Contents Contents Regulatory Matters Regulatory Matters Safety of Medicines Safety of Medicines Signal Feature Feature

prepared in collaboration with the WHO Collaborating Centre for International Drug Monitoring,

Uppsala, Sweden

TheThe aim aim of of the the Newsletter Newsletter is is to to No.No. 6, 3, 2012 2012

disseminatedisseminate information information on on the the

safetysafety and and efficacy efficacy of of

pharmaceuticalpharmaceutical products, products, based on communications received based onfrom communications our network of received "drug from our network of "drug information officers" and other TheThe WHO WHO Pharmaceuticals Pharmaceuticals Newsletter Newsletter provides provides you you wit withh informationsources such officers" as specialized and other sources such as specialized thethe latest latest information information on on the the safety safety of of medicines medicines a andnd bulletins and journals, as well as legallegal actions actions taken taken by by regulatory regulatory authorities authorities acros acrosss the the partnersbulletins in WHO. and journals, The information as well as partners in WHO. The information world.world. It It also also provides provides signals signals from from the the Uppsala Uppsala is produced in the form of résumés MonitoringMonitoring Centre's Centre's SIGNAL SIGNAL document. document We thank you inis English,produced full in thetexts form of which of résumés may in English, full texts of which may for your interest in this publication and wish you a be obtained on request from: healthy and fulfilling year in 2013. be obtained on request from: Quality Assurance and Safety: The feature article in this issue gives you…

Medicines, EMP-HSS, QualityWorld HealthAssurance Organization, and Safety: 1211 GenevaMedicines, 27, Switzerland, EMP-HSS, E-mail address: [email protected] World Health Organization, This Newsletter is also available on 1211 Genevaour Internet 27, Switzerland, website:

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Box 1051 Contents Contents Regulatory matters Regulatory matters Safety of medicines Safety of medicines Signal Feature Feature

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TAB LE OF CONTENTS

Regulatory Matters Agomelatine ...... 4 Denosumab ...... 4 Intravenous 0.18% saline/4% glucose solution (‘hypotonic saline’) in children ...... 5 Ondansetron ...... 5 Proton Pump Inhibitors and Methotrexate ...... 6

Safety of medicines Dabigatran etexilate mesylate ...... 7 Human papillomavirus vaccine (Cervarix) ...... 7 Non-steroidal anti-inflammatory drugs (NSAIDs) ...... 7 Over-The-Counter Eye Drops and Nasal Sprays ...... 8 Simvastatin ...... 8

Signal Ethinylestradiol/Drospirenone and Spinal cord infarction ...... 10 Fesoterodine – GI haemorrhage ...... 11

WHO Pharmaceuticals Newsletter No. 6, 2012 • 3

REGULATORY MATTERS

Denosumab hypocalcaemia, including those Agomelatine with severe renal impairment. In patients receiving 120 mg Fatal cases of severe denosumab, supplementation Risk of dose-related symptomatic of calcium and vitamin D is hepatotoxicity and liver hypocalcaemia required unless failure UK. The MHRA reported that hypercalcaemia is present; if UK. The Medicines and cases of severe symptomatic hypocalcaemia occurs, Healthcare products hypocalcaemia have occurred additional calcium Regulatory Agency (MHRA) in patients receiving supplementation may be announced that there have denosumab 120 mg (Xgeva®) necessary. or 60 mg (Prolia®). Some of been several serious cases of Reference: hepatotoxicity reported with these cases were fatal in those Drug Safety Update, October receiving the 120 mg dose. agomelatine (Valdoxan®, 2012, Volume 6, issue 3, A3 Thymanax®). These include The MHRA advised health-care MHRA, (www.mhra.gov.uk ). six reports worldwide of professionals that pre-existing hepatic failure. The agency hypocalcaemia must be advised health-care corrected prior to initiating Denosumab professionals that the existing denosumab, and recommendations to perform supplementation of calcium liver function tests in all Association with the risk and vitamin D is required in all patients receiving agomelatine of atypical femoral patients receiving the 120 mg at treatment initiation and fractures dose unless hypercalcaemia is during treatment have been present. Although Canada. AMGEN Canada Inc., extended to include testing hypocalcaemia most commonly in consultation with Health when the dose is increased. occurs within the first 6 Canada, informed health-care Agomelatine should be months of treatment, it may providers of new important immediately discontinued if occur at any time. safety information regarding patients present with the risk of atypical femoral symptoms or signs of potential Hypocalcaemia is a known risk fractures associated with liver injury, or if an increase in with denosumab use, denosumab (Prolia®) serum transaminases in liver especially in patients with treatment. According to the function tests exceeds 3 times severe renal impairment manufacturer, there have been the upper limit of normal. It is (creatinine clearance <30 no confirmed Canadian cases also recommended that mL/min; estimated glomerular of atypical femoral fractures patients should be informed of filtration rate [eGFR] 15 – 29 associated with denosumab to the symptoms of potential liver mL/min/1.73m 2) or receiving date. Amgen proactively injury and advised to stop dialysis. Severe symptomatic evaluated the potential for taking agomelatine hypocalcaemia, including three atypical femoral fractures in immediately and seek urgent fatal cases, has been reported patients treated with the drug medical advice if these in patients receiving in clinical trials and the post symptoms appear. denosumab 120 mg. Severe marketing setting. symptomatic hypocalcaemia Agomelatine is an has also been reported in Cases of atypical femoral antidepressant indicated for patients at increased risk of fracture have been confirmed the treatment of major hypocalcemia receiving in patients receiving depressive episodes in adults. denosumab 60 mg. denosumab participating in the Agomelatine is a melatonin on-going open label extension MT1 and MT2 receptor agonist, Signs and symptoms of study of the pivotal phase 3 and antagonist at the serotonin hypocalcaemia include altered fracture trial in 5-HT 2C receptor, thereby mental status, tetany, seizures postmenopausal osteoporosis increasing levels of dopamine and QTc prolongation. (FREEDOM). Events of atypical and noradrenaline in areas of Hypocalcaemia with femoral fracture have occurred the brain involved in mood denosumab most commonly very rarely (<1/10,000) based control. occurs within the first 6 on 31,266 subject years of months of dosing, but it can exposure to denosumab in Reference: occur at any time during bone loss studies. Drug Safety Update, October treatment 2012, Volume 6, issue 3, A1 It is recommended that, during MHRA, (www.mhra.gov.uk ). Periodic monitoring of calcium denosumab treatment, health- levels (at the discretion of the care professionals should prescriber) is recommended advise the patients to report after use of denosumab in new or unusual thigh, hip, or patients predisposed to groin pain. Patients presenting WHO Pharmaceuticals Newsletter No. 6, 2012 • 4

