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

Uppsala, Sweden

TheThe aim aim of of the th eNewsletter Newsletter is is to to No.No. 6, 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 document. 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 This is the last issue of the newsletter in 2013. We be obtained on request from: thank you for your interest in this publication and wish Quality Assurance and Safety: The feature article in this issue gives you… you a very good year in 2014. 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

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TAB LE OF CONTENTS

Regulatory Matters Apixaban, dabigatran and rivaroxaban ...... 4 Bevacizumab ...... 4 Combined hormonal contraceptives ...... 5 Dexmedetomidine hydrochloride ...... 6 Ezogabine ...... 6 patches ...... 7 Low Molecular Weight Heparins ...... 7 Mefloquine ...... 8 Ofatumumab and rituximab ...... 8 Over-the-Counter Topical Antiseptic Products ...... 9 Ponatinib ...... 9 - or paliperidone-containing products ...... 10 Rotavirus vaccination ...... 11 Salbutamol and terbutaline ...... 11 Thiocolchicoside ...... 12 Tigecycline ...... 12 Trastuzumab emtansine and trastuzumab ...... 13 Vancomycin ...... 13

Safety of medicines Antiepileptic drugs ...... 14 Atomoxetine ...... 15 ...... 15 Cinacalcet ...... 15 -containing contrast agents ...... 16 Sodium ...... 17

Signal Abiraterone and Thrombocytopenia ...... 18 Response from Janssen ...... 23 Baclofen and Renal failure ...... 26 Golimumab and Meningitis ...... 27 Response from Janssen Biologics B.V...... 29 Pazopanib and Pericardial Effusion ...... 30

WHO Pharmaceuticals Newsletter No. 6, 2013 • 3

REGULATORY MATTERS

apixaban and rivaroxaban, for increase the risk of major Apixaban, all doses and indications: bleeding • A lesion or condition, if • Attention should be paid to dabigatran and considered a significant risk rivaroxaban renal function. Impaired factor for major bleeding. renal function may This may include: constitute a contraindication Risk of serious o current or recent or recommendation not to haemorrhage—clarified gastrointestinal ulceration use the anticoagulant contraindications apply o presence of malignant to all three medicines medicine, or may require a neoplasm at high risk of dose reduction; UK. The Medicines and bleeding recommendations differ for Healthcare products o recent brain or spinal Regulatory Agency (MHRA) the three medicines announced that the injury • The contraindications, o contraindications for recent brain, spinal, or posology, and warnings and dabigatran (Pradaxa®) which ophthalmic surgery precautions for use specific o include a range of conditions recent intracranial to each medicine, together where the patient is at haemorrhage with the individual’s risk significant risk of major o known or suspected bleeding, also applied to the factors for bleeding (eg, oesophageal varices other two new oral renal function), should be o anticoagulants apixaban arteriovenous considered before (Eliquis®) and rivaroxaban malformation prescribing these medicines (Xarelto®). o vascular aneurysms, or major intraspinal or Dabigatran is a potent, orally It is also notified that there is active, direct inhibitor of free intracerebral vascular no specific available thrombin, fibrin-bound abnormalities for any of these three new oral thrombin and thrombin- • Concomitant treatment with anticoagulants. induced platelet aggregation. any other anticoagulant (See WHO Pharmaceuticals Apixaban and rivaroxaban are agent—eg, unfractionated Newsletters Nos. 1 and 6, direct, highly selective, orally heparin, low molecular 2012 for safety review of post- active inhibitors of activated market reports of serious weight heparin (such as factor X (factor Xa). bleeding events in the USA, enoxaparin or dalteparin), Australia and New Zealand; All three new oral heparin derivatives (such as anticoagulants are licensed for: Risk of serious haemorrhage, fondaparinux), or oral • prevention of venous need for renal function testing anticoagulants (such as in UK, and No.4, 2012 for thromboembolic events in warfarin). Exceptions are modifications to product adults who have had switching of therapy to or information for clearer elective total hip- guidance in EU). from the medicine, or when replacement or knee- unfractionated heparin is Reference: replacement surgery given at doses necessary to Drug Safety Update, October • prevention of stroke and maintain an open central 2013, Volume 7, issue 3, A1 systemic embolism in adults MHRA, (www.mhra.gov.uk ). venous or arterial catheter with non-valvular and one or more Additional advice and Bevacizumab cardiovascular risk factors information for health-care professionals: Necrotising fasciitis Rivaroxaban is additionally • Special care should be licensed for: taken when deciding to Australia. The Therapeutic • treatment of deep-vein Goods Administration (TGA) prescribe these thrombosis and pulmonary advised health professionals anticoagulant medicines to embolism, and prevention that the Product Information patients with other of their recurrence, in (PI) for bevacizumab conditions, procedures, and (Avastin®) was updated to adults concomitant treatments include a precaution about (eg, non-steroidal anti- necrotising fasciitis. It is The following contraindications inflammatory drugs, recommended that now apply to all three new oral bevacizumab be discontinued antiplatelets), which may anticoagulants, dabigatran, and appropriate therapy

WHO Pharmaceuticals Newsletter No. 6, 2013 • 4

REGULATORY MATTERS initiated promptly upon Combined hormonal prescribing a contraceptive. diagnosis. Doctors should also consider contraceptives how the risk of VTE with a Bevacizumab is an particular CHC compares with antineoplastic agent, a human Benefits continue to other CHCs. monoclonal antibody that outweigh risks selectively binds and inhibits The CHMP opinion, in the biological activity of human Europe. The European agreement with the previous vascular endothelial growth Medicines Agency completed recommendation by the factor (VEGF). Inhibition of its review of combined Pharmacovigilance Risk VEGF activity reduces the hormonal contraceptives Assessment Committee vascularisation of tumours, (CHCs), particularly of the risk (PRAC), will now be sent to the thereby hindering their growth. of venous thromboembolism European Commission for the (VTE) associated with their adoption of a legally binding Necrotising fasciitis is a life- use. The European Medicines decision to update the product threatening bacterial infection Agency’s Committee for information of all CHCs of the soft tissue. It is Medicinal Products for Human throughout the EU. characterised by rapidly Use (CHMP) concluded that the spreading necrosis of benefits of CHCs in preventing Health-care professionals are superficial fascia and unwanted also advised that: subcutaneous tissue. continue to outweigh their • When prescribing a CHC, Symptoms may include sudden risks, and that the known risk careful consideration should severe pain in the affected of VTE with all low-dose CHCs be given to the individual area; redness, heat, swelling, ( < 50 mcg) is woman’s current risk or fluid-filled blisters in the small. Differences exist factors, particularly those skin; scaling, peeling, or between CHCs in their risk of discoloured skin over the VTE depending on the type of for VTE, and the difference affected area; and fever. Other they contain. in risk of VTE between symptoms may include Currently available data products. CHCs are confusion, fainting or dizziness. indicate that CHCs containing contraindicated if a woman Internationally, necrotising the has one serious or multiple fasciitis has been reported in a , risk factors that put her at or have the small number of patients high risk of blood clots. lowest risk of VTE. receiving bevacizumab in both • Because a woman’s clinical trials and in the The review also looked at the individual risk factors will postmarket setting. Some of risk of arterial change over time, there is a these cases have been fatal. thromboembolism (ATE). This need to regularly re-assess There have been no reports of risk is very low and there is no necrotising fasciitis in patients evidence for a difference in the the suitability of her receiving bevacizumab in level of risk between products contraceptive. It is also Australia. depending on the type of important to raise The reported cases show progestogen. awareness of the signs and occurrence of necrotising The review reinforced the symptoms of VTE and ATE fasciitis in patients with several importance of ensuring that when prescribing a CHC. different types of cancers. clear and up-to-date • Health-care professionals However, it has been found information is provided to should always consider the that the incidence of the women who use these possibility of a CHC- infection associated with medicines and to the associated bevacizumab is rare and healthcare professionals giving usually secondary to wound advice and clinical care. thromboembolism when healing complications, presented with a woman gastrointestinal perforation or The product information of who has symptoms. fistula formation. CHCs will be updated to help women make informed (See WHO Pharmaceuticals (See WHO Pharmaceuticals decisions about their choice of Newsletter No.2, 2013 for Newsletter No.3, 2013 for contraception together with review of Diane 35 and other Cases of necrotizing fasciitis in their healthcare professional. It medicines started following the Canada) is important that women are decision by the French made aware of the risk of VTE Reference: medicines regulatory agency to and its signs and symptoms, Medicines Safety Update Vol 4, suspend the drug in EU and and that doctors take into No. 4, August 2013 Canada and No.4, 2013 for consideration a woman’s (www.tga.gov.au ). benefits of Diane 35 and its individual risk factors when

WHO Pharmaceuticals Newsletter No. 6, 2013 • 5

REGULATORY MATTERS generics outweigh risks in setting, dexmedetomidine is of the risk of abnormalities to certain patient groups in EU). indicated for sedation of the retina. It is advised that initially intubated patients. ezogabine use be limited to Reference: However, use of the drug by patients who have not Press release, EMA, 22 continuous infusion should not responded adequately to November 2013 exceed 24 hours. several alternative therapies to (www.ema.europa.eu ). Dexmedetomidine is also decrease the frequency of indicated for procedural seizures, or epilepsy, and for Dexmedetomidine sedation. It can be used for whom the benefits of non-intubated patients before treatment outweigh the risks. hydrochloride and/or during surgeries and Ezogabine is approved as other procedures. adjunctive treatment of Risk of cardiovascular Atrial fibrillation, bradycardia partial-onset seizures in adult events and hypotension are all listed patients 18 years and older. Australia. The TGA reminded as adverse effects or Pigment changes in the retina health professionals that precautions in the current PI have the potential to cause careful patient selection and for dexmedetomidine. There is serious eye disease with loss of consideration of the setting in a warning in the Precautions vision. It is not yet known which dexmedetomidine section regarding use in the whether the retinal pigment hydrochloride (Precedex®) is elderly, in patients with high changes caused by ezogabine used are crucial to ensuring its vagal tone, or chronic lead to visual impairment, safe use and that it should only diseases, such as diabetes and although several patients have be used for the approved , and with been reported to have indications and should be concomitant drugs with a impaired visual acuity. In some administered in accordance similar pharmacological action. cases, retinal abnormalities with the instructions in the PI. In the past 10 years, the TGA have been observed in the It is also reminded that a has received a small number of absence of skin discoloration. controlled infusion device spontaneous reports of The skin discoloration in the should be used for the cardiovascular events involving reported cases appeared as administration of dexmedetomidine (of a kind blue pigmentation, dexmedetomidine, and the listed as known adverse events predominantly on or around dose and rate of infusion in the PI). the lips or in the nail beds of should not exceed that Reference: the fingers or toes, but more recommended in the PI. widespread involvement of the Medicines Safety Update Vol 4, face and legs has also been Particular caution is required in No. 4, August 2013 reported. Scleral and the following situations: (www.tga.gov.au ). conjunctival discoloration, on • patients with hypovolaemia, the white of the eye and inside as dexmedetomidine Ezogabine eyelids, has been observed as decreases sympathetic well. The skin discoloration nervous system activity generally occurred after four • patients with some level of Linked to retinal years of treatment with autonomic system abnormalities and blue ezogabine, but has appeared dysfunction, such as those skin discoloration sooner in some patients. with diabetes and the USA. The U.S. Food and Drug In light of this new safety elderly Administration (FDA) warned information all patients taking the public that ezogabine • patients of all ages with ezogabine should have a (Potiga®) can cause blue skin high vagal tone baseline eye exam and periodic discoloration and eye eye exams that should include • with concomitant use of abnormalities characterized by visual acuity testing and vasodilators, negatively pigment changes in the retina. dilated fundus photography, chronotropic agents, and/or The US FDA does not currently and may include fluorescein other agents with alpha2- know if these changes are angiograms (FA), ocular reversible. The US FDA adrenoceptor coherence tomography (OCT), approved changes to the drug activity, such as clonidine perimetry, and label, underscoring risks of electroretinograms (ERG). and droperidol. abnormalities to the retina in Ezogabine should be the eye, potential vision loss, discontinued if ophthalmic Dexmedetomidine is a and skin discoloration, all of changes are observed unless relatively selective alpha2- which may become permanent. no other treatment options are adrenoceptor agonist used for The revised label includes a available. If a patient develops sedation. In an intensive care new boxed warning, because skin discoloration, serious WHO Pharmaceuticals Newsletter No. 6, 2013 • 6

