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prepared in collaboration with the WHO Collaborating Centre for International Drug Monitoring, The aim of the Newsletter is to disseminate information on the safety and efficacy of pharmaceutical products, The WHO Pharmaceuticals Newsletter provides you with the latest information on the safety of medicines and based on communications received legal actions taken by regulatory authorities across the from our network of "drug world. It also includes a section on Signals from the information officers" and other Uppsala Monitoring Centre. sources such as specialized bulletins and journals, as well as The feature article in this issue gives you a brief partners in WHO. The information summary of WHO activities to support patient reporting is produced in the form of résumés of adverse drug reactions. in English, full texts of which may be obtained on request from: Quality Assurance and Safety: Medicines, EMP-HSS, World Health Organization, 1211 Geneva 27, Switzerland, E-mail address: [email protected] This Newsletter is also available on our Internet website: Further information on adverse reactions may be obtained from the WHO Collaborating Centre for International Drug Monitoring Regulatory matters Safety of medicines World Health Organization 2012
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TABLE OF CONTENTS Regulatory Matters Aliskiren containing medicines .4 Citalopram hydrobromide .6 Fluoroquinolone .7 Pneumovax® 23 (pneumococcal vaccine polyvalent) .8 Strontium ranelate .8 Safety of Medicines Benzyl alcohol-containing parentral products . 10 Orlistat-containing medicines . 12 Proton Pump Inhibitors (PPIs) . 13 Statins and HIV or Hepatitis C Protease inhibitors. 14 Donepezil – SSRI and SNRI – interaction and Serotonin syndrome . 15 Response from Marketing Authorization Holders (MAH) regarding a signal of Donepezil and Serotonin Syndrome . 19 Ranolazine and Hallucination . 21 Response from MAH regarding a signal of Ranolazine and Hallucination. 23 Empowering patients in pharmacovigilance: current developments in WHO . 26 WHO Pharmaceuticals Newsletter No. 2, 2012 • 3 REGULATORY MATTERS for guidance on their monitored during the course of Aliskiren containing (See WHO Pharmaceuticals Heart rate and blood pressure Newsletter No.1, 2012 for should be measured in all New contraindications contra-indication in patients patients before treatment with with diabetes taking an ACE atomoxetine is started, after and warnings for inhibitor or an ARB in Canada). the dose is increased, and aliskiren containing periodically during treatment to detect possible clinically Press release, EMA, Europe. The European important increases, 16 February 2012 Medicines Agency (EMA) particularly during the first few ( finalized a review of aliskiren months of therapy. containing medicines, (See WHO Pharmaceuticals recommending that these Newsletter No.2, 2006 for medicines should be recommended new warnings in contraindicated in patients with UK, No.6, 2011 for association diabetes or moderate to severe Risk of increased blood with increased blood pressure renal impairment who take pressure and/or heart and increased heart rate in angiotensin converting enzyme Canada and No.1, 2012 for (ACE) inhibitors or angiotensin Australia. The Therapeutic increases in blood pressure receptor blockers (ARBs). In Goods Administration (TGA) and heart rate in the UK). addition, the Agency advised health-care recommended the inclusion of professionals of important a warning that the combination safety information regarding Medicines Safety Update of aliskiren and ACE inhibitor the risk of clinically significant Vol. 3, No. 1, February 2012 or ARB is not recommended in increases in blood pressure ( all other patients because and/or heart rate with the use adverse outcomes cannot be of atomoxetine (Strattera®). Health-care professionals are The EMA advised that doctors advised that atomoxetine is should stop prescribing Drug interactions with contraindicated in patients with aliskiren-containing medicines ritonavir-boosted Human symptomatic cardiovascular to patients with diabetes (type diseases, moderate to severe Immunodeficiency Virus I or type II) or with moderate hypertension or severe (HIV) protease inhibitor to severe kidney impairment cardiovascular disorders whose who are also taking an ACE condition would be expected to USA (1). The U.S. Food and inhibitor or ARB, and should deteriorate if they experienced Drug Administration (US FDA) consider alternative clinically important increases in notified health-care antihypertensive treatment as blood pressure or heart rate. professionals and patients that necessary and that the balance drug interactions between the of benefits and risks of It is also advised that hepatitis C virus (HCV) continuing treatment should be atomoxetine should be used protease inhibitor boceprevir considered carefully for all with caution in patients whose (Victrelis®) and certain other patients receiving underlying medical conditions ritonavir-boosted human aliskiren-containing medicines could be worsened by immunodeficiency virus (HIV) in combination with an ACE increases in blood pressure or protease inhibitors (atazanavir, inhibitor or an ARB. heart rate, such as patients with hypertension, tachycardia lopinavir, darunavir) can The EMA also advised that or cardiovascular or potentially reduce the patients should discuss their cerebrovascular disease. The effectiveness of these treatment with their doctor at drug should be used with medicines when they are used their next scheduled (non- caution in patients with, or together. The US FDA will be urgent) appointment. They with a family history of, updating the boceprevir drug should not stop any of their congenital or acquired QT label to include information treatment before speaking to about these drug interactions. their doctor, because stopping Boceprevir is a HCV protease anti-hypertensive medication Patients should be screened for inhibitor used with the without medical supervision pre-existing or underlying medicines peginterferon alfa can put them at risk. Patients cardiovascular or and ribavirin to treat chronic in clinical trials with aliskiren cerebrovascular conditions (long-lasting) hepatitis C should contact their study site before initiation of treatment with atomoxetine and infection in adults. HIV protease inhibitors are a class WHO Pharmaceuticals Newsletter No. 2, 2012 • 4 REGULATORY MATTERS of anti-viral drugs used to treat are needed to assess the Canada, alerted the risk of HIV infection. Ritonavir is an clinical impact of these drug- fatal outcome associated with HIV protease inhibitor used to interaction findings on these the inadvertent intrathecal "boost" other HIV protease administration of bortezomib inhibitors, increasing their Studies on the efficacy and levels in the blood and making safety of boceprevir when used Since the first global approval them more effective. in patients co-infected with of the drug in May 2003, three A drug interaction study HIV and hepatitis C are cases of inadvertent showed that taking boceprevir ongoing. While data from these intrathecal administration with with ritonavir (Norvir®) in studies are awaited, the CHMP fatal outcome have been combination with atazanavir has recommended updating reported worldwide; these (Reyataz®) or darunavir the product information to occurred in France and Italy. (Prezista®), or with Kaletra® inform prescribers and patients Each case occurred when (lopinavir/ritonavir) reduced of the findings as a intrathecal oncology the blood levels of the HIV precautionary measure. chemotherapy was scheduled medicines and boceprevir in at the same time as the The CHMP recommended that bortezomib intravenous doctors treating patients co- The US FDA recommended infected with hepatitis C and that patients should not stop HIV should be aware of the It is advised that: taking any of their medicines findings of the drug interaction bortezomib should only be without talking to their health- study. They should not co- administered via the care professional. Patients administer boceprevir with approved intravenous (IV) should contact their health- ritonavir-boosted darunavir or care professional if they have lopinavir in HIV and hepatitis C health-care professionals any questions or concerns. The co-infected patients. Co- are encouraged to agency also recommended administration of boceprevir administer chemotherapy health-care professionals who with ritonavir-boosted intended via the have started patients infected atazanavir may be considered intrathecal route at a with both chronic HCV and HIV on a case-by-case basis if different time than other on boceprevir and deemed necessary in patients parenteral chemotherapy. antiretroviral therapy with suppressed HIV viral loads Different connectors containing a ritonavir-boosted and with an HIV strain without should be used for protease inhibitor to closely any suspected resistance to medicinal products to be monitor patients for HCV the HIV regimen. Increased administered via the treatment response and for clinical and laboratory intrathecal or intravenous potential HCV and HIV virologic monitoring is warranted. The CHMP recommended that health-care professionals are encouraged to clearly Europe (2). The European patients should not stop taking label syringes with the Medicines Agency(EMA) any of their medicines without name of the medicinal recommended updating the talking to their health-care product and route of prescribing information for professional. Patients should administration to be used boceprevir (Victrelis®) with contact their health-care and ensure procedures are information about drug professional if they have any in place to enforce a interactions between this questions or concerns. double check of syringe hepatitis C medicine and the labelling before ritonavir-boosted HIV protease (1) FDA Drug Safety inhibitors atazanavir, darunavir Communication, US FDA, train and inform health- care professionals The EMA's Committee for involved in administration Medicinal Products for Human (2) Press release, EMA, and/or management of Use (CHMP) concluded that the 16 February 2012 oncology chemotherapy lower blood levels seen in the ( on dangers of intrathecal drug interaction study could administration of mean that the medicines are bortezomib and the above less effective when given risk minimization together to patients who are co-infected with hepatitis C and HIV. However, the Committee acknowledged that Advisories, Warnings and Canada. Janssen Inc., in data from ongoing clinical Recalls, Health Canada, consultation with Health studies in co-infected patients WHO Pharmaceuticals Newsletter No. 2, 2012 • 5 REGULATORY MATTERS professional immediately if medicines such as ( they experience signs and cimetidine or omeprazole symptoms of an abnormal which are known to inhibit heart rate or rhythm while the metabolism of taking citalopram citalopram, or those known hydrobromide. These include to metabolise poorly via dizziness, palpitations, syncope or seizures. Patients should be Association with dose- cautioned not to stop taking recommended maximum citalopram hydrobromide or to daily dose is 20 mg; change the dose without first the recommended starting Canada (1). Lundbeck Canada, consulting their health-care dose in the elderly is in collaboration with Health professional. Withdrawal Canada, informed that symptoms such as dizziness, citalopram hydrobromide feelings of agitation or anxiety, In addition, citalopram is (Celexa®), should no longer difficulty concentrating, contraindicated in patients with be used at doses greater than abnormal dreams, nausea or congenital long QT syndrome. 