REGULATORY MATTERS with such symptoms should be individual clinical needs and dependency, and intensive evaluated for an incomplete possibility of increased anti- care units. femoral fracture, and the diuretic hormone secretion Egypt (2). The contralateral femur should also should be taken into account – Pharmacovigilance Committee- be examined. fluid balance, plasma and Central Administration for urinary electrolyte The Warnings and Precautions Pharmaceutical Affairs (CAPA) concentrations must be section of the Product decided to contraindicate the carefully monitored during monograph was updated to use of Intravenous (I.V.) treatment. reflect this new information on solution containing 0.18% NaCl atypical femoral fractures. Acute symptomatic in children aged 16 years or hyponatraemic encephalopathy less, except under expert Reference: is a medical emergency. medical supervision in Advisories, Warnings and Health-care professionals paediatric specialist settings Recalls, Health Canada, 16 should therefore be aware of such as kidney, heart, liver, November 2012 (www.hc- and take prompt action if high-dependency and intensive sc.gc.ca ). children receiving hypotonic care units. intravenous fluids develop the In addition, the signs and symptoms of Intravenous 0.18% Pharmacovigilance Committee hyponatraemia (headache, also requested that all saline/4% glucose nausea, seizures, lethargy, Marketing Authorization coma, cerebral oedema). solution (‘hypotonic Holders of I.V. solution saline’) in children Following the restart of a containing 0.18% NaCl in public inquiry primarily into the Egypt to distribute "Dear Contraindicated in deaths of three children in the Healthcare Professional children except under UK who died of cerebral Communication (DHPC)" to expert medical oedema secondary to HealthCare settings to where hyponatraemia after your product is distributed to supervision in paediatric administration of intravenous inform them with the new specialist settings hypotonic saline, the safety information. UK (1). The MHRA announced Commission on Human Reference: that four children have died of Medicines (CHM) has recently (1) Drug Safety Update, cerebral oedema caused by reviewed all data on the October 2012, Volume 6, issue very low levels of serum benefits and risks of this 3, A2 MHRA, sodium after receiving solution when used in children. intravenous hypotonic saline (www.mhra.gov.uk ). (0.18% saline/4% glucose There have been over 50 (2) Newsletter of the Egyptian solution) in hospital. This reported permanent Pharmaceutical Vigilance solution is now contraindicated neurological injuries or deaths center, No. 35, Volume 3 in children except under expert in children worldwide as a December 2012. medical supervision in result of iatrogenic paediatric specialist settings – hyponatraemia associated with such as renal, cardiac, liver, the use of hypotonic Ondansetron high dependency and intensive intravenous fluids, often in care units. previously healthy children Dose restriction for undergoing routine elective intravenous use due to The MHRA also advised health- surgery. In addition, several dose-dependent QT care professionals to remove published studies and reviews interval prolongation 0.18% saline/4% glucose have demonstrated intravenous infusions from hyponatraemia after Canada. GlaxoSmithKline Inc., stock and general use in areas administration of hypotonic in consultation with Health that treat children and ensure intravenous fluids such as Canada, informed of new that suitable alternatives are 0.18% saline/4% glucose. information regarding the risk available (in line with local of electrocardiographic QT guidelines) and to restrict On the basis of the evidence interval prolongation availability of 0.18% saline/4% from the review, the CHM associated with ondansetron glucose intravenous infusions concluded that the use of (ZOFRAN®). A recently to critical care and specialist 0.18% saline/4% glucose completed study identified a wards. If hypotonic should be contraindicated in all dose-dependent prolongation intravenous fluids do need to but a limited group of children of the corrected QT interval be prescribed to children treated by experts in paediatric (QTc) among healthy subjects (according to the strict specialist settings, such as treated with ondansetron. QTc conditions above), the child’s renal, cardiac, liver, high interval prolongation can lead to Torsade de Pointes (TdP), a WHO Pharmaceuticals Newsletter No. 6, 2012 • 5