REGULATORY MATTERS consideration should be given is requiring the manufacturer to decrease the risk of spinal to changing to an alternate of fentanyl to print the name column bleeding and medication. Patients who are and strength of the drug on subsequent paralysis after taking ezogabine and develop the patch in long-lasting ink, in spinal injections, including any changes in their vision or a colour that is clearly visible epidural procedures and any discoloration of their skin, to patients and caregivers. The lumbar punctures. These new including of their lips and nail current ink colour varies by timing recommendations, beds, should contact their strength and is not always which can decrease the risk of health care professional right easy to see. This change is epidural or spinal hematoma, away. intended to enable patients will be added to the labels of and caregivers to more easily anticoagulant drugs known as Patients should not stop taking find patches on patients’ low molecular weight heparins, ezogabine without talking to bodies and see patches that including Lovenox® and their health-care professional. have fallen off, which children generic enoxaparin products Stopping such treatment or pets could accidentally and similar products. suddenly can cause serious touch or ingest. The and life-threatening medical Epidural or spinal hematomas manufacturers of generic problems such as recurrence of are a known risk of enoxaparin fentanyl patches are being seizures. in the setting of spinal requested to make similar procedures and are already (See WHO Pharmaceuticals changes. described in the Boxed Newsletter NO.3, 2013 for link Patients are recommended to Warning and the Warnings and to retinal abnormalities and be aware that patches that are Precautions sections of the blue skin discoloration in the not stuck to the skin tightly labels for Lovenox® and USA). enough may accidentally fall generic enoxaparin products. References: off a patient and stick to However, these serious FDA Drug Safety someone in close contact, such adverse events continue to Communication, US FDA 1 as a child. Used fentanyl occur. To address this safety November 2013 patches require proper disposal concern, the US FDA worked (www.fda.gov ). after use ― fold the patch, with the manufacturer of sticky sides together, and flush Lovenox®, Sanofi-Aventis, to it down the toilet right away. further evaluate this risk and Fentanyl patches to update the Warnings and (See WHO Pharmaceuticals Precautions section of the Newsletter No.2, 2009 for Lovenox label with these Packaging changes to Warning about accidental child additional timing minimize risk of exposure and No.4, 2005 for recommendations. The labels accidental exposure labelling update in Canada) for generic enoxaparin USA. The US FDA required References: products will also be revised colour changes to the writing FDA Drug Safety accordingly, as will those of on fentanyl (Duragesic® and Communication, US FDA 23 other low molecular weight generics) pain patches so they September 2013 heparin-type products. can be seen more easily. The (www.fda.gov ). US FDA continues to learn of It is important to note that all deaths from accidental anticoagulants carry the risk of exposure to fentanyl patches. Low Molecular causing spinal bleeding when Fentanyl patch is a strong used in conjunction with prescription pain medicine that Weight Heparins epidural/spinal anaesthesia or contains a narcotic . spinal puncture. The US FDA is Recommendations to continuing to evaluate the Patients and health-care decrease risk of spinal safety of other anticoagulants professionals are reminded column bleeding and to determine if additional label that fentanyl patches are changes are needed. dangerous even after they’ve paralysis been used because they still USA. The US FDA References: contain high amounts of strong recommended that health-care FDA Drug Safety narcotic pain medicine. professionals carefully consider Communication, US FDA 6 Accidental exposure to these the timing of spinal catheter November 2013 patches can cause serious placement and removal in (www.fda.gov ). harm and death in children, patients taking anticoagulant pets, and others. drugs, such as enoxaparin, and delay dosing of anticoagulant In an effort to minimize the medications for some time risk of accidental exposure to interval after catheter removal fentanyl patches, the US FDA WHO Pharmaceuticals Newsletter No. 6, 2013 • 7

REGULATORY MATTERS

Mefloquine • To minimise the risk of risk of reactivation of hepatitis these adverse reactions, B virus (HBV) infection. The revised labels also include Strengthened warnings mefloquine must not be additional recommendations used for chemoprophylaxis on neuropsychiatric side for screening, monitoring, and in patients with active or a effects managing patients on these UK. The MHRA announced that, history of psychiatric drugs to decrease this risk. although the risk of disturbances such as In patients with prior HBV neuropsychiatric side effects depression, anxiety infection, HBV reactivation with mefloquine is well- disorders, schizophrenia, or may occur when the body’s established, a recent review of other psychiatric disorders immune system is impaired. the prescribing information has • If neuropsychiatric HBV reactivation has occurred led to strengthened warnings in patients with prior HBV and new measures to help reactions or changes to exposure who are later treated minimise risks. The overall mental state occur during with drugs classified as CD20- safety profile of the drug has mefloquine directed cytolytic antibodies, also been clarified in the chemoprophylaxis, the including ofatumumab and product information. patient should be advised to rituximab. Some cases have Mefloquine (Lariam®) is used stop taking mefloquine and resulted in fulminant hepatitis, for prophylaxis and treatment seek medical advice as soon hepatic failure, and death. of Plasmodium falciparum as possible so that it can be Ofatumumab is used to treat malaria. Official guidance on replaced by another chronic lymphocytic leukemia the appropriate use of medicine for malaria (CLL) in patients who have antimalarial medicines and the prevention further disease after treatment prevalence of resistance should with the anti-cancer drugs be considered when fludarabine and alemtuzumab. prescribing mefloquine . It is also notified that the Marketing Authorisation Holder Rituxan is used to treat non- Updated information and is issuing a letter to health- Hodgkin’s lymphoma and CLL. advice for health-care care professionals, a prescriber It is also used to treat other professionals: checklist, and patient alert medical conditions, including • Psychiatric symptoms card to aid compliance with rheumatoid arthritis, associated with use of these warnings, and to ensure granulomatosis with mefloquine such as patients are more aware of the polyangiitis, and microscopic polyangiitis. nightmares, acute anxiety, neuropsychiatric side effects and to react promptly when depression, restlessness, or To decrease the risk of HBV these occur in malaria reactivation, the US FDA confusion should be chemoprophylaxis. regarded as potentially recommended that health-care (See WHO Pharmaceuticals professionals: prodromal for a more Newsletter NO.5, 2013 for risk • Screen all patients for HBV serious event of serious psychiatric and infection before starting • Cases of suicide, suicidal nerve side effects in the USA) treatment with ofatumumab thoughts, and self- Reference: or rituximab by measuring endangering behaviour such Drug Safety Update, November hepatitis B surface antigen as attempted suicide have 2013, Volume 7, issue 4, A5 (HBsAg) and hepatitis B been reported in association MHRA, (www.mhra.gov.uk ). core antibody (anti-HBc). with use of mefloquine • Consult with hepatitis • Adverse reactions may experts regarding occur and persist up to Ofatumumab and monitoring and use of HBV several months after rituximab antiviral therapy when discontinuation of screening identifies patients mefloquine because of its New boxed warning, at risk of HBV reactivation long half-life. In a small recommendations to due to evidence of prior number of patients, decrease risk of hepatitis HBV infection. dizziness or vertigo and loss B reactivation • Monitor patients with of balance have been USA. The US FDA approved evidence of prior HBV reported to continue for changes to the prescribing information of ofatumumab infection for clinical and months after (Arzerra®) and rituximab laboratory signs of hepatitis discontinuation of the drug (Rituxan®) to add new Boxed B or HBV reactivation Warning information about the WHO Pharmaceuticals Newsletter No. 6, 2013 • 8

REGULATORY MATTERS

during ofatumumab or required to decrease risk procedures to restore blood rituximab therapy and for of infection flow. several months thereafter, USA. The US FDA requested The US FDA asked, and Ariad since reactivations have label and packaging changes to Pharmaceuticals agreed, to occurred several months enhance the safe use of certain suspend marketing and sales following completion of over-the-counter (OTC) topical of ponatinib, because of the therapy with these drugs. antiseptic products. This risk of life-threatening blood request is the result of their clots and severe narrowing of • In patients who develop on-going evaluation of blood vessels. The US FDA will reactivation of HBV while on infrequent but continuing continue to evaluate the drug ofatumumab or rituximab, reports of infections resulting to further understand its risks immediately discontinue the from antiseptic products and potential patient drug and start appropriate labelled for preoperative or pre populations in which the treatment for HBV. Also injection skin preparation. benefits of the drug may When used properly, topical discontinue any outweigh the risks. Patients antiseptics are safe and currently receiving the drug the patient is effective products to reduce should discuss with their receiving until the HBV the number of bacteria on health-care professionals the infection is controlled or patients’ skin prior to surgery risks and benefits of continuing resolved. Because of or injections. However, most treatment with the drug. The insufficient data, no often, contamination of topical US FDA provided instructions recommendation can be antiseptics occurs when to health-care professionals organisms are introduced into whose patients have been made regarding the the product by users. taking ponatinib and are resumption of ofatumumab Therefore, health-care benefiting from the drug, on or rituximab in patients who professionals and patients how to continue those patients develop HBV reactivation should follow all label on the drug. hepatitis. directions to decrease the chances of infection. Ponatinib is a prescription medicine used to treat adults For Patients: References: diagnosed with chronic phase, • Before receiving FDA Drug Safety accelerated phase, or blast ofatumumab or rituximab, Communication, US FDA 13 phase chronic myeloid tell your health-care November 2013 leukemia (CML) or Philadelphia professional if you have or (www.fda.gov ). chromosome-positive (Ph+) have had any severe acute lymphoblastic leukemia infections, including HBV. (ALL), who are no longer Ponatinib benefiting from previous • If you have had HBV treatment or who did not infection, your health-care Risk of serious blood tolerate other treatment. At professional should monitor clots in arteries and the time of ponatinib’s you for HBV infection during veins approval in December 2012, treatment and for several the drug label contained USA(1). The US FDA months after you stop information about the risks of investigated an increasing treatment with ofatumumab blood clots in the Boxed frequency of reports of serious Warning and Warnings and or rituximab. and life-threatening blood clots Precautions sections. and severe narrowing of blood References: vessels (arteries and veins) of Patients taking the drug should FDA Drug Safety patients taking ponatinib seek immediate medical Communication, US FDA 25 (Iclusig®). Data from clinical attention if they experience September 2013 trials and post market adverse symptoms suggesting a heart (www.fda.gov ). event reports show that attack such as chest pain or serious adverse events have pressure, pain in their arms, occurred in patients treated back, neck or jaw, or shortness Over-the-Counter with the drug, including heart of breath; or symptoms of a Topical Antiseptic attacks resulting in death, stroke such as numbness or Products worsening coronary artery weakness on one side of the disease, stroke, narrowing of body, trouble talking, severe large arteries of the brain, , or dizziness. Label changes and severe narrowing of blood Europe(2). The CHMP made single-use packaging vessels in the extremities, and a number of recommendations the need for urgent surgical to help minimise the risk of WHO Pharmaceuticals Newsletter No. 6, 2013 • 9

REGULATORY MATTERS blood clots obstructing arteries Risperidone- or associated with an increased or veins in patients taking rate of cataract surgical ponatinib (Iclusig®). paliperidone- complications. containing products The CHMP recommended that It is recommended that ponatinib should not be used in cataract surgeons should patients who have had a heart Risk of Intraoperative inquire about current or prior attack or stroke in the past, Floppy Iris Syndrome use of risperidone- or unless the potential benefits to (IFIS) paliperidone-containing them outweigh the risks. In Canada (1). Janssen Inc., in products and approach the addition, the cardiovascular consultation with Health surgery with caution. If IFIS is risks of all patients should be Canada, provided health-care suspected, modifications to assessed and measures should professionals with important surgical technique may be be taken to reduce risks before new safety information required. starting and during treatment regarding the risk of UK (2). The MHRA announced with ponatinib. Patients who Intraoperative Floppy Iris that cases of IFIS during have high blood pressure Syndrome (IFIS) associated cataract surgery have been should have their blood with the use of risperidone reported in patients taking the pressure controlled and health- (Risperdal®, Risperdal® M- atypical antipsychotics care professionals should Tab®, Risperdal® Consta®), risperidone or paliperidone. consider interrupting treatment paliperidone (Invega®) and if is not paliperidone palmitate (Invega The MHRA advised that controlled. Treatment with the Sustenna®). These products primary-care physicians should drug should be stopped are primarily prescribed for the document the use of α1- immediately in any patient treatment of schizophrenia; adrenergic antagonists— with signs of blood clots however, the risk applies to all including risperidone and obstructing arteries or veins. patients undergoing cataract paliperidone—when making a referral for cataract surgery. The CHMP’s recommendations surgery, who have been When taking a medication follow a review of updated exposed to these products, history before cataract data indicating that irrespective of indication. The surgery, patients should be blood clots were occurring at a WARNINGS AND questioned about current or higher rate than was observed PRECAUTIONS section of the past use of risperidone or at the time of the medicine’s Product Monographs for these paliperidone. Cataract initial authorisation. Conditions drugs were updated to include surgeons should approach related to blood clots, such as this new safety information. surgery with caution in people heart attacks and strokes, According to Health Canada, with such a medication history. were already considered to be cases of IFIS were reported If IFIS is suspected, measures possible side effects of with the use of risperidone. No to prevent the iris from ponatinib and were listed in reports were received with the prolapsing during cataract the EU product information. use of paliperidone. surgery may be required. The The EMA plans to conduct a Paliperidone is the major potential benefit of stopping further in-depth review of active metabolite of risperidone or paliperidone relevant data on the benefits risperidone and they are before cataract surgery on the and risks of ponatinib and will pharmacologically very similar. risk of IFIS has not been make recommendations on Therefore, a risk of IFIS in established and must be whether there should be patients undergoing cataract weighed against the risk of further changes to how the surgery and receiving stopping antipsychotic therapy. medicine is used. paliperidone cannot be excluded. The MHRA also notified that , References: to date, no cases of IFIS have (1) FDA Drug Safety IFIS is a recently described been reported for paliperidone; Communication, US FDA 7 intraoperative complication however, this drug is an active November 2013 that has been observed during metabolite of risperidone and (www.fda.gov ). cataract surgery in patients has α1-adrenergic antagonist (2) Press release, EMA, 22 receiving risperidone. IFIS is actions. Therefore, this November 2013 characterized by a triad of information and advice applies (www.ema.europa.eu ). intraoperative signs (billowing also to paliperidone. of a flaccid iris stroma, progressive intraoperative Reference: pupil constriction and a (1) Advisories, Warnings and propensity for iris prolapse) Recalls, Health Canada, 14 that may present with varying November 2013 (www.hc- degrees of severity and is sc.gc.ca ).