40 mg per day due to study vomiting may occur when SSRI Citalopram should be used results indicating a dose- treatment is discontinued, with caution in patients at dependent potential for QT particularly if this is abrupt. higher risk of developing prolongation. 20 mg per day is In the event that citalopram prolongation of the QT interval, the maximum recommended hydrobromide is discontinued including those with congestive dose for patients with hepatic or the dose is reduced, health- heart failure, bradyarrhythmias, impairment, patients who are care professionals should a predisposition to 65 years of age or older, monitor patients closely for the patients who are CYP2C19 re-emergence or worsening of hypomagnesaemia and poor metabolizers, or patients any symptoms of depression. concomitant medicines that who are taking concomitant prolong the QT interval. cimetidine or another CYP2C19 The manufacturer is working inhibitor. Citalopram closely with Health Canada to There are also new monitoring determine if there is a need to recommendations for patients contraindicated in patients with include further information congenital long QT syndrome regarding QT prolongation in hypokalaemia and or known QT interval addition to that already hypomagnesaemia should present in the labelling for be corrected prior to escitalopram oxalate initiation of treatment and ECG monitoring is (Cipralex®), a drug related to recommended in patients with citalopram hydrobromide. magnesium levels should risk factors for Torsade de be periodically monitored; Pointes such as congestive Australia (2). The TGA more frequent ECG heart failure, recent announced that a study of monitoring should be myocardial infarction, citalopram's effect on cardiac considered for patients at bradyarrhythmias or in conduction, which showed higher risk of QT patients taking concomitant dose-dependent QT medications that prolong the prolongation with the medicine, QT interval as well as in has led to the recommended It is also reminded health-care patients with altered maximum daily dose of professionals that suddenly citalopram metabolism (e.g. citalopram being reduced to stopping citalopram may cause liver impairment). 40 mg, along with other withdrawal symptoms. If important changes to dosing citalopram is discontinued or Patients at particular risk for recommendations for the dose reduced, the patient developing prolongation of the should be monitored closely for QT interval include those with the re-emergence or underlying heart conditions Given the above study results, worsening of any symptoms of and those who are predisposed the following changes to dose to low blood levels of recommendations have been potassium and magnesium. A similar study of escitalopram Hypokalaemia and found much more limited dose- hypomagnesaemia should be dependent QT prolongation. No maximum daily dose of corrected before administering changes to dosing citalopram is 40 mg; citalopram hydrobromide. recommendations for in people over 65 years of escitalopram have been made. Patients should be advised to age, those with hepatic contact a health-care dysfunction, those taking (See WHO Pharmaceuticals Newsletters No. 5, 2011 for WHO Pharmaceuticals Newsletter No. 2, 2012 • 6 REGULATORY MATTERS abnormal heart rhythms risks. Co-administration of antibiotics (AVELOX®, CIPRO®, associated with high doses in domperidone with CIPRO® XL, and LEVAQUIN®). the USA and No. 1, 2012 for ketoconazole is contraindicated. Fluoroquinolones have QT interval prolongation in the Caution should be exercised neuromuscular blocking when using domperidone activity and may exacerbate concomitantly with other muscle weakness in patients CYP3A4 inhibitors, which may (1) Advisories, Warnings and with myasthenia gravis. increase plasma levels of Recalls, Health Canada, Exacerbation of myasthenia gravis symptoms in patients ( Patients should be advised to with myasthenia gravis can (2) Medicines Safety Update stop taking domperidone and lead to a requirement for Vol 3, No. 1, February 2012 seek immediate medical respiratory support in some ( attention if they experience patients. It is advised that signs or symptoms of an fluoroquinolone antibiotics abnormal heart rate or rhythm should be avoided in patients while taking domperidone. with a known history of These include dizziness, myasthenia gravis. Association with serious palpitations, syncope or The association between the ventricular arrhythmias exacerbation of myasthenia and sudden cardiac The manufacturers of all gravis and fluoroquinolone use domperidone products are has been established based on Canada. The manufacturers of working with Health Canada to the review of post-marketing domperidone, in collaboration include this new drug dosage reports. Cases of serious with Health Canada, informed and usage recommendations, adverse events, including health-care professionals that as well as information about deaths and requirement for the domperidone should be the risk of serious ventricular ventilatory support have been initiated at the lowest possible arrhythmias and sudden associated with fluoroquinolone dose in adults, including in cardiac death in all Canadian use in patients with patients with Parkinson's Product Monographs for the myasthenia gravis. Exacerbation of symptoms of epidemiological studies have (See WHO Pharmaceuticals myasthenia gravis was already shown that the use of Newsletters No. 2, 2007 for included as an undesirable domperidone may be heart rate and rhythm effect in earlier versions of the associated with an increased disorders in Canada). Product Monographs of these risk of serious ventricular medicines. To reinforce the arrhythmias or sudden cardiac warning, the Product death, particularly in patients Advisories, Warnings and Monographs for the innovator taking daily doses greater than Recalls, Health Canada, fluoroquinolone antibiotics 30 mg, and in patients older have been revised under the than 60 years of age. ( Warnings and Precautions Caution should be exercised section to include information when using domperidone that they may exacerbate concomitantly with drugs that muscle weakness in patients prolong the QT interval, in with myasthenia gravis. Association with patients who have existing worsening of symptoms (See WHO Pharmaceuticals prolongation of cardiac Newsletters No. 6, 2011 for conduction intervals, of myasthenia gravis in risk of worsening of symptoms particularly QTc, and in patients with myasthenia of myasthenia gravis in patients with significant electrolyte disturbances or Canada. The manufacturers of underlying cardiac disease the fluoroquinolone innovator such as congestive heart products (Bayer Inc. and Advisories, Warnings and Janssen Inc.) in consultation Recalls, Health Canada, 9 March 2012 Domperidone should be with Health Canada informed ( initiated at the lowest possible of important updates reflecting dose, which may be adjusted the potential for the upward with caution to achieve exacerbation of myasthenia the desired effect as needed. gravis symptoms in patients In addition, the expected with myasthenia gravis to the benefit of an increased dose labelling for fluoroquinolone should outweigh the potential WHO Pharmaceuticals Newsletter No. 2, 2012 • 7 REGULATORY MATTERS Immunisation has reviewed the place of Pneumovax 23 in myopathy/rhabdomyolysis the National Immunisation when used with lovastatin. vaccine polyvalent) Program and their updated recommendations have been Updated revaccination Communication, US FDA, 28 February 2012 Australia. The TGA advised It is noted that this advice health-care professionals not does not apply to Prevenar®, to routinely revaccinate Prevenar® 13 and Synflorix® immunocompetent individuals pneumococcal conjugate Strontium ranelate with Pneumovax® 23. Revaccination should be No longer recommended considered for patients at a Medicines Safety Update for use in immobilised high risk of serious Vol. 3, No. 1, February 2012 patients or patients with pneumococcal disease, ( provided that at least five thromboembolism (VTE); years have passed since the previous dose of Pneumovax update of warnings regarding serious skin reactions. In April 2011 the TGA advised Class labelling change health-care professionals not Europe. The CHMP has USA. The US FDA approved to administer a second or finalised a review of strontium important safety label changes subsequent dose of ranelate (Protelos® and for statins. The changes Pneumovax® 23 vaccine Osseor®). The Committee include removal of routine pending the outcome of a concluded that these medicines monitoring of liver enzymes review of an apparent remain an important treatment from drug labels. Information increased rate of injection site for women with osteoporosis, about the potential for reactions following but that changes to the generally non-serious and administration of the second prescribing advice are reversible cognitive side effects dose. This review has been necessary to better manage and reports of increased blood completed and the TGA associated risks. sugar and glycosylated advised health-care hemoglobin (HbA1c) levels has The review of these medicines professionals not to routinely been added to the statin was started following the revaccinate immunocompetent labels. The lovastatin label has publication of a study in France individuals. Revaccination of been extensively updated with identifying 199 severe adverse patients at high risk of serious new contraindications and dose reactions reported with these pneumococcal disease should limitations when it is taken medicines from January 2006 be in accordance with the with certain medicines that can to March 2009. Around half of Product Information. increase the risk for muscle these were VTE events, and Pneumovax® 23 is used to about a quarter related to skin prevent life-threatening reactions. VTE and severe skin The US FDA recommended infections by pneumococcal reactions are known risks of that health-care professionals bacteria. The TGA review these medicines and have should perform liver enzyme noted that the adverse events been kept under close review tests before initiating statin observed were consistent with by the CHMP. The risk of VTE therapy in patients and as the known high rates of local was identified in clinical trials