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2020 WHO Pharmaceuticals

No.5 NEWSLETTER

The WHO Pharmaceuticals Newsletter provides you

with the latest information on the safety of medicines WHO Vision for Medicines Safety and legal actions taken by regulatory authorities around No country left behind: the world. It also provides signals based on information worldwide pharmacovigilance for safer medicines, safer patients derived from the WHO global database of individual case safety reports, VigiBase.

The aim of the Newsletter is to disseminate regulatory information on the safety of pharmaceutical products, based on communications received from our network of national pharmacovigilance centres and other sources such as specialized bulletins and journals, as well as partners in WHO.

The information is produced in the form of résumés in English, full texts of which may be obtained on request from:

Safety and Vigilance: Medicines, EMP-HIS, World Health Organization, 1211 Geneva 27, Switzerland, Contents E -mail address: [email protected] This Newsletter is also available at: Regulatory matters http://www.who.int/medicines Safety of medicines

Signal

WHO Pharmaceuticals Newsletter No. 5, 2020

ISBN 978-92-4-001453-4 (electronic version) ISBN 978-92-4-001454-1 (print version)

© World Health Organization 2020

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Table of Contents

Regulatory Matters Alfuzosin ...... 4 ...... 4 Benidipine ...... 4 Canagliflozin ...... 4 Hydroxychloroquine ...... 5 Opioid ...... 5 Pentoxifylline ...... 5 Piperacillin, Tazobactam ...... 5 Relugolix ...... 5 Tinidazole ...... 6 Ulipristal acetate ...... 6 X-ray contrast media ...... 6

Safety of medicines ...... 7 Beta-lactam antibiotics, non-steroidal anti-inflammatory drugs, intravenous iron preparations and rocuronium ...... 7 , other antipsychotics ...... 7 Cyproterone ...... 8 Denosumab ...... 8 Emollient ...... 8 Glecaprevir/pibrentasvir (combination) ...... 8 Isotretinoin ...... 9 ...... 9

Information Note Sodium ...... 10

Signal and osteonecrosis of the jaw (ONJ) ...... 11 and Bradycardia – national signal from Peru with potential global relevance ...... 18

WHO Pharmaceuticals Newsletter No. 5, 2020 • 3 Regulatory Matters

Alfuzosin reported in clinical trials and in cases were evaluated by the post-marketing use worldwide. SRP, PvPI, and IPC who found Risk of palpitations There were 21 cases of a strong causal relationship diverticulitis. between benidipine and associated photosensitivity India. The National For post-marketing use of reaction. Coordination Centre - baricitinib outside of clinical Pharmacovigilance Programme trials, 35 spontaneous cases of Reference: of India (NCC-PvPI) has made diverticulitis were reported Based on the communication a recommendation to the worldwide up until 2019. Of from NCC-PvPI, IPC India Central Drugs Standard Control these, 25 cases included a (ipc.gov.in) Organisation (CDSCO) to medical history of diverticulitis request that the patient and/or chronic use of NSAIDs, information leaflet (PIL) for or opioids, alfuzosin should be revised to which are known important risk incorporate palpitations as a factors for diverticulitis. Canagliflozin clinically significant . Health-care professionals are Risk of amputations advised to use baricitinib with removed Alfuzosin is used for the caution in patients with treatment of benign prostatic diverticular disease and in hyperplasia. USA. The US Food and Drug those concomitantly treated Administration (FDA) has Between July 2011 and with medications associated announced that the boxed November 2019, the NCC-PvPI with an increased risk of warning about the risk of received a total of three diverticulitis. amputation with the use of individual case safety reports Also, health-care professionals canagliflozin (Invokana® and (ICSRs) of alfuzosin associated should advise patients on Invokamet®) has been palpitations. The cases were baricitinib to seek immediate removed from the prescribing evaluated by the Signal Review medical care if they experience information. Panel (SRP), PvPI, and Indian severe abdominal pain Pharmacopeia Commission Canagliflozin is a sodium- especially accompanied with glucose cotransporter-2 (IPC) who found a strong , nausea and vomiting or causal relationship between (SGLT2) inhibitor. It lowers other symptoms of blood sugar by causing the alfuzosin associated diverticulitis. palpitations. kidneys to remove sugar from Reference: the body through the urine. It Reference: Drug Safety Update, MHRA, is used to reduce the risk of Based on the communication 26 August 2020 major heart-related events from NCC-PvPI, IPC India (www.gov.uk/mhra) such as heart attack, stroke or (ipc.gov.in) death in patients with type 2 , and to reduce the

risk of end-stage disease, worsening of kidney Benidipine function, heart-related death, Baricitinib and being hospitalized for heart Risk of photosensitivity failure in certain patients with Increased risk of reaction type 2 diabetes and diabetic diverticulitis kidney disease. India. The NCC-PvPI has made The FDA’s review of new United Kingdom. The a recommendation to the data demonstrated Medicines and Healthcare CDSCO to request that the PIL additional heart and kidney Products Regulatory Agency for benidipine is revised to related benefits. (MHRA) has announced that incorporate photosensitivity as the risk of diverticulitis has a clinically significant adverse Safety information from recent been added to the product drug reaction. clinical trials also suggests that information for baricitinib the risk of amputation, while Benidipine is used for the (Olumiant®). still increased with treatment of and canagliflozin, is lower than Baricitinib is a Janus kinase long term prophylactic previously described. The FDA inhibitor and is indicated for management of angina has concluded that the boxed the treatment of moderate to pectoris. severe active rheumatoid warning should be removed. Between July 2011 and arthritis in adults. Health-care professionals and November 2019, the NCC-PvPI patients should continue to A European review has received a total of five ICSRs recognize the importance of assessed cases of diverticulitis reporting benidipine associated preventative foot care and associated with baricitinib photosensitivity reaction. The

WHO Pharmaceuticals Newsletter No. 5, 2020 • 4 Regulatory Matters monitor for new pain, Opioid found a strong causal tenderness, sores, ulcers and relationship between infections in the legs and feet. Naloxone helps reverse pentoxifylline use and palpitations. Reference: opioid overdose MedWatch, US FDA, 26 August Reference: 2020 (www.fda.gov) USA. The FDA has requested Based on the communication that manufacturers of opioid from NCC-PvPI, IPC India (See also WHO Pharmaceuticals Newsletter pain relievers and medicines to (ipc.gov.in) No.3, 2020: Risk of diabetic ketoacidosis in treat opioid use disorder UK; No.1, 2020: Updated advice on (OUD), add new monitoring ketone bodies in Ireland) recommendations about naloxone to the prescribing information. Piperacillin, Opioids have serious risks Tazobactam Hydroxychloroquine including misuse and abuse, addiction, overdose and death. Risk of acute generalised Risk of prolonged QT, Naloxone is used to block the exanthematous pustulosis ventricular effects of opioids (e.g. (AGEP) countering decreased Japan. The Ministry of Health, breathing) and can help India. The NCC-PvPI has made Labour and Welfare (MHLW) reverse opioid overdose to a recommendation to the and the Pharmaceuticals and prevent death. CDSCO to request that the PIL Medical Devices Agency for piperacillin/tazobactam is (PMDA) have announced that The FDA encourages health- revised to incorporate acute the package insert for care professionals to raise generalised exanthematous hydroxychloroquine awareness of the availability of pustulosis (AGEP) as a clinically (Plaquenil®) should be revised naloxone when they prescribe significant adverse drug to include prolonged QT and opioid pain relievers or reaction. ventricular tachycardia as medicines to treat OUD. adverse drug reactions. Health-care professionals Piperacillin/tazobactam is used for the treatment of moderate Hydroxychloroquine is should educate patients on how to severe lower respiratory indicated for cutaneous to recognize respiratory tract infections. erythematosus and systemic depression and how to lupus erythematosus. administer naloxone. Between July 2011 and November 2019, NCC-PvPI A total of four cases of Reference: received a total of six ICSRs prolonged QT and ventricular MedWatch, US FDA, 23 July reporting tachycardia (including torsades 2020 (www.fda.gov) piperacillin/tazobactam de pointes) were reported in associated AGEP. The cases patients that used were evaluated by the SRP, hydroxychloroquine in Japan PvPI, and IPC who found a during the previous three strong causal relationship years. A causal relationship Pentoxifylline between between the drug and event piperacillin/tazobactam use could not be established for Risk of palpitations and AGEP. any of these cases. One case of India. The NCC-PvPI has made patient mortality has been Reference: a recommendation to the reported and a causal Based on the communication CDSCO to request the revision relationship could not be from NCC-PvPI, IPC India of the PIL for pentoxyphylline established for that case. (ipc.gov.in) to incorporate palpitations as a The MHLW and PMDA have clinically significant adverse concluded that a revision of the drug reaction. package insert is necessary. Pentoxifylline is a vasodilator Reference: indicated for the treatment of Relugolix Revision of Precautions, atrial and atriovenous MHLW/PMDA, 8 September circulatory disorder. Risk of severe abnormal 2020 (www.pmda.go.jp/english/) uterine bleeding in patients Between July 2011 and with submucosal fibroid November 2019, the NCC-PvPI received a total of four ICSRs Japan. The MHLW and the reporting palpitations PMDA have announced that the associated with pentoxifylline package insert for relugolix use. The cases were evaluated (Relumina®) should be revised by the SRP, PvPI, and IPC who WHO Pharmaceuticals Newsletter No. 5, 2020 • 5 Regulatory Matters to include the risk of severe strong causal relationship No.3, 2020: Licence suspension due to liver abnormal uterine bleeding in between tinidazole use and injury in UK; No.1, 2020: Risk of hepatic patients with submucosal skin hyperpigmentation. injury in EU; No.5, 2018: New measures to fibroid in the careful minimize risk of liver injury in EU and Reference: Canada) administration section. Based on the communication

