sign in sign up
<<
Home , Cholesterol, Ketotifen, Nicergoline

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. 5, 3, 2013 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 documents. document inis English,produced full in thetexts form of which of résumés may in English,be obtained full texts on request of which from: may 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:

http://www.who.int/medicineE-mail address: [email protected] Further information on adverse reactions may be obtained from the This Newsletter is also available on WHO Collaborating Centre for Internationalour Drug Internet Monitoring website: http://www.who.int/medicineBox 1051 s 751 40 Uppsala

Tel: +46-18-65.60.60 Further Fax:information +46-18-65.60.80 on adverse reactionsE-mail: may [email protected] obtained from the Internet:WHO http://www.who-umc.org Collaborating Centre for International Drug Monitoring

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

© World Health Organization 2013

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e- mail: [email protected]).

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.

Printed by the WHO Document Production Services, Geneva, Switzerland

TAB LE OF CONTENTS

Regulatory Matters Acetaminophen ...... 4 Caffeine for apnoea of prematurity ...... 4 Calcitonin medicines ...... 4 Codeine ...... 5 Diclofenac ...... 6 derivatives ...... 6 Filgrastim and pegfilgrastim ...... 7 -containing medicines ...... 7 Intravenous iron-containing medicines ...... 8 , oral ...... 8 Hydrochloride ...... 9 ...... 10 ...... 10 for intravenous use ...... 11 ...... 11 Sunitinib malate ...... 11

Safety of medicines Nitrofurantoin ...... 13 Panitumumab ...... 13 Pazopanib hydrochloride...... 13 Rituximab ...... 14 Vemurafenib ...... 14

Signal and Rhabdomyolysis ...... 15 Roflumilast and Melaena ...... 18 Tapentadol and Delusion ...... 23

WHO Pharmaceuticals Newsletter No. 5, 2013 • 3

REGULATORY MATTERS

with other drugs already citrate). All product doses Acetaminophen known to have such an should be prescribed as association, when assessing caffeine citrate, taking into patients with potentially drug- account the different strengths Association with risk of induced skin reactions. Any of the marketed products. serious skin reactions patient who develops a skin Caffeine (citrate) is authorised USA. The U.S. and Drug rash or reaction while using for treatment of apnoea of Administration (FDA) notified acetaminophen or any other premature newborns and may health-care professionals and pain reliever/fever reducer be given orally or patients that acetaminophen should stop the drug and seek intravenously. has been associated with a risk medical attention right away. of rare but serious skin Anyone who has experienced a There is no change to the reactions. Acetaminophen is a serious skin reaction with formulation of these products. common active ingredient to acetaminophen should not take The new packaging of Viridian treat pain and reduce fever; it the drug again and should Pharma products displaying is included in many contact their health-care the new name may not be prescription and over-the- professional to discuss immediately available. counter products. These skin alternative pain relievers/fever However, all packaging reactions, known as Stevens- reducers. (current and new) has dual Johnson Syndrome (SJS), toxic labelling, which clearly states The US FDA will require that a epidermal necrolysis (TEN), the strengths of both caffeine warning be added to the labels and acute generalized and caffeine citrate. of prescription drug products exanthematous pustulosis containing acetaminophen to (AGEP), can be fatal. These Doses specified when address the risk of serious skin reactions can occur with first- prescribing should always be reactions. The US FDA will also time use of acetaminophen or expressed as caffeine citrate request that manufacturers at any time while it is being because of a risk of confusion add a warning about serious taken. Other drugs used to and potential for dosing errors skin reactions to the product treat fever and pain/body (2 mg caffeine citrate is labels of OTC acetaminophen aches (e.g., non-steroidal anti- equivalent to 1 mg caffeine). drug products marketed under inflammatory drugs, or a new drug application and will Health-care professionals are NSAIDS, such as and encourage manufacturers of also advised that caffeine naproxen) also carry the risk drug products marketed under citrate is for use in neonatal of causing serious skin the OTC monograph do the intensive care units only, and reactions, which is already same. treatment must be initiated described in the warnings under the supervision of a section of their drug labels. References: physician experienced in FDA Drug Safety This new information resulted neonatal intensive care Communication, US FDA from the Agency’s review of Reference: 1 August 2013 (www.fda.gov ). the FDA Adverse Event Drug Safety Update, August Reporting System (FAERS) 2013, Volume 7, issue 1, A2 database and the medical Caffeine for apnoea MHRA, (www.mhra.gov.uk ). literature to evaluate cases of serious skin reactions of prematurity associated with Calcitonin medicines acetaminophen. It is difficult All products to be named to determine how frequently and prescribed as Important changes to serious skin reactions occur caffeine citrate the availability and with acetaminophen, due to UK. The MHRA announced that conditions of use the widespread use of the the name of caffeine products drug, differences in usage Canada Health Canada supplied by Viridian Pharma among individuals (e.g., informed of important changes Limited is being changed to occasional vs. long-term use), to the availability and caffeine citrate in order to and the long period of time recommended conditions of minimise potential risk to that the drug has been on the use of drugs containing premature newborns when market; however it is likely calcitonin. Calcitonin is used as prescribing or dispensing. This that these events (i.e., SJS, a nasal spray to treat change brings the Viridian TEN, and AGEP) occur rarely. osteoporosis in products in line with the postmenopausal women and as It is recommended that health- naming of other products an injection to treat Paget's care professionals should be available on the UK market (ie, disease and hypercalcemia. aware of this rare risk and which are already named in consider acetaminophen, along the salt form as caffeine WHO Pharmaceuticals Newsletter No. 5, 2013 • 4

REGULATORY MATTERS

A safety review conducted by indication for injectable use in ensure that only children for Health Canada concluded that Paget's disease in EU) whom the benefits are greater there is a slightly increased Reference: than the risks are given the risk of associated with medicine for pain relief. The Advisories, Warnings and the prolonged use of calcitonin CMDh agreed with the PRAC’s Recalls, Health Canada, products. A review of the conclusions and endorsed the 31 July 2013 (www.hc- benefits and risks of the nasal following recommendations: sc.gc.ca ). spray products found that • Codeine-containing there was not enough evidence medicines should only be used of benefit to continue using Codeine to treat acute moderate pain in calcitonin nasal sprays in children above 12 years of treating osteoporosis, given age, and only if it cannot be the increased risk of cancer. Restrictions on use of codeine for pain relief in relieved by other painkillers As a result of these reviews, children such as paracetamol or calcitonin nasal spray products ibuprofen, because of the risk will no longer be authorized for Europe. The Coordination of respiratory sale in Canada as of October 1, Group for Mutual Recognition associated with codeine use. 2013. and Decentralised Procedures – Human (CMDh) endorsed by • Codeine should not be Calcitonin injectable products consensus a series of risk- used at all in children (aged will continue to be authorized minimisation measures to below 18 years) who undergo for sale in Canada. The address safety concerns with surgery for the removal of the benefits of these products are codeine-containing medicines tonsils or adenoids to treat considered to outweigh the when used for the obstructive sleep apnoea, as risks when the product is used management of pain in these patients are more as directed in the Product children. Codeine is an opioid susceptible to respiratory Monograph (i.e., for Paget's that is authorised as a problems. disease and hypercalcemia). painkiller in adults and • The product information of However, the labels for children. The effect of codeine these medicines should carry a calcitonin injectable products on pain is due to its conversion warning that children with are being updated to include a into morphine in the patient’s conditions associated with new warning about this risk, body. breathing problems should not and to recommend that use codeine. treatment with calcitonin This follows a review of these solution for injection be limited medicines by the European The risk of side effects with Medicines Agency’s to the shortest possible time, codeine may also apply to using the minimum effective Pharmacovigilance Risk adults. Codeine should dose. Treatment of Assessment Committee therefore not be used in people symptomatic Paget's disease (PRAC), which investigated of any age who are known to reports of serious and fatal with calcitonin medicine should be ultra-rapid metabolisers nor respiratory depression in be limited to patients who are in mothers children after taking codeine unable to use other (because codeine can pass to for pain relief. Most of the treatments. the baby through ). cases occurred after surgical The product information for Patients who are taking a removal of the tonsils or codeine should also include calcitonin medicine and who adenoids for obstructive sleep general information for have questions should speak to apnoea (frequent interruption healthcare professionals, their health care practitioner of breathing during sleep). patients and carers on the risk before making any change to of morphine side effects with their treatment. There are Some of the children who had codeine, and how to recognise other authorized suffered severe side effects their symptoms. in Canada for the treatment of had evidence of being ‘ultra- osteoporosis, Paget's disease rapid metabolisers’ of codeine. (See WHO Pharmaceuticals and hypercalcemia. Patients In these patients, codeine is Newsletters No.4, 2013 for should speak to their converted into morphine in the restricted use as analgesic in body at a faster rate than pharmacist regarding the safe children and adolescents under normal, resulting in high levels disposal of calcitonin nasal 18 in the UK). spray products. of morphine in the blood that can cause toxic effects such as Reference: (See WHO Pharmaceuticals respiratory depression. Press release, EMA, 28 June Newsletters No.4, 2012 for 2013 (www.ema.europa.eu ). intranasal formulation for The PRAC concluded that a osteoporosis treatment to be number of risk-minimisation withdrawn; new restriction to measures are necessary to WHO Pharmaceuticals Newsletter No. 5, 2013 • 5