clinically indicated thereafter. reactions which occur more and the risk of severe skin If serious liver injury with commonly after a repeat dose reactions had been reported clinical symptoms and/or of Pneumovax® 23. The post marketing. Information on hyperbilirubinemia or jaundice review concluded that the these risks had been included occurs during treatment, adverse events were not due in the product information as therapy should be interrupted. to a problem with the vaccine warnings or listed as reported If an alternate etiology is not manufacturing or handling. found, the statin should not be This advice differs from that in The CHMP has reviewed all the current Australian available data on the safety of Health-care professionals Immunisation Handbook, these medicines. The data should follow the which recommends routine show that the risk of VTE is recommendations in the revaccination five years after higher in patients with a lovastatin label regarding the first dose. The Australian history of VTE, as well as in drugs that may increase the Technical Advisory Group on patients who are temporarily WHO Pharmaceuticals Newsletter No. 2, 2012 • 8 REGULATORY MATTERS or permanently immobilised. hepatitis, interstitial Vandetanib is only available The number of cases of VTE in nephropathy, interstitial lung through a Restricted elderly patients is also shown Distribution Program. Only to be higher with the drug patients should stop prescribers enrolled in the compared with placebo. treatment immediately when CAPRELSA Restricted symptoms of severe allergic Distribution Program can The data also show that the reactions, including skin rash, prescribe the drug. In order to incidence rate of serious skin occur. Treatment should not be prescribe CAPRELSA, reactions such as drug rash re-started at any time in these physicians are required to with eosinophilia and systemic complete mandatory online symptoms (DRESS), Stevens- training which includes a full Johnson syndrome (SJS) and (See WHO Pharmaceuticals description of important safety toxic epidermal necrolysis Newsletter No. 1, 2008 for issues, patient screening and (TEN) is low and no possible reports of severe allergic selection criteria, dosage and mechanism of action has been reactions associated with administration guidelines, ECG identified so far. Because the strontium ranelate in the UK and electrolyte monitoring best results in managing these and No. 3, 2008 for ADR requirements, drug interaction conditions come from early update in Australia). information, and an overview diagnosis and immediate of the patient enrolment discontinuation of any suspect Press release, EMA, drug, it is very important that doctors and patients are alert ( to the time-to-onset and signs Advisories, Warnings and and symptoms of these Recalls, Health Canada, 15 February 2012 ( The CHMP advised that: • doctors should not Serious risk of abnormal prescribe strontium ranelate to patients with current VTE or a Canada. AstraZeneca Canada history of VTE, as well as Inc., in consultation with patients who are temporarily Health Canada, informed of or permanently immobilized; important information patients with current VTE regarding serious risks of QTc or a history of VTE, and those prolongation, Torsade de who are temporarily or Pointes, and sudden death for permanently immobilised are vandetanib (CAPRELSA®). advised to discuss their Cases of Torsade de Pointes treatment with their doctor at and sudden deaths were their next scheduled reported in clinical trials. In addition to them, rash and when treating patients other skin reactions, diarrhea, over 80 years of age at risk of hypertension and vision VTE, doctors should re- abnormalities have also been evaluate the need to continue reported in patients taking the treatment with strontium drug. Vandetanib use should be carefully considered based prescribers should make on a risk-benefit assessment in patients aware of the time-to- patients with indolent, onset and likely signs and asymptomatic or slowly symptoms of severe skin progressive disease because of reaction such as DRESS, SJS the significant treatment- or TEN. The highest risk for occurrence of SJS or TEN is within the first weeks of Health Canada has recently treatment and usually around approved the drug as a three to six weeks for DRESS. monotherapy for the treatment Symptoms or signs of SJS or of symptomatic or progressive TEN include progressive skin medullary thyroid cancer in rash, often with blisters or adult patients with mucosal lesions; symptoms of unresectable locally advanced DRESS include rash, fever, or metastatic disease. eosinophilia and systemic involvement (e.g. adenopathy, WHO Pharmaceuticals Newsletter No. 2, 2012 • 9 SAFETY OF MEDICINES scientific advisory group into No. 1, 2008 for temporary market suspension of aprotinin worldwide, and No. 5, 2011 for The Committee found that the benefits outweigh the risks Lifting suspension of there were a number of when it is used as authorized aprotinin recommended problems with the way the BART study was conducted, which cast doubt on the recommended that the previous conclusions. These Press release, EMA, suspension of the marketing included the imbalances in the 17 February 2012 authorisations for aprotinin- way blood-thinning medicines ( containing medicines in the such as heparin were used, European Union (EU) be lifted. inappropriate monitoring of the This follows a full review of the use of these medicines and benefits and risks of all how problems with the way antifibrinolytic medicines, containing parentral that data from some patients which found that the results of were excluded from the initial the BART study on which the analysis. The Committee found suspension was based are that the BART study's results were not replicated in other The CHMP concluded that studies and that the overall Saudi Arabia The Saudi Food aprotinin's benefits in data available showed that and Drug Authority (SFDA) preventing blood loss outweigh aprotinin's benefits are greater advised health-care its risks in patients undergoing than its risks in the restricted professionals about the isolated heart bypass surgery potential risk of developing who are at high risk of major As a condition of the lifting of Gasping Syndrome in neonates blood loss. It should only be the suspension, the Committee and infant after administering used in this narrower group of also recommended that parentral products that contain patients once the doctor has doctors be warned of the risk benzyl alcohol (BA) as a assessed the benefits and risks of giving patients too little of treatment carefully and heparin, as well as the considered alternative In the US, 16 cases of fatalities establishment of a registry to of pre-term neonates weighing record information on the use 2.5 Kg where flush solutions Aprotinin was suspended as a of aprotinin in the EU. contained 0.9% BA used precautionary measure on the The review also included the periodically. The fatal reaction recommendation of the CHMP, antifibrinolytic medicines was gasping syndrome, the following the preliminary aminocaproic acid and symptoms may include results of the BART study, a tranexamic acid, which have metabolic acidosis, seizure, randomised controlled trial in been used since the 1960s in bradycardia, gasping high-risk heart surgery patients undergoing dental or respiration and cardiovascular patients. These results surgical procedures or at risk appeared to show an increased of complications from bleeding. death rate in patients receiving A report estimated the fatal The Committee found no new aprotinin after 30 days intake of BA was 130 safety concerns for these compared to patients taking mg/kg/day. However, another medicines. However, it noted other medicines, and led to the study reported that the that there is very limited early discontinuation of the average intake of BA in information available on some study by its data safety children who experienced of the conditions that these monitoring board. gasping syndrome was 99 to medicines are used to treat. 234 mg/kg, while a control The current review was started Therefore, the Committee group of infants received 27 to after the publication of the recommended a restricted list 99 mg/kg. However, it should final results of the BART study of conditions in which they be noted that there is a and looked at this study's should be used based on the limitation in determining the results, as well as the results currently available evidence. volume of flush solution used of other clinical studies, data The Committee also requested in these reports. It could be from the scientific literature, that a study be carried out to argued that quantity of BA reports of side effects and gather more information on delivered by medications is information submitted by the how tranexamic acid should be lower than that available in companies that market optimally dosed in children. saline and sterile water. antifibrinolytic medicines. The However, the minimum toxic CHMP also took the views of its (See WHO Pharmaceuticals level has not been established, Newsletter No. 6, 2007 and and therefore, the safety of WHO Pharmaceuticals Newsletter No. 2, 2012 • 10 SAFETY OF MEDICINES use of medicines containing BA anaphylaxis. Surgeons are the planned 524 subjects in neonates has not been reminded to have competent showed a higher mortality rate personnel and emergency and a lower clinical cure rate facilities available for at least 1 among subjects treated with a The World Health Organization hour after administration of fixed seven-day course of the appealed for a mandatory the blue dye. Blue dyes such drug 1g q8h compared to declaration of all excipients as Patent Blue V imported from those treated with a fixed ten- involved in pharmaceutical the EU are used in lymphatic day course of imipenem- manufacturing especially in mapping for sentinel lymph developing countries. Similar node biopsy (SLNB) in breast recommendation was raised by Doripenem is approved in surgery. Patent Blue V does the Advisory Committee for Canada for the treatment of not carry a UK marketing Pharmacovigilance at SFDA, adults with Nosocomial especially for BA content. Pneumonia, including VAP, On the basis of a clinical study complicated Intra-Abdominal Therefore, the SFDA issued a (the ALMANAC trial) and Infections (cIAI) and circular to all health-care follow-up program (the NEW complicated Urinary Tract professionals to include the START program) serious Infections (cUTI), including following considerations: allergic reactions were Pyelonephritis. The approved the use of benzyl alcohol estimated at an incidence rate dosage of the drug for patients containing diluents in of 0.1%. Since 1975 a total of with nosocomial pneumonia preparing injectable 70 case reports of allergic including VAP is 500 mg medicines for paediatric reactions with Patent Blue V administered as a one or four were reported to the Medicines hour intravenous infusion and Healthcare products every eight hours for seven to when applicable, use Regulatory Agency (MHRA). 