1, 2). But which antiepileptic drug is exposed to phenobarbital — an impor- safest in pregnancy? An editorial in the tant finding as this antiepileptic drug is British Medical Journal reports on data still widely used in many countries. now available from pregnancy registries set up in the late 1990s (3). The potential for antiepileptic drugs to cause developmental delay in childhood To date, the UK Epilepsy and Pregnancy is even more difficult to measure than Registry has recruited more than 3500 major congenital malformation. A study women, of whom 72% were given anti- (2) found that valproate monotherapy in epileptic monotherapy. The overall rate of pregnancy was associated with de- major congenital malformation in women creased verbal IQ when compared with given antiepileptic drugs during preg- carbamazepine or phenytoin mono- nancy was 4.2% compared with 3.5% in therapy, and that this was dose women with epilepsy who were not given related. such drugs (4). By three months of age, infants exposed to sodium valproate It was also reported that 30% of children monotherapy during gestation had the exposed to valproate needed special highest frequency of major congenital educational support in school, compared malformation (6.2%), confirming similar with 36% of those exposed to mono- findings from an Australian register (5). therapy with other antiepileptic drugs. Lamotrigine monotherapy was associated Similar results were reported in a Finnish with a 3.2% frequency of malformation, study. A further study has, however, but in a multivariate analysis this fre- shown adverse neuro-developmental quency was not significantly different from effects in children exposed to a variety of that seen with valproate monotherapy. antiepileptic drugs during gestation, not The risk with lamotrigine at doses above only valproate. The neurodevelopment 200 mg a day was similar to that of effects of antiepileptic drugs (NEAD) valproate doses of 1000 mg/day. Car- study is currently investigating behav- bamazepine was associated with the ioural outcomes in children exposed to lowest frequency of major congenital antiepileptic drugs in pregnancy malformation (2.2% for monotherapy). (www.neuro.mcg.edu/np/NEAD.htm). Polytherapy with antiepileptic drugs was associated with a significantly higher It remains to be seen whether any of the frequency of major malformation than newer antiepileptic drugs will prove to be monotherapy (6% v 3.7%). less teratogenic.

246 WHO Drug Information Vol 20, No. 4, 2006 Safety and Efficacy Issues

References To date, a total of 15 confirmed cases of GBS among individuals 11Ð19 years of 1. Commission on Genetics, Pregnancy and age occurring within six weeks of vacci- the Child, International League against nation with Menactra¨ have been re- Epilepsy. Guidelines for the care of women of ported to the Vaccine Adverse Event childbearing age with epilepsy. Epilepsia Reporting System (VAERS). Two addi- 1993;34:588Ð9. tional cases have been confirmed in 2. Adab N, Tudur SC, Vinten J, Williamson P, persons 20 years of age and older. At Winterbottom J. Common antiepileptic drugs this time, CDC and FDA cannot deter- in pregnancy in women with epilepsy. mine with certainty whether Menactra¨ Cochrane Database Syst Rev 2004;(3): does increase the risk of GBS in persons CD004848. who receive the vaccine and, if so, to what degree. 3. Editorial. Teratogenicity of antiepileptic drugs. BMJ 2006;333:615Ð616 In October 2005, reports indicating a possible association between Guillain- 4. Morrow JI, Russell A, Gutherie E, Parsons Barré Syndrome (GBS) and meningo- L, Robertson I, Waddell R, et al. Malformation risks of anti-epileptic drugs in pregnancy: a coccal conjugate vaccine (MCV4) ¨ prospective study from the UK Epilepsy and (Menactra ) were made to the Vaccine Pregnancy Register. J Neurol Neurosurg Adverse Event Reporting System Psychiatry 2006;77: 193Ð8. (VAERS). GBS is a serious neurologic disorder involving inflammatory demyeli- 5. Vajda FJ, O’Brien TJ, Hitchcock A, Graham nation of the peripheral nerves. During J, Cook M, Lauder C, et al. Critical relationship March 2005—February 2006, eight between sodium valproate dose and human confirmed cases had occurred within 6 teratogenicity: results of the Australian register weeks (i.e., the time window of elevated of anti-epileptic drugs in pregnancy. J Clin risk noted for GBS after administration of Neurosci 2004;11: 854-8. other vaccines) after MCV4 vaccination. 6. Wyszynski DF, Nambisan M, Surve T, Nine additional GBS cases were reported Alsdorf RM, Smith CR, Holmes LB. Increased to VAERS during March—September rate of major malformations in offspring 2006. Although data suggest a small exposed to valproate during pregnancy. increased risk for GBS after MCV4 Neurology 2005;64: 961Ð5. vaccination, the inherent limitations of VAERS and the uncertainty regarding 7. Holmes LB, Wyszynski DF, Lieberman E. The AED (Antiepileptic Drug) Pregnancy background incidence rates for GBS Registry: a 6-year experience. Arch Neurol require that these findings be viewed with 2004;61: 673Ð8. caution.

References Meningococcal vaccine and 1. FDA MedWatch alert: Menactra¨ (Meningo- Guillain Barré syndrome coccal Conjugate Vaccine A, C, Y, and W135): Posted 10/23/2006. http://www.fda.gov United States of America — The Food and Drug Administration (FDA) and 2. FDA News, P05-66, 30 September 2005. Centers for disease Control ( CDC) have updated an October 2005 alert to con- 3. VAERS at http://www.vaers.hhs.gov sumers and health care providers regard- 4. FDA and CDC Update Information on ing reports of Guillain Barré syndrome Menactra¨ Meningococcal Vaccine and (GBS) following administration of Menin- Guillain Barre Syndrome. 20 October 2006 at gococcal Conjugate Vaccine A, C, Y, and http://www.fda.gov/bbs/topics/news/2005/ W135 (Menactra¨). new01238.html

247 Safety and Efficacy Issues WHO Drug Information Vol 20, No. 4, 2006

5. CDC. Guillain-Barré syndrome among 3. The Evolution of the Abbe Refractometer recipients of Menactra¨ meningococcal _Richard A. Paselk_ http://www.humboldt.edu/ conjugate vaccine—United States, June— index.html, Humboldt State University, Arcata July 2005. MMWR 2005;54:1023—5. CA 95521 at _http://www.humboldt.edu/ %Escimus/Essays/EvolAbbeRef/EvolAbbe 6. Fact sheet for health-care workers on GBS Ref.htm_ and http://www.humboldt.edu/ and Menactra¨ is available at http:// ~scimus/Essays/EvolAbbeRef/EvolAbbeRef. www.cdc.gov/nip/vacsafe/concerns/gbs/ htm menactra.htm. 7. Vaccine Information Statement and fact Imatinib and sheet with information on vaccine and reported GBS cases is available at http:// cardiac dysfunction www.cdc.gov/nip/publications/vis/default.htm. Canada — Recent safety reports have been received on significant left ventricu- Panama mystery illness lar ejection fraction reduction or conges- traced to diethylene glycol tive heart failure and use of imatinib mesylate (Gleevac¨). Imatinib mesylate Panama — Reports have been received is indicated for the treatment of adult of another incident of diethylene glycol patients with Philadelphia chromosome- (DEG) poisoning, this time in Panama. By positive, chronic myeloid leukemia (CML) 29 October 2006, a total of 82 persons — and for the treatment of adult patients including 35 hospitalized and 38 fatal with unresectable and/or metastatic cases — had been affected by acute malignant gastrointestinal stromal tumors renal insufficiency syndrome after using (GIST). suspected products, including topical skin creams and an expectorant syrup without A recently published article in Nature sugar (1). The majority of reports have Medicine reported ten patients treated been of elderly patients. DEG is a highly with imatinib who developed significant toxic organic solvent that can cause acute left ventricular ejection fraction reduction renal failure and death when ingested. In and congestive heart failure (CHF). this case, a material labelled as glycerin Although several of these individuals had purportedly contained a mixture of 1% pre-existing conditions including hyper- glycerol, 25% DEG and 75% unknown tension, diabetes and prior coronary material (1). artery disease, and had received other drugs, they were subsequently diagnosed This is yet another instance in a continu- with CHF. ing litany of DEG poisonings. Although there are a number of high tech methods The same article reports an animal study which can detect contamination or substi- that examined the effects of imatinib tution, purity of glycerol and presence of mesylate on cardiac cells from the propylene glycol can be tested by a mouse. The authors hypothesize that relatively cheap technoogy such as development of cardiac dysfunction may refractometry (2, 3). be related to inhibition of Abl kinase which triggers the stress response in References cardiomyocytes and induces cell death. In 1. Ministerio de Salud, Caja de Seguro Social, addition, recently obtained data from a Panama. Comunicado No. 27, 29/10/2006. pre-clinical carcinogenicity study of http://www.minsa.gob.pa imatinib has demonstrated an incidental 2. Communication from Tom Layloff, Supply finding of cardiomyopathy in rats. Chain Management Systems. tlayloff@pfscm. org

248 WHO Drug Information Vol 20, No. 4, 2006 Safety and Efficacy Issues

While the frequency of reported cardiac estimated that only 1%Ð10% of all ARs events remains less than 1% in the are reported. Health professionals have current prescribing information for identified barriers to reporting that relate imatinib, CHF and left ventricular dys- to the inconvenience and lack of user- function have occasionally been re- friendliness of reporting. The new user- ported. Pending further information on friendly online AR reporting form will this issue, it is recommended that: make the process more convenient and should contribute to increased AR report- ¥ Any patients with known cardiac dis- ing. ease or risk factors for cardiac failure, should be monitored carefully. Reference: Canadian Adverse Reaction Newsletter. Volume 16, Issue 4, October 2006 ¥ Any patient with symptoms or signs suggestive of congestive heart failure SSRI-tricyclic antidepressant should receive timely and thorough interaction evaluation and treatment. New Zealand — Prescribers are re- ¥ In patients with known underlying heart minded of the potential for interactions to disease or in elderly patients, a base- occur when a selective serotonin re- line evaluation of left ventricular ejec- uptake inhibitor (SSRI) antidepressant is tion fraction is recommended prior to co-prescribed with a tricyclic antidepres- initiation of therapy. sant (TCA). Concurrent use of SSRIs can elevate TCA plasma levels 2Ð4 fold, with Reference: Communication from the licence resultant toxicity. holder 21 September 2006 on http://www.hc- sc.gc.ca Reported symptoms include constipation, urinary hesitancy, seizures and delirium Online reporting of adverse (1). Serotonin syndrome is another reactions potential consequence of concurrent therapy. While TCAs and SSRIs can Canada — Health Canada’s MedEffect separately cause serotonin syndrome due Web site has been updated to accept to their serotonergic properties, this risk is online transmittable reports of suspected increased when they are used together. adverse reactions (ARs) to health prod- Serotonin syndrome is a dose-dependent ucts marketed in Canada. Now, in addi- toxic state caused by excess serotonin tion to the previous reporting methods, within the central nervous system and is health care professionals and consumers characterized by mental, autonomic and can submit reports of ARs online. Upon neuromuscular changes. the online submission of a report, the system will generate a file that can be Clinical features include confusion, printed and stored electronically by the agitation, hyperactivity, sweating, tachy- reporter. Information related to the cardia, ataxia, hypertonia and tremor. identity of the patient and the reporter of Prompt withdrawal of the suspect medi- the AR will be protected as per the cines and supportive care are key to the Access to Information Act and the Pri- treatment of serotonin syndrome (2). vacy Act. Extracted from Prescriber Update, Volume 27, Underreporting of ARs is a well-known Number 1, June 2006. at: http://www.medsafe. global issue. International studies have govt.nz/pProfs/PUarticles.htm