REGULATORY MATTERS

Diclofenac IV), ischaemic any of the following disease, peripheral arterial indications: disease or cerebrovascular New measures to • symptomatic treatment of disease. minimise cardiovascular • Patients with significant risk chronic pathological risks factors for cardiovascular cognitive and Europe. The CMDh endorsed events (e.g. , neurosensorial impairment by majority new safety advice hyperlipidaemia, in the elderly (excluding for diclofenac-containing mellitus, smoking) should Alzheimer’s disease and only be treated with medicines that are given by other ); means such as capsules, diclofenac after careful • ancillary treatment of tablets, suppositories or consideration. injections, intended to have an • As the cardiovascular risks intermittent in effect on the whole body of diclofenac may increase symptomatic peripheral (known as a systemic effect). with dose and duration of arterial occlusive disease The new advice aims to exposure, the shortest (PAOD stage II); minimise the risks of effects on duration possible and the • ancillary treatment of the heart and circulation from lowest effective daily dose Raynaud’s syndrome; these medicines. should be used. The • patient's need for ancillary treatment of visual This follows a recent review by symptomatic relief and acuity decrease and visual PRAC, which found that the response to therapy should field disturbances effects of systemic diclofenac be re-evaluated presumably of vascular on the heart and circulation periodically. are similar to those of selective origin; • In the light of the above, all COX-2 inhibitors, another • acute retinopathies of patients receiving regular group of painkillers. This vascular origin; diclofenac therapy should applies particularly when • be reviewed at the next prophylaxis of diclofenac is used at a high scheduled appointment. headache; dose and for long-term • orthostatic ; treatment. The PRAC therefore (See WHO Pharmaceuticals • symptomatic treatment of recommended that the same Newsletters No.4, 2013 for precautions already in place to New contraindications and veno-lymphatic minimise the risks of blood warnings after a Europe-wide insufficiency. clots in the with review of cardiovascular safety selective COX-2 inhibitors in the UK, and No.6, 2012 for This is based on a review of should be applied to need for updated treatment data showing an increased risk diclofenac. The CMDh agreed advice for diclofenac in follow- of fibrosis and ergotism with with the PRAC conclusion that on review in EU). these medicines. although the benefits of Reference: Fibrosis can be a serious, systemic diclofenac still Press release, EMA, 28 June sometimes fatal disease, which outweigh the risks, those risks 2013 (www.ema.europa.eu ). is often difficult to diagnose were similar to the risks with because of delayed symptoms COX-2 inhibitors, and it and may be irreversible. The endorsed the recommendation Ergot derivatives CHMP noted that there is a that similar precautions should plausible mechanism by which be applied. New restrictions on use ergot derivatives could cause Diclofenac is a widely used of medicines containing fibrosis and ergotism. Given medicine for relieving pain and ergot derivatives that the evidence for these , particularly in medicines’ benefits in these painful conditions such as Europe. The European indications was very limited, . It belongs to a group Medicines Agency’s Committee the CHMP concluded that the of medicines called ‘non- for Medicinal Products for benefits in the concerned steroidal anti-inflammatory Human Use (CHMP) indications did not outweigh drugs’ (NSAIDs). recommended restricting the the risk of fibrosis and use of medicines containing ergotism. Health-care professionals are , informed that, , Health-care professionals are • Use of diclofenac is contra- dihydroergotoxine, also advised that patients indicated in patients with or a combination of currently taking these established congestive with medicines for any of the above heart failure (New York caffeine. These medicines indications should have their Heart Association class II- should no longer be used for treatment reviewed at a

WHO Pharmaceuticals Newsletter No. 5, 2013 • 6

REGULATORY MATTERS routine (non-urgent) medical colony-stimulating factors (G- Flupirtine-containing appointment. CSF) used to stimulate the proliferation and differentiation medicines Ergot derivatives that are only of granulocytes, especially indicated for these conditions polymorphonuclear, in various Restrictions in the use of will have their marketing forms of neutropenia induced oral flupirtine authorisations suspended by chemotherapy. Filgrastim is across the European Union Europe. The CMDh endorsed also used to help release blood (EU). Some ergot derivatives new recommendations to stem cells from the are approved in some EU restrict the use of oral marrow of healthy donors. Member States for use in other flupirtine medicines and therapeutic indications, The postmarketing adverse suppositories. Flupirtine is a including other circulatory reaction reports provide good non-opioid analgesic that has disorders, treatment of evidence of a temporal and been used to treat pain, such dementia (including causal association between as pain associated with muscle Alzheimer’s disease) and filgrastim or pegfilgrastim tension, cancer pain, treatment of acute migraine. treatment and CLS. However, menstrual pain and pain These indications were not the benefits of filgrastim and following orthopaedic surgery included in the CHMP review. pegfilgrastim continue to or injuries. These medicines Therefore these products will outweigh the risks. Healthcare should now only be used for remain authorised and may professionals should note the treating acute pain in adults continue to be used in those following to help manage and who cannot use other indications. minimise the risk of CLS: painkillers, such as non- steroidal anti-inflammatory (See WHO Pharmaceuticals Health-care professionals are drugs (NSAIDs) and weak Newsletters No.4, 2008 for advised the following: opioids, and treatment should new warning on fibrosis in EU). • Closely monitor all patients not last longer than two and healthy donors for CLS Reference: weeks. In addition, patients’ Press release, EMA, 28 June symptoms, which function should be 2013 (www.ema.europa.eu ). commonly have rapid checked after each full week of treatment and treatment onset. Symptoms include: should be stopped if the generalised body swelling; Filgrastim and patient has any signs of liver puffiness (which may be problems. Flupirtine must also pegfilgrastim associated with less- not be used in patients with frequent urination); pre-existing liver disease or Risk of potentially life- difficulty breathing; abuse problems or in threatening abdominal swelling; and patients taking other medicines known to cause liver problems. leak syndrome tiredness UK. The Medicines and • Give standard symptomatic In addition to oral medicines Healthcare products treatment immediately if and suppositories, this review Regulatory Agency (MHRA) symptoms occur also covered injectable announced that capillary leak flupirtine medicines which were • Advise patients and healthy syndrome (CLS) has been being given as a single reported in recipients of donors to contact their injection for pain following filgrastim, including patients doctor immediately if they surgery. The PRAC concluded undergoing chemotherapy and develop CLS symptoms that the benefits of injectable a healthy donor undergoing • Any suspected adverse flupirtine continue to outweigh peripheral blood progenitor- reactions to filgrastim or their risks when used in this mobilisation; it has also been way. Doctors using the pegfilgrastim should be reported in recipients of injectable flupirtine should also pegfilgrastim undergoing reported on a Yellow Card follow relevant advice to chemotherapy. Episodes varied minimise risk to patients. in severity and frequency. CLS Reference: is characterised by: Drug Safety Update, With regard to the evidence of hypotension and oedema; September 2013, Volume 7, efficacy, the review highlighted hypoalbuminaemia; and issue 2, A1 MHRA, a lack of sufficient data on the haemoconcentration, and may (www.mhra.gov.uk ). benefits of flupirtine in chronic be fatal unless promptly pain. In particular, there was a diagnosed and managed. lack of efficacy data on the use of flupirtine for longer than Filgrastim (Neupogen®) and eight weeks. pegfilgrastim (Neulasta®) are recombinant granulocyte WHO Pharmaceuticals Newsletter No. 5, 2013 • 7

REGULATORY MATTERS

Based on the findings of this the benefits of these medicines Reference: review, health-care are greater than their risks, Press release, EMA, 28 June professionals were advised of provided that adequate 2013 (www.ema.europa.eu ). the following updated measures are taken to recommendations: minimise the risk of allergic reactions. • oral flupirtine medicines and suppositories should Intravenous iron medicines are Ketoconazole, oral only be used to treat adults used when iron supplements given by mouth cannot be with acute pain and only if Potentially fatal liver used or do not work. All treatment with other injury, risk of drug intravenous iron medicines interactions and adrenal painkillers (such as NSAIDs have a small risk of causing gland problems and weak opioids) is allergic reactions which can be contraindicated; life-threatening if not treated USA (1). The US FDA took • the duration of treatment promptly. The Committee several actions related to ketoconazole (Nizoral®) oral with flupirtine should not therefore concluded that measures should be put in tablets, including limiting the exceed two weeks and place to ensure the early drug’s use, warning that it can patients’ liver function detection and effective cause severe liver injuries, should be checked after management of allergic which may potentially result in each full week of reactions that may occur. Iron liver transplantation or death treatment; preparations should only be and by decreasing the body’s • treatment must be stopped given in an environment where production of , in any patient with resuscitation facilities are available, so that patients who and advised that it can lead to abnormal liver function develop an allergic reaction harmful drug interactions with tests results or symptoms can be treated immediately. In other medications. of liver disease; addition, the CHMP considered The US FDA approved label • flupirtine must not be used that the current practice of changes and added a new in patients with pre-existing first giving the patient a small Guide to address liver disease or alcohol test dose is not a reliable way these safety issues including a to predict how the patient will abuse problems or in strong recommendation respond when the full dose is patients taking other against its use given. A test dose is therefore medicines known to cause (contraindication) in patients no longer recommended but with liver disease, and new liver problems; instead caution is warranted recommendations for assessing • healthcare professionals with every dose of intravenous and monitoring patients for should review the treatment iron that is given, even if liver toxicity. As a result, of patients taking flupirtine previous administrations have ketoconazole oral tablets been well tolerated. taking into account the should not be a first-line recommendations above. The CHMP also considered treatment for any fungal that, during pregnancy, allergic infection. Ketoconazole should Reference: reactions are of particular be used for the treatment of Press release, EMA, 28 June concern as they can put both certain fungal infections, 2013 (www.ema.europa.eu ). the mother and unborn child at known as endemic mycoses, risk. Intravenous iron only when alternative medicines should therefore not therapies are not Intravenous iron- be used during pregnancy available or tolerated. containing unless clearly necessary. It is also recommended that Treatment should be confined medicines health-care professionals to the second or third should assess the liver status trimester, provided the of the patient before starting Risk of allergic reactions benefits of treatment clearly oral ketoconazole, and monitor with intravenous iron- outweigh the risks to the ALT levels during containing medicines unborn baby. The Committee treatment. Adrenal function also recommended further Europe. The CHMP completed should be monitored in activities, including yearly its review of intravenous iron- patients with adrenal reviews of allergic reaction containing medicines used to insufficiency or with borderline reports and a study to confirm treat iron deficiency and adrenal function and in the safety of intravenous iron anaemia associated with low patients under prolonged medicines. iron levels and concluded that periods of stress (major surgery, intensive care, etc.). WHO Pharmaceuticals Newsletter No. 5, 2013 • 8