REGULATORY MATTERS potentially life-threatening dizziness, palpitations, It is recommended that heart rhythm abnormality. syncope). patients should not stop taking their medication unless they Recommendations based on There are no changes to have been advised to do so by this new study are as follows: recommended oral dosing in their health-care professional. • The new maximum adults. There are no changes Patients using PPIs and recommended single to recommended oral or methotrexate should consult intravenous (IV) dose is intravenous dosing in children. with their doctor if they have 16 mg infused over 15 Reference: any concerns about their minutes. Advisories, Warnings and health or these products. • The 32 mg IV dose and Recalls, Health Canada, 3 the 8 mg IV dose followed Health-care practitioners are October 2012 (www.hc- by a 1 mg/hour reminded that PPIs, in general, sc.gc.ca ). continuous infusion are no should be prescribed at the longer recommended and lowest dose and for the should not be used. Proton Pump shortest duration of therapy • Avoid ondansetron in appropriate to the condition patients with congenital Inhibitors and being treated. As noted in the long QT syndrome. Use Methotrexate drug labels, a temporary caution if administering withdrawal of the PPI may be ondansetron to patients Interaction of proton considered by the health-care with other risk factors for pump inhibitors with practitioner in some patients QT interval prolongation, receiving treatments with high- such as electrolyte methotrexate dose methotrexate. abnormalities, congestive Canada. Health Canada (See WHO Pharmaceuticals heart failure, informed that the labelling for Newsletter No. 2, 2010 for bradyarrhythmias or use methotrexate and Proton Pump updates on warning about of other medicines that Inhibitors (PPIs) is being interaction between clopidogrel can lead to either QT updated to include information and proton pump inhibitors in prolongation or electrolyte on a potential interaction Europe and New Zealand and abnormalities. between these products. The No. 3, 2010 for updated advice • Hypokalemia, new information will be in the on possible interactions in UK). hypomagnesemia, and "Warnings and Precautions" hypocalcemia should be section of the methotrexate Reference: corrected prior to and the PPIs labelling. The use Advisories, Warnings and ondansetron of high-dose methotrexate and Recalls, Health Canada, 19 administration. of PPIs at the same time by October 2012 (revised 24 patients may increase the October, 2012) (www.hc- Physicians are recommended amount of methotrexate in the sc.gc.ca ). to assess their patients for risk blood leading to side effects. factors for QT interval The possible risks to health prolongation or TdP before include kidney failure, low red prescribing ondansetron. For blood cell count, inflammation adults treated with intravenous of the digestive tract, irregular ondansetron prior to heartbeat, muscle pain, chemotherapy, the usual dose infections, and diarrhea. is 8 mg infused over 15 minutes at least 30 minutes While a definite association prior to chemotherapy. It is between PPI use and an increase in methotrexate has recommended that the drug should not be administered not been confirmed, there more rapidly than have been a number of studies recommended as more rapid suggesting a possible infusion can lead to greater interaction between PPIs and QTc prolongation. methotrexate. The potential for an increased risk of It is also recommended that methotrexate side effects is patients should be advised to very likely, which is why contact their health-care Health Canada informed this professional if they experience change in labelling. Health signs or symptoms of an Canada will continue to abnormal heart rate or rhythm evaluate the scientific evidence while taking ondansetron (e.g., as it emerges and take appropriate action as needed. WHO Pharmaceuticals Newsletter No. 6, 2012 • 6