249 Safety and Efficacy Issues WHO Drug Information Vol 20, No. 4, 2006

References tant medications. In light of this safety information, the Product Monograph has 1. Tricyclics, SSRIs and antidepressants. In been revised to include the following Stockley IH (Ed). Stockley’s Drug Interactions 6th Edn. 2003: Great Britain, p.845Ð850. recommendations:

2. Hall M, Buckley N. Serotonin Syndrome. ¥ Telithromycin is contraindicated in Australian Prescriber 2003;26(3):62-63. patients with a previous history of hepatitis and/or jaundice associated Telithromycin: hepatic events with the use of this drug. and myasthenia gravis ¥ Telithromycin is contraindicated in patients who are hypersensitive to Canada — Based on information in telithromycin or to any macrolide anti- published case reports and post-market biotic. adverse event reports, the Canadian Product Monograph for telithromycin Physicians and patients should monitor (Ketek¨) has been revised to include for symptoms of hepatitis, such as fa- information on severe and sometimes tigue, malaise, anorexia, nausea, jaun- fatal hepatotoxicity and also includes dice, bilirubinuria, acholic stools, liver updated information regarding syncope tenderness, hepatomegaly, or pruritus. and use in patients with myasthenia gravis. Telithromycin is not recommended for Acute liver failure including fulminant patients with myasthenia gravis. Patients hepatitis and hepatic necrosis leading to should be cautioned about the potential liver transplant or death have been effects of syncope. observed during or immediately after the completion of telithromycin treatment. Reference: Health Canada Endorsed Impor- Exacerbations of myasthenia gravis have tant Safety Information on Ketek¨ (telithromycin). 29 September 2006 at http:// led to death or life-threatening acute respiratory failure with a rapid onset, while syncope, usually associated with BioGlue®: chronic vagal syndrome, has been reported. inflammation Alterations in hepatic enzymes have Canada — BioGlue® is the commercial been commonly observed in clinical name of a surgical adhesive composed of studies with telithromycin. Hepatitis and bovine serum albumin (BSA) and glutar- hepatocellular injury were observed aldehyde (1). The glutaraldehyde mol- infrequently. Most post-marketing cases ecules covalently bond the BSA mol- of hepatic dysfunction were reversible ecules to each other and, upon applica- after discontinuation. However, cases of tion, to tissue proteins at the repair site severe hepatotoxicity, including necrosis, (2). BioGlue¨ was originally licensed for hepatic failure and death have occurred. sale in Canada in 2000 for use in the In some of these cases liver injury repair of acute aortic dissections and occurred after administration of only a pulmonary tissues. In 2003, its indication few doses of telithromycin and pro- was expanded to include the repair of gressed rapidly. The mechanism underly- most other soft tissues. BioGlue¨ is ing severe hepatocellular injury is un- indicated for use as an adjunct to stand- known. Severe reactions, in some but not ard methods of surgical repair (e.g., all cases, have been associated with sutures, staples, electrocautery and serious underlying diseases or concomi- patches) to bond, seal or reinforce soft

250 WHO Drug Information Vol 20, No. 4, 2006 Safety and Efficacy Issues

tissue (1). It may also be applied alone to 2. Furst W, Banerjee A. Release of glutaralde- seal or reinforce damaged parenchyma hyde from an albumin-glutaraldehyde tissue when other procedures are ineffective or adhesive causes significant in vitro and in vivo impractical (1). toxicity. Ann Thorac Surg 2005;79(5):1522-9. Health Canada has received 13 domestic 3. Erasmi AW, Sievers HH, Wolschlager C. Inflammatory response after BioGlue applica- reports of adverse incidents suspected of tion. Ann Thorac Surg 2002;73(3):1025-6. being associated with BioGlue¨ in 2004 and 2005. Seven of the reports described 4. Ngaage DL, Edwards WD, Bell MR, et al. A events consistent with ongoing inflamma- cautionary note regarding long-term sequelae tory processes upon reoperation at sites of biologic glue. J Thorac Cardiovasc Surg where BioGlue¨ had been used months 2005;129(4):937-8. earlier. In 4 of the 7 cases, BioGlue¨ was suspected of contributing to a sterile Beware the triple whammy! discharge or persistent infection. In the other 3 cases, foreign-body reactions Australia — The Australian Adverse Drug were reported that required the removal Reactions Committee (ADRAC) has of BioGlue¨-containing masses at the previously warned prescribers about the surgical site. ‘triple whammy’ — a combination of an ACE inhibitor (ACEI) or an angiotensin II Severe, active inflammation surrounding receptor antagonist (A2RA), a diuretic a BioGlue¨ remnant with multiple granu- and an NSAID (including a COX-2 selec- locytes and histiocytes and a massive tive NSAID), which may predispose foreign-body reaction with numerous vulnerable patients to renal failure (1Ð3). multinucleated giant cells has been Risk factors include advanced age, pre- reported at 3 months after BioGlue¨ existing renal impairment and dehydra- application (3). Intense, focal acute and tion. In 2005, ADRAC received 21 reports chronic nongranulomatous inflammation of renal failure in patients who were has also been observed at a site where exposed to the triple whammy. In a persistent concretions of BioGlue¨ were number of cases, precipitating factors identified 2 years after application (4). included an acute illness, dehydration, digoxin toxicity or the recent addition of Although “inflammatory and immune an NSAID to a patient already on an ACEI response” is listed among the possible or an A2RA and a diuretic. complications in the device labelling, resorption times are not discussed (1) The National Prescribing Service (NPS) and additional long-term studies would has recently released Indicators of help to evaluate these effects (2). The Quality Prescribing in Australian General medical literature suggests that, even Practice: a manual for users, available when BioGlue¨ appears to yield a clear from the NPS website. One of the proc- benefit, it should be used sparingly and ess indicators is entitled Good prescribing its toxic potential should be considered (avoiding the ‘triple whammy’) and (2, 4). reinforces the message that risk of the Extracted from Canadian Adverse Reaction triple whammy should be avoided if Newsletter. Volume 16, Issue 4, October 2006 possible and extreme caution should be taken with ACEIs or A2RAs and NSAIDs References in patients with renal impairment. There are now many combination products 1. BioGlue Surgical Adhesive [Canadian instructions for use]. Kennesaw (GA): Cryolife, available that contain both an ACEI or an Inc.; 2004. A2RA and a diuretic.

251 Safety and Efficacy Issues WHO Drug Information Vol 20, No. 4, 2006

ADRAC advises that prescribers avoid more, it is no longer considered safe or the triple whammy wherever possible. appropriate to continue dosing until However, if these drugs are necessary, gastrointestinal adverse effects occur (1). prescribers should be alert for situations such as illness, dehydration or initiation of Patients should be warned of the symp- an NSAID, which may predispose pa- toms of colchicine toxicity and advised to tients on this combination to renal failure, immediately discontinue therapy and see and advise patients to seek medical their doctor if symptoms occur. advice during such episodes. Extracted from Prescriber Update, Volume 27, Extracted from Australian Adverse Drug Number 1, June 2006. at: http://www.medsafe. Reactions Bulletin, Volume 25, Number 5, govt.nz/pProfs/PUarticles.htm October 2006. References Reference 1. ADRAC, Thomas M. Diuretics, ACE inhibi- 1. Medsafe Pharmacovigilance Team. Colchi- tors and NSAIDs - the triple whammy. MJA cine: Lower doses for greater safety. Pre- 2000; 172: 184-5. scriber Update 2005;26(2):26-27. http:// www.medsafe.govt.nz/profs/PUArticles 2. Boyd IW, Mathew TH, Thomas MC. COX-2 colchdose. htm inhibitors and renal failure: the triple whammy revisited. MJA 2000; 173: 274 (corr. MJA 2000; 173: 504). Nitrofurantoin: monitor lung function in long-term use 3. ADRAC. ACE inhibitor, diuretic and NSAID: a dangerous combination. Aust Adv Drug New Zealand — An earlier article in React Bull 2003; 22: 14-15. Prescriber Update reported a case of fatal interstitial lung disease resulting from Colchicine: safe use is critical long-term nitrofurantoin therapy (1). The Centre for Adverse Reactions Monitoring New Zealand — Colchicine in overdose continues to receive reports of acute and is extremely toxic and has resulted in chronic pulmonary adverse reactions fatalities. Prescribers are reminded that associated with nitrofurantoin. Acute colchicine is now indicated as second-line pulmonary reactions typically have therapy in the treatment of acute gout, hypersensitivity-type features and occur after nonsteroidal anti-inflammatory 1Ð2 weeks after initiation of nitrofurantoin. drugs. Corticosteroids are recommended Chronic pulmonary reactions mainly where both are contraindicated (1). involve older persons, are often insidious in onset and associated with therapy of Due to the risk of dose-related serious six months or longer. Interstitial lung adverse effects, the use of high doses of disease and pulmonary fibrosis may colchicine to treat acute gout is no longer develop so it is important to avoid any appropriate, especially in elderly patients, delay in the recognition of nitrofurantoin- patients with impaired hepatic or renal induced lung changes. function, and patients who weigh less than 50 kg. The dosing interval for colchi- The pulmonary function of patients cine has been increased from 2Ð3 hourly undergoing prolonged nitrofurantoin to six hourly. For otherwise healthy adults therapy should be monitored. This in- the maximum dose of colchicine in the volves careful vigilance for early features first 24 hours is 2.5 mg and the total dose of emerging pulmonary toxicity which may given in an acute attack should not be evidenced by cough or shortness of exceed 6 mg over four days. Further- breath, indicating the need for prompt

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withdrawal and further investigation interstitial nephritis in the Auckland including chest x-ray and spirometry. region, perhaps due to their widespread Patients should be informed of the use (4). This suggests that prescribers warning symptoms and encouraged to should be vigilant for this adverse reac- report these early. Patients who have tion when using omeprazole or other experienced pulmonary toxicity with proton pump inhibitors. nitrofurantoin should not be re-exposed. Extracted from Prescriber Update, Volume 27, Extracted from Prescriber Update, Volume 27, Number 1, June 2006. at: http://www.medsafe. Number 1, June 2006. at: http://www.medsafe. govt.nz/pProfs/PUarticles.htm govt.nz/pProfs/PUarticles.htm References Reference 1. Savage R. Omeprazole-induced interstitial 1. Tatley M. Pulmonary reactions with nitro- nephritis. Prescriber Update 2001; No.20 furantoin. Prescriber Update 2002;23(2):24- (Feb):11-13. www.medsafe.govt.nz/profs/ PU 25. www.medsafe. govt.nz/profs/PUarticles/ articles/omeprazole.htm nitrofurant.htm 2. Pfizer New Zealand Ltd. Somac (panto- Proton pump inhibitors prazole) tablets data sheet 4 April 2005. www.medsafe. govt.nz/profs/Datasheet/s/ and interstitial nephritis somactab.htm