58 acceptable alternative of these reports have been medicines that do not The use of doripenem 1 g received since 2007, 26 of contain benzyl alcohol; every eight hours in a fixed which were serious reactions. health-care professionals seven-day course has been With currently increasing should be aware about the associated with a higher usage of Patent Blue V in the potential risk of Gasping mortality rate and a lower UK, the number of serious syndrome and to weight clinical cure rate compared to allergic reactions reported to the benefits compared to a fixed ten-day course of us is also expected to rise. potential risk when using imipenem-cilastatin. Treatment benzyl alcohol-containing duration should be guided by parenteral products. Drug Safety Update, the severity of illness, infecting February 2012, Volume 5, pathogen and the patient's issue 7, A2, MHRA clinical response. Personal communication from ( SFDA, 25 February 2012 The Canadian Product ( Monograph contains information on the recommended dose and duration of treatment in the Higher mortality rate Dosage and Administration and a lower clinical cure section. However, based on Risk of serious allergic rate observed during a the new information from this comparative clinical trial investigational VAP study, the UK. The UK Pharmacovigilance Canada. Janssen Inc., in Product Monograph will be Expert Advisory Group of the consultation with Health updated regarding the Commission on Human Canada, informed of new treatment of VAP. Medicines advised health-care safety information regarding professionals that emergency the use of doripenem measures should be available Advisories, Warnings and (DORIBAX®) in the treatment to treat patients that may Recalls, Health Canada, of ventilator-associated experience allergic reactions or pneumonia (VAP). A ( prospective, randomized, Blue dyes (e.g. Patent Blue double-blind, double-dummy, V®, isosulfan blue) used for multicentre Phase III study of imaging purposes during an investigational use of the surgery are associated with the drug in VAP was prematurely occurrence of serious allergic terminated when interim reactions, including analyses of data from 274 of WHO Pharmaceuticals Newsletter No. 2, 2012 • 11 SAFETY OF MEDICINES the first dose (or if more than Orlistat-containing two weeks have passed since the previous dose); Under review in light of initiate appropriate serious adverse events treatment if clinically important Positive benefit-risk Canada. Health Canada heart-related symptoms occur. balance of orlistat- informed of an on-going safety Symptoms include containing medicines review of fingolimod bradyarrhythmia or (Gilenya®). The review was atrioventricular block. Continue Europe. Finalizing its review initiated following reports of to manage and monitor on orlistat-containing serious adverse events, patients until symptoms have medicines and the possible risk including 11 deaths reported of severe liver injuries, the internationally. No deaths have measure blood pressure CHMP concluded that the been reported in Canada. regularly as fingolimod is benefit of these medicines known to increase blood According to Health Canada, continue to outweigh their Currently, it is not clear risks in the treatment of obese whether the deaths were Health Canada advised that or overweight patients with a caused by fingolimod or patients taking fingolimod who body mass index of 28 kg/m2 whether other factors may experience symptoms of heart have played a role. Four of the problems should report them The Committee recommended 11 reports involved serious immediately. Symptoms that the product information heart-related events (three include chest pain, slow or for these products should be involved heart attacks and one irregular heartbeat, or feeling harmonized to ensure that the involved a disturbance of the dizzy. Patients should not stop information on possible very heart rhythm), while the other taking fingolimod without first rare liver-related side effects is seven are unexplained. Among consulting a health-care the same for all orlistat- these seven is a report professional. Patients who containing medicines. This involving a patient in the have any questions or review included the centrally United States who died within concerns about their authorized medicines Xenical® 24 hours of taking the first fingolimod therapy should which is available as capsules speak to their healthcare (120 mg) and Alli® which is At the time of authorization, it available as capsules (60 mg) was known that fingolimod can Before starting fingolimod, and chewable tablets (27 mg) be associated with certain patients should tell their doctor which can be obtained without types of heart rhythm if they are taking other a prescription (‘over-the- disturbances. The Canadian medications such as drugs counter') as well as nationally labelling contains several used to treat abnormal heart authorized orlistat-containing important warnings with rhythms, beta blockers or respect to these risks. At this calcium channel blockers, or if The risk of very rare liver- time, when the drug is used as they have a history of heart- related side effects in recommended in the related problems such as low association with orlistat has authorized Canadian drug label, heart rate, heart rhythm been under close review by the the benefits of fingolimod are disorders, congestive heart CHMP since 2001 for Xenical®, considered to outweigh the failure, or fainting. when the product information Health Canada continues to was updated to reflect post- Health Canada advised health- assess all available information, marketing reports of liver care professionals to continue including information from the reactions in association with to follow the labelling company (Novartis), and orlistat. The current product instructions closely, information from other information for orlistat- particularly with respect to regulators. Health Canada will containing medicines lists patient monitoring. Specifically, take appropriate action based hepatitis, cholelithiasis and a the label recommends that on the results of its review. change in liver enzyme levels as potential liver-related side obtain an ECG before the first dose if one is not available Advisories, Warnings and The CHMP reviewed all in the last six months; Recalls, Health Canada, available data on the risk of observe patients for signs 27 February 2012 liver injury and other side ( effects with orlistat, including bradyarrhythmia, including post-marketing surveillance, periodic assessment of heart data from the studies rate, for at least six hours after supporting the marketing WHO Pharmaceuticals Newsletter No. 2, 2012 • 12 SAFETY OF MEDICINES authorisations and population- healthcare professional if they based studies in the published Inhibitors (PPIs) experience watery stool that literature, and results of an does not go away, abdominal ‘expected versus observed' pain, and fever while taking analysis of reports of severe Possible risk of liver injuries conducted by the Clostridium Difficile- patients should use the marketing authorization Associated Diarrhoea lowest dose and shortest holders at the request of the duration of PPI therapy appropriate to the condition USA. The US FDA notified the The CHMP considered that public that the use of PPIs there was no strong evidence which include rabeprazole Canada (2). Health Canada that orlistat increased the risk sodium, dexlansoprazole, informed of a possible of severe liver injury, and esomeprazole magnesium, association between the use of there was no known omeprazole, lansoprazole, PPIs and an increased risk of mechanism by which orlistat omeprazole and pantoprazole CDAD and announced that was expected to cause liver sodium, may be associated Health Canada is assessing this disorders. The Committee with an increased risk of data on an on-going basis. concluded that the number of Clostridium difficile–associated The studies acknowledge reported severe liver reactions diarrhoea (CDAD). A diagnosis important limitations with in orlistat users was low and of CDAD should be considered regards to study design and below the background rate for patients taking PPIs who the impossibility of establishing expected in these people, develop diarrhoea that does a definite cause-and-effect given the large number of not improve. The US FDA is relationship between PPIs and users. A pattern was not seen working with manufacturers to an increased risk of CDAD, as in the type of liver problems include information about the there are a number of other reported, and in most cases increased risk of CDAD with factors that may play a role. there were other factors which use of PPIs in the drug labels. While a definite association were likely to increase the risk The US FDA is also reviewing between PPI use and CDAD of liver injury, such as existing the risk of CDAD in users of has not been confirmed, the health problems or the use of histamine H2 receptor possibility has not been ruled other medicines. The blockers. H2 receptor blockers out at this time. The potential Committee considered that are used to treat conditions for an increased risk of C. while there may be very rare such as gastroesophageal difficile infection is identified in cases of serious liver injury for reflux disease (GERD), the Canadian labelling for PPI which causality with orlistat stomach and small intestine drugs. Health Canada will cannot be excluded, the cases ulcers, and heartburn. continue to monitor this issue, do not provide good evidence evaluate the scientific evidence of a causal association. The Clostridium difficile (C. difficile) as it emerges and take CHMP also noted that is a bacterium that can cause appropriate action as published population-based diarrhoea that does not studies suggest that obesity improve. Symptoms include may be associated with a watery stool, abdominal pain, Health Canada advised that higher risk of liver disease. and fever, and patients may go patients taking a PPI who on to develop more serious develop a diarrhoea that does (See WHO Pharmaceuticals intestinal conditions. The not improve should speak to a Newsletters No. 5, 2009 for disease can also be spread in health-care professional early communication about an immediately as this may be on-going safety review and CDAD. Symptoms include No. 4, 2010 for labelling The US FDA recommended severe watery or bloody change due to reports of that patients should diarrhoea (at least three bowel severe liver injury in the USA immediately contact their movements per day for two or and the reports in WHO Global health-care professional and more days); fever; loss of seek care if they take PPIs and appetite; nausea; and develop diarrhoea that does abdominal pain or tenderness. not improve. The agency Press release, EMA, Patients taking a PPI should informed health-care 16 February 2012 talk with their doctor or professionals that: ( pharmacist if they have a diagnosis of CDAD questions or concerns about should be considered for PPI their antacid treatment. users with diarrhoea that does not improve; Health-care professionals are advise patients to seek reminded that PPIs should be immediate care from a prescribed at the lowest dose WHO Pharmaceuticals Newsletter No. 2, 2012 • 13 SAFETY OF MEDICINES and shortest duration of therapy appropriate to the condition being treated. A diagnosis of CDAD should be considered for any patient who has risk factors for CDAD and who has persistent or severe References: (1) FDA Drug Safety Communication, US FDA, 8 February 2012 ( (2) Advisories, Warnings and Recalls, Health Canada, 16 February 2012 ( Statins and HIV or Hepatitis C Protease inhibitors Interaction increases risk of muscle injury USA. The US FDA notified health-care professionals of updates to the prescribing information concerning interactions between HIV or HCV protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for myopathy. The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal. The US FDA recommended that health-care professionals should follow the recommendations in the prescribing information when prescribing HIV or HCV protease inhibitors with Reference: FDA Drug Safety Communication, US FDA, 1 March 2012 ( WHO Pharmaceuticals Newsletter No. 2, 2012 • 14 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 25). 