SAFETY OF MEDICINES

Human was chronic fatigue syndrome Dabigatran etexilate (CFS) – the level of reporting papillomavirus for which was found to be well mesylate vaccine (Cervarix) within the expected background incidence rate. An Safety review of post- Cervarix: safety review ecological study and a self- market reports of shows balance of risks controlled case series study serious bleeding events and benefits remains using the Clinical Practice Research Datalink (CPRD) also USA. The U.S. Food and Drug clearly positive did not find an increased risk Administration (US FDA) UK. The MHRA announced that of fatigue syndromes with evaluated new information a safety review conducted at Cervarix®. about the risk of serious the end of its routine use bleeding associated with use of during the on-going human Reference: the anticoagulants dabigatran papillomavirus (HPV) Drug Safety Update, November (Pradaxa®) and warfarin immunisation programme 2012, Volume 6, issue 4, H2 (Coumadin®, Jantoven®, and found that no new risks have MHRA, (www.mhra.gov.uk ). generics). This assessment been identified for HPV vaccine was done using insurance Cervarix®, and that the claims and administrative data balance of its risks and Non-steroidal anti- from the US FDA’s Mini- benefits remains clearly inflammatory drugs Sentinel pilot of the Sentinel positive. Cervarix® was (NSAIDs) Initiative. The results of this replaced in the programme by assessment indicate that the HPV vaccine Gardasil® Pharmacovigilance Risk bleeding rates associated with from September 2012. Since new use of dabigatran do not September 2008 the human Assessment Committee appear to be higher than papillomavirus (HPV) vaccine to consider need for bleeding rates associated with Cervarix® has been used updated treatment new use of warfarin, which is extensively in the UK routine advice for diclofenac in consistent with observations HPV immunisation programme follow-on review from the large clinical trial to prevent cervical cancer. used to approve Pradaxa®. Europe. The European The US FDA is continuing to The MHRA previously reported Medicines Agency (EMA) evaluate multiple sources of on the safety of the vaccine finalised a review of recently data in the ongoing safety following the first and second published information on the review of this issue. The US year of use and the agency cardiovascular safety of non- FDA has not changed its conducted a further safety steroidal anti-inflammatory recommendations regarding review of the totality of the UK drugs (NSAIDs). The Agency’s the drug. experience with Cervarix® up Committee for Medicinal to the end of July 2012. No Products for Human Use (See WHO Pharmaceuticals new safety concerns were (CHMP) concluded that Newsletters No. 1, 2012 for identified and the number and evidence from newly available safety review of post-market nature of adverse reaction published data sources, reports of serious bleeding (ADR) reports received was as including meta-analysis of events in the USA, Australia expected after administration clinical trials and observational and New Zealand; Risk of of at least 6 million doses of studies, and the results of a serious haemorrhage, need for the vaccine in the UK. European Union-funded renal function testing in UK, independent research project, No.3, 2012 for updated Before Cervarix® was first the ‘safety of non-steroidal labelling regarding renal used the MHRA anticipated anti-inflammatory drugs' function assessment and use in that a range of medical (SOS) project, on the patients with severe valvular conditions naturally prevalent cardiovascular safety of this disease or prosthetic heart in the adolescent female class of medicines confirm valves in Canada and Saudi population would occur in findings from previous reviews, Arabia and No.4, 2012 for temporal association with conducted in 2005 and 2006. modifications to product vaccination and might be information for clearer reported as suspect side Most of the data related to the guidance in EU). effects. Statistical methods three most widely used were therefore put in place to NSAIDs – diclofenac, ibuprofen Reference: rapidly assess whether such and naproxen. In relation to FDA Drug Safety reports were consistent with naproxen and ibuprofen, the Communication, US FDA 2 chance, or whether they could CHMP was of the opinion that November 2012 be new side effects of the the current treatment advice (www.fda.gov ). vaccine. One such condition adequately reflects the

WHO Pharmaceuticals Newsletter No. 6, 2012 • 7

SAFETY OF MEDICINES knowledge regarding the coma have occurred. Ingestion result from such drug safety and efficacy of these of only a small amount (1-2 interactions. medicines. mL; for reference, there are 5 Following further consideration mL in a teaspoon) of the eye For diclofenac, the latest by the Pharmacovigilance drops or nasal spray can lead evidence appears to show a Expert Advisory Group of the to serious adverse events in consistent but small increase in Commission on Human young children. the risk of cardiovascular side Medicines, the MHRA published effects for diclofenac compared Most of these redness-relief an article summarises the with other NSAIDs, similar to eye drops and nasal evidence underlying the new the risks of COX-2 inhibitors, decongestant sprays currently advice that the maximum another class of painkillers. As do not come packaged with recommended dose for a follow-on to this review, the child-resistant closures, so simvastatin in conjunction with Agency’s new children can accidentally ingest amlodipine and diltiazem is Pharmacovigilance Risk the drug if the bottles are now 20 mg/day. The Assessment Committee (PRAC) within easy reach. These prescribed doses of amlodipine will now assess all available products are sold under and diltiazem need not be data on diclofenac (both various brand names, as changed. published and unpublished) to generics, and as store brands. In summary, the available consider the need for updated The US FDA recommended evidence supports the treatment advice. that consumers should store recommendation that the Reference: these products out of reach of maximum daily dose of Press release, EMA, 19 October children at all times. It is also simvastatin should not exceed 2012 (www.ema.europa.eu ). recommended to call local 20 mg when co-administered poison control center with amlodipine or diltiazem: immediately if a child • concomitant use of Over-The-Counter accidentally swallows OTC either amlodipine or redness-relief eye drops or Eye Drops and Nasal diltiazem increases the nasal decongestant spray. Sprays exposure to Reference: simvastatin through Serious adverse events FDA Drug Safety CYP3A4 interactions Communication, US FDA 25 from accidental ingestion • the incidence of October 2012 (www.fda.gov ). by children myopathy is increased USA. The US FDA warned with higher doses of health-care professionals and Simvastatin simvastatin when co- the public that accidental administered with ingestion by children of over- amlodipine or diltiazem, Evidence supporting compared to the the-counter eye drops used to recent advice on dose relieve redness and nasal absence of amlodipine decongestant sprays can result limitations with or diltiazem, or lower in serious and life-threatening concomitant amlodipine doses of simvastatin or diltiazem adverse events. The eye drops • approximately 75% of and nasal sprays that have UK. In August 2012 the MHRA the LDL-lowering effect been involved in the cases of published advice that is apparent at lower accidental ingestion contain simvastatin is contraindicated doses of simvastatin the active ingredients with concomitant use of certain and only an additional tetrahydrozoline, medicines, such as ciclosporin, 6% effect would be oxymetazoline, or naphazoline. danazol, and gemfibrozil. In expected by doubling addition, the recommendations The cases of accidental the dose from 20 mg for the maximum dose of ingestion reviewed by the US to 40 mg simvastatin changed when FDA occurred in children 5 used with a number of other In the absence of further years of age and younger. No medicines, including evidence, the recommendation deaths were reported; however, amlodipine and diltiazem. for a maximum daily dose of serious events requiring These changes were driven simvastatin of 20 mg applies hospitalization such as nausea, primarily by concerns about an with amlodipine at doses of vomiting, lethargy, tachycardia, increased risk of myopathy both 10 mg and 5 mg. decreased respiration, and/or rhabdomyolysis at bradycardia, hypotension, (See WHO Pharmaceuticals higher plasma concentrations hypertension, sedation, Newsletter No. 4, 2011 and of simvastatin, which may somnolence, mydriasis, stupor, No.1, 2012 for new restrictions, hypothermia, drooling, and contraindications, and dose WHO Pharmaceuticals Newsletter No. 6, 2012 • 8