REGULATORY MATTERS

They should review all formulations of ketoconazole neurologic side effects may concomitant medications for (such as creams, ointments persist or become permanent. the potential for drug and shampoos) can continue to The neurologic side effects can interactions with ketoconazole be used as the amount of include dizziness, loss of tablets. ketoconazole absorbed balance, or ringing in the ears. throughout the body is very The psychiatric side effects can According to the US FDA, the low with these formulations. include feeling anxious, topical formulations of mistrustful, depressed, or ketoconazole have not been It is recommended that having hallucinations. associated with liver damage, patients currently taking oral adrenal problems, or drug ketoconazole for fungal Neurologic side effects can interactions. These infections should make a non- occur at any time during drug formulations include creams, urgent appointment with their use, and can last for months to shampoos, foams, and gels doctor to discuss suitable years after the drug is stopped applied to the skin. alternative treatments. Doctors or can be permanent. should no longer prescribe oral Mefloquine hydrochloride is ketoconazole and should Suspension of marketing indicated for the treatment of review patients’ treatment authorisations for oral mild to moderate acute malaria options. ketoconazole caused by mefloquine- recommended Ketoconazole is an antifungal susceptible P. falciparum and Europe (2). The CHMP medicine used to treat P. vivax , and prevention of recommended that the infections caused by malaria infections by P. marketing authorisations of dermatophytes and yeasts. falciparum (including chloroquine-resistant P. oral ketoconazole-containing The European Medicines falciparum ) and P. vivax . It medicines should be Agency is aware that was previously marketed under suspended throughout EU. The ketoconazole is used off-label the brand name Lariam©; CHMP concluded that the risk for treating patients with however, the Lariam product is of liver injury is greater than Cushing’s syndrome. In order not currently marketed. the benefits in treating fungal to ensure that these patients Generic mefloquine products infections. will not be left without are available in the US. Having assessed the available treatment, national competent data on the risks with oral authorities may make these The US FDA recommended ketoconazole, the CHMP medicines available under that patients, caregivers, and concluded that, although liver controlled conditions. health-care professionals injury such as hepatitis is a References: should watch for these side effects. When using the drug known side effect of antifungal (1) FDA Drug Safety to prevent malaria, if a patient medicines, the incidence and Communication, US FDA 26 develops neurologic or the seriousness of liver injury July 2013 (www.fda.gov ). psychiatric symptoms, with oral ketoconazole were (2) Press release, EMA, 26 July mefloquine should be stopped, higher than with other 2013 (www.ema.europa.eu ). . The CHMP was and an alternate medicine concerned that reports of liver should be used. If a patient injury occurred early after Mefloquine develops neurologic or psychiatric symptoms while on starting treatment with Hydrochloride recommended doses, and it mefloquine, the patient should was not possible to identify contact the prescribing health measures to adequately reduce Risk of serious care professional. The patient this risk. The Committee also psychiatric and nerve should not stop taking concluded that the clinical side effects mefloquine before discussing symptoms with the health care benefit of oral ketoconazole is USA. The US FDA advised the professional. uncertain as data on its public about strengthened and effectiveness are limited and updated warnings regarding References: do not meet current standards, neurologic and psychiatric side FDA Drug Safety and alternative treatments are effects associated with Communication, US FDA available. mefloquine hydrochloride. A 29 July 2013 (www.fda.gov ). boxed warning was added to Taking into account the increased rate of liver injury the drug label. The US FDA and the availability of revised the patient Medication alternative antifungal Guide dispensed with each treatments, the CHMP prescription and wallet card to concluded that the benefits did include this information and not outweigh the risks. Topical the possibility that the WHO Pharmaceuticals Newsletter No. 5, 2013 • 9

REGULATORY MATTERS

Meprobamate It is advised that health-care include muscle spasms (often professionals should no longer involving the head and neck), prescribe 282 MEP® and are and tardive dyskinesia. The Market Withdrawal of advised to transition their risk of acute neurological 282 MEP® patients to alternative effects is higher in children, (Meprobamate- therapies before October 28th, although tardive dyskinesia is Containing Medicine) 2013. Pharmacists are advised reported more often in the Canada. PENDOPHARM, in that dispensing should cease elderly, and the risk is collaboration with Health by October 28th, 2013. To increased at high doses or with Canada, informed of the ensure full inventory depletion, long-term treatment. The market withdrawal of 282 282 MEP® should be removed evidence indicated that these MEP®. Following the review of from pharmacy inventory by risks outweighed the benefits safety and efficacy information October 28th, 2013. of metoclopramide in conditions requiring long-term for 282 MEP® mostly focused (See WHO Pharmaceuticals treatment. There have also on its meprobamate content, Newsletters No.2, 2008 for been very rare cases of serious Health Canada has concluded, benefit/risk profile adjudged no effects on the heart or in the light of the risk of longer favourable in the UK). overdose/abuse/misuse, that circulation, particularly after the benefit-risk profile is no Reference: injection. Advisories, Warnings and longer considered favourable. The Committee recommended Recalls, Health Canada, that metoclopramide should 282 MEP® is indicated for the 29 August 2013 (www.hc- only be prescribed for short- relief of pain of various origins, sc.gc.ca ). accompanied by muscle spasm term use (up to five days), and anxiety. Each that it should not be used in contains as medicinal Metoclopramide children below one year of age ingredients acetylsalicylic acid and that in children over one (350 mg), codeine phosphate year of age, it should only be Recommends changes to (15 mg), meprobamate (200 used as a second-choice mg), and caffeine (15 mg, reduce the risk of treatment for the prevention of equivalent to 30 mg caffeine neurological side effects delayed nausea and vomiting citrate). As of July 30th, 2013, Europe. The CHMP after chemotherapy and for the PENDOPHARM discontinued the recommended changes to the treatment of post-operative sale of the drug. use of metoclopramide- nausea and vomiting. In containing medicines in EU, adults, it may be used for the Meprobamate has a narrow including restricting the dose prevention and treatment of therapeutic index and may and duration of use of the nausea and vomiting such as cause serious adverse events medicine to minimise the that associated with (including overdose, loss of known risks of potentially chemotherapy, radiotherapy, consciousness, abuse, serious neurological side surgery and in the pharmacodependence and effects. management of migraine. In withdrawal symptoms), even addition, the maximum under normal conditions of Metoclopramide-containing recommended doses in adults use. Since the approval of medicines have been and children should be meprobamate, other authorised separately in restricted, and higher strength medications (e.g., muscle individual Member States of formulations removed from the relaxants, anxiolytics, the EU, with differing licensed market. ) have largely indications such as nausea and displaced the use of vomiting of various causes (for (See WHO Pharmaceuticals meprobamate in Canada and in example after treatment with Newsletters No.1, 2010 for risk other countries. Taking this anticancer chemotherapy or for development of movement new safety information and the radiotherapy, after surgery, or disorders including tardive available efficacy data into associated with migraine) and dyskinesia in Australia and account, Health Canada gastrointestinal motility No.1, 2009 for warning against concluded that the risks of 282 disorders (conditions in which chronic use in the USA). MEP® (meprobamate- the normal passage of food Reference: containing medicine) outweigh through the gut is delayed). Press release, EMA, 26 July the benefits under normal 2013 (www.ema.europa.eu ). conditions of use. Following the The review confirmed the well- discontinuation of 282 MEP®, known risks of neurological no medications containing effects such as short-term meprobamate will be available extrapyramidal disorders, a in Canada. group of involuntary movement disorders that may

WHO Pharmaceuticals Newsletter No. 5, 2013 • 10

REGULATORY MATTERS

Ondansetron for exceed 16 mg (infused over at long-term clinical studies of least 15 minutes) retigabine and a intravenous use compassionate use Dilution administration in programme. These studies also patients aged 65 years or Dose-dependent QT observed blue-grey older: interval prolongation discolouration of the nails, lips, UK. The MHRA issued new • All intravenous doses for or skin. These reports are guidance for intravenous use prevention of CINV should be considered to be very common of ondansetron. Ondansetron diluted in 50–100 mL saline or (ie, occurring in ≥1/10 (Zofran® and its generics) is other compatible fluid and patients) after prolonged indicated for the prevention infused over at least 15 retigabine treatment. minutes and treatment of nausea and Patients who are currently vomiting induced by cytotoxic Repeat dosing in all adults receiving retigabine treatment chemotherapy and (including elderly patients): should be reviewed at a radiotherapy, and for the routine appointment. prevention and treatment of • Repeat intravenous doses Comprehensive ophthalmic postoperative nausea and of ondansetron should be given examination should be done at vomiting. Prolongation of QTc no less than 4 hours apart the start of treatment and at interval and cardiac (See WHO Pharmaceuticals least every 6 months arrhythmia, including Torsade Newsletters No.4 2012 for new thereafter during treatment. de Pointes, are known risks dose restriction for intravenous Treatment should only with ondansetron. use due to dose-dependent QT continue after a careful The MHRA announced that the interval prolongation in UK and reassessment of the balance of results of a study that showed No.6 2012 in Canada and benefits and risks if pigment ondansetron causes a dose- No.1, 2013 for product changes are detected. dependent prolongation of removal due to potential for (See WHO Pharmaceuticals QTc, together with other data serious cardiac risks in the Newsletters No.4, 2013 for sources, have enabled greater USA). restriction on use understanding of the relation Reference: recommended due to risk of between dose and risk of QT Drug Safety Update, July 2013, retinal pigmentation in EU). prolongation. As a result, Volume 6, issue 12, A3 MHRA, further specific guidance is Reference: (www.mhra.gov.uk ). available for intravenous Drug Safety Update, July 2013, ondansetron in relation to: Volume 6, issue 12, A2 MHRA, repeat dosing in all adults; Retigabine (www.mhra.gov.uk ). dosing for prevention of chemotherapy-induced nausea and vomiting (CINV) in Restricted to last-line Sunitinib malate patients aged 75 years or use, and new monitoring older; and dilution and requirements after Association with administration for prevention reports of pigment Stevens-Johnson of CINV for patients age 65 changes in ocular tissue, Syndrome and Toxic years or older. skin, lips, or nails Epidermal Necrolysis New advice for health-care UK. The MHRA announced that Canada. Pfizer Canada Inc., in professionals are the retigabine (Trobalt®) should collaboration with Health followings, now only be used as an Canada, informed that a adjunctive treatment for drug- statement was added to the Patients aged 75 years or resistant partial onset seizures Product Monograph about a older: with or without secondary potential association between • A single dose of generalisation in patients age the use of sunitinib malate intravenous ondansetron for 18 years or older with (Sutent®) and severe the prevention of CINV must epilepsy, where other cutaneous reactions suggestive not exceed 8 mg (infused over appropriate drug combinations of Stevens-Johnson Syndrome at least 15 minutes) have proved inadequate or (SJS) and Toxic Epidermal have not been tolerated. This Necrolysis (TEN). Early Adult patients younger than 75 restricted indication is due to recognition is important in years: reports of pigment changes. improving prognosis. Cases of TEN and SJS, including fatal • A single dose of Pigment changes (ie, cases have been very rarely intravenous ondansetron for discolouration) of ocular reported, mostly in the post- prevention of CINV must not tissue—including the retina— marketing setting, in patients have been reported in two who have used the drug. WHO Pharmaceuticals Newsletter No. 5, 2013 • 11

REGULATORY MATTERS

It is advised that, if signs or symptoms of SJS or TEN are present, treatment should be discontinued. If the diagnosis of SJS or TEN is confirmed, treatment must not be restarted. Sutent is indicated for the treatment of gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance. It is also indicated for the treatment of metastatic renal cell carcinoma (MRCC) of clear cell histology and for the treatment of patients with unresectable locally advanced or metastatic, well- differentiated pancreatic neuroendocrine tumours (pancreatic NET), whose disease is progressive.