WHO Pharmaceuticals Newsletter No. 6, 2013 • 10

REGULATORY MATTERS

(2) Drug Safety Update, department visits for acute maintaining uterine November 2013, Volume 7, gastroenteritis in young quiescence. Use of oral SABAs issue 4, A6 MHRA, children have declined and has been associated with a risk (www.mhra.gov.uk ). hospitalisations for rotavirus of serious and potentially fatal gastroenteritis in the under- cardiovascular events such as five year age group have been myocardial infarction and Rotavirus reduced by over 70%. Based pulmonary oedema in the vaccination on the established benefits of mother and cardiomegaly in rotavirus vaccination and the the fetus, which increased with rare occurrence of duration of use. Therefore, the Risk of intussusception intussusception, both the risks associated with use of the Australia. The TGA advised World Health Organization and oral formulations were health professionals that a the Australian Technical considered to outweigh the recently completed study Advisory Group on benefits. confirmed that there is an Immunisation have The product information for elevated risk of intussusception recommended the continued salbutamol and terbutaline will following the first and second use of rotavirus vaccine for be amended to remove the doses of rotavirus vaccines, infants. Rotarix® and RotaTeq®. obstetric indications from the Health professionals are (See WHO Pharmaceuticals oral products; there will also advised that information about Newsletter No.2, 2011 for risk be no reference to use of oral the risk of intussusception of intussusception in Australia) products in the product following rotavirus vaccination Reference: information for parenteral formulations. has been added to the Medicines Safety Update Vol 4, postmarketing adverse events No. 5, October 2013 The parenteral SABA sections of the Product (www.tga.gov.au ). formulations were considered Information of these vaccines. to be efficacious in short-term Health professionals should use up to 48 hours. A short advise parents and caregivers Salbutamol and delay to the onset of of the risks and signs of terbutaline premature labour enables intussusception, and the transfer of the patient to importance of seeking early facilities that enable Restricted use for medical attention if they administration of suspect their child has tocolysis in premature and that can intussusception. labour support neonatal care. UK. The MHRA announced that The TGA, working in Additional advice will be added the use of short-acting β2 collaboration with state health to the product information for (SABAs), salbutamol authorities, completed an parenteral SABA formulations and terbutaline, for tocolysis in investigation into this to promote pretreatment premature labour was association. According to the screening for pre-existing restricted to 48 hours’ TGA, there was clear evidence heart disease, and to advise maximum parenteral use of an elevated risk of continuous monitoring of under specialist supervision, intussusception following the mother and fetus during after a European safety review. first dose of both rotavirus treatment. vaccines. There was also some Oral SABAs should not be used elevated risk of intussusception in any obstetric indication. The Health-care professionals are 1–7 days following the second review was triggered by also advised that tocolysis dose of both vaccines. There reports of serious should not be initiated when: was no evidence of increased cardiovascular events, • Gestational age is less than risk of intussusception including myocardial infarction 22 weeks, or when there is following a third dose of and pulmonary oedema, after any condition to mother or tocolytic use in premature RotaTeq®. fetus for which prolongation labour Prior to the introduction of of would be rotavirus vaccination, there Salbutamol and terbutaline are hazardous SABAs with the obstetric were an estimated 10 000 • (Pre-existing) risk factors indication of inhibition of hospitalisations annually in for ischaemic heart disease children under five years due premature labour. or a pre-existing medical to rotavirus gastroenteritis. The oral SABA preparations condition mean that use of Since the introduction of were found to be ineffective in a SABA would be harmful Rotarix® and RotaTeq® onto the provision of acute tocolysis the National Immunisation in premature labour, and are (eg, pulmonary Program, emergency not consistently effective at hypertension, cardiac WHO Pharmaceuticals Newsletter No. 6, 2013 • 11

REGULATORY MATTERS

disorders such as of childbearing potential November 2013 hypertrophic obstructive who are not taking (www.ema.europa.eu ). cardiomyopathy or aortic appropriate contraceptive stenosis) measures. Tigecycline • Patients being treated with In patients with pre-existing systemic thiocolchicoside Increased risk of death heart disease there are further should have their treatment warnings, including the need USA. The US FDA notified reviewed at the next for assessment by a physician health-care professionals and experienced in cardiology. scheduled appointment, and their medical care appropriate alternative organizations of a new Boxed (See WHO Pharmaceuticals treatments should be Warning describing an Newsletter NO.4, 2007 for considered. increased risk of death when Myocardial ischemia in • Pharmacists should refer intravenous tigecycline pregnancy in Canada) (Tygacil®) is used for FDA- any patients who present a Reference: approved uses as well as for repeat prescription to their Drug Safety Update, November non-approved uses. It is 2013, Volume 7, issue 4, A3 treating physician. recommended that health-care MHRA, (www.mhra.gov.uk ). • Prescribers will be sent a professionals should reserve letter giving them further tigecycline for use in situations information on the when alternative treatments Thiocolchicoside restriction of indication of are not suitable. These changes to the Prescribing systemic thiocolchicoside. Information are based on an Restricting use by mouth Educational materials for or injection additional analysis that was prescribers and patients will conducted for FDA-approved Europe. The CHMP also be prepared. uses after FDA issuing a Drug recommended that the • The current findings do not Safety Communication about authorised uses for apply to topical this safety concern in thiocolchicoside-containing September 2010. medicines for use by mouth or preparations of injection should be restricted thiocolchicoside. This analysis showed a higher across EU. These medicines risk of death among patients are now recommended only as Thiocolchicoside is used as a receiving tigecycline compared adjuvant treatment for acute muscle relaxant in the to other antibacterial drugs: muscle contractures in spinal treatment of painful muscular 2.5% (66/2640) vs. 1.8% pathology, for adults and conditions. It is thought to act (48/2628), respectively. The adolescents from 16 years of on receptors in the nervous adjusted risk difference for age. It is not recommended for system that are involved in the death was 0.6% with longer-term treatment of regulation of muscle function. corresponding 95% confidence chronic conditions. In addition, interval (0.0%, 1.2%). In The Committee’s the dose of thiocolchicoside by general, the deaths resulted recommendations were based mouth or injection should be from worsening infections, on a review of available data restricted. complications of infection, or from pre-clinical and clinical other underlying medical Health-care professionals are studies, published literature conditions. also informed that; and post-marketing • The maximum experience, and consultations Tygecycline is FDA-approved to recommended oral dose is 8 with an expert working party treat complicated skin and skin structure infections (cSSSI), mg every 12 hours; on medicines safety. The Committee concluded that complicated intra-abdominal treatment duration should benefit-risk for the medicine infections (cIAI), and be no more than 7 remained positive provided community-acquired bacterial consecutive days. When appropriate risk-mitigating pneumonia (CABP). given intramuscularly, the measures were taken, References: including restricting the maximum dose should be 4 FDA Drug Safety maximum dose and duration of mg every 12 hours, for up Communication, US FDA 27 use and contra-indicating use to 5 days. September 2013 during pregnancy and lactation • Medicines containing (www.fda.gov ). and in children. thiocolchicoside should not Reference: be used during pregnancy Press release, EMA, 22 and lactation, nor in women

WHO Pharmaceuticals Newsletter No. 6, 2013 • 12

REGULATORY MATTERS

Trastuzumab • When preparing and Vancomycin emtansine and administering trastuzumab trastuzumab emtansine, health-care Risk of nephrotoxicity professionals should check: associated with o The prescription, to Potential risk for intravenous infusion of ensure that trastuzumab medication error due to vancomycin emtansine is the intended name confusion Australia. The TGA reminded medication to be health professionals of the risk Canada Hoffmann-La Roche administered; of nephrotoxicity associated Limited (Roche), in o with intravenous infusion of consultation with Health The dosage, to ensure vancomycin and the need for Canada, informed health-care that the recommended appropriate serum monitoring. professionals of the potential dose of trastuzumab Monitoring is especially risk for medication error due to emtansine is; important in patients with the similarity in the non- o The vial labels, to ensure renal impairment and/or other proprietary names of Kadcyla™ that the drug is risk factors, as well as in (trastuzumab emtansine) and trastuzumab emtansine patients who are being treated another with the drug for a prolonged medication, Herceptin® and not trastuzumab. period. Unmonitored and (trastuzumab), and the prolonged use of vancomycin importance of ensuring that The doses, treatment administered in an intravenous the correct product is schedules and authorized infusion to a renally administered to patients. indications for trastuzumab emtansine and trastuzumab compromised patient can On September 11, 2013, are different. The dosage for result in severe and potentially Health Canada authorized these drugs are as follows: irreversible nephrotoxicity. trastuzumab emtansine for the • Trastuzumab emtansine is Obesity and being elderly are additional risk factors for following indication: administered every 3 weeks vancomycin-induced Trastuzumab emtansine, as a (3.6 mg/kg) nephrotoxicity. single agent, is indicated for • Trastuzumab is the treatment of patients with administered every 3 weeks The PI and the Australian Therapeutic Guidelines include HER2-positive, metastatic (8 mg/kg loading dose; 6 breast cancer who received advice for effective monitoring mg/kg maintenance dose), both prior treatment with and dose adjustment of trastuzumab and a taxane, or weekly (4 mg/kg loading vancomycin. Monitoring is separately or in combination. dose; 2 mg/kg maintenance recommended for all patients Patients should have either dose) treated with this drug for a received prior therapy for prolonged period (more than metastatic disease, or It is also advised that health- 48–72 hours). developed disease recurrence care professionals must be Vancomycin is an amphoteric during or within 6 months of aware that confusion between glycopeptide antimicrobial drug completing adjuvant therapy. these drugs may lead to dosing used to treat potentially life- errors and potential harm to Health-care professionals are threatening infections that patients. In addition to the advised the following: cannot be effectively treated measures above, Roche • Trastuzumab emtansine with another less toxic drug. differentiated the packaging and trastuzumab are NOT for these drugs by the use of Reference: the same product. different colours. Such Medicines Safety Update Vol 4, • There is a potential risk for precautions should help to No. 4, August 2013 medication error between reduce the potential for (www.tga.gov.au ). medication errors. trastuzumab emtansine and trastuzumab. (See WHO Pharmaceuticals

• Health-care professionals Newsletter NO.3, 2013 for should use both the brand Potential medication errors name (Kadcyla™) and its resulting from name confusion in the USA). full non-proprietary name (trastuzumab emtansine) Reference: when prescribing the Advisories, Warnings and medication to patients. Recalls, Health Canada, 9 October 2013 (www.hc- sc.gc.ca ). WHO Pharmaceuticals Newsletter No. 6, 2013 • 13

SAFETY OF MEDICINES

associations, but that a causal products of a particular Antiepileptic drugs role of switching could not be drug may cause adverse ruled out in all cases. effects or loss of seizure New advice on switching The CHM considered the control between different characteristics of AEDs and • AEDs have been divided manufacturers’ products advised that they could be into three categories to help for a particular drug classified into three categories healthcare professionals based on therapeutic index, decide whether it is UK. The MHRA informed that solubility, and absorption to different antiepileptic drugs help prescribers and patients necessary to maintain (AEDs) vary considerably in decide whether it was continuity of supply of a their characteristics, which necessary to maintain specific manufacturer’s influences the risk of whether continuity of supply of a product switching between different specific manufacturer’s • If it is felt desirable for a manufacturers’ products of a product. These categories are patient to be maintained on particular drug may cause listed below: adverse effects or loss of a specific manufacturer’s seizure control. AEDs have • Category 1 – , product, this should be been divided into three risk- , prescribed either by , primidone based categories to help specifying a brand name, or health-care professionals For these drugs, doctors are by using the generic drug decide whether it is necessary advised to ensure that their to maintain continuity of patient is maintained on a name and name of the supply of a specific specific manufacturer’s manufacturer (otherwise manufacturer’s product product known as the Marketing Authorisation Holder) According to MHRA, concerns • Category 2 – valproate, about switching between lamotrigine, perampanel, • This advice relates only to different manufacturers’ retigabine, rufinamide, AED use for treatment of products of an oral AED have clobazam, clonazepam, epilepsy; it does not apply been raised by patients and oxcarbazepine, to their use in other prescribers. These include eslicarbazepine, indications (eg, mood zonisamide, topiramate switching between branded stabilisation, neuropathic originator and generic For these drugs, the need pain) products, and between for continued supply of a different generic products of a particular manufacturer’s particular drug. The main product should be based on Pharmacists are also advised reasons for these concerns are clinical judgement and that: the narrow therapeutic index consultation with patient • Dispensing pharmacists of some AEDs and the and/or carer, taking into should ensure the potentially serious account factors such as continuity of supply of a consequences of therapeutic seizure frequency and particular product when the failure. Drug–drug interactions treatment history prescription specifies it. If and the relatively low solubility • Category 3 - levetiracetam, the prescribed product is or (or both) of lacosamide, tiagabine, unavailable, it may be some AEDs are other gabapentin, pregabalin, important factors. necessary to dispense a ethosuximide, vigabatrin product from a different For these drugs, it is usually The Commission on Human manufacturer to maintain Medicines (CHM) reviewed unnecessary to ensure that continuity of treatment of spontaneous adverse reactions patients are maintained on received by MHRA and a specific manufacturer’s that AED. Such cases publications that reported product unless there are should be discussed and potential harm arising from specific reasons such as agreed with both the switching of AEDs in patients patient anxiety and risk of prescriber and patient (or confusion or dosing errors previously stabilised on a carer) branded product to a generic. MHRA advised that • Usual dispensing practice Following this review, CHM • Different AEDs vary concluded that reports of loss can be followed when a considerably in their of seizure control and/or specific product is not worsening of side effects characteristics, which stated around the time of switching influences the risk of between products could be whether switching between Reference: explained as chance different manufacturers’ Drug Safety Update, November WHO Pharmaceuticals Newsletter No. 6, 2013 • 14