New Zealand — Acute renal impairment 3. Wyeth (NZ) Limited. Zoton (lansoprazole) caused by interstitial nephritis is a recog- capsules data sheet 17 May 2002.www. nized complication of treatment with medsafe.govt.nz/profs/Datasheet/z/zotoncap. omeprazole. Presenting symptoms may htm be non-specific and include malaise, fever, nausea, lethargy, weight loss, rash 4. Simpson IJ, Marshall MR, Pilmore H, et al. and eosinophilia. Patients known to be Proton pump inhibitors and acute interstitial nephritis Ð report and analysis of 15 cases. taking omeprazole who exhibit these Nephrology (In Press). symptoms should undergo urine micro- scopy and assessment of renal function. If either or both are abnormal, omepraz- Package insert changes ole should be withdrawn pending nephrol- Singapore — The Health Sciences ogy assessment (1). Interstitial nephritis Agency (HSA) has approved the following should also be considered if there is an package insert changes in accordance unexpected rise in serum creatinine. with safety updates from January to March 2006. Since publishing information about omeprazole induced interstitial nephritis 1. Calcitriol (Calcijex¨, Abbott) in 2000 (1), there have been 21 further Under “Precautions”, it is stated that use cases reported to the Centre for Adverse of vitamin D analogs and cardiac glyco- Reactions Monitoring; nine were reported sides may result in cardiac arrhythmias. in 2005 alone. Interstitial nephritis has Its effects may be reduced in patients also been reported with pantoprazole (2) taking barbiturates or anticonvulsants. and lansoprazole (3); the Centre for Corticosteroids may counter the effects of Adverse Reactions Monitoring has vitamin D analogs. Rare cases of hyper- received three such reports for panto- sensitivity reactions including anaphylaxis prazole. This reaction is thought to be and localised redness or pain at injection rare but proton pump inhibitors are now site have been reported. believed to be the commonest cause of

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2. Clarithromycin (Klacid¨, Abbott) CYP3A4 inhibitor) can greatly increase Contraindicated with concommitant use of fluticasone propionate plasma concentra- ergotamine or dihydroergotamine. Under tions resulting in markedly reduced warnings, clarithromycin should only be cortisol concentrations, Cushing used in pregnancy after risk/benefit syndrome and adrenal suppression. assessment. Pseudomonas colitis is Caution should be exercised when possible with clarithromycin/macrolide CYP3A4 inhibitors, e.g. ketoconazole, are therapy. It is cautioned that cross-resist- coadministered with fluticasone. ance between clarithromycin and other macrolide drugs is possible. New drug 6. Lidocaine, Prilocaine interactions include HMG-CoA reductase (Emla Cream¨, AstraZeneca) therapy, cisapride, pimozide, quinidine, Patients with G6PD deficieny or congeni- disopyramide, colchicine and ritonavir. tal or idiopathic methaemoglobinaemia are more susceptible to drug induced New ADRs include hypoglycaemia in methaemoglobinaemia. If eye contact patients on oral hypoglycaemic agents or occurs, loss of protective reflexes may insulin, leucopenia and thrombocytope- allow corneal irritation and potential nia, ventricular tachycardia, Torsades de abrasion. Patients treated with anti- Pointes, pancreatitis, convulsions and arrhythmic drugs class III (e.g. amiodar- interstitial nephritis. one) should be under close surveillance and ECG monitoring as cardiac effects 3. Ciclosporin (Gengraf¨, Abbott) may be additive. The results of intracuta- New drug interactions documented with neous injections of live vaccines (e.g. colchicine, quinopristin/dalfopristin, BCG) should be monitored as lidocaine amiodarone, orlistat and St John’s Wort. and prilocaine have bacteriocidal and Ciclosporin potentially enhances the toxic antiviral properties in concentrations effects of colchicine especially in patients above 0.5Ð2%. Caution should be exer- with renal dysfunction. Close monitoring cised when using Emla¨ in pregnant is required in patients concurrently taking women. digoxin or colchicine. Myotoxicity has been reported with concomitant adminis- 7. Nimesulide (Nidol¨, tration with HMG-CoA reductase inhibi- IDS Pharmaceuticals) tors. Maximum dose is reduced to 100 mg twice daily. Some new contraindications 4. Daunorubicin include patients with a history of hepato- (Daunorubicin¨, Pfizer) toxic reactions to nimesulide, cerebrovas- Contraindicated in pregnancy. New safety cular bleeding, severe coagulation information added to the sections on disorders, severe heart failure, children cardiac toxicity and bone marrow depres- under 12 years, third trimester of preg- sion. Significant hepatic or renal impair- nancy and lactation. Avoid concomitant ment can enhance the toxicity of recom- administration of hepatotoxic drugs and mended doses of daunorubicin. A rise in alcohol abuse. New drug interactions blood urea or uric acid can also occur include valproic acid, lithium, methotrex- with rapid destruction of leukaemia cells. ate and ciclosporin. Monitoring is thus required. Drug interaction includes vaccines and live virus. 8. Propafenone (Rytmonorm¨, Abbott) Drugs that inhibit CYP2D6, CYP1A2 and 5. Fluticasone (Flixotide¨, GSK) CYP3A4, might lead to increased levels Very rare cases of increased blood of propafenone. Propafenone should be glucose levels reported. Ritonavir (a used with caution in nursing mothers.

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New ADRs include hepatitis, anorexia, galactorrhea. New drug interactions syncope, hepatocellular injury, jaundice include quinidine, lithium, prazosin, and lupus syndrome. midazolam, neuromuscular blockers, acetylsalicylic acid, ethanol, simvastatin/ New precautions added were: (1) Each lovastatin and grapefruit juice. patient should be evaluated electro- 11. Vinorelbine graphically and clinically prior to and (Navelbine¨,Orient Europharma) during propafenone therapy to determine Contraindicated in patients with neutrophil if the therapy is warranted; (2) Propaf- counts <1500/mm3 or with current or enone may worsen myasthenia gravis; (3) recent severe infection. New precautions: Propafenone may affect both the pacing (1) dose limiting neutropenia where and sensing thresholds of artificial pace- treatment should be delayed till recovery makers; (4) there is a predisposition of if neutrophil count <1500/mm3 and patients taking this class of drugs with platelet count <75000/mm3. (2) In severe significant structural heart disease to liver impairment, dose should be reduced serious adverse events. by 33% and haematological parameters 9. Ritonavir (Norvir¨, Abbott) closely monitored. (3) Combination of Pancreatitis has been observed in pa- Navelbine¨ with other bone marrow toxic tients receiving ritonavir, including those drugs (e.g. cisplatin) may exacerbate who developed hypertriglyceridaemia myelosuppressive adverse effects. A new especially patients with advanced HIV. list of ADRs has been added. Navelbine¨ New onset diabetes mellitus, exacerba- should not be used in pregnant or lactat- tion of pre-existing diabetes mellitus and ing patients. hyperglycaemia have been reported in 12. Fluoxetine HIV-infected patients receiving protease (Prozac Dispersible¨, Eli Lilly) inhibitor therapy. In some cases, diabetic A new contraindication states that if flu- ketoacidosis occurred and in others, oxetine has been prescribed chronically hyperglycaemia persisted despite and/or at a high dose, a longer interval of removal of protease inhibitor. discontinuation (>5 weeks) should be considered when switching to monoam- Some new drug interactions include ine-oxydase inhibitors (MAOI). Serious ritonavir with erectile dysfunction agents, and fatal cases of serotonin syndrome herbal products and HMG-CoA reductase have been reported in patients treated inhibitors. Cardiac and neurologic events with fluoxetine and MAOI in close tempo- have been reported when ritonavir has ral proximity. It is warned that there is a been coadministered with disopyramide, possibility of suicide in depression which mexiletine, nefazodone, or fluoxetine. may persist till significant remission Some new ADR terms include myocardial occurs. Cases of suicidal ideation and infarction and menorrhagia. behaviours have been reported during 10. Verapamil (Isoptin¨, Abbott) fluoxetine/antidepressant therapy or early New contraindications include congestive after treatment discontinuation. Close heart failure, atrial fibrillation/flutter and supervision of high-risk patients is recom- concomittant Wolff-Parkinson-White mended. syndrome. Use with caution in patients Reference: Package insert amendments with first degree AV block, hypotension, reflecting safety issues. Adverse Drug Reac- bradycardia and severely impaired liver tion News. Vol.8 No.2 Page 4.at http:// function. New ADRs include abdominal www.hsa.gov.sg/cda/ discomfort/pain, impotence and

255 Safety and Efficacy Issues WHO Drug Information Vol 20, No. 4, 2006

Leflunomide and peripheral reporting, 15 patients had not recovered and the outcome was unknown for the neuropathy remaining cases. Australia — Leflunomide is a disease The cases reported to ADRAC are similar modifying anti-rheumatic prodrug to those recently described by Martin et al (DMARD) with immunosuppressive (1). The temporal association of leflun- properties. It has been available in omide with peripheral neuropathy and Australia since 2000 for the treatment of recovery on dechallenge suggest a active rheumatoid arthritis. causal relationship. The clinical features resemble the sensory peripheral neuropa- To date, ADRAC has received 659 thy attributable to the vasculitic compo- reports in association with leflunomide, nent of rheumatoid disease itself. Accord- 30 of which described neuropathy or ingly, the association may be difficult to peripheral neuropathy. Leflunomide was recognise but prescribers should consider the sole suspected drug in 24 of these the possible role of leflunomide in pa- cases. Ages ranged from 33 to 90 years. tients who complain of sensory problems The daily dose of leflunomide was 20 mg in the feet because in such cases the in 24 cases, 10 mg in 1, 30 mg in 1, and condition is potentially reversible if the not stated in the remaining cases. The drug is ceased. time to onset (n=21) ranged from 2 weeks to 20 months. Extracted from Australian Adverse Drug Reactions Bulletin, Volume 25, Number 5, Most reports described insidious onset October 2006. of bilateral sensory changes such as Reference numbness, hypoaesthesia, paraesthesia, or painful burning sensations affecting 1. Martin, K et al. Neuropathy associated with the feet and (in a few cases) the hands. leflunomide: a case series. Ann Rheum Dis Clinical findings variously included 2005; 64: 649-50. reduced sensation to light touch and pin prick, decreased vibration sense distally, Ezetimibe and depression? and in one case ‘foot drop’ was noted. Decreased or absent tendon reflexes Australia — Ezetimibe (Ezetrol®) was were also noted in some cases. registered in Australia in June 2003 for treatment of hypercholesterolaemia. Nine reports included the results of nerve Since then, ADRAC has received 265 conduction studies which supported a reports of suspected adverse reactions diagnosis of significant length-dependent associated with the use of this drug. sensory or sensorimotor neuropathy. Twelve of the reports describe depression Symptoms persisted and became worse (9) or depressed mood (3) in patients with continued use of leflunomide in aged 60 to 82 years. In all cases, several cases. ezetimibe was the sole suspected drug. An unusual feature was the rapid onset of Recovery was documented after with- symptoms — within four days in 7 of the drawal of leflunomide in 6 patients, 3 reports and at 4Ð6 weeks in another 3. In of whom were treated with ‘cholestyr- one report, the symptoms resolved after amine washout’ (which reduces the the dose was reduced from 10 mg to 5 elimination half-life of the active metabo- mg daily, and another report described lite of leflunomide from more than one exacerbation of pre-existing depression week to about one day). At the time of after the second dose.