SAFETY OF MEDICINES limitations in the USA and No. 5, 2012 for updated advice on drug interactions and contraindications in the UK.) Reference: Drug Safety Update, October 2012, Volume 6, issue 3, H1 MHRA, (www.mhra.gov.uk ).

WHO Pharmaceuticals Newsletter No. 6, 2012 • 9

SIGNAL

A signal is defined by WHO 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. A signal is a hypothesis together with data and arguments and it is important to note that a signal is not only uncertain but also preliminary in nature.

The signals in this Newsletter are based on information derived from Individual Case Safety Reports (ICSRs) available in the WHO Global ICSR database, VigiBase™. The database contains over 7 million reports of suspected adverse drug reactions, submitted by National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring. VigiBase is, on behalf of the WHO, maintained by the Uppsala Monitoring Centre (UMC) and periodic analysis of VigiBase data is performed in accordance with UMC’s current routine signal detection process. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of SIGNAL (page 15). For information on the UMC Measures of Disproportionate Reporting please refer to WHO Pharmaceuticals Newsletter Issue No. 1 2012.

UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific research within the field of pharmacovigilance. UMC’s vision is to improve worldwide patient safety and welfare by reducing the risk of medicines. For more information, visit www.who-umc.org. To leave a comment regarding the signals in this Newsletter, please contact: the Uppsala Monitoring Centre, Box 1051, SE-751 40 Uppsala, Sweden. E-mail: [email protected] .

Ethinylestradiol/Drospirenone and Spinal cord infarction

Response from Bayer Healthcare

It is estimated that spinal cord infarction accounts litigation procedures (2). Treatment duration for 1% of stroke hospitalizations 1. Because of the varied between 3 and 7 years of partly rarity of spinovascular disease compared to intermittent intake of EE/DRSP. In 3 cases cerebrovascular disease, only few large clinical magnetic resonance imaging (MRI) confirmed investigations exist, mostly discussing spinal cord spinal cord infarction at thoracical and/or cervical ischemia due to aortic surgery. Pathogenesis and level. Patient age varied between 32 and 49 years natural history of spontaneous or nonsurgical at the time of the event. Risk factors for ATE spinal cord infarctions remains largely unknown 2. (smoking, hypercholesterinaemia, advanced age, migraine, protein S deficiency) were reported in Spinal cord infarction was not reported in three cases. Drospirenone + Ethinylestradiol (EE/DRSP) clinical studies analyzed to date, which included over The frequency of spinal cord infarction with EE/ 9,800 women. DRSP reported to Bayer Pharma is 0.06 reports per 1 million treatment years, based on 67.2 Post authorization safety studies investigating the million treatment years estimated cumulative total arterial (ATE) and venous thromboembolism (VTE) exposure with EE/DRSP. risk with EE/DRSP have included over 130,000 treatment years; one case of spinal cord infarction As of last PSUR, the cumulative reporting was derived from these populations. frequency for non-cerebral and cerebral ATE with EE/DRSP was 0.1 per 10,000 treatment years. There are no published case reports on spinal cord Within that dataset, the proportion of spinal cord infarction in association with EE/DRSP. infarction was 0.6%. By comparison, a cohort A cumulative retrieval in Bayer Pharma's study of COC users reported an ATE incidence rate worldwide safety database of all cases applying of 1-2 ATE per 10,000 treatment years 3. the MedDRA term (PT): "Spinal cord infarction' in association with all EE/DRSP products irrespective Conclusion of causality revealed a total of four cases, As stated in the companies' Reference Safety including all three UMC cases. Cases were all Information (RSI) of EE/DRSP containing COCs medically confirmed, originated from US (2), and implemented in local labelling, Germany (1) and Denmark (1) and were either "epidemiological studies have suggested an received as spontaneous reports (1), from a association between the use of COCs and an postmarketing-surveillance study (1) or via WHO Pharmaceuticals Newsletter No. 6, 2012 • 10