SAFETY OF MEDICINES

2013, Volume 7, issue 4, A1 akathisia, hypomania or The solvent vial and the MHRA, (www.mhra.gov.uk ). mania. Parents and caregivers concentrate vial each contain should also be advised of the an overfill to compensate for importance of seeking liquid lost during the initial Atomoxetine immediate medical attention if dilution process. Therefore, the such signs are identified. entire contents of the solvent Risk of suicidal ideation Reference: vial must be added to the concentrate vial to ensure that and behaviour in Medicines Safety Update Vol 4, the resulting concentrate- children and adolescents No. 5, October 2013 solvent mixture contains the (www.tga.gov.au ). Australia. The Therapeutic intended concentration of 10 Goods Administration (TGA) mg/mL cabazitaxel and has a informed that serious adverse Cabazitaxel minimal extractable volume of events were reported to the 6 mL. TGA, including one case involving the death of a child Risk of medication error The required volume of the receiving atomoxetine; TGA resulting in overdose concentrate-solvent mixture emphasized the importance of should be diluted immediately UK. The MHRA advised that all health professionals (within 1 hour) to prepare the health-care professionals adequately informing parents solution for infusion, as involved in the preparation of and caregivers of the risks of described in the Summary of cabazitaxel (Javtana®) suicidal ideation and behaviour Product Characteristics, which solution for infusion should be in children and adolescents should be consulted before aware that the entire contents being prescribed atomoxetine preparing the cabazitaxel of the solvent vial must be (Strattera®). solution for infusion. added to the concentrate vial Atomoxetine is indicated for to produce a concentrate- Reference: the treatment of Attention solvent mixture with the Drug Safety Update, November Deficit Hyperactivity Disorder intended concentration of 10 2013, Volume 7, issue 4, A4 (ADHD), as defined by DSM-IV mg/mL cabazitaxel. MHRA, (www.mhra.gov.uk ). criteria, in children aged 6 Pharmacists should review years and over, adolescents worksheets that are used in and adults. The risks of the preparation of cabazitaxel Cinacalcet suicidal ideation and behaviour to ensure that they correctly with atomoxetine are well inform pharmacy staff to add New warnings for the known and are reinforced in the entire content of the risk of QT prolongation the Product Information in the solvent vial to the concentrate and precautions section, as well as vial. Canada. Health Canada in a boxed warning. Cabazitaxel in combination completed a safety review of It is recommended that, when with or cinacalcet (Sensipar®) that considering prescribing is indicated for identified a possible link atomoxetine in children and the treatment of patients with between the drug and adolescents, health -refractory metastatic abnormal heart rhythm professionals should carefully cancer previously associated with low blood weigh the risks of suicidality treated with a - . Stronger warnings against the benefits of containing regimen. It is were added to the drug label atomoxetine therapy. Patients supplied as a vial of to inform patients about the who are prescribed concentrate and a vial of risk of QT prolongation and atomoxetine should be solvent. The concentrate must arrhythmia associated with the carefully monitored for first be diluted with the solvent use of cinacalcet and to advise suicidality, especially in the supplied before adding to the health professionals to monitor first few months of treatment infusion solution. and report heart-related side and whenever there is a effects. There have been reports of change in dose. Parents and medication error that have Cinacalcet is used for treating caregivers should be warned of occurred because the entire fill disorders of the parathyroid the risks and alerted to the volume of the solvent vial was gland that result in abnormal need to monitor for signs of not added to the concentrate blood calcium levels. unusual changes in behaviour vial. This has resulted in some Cinacalcet is well known to or precursors of suicidality, patients receiving a higher cause hypocalcemia. The risk such as anxiety, agitation, dose (15–20% higher) of of low blood calcium associated panic attacks, insomnia, cabazitaxel than was intended. with the use of the drug is irritability, hostility, clearly outlined on the aggressiveness, impulsivity, Canadian drug label. Low blood WHO Pharmaceuticals Newsletter No. 6, 2013 • 15

SAFETY OF MEDICINES calcium can cause electrical Health-care professionals are (GBCA) vary among the changes in the heart known as recommended to: agents, while NSF “QT prolongation” and • Carefully monitor patients development is considered a arrhythmia. Arrhythmia can be for signs of low blood potential class-related effect of serious and, in some cases, calcium. all GBCAs. may lead to sudden death. QT • Prescribe cinacalcet with Gadolinium (Gd)-containing prolongation and arrhythmia contrast agents (GBCA) are were reported in a small caution in patients with indicated for providing contrast number of patients with low other risk factors for QT enhancement in the magnetic blood calcium treated with prolongation, such as resonance imaging (MRI) cinacalcet. Health Canada known congenital long QT investigations. Eight GBCA reviewed all available syndrome (an inherited products are currently information. heart condition), or in authorized for sale in Canada: According to Health Canada, it patients who are taking gadofosveset trisodium is difficult to determine with other drugs known to cause (Ablavar®) gadobutrol certainty what role cinacalcet QT prolongation. (Gadovist®), gadopentetate may have played in the • For patients treated with dimeglumine (Magnevist®), development of QT gadobenate dimeglumine cinacalcet for chronic prolongation or arrhythmia, as (MultiHance®), gadodiamide other risk factors were present kidney disease and (Omniscan™), at the same time. However, receiving dialysis, reduce gadoversetamide given the effect of low blood dose or stop use if low (OptiMARK™), gadoteridol calcium on the heart, the blood calcium, signs of QT (ProHance®) and gadoxetate possibility of developing QT prolongation, or arrhythmia disodium (Primovist®). prolongation or arrhythmia continue. For these Health Canada has worked with the use of cinacalcet could with the Canadian Marketing not be ruled out. patients, cinacalcet should not be started if they have Authorization Holders of the Patients are recommended severe hypocalcemia. GBCAs to update the that: prescribing information for • Before starting cinacalcet, these agents. (See WHO Pharmaceuticals talk to their doctor if they Newsletter No. 2, 2013 for NSF can result in fatal or have heart rhythm cautions against use in children debilitating systemic fibrosis. problems or take medicines in Canada) In such cases, the skin fibrosis known to cause heart Reference: extends beyond the dermis and involves subcutaneous rhythm problems or if they Advisories, Warnings and tissues, muscles and internal have low levels of blood Recalls, Health Canada, 15 organs. calcium, or have/had heart October 2013 (www.hc- problems (low blood sc.gc.ca ). NSF cases have been reported pressure or worsening heart following single and multiple failure). administrations of GBCAs. It is Gadolinium- not always possible to identify • Tell their doctor if they containing contrast a single causal agent. NSF has experience an unusually agents also been reported to occur fast or pounding heartbeat. following the sequential • Tell their doctor administration of some lower Update on Nephrogenic immediately if they start to risk GBCAs. Systemic get numbness or tingling Fibrosis/Nephrogenic Repeated or higher than around the mouth, muscle Fibrosing Dermopathy recommended doses of a GBCA aches or and and the degree of renal (NSF/NFD) seizures. These may be function impairment at the Canada. Health Canada signs that calcium level is time of exposure are risk announced that current factors for NSF. The risk of too low. evidence suggested that the NSF in patients with mild to • Talk to their doctor or extent of risk for a rare and moderate renal insufficiency is pharmacist about any potentially fatal disease, not well characterized, and the questions or concerns Nephrogenic Systemic Fibrosis cautious utilization of the regarding cinacalcet (NSF) in patients with kidney lowest possible dose of GBCA treatment. disease following exposure to in these patients is any specific Gadolinium (Gd)- recommended. When containing contrast agents administering a GBCA, the

WHO Pharmaceuticals Newsletter No. 6, 2013 • 16

SAFETY OF MEDICINES recommended dose should not provided for patients and be exceeded and a sufficient prescribers. period of time should be The most recent publications allowed for elimination of the on an association between agent from the body prior to fetal valproate exposure and any re-administration. neurodevelopmental delay or For patients receiving autism spectrum disorder have hemodialysis, health-care prompted a re-evaluation of professionals may consider the balance of benefits and prompt hemodialysis following risks of this medicine. A GBCA administration in order European review is underway to enhance the contrast to evaluate all currently agent's elimination. However, available evidence on the it is not known currently if association between fetal hemodialysis can help to valproate exposure and prevent NSF. neurodevelopmental delay or autism spectrum disorder. (See WHO Pharmaceuticals Newsletters No.6, 2009 for risk Health-care professionals are of nephrogenic systemic reminded that sodium fibrosis in patients with renal valproate should not be used impairment in Canada and during pregnancy and in

No.1, 2008 for risk of women of childbearing nephrogenic systemic fibrosis potential unless clearly in Australia.) necessary. Women of

Reference: childbearing potential should not start treatment with Advisories, Warnings and sodium valproate without Recalls, Health Canada, 14 specialist neurological or November 2013 (www.hc- psychiatric advice as sc.gc.ca ). appropriate depending on the indication. Adequate counselling should be made Sodium valproate available to all women with epilepsy of childbearing Risk of potential to weigh the risk of neurodevelopmental teratogenic and delay in children neurodevelopmental effects following maternal use against the benefits of

UK. The Medicines and treatment. Healthcare products (See WHO Pharmaceuticals Regulatory Agency (MHRA) Newsletter No.3, 2013 for announced that there is new Contraindicated for pregnant evidence on women for prevention of neurodevelopmental delay in migraine and No. 4, children following maternal use 2012 for risk of impaired of sodium valproate. Sodium cognitive development in valproate (Epilim®) has been children exposed in utero in authorised since 1973 for the the USA). treatment of epilepsy. Reference: Depakote® is the brand of sodium valproate authorised Drug Safety Update, November 2013, Volume 7, issue 4, A2 for the treatment of the manic phase of bipolar disorder. The MHRA, (www.mhra.gov.uk ). use of sodium valproate is associated with a greater risk of some types of these malformations (in particular neural tube defects) than with some other antiepileptic drugs. This risk is clearly reflected in the product information

WHO Pharmaceuticals Newsletter No. 6, 2013 • 17

SIGNAL

A signal is defined by WHO as reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. A signal is a hypothesis together with data and arguments and it is important to note that a signal is not only uncertain but also preliminary in nature.

The signals in this Newsletter are based on information derived from Individual Case Safety Reports (ICSRs) available in the WHO Global ICSR database, VigiBase™. The database contains over 7 million reports of suspected adverse drug reactions, submitted by National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring. VigiBase is, on behalf of the WHO, maintained by the Uppsala Monitoring Centre (UMC) and periodic analysis of VigiBase data is performed in accordance with UMC’s current routine signal detection process. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of SIGNAL section (page 33). For information on the UMC Measures of Disproportionate Reporting please refer to WHO Pharmaceuticals Newsletter Issue No. 1, 2012.

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

Abiraterone and Thrombocytopenia

Dr. Raquel Herrera Comoglio, Argentina

clinical condition (metastatic ) and Summary the scarcity of data in many reports, the analysis Drug-induced thrombocytopenia (DIT) is a of these 25 cases (after removal of one duplicate) relatively common clinical disorder that can be a from VigiBase would suggest that abiraterone may consequence of decreased platelet production decrease platelet count, possibly through the (mainly because of bone marrow cytotoxicity) or platelet production process. accelerated platelet destruction (especially through immune mediated mechanisms). Introduction Abiraterone has been approved since 2011 in In -resistant prostate cancer (CRPC) it combination with prednisone for the treatment of has been suggested that from non patients with metastatic castration-resistant gonadal sources (both adrenal and intratumoral) prostate cancer (mCRPC). Abiraterone is an continue to drive receptors' (AR) inhibitor of the enzyme 17a-hydroxylase/C17,20- signaling and contribute to prostate cancer lyase (CYP17), which catalyses the conversion of progression after androgen deprivation therapy. and into Systemic inhibition of androgen may precursors (dihydroepiandrosterone, DHEA, and be achieved through the inhibition of CYP17, which ) in testicular, adrenal and blocks two sequential reactions involved in the prostatic tumour tissues. final stages of androgen production. 1 Thrombocytopenia (or decreased platelet count) is Abiraterone is a potent and selective not listed in the product information for CYP17 inhibitor, including both 17,20-lyase and abiraterone. No case reports for thrombocytopenia 17-alpha-hydroxylase activities. 2,3,4 It blocks the during or after abiraterone treatment were found synthesis of androgens in the testis, adrenal published. Thrombocytopenia with the use of glands, and prostate, without causing adrenal abiraterone is mentioned as occurring in two insufficiency, which is a known side effect of the patients out of 39 in an observational study of the non-selective CYP17 inhibitor keto-conazole. The compassionate use of this drug. effect of abiraterone on CYP17 differs from the effect of in being irreversible, From September 2011 up to April 16 th 2013, 26 selective and 10-times more potent. 1-5 In order to Individual Case Safety Reports (ICSRs) with the avoid or prevent clinical consequences of combination abiraterone and thrombocytopenia abiraterone's effect on endogenous were retrieved from the WHO Global ICSR Database, VigiBase™. In spite of the very complex WHO Pharmaceuticals Newsletter No. 6, 2013 • 18