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 Donepezil – SSRI and SNRI – interaction and Serotonin syndrome Donepezil is a specific and reversible inhibitor of Donepezil is a specific and reversible inhibitor of acetylcholinesterase used to treat Alzheimer's acetylcholinesterase, the dominating disease. A number of combinations of donepezil cholinesterase in the brain 1 The pathogenesis of and the adverse reaction serotonin syndrome Alzheimer's disease has been linked to the appeared in VigiBase. This is not listed for deficiency of the neurotransmitter acetylcholine donepezil. The reports showed that different and the acetylcholinesterase inhibitors were antidepressants like serotonin reuptake inhibitors subsequently introduced as treatment for SSRIs, selective serotonin-norepinephrine Alzheimer's. Its efficacy is believed to be attained reuptake inhibitors (SNRIs) and a serotonin through the augmentation of acetylcholine- antagonist and reuptake inhibitor (SARI) were co- mediated synaptic transmission. It is also shown reported with donepezil suspected to cause this that this type of drug protects cells from the effect. An extended search was made to toxicity of free radicals and β–amyloid-induced investigate a possible interacting effect between donepezil and antidepressants. After removing injury. 2 Studies in rats and mice show effects on suspected duplicates 13 reports from six countries serotonin or serotonin receptors in brain but the remained. In four cases donepezil was added to effect in humans remains unclear.3,4 Serotonin pre-existing SSRI/SNRI/SARI treatment and in five syndrome is not listed for donepezil. cases SSRI/SNRI/ SARI was added to pre-existing Serotonin syndrome is a potentially life- donepezil treatment. In three of the four cases threatening reaction that may occur in patients where donepezil was added to pre-existing using drugs that elevate the serotonin levels. The treatment the reporters suspected an interaction most common drugs causing this reaction are between donepezil and the other drug/drugs. monoamine oxidase inhibitors (MAO-inhibitors), Studies in the brain of mice and rats have shown tri-cyclic antidepressants (TCAs) and selective that donepezil seem to affect serotonin levels and serotonin reuptake inhibitors (SSRIs), SNRIs and serotonin receptors, however there is limited SARIs.5 The excess serotonin activity in receptors information in literature about donepezil's in the central nervous system and peripheral serotonergic effects in human brain. These serotonin receptors results in myoclonus, spontaneous reports from several countries hyperreflexia, diaphoresis, mental changes, indicate that donepezil might have an effect on autonomic symptoms, shivering, tremor and in serotonin levels in human brain and that there severe cases neuromuscular rigidity, delirium and might be an interacting effect of this drug and life-threatening hyperthermia. Complications are SSRIs/SNRIs/SARIs. common and include dehydration, infection, respiratory and renal failure and disseminated intravascular coagulation. 5,6 The primary treatment consists of discontinuation of suspected WHO Pharmaceuticals Newsletter No. 2, 2012 • 15 drugs and sometimes administration of serotonin venlafaxine could be both pharmacokinetic and receptor antagonists. The symptoms of the pharmacodynamic. syndrome usually resolve within 24 hours if Time to onset of serotonin syndrome (counted discontinuing the causative drugs, but confusion from the start date of the latest added suspected may last for days and complications may result in drug until the onset of signs of serotonin syndrome) was listed in four reports and was: the same day, three days, four days and 15 days. Reports in VigiBase There was also one report that listed serotonin A total of eleven reports of donepezil and syndrome to have occurred within a month (no serotonin syndrome exist in VigiBase specific start date was listed for the drug, only the (20 October 2011). The reports showed that month), one report listed the syndrome to have different selective serotonin reuptake inhibitors started two days after the patient started taking (SSRIs), selective serotonin-norepinephrine donepezil (although no dates were listed for the reuptake inhibitors (SNRIs) as well as a serotonin other drugs taken concomitantly) and one report antagonist and reuptake inhibitor (SARI) were co listed the adverse reaction to start one day before reported with donepezil suspected to cause this donepezil was added (but since it was unclear if effect. The majority of the reports contained SSRIs the tremor the patient experienced the day before and SNRIs. In order to investigate a possible starting treatment with donepezil was a sign of interacting effect a new search was performed serotonin syndrome, this case will be kept in the where all other reports containing SSRIs and evaluation). The time to onset of the reaction SNRIs, donepezil and serotonin syndrome were seem to be plausible when comparing to a post- extracted from VigiBase. Table 1 lists the drugs marketing surveillance study aiming to identify found co-reported as suspected with donepezil to serotonin syndrome cases in United Kingdom in cause serotonin syndrome. In total 27 reports the late nineties. Out of 19 patients identified with were found, out of which 13 were left when serotonin syndrome the time to onset was less suspected duplicates were removed. These than 14 days for all.9 thirteen reports came from six different countries: Australia, France, Germany, Switzerland, United Most of the patients were, as expected for Kingdom and USA. Two of the reports from USA Alzheimer's disease, quite old. In eight of the nine have been published.7,8 reports where age was listed the age varied between 72-85 years and there was one patient In four cases donepezil was added to an existing that was 40 years old. Dechallenge was listed in all treatment with SSRI/SNRI/SARI and in five cases but one report. In all of the thirteen reports the it was instead an SSRI/SNRI/SARI that was added SSRIs/SNRIs/the SARI were withdrawn when to pre-existing donepezil treatment. There was serotonin syndrome was suspected. Totally eleven also one case where the drugs were started on the patients recovered and two patients died. In two same day and three cases where there was no cases donepezil was withdrawn at the same time information on the administration order of the as the SSRIs/SNRIs/the SARI. In one of these the drugs. In the four cases where donepezil was SARI trazodone was withdrawn but myoclonus added to pre-existing treatment the reporter persisted for over 24 hours which lead to suspected an interaction between donepezil and withdrawal of donepezil as well, two days later. No other drugs in three of the reports. In one of those more information exists on the event but the reports the reporter also hypothesized that an reporter listed the patient as recovering. interaction between donepezil, mirtazapine and WHO Pharmaceuticals Newsletter No. 2, 2012 • 16 Table 1. Overview of individual case reports for donepezil and serotonin syndrome Other reported ADRs Interaction with Donepezil suspected by reporter Tremor, hyperreflexia Rhabdomyolysis, fever, Agitation, tremor, confusion, Yes, between venlafaxine, mirtazapine Yes, between donepezil and fluoxetine antagonistic properties) Fatigue, myoclonus trazodone was added to preexisting donepezil treatment. Extrapyramidal syndrome w No ("the reporter sees a causal urinary retention, dysphagia, relationship between duloxetine & the rigor, disorientation, events but can't evaluate if there was repeated finger movement, an interaction") Convulsions NOS, hypertension NOS, confusion, short term memory loss, muscle rigidity, tensing, cramping, hyperthermia etc. Fever, urinary tract infection, decreased alertness, dehydration, failure to thrive Urinary incontinence, confusional state, delirium, decreased appetite Altered mental status, acute onset of chills, reduced appetite, urinary incontinence, elevation of body temp Diarrhea, tremulousness, myoclonus, hyperreflexia, gait instability, fever Sweating increased, Yes, between donepezil and paroxetine confusion, hypertension WHO Pharmaceuticals Newsletter No. 2, 2012 • 17 cases this is indicative for an interaction. In one of Literature and labelling these cases donepezil was added last but SSRIs were added only two and five days before In vitro studies have shown that the cytochrome donepezil followed by symptoms of serotonin P450 isoenzymes CYP3A4 and to some extent syndrome four days after donepezil was added. In CYP2D6 are involved in the metabolism of another case where donepezil was added to a pre- donepezil. Interaction studies in vitro have also existing SSRI treatment donepezil was added six shown that drugs like ketokonazol and kinidin weeks after the SSRI which makes the (inhibitors of CYP3A4 and CYP2D6 respectively) confounding less. However, in this case we do not inhibits the metabolism of donepezil. 