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In 5 patients, symptoms abated on the term “de novo” refers to the use of withdrawal of ezetimibe but recurred on this regimen from the time of transplanta- rechallenge. One of these documented 2 tion. positive rechallenges with identical time to onset and noted suicidal ideation after Based on information from recent clinical continued use of ezetimibe. In addition to trials, the use of sirolimus, mycopheno- the 5 reports of positive rechal-lenges 4 late mofetil (MMF), and corticosteroids, in patients had recovered after ceasing combination with IL-2 receptor antibody ezetimibe and a further patient was (IL2R Ab) induction, is not recommended recovering with antidepressant treatment in the de novo organ transplant setting. after withdrawal of ezetimibe. Sirolimus is authorized solely for the prevention of renal transplant rejection. It Reports of depression/depressed mood, is recommended that sirolimus be used as a proportion of total reports received, initially in combination with cyclosporine are higher for ezetimibe (4.5%) than for and steroids. other hypolipidaemic agents: 3% for pravastatin (16/511) and simvastatin (86/ The safety and efficacy of sirolimus as 2,784); 2.4% for atorvastatin (39/1,573) immunosuppressant therapy have not and fluvastatin (6/255); 1.9% for gemfi- been established in liver or lung trans- brozil (12/619); and for the database as a plant patients, and therefore, such use is whole (1.4%). not recommended. Reference: Health Canada Endorsed Impor- The Ezetrol¨ product information does tant Safety Information on Rapamune¨ not mention depression as a finding in (sirolimus). 18 August 2006, http:// http:// clinical trials of this medicine. Further, www.hc-sc.gc.ca depression occurs commonly from other causes. However, the pattern of reporting suggests a possible causal association Safety update for oseltamivir between ezetimibe and depression, particularly in elderly patients in the early United States of America — The manu- phase of treatment, where careful moni- facturer of oseltamivir phosphate toring is advisable. ADRAC will continue (Tamiflu¨) has advised health profession- to monitor reports of depression in als of a recent revision to the product association with ezetimibe. label as a result of adverse events reported during postmarketing clinical Reference: Ezetrol¨ (ezetimibe) Product use. Oseltamivir is indicated for the Information. Merck Sharp & Dohme (Aust.) Pty treatment of uncomplicated acute illness Ltd (version dated Nov. 2005). due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days. Oseltami- Sirolimus: acute rejection in vir is also indicated for the prophylaxis of renal transplant patients influenza in patients 1 year and older.

Canada — Increased risk of rejection in The revised package insert now includes de novo renal transplant patients receiv- information and guidance on neuropsy- ing sirolimus (Rapamune¨), mycopheno- chiatric events following reports (mostly late mofetil, and corticosteroid, used in from Japan) of self-injury and delirium combination with interleukin-2 receptor with the use of oseltamivir in patients with antibody induction have been reported in influenza. The reports were primarily an investigational setting. In this setting, among paediatric patients. The relative

257 Safety and Efficacy Issues WHO Drug Information Vol 20, No. 4, 2006

contribution of the drug to these events is Once-daily dosing is possible with the not known. Patients with influenza should prolonged-release formulation. Peak be closely monitored for signs of abnor- plasma concentrations are reached seven mal behavior throughout the treatment hours after an oral dose, with a steady period. In addition, the following state- state reached in six days. Bioavailability ment has been added to the patient depends on the patient’s metabolism. information: Darifenacin is extensively metabolised in the liver and its pharmacokinetics are People with the flu, particularly children, affected by moderate hepatic impairment. may be at an increased risk of self-injury As the metabolism involves cytochrome and confusion shortly after taking osel- P450 2D6 and 3A4, there are several tamivir and should be closely monitored potential drug interactions. The risk of for signs of unusual behavior. A health adverse events may be increased by care professional should be contacted CYP2D6 inhibitors such as cimetidine, immediately if the patient shows fluoxetine and paroxetine. Daily doses of any signs of unusual behavior. darifenacin should not exceed 7.5 mg if the patient is taking an inhibitor of Reference: www.fda.gov/medwatch. Tamiflu¨ CYP3A4 such as itraconazole. The complete product information at http:// anticholinergic adverse effects of www.rocheusa.com/products/tamiflu/pi.pdf. T T tricyclic antidepressants and drugs for Parkinson disease may be increased by Darifenacin hydrobromide darifenacin. for overactive bladder: what Compared with placebo, patients taking clinical advantage? darifenacin complain more frequently of dry mouth and constipation. These Australia — Darifenacin hydrobromide adverse effects appear to increase with (Enablex¨) 7.5 mg and 15 mg prolonged- the dose. Other adverse effects include release tablets have been approved ifor altered vision, dyspepsia and abdominal overactive bladder. pain. Caution is needed if darifenacin is considered for patients with decreased The contraction of detrusor smooth gastrointestinal motility or at risk of muscle involves stimulation of muscarinic urinary retention. receptors by acetylcholine. Anticholinergic drugs have therefore been used to relax Darifenacin has been studied in people the bladder in patients with urge inconti- with overactive bladder. These people nence. These drugs have unwanted have urinary urgency, but not all of them systemic effects so there is a need for a have urge incontinence. The benefits of drug with an action that is more specific darifenacin may be less certain in these to the bladder. The M3 muscarinic patients. Although it achieved statistical receptor has been a target for drug advantages over placebo, the absolute development as it is thought to be the changes may be small. For example, a subtype responsible for bladder contrac- patient given darifenacin 15 mg will have tion. one less micturition per day than a patient given a placebo. They may also have one Darifenacin is an anticholinergic drug less episode of urgency per day. which has a greater affinity for the M3 Darifenacin does not decrease the receptor than for other subtypes. Its number of times a patient is awoken by action diminishes the frequency of detru- their overactive bladder significantly more sor contractions and increases bladder than placebo (1). capacity.

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Comparative studies are limited, but intravenous infusion. It is extensively tolterodine has been included in a distributed in the body and has a serum placebo-controlled trial of darifenacin. half-life of 40 hours. The tissue half-life is Unfortunately, a comparative analysis of not known. Tigecycline is not extensively the 15 mg dose of darifenacin was not metabolised and so most of the drug is carried out for all the outcomes. excreted unchanged in the urine and Darifenacin only achieved a statistical faeces. advantage over tolterodine for some The safety and efficacy of tigecycline outcomes if it was given at a daily dose of were evaluated for the treatment of skin 30 mg. Darifenacin’s selective action and skin-structure infections from pooled does not appear to give it a large clinical data of two trials totalling 1116 hospital- advantage. ized adults. Soft tissue infections, ab- scesses and infected ulcers were the Article drawn from: The Australian prescriber. Volume 29, Number 5, October 2006 at most common type of infections in these www.australianprescriber.com patients. Cure rates for tigecycline and vancomycin/aztreonam were similar in Reference trials. Both treatments were equally effective in patients with underlying 1. Haab F, Stewart L, Dwyer P. Darifenacin, an comorbidities such as diabetes mellitus M3 selective receptor antagonist, is an and peripheral vascular disease (1). effective and well-tolerated once daily treatment for overactive bladder. Eur Urol The safety and efficacy of tigecycline 2004;45:420-9. were also evaluated for the treatment of complicated intra-abdominal infections, Tigecycline for serious such as complicated appendicitis. Similar levels of drug efficacy were infections reflected in patients who were microbio- Australia Ð Tigecycline (Tygacil¨) logically evaluable (2). Although tige- vials containing 50 mg lyophilised powder cycline has in vitro activity to multidrug for reconstitution have been approved for resistant bacteria, there were limited data complicated skin and soft tissue infec- in these trials to support its use in pa- tions and complicated intra-abdominal tients with these infections. However, infections. tigecycline was effective at eradicating MRSA in 25 out of 32 patients with Tigecycline is structurally related to the complicated skin infections (1). tetracycline class of antibiotics and is a The most common drug-related adverse derivative of minocycline. It has broad events reported by tigecycline recipients spectrum in vitro activity against Gram- were nausea and vomiting. Overall there positive, Gram-negative and anaerobic were 30 deaths in the tigecycline groups organisms and also tetracycline-resistant and 18 deaths in the control groups. One bacteria. Coverage includes multiresistant death of a tigecycline recipient, after bacteria such as methicillin-resistant septic shock, was possibly related to the Staphylococcus aureus (MRSA) and study drug. vancomycin-resistant enterococci. Tigecy- cline has poor activity against Pseudo- Tigecycline is not recommended for monas species. pregnant women or children. Tetracycline class effects, such as photosensitivity, Tigecycline is not absorbed from the gut may also occur in patients taking tige- so it must be administered by slow cycline.

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Tigecycline provides an alternative References antibiotic therapy for the treatment of serious infections in hospitalised adults. 1. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. The efficacy and safety of However, its effectiveness in treating tigecycline in the treatment of skin and multidrug resistant infections remains to skin-structure infections: results of 2 double- be fully evaluated. Advice from an infec- blind phase 3 comparison studies with tious disease specialist or bacteriologist vancomycin-aztreonam. Clin Infect should be sought before using Dis 2005;41:S341-53. tigecycline. 2. Babinchak T, Ellis-Grosse E, Dartois N, Article drawn from The Australian prescriber. Rose GM, Loh E. The efficacy and safety of Volume 29, Number 5, October 2006 at tigecycline for the treatment of complicated www.australianprescriber.com intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis 2005;41: S354-67.

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unexpected adverse drug reactions. A signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually, more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information". All signals must be validated before any regulatory decision can be made.

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Rational Use of Medicines

The role of prescribed and defined daily doses in pharmacoepidemiology

In pharmacoepidemiological studies, it is important to use one single measurement for the volume of drugs prescribed, dispensed or consumed. For many years, the defined daily dose (DDD) has been the globally accepted standard unit for such assessments. A DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults (1). However, the DDD for a drug may deviate from the prescribed daily dose (PDD) (2Ð4). This may limit its usefulness unless the DDD/PDD ratio is known. Both DDD and PDD have been particularly useful in study- ing patient adherence since reports increasingly indicate that adherence to long- term drug therapy is low (5).

As an example, prescription refill adherence to corticosteroids used for asthma/chronic obstructive pulmonary disease (COPD) treatment has been found to be only 34% (6). This case provided the background for the study described below, where refill adherence was determined by comparing patient prescribed doses to data from pharmacies in Jämtland, Sweden (6). Although data bases of pharmacy records are pre- ferred compared to prescription collection, many data bases only have information about drug volumes actually dispensed and not the prescribed doses. Furthermore, a large proportion of the prescriptions issued are not dispensed (7). When prescribed doses are not listed in the available data bases, dispensed drug volumes in DDDs can serve as a proxy for patient dosing and refill adherence, providing that the PDDs do not deviate from the DDDs to any great extent.

Asthma/COPD drugs: PDDs are the pharmacy record data base of the critical to determining DDDs County of Jämtland with approximately 120 000 inhabitants. The data base holds The present study* was conducted with information on all drugs dispensed to a the aim of improving the rational use of representative sample of 17 000 inhabit- medicines through application of DDDs ants (9, 10). Information relating to and PDDs to data available concerning dispensing include: age and sex of the the treatment of asthma and COPD in patient, dispensation date, name of the Sweden. DDDs for different drug sub- drug, its ATC-code, drug volume dis- stances are available from the WHO pensed, and prescribed dose with code Collaborating Centre of Drug Statistics numbers for patients and prescribers. The Methology (1). The prescribed doses for identity of the patients and prescribers, as the dispensing of asthma/COPD drugs well as medical conditions, remain used in Sweden were obtained from confidential.