SIGNAL increased risk of arterial and venous thrombotic References and thromboembolic diseases ". Events occur 1. Sandson TA, Friedman JH. Spinal cord rarely and may very rarely involve spinal cord infarction: report of 8 cases and review of the arteries resulting in spinal cord infarction and literature. Medicine. 1989;68:282-292. leading to significant morbidity. Accordingly, the company considers them listed events. The 2. Wiebers, David O., Feigin, Valery L., Brown, seriousness of the condition is reflected in the RSI Robert D. in: Handbook of Stroke (2nd of EE/DRSP stating that "arterial thromboembolic Edition)Lippincott Williams & Wilkins, 2006 events may be life-threatening or may have a fatal outcome No new safety finding arises from the 3. Dinger, J.C., Heinemann, L.A. and Kuhl- analysis of these cases. Reports of ATE including Habich, D. The safety of a drospirenone-containing vascular involvement of the spinal cord will oral contraceptive: Final results from the European continued to be closely monitored. active surveillance study on oral contraceptives based on 142,475 women-years of observation. The company's assessment of the benefit-risk Contraception 2007; 75(5): 344-54 balance for EE/DRSP remains favourable. This is supported by consistent clinical findings over a 15- year period and up to 10 years of post-marketing study results.

Fesoterodine – GI haemorrhage Dr Richard Hill, Australia

Summary Labelling VigiBase™ contains seven reports of GI haemorrhage is not labelled in either the US gastrointestinal haemorrhage following use of the product label 4 or the UK Summary of Product muscarinic receptor antagonist fesoterodine. A Characteristics (SPC) 2. Labelled gastrointestinal number of the reports describe short time to adverse effects include abdominal pain, dyspepsia, onsets and in most cases recovery occurred on constipation and diarrhoea. According to the US stopping fesoterodine. A plausible mechanism for product label "fesoterodine should be used with this adverse reaction involves reduction in gastric caution in patients with decreased gastrointestinal motility and consequent increased exposure to motility, such as those with severe constipation." 4 gastric irritants, particularly concomitant drugs. In the UK SPC, "decreased gastrointestinal motility" is included under special warnings and Fesoterodine precautions for use. 2 Fesoterodine is a muscarinic receptor antagonist used for the treatment of symptoms associated Reports in VigiBase with overactive bladder. The usual dose is 4-8 mg This signal was identified during a pilot study daily. Fesoterodine is rapidly hydrolysed to the investigating electronic health records (EHRs) as active metabolite 5-HMT (the same active an additional source of reference during signal metabolite as tolterodine), which is subsequently detection in the WHO Global ICSR database, metaboli¬sed by CYP3A4 and CYP2D6. 1 Elevated VigiBase™. The EHRs used in the study came from plasma levels of 5-HMT may occur in the presence The Health Improvement Network (THIN), an of potent inhibitors of CYP3A4 and CYP2D6. 2 electronic medical record data resource covering three and a half million active patients in the UK. Fesoterodine is said to have relatively increased After elimination of one duplicate, VigiBase selectivity for muscarinic M2 and M3 receptors and contains seven reports of GI haemorrhage decreased selectivity for Ml receptors. 3 This may following fesoterodine use, received from five result in less cognitive impairment compared to countries (Germany and the US two each; nonselective antimuscarinic drugs, but is not Netherlands, Switzerland and UK one each) as expected to reduce gastrointestinal adverse effects shown in Table 1. such as decreased gastrointestinal motility and constipation. Comment GI haemorrhage The reports are notable for the short time to onset in four of seven reports and positive dechallenge This association was detected for the WHO-ART (recovery after stopping fesoterodine) in five of High Level Term (HLT) GI haemorrhage, which seven reports. Two of the reports list concomitant contains the Preferred Terms (PTs) GI non-steroidal anti-inflammatory drugs (NSAIDs) haemorrhage, haematemesis, haemorrhage and three other reports list other concomitant rectum and melaena. medications (oxycodone, bendroflumethiazide, WHO Pharmaceuticals Newsletter No. 6, 2012 • 11

SIGNAL tramadol) described as being associated with VigiBase additionally contains 52 reports with the "gastric irritation" in UK SPCs. No reports mention HLT GI haemorrhage in association with constipation as an ADR and no reports list tolterodine, and a published review states that concomitant CYP2D6 or CYP3A4 inhibitors. gastrointestinal haemorrhage and decreased GI motility have been reported infrequently in Discussion association with tolterodine use. 5 Six reports in VigiBase contain sufficient information regarding time to onset and recovery Conclusion after dechallenge to support an association Reports in VigiBase lend support to an association between fesoterodine and gastrointestinal between fesoterodine and GI bleeding. Key bleeding. Gastrointestinal adverse effects, features in the reports include rapid time to onset, including abdominal pain, diarrhoea, dyspepsia, recovery on stopping fesoterodine, and co- and constipation, are common with fesoterodine 2 administration with drugs known to cause gastric and it is possible to envisage at least two irritation, suggesting a possible mechanism for this mechanisms which may explain this association. adverse reaction. A recent meta-analysis found that fesoterodine is associated with a doubling of risk of constipation compared to placebo. Chronic constipation is References already a significant health problem in the elderly, 1. Review of fesoterodine. Expert Opin. Drug the same group of patients prescribed Saf. 2011. 10(5): 805-808. fesoterodine, and constipation itself increases the risk of other sequelae such as haemorrhoids, 2. SPC for fesoterodine (TOVIAZ). URL: which may result in bleeding. 3 http://www.medicines.org.uk/emc Accessed: 2012-02-09 Secondly, drugs with antimuscarinic activity, such as fesoterodine, can reduce gastric motility, 3. Overactive bladder drugs and constipation: a possibly reducing the absorption of concomitantly meta-analy-sis of randomized, placebo-controlled administered medications. The US product label trials. Dig Dis Sci 2011; 56: 7-18. for fesoterodine specifically mentions this as a 4. US product label for fesoterodine (TOVIAZ). possible mechanism for some drug interactions. 4 URL: In the case of drugs which are gastric irritants, http://www.accessdata.fda.gov/scripts/cder/drugs this reduced absorption may result in increased atfda Accessed: 2012-02-09 gastric irritation, with consequent GI bleeding. 5. Garely AD, Burrows L. Benefit-Risk Clearly, this will also apply to non-prescription medicines, such as 'over-the-counter' NSAIDs, Assessment of Tolterodine in the Treatment of Overactive Bladder in adults. Drug Safety 2004; which may not be captured in full on spontaneous ADR reports. 27 (13): 1043-1057