Reference: Advisories, Warnings and Recalls, Health Canada, 9 September 2013 (www.hc- sc.gc.ca ).

WHO Pharmaceuticals Newsletter No. 5, 2013 • 12

SAFETY OF MEDICINES

Panitumumab Pazopanib Nitrofurantoin hydrochloride Importance of Reminder on precautions establishing wildtype Important change to for use, especially renal RAS (KRAS and NRAS) frequency of serum liver impairment in (elderly) status before treatment test monitoring for patients of metastatic colorectal UK. The MHRA reminded that cancer Canada. GlaxoSmithKline Inc., use of nitrofurantoin for UK. The MHRA announced that in consultation with Health urinary tract infections is evidence of wildtype rat Canada, informed that contraindicated in patients with sarcoma viral oncogene (RAS) pazopanib hydrochloride <60 mL/min creatinine status (at exons 2, 3, and 4 of (Votrient®) is associated with clearance. Health-care KRAS and NRAS) is required hepatotoxicity including professionals should be aware before initiating treatment with hepatic failure and fatalities of a patient’s current renal panitumumab (Vectibix®) and the drug should not be function when prescribing, alone or in combination with used in patients who have especially for elderly patients other chemotherapy in the baseline plasma treatment of metastatic Nitrofurantoin is an oral concentrations >1.5 X Upper colorectal cancer. Inferior antibiotic used in the Limit of Normal (ULN) with progression-free survival and treatment of urinary tract direct bilirubin >35% and ALT overall survival have been infections. The antibacterial elevations of >2 X ULN, or who shown in patients with RAS efficacy in this infection have moderate or severe mutations beyond KRAS exon depends on the renal secretion hepatic impairment (Child 2 who received panitumumab of nitrofurantoin into the Pugh B and C). These are not urinary tract. In patients with combined with FOLFOX new recommendations, and (oxaliplatin-containing) renal impairment, renal remain unaltered from the secretion of nitrofurantoin is chemotherapy versus FOLFOX previously approved Product alone reduced, which can result in Monograph. treatment failure. These findings are important It is also advised that Nitrofurantoin is therefore and emphasise that physicians are asked to contraindicated in those with panitumumab is monitor serum liver tests <60 mL/min creatinine contraindicated in combination before initiation of treatment, clearance. with oxaliplatin-based during treatment with chemotherapy in patients with It is also advised that the pazopanib hydrochloride and mutant RAS(at exons 2, 3, or 4 product information should be interrupt, reduce or of KRAS and NRAS), or in consulted in relation to discontinue dosing as whom RAS status is unknown. established risks of recommended in the Product nitrofurantoin, which include: It is also important that Monograph. Testing of serum evidence of wildtype RAS pulmonary toxicity; hepatic liver and bilirubin toxicity; peripheral status is established before levels during treatment has initiation of treatment with neuropathy; and increased in frequency to panitumumab in all patients. contraindications in G6PD include monitoring during Health-care professionals are deficiency and acute weeks 2, 4, 6, 8 and months 3 also advised that RAS mutation and that guidance on the & 4, and as clinically indicated. status should be determined appropriate use of antibiotics Periodic monitoring should by an experienced laboratory and the prevalence of continue after Month 4. using a validated test method resistance (such as NICE Pazopanib hydrochloride is a guidance) should be Panitumumab is a treatment inhibitor considered when prescribing for adults with metastatic indicated for the treatment of nitrofurantoin colorectal cancer. It is given patients with metastatic renal Reference: alone or in combination with cell (clear cell) carcinoma as other chemotherapy. Drug Safety Update, August first-line systemic therapy or 2013, Volume 7, issue 1, A3 Reference: as second line systemic therapy after treatment with MHRA, (www.mhra.gov.uk ). Drug Safety Update, cytokines for metastatic September 2013, Volume 7, disease. It is also indicated for issue 2, A2 MHRA, the treatment of patients with (www.mhra.gov.uk ). selective subtypes of advanced soft tissue sarcoma who have received prior chemotherapy

WHO Pharmaceuticals Newsletter No. 5, 2013 • 13

SAFETY OF MEDICINES for metastatic disease, or who Rituximab is an anti-CD20 treatment with vemurafenib. have progressed within 12 monoclonal antibody indicated These findings suggest that months after (neo) adjuvant in the treatment of Non- ZELBORAF can cause therapy. Hodgkin’s Lymphoma (NHL), paradoxical activation of Chronic Lymphocytic Leukemia extracellular signal-regulated Concomitant use of pazopanib (CLL), kinase (ERK) signaling in the hydrochloride and (RA), Granulomatosis with RAS-mutant leukemic cell increases the risk of ALT Polyangiitis (GPA, also known population, which could lead to elevations. Concomitant use of as Wegener's Granulomatosis) leukemic cell proliferation. the drug and should be and Microscopic Polyangiitis Vemurafenib should be used undertaken with caution and (MPA). with caution in patients with close monitoring. Reference: prior or concurrent Reference: associated with RAS mutation. Advisories, Warnings and Advisories, Warnings and Recalls, Health Canada, 29 July 2. DRESS Syndrome Recalls, Health Canada, 9 2013 (www.hc-sc.gc.ca ). August 2013 (www.hc- Cases of DRESS syndrome sc.gc.ca ). were reported with the use of Vemurafenib vemurafenib. The cases of DRESS syndrome were Rituximab characterized by rash, Risks of malignancy eosinophilia, and systemic Hepatitis B Virus (HBV) progression and Drug involvement (e.g. fever, recurrence in patients Rash with Eosinophilia lymphadenopathy, elevated and updates on and Systemic Symptoms transaminases and renal insufficiency). The typical time screening and Canada. Hoffmann-La Roche to onset was 7-25 days. management Limited (Roche Canada), in collaboration with Health Vemurafenib treatment should Canada. Hoffmann-La Roche Canada, informed of important be permanently discontinued in Limited (Roche), in new safety information patients who develop DRESS consultation with Health associated with vemurafenib syndrome. Canada, informed that use of (Zelboraf®) regarding the risk Reference: rituximab (Rituxan®) was of malignancy progression as shown to be associated with Advisories, Warnings and well as the risk of Drug Rash Recalls, Health Canada, 20 reactivation of hepatitis B virus with Eosinophilia and Systemic in seropositive patients. It is August 2013 (www.hc- Symptoms (DRESS sc.gc.ca ). advised that all patients be Syndrome). screened for hepatitis B virus (HBV) before initiation of Vemurafenib is indicated as a treatment with the drug and monotherapy for the treatment rituximab is not to be used in of proto-oncogene patients with active hepatitis B serine/threonine- kinase viral disease. It is also advised B-Raf (BRAF) V600 mutation- positive unresectable or that, prior to starting treatment in HBV seropositive metastatic melanoma. A patients, consultation with a validated test is required to liver disease expert is identify BRAF V600 mutation recommended to determine status. on-going monitoring of HBV 1. Progression of Malignancies reactivation and its Associated with Rat Sarcoma management. Viral Oncogene (RAS) Mutation

The use of rituximab has been Based on its mechanism of associated with HBV action, vemurafenib may cause reactivation in patients with progression of cancers positive HBV surface antigen associated with RAS (HBsAg+ve) and in those with mutations. A recent article negative HBV surface antigen reported a case of accelerated plus positive anti-HB core growth of a pre-existing antibody (HBsAg- neuroblastoma RAS (NRAS)- ve/HBcAb+ve), particularly mutated chronic when administered in myelomonocytic leukemia in a combination with or 76-year-old patient shortly chemotherapy. after he had initiated a WHO Pharmaceuticals Newsletter No. 5, 2013 • 14

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 8 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 section (page 23). 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 risks 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] .

Mirtazapine and Rhabdomyolysis Signal from UMC Mirtazapine acts by enhancing the release of Summary noradrenaline and by blocking central presynaptic The drug-adverse drug reaction (ADR) receptors. It is a potent antagonist at combination mirtazapine and rhabdomyolysis was (H 1) receptors which is responsible for identified as a potential signal in 2000. This follow- the drug's sedative properties. 3 up shows that in February 2013, the WHO Global Individual Case Safety Report (ICSR) Database, Mirtazapine is primarily used as an anti- VigiBase™, contained 47 ICSRs, but the ADR is not depressant, but can also be prescribed to treat labelled in the UK Summary of Product anxiety disorders such as Obsessive-Compulsive Characteristics or US FDA Label. A literature Disorder (OCD), panic disorder and post-traumatic search reveals that four of the cases found in stress. It has been investigated in the VigiBase have been published and the information management of nausea and vomiting. Mirtazapine these provide together with the assessment of the is generally well tolerated and has a faster onset other ICSRs suggest that the association of of efficacy (one week) than other comparable rhabdomyolysis with mirtazapine is a signal and antidepressants. As the should be investigated further. isoenzyme CYP3A4 is involved in the of mirtazapine, caution is advised when mirtazapine is given with potent inhibitors of this Introduction isoenzyme. The concomitant use of mirtazapine The drug-ADR combination mirtazapine and with monoamine oxidase inhibitors (MAOIs) rhabdomyolysis was published in the Signal intended to treat psychiatric disorders is document in 2000 describing 15 Individual Case contraindicated as it may lead to Safety Reports (ICSRs) from six countries with syndrome. 3 myositis, rhabdomyolysis and neuroleptic malignant syndrome in relation to either Mirtazapine is usually administered orally, but may mirtazapine or . 1 Mirtazapine and also be given by intravenous infusion. The initial rhabdomyolysis was again highlighted during a oral daily dose is 15-30 mg for the treatment of research project at the UMC and prompted further depression, but may be increased gradually review. 2 according to response. The usual dose ranges between 15 and 45 mg once or twice daily. 3,4 The mianserin analogue, mirtazapine, is a noradrenergic and specific Common side effects of mirtazapine are increased (NaSSA) and is broadly classified appetite and weight, oedema, and drowsiness or sedation in the first weeks of treatment. Other less as a centrally acting presynaptic α2-adrenergic antagonist. Structurally it can be common or rare side effects of interest include classified as a antidepressant. paraesthesia, convulsions, tremor, myoclonus, WHO Pharmaceuticals Newsletter No. 5, 2013 • 15