*Dan Haupt, Department of Health Sciences, Luleå Technical University, 971 87 Luleå, Sweden and J. Lars G. Nilsson, NEPI Foundation, 118 81 Stockholm, Sweden. Correspondence to: [email protected]

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The study was carried out during the It was possible to calculate the DDD/PDD period 2000-2004. It included patients 20 ratios for 15 of 18 asthma/COPD drugs. years and older (since DDDs are based on adult doses). Patients were grouped in For three drugs — the short acting 10-year age groups. Drugs were selected adrenergics salbutamol (R03AC02) and from ATC code group R03 — drugs for terbutaline (R03AC03) and the combina- inhalation and oral use (1). This includes: tion product of salbutamol and ipratropium (R03AK04) — over 95% were ¥ R03AC selective beta-2-adrenoreceptor prescribed to be used “when needed”. No agonists DDD/PDD ratios were therefore determined for these drugs. For the youngest ¥ R03AK adrenergics and other drugs for age group, 20Ð29 years, the number of obstructive airway disease; combination prescriptions for 9 of the drugs was too drugs for inhalation low to make a determination of the DDD/ ¥ R03BA glucocorticoids PDD ratios meaningful. ¥ R03BB anticholinergics PDDs were obtained from the pharmacy record data base of the same county. ¥ R03C adrenergics for systemic use Data on R03 drugs from this data base ¥ R03D other systemic drugs for obstruc- (11) have previously been determined to tive airway disease. correlate closely with data from the national register (8). The ratios are likely Only prescriptions with precise posology/ to be representative of the current dosing instructions (e.g. one inhalation situation in the rest of Sweden. twice a day) were included. Conse- quently, all prescriptions with instructions The DDD/PDD ratios for most drugs such as “to be used when needed” were showed only small variations between the excluded. different age groups. For fluticasone there was a two-fold variation among the age For each 10-year age group of patients groups with higher ratios for young and and for each ATC-group at the 5th level elderly patients. The reason for this is not (e.g. R03AC02 for salbutamol) the PDD clear. For ipratropium bromide the ratio for each prescription was computed. The increased by age. It is apparent that DDD-values for each drug were divided doctors prescribed lower doses of this with the computed PDD value and the anticholinergic drug to older patients, mean DDD/PDD ratio for each substance although no such recommendation is and for each 10-year age group was then included in the specifications for the drug calculated. For drugs with less than 20 (12). registered prescriptions over the five year study period the DDD/PDD ratios were Of 15 drugs, the mean DDD/PDD ratios not determined. were close to 1 for 10. Two drugs, formoterol for inhalation and terbutaline For the period 2000Ð2004, 1812 patients for oral use, had DDD/PDD ratios of 0.7 20 years and older were registered in the and 0.6, respectively, showing that 1.4 pharmacy record data base as having and 1.6 DDDs were the average pre- acquired R03 drugs from pharmacies in scribed doses for these drugs. For three the county. The number of dispensations other drugs, fluticasone, ipratropium was 23 223. The DDD/PDD ratios for the bromide, and theophylline the ratios were different drug substances and the differ- 1.7, 2.7 and 1.4 respectively, indicating ent age groups are presented in Table 1. that the average prescribed dose for

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Table 1. DDD and PDD for asthma/COPD drugs in Sweden 2000Ð2004 Mean DDD/PDD ratios DDD/ ATC- Substance Brand PDD code name Age groups ratio 20-29 30-39 40-49 50-59 60-69 70-79 80+

R03AC02 Salbutamol Ventoline2 ND1 ND1 ND1 ND1 ND1 ND1 ND1 ND1 inhalation R03AC03 Terbutaline Bricanyl inhalation ND1 ND1 ND1 ND1 ND1 ND1 ND1 ND1 R03AC12 Salmeterol Serevent 1 1.1 1 1.1 0.7 1.1 1 1 R03AC13 Formoterol Oxis2 0.5 0.5 0.8 0.9 0.9 0.7 0.7 0.7 R03AK04 Salbutamol + ipratropium Combivent ND1 ND1 ND1 ND1 ND1 ND1 ND1 ND1 bromide R03AK06 Salmeterol + fluticasone Seretide 1.1 1 1.1 1.1 1 1 1 1 R03AK07 Formoterol + budesonide Symbicort 0.7 0.8 0.8 1.1 1.7 0.8 0.7 0.9 R03BA01 Beclo- Becotide2 0.8 ND1 0.5 0.7 1 1 0.8 0.8 metasone R03BA02 Budesonide Pulmicort 0.8 0.9 1 1.1 1.1 1 1 1 R03BA05 Fluticasone Flutide ND3 2.6 1.1 1.1 1.9 1.1 2.4 1.7 R03BA07 Mometasone Asmanex ND3 ND3 ND3 1.2 0.8 ND3 ND3 1 R03BB01 Ipratropium Atrovent ND3 1 1.2 3.3 2.6 3.4 4.8 2,7 bromide R03BB04 Tiotropium Spiriva ND3 111.1 1 1 1 1 bromide R03CC02 Salbutamol Ventoline ND3 ND3 ND3 ND3 1ND3 ND3 1 oral R03CC03 Terbutaline Bricanyl ND3 ND3 ND3 ND3 0.5 0.6 ND3 0.6 oral R03CC12 Bambuterol Bambec ND3 ND3 ND3 ND3 1ND3 ND3 1 R03DA04 Theophylline Theo-Dur2 ND3 ND3 ND3 ND3 1.6 1.2 ND3 1.4 R03DC03 Montelukast Singulaire 1 1 1 1 1 1 1 1

1. Not determined since over 95 % did not have dosing instrucftions. 2. This is the most common brand but others were also used. 3. Not determined due to low number of prescriptions.

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fluticasone was about 0.6 DDDs, for 4. Muller A, Monnet DL, Talon D, Hénon T, ipratropium bromide about 0.4 DDDs and Bertrand X. Discrepancies between prescribed for theophylline 0.7 DDDs. The ratios for daily doses and WHO defined daily doses of oral terbutaline and for theophylline were antibacterials at a university hospital. Br J Clin only determined in two age groups due to Pharmacol 2006;61:585-591 the low number of prescriptions. The 5. World Health Organization. Adherence to values are therefore uncertain. long-term therapies. Evidence for action. Geneva: World Health Organization, 2003. Unfortunately, the study remained limited ISBN 924 154599 2. to Swedish data because published PDD data for R03 drugs from other countries is 6. Andersson K, Melander A, Svensson C, unavailable. However, the study drugs Lind O, Nilsson JLG. Repeat prescriptions Ð refill adherence in relation to patient and are widely used internationally and dosing prescriber characteristics, reimbursement recommendations are based on similar level and type of medication. Eur J Public documentation in many countries. Ap- Health 2005; 15:621-626 proximately 70% of total sales of drugs in Sweden are from transnational pharma- 7. Nilsson JLG, Johansson H, Wennberg M. ceutical companies (13). Given the Large differences between prescribed and multinational nature of the pharmaceutical dispensed medicines could indicate undertreatment. Drug Inf J 1995;29:1243-1246 industry, the DDD/PDD ratios presented are therefore likely to be of relevance to 8. Wettermark B, Hammar N, Fored CM, other countries. Leimanis A, Otterblad Olausson P, Bergman U, Persson I, Sundström A, Westerholm B, It was concluded from the study that for Rosén M. A new Swedish prescribed drug the majority of asthma/COPD drugs register Ð Opportunities for pharmaco- prescribed in Sweden, DDDs agree with epidemiological research and experience from the first six months. Pharmacoepidemiol drug the PDDs. For the cited drugs, the DDDs safety. Available on line, August 2006. can therefore be used to estimate patient dosing and to evaluate to what extent 9. Boethius G and Wiman F. Recording of patients have access to continuous drug prescriptions in the county of Jamtland, therapy over a defined period of time. Sweden. I. Methodological aspects. Eur J Clin Pharmacol 1977; 12: 31Ð35. References 10. Wessling A. Continous recording of drug prescribing in Sweden 1974Ð1983. Methods 1. Guidelines for ATC classification and DDD and examples of utilization of data. Eur J Clin assignment 2006. WHO Collaborating Centre Pharm 1987;33:7Ð13. for Drug Statistics Methodology, Oslo, Norway. www.whocc.no 11. Haupt D, Wettermark B, Nilsson JLG. Dispensed volumes of drugs for inhalation 2. Lee D, Bergman U. Studies of drug utiliza- related to the combined prevalence of asthma tion. Pharmacoepidemiology 3rd ed, Strom D and COPD in Sweden. Eur Resp J submitted ed. John Wiley & Sons, Ltd, Chichester, sept. 2006. England 2000 pp. 463-481 12. Monography for Atrovent in FASS 2006. 3. Hach I, Maywald U, Meusel D, König JU, www.fass.se (in Swedish). Kirch W. Continuity of long-term medication 13. Information from the website of The use after surgical hospital stay. Eur J Clin Swedish Association of Pharmaceutical Pharmacol 2005;61:433-438 Industry (www.lif.se).

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Topics of Current Interest

Development of medicines aimed at stimulating research, develop- for neonates ment and authorization of medicines for children. It is expected that this will result The development of safe and effective in an increase of clinical trials in children, medicines for newborn babies requires including neonates. The workshop pro- stronger cooperation between research- vided a platform for a multidisciplinary ers, developers and regulators. This was scientific dialogue among European one of the main conclusions of a work- experts to identify appropriate measures shop, organized by the European Medi- to encourage high-quality research into cines Agency (EMEA) on 11 October medicines for neonates, while also putting 2006. in place safeguards and precautions to protect this highly vulnerable patient Highlighting EMEA’s commitment to population. stimulate multidisciplinary cooperation in the development of medicines for chil- Notes dren, the workshop brought together 1. The proceedings of the conference are some 70 experts from academia and available on the EMEA website at http:// learned societies, industry and regulatory www.emea.europa.eu authorities, and also healthcare professionals involved in looking after and 2. The EMEA Paediatric Working Party (PEG) treating newborn and premature babies. has prepared four concept papers focusing on organ immaturity in neonates. The Concept The participants discussed the impact of Paper on the Impact of Brain Immaturity when organ immaturity and the rapid changes investigating medicinal products intended for in the first days and weeks of life when Neonatal use, the Concept Paper on the Impact of Lung and heart Immaturity when investigating medicines for neonates. The investigating medicinal products intended for outcome of the workshop — together with Neonatal use and the Concept Paper on the a series of concept papers on the impact Impact of Liver Immaturity when investigating of brain, liver, kidney, heart and lung medicinal products intended for Neonatal use. immaturity prepared by the Agency’s A Discussion Paper on Renal Immaturity when Paediatric Working Group will form the Investigating Medicinal Products for Paediatric basis of a future EMEA guideline on this Use has also been published. issue. Other aspects covered during the workshop included formulations appropri- 3. On 4 October 2006, the European Commis- ate for neonates, ethical aspects in sion released a draft document on Ethical Considerations for Clinical Trials Performed in relation to the conduct of clinical trials Children. Recommendations of the Ad Hoc in newborn babies, novel study design Group for the development of implementing methods and safety and pharmaco- guidelines for Directive 2001/20/EC relating to vigilance aspects. good clinical practice in the conduct of clinical trials on medicinal products for human use. The workshop was organized in the framework of the entry into force of the Reference: EMEA Press Release, Doc. Ref. new European legislation on medicines EMEA/416788/2006, 25 October 2006. http:// for children which will introduce incentives www.emea.europa.eu.