1 This means have the information on the exact time of the that these drugs and other inhibitors of these onset of the syndrome. But even if these two enzymes could inhibit the metabolism of donepezil cases might have confounding factors there is one and thus lead to higher concentrations of the drug. report where a 76 year-old female had been There are no human studies on serotonin or treated with the drug fluoxetine (SSRI) for two serotonin receptors with donepezil. An in vitro years and when donepezil was added the serotonin study on rats showed changes in serotonin levels syndrome occurred within 15 days. In this case it by acute doses of donepezil3 and another study on is not very likely that the SSRI is causing the mice showed that twice daily treatment of syndrome on its own. This is by itself a strong donepezil for two weeks significantly increased enough case to suspect an interaction. It is also striatal 5HT2A mRNA levels.4 important to notice that in three of the four cases where donepezil was added to pre-existing Alzheimer's disease has itself shown to affect treatment with SSRIs/SNRIs the reporter serotonin receptors.10 It has also been shown that suspected an interaction to have occurred and in serotonergic transmission is impaired in one report the reporter hypothesized that an Alzheimer's disease. 11 interaction could be both pharmacokinetic and pharmacodynamic. We suggest awareness of this Discussion/Conclusion possible interaction for all prescribers that are The reports in VigiBase indicate an interaction using these drugs together. between donepezil and SSRIs and SNRIs, causing serotonin syndrome. It is known that drugs that inhibit CYP2D6, could inhibit the metabolism of 1. SPC for donepezil (Aricept).URL: donepezil, leading to higher concentrations of the drug. There are studies that show an effect of Accessed: 9 November 2011. donepezil on serotonin levels and serotonin 2. Tabet N. Acetylcholinesterase inhibitors receptors in mice and rats3,4and so it is possible for Alzheimer's disease: anti- that donepezil is in itself affecting this substance inflammatories in acetylcholine clothing! but it is still unclear exactly what effect the drug Age and Ageing, July 2006; 35 (4): 336- has on these systems and on serotonin levels in 3. Sherman E, Rossi S, Szasz B, Juranyi Z, In nine of the cases the age might have been a Fallon S, Pomara N. et al. Changes in contributory factor (varying from 72-85 in all but cerebral neurotransmitters and one case where age was listed), since the metabolites induced by acute donepezil metabolism slows down with age. This was also and memantine administrations: A listed as the probable cause of the syndrome in microdialysis study. Brain research one of the reports from the USA; "poor drug bulletin, December 2005; (69): 204-213. excretion and half-life prolongation probably 4. Hayslett RL, Tizabi Y, Effects of donepezil, caused the syndrome".7 With age more drugs are nicotine and haloperidol in the central often used together and the possible interaction serotonergic system in mice: Implications mechanisms might be more complex. This as well for Tourette's syndrome. Pharmacology, as the fact that Alzheimer's disease in itself is biochemistry and behavior 2005; (81): affecting serotonin levels are factors that might be confounders in these cases. 5. Slettedal J K, Nilssen D O, MAgelssen M, Løberg E M, Mæhlen J. Brain pathology in The reports in VigiBase could in some cases be the fatal serotonin syndrome: Presentation of result of a SSRI/SNRI acting alone. It is not two cases. Neuropathology 2011; 31: possible to say to what extent donepezil was involved in the possible interaction when the 6. Sternbach H. The serotonin syndrome, patients were already treated with donepezil and a Am J Psychiatry, June 1991; 148(6): 705- SSRI/SNRI was added followed by the syndrome. However when the patient was already treated 7. Yee AH, Eeko F, Wijdicks M. A perfect with a SSRI/SNRI and donepezil was added storm in the emergency department. followed by the syndrome the same day as in one Neurocrit care, April 2010; 12: 258-260 case or within four or 15 days as in two other WHO Pharmaceuticals Newsletter No. 2, 2012 • 18 8. Pearce S, Ahmed N, Veras GM. A case changes in dementia of the alzheimer study of Delayed Serotonin syndrome: type Journal of Neurochemistry. Lessons learned. The consultant December 1984; 43(6): 1574-1581. pharmacist 2009; 24(1): 64-68. 11. Lorenzi C, Marcone A, Pirovano A, Marino 9. FJ Mackay, NR Dunn, Rd Mann, E, Cordici F, Delmonte D et al. Serotonin Antidepressants and the serotonin transporter and saitohin genes in risk of syndrome in general practice British Alzheimer's disease and frontotemporal Journal of General Practice, lobar dementia: preliminary findings. November 1999; 871-874. Neurol Sci. December 2010; 31(6):741-9. 10. Cross AJ, Crow TJ, Ferrier IN, Johnson JA, Bloom SR, Corsellis JA. Serotonin receptor Response from Marketing Authorization Holders (MAH) regarding a signal of Donepezil and Serotonin Syndrome Donepezil has demonstrable effects on cognitive and global function parameters in patients with Alzheimer disease (AD) is the most common form Alzheimer's disease. Steady state is achieved of dementia, effecting more than 35 million people within three weeks and there is little diurnal worldwide. Age is the primary risk factor for AD. variability. Elimination is mainly renal and there is The incidence of the disease doubles every five no evidence of enterohepatic re-circulation.6 years after 65 years of age with the chance of Donepezil is primarily metabolized by the receiving a diagnosis of AD approximately one in cytochrome P450 (CYP) isoenzymes 2D6 and 3A47, three by the age of 85.1 and has minimal inhibitory activity against these Serotonin syndrome is a potentially life- isoenzymes8, and a low potential to interact with threatening condition that occurs due to excess drugs that inhibit CYP 2D6 and CYP 3A4, e.g. serotonergic agonism of central nervous system cimetidine and ketoconazole8,9. In addition a study receptors and peripheral serotonergic receptors. in healthy volunteers indicated that there were no Signs of excess serotonin range from mild cases of significant differences in either the PK or tremor and diarrhea to life-threatening cases of tolerability of donepezil HCl or sertraline HCl (a delirium, neuromuscular rigidity and hyperthermia. SSRI metabolized by CYP3A4 and CYP 2D The true incidence of serotonin syndrome is pathways) during multiple-dose co-administration unknown. However, it has been noted that the at steady-state.10 apparent increase in incidence is consistent with the increase in use of proserotonergic agents, Clinical Trial Experience including selective serotonin-reuptake inhibitors In the donepezil clinical studies analyzed to date, (SSRIs) and selective serotonin-norepinephrine which have included over 6 million patient days of reuptake inhibitors (SNRIs) and other exposure there have been no reports of a serious antidepressant agents.2 Serotonin syndrome is adverse event of serotonin syndrome. The more likely to occur after chronic ingestion of a majority of these patient days of exposure were in serotonergic agent, and is most often seen in studies that allowed the concomitant use of SSRIs patients who are on multiple serotonergic agents. and SNRIs as well as other medications with However, serotonin syndrome has been reported serotonergic activity. 11 In a recent study of in patients on a single serotonergic agent at a donepezil 23 mg in patients with severe AD, over therapeutic dose.3 27% of the subjects were receiving concomitant Individuals with AD are known to have a high rate antidepressants at baseline.12 of depression. One study examined the use of 4 drug classes in patients with AD and found that Post-marketing Experience greater than 30% of AD patients were receiving Aricept (donepezil hydrochloride) was first antidepressants.4 marketed in the US in 1997 and is now available in over 90 countries with over 6.5 billion patient days of exposure. A review of the post marketing Donepezil is a potent, selective, reversible, central spontaneous and literature reports of serotonin inhibitor of acetylcholinesterase. A study of syndrome13 where donepezil was considered as a donepezil's effect on the rat cortex found that suspect product indicates that: donepezil elevated extracellular the incidence of such reports was very rare acetylcholinesterase without any effect on the with less than one report received for every level of serotonin (5-HT).5 three years of marketing (reporting rate of WHO Pharmaceuticals Newsletter No. 2, 2012 • 19 approximately two per ten million years of guideline for out-of-hospital management, patient exposure); Clinical Toxicology, 45:4, 315-332. all of the patients had other risk factors for 4. Zhu, C. et al. Utilization of serotonin syndrome including the use of one Antihypertensives, Antidepressants, or more known serotonergic agents, and age; Antipsychotics and Hormones in Alzheimer there were no reports of a positive rechallenge Disease. Alzheiemer Disease and and one report of a negative rechallenge; Associated Disorders. 2011:25(2): 144-148. the reports generally had only minimal 5. Giacobini E, Zhu X D, Williams E, Sherman information concerning the event, the drug exposure, and/or the patient's past medical KA. The effect of the selective reversible acetylcholinesterase inhibitor E2020 on extracellular acetylcholine and biogenic Therefore while there are cases where a amine levels in rat cortex. relationship to the donepezil therapy cannot be excluded, there is no single case that suggests Neuropharmacology. February 1996; donepezil therapy is the precipitating factor in the development of serotonin syndrome. 6. Summary of Product Characteristics, 7. Tiseo PJ, Perdomo CA, Friedhoff LT. The very rare reports of serotonin syndrome in Metabolism and elimination of 14C- patients who were receiving both a pro- donepezil in healthy volunteers: a single- serotonergic agent and donepezil contain multiple dose study. Br J Clin Pharmacol 1998; 46 confounders. The rate of reporting is consistent (Suppl. 1): 19–24. with these events being due solely to the SSRI/SNRI given the high concomitant use of such 8. Tiseo PJ, Perdomo CA, Friedhoff LT. agents in the population receiving donepezil Concurrent administration of donepezil HCl therapy. The currently available data, including and cimetidine: assessment of the lack of evidence suggesting that donepezil pharmacokinetic changes following single increases serotonin, either directly or through a and multiple doses. Br J Clin Pharmacol pharmacokinetic interaction, does not suggest 1998; 4 6(Suppl. 1): 25–9. donepezil therapy is associated with an increased 9. Tiseo PJ, Perdomo CA, Friedhoff LT. risk of serotonin syndrome. Reports of serotonin syndrome will continue to be monitored closely. Concurrent administration of donepezil HCl and ketoconazole: assessment of I. Surick, MD, MPH pharmacokinetic changes following single and multiple doses. Br J Clin Pharmacol Woodcliff Lake, NJ 1998; 46 (Suppl. 1): 30–4. 10. Nagy, C. et al. Concurrent administration United States, December 2011. of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety 1. Querfurth, H., LaFerla, F. Alzheimer's following single and multiple oral doses. Br Disease. N Engl J Med 2010;362:329-44. J Clin Pharmacol. November 2004; 58 2. Boyer, E., Sharron, M. The Serotonin Syndrome. N Engl J Med 2005;352:1112- 11. Data available in-house. 12. Data available in-house. 3. Selective serotonin reuptake inhibitor 13. Manufacturer's International Adverse poisoning: An evidence-based consensus Event database.