SIGNAL synthesis, prednisone or prednisolone have to be reviewed case by case. The ICSRs came from the administered together with abiraterone. United Kingdom (seven), Germany (seven), the United States (six), Spain, Austria and Canada Normal platelet count in humans ranges from (two cases each). A likely duplicate report from 150x10 9/L to 400x10 9/L. Thrombocytopenia is Germany was identified, therefore only 25 cases usually defined as the platelet count <100x10 9/L were considered. The two ICSRs from Spain (case or >50% drop in the platelet count from the 4 and case 13) show many similarities but have baseline. Severe thrombocytopenia, defined as a been considered as two different reports. Most of platelet count <50x10 9/L, involves a greater risk the ICSRs (88%) are spontaneous reports and of bleeding. With a platelet count below 10x10 9/L, data are scarce in many of them. Age (reported in the risk for spontaneous bleeding 12 ICSRs) ranged from 58 to 85 years, and (mucocutaneous, intracranial or gastrointestinal) masculine sex is stated in all cases but two. The increases rapidly and may even result in patient dose for abiraterone (1 g daily) was reported in 23 mortality. 6,7 cases (92%). The reports were classed as serious Drug-induced thrombocytopenia (DIT) is a in all but one ICSR (96%), and there were three relatively common adverse drug reaction; when fatal cases. The main characteristics of the ICSRs severe, its consequences may be serious. 7,8 Two are shown in Table 1. main pathways for DIT have been described: a Abiraterone is reported as the only suspected drug decrease in platelet production — mainly because in 20 ICSRs (80%), and in 10 ICSRs (40%), of bone marrow toxicity, i.e. a non-immune abiraterone is the only drug mentioned. Co- mechanism; and an increase in platelet suspected drugs are prednisolone (two cases), destruction, predominantly caused by immune prednisone (two cases, in one case together with mechanisms but also by non-immune an unspecified antiplatelet therapy), and mechanisms. 7,11 teicoplanin (one case). Prednisone is reported as a Drug-induced non-immune thrombocytopenia can concomitant drug in seven other cases and result from a loss of bone marrow cellularity and prednisolone in three cases. Suspected and an impairment of megakaryocyte proliferation and concomitant medications are shown in Table 1. maturation. 9 The time course of DIT related to Time to onset is stated in 12 out of 25 ICSRs marrow suppression is generally slow, reflecting (48%). Apart from one case which reports — the time required to deplete the megakaryocyte perhaps by mistake — a minus 15 days time to population. 9 Cytotoxic chemotherapy causes onset, the remaining 11 ICSRs (44%) report times thrombocytopenia by bone-marrow suppression; to onset ranging from 18 days to four months. In selective inhibition of megakaryocyte production, seven cases, where time to onset cannot be mediated by thiazide diuretics, , determined, the duration of treatment for tolbutamide and antivirals, could lead to isolated abiraterone has been reported as one month (four thrombocytopenia. 6, 8 cases), three days, and 76 days; one report Non-immune platelet destruction, associated with mentions 18 cycles. a small number of antineoplastic agents such as Platelet count was reported in eight ICSRs. bleomycin, can occur in thrombotic Thrombocytopenia was severe in four cases (one microangiopathy. Drug-induced immune case with 5,000 platelets and three cases with thrombocytopenia is characterized by drug- 19,000 platelets). Moderate thrombocytopenia was dependent antibodies that bind to platelets and reported in three ICSRs with a platelet count of cause their destruction, and can be triggered by a 39,000 (case 2), 26-24,000 (case 24), and wide range of medications, including cytotoxic 54,000/46,000 (case 25) and two cases reported agents. In immunemediated thrombocytopenia, mild thrombocytopenia (100,000 platelets in case time to onset is reported. 9 and 68,000 platelets in case 19). to be on the order of 1 to 2 weeks following the Abiraterone was withdrawn in seven cases: two patient's first exposure to an immunogenic drug, patients recovered (one with sequelae), two and of 2-3 days if the drug has been taken patients were reported as not recovered at the previously. Heparin-induced thrombocytopenia, date of report, there was one case with unknown which affects up to 10% of patients treated outcome, one death, and one with no reported (especially with unfractionated heparin), produce outcome. Dose was reported as not changed in immune complexes that induce platelet activation seven cases: in four cases the reported outcome and typically occurs five or more days after the was "recovered" (two cases) or "recovering" (two start of heparin therapy. It can be complicated by cases), in one case the outcome was "not arterial or venous thrombotic events. 8,10 recovered" and the outcome was unknown in the two remaining cases. Recurrence after rechallenge Reports in VigiBase is mentioned in one report, with no more data A total of 26 Individual Case Safety Reports available. (ICSRs) were retrieved from the WHO Global ICSR In 11 ICSRs (44%), causality was assessed as Database, VigiBase™ on April 16 th 2013 and possible, and in nine (37.5%) causality is not

WHO Pharmaceuticals Newsletter No. 4, 2013 • 19

SIGNAL reported. Among the remaining five ICSRs, two platelets, WBC) during treatment occurred in were reported as conditional, two as very greater than 5% of subjects in the abiraterone likely/certain and one as not related. acetate group or in greater than 3% of subjects in the placebo group". 4 Anaemia is co-reported as an in four reports (one of which also reported spleen A PubMed search using the search query enlarged), and leucocytopenia is co-reported in "abiraterone AND thrombocytopenia" retrieved two reports. There was one patient with only one result, an article in German reporting the myelodysplasia. Progression of pre-existing first clinical experiences of abiraterone in disease is reported as an adverse drug reaction in compassionate use. 12 In this article, two patients, case 20 (with fatal outcome) and case 22. of 39 treated with , presented with thrombocytopenia. No results were found for Three deaths were reported. Case 7 reports the PubMed searches using the search query death of a man after 76 days of abiraterone "abiraterone AND platelet" or "abiraterone AND treatment; no time to onset is reported. Other megakaryocyte". adverse effects are also reported for this patient, including oedema peripheral and . In the published reports of two Phase III Case 20 reports the death of a man after three abiraterone trials, (COU-AA-301 final report 13 and days of abiraterone/prednisone treatment (disease COU-AA-302 interim analysis 14 ) there is no progression is also mentioned as an adverse mention of thrombo-cytopenia or a decrease in effect). In case 24, a 63-year-old patient with platelet counts as an adverse effect. Of note, case advanced metastasic prostate cancer (bone and 5 reports thrombocytopenia in a participant of the liver metastases and urinary tract obstruction) COU-AA-302 trial. presented with acute renal failure, In www.clinicaltrials.gov only one clinical trial with thrombocytopenia and hyperbilirubinemia 58 days abiraterone has results posted (March 2013). after starting abiraterone/prednisone treatment; Neither thrombocytopenia nor platelet count thrombocytopenia was assessed as not related, decreased are listed as adverse events. 15 hepatic insufficiency as possible and hyperbilirubinaemia as probable (patient from clinical trial). Discussion Many ICSRs are incomplete. Metastatic cancer Of the three ICSRs from clinical trials, in two, the with bone marrow involvement can also cause association between abiraterone and thrombo-cytopenia and can act as a confounder: thrombocytopenia was assessed as certain or very out of five cases reporting concomitant anaemia or likely and in the other case (described above) as pancytopenia, in three cases (case 5, 11 and 19) not related. In case 5 (from clinical trial COU-AA- bone marrow puncture found evidence of 302, causality assessed as certain) a 69-year-old carcinosis, and in case 9, spleen enlargement is patient was hospitalized because of grade 3 also reported with thrombocytopenia and thrombocytopenia, which worsened in spite of normocytic anaemia. In spite of these two main administration of one pack of platelet concentrate limitations, the analysis of the 25 ICSRs seems to together with two packs of blood cells concentrate; show a predominant pattern of onset of two or he also presented with grade 2 anaemia; further more weeks, which would be consistent with a biopsia revealed carcinosis. In case 25, with drug-induced thrombocytopenia through a non- causality assessed as very likely/certain, a 70- immune mechanism. year-old patient hospitalized because of symptoms of pulmonary embolism 66 days after having In case 15, thrombocytopenia may be related to started the therapy with abiraterone also the co-suspected drug teicoplanin (time to presented with non-serious thrombocytopenia thrombo-cytopenia onset is reported 11 days after (54.000 platelets/mL). This patient, with a medical teicoplanin treatment and 56 days after history of pulmonary embolism and with a long- abiraterone treatment). In all other cases with co- term dalteparin treatment as preventive therapy, suspected or concomitant drugs, temporal was diagnosed with acute myeloid leukemia two relationships suggest that abiraterone is the most months later . likely causative agent. Diclofenac can cause thrombocytopenia - chronic and silent or acute, Literature and Labelling through an immune mechanism: in case 5 (causality assessed as "certain"), There is no reference to thrombocytopenia as a thrombocytopenia's onset occurred after 46 days possible side effect of abiraterone in the US FDA of abiraterone therapy and 5 months of diclofenac label or the European Medicines Agency Summary treatment. 16 , that can rarely cause of Product Information. 2,3 The Australian Public thrombocytopenia, was given from an unknown Assessment Report does not mention date in case 3, 19 and 23, and for 22 months in thrombocytopenia as an adverse effect of case 5. Clopidogrel, that impairs platelet function, abiraterone, although on page 88 it is stated that was given from an unknown date to a patient who "(in study COU-AA-301). No other haematologic recovered from thrombocytopenia with no dose Grade 2, 3 or 4 abnormality (i.e. neutrophils, changes (case 23). Serotonin reuptake-inhibitors

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(SSRIs) have been linked to platelet dysfunction URL: http://www.ema.europa.eu/docs/en_GB/ as a consequence of serotonin-uptake blockade document_library/EPAR_-_Product_Information/ into platelets: however, in case 6, no dates are human/002321/WC500112858.pdf given for citalopram, and in case 23 duloxetine Accessed 11 June 2013. was given from an unknown date. In case 25, the 3. Food and Drug Administration. Zytiga. patient had long-term treatment with dalteparin URL: because of a history of pulmonary embolism and http://www.accessdata.fda.gov/drugsatfda_docs/ presented with pulmonary embolism and label/2011/202379lbl.pdf thrombocytopenia 68 days after starting treatment Accessed 11 June 2013. with abiraterone. 4. Therapeutics Good Administration. Australian Gender differences in platelet function are well Public Assessment Report for abiraterone acetate. known, although the role of endogenous and Department of Health and Ageing. Australian synthetic has not been fully Government. October 4th 2012. Accessed 11 June elucidated. 17 Androgens affect red blood cell 2013. production and anaemia is a known effect of testosterone suppression. It has been 5. Nandha R. Abiraterone acetate: A novel drug hypothesized that sex hormones may have a role for castration-resistant prostate carcinoma. J in the production of platelets from Postgrad Med. 2012;58:203-6. megakaryocytes. 17 For instance, it has been shown that in vitro human platelet aggregation induced 6. Sekhon SS, Roy V Thombocytopenia in adults. by arachidonic is enhanced by androgens, and Practical approach to evaluation and management. androgen therapy has improved platelet counts in South Med J. 2006 May;99(5):491-8. patients with myelodysplasia and 7. van den Bemt PM, Meyboom RH, Egberts AC. 18,19 thrombocytopenia. The drop in endogenous Drug-induced immune thrombocytopenia. Drug androgens through CYP17 inhibition by abiraterone Saf. 2004;27(15):1243-52. may be a factor in the development of thrombocytopenia in patients with other 8. Visentin GP, Liu CY Drug-induced predisposing factors. thrombocytopenia. Hematol Oncol Clin North Am. 2007 Aug;21(4):685-96. Conclusion 9. Arnold DM, Nazi I, Warkentin TE, Smith JW, In most of the ICSRs entered into VigiBase, the Toltl LJ, George JN, Kelton JG. Approach to the temporal relationship between abiraterone and diagnosis and management of drug-induced thrombocytopenia suggests a possible causal immune thrombocytopenia. Transfus Med Rev. relationship. Platelets have a circulating lifespan of 2013 Jul;27(3):137-45. around 10 days, and about one third of the 10. Kenney B, Stack G. Drug-induced platelets are sequestered in the spleen at any 9 thrombocytopenia. Arch Pathol Lab Med. time. Approximately 100 x 10 platelets must be 2009;133:309-314. released from mature megakaryocytes into the circulation each day in order to maintain a normal 11. Aster RH, Curtis BR, McFarland JG, Bougie platelet count.20 In the ICSRs, abiraterone DW Drug-induced immune thrombocytopenia: treatment durations range from 18 days to four pathogenesis, diagnosis, and management. J months. The temporal relationship between the Thromb Haemost. 2009 Jun;7(6):911-8. start of abiraterone therapy and reported 12. Heck MM, Höppner M, Horn T, Thalgott M, thrombocytopenia would suggest a process Gschwend JE, Retz M. Compassionate use of affecting platelet production, more prolonged than abiraterone and cabazitaxel: first experiences in the mechanism of immune DIT. In the literature, docetaxel-pretreated castration-resistant prostate an observational study 12 reports two cases of cancer patients. Urologe A. 2012 Mar;51(3):390- thrombocytopenia (5%) in 39 patients treated with 7. abiraterone and this combined with the analysis of reports in VigiBase, would suggest that 13. Fizazi K, Scher HI, Molina A, Logothetis CJ, abiraterone might be associated with Chi KN, Jones RJ, et al. Abiraterone acetate for thrombocytopenia, and requires further treatment of metastatic castration-resistant investigation. prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, References placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. 1. Carden CP, Attard G, de Bono JS. Targeting CYP17: established and novel approaches in 14. Ryan CJ, Smith MR, de Bono JS, Molina A, prostate cancer. Curr Opin Pharmacol. 2008 Logothetis CJ, de Souza P, et al. Abiraterone in Aug;8(4):449-57. Metastatic Prostate Cancer without Previous Chemotherapy. 2013; 368(2):138-48. 2. European Medicines Agency. Zytiga, abiraterone acetate INN.