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Plan for paediatric essential greater regional research partnership to combat the most neglected diseases medicines such as sleeping sickness, kala azar and With millions of children dying every year malaria. Since the first meeting of the from treatable diseases, United Nations Drugs for Neglected Diseases initiative agencies have devised a plan aimed at (DNDi) in 2003, significant progress has increasing children’s access to essential been made. Clinical research platforms medications. WHO and UNICEF held a for leishmaniasis and sleeping sickness joint meeting in Geneva in August 2006 have been established on the continent, to form a strategy to expand access to and African scientists have contributed to paediatric formulations and improve the the clinical trials of a new drug for ma- medicines and prescribing guidelines for laria. the entire range of infant and child care However, new drugs and diagnostics are needs. desperately needed: Only 1.3% (21 out of Some 10 million children die every year, 1556) of new drugs developed over 30 many of them from diarrhoea, HIV and years have been for neglected tropical AIDS, malaria, respiratory tract infection diseases and tuberculosis, even though or pneumonia. Effective treatments for these diseases account for 12% of the these illnesses exist, but there is a lack of global disease burden. treatment guidelines and paediatric formulations. DNDi is a not-for-profit drug development initiative established in 2003 by five Under the plan, UNICEF’s supply division publicly-funded research organizations said it would work with industry to pro- (Kenya Medical Research Institute, Indian mote the development of paediatric Council of Medical Research, Oswaldo formulations for HIV and AIDS medica- Cruz Foundation Brazil, Malaysian tions. It also promised to work towards Ministry of Health, and the Institut Pas- painless remedies, better-tasting medica- teur), the WHO Tropical Diseases Re- tions and new mini-tablets to treat other search Programme (TDR), and Médecins diseases, as well as to emphasize the Sans Frontières. DNDi aims to develop 6 importance of climate zone considera- to 8 new, improved and field-relevant tions in creating and distributing new drugs by 2014 for neglected diseases. formulations. DNDi is currently conducting two large, WHO will work towards ameliorating the multicentre clinical trials. The first on cost of many medicines, especially for paromomycin, a treatment for leishmania- children in resource-poor settings sis in Africa, and the second for co- Reference: UN Agencies present plan to bring administration of nifurtimox-eflornithine essential medicines to children New York, 14 for sleeping sickness. The new treat- August 2006 at http://www.who.int/ ments are expected to be available to mediacentre/news/releases/2006/pr42/en/ patients within 3 years. DNDi supports index.html and http://www.unicef.org/” training of members in various aspects of clinical trials, thus building expertise in 200 African scientists clinical research for both diseases so that new treatments and diagnostics can be join forces effectively evaluated and registered by Over 200 African scientists from 23 scientists from the endemic regions. countries met in September 2006 at an international conference to engender Another focus group meeting at the conference is on fixed-dose artesunate-

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based combination therapies (FACT) for More than one billion people are afflicted chloroquine-resistant malaria. DNDi and by these diseases. Their impact can be its partners will bring the new, easier to measured in the impaired growth and use artesunate-amodiaquine combina- development of children, complications tion to patients in Africa. during pregnancies, underweight babies, significant and sometimes disabling Reference: http://www.who.int/mediacentre/ disfigurements, blindness, social stigma, news/releases or [email protected] and reduced economic productivity and household incomes. These effects can New strategy to fight now be dramatically reduced by scaling up interventions using effective drugs of tropical diseases proven quality — the majority donated by WHO and a group of more than 25 companies or costing less than US$ 0.40 partner organizations has unveiled a new per person per year. strategy to fight some of the most neglected tropical diseases that destroy the Reference: WHO Press Release, 26 October 2006 at http://www.who.int/mediacentre/news/ lives and health of poor people by com- releases bining treatment regimens for different diseases, but which require common resources and delivery strategies for ICH efforts to improve control or elimination. processes

The approach is set out in a newly The International Conference on Harmo- published manual, Preventive Chemo- nization (ICH) Steering Committee and its therapy in Human Helminthiasis, and expert working groups met in Chicago, focuses on how and when a set of low- USA, from 21Ð26 October 2006. cost or free drugs should be used in developing countries to control diseases ICH aims to collaborate with accredited caused by worm infections. Drugs that Standards Development Organizations to are effective against a broad range of leverage the development of technical worm infections will simultaneously standards for ICH e-Inititatives. This prevent or treat the four most common decision follows the outcome of a series diseases caused by worms: river blind- of discussions on improving the efficiency ness (onchocerciasis), elephantiasis of the ICH process that started at the (lymphatic filariasis), schistosomiasis, and Steering Committee meeting in May, soil-transmitted helminthiasis. Significant 2005. Additionally it is likely that the opportunities also exist to integrate these resulting standards would be taken up by efforts with the prevention and control of many non-ICH countries and organiza- diseases such as trachoma. tions.

The second key component of the strat- Expanding ICH standards would fulfill egy brings together dozens of agencies, ICH’s vision of the future development of NGOs, pharmaceutical companies and more efficient processes and increased others into a coordinated assault on uniformity of drug development require- neglected diseases. These organizations ments globally without compromising the are integrating their expertise and re- quality, safety, and efficacy standards sources to deliver the manual’s protocols expected by practitioners and patients. for wide-scale drug use.

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In order to keep pace as science evolves Anticounterfeiting Taskforce and with a view to reduce, refine and replace animal testing, expert groups develops strategy were convened during the meeting to The World Health Organization (WHO) revise the guidelines on Genotoxicity and and its partners have officially launched the Non-clinical Safety Studies for the the International Medical Products Anti- Conduct of Human Clinical Trials. The counterfeiting Taskforce (IMPACT) at a groups had very productive discussions meeting in Germany on 15 November and worked on significant revisions of the 2006. IMPACT is made up of WHO guideline requirements. Member States and more than 20 other major stakeholders, including Interpol, the Quality experts from both the chemical World Customs Organization, patient and and biotech areas held a Quality Strategy health professional organizations, and Session to identify those areas in phar- associations representing pharmaceutical maceutical quality which need to be manufacturers and wholesalers. addressed across all products at ICH level towards the goal of achieving Counterfeiters and their allies engage in harmonized submissions. Discussions will elaborate conspiracies to disguise activi- continue at the next ICH meeting. ties. They establish fictitious businesses and front companies; exploit weaknesses A draft guideline on Pharmacogenomics in border control; use false documents to (E15) reached Step 2. This document will obtain pharmaceutical ingredients and describe harmonized terminology for use manufacturing equipment to replicate in regulatory documentation. genuine products. In sum, their actions are meant to disguise the extent of the ICH also adopted a new topic entitled crime and this makes detection and Development Safety Update Reports reporting extremely difficult. (E2F) which will harmonize the requirements for annual clinical trial reporting in Following the launch, IMPACT has the three regions. proposed a global plan to combat counterfeit medical products. As a first step, it The Gene Therapy Discussion Group has released a preliminary report on has also finalized the Document on estimates of the number of counterfeit Inadvertent Germline Transmission which products thought to be circulating on presents scientific principles to address world markets. the risk of inadvertent germline integra- tion during development of a gene Until now, the number of counterfeit therapy product. The group also made medicines has generally been estimated progress on two new Considerations at approximately 10% of the global Documents on Vector/Viral Shedding and medicines market. As the capacity to Oncolytic Viruses. collect and analyse information improves, a better understanding of the situation is The next ICH Steering Committee Meet- possible. A rapid overview of the situation ing will be held in Brussels, Belgium, from shows that counterfeiting is greatest in 7Ð10 May 2007. those regions where regulatory and legal oversight is weakest. Reference: ICH Steering Committee Meeting. Press Release. Leveraging ICH Efforts to Increase Globalization. http://www.ich.org Most developed countries with effective regulatory systems and market control

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currently have a very low proportion of Colombia: According to the Association counterfeiting, i.e. less than 1% of market of Colombian Pharmaceutical Industries value. However, indicators do point to an (ASINFAR), it is estimated that out of a increase in the prevalence of counterfeit total US$1300 million in annual medicines medicines even in developed countries. sales, almost 5 percent stem from contraband, counterfeiting or adulteration. Many developing countries of Africa, parts of Asia, and parts of Latin America have Dominican Republic: The Public Health areas where more that 30% of medicines Department has reported that 50% of on sale can be counterfeit. Other devel- pharmacies operate illegally and that, oping markets, however, have less than according to statistics, 10% of the medi- 10%; overall, a reasonable estimate is cines that arrive in the country are fake. between 10% and 30%. Many of the Some of the medicines found had expired countries which were part of the Soviet over10 years ago! Union have a proportion of counterfeit medicines which is above 20% of market El Salvador: INQUIFAR, the Association value. Medicines purchased over the of Pharmaceutical Companies, has Internet from sites that conceal their denounced the widespread availability of actual physical address are counterfeit in counterfeit drugs on the domestic market. over 50% of cases. According to a local drug manfacturer, the commercialization of counterfeit medi- In addition to the huge differences some- cines currently causes economic losses times recorded between regions, varia- of around US$40 million per year to the tions can also exist within countries — country’s pharmaceutical industry. city versus rural areas, city versus city — and can also be time-sensitive. The India: Indian pharmaceutical companies difficult of capturing data furthermore have suggested that in major cities, one reflects the complexity of a situation that, in five strips of medicines sold is fake. by its very nature, is informal and illegal They claim a loss in revenue of between and where the evidence itself is con- 4% and 5% annually. The industry also sumed. estimates that spurious drugs have grown from 10 to 20% of the total market. Overview of country reports Indonesia: The International Pharmaceu- Angola: According to the head of the National Department of Intellectual tical Manufacturers Group (IPMG) in Copyright Crime of the Economic Police, Indonesia has estimated that pirated drugs constitute 25% of Indonesia’s US$2 approximately 70% of medicines used by the population may be forgeries. billion pharmaceutical market. According to IPMG, fake drugs hit foreign pharma- Cambodia: A Cambodian Health Ministry ceutical companies’ profits and pose a survey conducted in 2002 revealed that potential serious public health threat. 13% of drugs on the domestic market were counterfeit or substandard, espe- Kenya: A random survey by the National cially antimalarial drugs and antibiotics. Quality Control Laboratory (NQCL) and the Pharmacy and Poisons Board found China: China’s Research and Develop- the almost 30% of drugs in Kenya are ment-based Pharmaceutical Association counterfeit. Some of the drugs have been estimates that about 8% of over-the- described as no more than just chalk and counter drugs sold in China are counter- water being marketed as original pharma- feit. ceutical products. According to figures