Relugolix is indicated for relief from NCC-PvPI, IPC India of menorrhagia, lower (ipc.gov.in) abdominal pain, lumbar pain and anaemia associated with X-ray contrast media uterine fibroids. Risk of contrast-induced A total of 13 cases of severe Ulipristal acetate encephalopathy abnormal uterine bleeding were reported in patients using Revocation of marketing Japan. The MHLW and the relugolix in Japan during the authorizations PMDA have announced that the previous three years. For 10 of recommended package inserts for X-ray the 13 cases, a causal contrast media including relationship between the drug Europe. The European iopamidol (Iopamiron®), and event was reasonably Medicines Agency (EMA) has iohexol (Omnipaque®) and possible. No patient mortalities announced that the meglumine iotroxate have been reported. Pharmacovigilance Risk (Biliscopin®) should be revised Patients should be carefully Assessment Committee (PRAC) to include contrast-induced monitored and if any has recommended the encephalopathy as an adverse abnormalities are observed, revocation of the marketing drug reaction. appropriate measures should authorizations for ulipristal X-ray contrast media is be taken. Patients should be acetate preparations (Esmya® indicated for several methods instructed to immediately and generic medicines) when such as arteriography by digital contact a medical institution if used to treat symptoms of X-ray method, computer- they experience heavy bleeding uterine fibroids, due to the risk assisted tomography and at one time. of liver injury. intravenous urography. Reference: Ulipristal acetate is indicated A total of 11 cases of contrast- Revision of Precautions, for the treatment of moderate induced encephalopathy in MHLW/PMDA, 8 September to severe symptoms of uterine patients exposed to X-ray 2020 (www.pmda.go.jp/english/) fibroids in women who have contrast media have been not reached the menopause. reported in Japan during the Ulipristal acetate is also used previous three years, including as a single-dose medicine for five cases for which a causal emergency contraception. The relationship between the drug Tinidazole recommendation does not and event was reasonably apply for use of ulipristal as a possible. Risk of skin contraception. hyperpigmentation The MHLW and PMDA have The PRAC considered all the concluded that a revision of the available evidence including India. The NCC-PvPI has made package inserts was necessary. cases of serious liver injury. a recommendation to the Because it was not possible to Reference: CDSCO to request that the PIL identify which patients were Revision of Precautions, for tinidazole is revised to most at risk or measures that MHLW/PMDA, 20 July 2020 incorporate skin could reduce the risk, the PRAC (www.pmda.go.jp/english/) hyperpigmentation as a concluded that the risks of the clinically significant adverse medicines outweighed the drug reaction. benefits and that they should Tinidazole is used for the not be marketed in the EU. treatment of amoebiasis and The PRAC recommendation will giardiasis in adult patients only now be forwarded to EMA’s and in the treatment of Committee for Medicinal anaerobic infections. Products for Human Use Between July 2011 and (CHMP), which will adopt the November 2019, the NCC-PvPI EMA’s opinion. received a total of 13 ICSRs of Reference: tinidazole associated skin EMA, 4 September 2020 hyperpigmentation. The cases (www.ema.europa.eu) were evaluated by the SRP, PvPI, and IPC who found a (See also WHO Pharmaceuticals Newsletter WHO Pharmaceuticals Newsletter No. 5, 2020 • 6 Safety of Medicines

Allopurinol Beta-lactam MHRA has announced that monitoring blood Interaction with antibiotics, non- concentrations of clozapine or steroidal anti- preparations (Clozaril®, Denzapine® and Zaponex®) mercaptopurine: Bone inflammatory drugs, for toxicity is advised in certain marrow suppression clinical situations. Blood level intravenous iron monitoring of other New Zealand. The Medsafe antipsychotics for toxicity may has announced that co- preparations and also be helpful in certain administration of allopurinol rocuronium circumstances. with azathioprine or mercaptopurine can lead to Risk of Kounis syndrome Clozapine and other life-threatening antipsychotic medicines are suppression. New Zealand. The Medsafe indicated to treat symptoms has reminded health-care related to psychosis, including Allopurinol is a xanthine professionals that Kounis schizophrenic disorders and oxidase inhibitor used to syndrome has been associated some forms of bipolar disorder. reduce hyperuricaemia in with a variety of medicines patients with gout. including beta-lactam The MHRA received two Azathioprine is an antibiotics, non-steroidal anti- separate reports raising immunosuppressive agent, and inflammatory drugs, concerns regarding the need mercaptopurine is a cytotoxic intravenous iron preparations for monitoring of clozapine drug used in the treatment of and rocuronium. blood levels in one report and leukaemia. Azathioprine is monitoring antipsychotic blood metabolized to Kounis syndrome is a levels during long-term high- mercaptopurine, which is reaction dose antipsychotic use in the metabolized into an inactive affecting the coronary arteries. other. compound by . The underlying mechanism for Kounis syndrome is mast cell Expert Advisory Groups of the Inhibition of xanthine oxidase activation and release of Commission on Human by allopurinol increases plasma inflammatory mediators. Medicines considered safety concentrations of the active data for clozapine and other metabolites of azathioprine and The CARM recently received a antipsychotic drugs and mercaptopurine, which may report of coronary artery advised that blood lead to life-threatening spasm associated with the use concentrations of clozapine , of amoxicillin/clavulanic acid in should be monitored for or pancytopenia. a male patient. toxicity in certain clinical situations (e.g. a patients Concomitant use of allopurinol Management of Kounis stopping smoking, with and azathioprine or syndrome involves removing , and/or with poor mercaptopurine is not the offending allergen, metabolism). The Groups also recommended. If co- managing the acute coronary advised that blood level administration is necessary, vasospasm, and treating the monitoring of other the dose or azathioprine or allergic response. Careful antipsychotic drugs may be mercaptopurine should be selection and use of medicines helpful in certain reduced. are needed when managing the circumstances. acute condition to avoid further Up to June 2020, the Centre histamine release or Also, health-care professionals for Adverse Reactions exacerbation of coronary are advised that if blood Monitoring (CARM) had vasospasm. clozapine level monitoring is received 14 cases describing an carried out, this should be in interaction between allopurinol Reference: addition to the required blood and azathioprine. In 13 of the Prescriber Update, Medsafe, tests to manage the risk of cases the patients experienced September 2020 agranulocytosis. . Two (www.medsafe.govt.nz/) recent cases reported Reference: pancytopenia. Drug Safety Update, MHRA, 26 August 2020 Reference: (www.gov.uk/mhra) Prescriber Update, Medsafe, Clozapine, other September 2020 (www.medsafe.govt.nz/) antipsychotics

(See also WHO Pharmaceuticals Newsletter Monitoring blood No.1, 2016: Interaction with 6- mercaptopurine and azathioprine in concentrations advised Australia) United Kingdom. The

WHO Pharmaceuticals Newsletter No. 5, 2020 • 7 Safety of Medicines

Cyproterone stopping denosumab (Prolia®) the presence of a naked flame, for osteoporosis. fabric with emollient dried on is easily ignited. Although Risk of meningioma Denosumab is indicated for emollients are not flammable in treatment of osteoporosis and themselves or when on the New Zealand. The Medsafe bone loss associated with skin, but when dried on to has announced that exposure hormone ablation in men with fabric they act as an to cyproterone may increase prostate or with long- accelerant. the risk of meningioma. term systemic glucocorticoid Cyproterone is an antiandrogen therapy in adult patients. In July 2020, the MHRA launched a campaign to raise treatment indicated for: From 2015 to June 2020, 44 awareness of this important inoperable carcinoma of the cases of vertebral fracture, risk. A toolkit of resources is prostate, reduction of drive in including multiple fractures, available for health and social sexual deviations in men, and have been reported in the UK care professionals to support for severe signs of in post-marketing settings in the safe use of emollients. androgenisation in women. patients after stopping or A recent cohort study in France delaying ongoing treatment Health-care professionals are has demonstrated a dose- with denosumab. encouraged to inform patients and caregivers of the risks with dependent association between Health-care professionals emollient products. and the should evaluate a patient’s risk of meningioma. This risk individual factors for benefits Reference: increases as the cumulative and risks before initiating Drug Safety Update, MHRA, dose rises. treatment with denosumab, 26 August 2020 Up until March 2020, the CARM particularly in patients at (www.gov.uk/mhra) increased risk of vertebral received two reports of (See also WHO Pharmaceuticals Newsletter meningioma associated with fractures (e.g. previous No.1, 2019; Risk of severe and fatal burns in cyproterone. Both patients vertebral fracture). Patients UK; No.3, 2013: May cause skin irritation, were women who had been should not stop denosumab particularly in children with eczema in UK) without specialist review. treated with cyproterone for more than 10 years. Reference:

Cyproterone is contraindicated Drug Safety Update, MHRA, in patients with a meningioma 26 August 2020 Glecaprevir/ or a history of meningioma. If (www.gov.uk/mhra) a patient treated with (See also WHO Pharmaceuticals Newsletter pibrentasvir cyproterone is diagnosed with No.3, 2019: Risk of hypercalcaemia and (combination) meningioma, treatment must multiple vertebral fractures in Japan; No.4, be permanently stopped. 2018: Risk of multiple vertebral fractures in Risk of hepatic toxicity Japan) Reference: Prescriber Update, Medsafe, New Zealand. The Medsafe has announced that severity of September 2020 (www.medsafe.govt.nz/) liver disease should be assessed before administrating (See also WHO Pharmaceuticals Newsletter Emollient a combination of two direct- No.4, 2020: Restrictions in use due to risk of acting antivirals (DAAs), Risk of severe and fatal meningioma in Ireland and UK; No.3, 2020: glecaprevir and pibrentasvir Restrictions in use due to risk of burns meningioma in EU) (Maviret®). United Kingdom. The The combination of glecaprevir MHRA has informed health-care and pibrentasvir is used for the professionals of the recent treatment of chronic hepatitis campaign to promote C. Glecaprevir and pibrentasvir Denosumab awareness of the risk of severe are metabolized in the liver, and fatal burns, and of the and therefore patients with Increased risk of multiple availability of new resources to impaired liver function will be vertebral fractures support safe use of emollients. exposed to increased levels of these antivirals, increasing the Emollients, known as skin United Kingdom. The risk of adverse reactions. MHRA has announced that the creams, are used to help Commission on Human manage different dry skin In August 2019, the US FDA Medicines’ Pharmacovigilance conditions such as eczema, warned about the rare Expert Advisory Group psoriasis and ichthyosis. occurrence of serious liver injury with use of hepatitis C suggested that there is an Emollients can transfer from medicines. This was based on increased risk of multiple the skin onto clothing, bedding, 63 reported cases of worsening vertebral fractures after dressings and other fabrics. In WHO Pharmaceuticals Newsletter No. 5, 2020 • 8 Safety of Medicines liver function associated with dysfunction during treatment Topiramate is indicated to treat DAA treatment, which and persistence of these epilepsy and to prevent sometimes led to liver failure adverse effects for some time migraines. and death. after discontinuation. The CARM received a report of The Medicines Adverse Depression, anxiety and patient who experienced pre- Reactions Committee (MARC) psychotic symptoms, including seizure symptoms after reviewed the risk of serious suicidal thoughts/attempts and changing brands of topiramate. liver injury in patients taking suicide, have been reported in The Medsafe recommends the drug to determine the patients treated with prescribers follow the MHRA’s impact for New Zealand isotretinoin. All patients taking advice on switching brands of prescribers and patients. isotretinoin should be antiepileptic medicines. Brand monitored for signs of switches for topiramate must Before starting treatment, the depression by the prescriber be carefully considered, taking patient’s liver function should and referred for appropriate into consideration factors such be assessed. The drug can be treatment if necessary. Also, it as seizure frequency and used in patients with mild liver is important to remember that treatment history. impairment, but is not psychiatric symptoms may not recommended in patients with Reference: be fully alleviated after moderate liver impairment and Prescriber Update, Medsafe, discontinuation. is contraindicated in patients September 2020 with severe liver impairment. Isotretinoin has also been (www.medsafe.govt.nz/) associated with reports of The CARM has not received any sexual dysfunction, reports of liver-related adverse predominantly involving reactions in association with erectile dysfunction, decreased Maviret®. libido and vaginal dryness, Reference: although they are currently Prescriber Update, Medsafe, thought to be rare. September 2020 Additionally, isotretinoin is a (www.medsafe.govt.nz/) powerful teratogen associated (See also WHO Pharmaceuticals Newsletter with a high frequency of severe No.2, 2019: Risk of hepatic impairment and and life-threatening birth jaundice in Japan) defects if there is exposure in utero. It is contraindicated in women of childbearing potential unless all the conditions of the Isotretinoin Prevention Programme are met. Risk of psychiatric reactions and sexual dysfunction Reference: Drug Safety Update, MHRA, United Kingdom. The 26 August 2020 MHRA has reminded health- (www.gov.uk/mhra) care professionals that (See also WHO Pharmaceuticals Newsletter isotretinoin (Roaccutane®, No.5, 2018: Risk of obsessive compulsive Reticutan® and Rizuderm®) disorder (OCD) in New Zealand; No.5, 2016: should only be used to treat Potential risk of psychiatric adverse events severe forms of acne that is in Australia; No.1, 2015: Possible risk of resistant to adequate courses psychiatric disorders in UK) of standard therapy due to the risk of teratogenic effects, potential psychiatric reactions and sexual dysfunction. Topiramate Isotretinoin is indicated for severe acne that is resistant to Brand change should be adequate courses of standard avoided antibacterial or topical therapy. New Zealand. The Medsafe The MHRA regularly reviews has reminded health-care the safety of isotretinoin, with professionals that changing the aim of examining the brands of topiramate should be available evidence for the avoided. possible risks of psychiatric adverse reactions and sexual WHO Pharmaceuticals Newsletter No. 5, 2020 • 9 Information Note

Sodium valproate The WHO Pharmaceuticals Newsletter No. 5, 2019, provided some information on sodium valproate. Additional information is provided below, outlining actions proposed by WHO. Medicines containing valproate (e.g. sodium valproate, valproic acid, divalproex) should be avoided in pregnant women or in females of child-bearing potential, unless alternative treatments are ineffective or not tolerated, because of the high risk of birth defects (such as spina bifida, facial, skull, limb and heart malformations) and developmental disorders in infants who are exposed to valproate in the womb. When alternative treatments are not available or appropriate, female patients prescribed valproate medicines should be made aware of the risk and use effective contraception methods. Valproic acid (sodium valproate) is included on the WHO Model Lists of Essential Medicines for the treatment of epilepsy in adults and children, and of bipolar disorder in adults. In 2021, the listings for valproic acid on the Model Lists will be revised to include a cautionary note to better highlight the safety risks associated with use in pregnant women and females of child-bearing potential. WHO will be updating its current guidelines on epilepsy management in 2021. As part of this process, the evidence review on question on “Management of epilepsy in women of child bearing age”, will be updated to inform the revised recommendation on the role of pharmacological interventions, including valproate and other antiseizure medicines.

WHO Pharmaceuticals Newsletter No. 5, 2020 • 10 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 reports of suspected adverse drug reactions available in the WHO global database of individual case safety reports (ICSRs), VigiBase. The database contains over 23 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. International pharmaceutical companies, when identified as uniquely responsible for the drug concerned, are invited to comment on the signal text. Signals are thereafter communicated to National Pharmacovigilance Centres, before being published in this Newsletter. Signal texts from UMC might be edited to some extent by WHO and may differ from the original version. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of Signal (page 24). 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. For more information, on the UMC Measures of Disproportionate Reporting etc., 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].