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15. A Phase 2 Study to Evaluate Safety and (AR): testosterone regulates AR expression. Blood. Efficacy of Abiraterone Acetate in Male Participants 2000 Apr 1;95(7):2289-96 With Prostate Cancer. 18. Li AJ, Karlan BY Androgen mediation of URL: http://clinicaltnals.gov/ct2/show/ thrombocy-tosis in epithelial NCT00924469. Accessed 11 June 2013. biology. Clin Cancer Res. 2005 Nov 16. Meyer O, Hoffmann T, Aslan T, Ahrens N, 15;11(22):8015-8. Kiesewetter H, Salama A. Diclofenac-induced 19. Wattel E, Cambier N, Caulier MT, Sautiere D, antibodies against RBCs and platelets: two case Bauters F, Fenaux P. Androgen therapy in reports and a concise review. Transfusion. 2003 myelodysplastic syndromes with Mar;43(3):345-917. Khetawat G, Faraday N, thrombocytopenia: a report on 20 cases. Br J Nealen ML, Vijayan KV, Bolton E, Noga SJ, Bray PF. Haematol 1994;87:205-8. Human megakaryocytes and platelets contain the receptor beta and 20. Daly ME. Determinants of platelet count in humans. Haematologica. 2011 Jan;96(1):10-3.

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Table 1. Abiraterone and thrombocytopenia - Characteristics of 25 cases retrieved in VigiBase TM

Case Age Time to Duration of Platelet Other suspected (S) or Dechallenge/ Outcome onset treatment count concomitant (C) drugs Rechallenge

1 - - - -/- Unknown

2 - - 39.000 -/- Unknown

3 69 3 m - Prednisone , leuprorelin, , metoprolol, -/- Not rec overed denosumab (all C)

4 83 1 m 5.000 Prednisone (C) -/- Not recovered

5 68 46 d 46 d 19.000 Leuprorelin , diclofenac, colecalciferol, calcium , Drug withdrawn/ - Recovered zoledronic acid (all C) Prednisolone (S)

6* 58 -15 d - Methadone, citalopram, hydrochloro thiaz ide, No dose change/ - Not recovered furosemide (all C)

7 - - 76 days - Prednisone (C) - Death

8 - - - No dose change/ - Unknown

9 - 4 weeks 100.000 -/- Unknown

10 73 4 m 19.000 Prednisone, fentanyl (all C) Drug withdrawn/ No Recovered wi th recurrence sequelae

11 85 32 days - Drug withdrawn/ - Not recovered

12 - - 34 or 42 days - Docetaxel (C) Prednisone (S) Drug withdrawn/ - -

13** 80 1 m 1m - Prednisone (C) Drug withdrawn/ - Not recovered

14 - - - Prednisolone (C) -/- Recovered

15 67 56 d Te icoplanin (S) -/- Not recovered

16 - - - -/- -

17 - - 18 cycles - -/- Unknown previously

18 - - - -/Reaction recur ring -

19 66 20 d 6-8 weeks 68.000 Prednisolone, leuprorelin Denosumab, No dose change Recovering 40.000 erythropoietin human fentanyl (all C) 53.000

20 *** - - Up to 3 days - Prednisone (S) -/- Unknown/ Death 21 - - - -/- Unknown

22 **** 75 42 d Prednisolone, amitryptiline, lansopra zole (all C) No dose change/ - Recovering

23 18 d Prednisone, leuprorelin, megestrol duloxetine , No dose change/ - Recovered denosumab, morphine paracetamol/hydrocodone , ergocalciferol, clopidogrel, metoprolol (all C)

24 63 28 d 26.000 Prednisone, degarelix, Drug withdrawn/ No Death 24.000 ibandronic acid, pantoprazole (all C) recurrence

25 70 68 d 53.000 Degarelix, zoledronic acid, dalteparin, Drug withdrawn/ - Unknown 26.000 pantoprazol (all C) Prednisolone (S)

*Abiraterone dose reported 500 mg **Possible duplicate of case 4 ***Abiraterone started on March 19 th 2012 – Death occurred on March 22 nd ****Abiraterone reported dose 1000 mg 2per day

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Response from Janssen This is in response to the WHO Signal report of 25 with progressive disease. Its incidence is Individual Case Safety Reports (ICSRs) that were approximately 13% to 30%; however, only 0.4% retrieved from VigiBase™. (September 2011 - to 1.65% of patients present with clinical signs April 16th 2013) of thrombocytopenia in patients and symptoms. Thus this disease-related cause for receiving abiraterone acetate. Data are provided thrombocytopenia typically goes undetected below from a thorough Company investigation in (Smith 1999). Bone marrow can also March 2013 to assess the potential causal result in anemia and thrombocytopenia (Neider relationship between thrombocytopenia and 2010). abiraterone acetate. The Company concludes that thrombocytopenia is not associated with the use of Preclinical and Clinical Data from abiraterone acetate, but continues to monitor and Company-sponsored Studies review the signal in Periodic Benefit Risk Evaluation Reports. Data from pivotal toxicology studies in rats (26 weeks) and monkeys (39 weeks), administered abiraterone at doses that were 5-fold and 2-fold Epidemiology higher, respectively, than clinical exposure, Thrombocytopenia is an expected condition in showed only a minimal decrease in platelet count patients with metastatic prostate cancer, in rats and no decrease in platelet count in particularly in patients with bone marrow monkeys. metastasis. The cause of the thrombocytopenia can be multifactorial, including the underlying In 2 randomized, placebo-controlled Phase 3 disease, concurrent medical conditions, or studies (COU-AA-301 and COU-AA-302) with concomitant therapies. A low platelet count may prostate cancer treated with abiraterone acetate, be caused by replacement of bone marrow with the incidence of thrombocytopenia and platelet metastatic prostatic carcinoma or the result of count decrease was similar among subjects who chronic disseminated intravascular coagulation received abiraterone acetate (3.0% and 1.2%, (DIC) syndrome (Ruffion 2000), which is common respectively) and those who did not (2.5% and in patients with prostate cancer and is associated 0.9%, respectively) (table 1).

Table 1: Treatment-emergent Adverse Events of Thrombocytopenia and Platelet Count Decreased (Integrated Safety Population) COU -AA -301 COU -AA -302 Combined Total Subjects (%) Total Subjects (%) Total Subjects (%) AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1333) (N=934) Thro mbocytopenia 30 (3.8%) 15 (3.8%) 10 (1.8%) 8 (1.5%) 40 (3.0%) 23 (2.5%) Platelet count decreased 14 (1.8%) 7 (1.8%) 2 (0.4%) 1 (0.2%) 16 (1.2%) 8 (0.9%)

Key: AA=Abiraterone acetate; MedDRA=Medical Dictionary for Regulatory Activities; N=number

Table 2: Treatment-Emergent Adverse Events of Thrombocytopenia, Event Rate per 100 Patient-Years of Exposure (Integrated Safety Population) COU -AA -301 COU -AA -302 Combined Total Events per 100 Total Events per 100 Total Events per 100 Subject-Years Subject-Years Subject-Years (%) AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=603.8) (N=199.6) (N=646.4) (N=466.3) (N=1250.2) (N=665.9) Thrombocytopenia 45 (7.5) 21 (10.5) 17 (2.6) 14 (3.0) 62 (5.0) 35 (5.3) Platelet count decreased 25 (4.1) 20 (10.0) 4 (0.6) 1 (0.2) 29 (2.3) 21 (3.2) Key: AA=Abiraterone acetate; MedDRA= Medical Dictionary for Regulatory Activities; N=Number of subjects

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The median exposure (i.e., time on treatment) to abiraterone acetate was approximately twice as Conclusion long as that of placebo. An analysis adjusted for Abiraterone acetate is indicated for the treatment the duration of exposure (with rates reported as of patients with castrate-resistant metastatic the number of events per 100 subject-years of prostate cancer. Thrombocytopenia due to exposure) showed lower rates of metastatic bone marrow involvement and DIC is thrombocytopenia and platelet count decreases in not uncommon in this disease stage. In addition, the abiraterone acetate group (5.0 and 2.3, many other concomitant medical conditions and respectively) than in the placebo group (5.3 and concurrent medications used in this patient 3.2, respectively) (Table 2). The data support the population may also cause thrombocytopenia. conclusion that thrombocytopenia is not associated These factors limit the ability to identify with the use of abiraterone acetate. thrombocytopenia as an adverse effect of abiraterone acetate. Based on the review of the Analysis of Individual Case Safety Company safety database, thrombocytopenia is Reports not considered associated with the use of abiraterone acetate. Key factors supporting this Recently, the Company searched its own safety conclusion include the available data on database for all medically confirmed and valid rechallenge, dechallenge, and plausible latency cases of thrombocytopenia, regardless of cases, all of which reported concomitant causality, that were reported in patients receiving medication or concurrent medical conditions, abiraterone acetate from launch (28 April 2011) th including but not limited to disease progression through March 15 2013. Seventy-one and bone metastases that confounded the case spontaneous, clinical study and registry cases assessment. In addition, analysis of data from 2 (median age of 69 years) from 19 countries were double-blind controlled studies demonstrated a retrieved. The latency from the initiation of similar incidence of thrombocytopenia between abiraterone acetate therapy to the first onset of subjects treated with abiraterone acetate and thrombocytopenia was <1 month in 11 cases, 1 to placebo that was lower with abiraterone acetate 3 months in 19 cases, 3 to 6 months in 8 cases, treatment once adjusted for exposure duration. >6 months in 7 cases, and not reported in 26 Based on all of the available safety data, cases. All cases were reviewed for a potential drug thrombocytopenia is not associated with the use of effect relationship in accordance with the CIOMS abiraterone acetate. Threshold Criteria (CIOMS Working Groups 1999). No sentinel cases were found. The only positive References rechallenge case did not report critical information to allow medical assessment. Of 11 cases 1. CIOMS Working Groups III and V. Guidelines reporting dechallenge information, 6 reported for Preparing Core Clinical-Safety Information on negative dechallenge (e.g., thrombocytopenia did Drugs. 2nd ed., Geneva: CIOMS; 2001; 29. not resolve after abiraterone acetate therapy was 2. Neider C, Haukland E, Pawinski A, Dalhaug A. withdrawn) and the rest recovered with platelet Anaemia and thrombocytopaenia in patients with transfusion or reported insufficient information. prostate cancer and bone metastases. BCM In summary, risk factors (such as concomitant Cancer. 2010; 10:284-290. medication, concurrent condition, or medical 3. Ruffion A, Manel A, Valignat C, Lopez JG, history) or insufficient information confounded Pernn-Fayolle O, Pernn P. Successful use of case assessment of a clear relationship between Samarium 153 for emergency treatment of thrombocytopenia and abiraterone acetate therapy disseminated intravascular coagulation due to in all 71 cases. The most frequently reported metastatic hormone refractory prostate cancer. J relevant concurrent medical conditions were Urol. 2000 Sep; 164(3 Pt 1):782. disease progression and bone marrow metastases/cancer/infiltration thrombocytopenia. 4. Smith JA, Soloway MS, Young MJ. Complications of Advance Prostate Cancer. Urology 1999; 56(6A):8-14.

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Baclofen and Renal failure

Prof. Michael Langman, United Kingdom

Summary The cases with raised creatinine are assumed to After the combination baclofen-renal failure was not add information. The 32 cases of renal failure identified as a possible signal, 67 Individual Case of unstated duration did not appear to present any Safety Reports (ICSRs) of renal failure [31 acute, features differing materially from the other 35, but 32 chronic or acute (not stated which), and four confidence in the reliability of separation between with chronic renal failure] in patients taking acute and chronic renal disease is likely to be baclofen were considered. Baclofen is excreted by limited. the kidneys and orally administered drug The ICSRs were entered into VigiBase from 1993 accumulation in patients with pre-existing to present and from eight countries, Germany, borderline renal function/compromised vascular United States, France, Australia, United Kingdom, systems could affect vascular control and worsen Ireland, Austria and Canada. The IC values for renal function. renal failure acute were: IC -0.89, IC 025 -1.44, for With baclofen given intrathecally, the renal failure: IC -0.43, IC 025 -0.98 and for renal consequences of possible central spread through failure chronic: IC -0.64, IC 025 -2.38. inadvertent subdural drug delivery, or wash back centrally in subarachnoid injection should be Literature and Labelling considered, with a direct drug effect on central The British National Formulary lists many cautions mechanisms modulating vascular control and when using baclofen in pre-existing disease such leading to renal failure. as psychiatric disease, respiratory disorders and bladder outlet obstruction. Recorded adverse Introduction effects include hypotension, respiratory or cardiovascular depression, and urinary The drug-ADR combination of baclofen and renal 4 failure was highlighted during testing of a new disturbances. The US FDA Label lists renal failure, oliguria, renal calculus as well as hypotension and quantitative method for detecting potential signals 2 at the UMC in 2012. 1 As of 15 November 2012, 67 bradycardia as adverse drug events. Individual Case Safety Reports (ICSRs) had been entered into the WHO Global ICSR Database, Discussion VigiBase™, raising a possible relationship between Baclofen is a GABA[B] receptor agonist. baclofen use and the occurrence of renal failure. Microinjection in rats into the paraventricular The drug is mostly used in treating chronic nucleus has been found to induce a dose- spasticity, as typically associated with spinal cord dependent fall of arterial pressure, accompanied damage and multiple sclerosis. Labelled adverse by reduced heart rate and reduced renal effects include hypotension and cardiovascular sympathetic nerve activity in a rat model which is depression. Kidney failure is labelled in the US FDA claimed to simulate chronic heart failure. 5 Label for the injection but not for the oral However, a second paper presents data, again in formulation and renal failure is not labelled in the rats, showing that intravenous baclofen, whilst UK Summary of Product Characteristics (SPC). 2,3 suppressing renal sympathetic activity, appear to prevent ischaemia-reperfusion injury. 6 No relevant Reports in VigiBase data from studies in humans could be found in a The 31 ICSRs of acute renal failure (21 male, nine search of PubMed. female, one sex not stated) and four of chronic Baclofen is normally excreted unchanged in the failure (two male and two female) were considered and therefore renal failure which might be case-by-case. Detail is, as usual, limited. Four present in some patients with chronic neurological ICSRs of acute renal failure are likely duplicates. disease e.g. cord transection with bladder outlet Patients were generally in the sixth decade of life obstruction, might be expected to lead to raised or older and often, where reported, receiving a blood drug levels. Central spread in intrathecal wide variety of other medications, including, but treatment, notably through posture and use of not only, cardiovascular, non-steroidal anti- dense preparations, could cause significant inflammatory and antibiotic medications. Several amounts of drug to the brain. Systemic reports list significant comorbidities such as absorption at other sites could also occur. septicaemia, and multi-organ failure that have to be taken into consideration as Experimental studies in pigs have shown that possible confounding factors. position and specific gravity (baricity) can affect drug distribution. 7 Central effects might also be Six of the acute cases were receiving intrathecal associated with inadvertent subdural drug baclofen, 19 oral, five unclear and one "other". administration as opposed to subarachnoid. 8