SI GNAL akathisia, arthralgia, myalgia, muscle rigidity, term overdose was reported (the patient had neuroleptic malignant syndrome and serotonin taken 840 mg) but it was unclear if it was syndrome. 3,5 intentional. There was also one case where an infant developed rhabdomyolysis following in utero Rhabdomyolysis is the breakdown of muscle fibers exposure to mirtazapine and venlafaxine, when that leads to the release of into the the mother attempted suicide by overdosing on bloodstream. Normally, myoglobin is loosely these medicines. 11 bound to plasma globulins and only small amounts reach the urine but when large amounts are Treatment dates were given on less than half of released the binding capacity of the plasma the ICSRs (21), ranging from four days to four protein is exceeded. Myoglobin is filtered out of years. The reported time to onset ranged from the body via the kidneys and may cause three days to seven months from starting obstruction in the tubules and renal dysfunction. mirtazapine. Rhabdomyolysis is one of the leading causes of acute renal failure and although it may be fatal, it Literature and Labelling is usually relatively benign. Rhabdomyolysis may Rhabdomyolysis is not labelled in the UK Summary be caused by any condition that damages skeletal of Product Characteristics (SPC) or US FDA Label muscles, especially injury or strainful exercise, the for mirtazapine, but it is, however, seen in toxic effect of drugs such as statins and/or association with the serious ADRs neuroleptic , illegal drugs and/or alcohol abuse. Other malignant syndrome and serotonin syndrome, risk factors include electrolyte abnormalities such both known for mirtazapine according to the US as hypokalaemia and hypernatraemia, infections, FDA Label information for Remeron. 9 The UK SPC electric shock and occlusion of blood supply to does not mention this association. muscles. Management may include the infusion of -containing fluids (to enhance urinary A literature search revealed four published cases, secretion of myoglobin) or hemodialysis. 6,7,8 all of which had been reported to VigiBase. The first concerns a 74 year old man from the US with Reports in VigiBase a history of major depressive disorder who was brought to the emergency department for odd As of 24 April 2013, 61 ICSRs mentioning behaviour. He had started taking mirtazapine four mirtazapine and rhabdomyolysis were found in the months earlier and had been using lisinopril for WHO Global ICSR Database, VigiBase™, with an IC two years. Three months prior to the incident he value of 0.81 and IC of 0.43. This number was 025 had had a dose increase of mirtazapine from 30 to reduced to 47 reports after duplicates were 45 mg per day and lisinopril from 10 to 30 mg per removed. Gender was provided for all ICSRs with day. The man was diagnosed with rhabdomyolysis 31 concerning men and 16 women. Age was and both drugs were discontinued. Other possible mentioned on 89% (42/47) of the ICSRs ranging confounders were ruled out and lisinopril was from a newborn (transplacental transmission) to reinstated with a negative rechallenge. The an 84 year old, with a median age of 43.5 years. authors found a causative relationship between Twelve countries, across three continents, had mirtazapine and rhabdomyolysis. 12 reported this suspected drug-ADR combination; The second case concerns an overdose where a 40 Germany had 17 cases, United States and year old man from Australia had been admitted to Switzerland six each, Spain five, Canada and the emergency department for attempted suicide. United Kingdom three each, Australia two and He had taken 1.8 g of mirtazapine together with Greece, Czech Republic, Denmark, France and the two litres of alcohol and developed Netherlands had one case each. The first ICSR rhabdomyolysis. Although the dose is not exactly entered into VigiBase was from Spain in 1999 and the same as that reported in VigiBase, it is the last was from Switzerland in 2012. believed to concern the same event. The author Mirtazapine was the sole suspected drug on 18 suggests that the rhabdomyolysis may have been ICSRs. Co-suspected or interacting drugs of caused by mirtazapine. 10 interest included , venlafaxine, In the third case a 40 year old man from Germany , , escitalopram, citalopram, taking risperidone (8 mg daily) and (2 , , , mg daily) after having developed a syndrome and which are all known to cause consistent with schizophrenia, was given rhabdomyolysis. 9 Concomitant drugs were mirtazapine (45 mg daily) for treatment of a reported on 21 ICSRs. following episode of major depression. When Where dose was stated, it was generally ranging treatment failed, the mirtazapine dose was from 15 to 45 mg daily. Among the ICSRs there increased to 60 mg daily and risperidone reduced were six cases of suicide attempt. In two of these to 3 mg daily whereafter the patient improved. Six cases suicide attempt is not specifically stated, but weeks after starting this combination therapy, the in one case the dose taken was 1.7 g and this case patient was admitted to hospital and diagnosed was also found in literature where it was described with pulmonary and rhabdomyolysis. as a suicide attempt. 10 In the other case, the Mirtazapine and risperidone were withdrawn and

WHO Pharmaceuticals Newsletter No. 4, 2013 • 16

SI GNAL replaced and after receiving medical therapy the References patient recovered. The authors suggest the causal 1. The Uppsala Monitoring Centre, Mianserin, relationship to be likely for the psychotropic Mirtazapine - Muscular injury, WHO Signal, March medications and the adverse events after having 2000. ruled out other confounders. 13 2. Juhlin K, Ye X, Star K, Norén GN. Outlier The final case describes a neonate being delivered removal to uncover patterns in adverse drug by emergency caesarean section in the 36th week reaction surveillance -a simple unmasking strategy of pregnancy after the mother had attempted (submitted for publication). suicide. The mother had overdosed on mirtazapine and venlafaxine 11 hours prior to this incident. 3. Martindale on mirtazapine. The newborn had to be resuscitated and URL: http://www.micro-medexsolutions.com. experienced seizures and rhabdomyolysis. Blood Accessed: 7 March 2013. samples showed extremely high concentrations of 4. UK SPC on mirtazapine (Mirtazapine). the two compounds. Both mother and child URL: http:// www.medicines.org.uk. survived. 11 Accessed: 7 March 2013. Discussion 5. DRUGDEX on mirtazapine. URL: http://www.micro-medexsolutions.com. Rhabdomyolysis is a serious ADR and may be due Accessed: 7 March 2013. to a number of causes. In the cases assessed in this analysis there are several confounders, such 6. PubMed Health on rhabdomyolysis. A.D.A.M. as co-reported drugs known to cause Medical Encyclopedia. rhabdomyolysis, alcohol intoxication and possible URL: http://www.ncbi.nlm.nih.gov/pub- infection. Rhabdomyolysis may be secondary to medhealth/PMH0001505. muscle rigidity seen in patients with serotonin Accessed: 7 March 2013. syndrome or neuroleptic malignant syndrome. Serotonin syndrome was listed in three cases and 7. Vanholder R, Sever MS, Erek E, Lameire N. neuroleptic malignant syndrome was listed in one Rhabdomyolysis. J Am Soc Nephrol. 2000 case. Other co-reported terms of interest included Aug;11(8):1553-61. hypertonia, convulsions, involuntary muscle 8. Taber's medical dictionary online on contractions and extrapyramidal disorders which rhabdomyolysis. URL: www.tabers.com. all might, theoretically and if severe enough, have Accessed: 8 March 2013. contributed to the rhabdomyolysis. 9. US FDA Label for mirtazapine (Remeron) Data on causality assessment, co-morbidities and URL: de-and re-challenge was extremely limited. In the http://wwwaccessdata.fda.gov/drugsatfda_docs/ 27 cases where information on causality label/2011/020415s022lbl.pdf). assessment was given, 21 were graded as Accessed: 8 March 2013. possible, three were not (yet) assessed, two were probable (one according to narrative information) 10. Kuliwaba A. Non-lethal mirtazapine overdose and one was recorded as unknown. 17 reports with rhabdomyolysis. Aust N Z J Psychiatry. 2005 provided information on co-morbidities, a few with April:39(4):312-3. possible confounders such as alcoholism and high 11. Hatzidaki E, Toutoudaki M, Christaki M, cholesterol ( use). De-challenge information Manoura A, Korakaki E, Saitakis E, et al. A non was provided on 30 of the ICSRs; the drug was fatal suicide attempt of a pregnant woman using withdrawn in 26 cases and in eight of these it was mirtazapine and venlafaxine. 45th Congress of the mentioned that the reaction abated. Only one European Societies of Toxicology, Rhodos, Greece, positive re-challenge was reported. Outcome was 5-8 October 2008. stated on 91% (43/47) of the ICSRs. 31 patients had recovered or were recovering, two of these 12. Khandat AB, Nurnberger JJ, Shekhar A. with sequelae, three had not recovered at the time Possible mirtazapine-induced rhabdomyolysis. Ann of reporting, one patient died and in eight cases Pharmacother. 2004 Jul-Aug;38(7-8):1321. the outcome was unknown. 13. Zink M, Knopf U, Argiriou S, Kuwilsky A. A case of pulmonary thromboembolism and Conclusion rhabdomyolysis during therapy with mirtazapine The reports found in VigiBase together with the and risperidone. J Clin Psychiatry. 2006 added information from the cases described in May;67(5):835. literature suggest that there is a positive causal relationship between mirtazapine and rhabdomyolysis that should be investigated further.

WHO Pharmaceuticals Newsletter No. 4, 2013 • 17

SI GNAL

Roflumilast and Melaena Dr. Tamás Paál, Hungary

Summary Introduction From November 2010 to January 2013, seven Roflumilast is a selective, long-acting inhibitor of Individual Case Safety Reports (ICSRs) of melaena the enzyme phosphodiesterase (PDE) type 4. PDE4 in association with roflumilast were entered into is an important regulator of cyclic adenosine the WHO Global ICSR Database, VigiBase™, monophosphate (cAMP) involved in inflammatory raising the possibility of a causal relationship. processes. Inhibition of PDE4 reduces the Although melaena in some of these cases could breakdown of cAMP, which in turn down-regulates have been caused by the patients' concomitant the inflammatory process. It is administered orally conditions (e.g. gastrointestinal neoplasm, for the treatment of inflammatory conditions of the duodenal ulcer, and proctitis) or their concurrent lung such as chronic obstructive pulmonary 1 medication (e.g. anticoagulant drugs), a causal disease (COPD). relationship cannot be ruled out. It is known that Melaena means black, tarry faeces, associated phosphodiesterase inhibitors, the group of drugs with gastrointestinal (GI) haemorrhage. It should to which roflumilast belongs, may cause be distinguished from haematochezia, which is gastrointestinal disturbances (duodenal ulcer, passage of bright red blood originating from the colitis), and melaena is an easily diagnosable lower GI tract. The black colour is caused by symptom of these adverse conditions. enzymatic oxidation of the iron in haemoglobin. Only blood that originates from a higher source (such as stomach or ) or very slow bleeding from the lower GI source allow enough time for this enzymatic breakdown. 2

Table 1. Characteristics of ICSRs in VigiBase TM indicating melaena during treatment with roflumilast

ICSR Country Reporter Age/ Roflumilast Other suspected (S) or Reactions (WHO -ART Gender dosage concomitant (C) drugs preferred terms) 1 Germany Physician 78/M Oral, 500 µg/day, Tiotropium, fluticasone/ (both C) -