Everolimus and osteonecrosis of the jaw (ONJ)

Anna Hegerius, Uppsala Monitoring Centre

Summary angiogenesis inhibition, soft tissue toxicity, and immunity dysfunction. Considering the mechanism Osteonecrosis of the jaw (ONJ) is a rare but of action of everolimus, it is reasonable to assume potentially serious and painful condition, originally that it may be involved in the development of ONJ. associated with the use of bisphosphonates. In recent years ONJ has been linked to several other Based on current data, the risk of ONJ due to drugs, including the mTOR inhibitor everolimus, everolimus treatment alone seems very low. used to treat advanced malignancies and to prevent However, combined with other drugs with a . During a UMC signal detection potential to cause ONJ and risk factors such as sprint, held in December 2018, the MedDRA diabetes or dental surgery, everolimus may act as a preferred term ‘osteonecrosis of jaw’ was trigger. Further studies in this area are required highlighted for the drug everolimus in VigiBase, the considering the increasing population of patients at WHO global database of individual case safety risk of ONJ and the adverse impact on the quality of reports (ICSRs). As of 3 February 2020, there were life for those affected. 117 reports for this drug–adverse drug reaction

(ADR) combination in VigiBase. Introduction ONJ is not labelled for everolimus, but related terms such as , jaw pain, oral pain, impaired The antineoplastic agent everolimus is indicated for wound healing and mucositis are. Among the cases the treatment of various (breast, in VigiBase and the scientific literature, the vast pancreatic, gastrointestinal, lung, and renal) and is majority concern patients with concurrent or past also used as an immunosuppressant to prevent therapy with drugs known (or suspected) to cause transplant rejection. In breast cancer treatment, ONJ, which makes it difficult to identify the everolimus is combined with the aromatase inhibitor offending drug. However, there are a few case exemestane. Everolimus inhibits the activity of reports where neither drugs nor risk factors mammalian target of rapamycin (mTOR), a serine- associated with ONJ were involved, implicating threonine kinase involved in cell growth and everolimus as an independent cause of ONJ. In 15 metabolism, resulting in a decrease of both of the VigiBase cases, the reaction abated when the hypoxia-inducible factors and vascular endothelial drug was withdrawn. (VEGF) levels, which reduces tumour growth and angiogenesis. Furthermore, the mTOR The exact pathophysiology of ONJ remains unclear, and VEGF pathways play a key role in regulating but several theories have been proposed and the bone homeostasis and immune responses.1, 2 mechanism is likely multi-factorial. Factors that Everolimus and (the other drug in the may cause ONJ are: bone remodelling (osteoclast) same class) are derivatives of sirolimus. inhibition, bone infection/inflammation,

WHO Pharmaceuticals Newsletter No. 5, 2020 • 11 Signal

Osteonecrosis of the jaw (ONJ) is characterised as exemestane (54 cases), zoledronic acid (54), oral lesions of exposed necrotic bone that persist for denosumab (38), (11) and fulvestrant at least eight weeks, with no previous history of (11). Zoledronic acid and denosumab are both radiation or metastasis to the area. This oral known to cause ONJ. Exemestane is a potent condition is rare but potentially serious and very oestrogen lowering agent, and a reduction in bone painful. A number of drugs are known to cause ONJ mineral density and an increased fracture rate has but it can also occur spontaneously.3 The condition been observed. Fulvestrant is an oestrogen receptor was first described in 2003, in a case report antagonist and may also cause osteoporosis, but including 36 patients who had been treated with there is no long-term data on the effects on bone. two different bisphosphonates,4 and was later Most co-reported reactions were malignant determined to be a drug class effect. In the neoplasm progression (13 cases), stomatitis (12), following years, other drugs were also associated fatigue (11), pain (10) and metastasis to bone (9). with the development of ONJ, such as the Stomatitis and metastasis to the bone (if located in monoclonal denosumab and the jaw) may have contributed to the ONJ. bevacizumab and the tyrosine kinase inhibitor The vast majority of the patients were administered sunitinib. More recently the mTOR inhibitor everolimus due to breast cancer (73 cases) or renal everolimus has also been implicated as a risk factor cancer (28 cases), and the dose varied between 5 for ONJ.5 Hence the term ‘Medication Related and 20 mg per day, with 10 mg being the most Osteonecrosis of the Jaw’ (MRONJ) was established common daily dose. Most cases had a reasonable in 2009 by the American Association of Oral and time to onset, with a median of 31 weeks, which is Maxillofacial Surgeons (AAOMS).3 In addition to the shorter than the median time to onset for use of antiresorptive and antiangiogenic agents, bisphosphonate-related ONJ (108 weeks) but longer several other risk factors for ONJ have been than the median time to onset for non- identified. These include dental surgery (e.g. tooth antiresorptive medications (20 weeks).11, 12 In 15 extraction), poor oral health, diabetes, smoking, cases the reaction abated when the drug was and concomitant use of .6, 7 withdrawn. The combination of antiangiogenics and Since several other drugs are known to cause ONJ, antiresorptives is known to increase the risk of ONJ all cases with drugs that have ONJ labelled were development,8, 9 but little is known about the risk of excluded from the case series. This resulted in 27 developing ONJ with antiangiogenics alone. remaining cases, but some of them could also be excluded since the narratives revealed that the patients had taken other ONJ-causing drugs. Some Reports in VigiBase cases had a medical history that may have During a UMC signal detection sprint held in contributed to the development of ONJ, e.g. December 2018, the MedDRA preferred term stomatitis, dental issues or bone metastasis. ‘osteonecrosis of jaw’ was highlighted for the drug A selection of reports is presented in Table 1. Case everolimus in VigiBase, the WHO global database of 1 concerns a female patient with metastatic breast individual case safety reports (ICSRs). cancer who developed ONJ five weeks after As of 3 February 2020, there were 117 reports for initiating everolimus (and exemestane) treatment. this drug–adverse drug reaction (ADR) combination Both drugs were withdrawn and the patient was in VigiBase. Based on the overall reporting of recovering when the report was sent. According to a adverse reactions for everolimus, and of the later publication of this case, the patient had no adverse reaction ONJ in VigiBase, the expected relevant past dental history and metastasis was value for the number of reports on the combination ruled out. The patient was treated with was 35, and the association was highlighted as cephalosporin for two weeks and after two months disproportionally reported, by IC analysis10. her condition had improved.13 The reports came from 15 countries across four In case 2, a female patient received everolimus for continents: Europe (76 reports), the Americas (16), advanced breast cancer and after nine days Asia (23), and Australia (1). More female than male experienced a range of adverse reactions including patients were affected (75% women), since the aphthae, throat pain and difficulty swallowing. She most common indication for everolimus in the case was also diagnosed with ONJ and had no relevant series was breast cancer, and the age range was medical history or concomitant medication. 29-82 years, with a median of 64 years. Physicians Everolimus treatment was continued and most of and other health professionals accounted for 95% the adverse reactions persisted, except for the of the reports and the rest were submitted by aphthae which resolved after laser therapy. The pharmacists and consumers/non-health time to onset was very short in this case, but not professionals. More than 90% of the cases were implausible.12 The reporter assessed the events as serious, including six fatalities (5%), but all were suspected to be related to the drug. not caused by the ONJ. Case 3 describes a female patient with metastatic In 18 cases, everolimus was the only reported drug, breast cancer who received everolimus for 19 days and in 26 cases it was the only suspected drug. The and then stopped the drug for one month due to a most frequently co-reported drugs were tooth extraction. The treatment was then resumed

WHO Pharmaceuticals Newsletter No. 5, 2020 • 12 Signal but again stopped after only two days due to ONJ recovering after the drug had been withdrawn. The onset. The reporter suspected the drug to have patient had no related medical history nor past drug caused the adverse reaction since the patient had therapy. recovered substantially two weeks after drug Case 5 presents a female patient of unknown age withdrawal. However, tooth extraction is also a who developed ONJ during treatment with trigger event for ONJ. everolimus for advanced breast cancer. The time to Case 4 concerns a female patient with recurrent onset is unknown, but the drug was withdrawn and breast cancer, treated with everolimus and a few the stomatitis resolved; the outcome of the ONJ other drugs (see Table 1) who developed ONJ. The was unknown. time to onset is unknown but the patient was

Table 1. Characteristics of a selection of case reports in VigiBase of everolimus in association with osteonecrosis of jaw (ONJ) Case Reporter Age/Sex Suspected (S) or Reactions (MedDRA Time to Action taken concomitant (C) preferred terms) onset drugs 1 Other health 76/F Everolimus (S) Osteonecrosis of jaw 5 weeks Drug withdrawn, professional Exemestane (C) recovering 2 Other health 61/F Everolimus (S) Osteonecrosis of jaw, 9 days Dose not changed, not professional aphthous ulcer, oropharyngeal recovered pain, dysphagia, furuncle, etc. 3 Physician 55/F Everolimus (S) Osteonecrosis of jaw 7 weeks* Drug withdrawn, Exemestane (C) recovering Pantoprazole (C) (C) Tramadol (C) Colecalciferol (C) 4 Physician 75/F Everolimus (S) Osteonecrosis of jaw Unknown Drug withdrawn, Exemestane (S) recovering Capecitabine (S) Rechallenge, outcome Cyclophophamide (S) unknown Fulvestrant (S) 5 Other health 75/F Everolimus (S) Osteonecrosis of jaw, Unknown Drug withdrawn, professional stomatitis outcome unknown for everolimus, recovered for stomatitis *The patient was treated with the drug for 19 days, halted treatment for a month due to a tooth extraction, and then resumed treatment for only two days before the ONJ occurred and the drug was withdrawn.