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Adverse cardiovascular effects centrally caused References might result in renal failure particularly in 1. Caster O, Norén GN, Madigan D, Bate A. individuals with compromised homoeostatic Large-scale regression-based pattern discovery: processes. the example of screening the WHO global drug For ICSRs where baclofen is given orally, the case safety database. Stat Anal Data Min. reports do not present compelling data to suggest 2010;3(4):197-208. that renal failure can be precipitated by baclofen. This is not a new drug and its adverse effects might be expected to be well-understood. Animal 2. US FDA Label for baclofen (Lioresal studies can be taken to suggest that central Intrathecal). URL: cardiovascular actions could be compromised by http://wwwaccessdata.fda.gov/scripts/cder/drugsa the drug and could predispose to kidney failure, tfda. Accessed: 16 January 2013. however other studies suggest the converse. 5,6 On 3. UK Summary of Product Characteristics for balance it is plausible that oral baclofen could baclofen (Lioresal). URL: accumulate in patients with borderline renal http://www.medicines.org.uk. Accessed: 16 function and further depress renal function. January 2013. For patients given intrathecal treatment, it could 4. Joint Formulary Committee. British National be speculated that extended use of intrathecally Formulary. 64th ed. : BMJ Group and administered drugs in patients who are older Pharmaceutical Press; 2012. and/or have multiple coincident illnesses could result in adverse effects not previously recognised. 5. Wang RJ, Zeng QH, Wang WZ, Wang W Note that the route of baclofen administration is GABA(A) and GABA(B) receptor-mediated not explicitly stated in a quarter of the acute renal inhibition of sympa¬thetic outflow in the failure ICSRs but in about a fifth intrathecal paraventricular nucleus is blunted in chronic heart treatment was given. Intrathecal use could result failure. Clin Exp Pharmacol Physiol. 2009;36:516- in inadvertently high concentrations in central 22. areas, activating mechanisms described in the 6. Kobuchi S, Tanaka R, Shintani T, Suzuki R, study by Wang et.al. 5 Inadvertent injection into the subdural space could have the same effect. Tsutsui H, Ohkita M, et al. Mechanisms underlying the renopro-tective effect of GABA against ischemia/reperfusion-induced renal injury in rats. Conclusion Pharmacol Exp Ther. 2011;338:767-74. The reported cases may suggest a hitherto unrecognised significant adverse effect. Although 7. Flack SH, Bernards CM. Cerebrospinal fluid the data collected are not compelling, a drug effect and spinal cord distribution of hyperbaric through intrathecal use seems plausible if bupivacaine and baclofen during slow intrathecal inadvertent central spread took place. Oral drug infusion in pigs. Anesthesiology 2010;112(1):165- use in patients with compromised renal excretory 73. mechanisms could also result in reduced drug 8. Epidural Blockade. leading to high circulating drug levels URL: http://www.nysora.com/ and possible adverse effects on cardiovascular regional_anesthesia/neuraxial_techniques/3026- control and worsened kidney function. epidural-blockade.html Accessed: 2 January 2013.

Golimumab and Meningitis Dr. Ariel E. Arias, Canada Although rare, the occurrence of meningitis has Summary already been reported in association with the other Golimumab is a monoclonal antibody that prevents anti-TNF products in the class. Current information the binding of tumor necrosis factors (TNF) to its supports a signal of meningitits in association with receptors and has been licensed for the treatment golimumab, and we recommend its inclusion in the of chronic inflammatory diseases such as product label. rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The drug was approved as Introduction late as in 2009. We discuss a series of eight Golimumab is described as a human IgG1 Individual Case Safety Reports (ICSRs) on the monoclonal antibody that forms high affinity, association of golimumab and meningitis that have stable complexes with both the soluble and the been received from five different countries to the transmembrane bioactive forms of human tumor WHO Global ICSR Database, VigiBaseTM. The necrosis factors (TNF), which prevents the binding association has been statistically of TNF to its receptors. 1,2,3 There is no evidence of disproportionately reported into the database. the golimumab antibody binding to other TNF

WHO Pharmaceuticals Newsletter No. 4, 2013 • 27

SIGNAL superfamily ligands; in particular, it did not bind or The indication for use was not reported in two neutralize human lymphotoxin. 1,3 Golimumab cases, and there was almost no information on the modulated the in vitro biological effects mediated length of the therapy or the reaction onset. There by TNF in several bioassays, including the was only one rechallenge reported in the ICSRs, expression of adhesion proteins responsible for and the effect of this was unknown. Four of the leukocyte infiltration, E-selectin, Intercellular case reports were reported by a physician or other Adhesion Molecule-1(ICAM-1), Vascular Cell health care professionals. The IC and the IC025 Adhesion Molecule-1 (VCAM-1), and the secretion values for the association were 1.53 and 0.36 of pro-inflammatory cytokines: IL-6 and 8, respectively. granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor Literature and Labelling (GM-CSF). TNF-a is an important mediator of We could not find any published reports of articular inflammation, and elevated TNF-a levels meningitis in association with golimumab use in in the blood, synovium, and joints have been the literature to date, although various types of implicated in the pathophysiology of several opportunistic and viral infections including , chronic inflammatory diseases such as rheumatoid and cases of new onset or exacerbation of central arthritis, psoriatic arthritis, and ankylosing nervous system demyelinating disorders are well spondylitis. Golimumab has been primarily labelled adverse drug reactions for this product. licensed in many countries for the treatment of There is no information on the risk of meningitis in rheumatoid arthritis, as well as any verified product informations. 1,2,3 The FDA spondyloarthropathies such as psoriatic arthritis label includes a warning for infections due to and ankylosing spondylitis. 1,2,3 It has been opportunistic infections including legionella and licensed in some countries for the treatment of listeria.3 Listeriosis in patients treated with TNF moderate to severe ulcerative colitis with an inhibitors can present as meningitis,6 however, inadequate response or intolerance to prior none of the reports in VigiBase have other treatment, or when requiring continuous infections co-reported. therapy. 3 Although clinical experience with golimumab is Discussion and Conclusion somewhat limited, after direct and indirect This relatively small series of cases reporting a comparisons on efficacy and safety, some authors suspected association between golimumab and the have concluded that infliximab, adalimumab, occurrence of meningitis have been observed in etanercept and golimumab offer similar several countries and in all ICSRs the anti-TNF benefit/risk ratios and could be regarded as antibody was reported as the only suspected drug. equivalent treatment alternatives in psoriatic Golimumab was generally reported to be used for arthritis. 4 However, because of the paucity of data a licensed indication and at the recommended available, similar types of adverse events as those dosage. An alternative product or combination of seen with other TNF-a inhibitors, need to be products that might explain the occurrence of the considered as of special concern for patients 5 suspected reaction was not readily identified from treated with golimumab therapy. We discuss here the ICSRs. The positive IC and IC values a series of eight Individual Case Safety Reports 025 showed that the meningitis-golimumab association (ICSRs) on the association of golimumab and has been statistically disproportionately reported meningitis that have been reported from five into the database. different countries to the WHO Global ICSR Database, VigiBase™. Although clinical experience with this product is limited, golimumab is considered to have a Reports in VigiBase relatively similar safety profile and to offer a similar benefit/risk ratio compared to other anti- Eight ICSRs of meningitis in association with goli- TNF products. 4,5 Meningitis is not commonly mumab have been reported to VigiBase from the associated with rheumatoid arthritis or United States, United Kingdom, Canada, Spain and spondyloarthropathies; however, it has been Switzerland as of May 2013. The subjects, six reported in association with various anti-TNF drugs females and two males, were between 36 and 64 used to treat such disorders including infliximab, years of age. The reaction was further described adalimumab, and etanercept. ICSRs of meningitis as viral meningitis in four cases and aseptic from various types of infectious origin have been meningitis in one case, with no additional observed in association with both infliximab and description in the three other cases. There were no etanercept therapy. 7-12 Interestingly, cases of fatalities but in four cases the outcome of the meningitis of non-infectious origin have also been reaction was unknown or not reported. reported. 13 Since golimumab is similar in structure Golimumab was the only suspected medicine in all to infliximab, it has been suggested that a the ICSRs and was used subcutaneously, mainly comparable pattern of opportunistic infections 50 mg once a month, to treat arthritis (three could be expected with it after further clinical reports), ankylosing spondylitis, psoriatic arthritis, use. 14 Since half of the cases in the series of and immune system disorder (in one case each). ICSRs with golimumab were reported as viral

WHO Pharmaceuticals Newsletter No. 4, 2013 • 28

SIGNAL meningitis, it would be interesting to know if 7. Cohen M, Baldin B, Thomas P, Le Brun C. golimumab could represent a particular risk for Neurological adverse events under anti-TNF alpha this type of adverse reaction. therapy [Evenements neurologiques sous traitement par anti-TNF alpha] Rev Neurol. 2012 As far as we know, the association has not been Jan;168(1):33-9. previously reported in the literature and the risk of meningitis is not mentioned in the product 8. Ma C, Walters B, Fedorak RN. Varicella zoster labelling for golimumab. Opportunistic infections meningitis complicating combined anti-tumor are well recognised adverse reactions of the anti- necrosis factor and corticosteroid therapy in TNF class of drugs. Meningitis is a particularly Crohn's disease. World J Gastroenterol. 2013 Jun serious and life threatening complication of several 7;19(21):3347-51. types of infectious diseases and is specifically 9. Peña-Sagredo JL, Hernández MV, Fernandez- mentioned in the product labelling of the other Llanio N, Giménez-Ubeda E, Muñoz-Fernandez S, anti-TNF products. Current information supports a Ortiz A, et al. Listeria monocytogenes infection in signal of meningitits in association with patients with rheumatic diseases on TNF-alpha golimumab, and we recommend its inclusion in the antagonist therapy: the Spanish Study Group product label. experience. Clin Exp Rheumatol. 2008 Sept-Oct; 26(5):854-9. References 1. Canadian Product Monograph for golimumab 10. Slifman NR, Gershon SK, Lee JH, Edwards ET, (Simponi). URL: http://webprod5.hc-sc.gc.ca/dpd- Braun MM. Listeria monocytogenes infection as a bdpp/index-eng.jsp. Accessed 30 July 2013. complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum. 2. EU Summary of Product Characteristics for 2003 Feb;48(2):319-24. golimumab (Simponi). URL: http://www.ema.europa.eu/ema/ 11. Ueda M, Tateishi T, Shigeto H, Yamasaki R, Accessed 30 July 2013. Ohyagi Y, Kira J. A case of acute disseminated encephalomyelitis associated with Epstein-Barr 3. US FDA Product Label for golimumab virus reactivation during infliximab therapy. Clin (Simponi). URL: Neurol. 2010 Jul;50(7):461-6. http://www.accessdata.fda.gov/scnpts/cder/drugs atfda/ index.cfm. Accessed 30 July 2013. 12. Yang C-T, Kuo C-F, Luo S-F, Yu KH. Discontinuation of anti-TNF-a therapy in a Chinese 4. Fénix-Caballero S, Alegre-del Rey EJ, cohort of patients with rheumatoid arthritis. Clin Castaño-Lara R, Puigventós-Latorre F, Borrero- Rheumatol. 2012 Nov;31(11):1549-57. Rubio JM, López-Vallejo JF. Direct and indirect comparison of the efficacy and safety of 13. Ramos-Casals M, Roberto-Perez-Alvarez, adalimumab, etanercept, infliximab and Diaz-Lagares C, Cuadrado MJ, Khamashta MA; golimumab in psoriatic arthritis. J Clin Pharm Ther. BIOGEAS Study Group. Autoimmune diseases 2013 Aug; 38(4):286-93. induced by biological agents. A double-edged sword? Autoimmun Rev 2010 Jan; 9(3):188-93. 5. Simsek I, Yazici Y. Safety and clinical efficacy of golimumab in the treatment of arthritides. Drug 14. Koo S, Marty FM, Baden LR. Infectious Healthc Patient Safety. 2010;2:169-80. complications associated with immunomodulating biologic agents. Infect Dis Clin North Am. 2010 6. De Kayser F. Choice of Biologic Therapy for Jun; 24 (2):285-306. Patients with Rheumatoid Arthritis: The Infection Perspective. Curr Rheumatol Rev. 2011 Feb; 7(1):77-87.