4 days 2 Germany Physician (clinical trial) 63/M Oral, 500 µg/day, Cefixime, tiotropium, hydrochlorothiazide/ Melaena, paroniria, nausea, 4 days* ramipril, /ipratropium, phenazone depression, chole-cystitis, (all C) diverticula, constipation,

proctitis 3 Germany Physician (clinical trial) 71/M Oral, 500 µg/day, Fluticasone/salmeterol, budesonide/ Melaena, , dyspnoea, 84 days, then 4 , tiotropium, , ramipril, diverticulosis colonic, GI months phenprocoumon, digitoxin, , neoplasm benign, anorexia,

valsartan, , pantoprazole, insulin, anaemia mirtazapine, , allopurinol (all C) 4 Germany Physician (clinical trial) 77/F Azithromycin (C) Oral, 500 µg/day, Melaena, nausea, abdominal 77 days* pain, gastritis, GI haemor-

rhage, duodenal ulcer 5 USA Not known 77/F Oral, once daily, 2.5 Azithromycin (C) Melaena, nausea, gastritis, months duodenal ulcer, GI haemor- rhage, abdominal pain

6 USA Consumer/non health- 80/M Oral, 500 µg/day, 2 Tiotropium, , acetylsalicylic acid, Melaena, nausea, dizziness professional months calcium, , , cyano- cobalamin, digoxin, , , fluticasone, , (all C) Bismuth (S) 7 Italy -/M Consumer/non health Oral, 500 µg/day, 1 Risedronic acid, , fluticasone/ Melaena, abdominal pain, back professional month salmeterol, , tiotropium, pain, gastritis

deflazacort (all C) *Re -challenge with roflumilast positive

WHO Pharmaceuticals Newsletter No. 4, 2013 • 18

SI GNAL

caused blood in the stool. Tiotropium may cause Reports in VigiBase constipation and intestinal obstruction, which may From November 2010 to January 2013, seven lead to hard and bloody stools. 7 Similarly, known Individual Case Safety Reports (ICSRs) (IC 1.23, ADRs of azithromycin are bloody diarrhoea and IC025 -0.03) in the WHO Global ICSR Database, constipation. 8 Constipation may also lead to VigiBase™, raised the possibility of a causal haemorrhoids (swollen in the rectum). 9 relationship between roflumilast administration However, blood in the stool formed this way can and the melaena. The ICSRs are better be classified as haematochezia than summarised in Table 1. melaena. Before starting any assessment, it should be noted Returning to the potential GI class adverse effects that there are similarities between the ICSRs 4 of PDE4 inhibitors, a somewhat different and 5 (female, 77 years old, 68 kg, same explanation was offered recently. It was pointed reactions, same dates of treatment and onset of out that for second-generation PDE4 inhibitors, reaction) that suggest that they describe the same including roflumilast, GI disturbances were the case, even if the ICSRs come from different most prevalent adverse drug reactions (ADRs). countries. For this reason, only the ICSR 4 was They could be accounted for by the ubiquitous used for further evaluation. distribution of PDE4 isoforms across many tissues. The most worrying potential toxicity generic to It should also be considered that there are three such PDE4 inhibitors could be . In recent ICSRs (2, 3 and 4) related to patients involved in human clinical trials with some PDE4 inhibitors the clinical trials with roflumilast. In these cases, the main reason for drop-outs was an incidence of reporting physician(s) classified the melaena as colitis, raising the possibility that it was secondary not related to the drug. According to the reporters, to arteritis. In clinical trials with cilomilast, another these patients had other alternative plausible PDE4 inhibitor, GI adverse effects including explanations for the development of the event, melaena did occur and were monitored with such as suspicion of an upper GI haemorrhage colonoscopy. Although the findings did not (even if not diagnosed), possibility of concurrent establish a relationship between melaena and haemorrhoids and/or active duodenal ulcer as well , the FDA concluded, from the low as concomitant treatment with an anticoagulant number of cases, that there was insufficient (phenprocoumon). evidence to rule it out in humans. 10 Literature and Labelling Discussion In an assessment of roflumilast made by The It is worth starting the assessment with the three Committee for Medicinal Products for Human Use cases describing clinical trial patients, in which the (CHMP) of the European Medicines Agency, it was reporting physicians classified the melaena as not pointed out that increased gastric acid secretion related to roflumilast treatment. If the casual and delayed gastric emptying were observed relationship between roflumilast administration during safety pharmacology studies. These effects and melaena could be completely ruled out in were possibly related to the class of PDE4 these three cases, the remaining three cases inhibitors. 3 Indeed, such effects of PDE inhibitors might not generate a signal. have been known for over forty years. For instance, Harris et al. described stimulation of According to the narrative in ICSR 2, the patient hydrochloric acid production by methylxanthines in went to the outpatient clinic 19 days after the first the isolated frog gastric mucosa by inhibition of dose of roflumilast because of bowel movement PDE that destroys cAMP. 4 Scratcherd et al. found difficulties (constipation and delayed gastric proof that methylxanthines can both initiate emptying are accepted ADRs of roflumilast3). The gastric secretion and potentiate histaminic- patient had also experienced, among other stimulated gastric secretion. 5 Moreover, according symptoms, blood in stool with known to CHMP, morphological changes in the GI tract haemorrhoids two days after the first dose of (erosion and ulceration) were seen in both rats roflumilast. When roflumilast treatment was and monkeys in higher doses. 3 Such changes were discontinued the symptoms stopped. When not normally expected at therapeutic doses in roflumilast was resumed intermittently, the humans, yet the approved European Summary of symptoms re-appeared. According to the reporter, Product Characteristics contains, in addition to the the concurrent haemorrhoids provided a more adverse reactions gastritis (uncommon, i.e. plausible alternative explanation for the >1/1,000 - <1/100) and constipation (rare, i.e. occurrence of blood in the stool than roflumilast >1/10,000 -<1/1,000), haematochezia as a rare treatment. However, this conclusion requires ADR. 6 closer scrutiny. The original reported term used by the investigator was "faecal occult blood (FOB) Assessing the concomitant medication in the with known haemorrhoids". FOB means small reports in Table 1, it is evident that all reported amounts of blood, not visible to the eye, in the patients took either blood anticoagulants stool indicating that bleeding has occurred (discussed above) or another drug that might have somewhere in the upper or lower GI tract. 11 In this

WHO Pharmaceuticals Newsletter No. 4, 2013 • 19

SI GNAL case it might have been caused by the mild expected to increase gastric acid secretion (which proctitis (inflammation of the rectum) that was may lead to other GI disturbances). Thus, there also reported. The reporting physician pointed out may be a plausible pharmacological explanation, that FOB might be a sign of the proctitis (i.e. and the causality chain, gastritis — duodenal ulcer haematochezia and not melaena); however, it — GI haemorrhage — melaena, is at least not would not explain why the patient, after impossible. discontinuation of the therapy "had recovered" and One could summarise the analysis of the three then, when roflumilast was later resumed, the clinical trial reports by saying that there is no symptoms re-appeared. Roflumilast is known to convincing evidence for the causal relationship cause constipation and delayed gastric emptying between roflumilast treatment and melaena. (so possibly also has a more global effect on gut However, if there is a pharmacologically plausible motility). Haemorrhoids are exacerbated by explanation for a causal relationship between a constipation, and the patient has a past history of medicine and an event, the fact that other haemorrhoids. However, there is no mention of plausible explanations may also exist is not haemorrhoids in the examination findings but a enough to rule out the possibility of an ADR colonoscopy revealed proctitis. The patient completely. reported blood in the stool only two days after the first dose of roflumilast, which may be too soon for Tiptropium may cause blood in faeces from the the drug to have caused constipation. The proctitis lower GI tract. Although the patient in ICSR 1 was appears to be a more plausible explanation for the treated with tiotropium, the reporter, a physician, visible blood in the stool, but it is not clear that was unlikely to have confused melaena with the roflumilast caused the proctitis. haematochezia. It is worth noting that the reporter in ICSR 7 was not a health care professional, and In ICSR 3 the patient, treated concomitantly with bleeding from the lower GI tract in this case might phenprocoumon, started roflumilast therapy on 23 have been mistaken for melaena. February. On 17 May he was admitted to hospital and reported having had melaena for Because of the confounding concomitant approximately four weeks. He also had a medical medication (tiotropium, acetylsalicylic acid and history of chronic gastritis. Roflumilast (and warfarin), ICSR 6 provides no convincing evidence perhaps phenprocoumon) therapy was of a causal relationship. discontinued on 17 May. Gastroscopy did not reveal a source of haemorrhage in the upper GI If one assesses the issue in a narrower context, tract. The patient was diagnosed with i.e. whether a causal relationship between diverticulosis and a solitary polyp in the ascending roflumilast administration and melaena can be colon. Phenprocoumon therapy was then established solely on the basis of the reports, the reintroduced (there are no exact dates in the result would be controversial. Four patients of the report, but it seems to have occurred earlier than assessed six (ICSRs 2, 3, 4 and 6) suffered from the reintroduction of roflumilast). Roflumilast was illnesses (proctitis, GI neoplasm, duodenal ulcer) resumed on 2 June but was discontinued on 17 and/or were treated with anticoagulant drugs that October at the patient's request. According to the could also account for the melaena. reporting physician, other plausible explanations, On the other hand, if one assesses the possible such as phenprocoumon therapy and undiagnosed relationship between a group of possibly GI haemorrhage, make a causal relationship interrelated GI adverse effects assuming that their between roflumilast treatment and melaena single root cause can be the administration of unlikely. However, roflumilast may have been roflumilast (or, in general, of PDE inhibitors) and responsible for the gastritis or have exacerbated their possible manifestations including melaena, it, which could have led to the mentioned GI the causality is plausible. It has been shown haemorrhage (causing melaena). If this were the previously that GI adverse effects of PDE inhibitors case, phenprocoumon may have made the have been suspected with various mechanisms for symptoms worse. decades.4,5,10 These mechanisms, increased The patient in ICSR 4 developed duodenal ulcers, gastric acid production (described as "possibly erosive antral gastritis, upper gastrointestinal related to the class of the compound" by the haemorrhage and tarry stool approximately two CHMP) and/or arteritis, may lead to manifestations months after the first dose of roflumilast. of the various GI reactions reported (duodenal Roflumilast was discontinued and the patient ulcer, gastritis, diverticulosis etc.); with recovered. The symptoms then re-occurred upon consequent, melaena particularly in sensitive re-challenge. The sender commented on the case patients (for example when treated with that, in the absence of any pharmacological anticoagulants). The fact that the GI indication that roflumilast could favour the manifestations have been reported as adverse occurrence of the patient's symptoms, the effects and not as concomitant sicknesses in all concurrent erosive antral gastritis provided a more cases, seem to support this explanation. plausible explanation. However, as described It is almost a philosophical question that, if the above, the literature states that PDE inhibitors are above analysis is true, what should be called "the"