Literature and labelling administered a bisphosphonate, these drugs accumulate in bone and the effect may last more ONJ is not labelled for everolimus (or temsirolimus) than 10 years,18 which makes it reasonable to in the most recent Summary of Product assume that previous intake of these drugs may Characteristics (SPC) in the United Kingdom but still be relevant for the development of ONJ. related terms such as stomatitis, jaw pain, oral pain, impaired wound healing and mucositis are.14 However, in addition to case 1 above, there are a ONJ has not been observed in clinical trials, but few other published case reports where gingival swelling and jaw pain have been.6 bisphosphonates or monoclonal antibodies were not Osteonecrosis is labelled for sirolimus, and since involved, implicating everolimus as an independent everolimus mimics sirolimus, it is reasonable to cause of ONJ. One case concerns a female breast assume that it might have a similar effect. cancer patient with no medical history of radiation, and metastasis to the mandible was ruled out. The In addition to the cases in VigiBase, there are patient had a tooth extracted four months prior to several case reports in the literature where the ONJ diagnosis, which may have contributed to everolimus is suspected of causing or contributing the onset.19 Another case describes a male patient to ONJ. However, in some of these cases, it is who had taken everolimus for 1.5 years (after a difficult to establish a causal link since the patient kidney transplant) when he was diagnosed with had also taken other drugs known to cause ONJ, for ONJ. He had no recent dental trauma, but he had example bisphosphonates.15-17 Even though many taken steroids, which may also have contributed to years may have passed since a patient was the adverse reaction.20

WHO Pharmaceuticals Newsletter No. 5, 2020 • 13 Signal

There are also case reports where the other mTOR extractions. There are a few case reports of ONJ in inhibitor temsirolimus has been combined with patients who neither taken other suspected drugs denosumab or bevacizumab, resulting in ONJ, and nor had any known risk factors. Based on current the authors describe a potential synergistic effect.21, data, the risk of ONJ due to everolimus treatment 22 alone, seems very low. However, combined with other drugs with the potential to cause ONJ and risk Furthermore, US FDA reviewed all ONJ cases in factors such as diabetes or dental surgery, FAERS on the drugs suspected to cause ONJ. This everolimus may act as a trigger. Although it is study was the first to show that the mTOR inhibitors impossible to conclude what role everolimus played everolimus and temsirolimus were also associated in each reported case, VigiBase data and published with the risk for ONJ, with 84 and 28 cases case reports still point to a potential causal respectively. However, compared to other drugs, association where the drug may at least have the risk of mTOR induced ONJ was low (<5%).23 contributed to the development of ONJ. Further The exact pathophysiology of ONJ has still not been studies in this area are required considering the fully understood but several theories have been increasing population of patients at risk of ONJ, the proposed and the mechanism is likely to be multi- seriousness of this condition, and the adverse factorial. Factors that may cause ONJ are: bone impact on the quality of life for those affected. remodelling (osteoclast) inhibition, bone Close collaboration between medical doctors and infection/inflammation, angiogenesis inhibition, soft dentists, as well as information to patients at risk, tissue toxicity, and immunity dysfunction.24 In are important aspects for the prevention, prompt relation to everolimus, pre-clinical studies have recognition and treatment of ONJ.27 shown that inhibition of mTOR decreases the maturation of osteoclasts and increases their apoptosis, which may explain how osteonecrosis References may occur.1 Furthermore, when VEGF activity is 1. Indo Y, Takeshita S, Ishii KA, Hoshii T, Aburatani inhibited, the healing of bone is impaired6. The H, Hirao A, et al. Metabolic Regulation of caused by everolimus explains Osteoclast Differentiation and Function. J Bone the impaired wound healing and the infection Miner Res. 2013;28(11):2392-9. susceptibility of treated patients. However, although infection and inflammation are often present when 2. Cobbold SP. The mTOR Pathway and Integrating ONJ is diagnosed, it has not been established Immune Regulation. Immunology. whether infection precedes or follows .25 2013;140(4):391-8. The wide range of time to onset of ONJ can be 3. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, explained by several factors, for example the Aghaloo T, Mehrotra B, et al. American potency, route of administration, and cumulative Association of Oral and Maxillofacial Surgeons dose of the drug used.26 One study showed that Position Paper on Medication-Related ONJ caused by non-antiresorptive medications had Osteonecrosis of the jaw-2014 Update. J Oral an earlier time to onset, a higher proportion of Maxillofac Surg. 2014;72(10):1938-56. cases lacking a trigger event, and greater likelihood of healing and shorter healing time, compared to 4. Marx RE. Pamidronate (Aredia) and Zoledronate ONJ caused by bone targeting agents, and the (Zometa) Induced Avascular Necrosis of the diagnosis of ONJ is often delayed.12 There is a risk Jaws: A Growing Epidemic. J Oral Maxillofac of underdiagnosis of ONJ due to lack of awareness, Surg. 2003;61(9):1115-7. strict diagnostic criteria, and the fact that early 5. Gnant M, Baselga J, Rugo HS, Noguchi S, Burris signs and symptoms of the condition are similar to HA, Piccart M, et al. Effect of Everolimus on the clinical presentation of stomatitis, which is a Bone Marker Levels and Progressive Disease in very common side effect of everolimus and most Bone in BOLERO-2. J Natl Cancer Inst. other drugs that may also cause ONJ.6 This means 2013;105(9):654-63. that there is probably under-reporting of ONJ; one study concluded that the occurrence of ONJ in renal 6. Fusco V, Santini D, Armento G, Tonini G, Campisi cancer patients receiving bisphosphonates and G. Osteonecrosis of jaw Beyond Antiresorptive targeted agents might be underestimated.8 (Bone-Targeted) Agents: New Horizons in Oncology. Expert Opin Drug Saf. 2016;15(7):925-35. Discussion and conclusion 7. Chiu CT, Chiang WF, Chuang CY, Chang SW. Among the cases in VigiBase, the vast majority Resolution of Oral Bisphosphonate and - concerned patients with concurrent or past therapy Related Osteonecrosis of the Jaw-A Serial Case with drugs known (or suspected) to cause ONJ, Analysis. J Oral Maxillofac Surg. which makes it difficult to identify the offending 2010;68(5):1055-63. drug. Furthermore, exemestane and fulvestrant 8. Fusco V, Porta C, Saia G, Paglino C, Bettini G, (often co-administered with everolimus), may also Scoletta M, et al. Osteonecrosis of the Jaw in play a part in the development of ONJ considering Patients With Metastatic Renal Cell Cancer their mechanism of action. Some patients also had Treated With Bisphosphonates and Targeted potential risk factors such as diabetes and tooth WHO Pharmaceuticals Newsletter No. 5, 2020 • 14 Signal

Agents: Results of an Italian Multicenter Study Stomatol (Roma). 2014;5(2 Suppl):26-. and Review of the Literature. Clin Genitourin 18. Diab DL, Watts NB. Bisphosphonate Drug Cancer. 2015;13(4):287-94. Holiday: Who, When and How Long. Ther Adv 9. Christodoulou C, Pervena A, Klouvas G, Galani E, Musculoskelet Dis. 2013;5(3):107-11. Falagas ME, Tsakalos G, et al. Combination of 19. Lee CYS, Lee KL, Hirata KY, Suzuki JB. Bisphosphonates and Antiangiogenic Factors Medication-Related Osteonecrosis of the Jaw Induces Osteonecrosis of the Jaw More with the mTOR Inhibitor Everolimus in a Patient Frequently than Bisphosphonates Alone. with Estrogen-Receptor Positive Breast Cancer: Oncology. 2009;76(3):209-11. A Case Report. Int J Oral Dent Health. 10. Norén GN, Hopstadius J, Bate A. Shrinkage 2016;2(3). Observed-to-Expected Ratios for Robust and 20. Akkach S, Shukla L, Morgan D. Everolimus- Transparent Large-Scale Pattern Discovery. Stat Induced Osteonecrosis of the Jaw in the Methods Med Res. 2013;22(1):57-69. Absence of Bisphosphonates: A Case Report. Br 11. Schiodt M, Vadhan-Raj S, Chambers MS, J Oral Maxillofac Surg. 2019;57(7):688-90. Nicolatou-Galitis O, Politis C, Coropciuc R, et al. 21. Nifosi AF, Nifosi L, Nifosi G. Osteonecrosis of the A Multicenter Case Registry Study on Jaw in a Patient Treated with Denosumab and Medication-Related Osteonecrosis of the Jaw in Temsirolimus. SAJ Case Reports. 2017;4(401). Patients with Advanced Cancer. Support Care Cancer. 2018;26(6):1905-15. 22. Santos-Silva AR, Belizario Rosa GA, Castro Junior G, Dias RB, Prado Ribeiro AC, Brandao 12. Nicolatou-Galitis O, Kouri M, Papadopoulou E, TB. Osteonecrosis of the Mandible Associated Vardas E, Galiti D, Epstein JB, et al. with Bevacizumab Therapy. Oral Surg Oral Med Osteonecrosis of the Jaw Related to Non- Oral Pathol Oral Radiol. 2013;115(6):e32-6. Antiresorptive Medications: A Systematic Review. Support Care Cancer. 2019;27(2):383- 23. Zhang X, Hamadeh IS, Song S, Katz J, Moreb 94. JS, Langaee TY, et al. Osteonecrosis of the Jaw in the United States Food and Drug 13. Yamamoto D, Tsubota Y, Utsunomiya T, Sueoka Administration's Adverse Event Reporting N, Ueda A, Endo K, et al. Osteonecrosis of the System (FAERS). J Bone Miner Res. Jaw Associated with Everolimus: A Case Report. 2016;31(2):336-40. Mol Clin Oncol. 2017;6(2):255-7. 24. Aghaloo T, Hazboun R, Tetradis S. 14. Electronic Medicines Compendium: Summary of Pathophysiology of Osteonecrosis of the Jaws. Product Characteristics for Everolimus Oral and maxillofacial surgery clinics of North (Afinitor®). Available from: America. 2015;27(4):489-96. https://www.medicines.org.uk/emc/product/66 58/smpc Accessed: 3 Feb 2020. 25. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, et al. Diagnosis and 15. Giancola F, Campisi G, Lo Russo L, Muzio LL, Di Management of Osteonecrosis of the Jaw: A Fede O. Osteonecrosis of the Jaw Related to Systematic Review and International Everolimus and Bisphosphonate: A Unique Case Consensus. J Bone Miner Res. 2015;30(1):3-23. Report? Ann Stomatol (Roma). 2013;4(Suppl 2):20-1. 26. Hamadeh IS, Ngwa BA, Gong Y. Drug Induced Osteonecrosis of the Jaw. Cancer Treat Rev. 16. Kim DW, Jung YS, Park HS, Jung HD. 2015;41(5):455-64. Osteonecrosis of the Jaw Related to Everolimus: A Case Report. Br J Oral Maxillofac Surg. 27. Nifosi AF, Zuccarello M, Nifosi L, Hervas Saus V, 2013;51(8):e302-4. Nifosi G. Osteonecrosis of the Jaw in the Era of Targeted Therapy and Immunotherapy in 17. Martini V, Bonacina R, Mariani U. Osteonecrosis Oncology. J Korean Assoc Oral Maxillofac Surg. of the Jaw in a Patient Treated with Zoledronic 2019;45(1):3-8. Acid and Everolimus: A Case Report. Ann