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Table 1. VigiBase™ reports of fesoterodine and GI haemorrhage

Case Age/Gender TTO Outcome Dose Concomitant drugs GI reactions

1 62/F 62 days positive dechallenge 12 mg aspirin GI haemorrhage nitrendipine ileus atenolol nausea nifedipine 2 68/F NS positive dechallenge; NS diclofenac GI haemorrhage acetylcysteine hospitalised bisoprolol ramipril Zolpidem 3 62/ F 3 days positive dechallenge 4 mg oxycodone melaena abdominal codeine pain diarrhoea amitriptyline 4 64/F 2 days positive dechallenge 8 mg progesterone estriol melaena cimicifuga racemosa 5 69/F 7 days positive dechallenge 4 mg atenolol melaena bendroflumethiazide haemorrhage rectum 6 F 2 days not known 8 mg sertraline GI haemorrhage tramadol abdominal distension

gabapentin 7 F NS not known NS NS GI haemorrhage (reported term: diarrhoea haemorrhagic)

TTO - time to onset; NS - not stated; Drugs in bold have known association with gastric irritation

Response Response from Pfizer Pfizer has conducted a search of the relevant medical literature and the company safety and clinical databases to identify cases of Search and analysis/review of the medical gastrointestinal haemorrhage using the literature and the Pfizer clinical and safety Gastrointestinal haemorrhage Standardized databases for gastrointestinal haemorrhage- MedDRA Query (SMQ, version 15.0, narrow event related terms do not indicate a risk of terms). A broad search of the medical literature gastrointestinal haemorrhage associated with for gastrointestinal haemorrhage-related events fesoterodine and therefore there are no newly reported with urinary antimuscarinic drugs identified issues that may impact on the (including fesoterodine, tolterodine, solifenacin, benefit/risk profile for fesoterodine. darifenacin and oxybuttynin using both generic and trade names) was conducted to assess Background whether there was evidence for association with The Uppsala Monitoring Centre (UMC) has the antimuscarinic mechanism of action. This identified 7 Individual Case Safety Reports (ICSR) search identified a published review, also identified related to Gastrointestinal haemorrhage from in the WHO report, where reference is made to the patients treated with fesoterodine (Toviaz) in the Pfizer Periodic Safety Update Report in which WHO ICSR VigiBase™ database. 1 Six of these gastrointestinal haemorrhage and decreased GI cases were reported by the UMC to contain motility were reported infrequently in association sufficient information regarding time to onset and with tolterodine use. 2 There were no other reports recovery after de-challenge to support a possible in the literature indicative of an association association between fesoterodine and between gastrointestinal haemorrhage events and gastrointestinal bleeding. The UMC proposed use of antimuscarinic drugs, including theoretical mechanisms by which drugs with fesoterodine, for treatment of overactive bladder. antimuscarinic activity, such as fesoterodine, may The Pfizer safety database contains cases of increase gastrointestinal bleeding by increasing Adverse Events reported spontaneously, cases the risk of constipation and may also reduce reported from Regulatory Authorities, cases gastrointestinal motility leading to increased published in the medical literature, and cases of exposure of the gastrointestinal tract to Serious Adverse Events reported from clinical trials concomitantly-administered gastric irritants such and other solicited sources. This database was as NSAIDs. searched for events contained within the