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from the Kenya Association of Pharma- The Association of Pharmaceutical ceutical Industries, counterfeit pharma- Laboratories of Peru (ALAFARPE) ceutical products account for approxi- estimates that the illegal pharmaceuticals mately US$130 million annually in sales trade in the country represents around in the country. US$ 40 million. This figure includes medicines that enter the country as Lebanon: The chief of Lebanon’s Na- contraband, are expired, counterfeit, tional Health Commission (NHC), has adulterated, with altered or missing labels estimated that 35% of pharmaceuticals or stolen from warehouses of the Ministry available in the Lebanese market are of Health, the armed forces, and police. counterfeit products. Mexico: During 2004, federal agents Around 200 pharmacies operate in seized — in two regions — approxi- downtown Lima with neither registration mately 60 tons of stolen, expired and nor authorization issued by the Ministry of counterfeit pharmaceuticals. There is Health. According to the Municipal Health concern in the pharmaceutical industry at Separtment, they sell 40% contraband the rapid growth in sales of counterfeit pharmaceuticals and 12% adulterated or and contraband products. Reportedly, the expired goods supplied by clandestine penetration of these illegal products is laboratories. During 2004, the Ministry of about 10% of the pharmaceutical market. Health seized ten tons of adulterated pharmaceuticals. Nigeria: The National Agency for Food, Drug Administration and Control Philippines: In 2003, the former director (NAFDAC) announced that the preva- of the Bureau of Food and Drug (BFAD), lence of counterfeit drugs has dropped to has estimated that 30% of drug store 16% at the beginning of 2006. outlets visited by food and drug deregula- tion officers carry and sell counterfeit Peru: Some US$66 million of counterfeit drugs. and adulterated pharmaceuticals are sold in Peru every year. In the capital alone, Russia: The Federal Service for Health there are 1800 stores devoted to this Sphere Supervision (FSHSS) reported illegal business. The General Directorate that 10% of all drugs on the Russian of Medicines, Supplies and Drugs market were counterfeit. However, other (DIGEMID) of the Department of Health sources estimate that the real figure could seized around 460 000 adulterated and be much higher. expired medicines in 2005. Reference: http://www.ho.int/medicines

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Regulatory Action and News

Bevacizumab approved chotic drug, for the symptomatic treat- for lung cancer ment of irritability in autistic children and adolescents. The approval is the first for United States of America — The Food the use of a drug to treat behaviours and Drug Administration (FDA) has associated with autism in children. These approved use of bevacizumab (Avastin¨) behaviours are included under the gen- in combination with carboplatin and eral heading of irritability, and include paclitaxel for initial systemic treatment of aggression, deliberate self-injury, and patients with unresectable, locally ad- temper tantrums. vanced, recurrent or metastatic, non- squamous, non-small cell lung cancer. Risperdal¨ has been approved since Approval was based on an improvement 1993 for the short-term treatment of in survival time when bevacizumab was adults with schizophrenia, and since 2003 added to a standard chemotherapy for the short-term treatment of adults with regimen. Lung cancer is the leading acute manic or mixed episodes associ- cause of cancer-related death in men and ated with extreme mood swings. The women. most common side effects of the use of risperidone included drowsiness, consti- The most serious adverse events associ- pation, fatigue and weight gain. ated with bevacizumab, including some fatal cases, were gastrointestinal perfora- Reference: FDA News, P06-163. 6 October 2006. tion, wound healing complications, haemorrhage, blockage of arteries, abnormally high blood pressure, albumin New treatment deficiency in blood and congestive heart for chronic hepatitis B failure. The most common adverse events included weakness, abdominal United States of America — The Food pain, headache, diarrhoea, nausea and and Drug Administration (FDA) has vomiting. approved telbivudine (Tyzeka¨) for the treatment of adults with chronic hepatitis Bevacizumab, in combination with intra- B (HBV), a serious viral infection that can venous 5-fluorouracil-based chemo- cause lifelong infection, scarring of the therapy, was previously approved for first- liver (cirrhosis), and eventually liver or second-line treatment of patients with cancer, liver failure, and death. metastatic cancer of the colon or rectum. Telbivudine is not a cure for hepatitis B, Reference: FDA News, P06-166. 12 October and long-term treatment benefits of this 2006 drug are not known. Use of telbivudine has not been shown to reduce the risk of Risperidone for irritability transmission of HBV to others through associated with autism sexual contact or blood contamination. United States of America — The Food The most common side effects were and Drug Administration (FDA) has elevated creatinine phosphokinase, upper approved risperidone (Risperdal¨) orally respiratory tract infection, fatigue, head- disintegrating tablets, an adult antipsy- ache, abdominal pain and cough. Also,

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after several weeks to months of telbi- WHO has published recommendations on vudine use, some patients developed the prevention of influenza. Most of the symptoms ranging from transient muscle population is likely to have been infected pain to muscle weakness. Those who with influenza A(H1N1), influenza developed muscle weakness experienced A(H3N2) and influenza B viruses. As a significant improvement in their symp- consequence, 1 dose of inactivated toms when telbivudine was discontinued. influenza vaccine should be immunogenic for individuals of all ages except young Patients should only stop Tyzeka after a children. Previously unimmunized chil- careful discussion with their doctor. As dren should receive 2 doses of inacti- has happened with other forms of treat- vated vaccine, with an interval of at least ment for hepatitis B, some patients who 4 weeks between doses. discontinued telbivudine experienced a sudden and severe worsening of their Reference: Weekly Epidemiological Record, hepatitis B. Therefore, patients who 2006,81:390 discontinue telbivudine should be closely monitored by their doctor for at least Sitagliptin phosphate several months. Some cases of lactic for diabetes acidosis and severe enlargement and accumulation of fat in the liver, including United States of America — The Food fatal cases, have been reported among and Drug Administration (FDA) has drugs in this class. approved sitagliptin phosphate (Januvia¨), the first diabetes treatment in Reference: FDA News, P06-175. 25 October a new class of drugs known as DPP-4 2006. inhibitors that enhances the body’s own ability to lower elevated blood sugar. Influenza virus vaccine composition: 2007 southern FDA approved Januvia¨ for use in hemisphere addition to diet and exercise to improve blood sugar levels in patients with type-2 World Health Organization — It is diabetes, alone or in combination with two recommended that vaccines to be used in other commonly prescribed oral diabetes the 2007 season (southern hemisphere medications, metformin or a PPAR Winter) contain the following: (peroxisome proliferator-activated receptor gamma) agonist, when either of ¥ an A/New Caledonia/20/99(H1N1)-like these drugs alone, along with diet and virus; exercise, do not provide adequate blood ¥ an A/Wisconsin/67/2005(H3N2)-like sugar control. virus (The currently used vaccine viruses are A/Wisconsin/67/2005 and A/ Sitagliptin phosphate was examined in a Hiroshima/52/ 2005.); and total of 2719 patients with type-2 diabetes, in studies lasting from 12 weeks to ¥ a B/Malaysia/2506/2004-like virus. more than a year. The most common side effects in clinical studies were upper As in previous years, national control respiratory tract infection, sore throat, and authorities should approve the specific diarrhoea. vaccine viruses used in each country. National public health authorities are Reference: FDA News, P06-169 17 October responsible for making recommendations 2006. regarding the use of the vaccine.

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Dronedarone marketing EMEA’s Committee for Medicinal Prod- application withdrawn ucts for Human Use (CHMP) had submitted a provisional opinion that NovoNorm¨ European Union — The European or Prandin¨ in combination with a thia- Medicines Agency (EMEA) has been zolidinedione could not be approved. formally notified by manufacturer of the decision to withdraw the application for a Reference: EMEA Press Release, http:// centralized marketing authorisation for www.emea.europa.eu and www.emea. the medicinal product dronedarone europa.eu/humandocs/Humans/EPAR/ novonorm/novonorm.htm and http:// hydrochloride (Multaq¨). www.emea.europa.eu/humandocs/Humans/ EPAR/prandin/prandin.htm. The indication applied for was rhythm and rate control in patients with atrial fibrilla- Abetimus marketing tion or atrial flutter (abnormalities of the heartbeat), to maintain normal sinus authorization request rhythm or to decrease ventricular rate. withdrawn

At the time of the withdrawal, it was under European Union — The manufacturer of review by the Agency’s Committee for abetimus sodium (Riquent¨) has notified Medicinal Products for Human Use the European Medicines Agency (EMEA) (CHMP). In its official withdrawal letter, of its decision to withdraw an application the company stated that the withdrawal of for a centralized marketing authorization. MULTAQ¨ was due to the fact that the Abetimus sodium was designated as an additional clinical data requested by the orphan medicinal product for the treat- CHMP cannot be provided within the ment of lupus nephritis on 20 November timeframe of the current procedure. 2001.

Reference: European Medicines Agency. Ref. At the time of the withdrawal, it was under EMEA/354409/2006, 8 September 2006. http:/ review by the Agency’s Committee for /www.emea.europa.eu Medicinal Products for Human Use (CHMP). Additional clinical data re- Repaglinide marketing quested by the CHMP to support the application cannot be provided within the authorization extension timeframe of the current application request withdrawn procedure.

European Union — The manufacturer of Reference: EMEA Press Release, EMEA/ repaglinide (NovoNorm¨ and Prandin¨) 410861/2006, 13 October 2006 http:// 0.5 mg, 1 mg and 2 mg tablets has www.emea.europa.eu notified the European Medicines Agency (EMEA) of its decision to withdraw the Imatinib mesilate: application for an extension of the marketing authorization to include use of revised indications NovoNorm¨ or Prandin¨ in combination European Union — The manufacturer of with a thiazolidinedione, such as rosiglita- imatinib mesilate (Glivec¨), 50 mg and zone or pioglitazone, for the treatment of 100 mg capsules and 100 mg and 400 type-2 diabetes. Both products are mg film-coated tablets, has notified the currently indicated for use in patients who European Medicines Agency (EMEA) of have non-insulin-dependent diabetes its decision to withdraw the application for (type-2 diabetes). a change to the marketing authorization.

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The change would have included treat- intestinal stromal tumours, and adult ment of aggressive systemic mastocyto- patients with dermatofibrosarcoma sis in adults. Imatinib mesilate was protuberans. designated as an orphan medicinal product for the treatment of mastocytosis During its meeting on 16Ð18 October on 26 August 2005. The Committee for 2006, the CHMP recommended an Medicinal Products for Human Use extension of the marketing authorization (CHMP) considered that the limited data for Glivec¨ to include treatment of myelo- provided did not support a positive dysplastic syndromes and myeloprolifera- benefit-risk balance. tive diseases, as well as treatment of adult patients with hypereosinophilic Glivec¨ is currently indicated for the syndrome and chronic eosinophilic treatment of adult and paediatric patients leukaemia. with Philadelphia chromosome positive chronic myeloid leukaemia, adult patients Reference: EMEA Press Release, EMEA/ with Philadelphia chromosome-positive 423844/2006, 23 October 2006. http:// acute lymphoblastic leukaemia, adult www.emea. europa.eu and www.emea. patients with Kit-positive unresectable europa.eu/humandocs/Humans/EPAR/glivec/ and/or metastatic malignant gastro- glivec.htm.

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Vigiflow Online for ¥ Streamlined reporting. pharmacovigilance ¥ Report download for local storage. The validation of Vigiflow case report management system has now been ¥ Multilingual. completed and version 3.0 was success- fully released in February 2006. ¥ Built-in statistics and data retrieval.

The Vigiflow web-based software allows ¥ Cost-effective and time-saving. seamless electronic transmission of adverse drug reaction (ADR) reports in ¥ User guide and online help available. (ICH) E2B format from healthcare professionals to their designated reporting Reference: The Uppsala Monitoring Centre. centres and onwards to the WHO data- http://www.who-umc.org base or other destinations such as the European medicines Agency (EMEA) or Scientific plant names the Food and Drug Administration (FDA). and synonyms The majority of reports so far submitted to The Uppsala Monitoring Centre’s work on the WHO database via Vigiflow have herbal synonyms in the form of lists of been received from Switzerland. Brazil, accepted scientific names and their latin Ghana and Morocco — all active mem- and vernacular synonyms has now been bers of the WHO Programme on Interna- published. tional Drug Monitoring — are using it to send in their ADR reports, plus eight other member national centres.