Response from Novartis

1 Introduction Transplant) under brand names Afinitor, Votubia and Certican/Zortress, respectively. On 26 March 2020, Novartis received a request to provide comments on osteonecrosis of the jaw (ONJ) in association with everolimus. Everolimus is 2 Novartis response marketed by Novartis for three broad indications (Oncology, complex (TSC) and 2.1 Everolimus indicated for Oncology and TSC

WHO Pharmaceuticals Newsletter No. 5, 2020 • 15 Signal

Novartis has been monitoring and providing last PSUR. analysis of ONJ as part of periodic safety update 2.1.1.1 Novartis global safety database reports (PSURs) in both TSC (since 2014) and oncology indications (since 2017). The Between 31 Mar 2019 and 31 March 2020, eight Pharmacovigilance Risk Assessment Committee cases were retrieved (seven cases of ONJ and one (PRAC) in its most recent assessment report case of necrosis) using the same MedDRA search (EMEA/H/C/PSUSA/00010268/201703) concurred strategy with PTs Chondronecrosis, Necrosis, with Novartis analysis (cut-off date 31 March 2019) Osteonecrosis and Osteonecrosis of jaw to the that there is no conclusive evidence of causal PSURs. All cases were reported in oncology association between ONJ and everolimus in indications. oncology and TSC settings and concluded that there was no sufficient data to warrant an update of the Noteworthy case definition: Well-documented cases SmPC for ONJ. The PRAC requested Novartis to with a HCP-confirmed diagnosis of ONJ with no continue monitoring ONJ and present updated alternative explanation (concomitant drugs, analysis in the next PSUR. risk/predisposing factors). 2.1.1 Methodology The cases retrieved are presented in Table 2-1 below Novartis is presenting the results of the evaluation of ONJ cases received since the cut-off date of the

Table 2-1 Case reports of ONJ

Case Reporter Age /sex Suspected drugs Dose Action taken PT TTO (days) 1 non-HCP/SR 65/M Everolimus UKN UKN Osteonecrosis of NR Mycophenolate jaw Mofetil, 2 HCP/SR 67/F Afinitor UKN Treatment Osteonecrosis of 44 Discontinued jaw 3 HCP/PMS 35/F Everolimus, UKN Treatment Osteonecrosis of 394 Zoledronic Acid Discontinued jaw 4 HCP/Lit 67/F , 2.5 mg UKN Osteonecrosis of NR , jaw Zoledronic Acid Everolimus 5 HCP/PMS 52/M Everolimus 5 mg NR Necrosis NR Lenvatinib 6 HCP/PMS 64/M Pazopanib 10mg , Treatment Osteonecrosis of 1669 Nivolumab 5 mg Discontinued jaw Lenvatinib Zoledronic Acid Everolimus 7 HCP/Lit 46/F Zoledronic Acid UKN NR Osteonecrosis of 455 Everolimus, jaw Exemestane 8 non-HCP/SR 60/F Everolimus 5mg NR Osteonecrosis of NR Lenvatinib jaw HCP= Health Care Professional; Lit= Literature, SR=Spontaneous Report, PMS= Post marketing surveillance, PT=Preferred Term, NR=Not reported, UNK= unknown; TTO=Time to onset

Of the eight cases, two were non-HCP and one was not be established. The review of the new cases is necrosis of unknown location. Four cases were consistent with the conclusion presented in previous confounded by use of bisphosphonates. Anti- PSURs. Novartis will continue to monitor ONJ cases angiogenic agent lenvatinib was a co-suspected in subsequent PSURs. medication in three cases. Furthermore the cases lacked sufficient information for a meaningful medical assessment. None of the eight cases met 2.1.1.2 Empirica Signal noteworthy criteria and hence a causal role could

WHO Pharmaceuticals Newsletter No. 5, 2020 • 16 Signal

Table 2-2 Measure of disproportionality Drug Event SOC SP+Lit+POP SP+Lit+POP Total N EB05 Afinitor Osteonecrosis of jaw Musculoskeletal and 104 0.617 connective tissue disorders Votubia Osteonecrosis of jaw Musculoskeletal and 2 0.146 connective tissue disorders Afinitor Osteonecrosis Musculoskeletal and 20 0.617 connective tissue disorders Votubia Osteonecrosis Musculoskeletal and 1 0.11 connective tissue disorders *SOC=System Organ Class, SP: Lit: POP=Spontaneous: Literature: Patient Oriented Program, EB05= The EB05 is the lower bound of the 90% confidence interval for the EBGM (Empiric Bayes Geometric Mean)

The EB05 (lower bound of the 90% confidence everolimus, Empirica Signal and Novartis Global interval for the EBGM (Empiric Bayes Geometric Safety Database search for ONJ was performed, Mean) score was less than one. with a cut-off date of 31 Mar 2020, in transplant patients treated with everolimus by using the 2.2 Everolimus indicated for prophylaxis of MedDRA version 22.1 with the PT Osteonecrosis of rejection of transplanted organs jaw. 2.2.1 Methodology 2.2.1.1 Empirica Signal In order to assess the association between ONJ and

Table 2-3 Measure of disproportionality

Drug Event SOC SP+Lit+POP SP+Lit+POP Total N EB05 Certican Osteonecrosis of Musculoskeletal and connective 3 0.06 jaw tissue disorders SOC=System Organ Class, SP=Spontaneous: LT=Literature: POP=Patient Oriented Program, EB05=lower bound of the 90% confidence interval for the EBGM (Empiric Bayes Geometric Mean)

2.2.1.2 Novartis Global Safety Database clinical trial or spontaneous reporting cases were retrieved. The search retrieved three LT cases for ONJ. No

Table 2-4 Case reports of ONJ Case Reporter Age/Sex Suspected drugs Dose Action PT TTO taken 1 HCP 69/M Everolimus NR NA PTLD NR Prednisolone NR Unknown Epstein-Barr virus infection NR Osteonecrosis of jaw 4 month NR Unknown Kidney transplant rejection NR NR NA 2 HCP 65/M Everolimus 10 mg BD TD Osteonecrosis of jaw 18 month Pain in jaw 18 month Prednisolone 10 mg OD Ongoing Exposed bone in jaw 18 month 3 HCP 65/M Everolimus 1mg BD TD Osteonecrosis of jaw NR and 0.75 Pain NR mg BD Hypophagia NR Weight decreased NR Resorption bone increased NR Prednisolone NR Unknown Sinus perforation NR Oroantral fistula NR NR=Not reported, NA=Not applicable, TD=treatment discontinued, PTLD=Post-transplant lymphoproliferative disorders, TTO=Time to onset