WHO Pharmaceuticals Newsletter No. 2, 2012 • 20 Ranolazine and Hallucination write "hallucinations" even though they often mean visual hallucinations. This general situation There are 13 reports of ranolazine and is reflected in the 13 reports in association with hallucination in VigiBase. Two of these reports had ranolazine in which "hallucination" was reported in diltiazem co reported and might be explained by nine cases without further presentation, visual an interaction between the drugs. Only two cases hallucination was reported in 3 cases and both had the time to onset reported which was the visual and auditory hallucinations were reported in same day as drug administration was started. The the remaining case. outcome was recovered in five cases and was unknown in the remaining eight cases. In the five VigiBase Reports cases in which recovery was documented, At the time of assessment (4 May 2011), VigiBase ranolazine was withdrawn in three cases, reduced had received 13 cases of hallucination in in dose in another case and there was no association with ranolazine (see Table 1). The information on withdrawal in the last case. In six association had an IC value of 1.47 with an IC025 of the eight cases where the outcome was of 0.58 (for further explanation of the IC value and reported as unknown, the reaction was reported to disproportionate reporting see The UMC Measures have abated with ranolazine withdrawal. Although of Disproportionate Reporting- a brief guide to information is lacking in most of the reports, the their interpretation, in the Signal section of WHO common factor for all is the use of ranolazine. The Pharmaceuticals Newsletter No.1, 2012). The 13 reports describing recovery after withdrawal or cases were submitted by two national centres: the reduction of dose of the drug further strengthen a US (12 cases) and the UK (one case). The patients strong support for the existence of a causal ranged in age from 52 to 93 years with a median of 77 years and there were two males and six females in the eight reports which provided information on age and gender. Ranolazine was Ranolazine is a recently marketed drug for the the only drug suspected in all but one of the 13 treatment of chronic angina pectoris.1 The cases. In the remaining case, an interaction mechanism of action is largely unknown but between ranolazine and diltiazem was suspected. ranolazine may have some antianginal effects Ranolazine is a substrate of cytochrome CYP3A4 through inhibition of the late sodium current in and inhibitors of CYP3A4 increase plasma cardiac cells. This reduces intracellular sodium concentrations of ranolazine. Potent inhibitors of accumulation and consequently decreases CYP3A4 are contraindicated and moderately potent intracellular calcium overload. Via its action to inhibitors such as diltiazem should be used with decrease the late sodium current, ranolazine is caution. Another case has diltiazem as a considered to reduce these intracellular ionic concomitant drug and it is possible that an imbalances during ischaemia.2 The approved interaction may have occurred in this case also. indication is as add-on therapy for the Eight of the cases have several concomitant drugs symptomatic treatment of patients with stable (see Table 1) which are generally typical of the angina pectoris who are inadequately controlled or drugs which might be expected to be used intolerant to first-line antianginal therapies (such concomitantly in this patient population. In the as beta-blockers and/or calcium antagonists). two cases where the time to onset was reported, it Common adverse reactions observed in clinical was reported as the same day as drug trials with ranolazine include dizziness, headache, administration was started. The outcome was constipation, nausea, vomiting and asthenia. recovered in five cases and was unknown in the Psychiatric reactions are listed as rare and include remaining eight cases. In the five cases in which anxiety, insomnia and disorientation. recovery was documented, ranolazine was withdrawn in three cases, reduced in dose in Hallucination is a perception of visual, auditory, another case and there was no information on tactile, olfactory or gustatory experiences without withdrawal in the last case. In six of the eight an external stimulus and with a compelling sense cases where the outcome was reported as of the reality, usually resulting from a mental unknown, the reaction was also reported to have disorder or as a response to a drug.3 The medical abated with ranolazine withdrawal. meaning of hallucination is generally consistent with the ordinary use of the word. In WHOART, In the 12 cases where the indication was reported, the preferred term "hallucination" describes all it was angina pectoris in ten cases, chest pain in types of hallucinations while MedDRA contains a one case and coronary artery disease in the other preferred term on each of auditory, gustatory, case, consistent with the approved use of the olfactory, synaesthetic, tactile, visual and mixed drug. Additional psychiatric adverse reactions were as well as the general term. In reporting reported in nine of the 13 cases. There did not hallucinations in general, many reporters simply appear to be any particular pattern to these additional reactions with reports of confusion WHO Pharmaceuticals Newsletter No. 2, 2012 • 21 disorientation, amnesia and delirium reported Table 1. VigiBase case reports of hallucination with ranolazine Case Gender/Age Other reactions Concomitant drugs Quetiapine, memantine, mirtazapine, Isosorbide, metoprolol, atorvastatin, confusional state furosemide, acetylsalicylic acid, warfarin, temazepam, clopidogrel Syncope, renal function abnormal, mental status changes, fall, drug level increased, delirium, confusional state, asthenia Delirium, aggressive Dizziness, ataxia, Doxazosin, nicotinic acid, glyceryl dreaming abnormal trinitrate, diltiazem Urinary tract infection, Acetylsalicylic acid, amlodipine, atenolol, Unknown* muscle contractions clopidogrel, colchicine, furosemide, involuntary, amnesia, glyceryl trinitrate, insulin, isosorbide, hypokinesia, apathy, lisinopril, metoclopramide, dysphonia, chest pain, multivitamins, pantoprazole, asthenia, medication simvastatin, warfarin Acetylsalicylic acid, cetirizine, clopidogrel, escitalopram, esomeprazole, glyceryl trinitrate, hydralazine, isosorbide, metoprolol, multivitamins, paracetamol, simvastatin Acetylsalicylic acid, carvedilol, incoherence, stupor, speech disorder, drug Diltiazem(interacting) prescribing error, drug interaction, dizziness, coordination abnormal, coma, medication error Pruritus, confusion, Acetylsalicylic acid, atorvastatin, disorientation, nausea bisoprolol, candesartan, fluticasone propionate/salmeterol xinafoate, furosemide, isosorbide, lansoprazole, spironolactone, theophylline, tiotropium WHO Pharmaceuticals Newsletter No. 2, 2012 • 22 Vomiting, nightmares, Lactobacillus acidophilus, vitamins, fish nausea, dyskinesia, oil, ergocalciferol, ascorbic acid, folic acid, plantago ovata, travoprost, promethazine, fluconazole, epinephrine, hydrocodone, clonazepam, levothyroxine, oxygen, gabapentin, pioglitazone, insulin glargine, acetylsalicylic acid, escitalopram, furosemide, metoprolol, carvedilol, valsartan Weight decrease, vomiting, appetite decreased * Although the outcome was reported as unknown, a positive dechallenge was also reported. lacking in most of the reports, the common factor Labelling and Literature is the use of ranolazine. Moreover, recovery was As mentioned in the Introduction, among apparently documented in ten reports after psychiatric reactions, the product labelling ranolazine was withdrawn or reduced in dose and mentions anxiety and insomnia as uncommon and this strongly supports the existence of a causal disorientation as rare. There are no reports of hallucination in association with ranolazine in the literature. In the clinical trial with the largest number of subjects (ranolazine: 3268, placebo: 1. SPC for Ranolazine (Latixa). URL: 3273), psychiatric disorders were reported at a rate of 7% compared with 5% in placebo but no Accessed 2 May 2011. individual term was reported at a rate greater than 3%.1 2. SPC for Ranolazine (Ranexa). URL: Discussion and Conclusion Accessed 2 May 2011. Case reports in VigiBase suggest that there is a 3. Harrison's Principles of Internal Medicine, signal for the association of ranolazine and AS Fauci et al eds, 17th edition, 2008, hallucination. There are 13 reported cases with a significant IC value. Although information is Response from MAH regarding a signal of Ranolazine and Hallucination The WHO identified "hallucination" as a potential Prior to identification of "hallucination" as a safety signal for ranolazine on 29 August 2011 and potential safety signal by WHO, the MAH for invited the Marketing Authorization Holders (MAH) ranolazine had already identified, analysed and for ranolazine (Gilead Sciences, Inc. in North managed the above mentioned signal. America and Menarini International Operations Through routine signal detection activities, Luxembourg S.A., MIOL in European countries) to "hallucination" was identified as a potential signal comment on the signal. for ranolazine. To further evaluate and A licensing agreement is in place between Gilead characterize the signal, the MAH initiated a and Menarini. Gilead is the holder of the global cumulative review of Individual Case Safety safety database and is responsible for production Reports (ICSRs) describing Adverse Drug of aggregate reports (including PSURs) and the Reactions (ADRs) included in the System Organ identification, investigation, monitoring and Class (SOC) "Psychiatric disorders". management of any safety issues specific to This review was presented within the Periodic ranolazine in collaboration with Menarini. Menarini Safety Update Report covering the period is responsible for the maintenance of the European 27 January 2010 to 26 July 2010. The cumulative Union Risk Management Plan (EU-RMP). review identified 13 ICSRs related to the medical concept of hallucination. Based on this review, WHO Pharmaceuticals Newsletter No. 2, 2012 • 23 there was some evidence of a causal relationship between ranolazine and "hallucination." Thus, "hallucination" was added to the Undesirable Effects - Postmarketing Experience section of the ranolazine Company Core Data Sheet (CCDS) on 5 October 2010. In the US, a labelling supplement to add "hallucination" as a postmarketing adverse reaction in the United States Prescribing Information (US PI) was submitted to the US Food and Drug Administration (FDA) on 1 October 2010 and was approved by the US FDA and implemented in the US PI on 11 July 2011. In the EU, a variation to incorporate "hallucination" as an uncommon ADR in the Psychiatric disorders SOC within Section 4.8 (Undesirable effects) of the EU-Summary of Product Characteristics (EU-SmPC) was submitted and was validated by the European Medicines Agency (EMA) on 18 February 2011. The Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion on the variation on 14 April 2011 and the European Commission approved the CHMP opinion on 17 June 2011. On 7 July 2011 another variation to introduce into Section 4.7 of the EU-SmPC the PT "hallucination" as an ADR potentially capable of interfering with the ability to drive and use machines was submitted to the EMA. This variation is still on-going. Within the EU, ranolazine has a Risk Management Plan. A revision of the EU-RMP to introduce "hallucination" as a newly identified risk is on-going, and the revised EU-RMP will be submitted to the EMA no later than 26 March 2012. Local labelling updates in other applicable territories based upon the updated CCDS are either on-going or planned. All adverse events received by the MAH are carefully reviewed for new safety signals. As a new safety signal is identified, the MAH takes appropriate actions to manage the risk associated with the signal, which could include but is not limited to updating the product labelling information or more urgent safety restrictions. Upon recognition of the signal for "hallucination", which occurred prior to its identification by WHO, the MAH managed, and communicated the signal to applicable regulatory authorities and prescribers. WHO Pharmaceuticals Newsletter No. 2, 2012 • 24 WHO Collaborating Centre Tel: +46-18-65 60 60 for International Drug Monitoring Fax: +46-18-65 60 88 E- Box 1051, SE-751 40 Uppsala, mail: [email protected] Accompanying statement to data released from the Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring Uppsala Monitoring Centre (UMQ in its role as the Some National Centres that contribute WHO Collaborating Centre for International Drug information to VigiBase make an assessment of Monitoring receives reports of suspected adverse the likelihood that a medicinal product caused reactions to medicinal products from National the suspected reaction, while others do not. Centres in countries participating in the WHO Time from receipt of a report by a National pharmacovigilance network, the WHO Centre until submission to UMC varies from Programme for International Drug Monitoring. country to country. Information obtained from Limited details about each suspected adverse UMC may therefore differ from those obtained reaction are received by the UMC. The directly from National Centres. information is stored in the WHO Global Individual Case Safety Report database, For the above reasons interpretations of VigiBase. It is important to understand the adverse reaction data, and particularly limitations and qualifications that apply to this those based on comparisons between information and its use. medicinal products, may be misleading. The supplied data come from a variety of The reports submitted to UMC generally describe sources. The likelihood of a causal no more than suspicions which have arisen from relationship is not the same in all reports. observation of an unexpected or unwanted Any use of this information must take these event. In most instances it cannot be proven that factors into account. a specific medicinal product (rather than, for Some National Centres strongly recommend that example, underlying illness or other concomitant anyone who intends to use their information medication) is the cause of an event. should contact them for interpretation. Reports submitted to National Centres come Any publication, in whole or in part, of from both regulated and voluntary sources. information obtained from UMC must include a Some National Centres accept reports only from medical practitioners; other National Centres accept reports from a broader range of reporters, regarding the source of the information, including patients. Some National Centres that the information comes from a variety include reports from pharmaceutical companies of sources, and the likelihood that the in the information submitted to UMC; other suspected adverse reaction is drug-related National Centres do not. is not the same in all cases, that the information does not represent The volume of reports for a particular medicinal the opinion of the World Health product may be influenced by the extent of use of the product, publicity, the nature of the Omission of this statement may exclude the reactions and other factors. No information is responsible person or organization from provided on the number of patients exposed to receiving further information from WHO Pharmaceuticals Newsletter No. 2, 2012 • 25 Empowering patients in pharmacovigilance: current developments in The Monitoring Medicines (MM) project was developed by the World Health Organization (WHO). It is a major international project, with the full title ‘Optimizing drug safety monitoring to enhance patient safety and achieve better health outcomes'. It started in September 2009 and is coordinated by the Uppsala Monitoring Centre (UMC), Sweden, with funds from the European Commission. 11 partners make the project consortium (see below) and represent a wide range of organizations dedicated to improving public health through the safe use of medicines. The project aims to improve patient safety both within the European Union and in other regions. One of the project objectives is to support and strengthen consumer reporting of suspected adverse drug reactions (ADRs). The project partners represent a wide range of organizations dedicated to improving public health through the safe use of medicines: - The Uppsala Monitoring Centre (UMC), Sweden; - Copenhagen HIV Programme, Denmark; - University of Ghana Medical School, Ghana; - Pharmacy and Poisons Board, Kenya; - Centre Anti Poison et de Pharmacovigilance du Maroc, Morocco; - Lareb, Netherlands Pharmacovigilance Centre; - Zuellig Family Foundation, the Philippines; - Medical Products Agency, Sweden; - Elliot Brown Consulting Ltd, UK; - National Patient Safety Agency, UK. In an increasing number of countries consumers are being encouraged to report adverse reactions to medicines. Organizations such as WHO and the European Commission acknowledge the role of the consumer in spontaneous reporting. Representatives of national pharmacovigilance centres requested WHO in 2008 to develop a handbook on how to establish a reporting system for medicine-related problems for the general public. The implementation of the task became feasible under the objectives of the Monitoring Medicines project. A WHO guidance document 'Safety Monitoring of Medicinal Products – Reporting system for the general public' is now available as a direct project deliverable. Anne Kiuru, Medical Products Agency, Sweden and Linda Härmark, Netherlands Pharmacovigilance Centre, Lareb, kindly assisted WHO in writing the original manuscript. It was later reviewed by members of the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) and selected national experts, and is an important step forward in strengthening patients around the world. In tandem to the document development, the UMC has been working on a tool to support the consumer reporting of ADRs. Several patient organizations have provided their inputs in developing this tool. WHO Pharmaceuticals Newsletter No. 2, 2012 • 26

The WHO guidance document and the tool were introduced to pharmacovigilance centres and consumer / patient organizations at a recent workshop in s-Hertogenbosch, the Netherlands, from 7 to 9 March 2012. The Netherlands Pharmacovigilance Centre, Lareb hosted this workshop and was a lead project partner for this activity. Participants came from Belgium, Croatia, Denmark, Moldova, Netherlands, Portugal, Philippines, Spain, Sweden, Switzerland and the United Kingdom and included a good mix of representatives from pharmacovigilance centres and patient / consumer organizations. Invited presentations, interactive sessions and hands-on exercises allowed workshop participants to share their experiences and common concerns related to patient reporting of ADRs. The elements of the new European Union (EU) pharmacovigilance legislation were presented and the expected impact in and outside the EU were also discussed at length. Piloting the UMC patient reporting tool in selected countries and any subsequent adaptation of the tool will form the next steps in this journey towards patient empowerment in pharmacovigilance. Participants at the workshop on patient reporting of ADRs, the Netherlands, 7-9 March 2012 WHO Pharmaceuticals Newsletter No. 2, 2012 • 27


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Dietary Supplement Containing Biologically Active Substances For Improved Immune Function William J. Hennen, Ph.D. Dr. William J. Hennen holds a Ph.D in Bio-organic chemistry. An accomplished researcher, professor and author, Dr Hennen hold more than 10 patents and has published over 30 research

JOURNAL OF BONE AND MINERAL RESEARCHVolume 12, Number 10, 1997Blackwell Science, Inc.© 1997 American Society for Bone and Mineral Research Long-Term Effects of Intravenous Pamidronate in Fibrous Dysplasia of Bone ROLAND D. CHAPURLAT,1 PIERRE D. DELMAS,1,2 DANIEL LIENS,1 and PIERRE J. MEUNIER1 Fibrous dysplasia of bone (FD) is a rare disorder characterized by proliferation of fibrous tissue in bone marrowleading to osteolytic lesions. It causes bone pain and fractures. To date the only treatment is orthopedic.Histological and biochemical similarities between FD and Paget's bone disease related to increased osteoclasticresorption led us to propose treatment with the bisphosphonate pamidronate. The aim of the study was to assessthe long-term effects of intravenous pamidronate in FD. In this open label phase III study, 20 patients with FD (11males and 9 females; mean age 31 years) received courses of 180 mg of intravenous pamidronate every 6 months(60 mg/day during 3 days by infusion). The mean duration of follow-up was 39 months (range 18 – 64). Severity ofbone pain, number of painful skeletal sites per patient, X-rays of all involved areas, serum alkaline phosphatase,fasting urinary hydroxyproline, and urinary type I collagen C-telopeptide were assessed every 6 months. Theseverity of bone pain and the number of painful sites appeared to be significantly reduced. All biochemical markersof bone remodeling were substantially lowered. We observed a radiographic response in nine patients with refillingof osteolytic lesions. A mineralization defect proven by bone biopsy was observed in one case. Four patientssustained bone stress lines, but no fracture occurred. We suggest that intravenous pamidronate alleviates bonepain, reduces the rate of bone turnover assessed by biochemical markers, and improves radiological lesions of FD.Few side effects were observed. (J Bone Miner Res 1997;12:1746–1752)