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Gastrointestinal haemorrhage SMQ specifically safety and clinical databases is very low and there from cumulative fesoterodine data (from the is insufficient evidence to link these events to the International Birth Date 20th April 2007 through use of fesoterodine. For those events identified by 28th May 2012). Of the 3,446 fesoterodine ICSRs the UMC that were present in the Pfizer safety in this database, 17 gastrointestinal haemorrhage- database and in which gastrointestinal irritant related events (0.5% of all fesoterodine cases in concomitant medications were present, the case the database) were identified. Nine of these cases narratives do not clarify whether or not the were consumer reports without medical concomitant medication could be directly confirmation. There were no deaths in this dataset responsible for the event. In addition, none of the and six of the cases reported hospitalization. Only narratives for these cases state whether the two of the cases co-reported constipation with the concomitant medications were also discontinued at gastrointestinal haemorrhage term indicating that the same time as fesoterodine, which may have the two outcomes are not necessarily linked. Six of led to the symptom improvement on de-challenge. the 7 cases identified by UMC appear to be Only two of the cases in the Pfizer safety database included in this dataset. The reported events did report constipation in addition to the not indicate a specific pattern and included (n): gastrointestinal haemorrhage event whilst none of Diarrhoea haemorrhagic (1), Gastric haemorrhage the cases identified in the UMC search report (1), Gastrointestinal haemorrhage (3), constipation events. Similarly, in clinical trials, Haematemesis (2), Haematochezia (5), Rectal gastrointestinal haemorrhage events were not haemorrhage (2) and Ulcer haemorrhage (3). associated with constipation in subjects exposed to fesoterodine in comparison with subjects exposed The clinical database of all completed double-blind to placebo. In double-blind clinical trials, and open label Phase 2-4 fesoterodine trials was gastrointestinal haemorrhage-related events did searched for terms contained within the not occur more frequently in subjects exposed to Gastrointestinal haemorrhage SMQ. Of 9,762 fesoterodine compared with those exposed to subjects exposed to fesoterodine, 16 subjects placebo. (0.2%) reported relevant events, only one of which was considered to be treatment-related (a Review of cases of gastrointestinal haemorrhage- case of Gastrointestinal haemorrhage). In double- related events in the literature for antimuscarinic blind clinical trials, 7 subjects of 6,132 exposed to drugs prescribed for overactive bladder, and in the fesoterodine (0.11%) and 7/3,993 (0.18%) Pfizer safety and clinical databases for subjects exposed to placebo experienced fesoterodine does not indicate a risk of gastrointestinal haemorrhage-related adverse gastrointestinal haemorrhage associated with events. In subjects for whom patient profiles are fesoterodine use. Pfizer will continue to monitor all available, the gastrointestinal event was reported adverse events reported to its clinical and safety with constipation by 2/15 subjects exposed to databases and will ensure that product labeling fesoterodine and 2/6 subjects exposed to placebo. appropriately reflects the benefit / risk profile for Treatment emergent events in the fesoterodine fesoterodine. exposed clinical dataset included the following (n): Anal haemorrhage (1), Gastrointestinal References haemorrhage (1, considered treatment-related), WHO Pharmaceuticals Newsletter (WHO-PN), June Haematemesis (1), Haematochezia (4), 2012. Garely AD, Burrows L. Benefit-Risk Hemorrhoidal haemorrhage (1), Occult blood Assessment of Tolterodine in the Treatment of positive (1), Rectal haemorrhage (7). Overactive Bladder in Adults. Drug Safety 2004; 27 (13): 1043-1057 Conclusions The reporting rate of gastrointestinal haemorrhage-related events in the fesoterodine

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WHO Collaborating Centre Tel: +46-18-65 60 60 Fax: for International Drug Monitoring +46-18-65 60 88 E-mail: Box 1051, SE-751 40 Uppsala, Sweden [email protected]

CAVEAT DOCUMENT

Accompanying statement to data released from the Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring

Uppsala Monitoring Centre (UMC) in its role as the WHO Some National Centres that contribute information to VigiBase Collaborating Centre for International Drug Monitoring make an assessment of the likelihood that a medicinal product receives reports of suspected adverse reactions to medicinal caused the suspected reaction, while others do not. products from National Centres in countries participating in the WHO pharmacovigilance network, the WHO Programme for Time from receipt of a report by a National Centre until submission to UMC varies from country to country. International Drug Monitoring. Limited details about each Information obtained from UMC may therefore differ from suspected adverse reaction are received by the UMC. The those obtained directly from National Centres. information is stored in the WHO Global Individual Case Safety Report database, VigiBase. It is important to understand the For the above reasons interpretations of adverse reaction limitations and qualifications that apply to this information and data, and particularly those based on comparisons its use. between medicinal products, may be misleading. The supplied data come from a variety of sources. The The reports submitted to UMC generally describe no more than likelihood of a causal relationship is not the same in all suspicions which have arisen from observation of an reports. Any use of this information must take these unexpected or unwanted event. In most instances it cannot be factors into account. proven that a specific medicinal product (rather than, for example, underlying illness or other concomitant medication) is Some National Centres strongly recommend that anyone who the cause of an event. intends to use their information should contact them for interpretation. Reports submitted to National Centres come from both Any publication, in whole or in part, of information obtained regulated and voluntary sources. Some National Centres accept from UMC must include a statement: reports only from medical practitioners; other National Centres accept reports from a broader range of reporters, including (i) regarding the source of the information, patients. Some National Centres include reports from (ii) that the information comes from a variety of sources, pharmaceutical companies in the information submitted to and the likelihood that the suspected adverse reaction is UMC; other National Centres do not. drug-related is not the same in all cases, (iii) that the information does not represent the opinion The volume of reports for a particular medicinal product may of the World Health Organization. be influenced by the extent of use of the product, publicity, the nature of the reactions and other factors. No information is Omission of this statement may exclude the responsible provided on the number of patients exposed to the product. person or organization from receiving further information from VigiBase.

2011

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