WHO Pharmaceuticals Newsletter No. 4, 2013 • 20

SI GNAL adverse reaction; the increased gastric acid effects.html. production and/or its possible sequel: the gastric Accessed: 20 December 2012. ulcer, and/or its plausible consequence: the 8. Azithromycin Side Effects. intestinal haemorrhage, and/or its symptom: the URL: http://www.drugs.com/sfx/azithromycin- melaena? side-effects.html. One possible answer is that, since patients are Accessed: 20 December 2012. now being encouraged to report their drug adverse 9. Haemorrhoids. URL: effects; listing of those symptoms that may be http://www.ncbi.nlm.nih.gov/pub- easily self-diagnosed may be advocated. medhealth/PMH0001337. Accessed: 20 December 2012. Conclusion Causal relationships between PDE inhibitors 10. Giembycz MA. An update and appraisal of the (including roflumilast) and various GI adverse cilo-milast Phase III clinical development reactions have pre¬viously been established. programme for chronic obstructive pulmonary Although melaena is one of the rare but plausible disease. Br J Clin Pharmacol. 2006;62:138-52. sequelae of these GI conditions, which is not in 11. Faecal occult blood. Lab Tests Online. itself a new adverse reaction but an easily URL: http:// recognisable symptom that is not yet labelled, the www.labtestsonline.org.au/understanding/analytes reports discussed here suggest that it is worth /fobt/ tab/all?pnnpreview=1. listing as a rare ADR of roflumilast. Accessed: 25 January 2013.

References 1. Giembycz MA, Fiel SK. Roflumilast: first phosphodies-terase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010;4:147-58. 2. Melaena. URL: http://www.gpnotebook.co.uk/simplepage.cfm?ID

=-2087059454. Accessed: 17 December 2012. 3. European Medicines Agency CHMP Assessment report: Daxas.

URL: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_- _Public_assessment_report/ human/001179/WC500095213.pdf. Accessed: 24 April 4. Harris JB, Nigon K, Alonso D. Adenosine-3-5'- monophosphate: intracellular mediator for methyl xanthine stimulation of gastric secretion. Gastroenterology 1969;57:377-84. 5. Scratcherd T, Case RM. The role of cyclic adeno-sine-3'-5'-monophosphate (AMP) in gastrointestinal secretion. Gut. 1969;957-61. URL: http://www.ncbi. nlm.nih.gov/pmc/articles/PMC1553053. Accessed: 19 December 2012. 6. Summary of Product Characteristics for roflumilast (Daxas)

URL: http://www.ema.europa.eu/docs/en_GB/document _library/EPAR

Product_Information/human/001179/WC5000 95209.pdf. Accessed: 17 December 2012.

7. Tiotropium Side Effects. URL: http://www.drugs.com/sfx/tiotropium-side-

WHO Pharmaceuticals Newsletter No. 4, 2013 • 21

SI GNAL

Response from Forest Laboratories COPD patients have been shown to have an phase 1 studies, had no effect on gastric pH in increased incidence of gastroduodenal erosions healthy subjects (Houghton et al. 2006). Subacute and ulcers (Fukumura et al. 1992). and chronic toxicity studies of roflumilast in mice, Epidemiological studies show an increased risk of hamsters, and dogs revealed no histological upper GI bleeding amongst COPD patients who are changes in the glandular stomach or intestine not exposed to roflumilast with an almost two-fold suggestive of GI toxicity. GI changes were seen in risk compared to controls [HR:1.93, 95% CI:1.73- rats and monkeys at doses 50- to 200- times 2.17] (Huang et al. 2012). Although the primary above the clinical dose of 500 [ig/day. These data etiology of these erosions/ulcers is the demonstrated that roflumilast, at therapeutic hypersecretion of gastric acid induced by doses, is unlikely to significantly stimulate acid hypoxemia or hypercapnia, additional risk factors secretion or produce GI bleeding. include advanced age, male gender, smoking history, comorbidities of heart failure, chronic Conclusion renal disease, hypertension, diabetes, and the use The available evidence does not suggest a causal of ulcerogenic medications. relationship between the occurrence of melaena Roflumilast, a selective phosphodiesterase type 4 and the use of roflumilast. Upper GI haemorrhage (PDE4) inhibitor indicated for severe COPD, was is known to be increased in the COPD population. first approved in 2010 and is now marketed in 43 The cases of melaena identified (5 cases out of countries. Through 2012, exposure is estimated at 286,000 patient-years of exposure) are 286,000 patient-years. A search of the roflumilast confounded and occur at a rate which is global safety database identified 5 cases of anticipated in a COPD population. Additionally, "melaena", 4 of which are medically-confirmed. evidence from pre-clinical and controlled clinical Events occurred in patients aged 60-80 years with studies does not support an association. latencies between 4 days and 4 months with no Nevertheless, the MAHs are committed to the clear pattern. Reports of these events present close monitoring of AE reports of melaena through confounding factors that could account for the their routine pharmacovigilance processes. melaena, including co-morbid conditions (e.g.; duodenal ulcer, gastritis, proctitis, heart failure), a References previous history of gastrointestinal bleeding, 1. Fukumura M, Machida M, Koide K, Yoshiike Y, and/or co-suspect medications (e.g., Mizuno T, and Shindo K (1992), Peptic Ulceration anticoagulants, ASA, azithromycin). in Patients with Chronic Obstructive Pulmonary Statistical signal detection efforts using the Disease. Digestive Endoscopy, 4: 417-420. doi: Empirica Signal tool, with data from VigiBase™ 10.1111/j.1443-1661.1992. tb00107. and AERS, did not identify a statistical signal 2. Houghton LA, Atkinson W, Whorwell PJ, (EB05 >2) for "melaena" or any of the preferred Morris J, Murdoch RD, Cooper SM, et al. Effects of terms that comprise the GI haemorrhage SMQ. cilomilast, a selective phosphodiesterase 4 Rates of upper GI AEs associated with inhibitor, on esophageal motility and pH, and haemorrhage, including "melaena", from the COPD orocecal and colonic transit: two single-center, clinical development program were infrequent and randomized, double-blind, placebo-controlled, two- slightly lower in roflumilast than in placebo. part crossover studies in healthy volunteers. Clin 15/6,563 COPD subjects exposed to roflumilast Ther. 2006 Apr;28(4):569-81. (0.23%) reported terms indicative of upper GI 3. Huang KW, Luo JC, Leu HB, Lin HC, Lee FY, haemorrhage compared to 18/5, 491 placebo- Chan WL, et al. Chronic obstructive pulmonary treated subjects (0.33%). "Melaena", specifically, disease: an independent risk factor for peptic ulcer was reported in 2 subjects in each arm with bleeding: a nationwide population-based study. roflumilast (0.03%) and placebo (0.04%). Aliment Pharmacol Ther 2012 Apr;35(7):796-802. Systematic hemoccult testing, conducted in five placebo-controlled studies with roflumilast, and follow-up gastrointestinal investigations

(colonoscopy) to detect GI bleeding, revealed no difference from placebo. Biologically, while first generation PDE4 inhibitors were reported to increase acid secretion due to gastric parietal cell stimulation, less activity is expected with later-generation inhibitors, including roflumilast, due to lower-affinity binding at the rolipram binding site in the gastric glands. Indeed, cilomilast revealed improved GI tolerability and, in

WHO Pharmaceuticals Newsletter No. 4, 2013 • 22

SI GNAL

Tapentadol and Delusion Dr. Ian Boyd, Australia gastrointestinal effects such as nausea and Summary constipation and nervous system disorders such as Tapentadol is a centrally acting synthetic analgesic dizziness, headache and somnolence. Common combining opioid and non-opioid (noradrenaline reactions include gastrointestinal effects such as reuptake inhibition) activity in a single . vomiting, dry mouth and diarrhoea, nervous In the WHO Global Individual Case Safety Report system disorders such as disturbance in attention, (ICSR) Database, VigiBase™, there are currently tremor and involuntary muscle contractions, (25 January 2013) 10 ICSRs of delusion in psychiatric effects such as anxiety, depressed association with tapentadol. The ICSRs are from mood, sleep disorder, nervousness, restlessness, the United States and Germany. The association skin disorders such as pruritus and hyperhidrosis, has an IC value of 3.05 with an IC025 value of fatigue, myalgia, vertigo, flushing and decreased 1 2.02. Tapentadol was the only drug suspected in appetite. six cases. The outcome was stated in seven ICSRs. Delusional disorder is an illness characterized by The patients were reported as recovered or the presence of non-bizarre delusions in the recovering in six cases and not recovered in one absence of other mood or psychotic symptoms, case. according to the Diagnostic Manual of Mental The association of delusion with tapentadol Disorders, Fourth Edition, Text Revision (DSM-IV- 2,3 appears to be a signal. The IC value is relatively TR). It defines delusions as false beliefs based high. Tapentadol was the only drug suspected in on incorrect inference about external reality that six of the 10 cases, the time to onset is persist despite the evidence to the contrary and particularly suggestive of a drug-induced effect these beliefs are not ordinarily accepted by other and the observation of recovery after dechallenge members of the person's culture or subculture. in four of six cases in which recovery was Non-bizarre refers to the fact that this type of documented is also supportive of the signal. In delusion is about situations that could occur in real addition, the observation in the product life, such as being followed, being loved, having an information that other psychiatric reactions infection, and being deceived by one's spouse. occurred commonly and uncommonly in clinical Delusional disorder is on a spectrum between 2 trials suggests that a mechanism for the more severe psychosis and overvalued ideas. development of another psychiatric reaction such The prevalence of delusional disorder in the United as delusion may be possible. The fact that delusion States is estimated in the DSM-IV-TR to be around has been reported in VigiBase at a similar level to 0.03%, which is considerably lower than the some of these reactions is also suggestive of a prevalence of schizophrenia (1%) and mood signal. disorders (5%). 2,3,4 Medications known to be associated with delusion include Introduction adrenocorticotropic hormones, anabolic steroids, Tapentadol is a centrally acting synthetic analgesic corticosteroids, , antibiotics (eg, combining opioid and non-opioid (noradrenaline cephalosporins, ), disulfiram and 2 reuptake inhibition) activity in a single molecule. It agents. has 18 times less binding affinity than morphine to the human mu-opioid receptor but was only 2-3 Reports in VigiBase times less potent in producing analgesia in As of 25 January 2013 there are 10 Individual models (on a dose per body weight basis). This Case Safety Reports (ICSRs) of delusion in low in vivo potency difference is consistent with its association with tapentadol in the WHO Global two mechanisms of action. Tapentadol has been ICSR Database, VigiBase™ (Table 1). The shown to inhibit noradrenaline reuptake in the association has an IC value of 3.05 with an IC 025 of rats resulting in increased noradrenaline value of 2.02. The ICSRs were submitted from the concentrations. In preclinical models, the analgesic United States (nine cases) and Germany (one activity due to the mu-opioid receptor agonist case). The patients ranged in age from nine to 88 activity of tapentadol can be antagonized by years with a median of 57 years but only eight selective mu-opioid receptor antagonists (e.g., cases provided this information. The gender naloxone), whereas the noradrenaline reuptake distribution was nine females and one male. inhibition is sensitive to noradrenaline modulators. 1 Tapentadol is indicated for the Tapentadol was the only drug suspected in six management of moderate to severe chronic pain cases. Other suspected drugs included other drugs unresponsive to non-narcotic analgesia. 1 which might be expected to be used in a pain management situation including oxycodone (three Very common adverse reactions observed in cases), (two cases), clinical trials with tapentadol include (one case) and (three cases).