Vigiflow offers significant benefits, including:

¥ No need for local software or hardware.

¥ Unlimited number of users.

¥ Simple, secure ADR reporting in E2B format.

¥ Improvement of report quality.

¥ Extensive optional data fields and free- text entries.

¥ Live access to latest versions of termin- Reference: The Uppsala Monitoring Centre. ologies (WHO-DD, MedDRA, WHO- http://www.who-umc.org ART) .

275 Recent Publications, Information and Events WHO Drug Information Vol 20, No. 4, 2006

Pharmaceutical inventory made available to all undergraduate control software medical programmes in the country. Outside the medical community, the The latest release of mSupply v1.94 development of the online AR course has pharmaceutical inventory control software generated interest and requests for has been announced. New features similar education initiatives from other include: health professions and consumers. ¥a French version under construction. An online module for naturopathic doctors has been posted on MedEffect (with a link ¥ better PDF generation support from the Canadian Association of Naturo- ¥ support for direct printing to label pathic Doctors website to the learning printers centre section of MedEffect) and will be integrated into the Canadian College of ¥ lots of new reports Naturopathic Medicine’s curriculum this fall. Another online module and corre- ¥ sends reports directly to Excel¨ sponding guidebook to assist consumers ¥ improvements to dispensary mode and patients on how to report ARs to their health care professional or Health ¥ demonstration available on http:// Canada will be made available on the www.msupply.org.nz/download MedEffect Web site. ¥ user guide http://www.msupply.org.nz/ Reference: Canadian Adverse Reaction files/ Newsletter. Volume 16, Issue 4, October 2006. mSupply remains free for use in single- Good governance user mode if you are in a developing country or your organization is not-for- in medicines procurement profit. Huge amounts of money are spent every year on pharmaceutical products; a Reference: http://www.msupply.org.nz or http://sussol.net market so large that it is extremely vulnerable to corruption. The World Health Organization (WHO) has launched Reporting adverse reactions a new initiative to assist governments to and continuing education promote greater transparency in medicines regulation and procurement. As a In collaboration with the Canadian first step, WHO is establishing an interna- Medical Association (CMA), Health tional expert group. Canada has developed a continuing medical education (CME) course entitled Before reaching patients, medicines change hands several times in the Physician Reporting of Adverse (Drug) Reactions. A number of reference re- production and distribution chain. Apart sources are available via hyperlinks to from the loss of resources and the danger posed to patients’ lives, corrupt practices Health Canada’s MedEffect Web site. also allow the entry into the medicines Future steps for the online course include chain of counterfeit and substandard products, further endangering the health posting on Health Canada’s MedEffect Web site and pilot testing in the medical of communities. undergraduate curriculum. If successful, Corruption may take on different forms this initiative will result in the course being such as bribery, soliciting payment from

276 WHO Drug Information Vol 20, No. 4, 2006 Recent Publications, Information and Events

suppliers, favouritism in selecting mem- WHO has encouraged individuals, civil bers of committees or in recruiting staff, society groups, government institutions, theft and embezzlement in the distribution academic and research institutions, the chain and health care facilities. private sector and other interested parties to contribute to the open hearings which To combat the problem, WHO plans to took place between 1 and 15 November. strengthen regulatory authorities and The initiative provided an opportunity for procurement practices by: everyone, including the general public, to contribute to developing a solution to a ¥ Stimulating legislative reform that will major public health challenge Ð how to establish laws against corruption with enhance innovation, research and devel- enforcement and punitive measures. opment to address diseases predomi- nantly affecting poor populations. ¥ Promoting standardized systems of checks and balances to limit or prevent The developing world continues to bear abuse by making publicly available the the highest burden of disease but repre- criteria, structures and procedures to sents only a small part of the treatment select regulatory and procurement staff market. While having to cope with a high and medical products. incidence of infectious diseases, develop- ¥ Encouraging ethical practices through ing countries are also seeing a rapid behaviour change activities and staff growth in non-communicable and chronic training. diseases. Many of the benefits of modern science are not reaching the poor, in WHO will compile a data base of best particular women and children, who are practices and successful experiences among the most vulnerable populations. already tried and tested in countries to promote good governance in the public The web-based hearings come a few pharmaceutical sector. A two-day meeting weeks before the start of formal discus- to determine strategies and set up the sions between Member States at an new initiative took place at WHO, Ge- Intergovernmental Working Group on neva, on 30Ð31 October 2006. Public Health, Innovation and Intellectual Property, taking place in Geneva from 4-8 Reference: WHO sets up network to combat December. The group will discuss a corruption in medicines procurement. Note for global strategy and plan of action to the Media, WHO/32. 30 October 2006 and enhance research and development to http://www.who.int/medicines/areas/policy/ respond to public health challenges. goodgovernance/home/en/index.html The parameters of the Intergovernmental Working Group were set out in WHA WHO public hearings on Resolution 59/24, which was based on innovation and intellectual recommendations of the Commission on property Public health Innovation and Intellectual property (CIPIH). Contributors to the All parties with an interest in the public hearings are invited to consult the upcoming Intergovernmental Working resolution and the CIPIH report at: http:// Group on Public Health, Innovation and www.who.int/gb/ebwha/pdf_files/WHA59/ Intellectual Property have been invited to A59_R24-en.pdf and http://www. who.int/ present their views to a web-based public intellectualproperty/documents/thereport/ hearing organized by the World Health en/ Organization (WHO).

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Reference: WHO public hearings: on public and lack of early access to medicines and health, innovation and intellectual property. innovative products. The Forum seeks to http://www. who.int?medicines identify, explore and exchange information and data on alternative mechanisms. Pharmaceutical Forum: better With the objective of finding a balance information, access and prices between controlling expenditure, improving access to medicines and rewarding The European Commission has set up innovation. the Pharmaceutical Forum to find practi- cal solutions to some of the key structural Assessing the effectiveness of and public health issues affecting the medicines in comparison with pharmaceutical industry. The Pharmaceu- other treatment options tical Forum brings together Member The Forum’s report makes a series of States, the pharmaceutical industry, recommendations on how to support public health and patient groups in a relative effectiveness systems to help voluntary process brokered by the Com- contain pharmaceutical costs as well as mission to achieve the benefits of Eu- stimulating innovation. Relative effective- rope-wide cooperation in areas which are ness assessment systems identify the partially governed by national law. most clinically efficiency and cost-effective medicines, and will help set a fair Europe needs to look urgently at the price for these medicines. structural issues affecting the competi- tively of the industry and respond to these Reference: European Union Press Release, challenges. The purpose of the Pharma- IP/06/1282, Brussels, 29 September 2006 at ceutical Forum is to push forward to http://ec.europa.eu/enterprise/phabiocom/ deliver concrete results by June next comp_pf_en.htm year. The progress report just adopted sets out a series of proposals for further Pharmacy education action. symposium: multidisciplinary Information to patients practice The Forum has identified ways to improve quality and access to information, such Registration is now open for the Fourth as: Pharmacy Education Symposium: Teach- ing for multidisciplinary practice to be held ¥ Developing a model package of infor- in Italy in July 2007. mation for patients on diseases (using diabetes as a first example). Programme summary ¥ Considering areas for harmonization of EU wide action on information on Day 1: Teaching and learning in a tradi- medicines. tional environment. ¥ Improving patient access to good quality Day 2: Teaching and learning in an health information. experiential environmen. Day 3: Teaching and learning in a virtual Control of expenditure environment. Several factors have generated significant changes in the pricing and reim- Reference: Pharmacy Education Symposium bursement mechanisms of most Member website at www.vcp.monash.edu.au/ States during recent years, including prato2007 rising expenditure on medicines, inequity

278 WHO Drug Information Vol 20, No. 4, 2006 Recent Publications, Information and Events

Pharmaceutical policy aspects of pharmaceuticals. These could include: prioritizing in and barriers to analysis conference in 2007 pharmaceutical innovation. Drug utilization aspects, regulatory issues, economi- A conference on pharmaceutical policy cal questions, cross-cultural aspects of analysis, including sociocultural, eco- medicines’ efficacy, safety and usage, nomic, regulatory and epidemiological quality indicators, methods of pharmaceu- aspects of pharmaceuticals and interna- tical policy analysis, effectiveness of tional health will be held from 19Ð21 rational use interventions, promotional September 2007, in Zeist, Netherlands. practices, role of consumers, access to Everybody who comes to the conference medicines, and international health. will be asked to submit a paper which will Ultimately, it will be the quality of the be discussed in groups during the confer- papers which determines the content of ence. The first stage of attending is to the meeting. submit a 300 word abstract. Reference: Enquiries and abstracts to Pieter Pharmaceutical policy analysis is increas- Stolk: pharmapolicy2007@pharm. uu.nl. P.O. ingly acknowledged as an important Box 80082, 3508 TB Utrecht, Netherlands. driver of evidence-based policy making on pharmaceuticals. In a world with Final guidance on ample diversity in perspectives and opinions about how to prioritize and quality systems regulate pharmaceutical policies, and where to intervene in daily practice, The US Food and Drug Administration robust data and valid research method- (FDA) has released the final version of ologies can, and should, make a differ- their Guidance for industry: quality ence. However, despite all the enthusi- systems approach to pharmaceutical asm and support for pharmaceutical CGMP regulations. This version finalizes policy research, the scientific quality of the draft which was published in October the field is yet rather limited in terms of 2004. The October 2nd Federal Register impact on policy makers and visibility in announcement notes that the Agency high-impact journals. The objectives of considered all comments received on the the Conference on Pharmaceutical Policy draft as they established the final version; Analysis are to: however no substantive changes were made. ¥ Build knowledge on the basis of a discussion of Pharmaceutical Policy The final version contains a number of Analysis papers submitted and re- clarifying edits. The guidance is intended viewed in advance of the meeting. to encourage the use of modern quality management system principles by the ¥ Focus on methods for Pharmaceutical regulated industry and to foster innova- Policy Analysis as a long-term outcome tion and continuous improvements in to fuel the field. pharmaceutical manufacturing. Alterna- tive approaches may be used so long as ¥ Create commitment to deliver publica- they satisfy the requirements of the tions in high-impact journals. applicable statutes and regulations.

The theme for the conference will be Reference: The Federal Register, Vol. 71, No. broadly interpreted to encourage submis- 190; pp. 57980 and 57981. 2 October 2006. sion of a range of papers on various http://www.fda.gov/cder/guidance/index.htm or topics related to international policy http://www.fda.gov/ohrms/dockets/default.htm.

279 Recent Publications, Information and Events WHO Drug Information Vol 20, No. 4, 2006

Newly available ¥ Current Good Manufacturing Practices guidance documents (CGMPs) The following guidance documents are • Bar Code Label Requirements—Ques- now available on the US Food and Drug tions and Answers Administration website: ¥ Compliance ¥ Fixed Dose Combinations, Co-Pack- aged Drug Products, and Single-Entity ¥ Quality Systems Approach to Pharma- Versions of Previously Approved Antiret- ceutical Current Good Manufacturing rovirals for the Treatment of HIV Practice Regulations

¥ Investigating Out-of-Specification Test Reference: http://www.fda.gov/cder/guidance/ Results for Pharmaceutical Production index.htm

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