WHO Pharmaceuticals Newsletter No. 5, 2020 • 17 Signal

In above indicated cases, there is limited a causal association of everolimus to the event of information regarding TTO, as well as alternative ONJ could not be established. explanations such as concomitant suspected drugs and/or risk factors (prednisolone in all three cases, rituximab in the first case (1), teeth extractions 3 References (available on request) history in the second case (2), and history of teeth extractions and parathyroidectomy in the third case 1. Keribin P. Guerrot D, Jardin F. Osteonecrosis of (3)), therefore, a causal association could not be the Jaw in a Patient Presenting With Post- established. Transplantation Lymphoproliferative Disorder Treated With Rituximab: A Case Report. Up to date, there is no confirmed clinical evidence American Association of Oral and Maxillofacial of an effect of ONJ with everolimus (indicated for Surgeons J Oral Maxillofac Surg -:1-7, 2017 prophylaxis of rejection of transplanted organs) alone. 2. Akkach S, et al. Everolimus-induced osteonecrosis of the jaw in the absence of Discussion and Conclusion bisphosphonates: a case report. Br J Oral Maxillofac Surg. 2019 Everolimus has been marketed for more than 10 years worldwide. The cumulative post-marketing 3. Law M, Walker R, Basu G. Everolimus associated patient exposure in oncology setting is over osteonecrosis of the jaw in kidney transplant 208,393 PTY, in TSC is over 23,522 PTY and in recipient. Kidney International Reports (2019) 4, Transplant setting is over 638,081 PTY. Based on S1-S437 analysis of years of clinical and post-marketing data

Fluorouracil and Bradycardia – national signal from Peru with potential global relevance César Luis Avalos Capristán, Pharmacovigilance and Technovigilance National Center of Peru

1. Abstract the global network for consideration. Fluorouracil is the third most used chemotherapeutic agent in the treatment of solid 2. Introduction malignant tumours worldwide. It has many side effects, including on the cardiovascular system. In a Fluorouracil belongs to a class of drugs called signal detection workshop focussing on Latin . It is administered intravenously American data in VigiBase, the WHO global and acts by reducing or stopping the growth of database of individual case safety reports, a signal cancerous cells in the body. Fluorouracil is generally related to fluorouracil and bradycardia was detected used in combination with other chemotherapeutic from Peruvian data using quantitative signal drugs to treat cancer of the colon or rectum, certain detection methods. Thirteen cases were observed types of breast cancer, pancreatic cancer, and where only 0.3 were statistically expected to be stomach cancer, where the dosing varies between seen. The review found that although bradycardia one and five days, often once monthly.1 has been described as an adverse reaction in literature reports, it is not included in the summary Among listed adverse events associated with the of product characteristics (SmPC) or national fact use of fluorouracil are diarrhoea, hand-foot sheets in Peru, nor in those of regulatory agencies syndrome (a.k.a. palmar-plantar in the USA, Spain, or Canada. The more general erythrodysesthesia), myelosuppression, mucositis, 2 term of arrythmia is mentioned in some SmPCs, and cardiotoxicities. Among listed cardiac side and sometimes appear. The literature, effects are chest pain, myocardial infarction, sudden including an observational study and a case series, cardiac death, pericarditis, and changes in the ECG, supports the finding of bradycardia in patients e.g. ST-T changes and arrhythmia, sometimes 3 undergoing . To summarise, in Peru specified as atrial fibrillation or tachycardia. The we have suggested including bradycardia in the appearance of the specific term bradycardia is not sections on adverse reactions, warnings and listed among the adverse effects associated with precautions in our national drug fact sheet for the fluorouracil in the summary of product product, and here we share this information with characteristics of fluorouracil in the USA or the UK. Bradycardia means a slow heart rhythm, often WHO Pharmaceuticals Newsletter No. 5, 2020 • 18 Signal defined as a frequency of less than 60 beats per identified in a signal detection workshop focussing minute.4 on Latin American data in VigiBase, carried out in

May 2019. It was detected using disproportionality analysis where the expected number of cases in Peru was calculated to be 0.3 while the number observed was 13 (IC025: 3.2). The data referred to 3. VigiBase reports in Table 1 includes the characteristics of all the 13 The combination of bradycardia and fluorouracil was Peruvian reports which formed the basis of the signal analysis.

N° Age Sex Indication Drugs Doses ADRs Time to Positive Positive (years) mg reported onset (days) dechallenge Rechallenge 1 66 F Colon Fluorouracil (S) 960mg Bradycardia 0 Yes Yes adenocarcinoma 2 76 M Colon cancer Fluorouracil (S) - Bradycardia 1 No - 3 56 M Gastric cancer Fluorouracil (S) - Bradycardia 1 Yes - 4 56 F Gastric cancer Fluorouracil (S)) - Bradycardia 1 Yes Yes

5 30 F Rectal cancer Fluorouracil (S) 500 mg Bradycardia 2 Yes - (C) 130 mg Calcium folinate (C) 250 mg 6 55 M Gastric malignant Fluorouracil (S) 1650 mg Bradycardia 0 Yes - neoplasm Oxaliplatin (C) 114 mg 7 69 M Malignant Fluorouracil (S) 3440 mg Bradycardia 1 - - neoplasm of the Oxaliplatin (C) 280 mg Peripheral colon neuropathy 8 89 M Malignant Fluorouracil (S) 1000 mg Bradycardia 1 - - neoplasm of the Oxaliplatin (C) 85 mg Hypertension colon Ondansetron (C) 24 mg 9 63 F Malignant Fluorouracil (S) 1000 mg Bradycardia 3 Yes - neoplasm of the (C) 100 mg vagina 10 68 M Gastric malignant Fluorouracil (S) 900 mg Bradycardia 0 - - neoplasm Cisplatin (C) - 11 42 F Gastric cancer Fluorouracil (S) 1580 mg Bradycardia 0 Yes Yes Cisplatin (C) 58 mg Headache (C) 75 mg 12 53 F Gastric malignant Fluorouracil (S) 3920 mg Bradycardia 3 Yes - neoplasm Cisplatin (C) 98 mg Docetaxel (C) 98 mg 13 58 M Malignant Fluorouracil (S) 3060 mg Bradycardia 1 Yes - neoplasm of the (C) 220 mg cecum

Table 1 includes four reports (1, 2, 3 and 4) that docetaxel, neither of which give bradycardia as an give fluorouracil as the only administered drug; the acknowledged adverse drug reaction.10,11,12,13,14,15 diagnoses for which fluorouracil was administered One of the four reports described the concomitant were in these cases colon adenocarcinoma, colon administration of ondansetron, and development of cancer and gastric cancer. bradycardia as an infrequent adverse reaction.16,17 The information shown in the reports indicates that Some of the other cases mention concomitantly administration of fluorouracil and its concomitants used drugs which potentially could have caused or (oxaliplatin, ondansetron) was on the same day, contributed to the event: Four other reports but not specifying a more detailed time for each one describe the concomitant administration of in relation to the event. oxaliplatin, a drug with the capacity to cause adverse cardiac effects.5,6,7,8,9 In the case of Four reports included the administration of cisplatin, oxaliplatin the development of bradycardia which in its labelling has bradycardia as an adverse associated with overdose is noted in the prescribing reaction,18 and in two of these, docetaxel was also information.8,9 One of the four reports (Case 5) administered. In three of the four reports described concomitant administration of calcium fluorouracil and the concomitant drugs were folinate, and two other (11 and 12) included administered on the same day, but the exact hour WHO Pharmaceuticals Newsletter No. 5, 2020 • 19 Signal of administration of each drug is not specified. In findings. In three cases (1, 3 and 11) the level of two of the four reports the bradycardia occurred on bradycardia ranged between 40 and 54 beats per the same day that administration of fluorouracil and minute. No cases reported additional symptoms of the concomitant drugs was started; equally, in the the bradycardia and only three cases (7, 8 and 11) other two reports the bradycardia started three gave any additional adverse drug reaction: days after administration of fluorouracil began. In headache, hypertension and peripheral neuropathy. addition, in these four cases fluorouracil was the Five of the Peruvian reports (Cases 6, 7, 8, 12 and only drug reported as suspected. 13) came from the same doctor while each of the Case 13 in Table 1 had concomitant administration others came from a different reporter. of irinotecan and fluorouracil. The information in the In VigiLyze, the combination bradycardia- fact sheet for irinotecan describes the appearance fluorouracil results in 139 reports from 23 countries of bradycardia in the section on adverse reactions.19 worldwide, with Peru third after the USA (34 The report only states that the administration of reports) and India (18 reports). Table 2 shows the both drugs was carried out on the same day but main characteristics of these cases (including the does not specify the exact time of administration. ones from Peru). Onset of bradycardia was on day 1-3 in all the Peruvian cases. None of the cases give any ECG

Table 2. Case series characteristics of 139 global reports on bradycardia with fluorouracil in VigiBase Feature N° of reports (%) Male / Female/ Information missing 80 (58) / 52 (37) / 7 (5) 0-17y /18-44y / 45-64y /65-74 y / 75+y/ information missing 1 (1) / 26 (19) / 50 (36) / 40 (29) / 9 (6) / 13 (9) Serious case* 71 (51) Fatal outcome 6 (4) Sole reported drug 31 (22) Time to onset 0-7 days / > 7 days/ information missing 77 (55) / 26 (19) / 36 (26) Positive dechallenge / Positive rechallenge 41 (29) / 4 (3) *Some countries cannot report seriousness to VigiBase due to limitations in their reporting format, so the true proportion of serious cases may be higher.