WHO Pharmaceuticals Newsletter No. 4, 2013 • 23

SI GNAL

Concomitant (but not suspected) drugs were one case the dose was increased from 50 mg to reported in five cases and also included drugs 100 mg; in another case the dose was doubled involved in a pain management setting such as from 100 mg to 200 mg; in the other case the oxycodone, morphine, NSAIDs and dose was increased but the details were not benzodiazepines. Tapentadol was reported to have provided. Another case appeared to describe the been administered orally, as expected, in all 10 reaction soon after the first dose and a further cases. The indication for use was included in seven case appeared to describe the reaction soon after ICSRs and included treatment for pain in each the second dose. case. The outcome was stated in seven ICSRs. The Time to onset was reported with clarity in only one patients were reported as recovered or recovering of the ICSRs and was two days after drug in six cases and not recovered in one case. In four administration began. In six other cases, however, of the six cases, the patient recovered after the reaction appeared to have occurred soon after dechallenge. the administration or an increase in the dose of Other reactions were described in seven ICSRs. In tapentadol. In one of these cases, the patient six of those ICSRs, other neuropsychiatric effects experienced delusion soon after an overdose of 26 were described including hallucination (three tablets. Three of the other cases reported the cases), anxiety and confusion (both two cases). reaction in association with an increase in dose: in

Table 1. Case overview of ICSRs in VigiBase™ of delusion in association with tapentadol

Case Age/Gender Other suspected (S) or concomitant (C) Reactions (WHO-ART preferred terms) Outcome drugs 1 61/F Paracetamol/oxycodone hydrochloride, Delusion, therapeutic response increas ed Not recovered cyclobenzaprine (both S) 2 28/M Morphine (C) Delusion, hallucination Recovered 3 80/F Sitagliptin, simvastatin, metamizole, Delusion, hallucination, confusion, aggressive Recovering citalopram, etoricoxib, lercanidipine, insulin reaction aspart/insulin aspart protamine, metoprolol, , xipamide, torasemide, acetylsal icylic acid (all C) 4 80/F None Delusion Unknown 5 -/F Duloxetine (S) Delusion, serotonin syndrome Recovered 6 34/F (C) Delusion, amenorrhoea, cardiac failure, depression, Recovered tremor, personality disorder, depersonalization, euphoria, crying abnormal, anxiety 7 -/F Phenobarbital, all other therapeutic products Delusion Recovered (both S) 8 53/F , cyclobenzaprine, oxycodone, Delusion, confusion, anxiety, dizziness, dry mouth Recovered paracetamol/ oxycodone hydrochloride, salbutamol, formoterol fumarate/budesonide, tamoxifen, , , phenobarbital (all C) 9 88/F None Delusion Unknown 10 52/F Alprazolam, , oxycodone (all S) Delusion, hallucination, arthralgia, myalgia, Unknown , , , intentional overdose paracetamol/ oxycodone hydrochloride (all C)

WHO Pharmaceuticals Newsletter No. 4, 2013 • 24

SI GNAL

delusion is consistent with the proposal that Literature and Labelling delusion is a signal. The product literature does not refer to delusion. However, other psychiatric reactions such as References anxiety, depressed mood, sleep disorder, 1. Therapeutic Goods Administration. Product nervousness and restlessness are described as Information for Palexia, CSL Limited, 5 November common and disorientation, confusion, agitation, 2012. perception disturbances, abnormal dreams and URL: https://www.ebs.tga.gov.au/ebs/picmi/ euphoria are described as uncommon. 1 There have picmirepository.nsf/pdf?OpenAgent&id=CP-2011- been no reports in the literature of delusion in PI-02119-3. Accessed: 18 February 2013. association with tapentadol. 2. Chopra S, Khan RA, Bourgeois JA, DM Hilty. Discussion and Conclusion Medscape Reference. Delusional Disorder. URL: Case reports in VigiBase suggest that there is a http://emedicine.medscape.com/article/292991- signal for the association of tapentadol and overview Accessed: 18 February 2013. delusion. Tapentadol was the only drug suspected 3. American Psychiatric Association. Diagnostic in six of the 10 cases. Other suspected drugs and statistical manual of mental disorders (DSM- included other drugs which might be expected to IV-TR). 4th ed, Text Revision (DSM-IV-TR). be used in a pain management situation including Washington, DC: American Psychiatric; 2000. oxycodone, cyclobenzaprine, phenobarbital and benzodiazepines and it is possible that these drugs 4. Sadock BJ. Delusional and shared psychotic may have made a contribution to the adverse disorder. Kaplan & Sadock's Synopsis of reaction observed. Psychiatry. 9th ed. 51120. Time to onset is suggestive of a signal. It was reported with clarity in only one of the ICSRs and was two days after drug administration began. In six other cases, however, the reaction appeared to have occurred soon after the administration or an increase in the dose of tapentadol, consistent with a drug-induced effect. Dechallenge is also possibly suggestive of a signal. The outcome was stated in seven ICSRs. The patients were reported as recovered or recovering in six cases and not recovered in one case. In four of these cases, the patients recovered or were recovering after the drug was reported to have been withdrawn. It is not surprising that neuropsychiatric effects may be associated with a drug such as tapentadol which combines both noradrenaline reuptake inhibition and mu-opioid receptor agonist activity. In addition, in the product information, psychiatric reactions such as anxiety, depressed mood, sleep disorder, nervousness and restlessness are described as common and disorientation, confusion, agitation, perception disturbances, abnormal dreams and euphoria are described as uncommon. The occurrence of delusion as an adverse reaction would not be inconsistent with these observations.

In VigiBase, many psychiatric reactions have been reported. These include hallucinations (which are perception disturbances) (110 cases), confusion (which includes disorientation) (100 cases), agitation (which includes restlessness) (60 cases), depression (51), anxiety (36), nervousness (22), sleep disorder (12), abnormal dreams (five) and euphoria (five). All of these terms are considered as common or uncommon in the product information and the presence of 10 ICSRs of

WHO Pharmaceuticals Newsletter No. 4, 2013 • 25

SI GNAL

Response from Grünenthal GmbH and Janssen Pharmaceuticals, inc.

Delusional disorders as defined in DSM-IV-TR are used interchangeably in some of the cases. require the presence of at least one non bizarre According to the definition of delusional disorder delusion persisting for at least one month. It is provided in the DSM-VI-TR1 classification, a also important to note that the diagnosis of prominent hallucination would preclude the delusion can only be made in the absence of other diagnosis of delusional disorder making the relevant psychiatric disorder, such as prominent diagnosis of delusional disorder in these cases auditory or visual hallucinations1. questionable, although most of the cases were medically confirmed. The signal of disproportionate reporting on tapentadol and delusion has been a topic of The rest of the cases lacked information on the internal review during the routine signal detection symptoms related to the diagnosis of delusional activities. The integrated analysis included data disorder, or there was missing information on from the clinical development program, important medical history or concomitant spontaneous reports and literature review with the treatment. Bearing in mind the challenges of conclusion that the review of evidence did not establishing an accurate psychiatric diagnosis, support an association between tapentadol these cases do not provide sufficient information administration and delusion. for a reasonable assessment. Although tapentadol as a centrally acting drug Clinical Experience already lists neuropsychiatric effects such as Perceptional disturbances, with its most prominent anxiety, disorientation, confusion and perception manifestation being hallucinations, have been disturbances including hallucinations, delusional identified as adverse drug reactions (ADRs) during disorder is a distinct medical concept. As the the clinical development program of tapentadol. diagnosis is clearly distinguished from other These are acknowledged class effects of mu-opioid psychiatric disorders, particularly hallucinations it agonist drugs in general. Further recognized cannot automatically be regarded as an expected neuropsychiatric ADRs include disorientation and drug reaction. confusion. To date, only 0.02% of subjects treated with Conclusion tapentadol experienced delusion during the clinical The integrated analysis revealed insufficient development program. All these events were non- evidence for an association between tapentadol serious, with mild or moderate intensity, and did and delusion. Therefore, currently delusion is not not lead to a change of the safety profile of regarded as a valid safety signal. The topic will tapentadol. however be reviewed on a routine basis to monitor for a change in the level of evidence. Postmarketing Experience Cases retrieved from the safety database with a Reference cumulative search for the Preferred Term 1. American Psychiatric Association. Diagnostic 'Delusion' were reviewed in detail. All cases were and Statistical Manual of Mental Disorders (DSM- sparsely documented, especially regarding medical IV-TR). Fourth Edition, Text Revision (DSM-IV-TR). history and the diagnosis, as symptoms or Washington, DC: American Psychiatric; 2000. circumstances describing the delusion were not mentioned.

More than a third of the cases reported hallucination concurrently. Furthermore the events of disorientation and confusion were reported, which confounded a clear medical assessment. With exception for one case, all other cases were medically confirmed. Overall, there were no cases with sufficient information providing phenomenological evidence regarding the diagnosis and lacking confounders.

Discussion

The review of post-marketing cases suggests that the distinction between hallucination and delusional disorder is often not made by the reporting health care professional and the terms

WHO Pharmaceuticals Newsletter No. 4, 2013 • 26

SI GNAL

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

WHO Pharmaceuticals Newsletter No. 4, 2013 • 27