Response from Janssen Biologics B.V. Simponi is one of several TNF-blocking agents that Simponi, have been associated with a variety of are available for the treatment of diseases such as infections, including serious infections, from all rheumatoid arthritis and ulcerative colitis. Janssen types of organisms, including bacterial, viral, and works closely with health authorities to accurately fungal organisms, and the prescribing information inform patients and prescribers about the safety for Simponi reflects this information. profile of Simponi. To date, meningitis has not Janssen will continue to monitor serious infections, been considered an adverse drug reaction for including meningitis, and all potential adverse Simponi. However, TNF-blocking agents, including reactions, reported with Simponi.

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Pazopanib and Pericardial Effusion Dr. Ian Boyd, Australia aspartate aminotransferase. The most important Summary serious adverse reactions identified in the RCC or Pazopanib is an orally administered, potent multi- STS trials were transient ischaemic attack, target tyrosine kinase inhibitor (TKI) of Vascular ischaemic stroke, myocardial ischaemia, Endothelial Growth Factor Receptors. It is myocardial and cerebral infarction, cardiac indicated for the first line treatment of advanced dysfunction, gastrointestinal perforation and renal cell carcinoma (RCC) and the treatment of fistula, QT prolongation and pulmonary, selective subtypes of advanced soft tissue sarcoma gastrointestinal and cerebral haemorrhage, all (STS). In the WHO Global Individual Case Safety adverse reactions being reported in <1% of Report (ICSR) Database, VigiBaseTM, there are treated patients. Other important serious adverse currently (25 January 2013) 11 ICSRs of reactions identified in STS trials included venous pericardial effusion in association with pazopanib. thromboembolic events, left ventricular The ICSRs are from the United States, Germany, dysfunction and pneumothorax. Fatal events that Greece, Ireland and Singapore. The association were considered possibly related to pazopanib has an IC value of 2.65 with an IC025 value of included gastrointestinal haemorrhage, pulmonary 1.68. There are two probable duplicates, which haemorrhage/haemoptysis, abnormal hepatic leaves a total of nine ICSRs. Pazopanib was the function, intestinal perforation and ischemic only drug suspected in all but one. The outcome stroke. 1 was stated in seven ICSRs. The patients were reported as recovered or recovering in four cases, Pericardial effusion is the accumulation of fluid in not recovered in two cases and the outcome was excess of normal in the pericardial cavity. It can fatal in one case. In all of these cases, the drug be confirmed by the demonstration of fluid in the was reported to have been withdrawn. In two of pericardial cavity by echocardiography. Pericardial the cases, the reaction recurred on rechallenge. effusion may present in either acute or chronic form. It may be the first sign of acute pericarditis. The association of pericardial effusion with It may also occur in heart failure and pazopanib appears to be a signal. Pazopanib was cardiomyopathy of various types, and in the only drug suspected in eight of the nine cases myxoedema. 2 The cause of abnormal fluid and causality is plausible in six cases. While the production depends on the underlying aetiology, time to onset is not particularly suggestive of a but it is usually secondary to injury or insult to the drug-induced effect, the observation of recovery pericardium (that is, pericarditis). Transudative after dechallenge in the three cases in which fluids result from obstruction of fluid drainage, recovery was documented, is also supportive of which occurs through lymphatic channels. the signal. In addition, the fact that the reaction Exudative fluids occur secondary to inflammatory, recurred on rechallenge in two cases is strongly infectious, malignant, or autoimmune processes suggestive. A report in the literature indicated that within the pericardium. 3 The fluid may be serious, pericardial effusion occurred in 3% of patients in a serofibrinous, serosanguineous or chylous. 2 clinical trial and the observation that pericardial effusion is associated with other TKIs points to the Signs and symptoms of pericardial effusion include fact that pericardial effusion may be a class effect chest pain, pressure or discomfort, light- of TKIs. Reports of pericardial effusion in VigiBase headedness or syncope, palpitations, , support this proposition. dyspnoea, hoarseness, anxiety and confusion, and hiccoughs. 3 Examination findings in patients with pericardial effusion include the classic Beck triad of Introduction pericardial tamponade: hypotension, muffled heart Pazopanib is an orally administered, potent multi- sounds and jugular venous distention. Other target tyrosine kinase inhibitor (TKI) of Vascular examination findings include pulsus paradoxus, Endothelial Growth Factor Receptors (VEGFR)-1, - pericardial friction rub, , hepatojugular 2, and -3, platelet-derived growth factor (PDGFR)- reflux, tachypnoea, decreased breath sounds, α and -β, and stem cell factor receptor (c-KIT). It Ewart sign (dullness to percussion beneath the is indicated for the first line treatment of advanced angle of left scapula), hepatosplenomegaly, renal cell carcinoma (RCC) and the treatment of weakened peripheral pulses, , and selective subtypes of advanced soft tissue sarcoma cyanosis. 3 (STS). The most common adverse reactions (experienced by at least 10% of the patients) of As an adverse drug reaction it occurs relatively any grade in the RCC and STS trials included: commonly in drug-induced systemic lupus erythematosus; it may also occur as an diarrhoea, hair colour change, skin 2 hypopigmentation, exfoliative rash, hypertension, immunological reaction to a drug. nausea, headache, , anorexia, , dysgeusia, stomatitis, weight decreased, pain, elevated alanine aminotransferase and elevated

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Reports in VigiBase Literature and Labelling As of 25 January 2013 there are 11 Individual The product literature does not refer to pericardial Case Safety Reports (ICSRs) of pericardial effusion effusion. There is a warning on the possibility of in association with pazopanib in the WHO Global cardiac dysfunction such as congestive heart ICSR Database, VigiBase™ (Table 1). The failure and decreased left ventricular function. association has an IC value of 2.65 with an IC025 Such cardiac dysfunction could result in the value of 1.68. The ICSRs were submitted from development of pericardial effusion but as none of Germany, the United States (four cases each), the reports document these other cardiac Greece, Ireland and Singapore (one case each). reactions, this does not appear to be a cause. In After the removal of two suspected duplicates the literature, pericardial effusion was repor¬ted from the US, the patients ranged in age from 21 to to occur in 3% of Asian patients in a Phase II trial 80 years with a median of 44 years. The gender of pazopanib with recurrent/metastatic undifferen- distribu¬tion was five females and four males. tiated nasopharyngeal carcinoma. 4 In addition, it has been noted that other tyrosine kinase Pazopanib was the only drug suspected in all but inhibitors such as nilotinib and dasatinib are one of the nine cases. The other suspected drug known to be associated with pericardial effusion. 5 was moxifloxacin. Concomitant drugs were Moreover, pericardial effusion is reported as an reported in four cases but there was little pattern adverse effect in the product informa¬tion of other in these reports apart from the use of TKIs including imatinib, nilotinib and dasatinib. antihypertensives (in three cases), proton pump inhibitors (two cases) and NSAIDs (two cases). Pazopanib was reported to have been Discussion and Conclusion administered orally, as expected, in all eight cases Case reports in VigiBase suggest that there is a which provided this information. The indication for signal for the association of pazopanib and use was clearly stated in seven reports and pericardial effusion. Pazopanib was the only drug included treatment of sarcoma (three cases), suspected in all but one of the nine ICSRs. In the metastatic renal cell carcinoma (three cases) and report in which there was another suspected drug malignant lung neoplasm (one case). (Case 4) pericardial effusion was present before pazopanib was commenced so pazopanib is Time to onset was reported in six of the reports. It unlikely to be a cause in this case. Two of the ranged from eight weeks to six months with a other reports have a doubtful association. In Case median of four months in five cases but in the 1, the reporter considered that pericardial effusion other case (Case 4) pericardial effusion was may have been caused by pleural lesions as a present before pazopanib was commenced so consequence of disease progression and the pazopanib is unlikely to be a cause in this case. patient died from disease progression soon after. Two of the other reports have a doubtful In Case 10, pericardial fluid was present before association. In Case 1, the reporter considered treatment commenced but there was increased that pericardial effusion may have been caused by fluid in association with pazopanib. pleural lesions as a consequence of disease progression and the patient died from disease Time to onset is not particularly suggestive of a progression soon after. In Case 10, pericardial signal. In the six reports in which causality is fluid was present before treatment commenced plausible, the time to onset ranged from eight but there was increased fluid in association with weeks to six months which appears rather long for pazopanib. Removal of Case 1, 4 and 10 from the a drug-induced effect. However, pericardial assessment results in six cases with a plausible effusion may be present without symptoms so it is association. possible that the time to onset was shorter than reported. The outcome was stated in seven ICSRs. The patients were reported as recovered or recovering Dechallenge is also possibly suggestive of a signal. in four cases, not recovered in two cases and the In the six reports in which causality is plausible, outcome was fatal in the remaining case although the out¬come was stated in four reports. The the outcome of the pericardial effusion was patients were reported as recovered in three cases unknown. In all of these cases, the drug was of these four and not recovered in the other case. reported to have been withdrawn. In two of these In all of the six cases, the drug was reported to cases (Case 5 and 7), the reaction recurred on have been withdrawn. Importantly, in two cases rechallenge. The drug was also withdrawn in the the reaction recurred on rechallenge. two cases where the outcome remains unknown. In the literature, pericardial effusion was reported Other reactions were described in six reports. In to occur in 3% of Asian patients in a Phase II trial general, these reactions appeared indicative of a of pazopanib with recurrent/metastatic patient population with severe disease and undifferentiated nasopharyngeal carcinoma. In included abnormal hepatic function (three cases), addition, it has been noted that other TKI such as pleural effusion, cardiac tamponade and fatigue nilotinib and dasatinib are known to be associated (each in two cases). with pericardial effusion. Moreover, pericardial effusion is reported as an adverse effect in the

WHO Pharmaceuticals Newsletter No. 4, 2013 • 31

SIGNAL product information of other TKIs including Drug Reactions: Definitions of Terms and Criteria imatinib, nilotinib and dasatinib. for their Use. CIOMS, Geneva, 1999. URL: http://www.cioms.ch/publications/ In VigiBase, there have been 5651 occurrences of reporting_adverse_drug.pdf/accessed 23 April pericardial effusion. Only 13 drugs have a hundred 2013. or more reports of the association and two of these are the TKIs dasatinib (120) and imatinib 3. Stnmel WJ, Ayub B, Contractor T, authors, (107). In addition, there are many reports with Fredi JL, editor. Pericardial Effusion. Medscape erlotinib (66), sunitinib (49), nilotinib (21), Reference: Drugs, Diseases and Procedures. URL: sorafenib (17) and gefitinib (14) and it seems http://emedicine.medscape.com/article/157325- likely that pericardial effusion is a class effect of overview#aw2aab6b2b3aa. Accessed: 23 April TKIs. 2013. 4. Lim WT, Thng C, Toh CK. A phase II study of References GW786034 (pazopanib) in Asian patients with 1. European Medicines Agency Summary of recurrent/metastatic undifferentiated Product Characteristics for pazopanib (Votnent). nasopharyngeal carcinoma. J Clin Oncol. URL: http:// 2010;28:5556. www.ema.europa.eu/docs/en_GB/document_librar y/ EPAR_-Product_Information/human/001141/ 5. Escalante CP, Zalpour A. Vascular endothelial WC500094272.pdf. Accessed: 23 April 2013. growth factor inhibitor-induced hypertension: basics for primary care providers. Cardiol Res 2. The Council for International Organizations of Pract 2011; doi:10.4061/2011/816897. Medical Sciences (CIOMS). Reporting Adverse

Table 1. Case overview of ICSRs in VigiBase™ of pericardial effusion in association with pazopanib

Case Age/ Gender Other suspected (S) or Reactions (WHO-ART preferred Outcome

concomitant (C) drugs terms)

1 75/F None Pericardial effusion Recovering 2 50/M None Pericardial effusion Recovered 3 77/M None Pericardial effu sion, hepatic enzymes increased, Not recovered medicine ineffective, cardiac tamponade

4 21/F Moxifloxacin(S), moxifloxacin(C) Pericardial effusion, multiple organ failure, cardiac Died but outcome of pericardial tamponade, pleural effusion, cardiomegaly, effusion unknown hepatorenal syndrome, pneumonia, renal failure chronic, hepatic failure, fatigue, hepatic function abnormal 5 39/F Lansoprazole, , Pericardial effusion, hepatic function abnormal, Recovered from initial (all C) oedema generalised, effusion (MedDRA term), episode but recurred on pleural effusion, serositis (MedDRA term) rechallenge with unknown recovery 6 80/F Ramipril, , pantoprazole, Pericardial effusion, fatigue, hypotension Unknown torasemide (all C)

7 42/M Metoprolol, , lisinopril, , Pericardial effusion, disease recurrence (MedDRA Unknown vitamins nos, prochlorperazine, term) hydromorphone, mirtazapine, ondansetron, amlodipine, ibuprofen (all C)

8* 42/M None Pericardial effusion Un known 9* 42/M Vitamins nos, prochlorperazine, mirtazapine, Pericardial effusion Unknown ondansetron, amlodipine, (all C) 10 30/F None Pericardial effusion, diarrhoea Not recovered 11 44/M Pregabalin, ibuprofen, glimepiride (all C) Perica rdial effusion, myalgia Recovered *Case 8 and 9 are probably duplicates of Case 7

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

CAVEAT DOCUMENT

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

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

2011

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