There were 13 global reports with a VigiBase fluorouracil intravenously for a diagnosis of an completeness score of 1.00; here we illustrate four unknown neoplasm. The patient presented with of these cases: bradycardia on the third day of administration, so the treatment was discontinued, with the 1. France: a male patient aged 53 was patient's recovery being observed. The report administered fluorouracil intravenous 6300 only indicates the administration of fluorouracil. mg/cycle to treat oropharyngeal cancer. On the third day of treatment the patient presented An expanded search was performed in VigiBase to with bradycardia, hypotension, bradypnea and retrieve additional cases of bradycardia but coded allergic shock. The report indicates that the otherwise. Among the terms considered were patient recovered after the suspension of the atrioventricular block (complete, first degree and treatment. second degree), cardiac arrest, abnormal electrocardiogram, sudden death. The few 2. India: a 20-year-old, 52 kg male patient was additional cases retrieved were, after assessment, given 900 mg/24 hr intravenously for a not considered relevant for the signal. diagnosis of nasopharynx malignancy; with only fluorouracil administration reported. On the second day of treatment the patient presented 4. Literature and labelling with bradycardia, observing recovery two days later, without having reported any suspension The information sheets/labelling of some of treatment. international regulatory agencies set out information on heart disorders or events associated 3. India: a 36-year-old male patient, 54 kg, who with the use of fluorouracil. However, bradycardia is was given intravenous fluorouracil 1000 mg/24 not listed in the section of adverse drug reactions, hr for nasal cavity neoplasia. The patient nor warnings and precautions in the country presented with bradycardia on the fifth day sources that were checked, such as the USA (Food after administration, with recovery being and Drug Administration - FDA), Spain (Agencia observed the same day. The report only Española de Medicamentos y Productos Sanitarios - indicates the administration of fluorouracil. AEMPS) and Canada (Health Canada). 4. India: a 41-year-old male patient, 68 kg and Three peer-reviewed publications describing cases 168 cm, who was given 750 mg/24 hr WHO Pharmaceuticals Newsletter No. 5, 2020 • 20 Signal or case series of bradycardia in relation to cardiotoxicity was not significantly different fluorouracil use were found: between patients with or without pre-existing cardiovascular disease (p = 0.095). Cardiotoxicities Talapatra K et al20 discussed a series of cases of six were more common with continuous infusion of patients (aged 38-59 years) who developed fluorouracil, when radiotherapy was given transient asymptomatic bradycardia (heart rate concurrently with fluorouracil, and when fluorouracil ≤50/minute) in a group of 207 patients who was used in combination with cisplatin. received chemotherapy with injectable fluorouracil and cisplatin (dose: cisplatin 75-100 mg/m2 and injectable 5-fluorouracil 750-1000 mg / m2 day one 5. Discussion and conclusion and with continued 5-fluorouracil infusion during day 2-5 of the treatment). None of the six patients There is a variety of probable causes for the had any comorbidities, except one with appearance of cardiotoxicity in general associated hypertension. The assessment of the six patients with the use of fluorouracil, among which are the indicated that there were no associated symptoms, dose and method of administration, use of such as chest pain, giddiness or sweating at the concomitant chemotherapeutic agents with time of the bradycardia. The serum electrolytes cardiotoxic potential, and concurrent radiotherapy. were checked in the patients during the episodes of Moreover, the clinical characteristics of the patients bradycardia, observing normal results. The authors (presence of pre-existing coronary lesions, arterial concluded that the case series shows a tendency for disease, or traditional cardiovascular risk factors) the development of asymptomatic bradycardia in and variability in the definitions of cardiotoxicity patients undergoing treatment with infusion of should be considered. Cardiotoxicity with fluorouracil. It may be argued that cisplatin and fluoropyrimidines tends to occur in association with hydration of the patient had a part to play in the the first cycle of administration. An average time of development of bradycardia but since the onset of symptoms is observed up to 12 hours after development of bradycardia appeared after the the start of the infusion, although heart conditions third day in all the patients, the authors consider may occur at any time during the infusion or even that this makes it likely that fluorouracil was a more up to 1-2 days after the infusion, as observed in the plausible cause. cases reported for bradycardia in Peru (84.6%) and globally (39.5%).23 Nakajima T et al21 described a male patient of Japanese origin, aged 78 years with a medical The cardiotoxicity associated with the use of history that included hypertension, and diagnosed fluorouracil is well known and has been reported: with stage III oesophageal cancer, who received a atrial fibrillation, ST-T changes and chest pain being combination of cisplatin and fluorouracil. The the most frequently observed symptoms. patient experienced episodes of bradycardia on the Cardiotoxicity in relation to the use of fluorouracil first day after cisplatin administration, and due to it requires close clinical supervision and, if it occurs, being asymptomatic it was decided to continue the treatment may require suspension of the drug. The planned 2-5 days of continuous infusion of effect of fluorouracil withdrawal (positive fluorouracil. On treatment day 4 his heart rate fell dechallenge) is evidenced in the cases of to 22 beats/min without other objective findings or bradycardia reported in Peru (62%), as well as subjective symptoms. With atropine treatment the worldwide (29%).24 rate temporarily improved. The treatment was interrupted, and a gradual improvement of the Khan et al. concluded that bradycardia events were patient’s heart rate ensued. Within two days of more common with a continuous infusion of stopping the treatment the rate had returned to fluorouracil, radiotherapy concurrent with normal. The authors discuss the fluorouracil, and when fluorouracil was used in 22 of the two drugs and speculate that the second combination with cisplatin. phase of a biphasic elimination curve of the cisplatin While information on adverse cardiac reactions is with a half-life of >100 hours could have acted found in the fact sheets of countries such as the synergistically with fluorouracil to adversely affect USA (Food and Drug Administration - FDA), Spain cardiomyocytes and the cardiac conduction system (Agencia Española de Medicamentos y Productos resulting in the bradycardia observed during its Sanitarios - AEMPS) and Canada (Health infusion. They conclude that while the combination Canada)5,6,7 including in some cases information on chemotherapy is a useful treatment for this type of increased heart rate, tachycardia; they do not cancer it may induce severe bradycardia and point describe bradycardia in the sections on adverse out the need for carefully monitoring patients. reactions, warnings and precautions. Khan MA et al22 carried out research on Cisplatin, ondansetron, oxaliplatin and irinotecan, cardiotoxicities, especially bradycardia, in cancer which were observed as concomitant drugs in some patients treated with chemotherapy regimens based of the Peruvian cases, include information about the on fluorouracil in the Pakistani population. development of bradycardia, notably for oxaliplatin Symptomatic cardiotoxicity was noted in 60 and irinotecan, only in association with overdose (19.9%) out of 301 patients. Bradycardia was the cases8,9 or as part of the appearance of cholinergic most common cardiotoxicity and was observed in diarrhoea or reaction.19 36 (12.0%) of the patients. The incidence of

WHO Pharmaceuticals Newsletter No. 5, 2020 • 21 Signal

The administration of fluorouracil and the perfusión EFG. [updated February 2019]. concomitant drugs is performed cyclically in Available at: different doses and ways.25 However, in the https://cima.aemps.es/cima/dochtml/ft/71868/ Peruvian cases, the information regarding the exact FT_71868.html moment of administration of each drug in relation 6. Health Canada [Internet]. Product monograph: to the event is not clear, making it difficult to fully Fluorouracil Injection USP 50 mg/mL (5 g/100 assess the causal relationship of each individual mL). [updated 17 April 2018]. Available at: drug to the adverse reaction. https://pdf.hres.ca/dpd_pm/00044861.PDF Capecitabine, another anticancer agent, is a 7. Dailymed [Internet]. LABEL: FLUOROURACIL- to fluorouracil which is metabolised to fluorouracil injection, solution. [updated 23 fluorouracil in the body.26 International regulatory February 2017]. Available at: agencies (eg. FDA, AEMPS and EMA) include https://dailymed.nlm.nih.gov/dailymed/drugInf information referring to the development of o.cfm?setid=66d451fe-2436-494c-80c5- bradycardia with the administration of 4528c8e34369 capecitabine.27,28,29 Taking this into account, it is relevant to consider including bradycardia as an 8. Health Canada [internet]. Product monograph: adverse reaction associated with the use of PrOXALIPLATIN Oxaliplatin Injection, fluorouracil in relevant drug information documents. Standard 5 mg/mL oxaliplatin. [updated 19 November 2018]. Available at: Peru has 10 registered pharmaceutical products https://pdf.hres.ca/dpd_pm/00048594.PDF that contain fluorouracil, none of which include bradycardia as an adverse reaction or a warning. It 9. Food and Drug Administration – FDA [Internet]. is therefore suggested to include in Peru ELOXATIN (oxaliplatin) injection for intravenous bradycardia in the sections on adverse reactions, use. [updated September 2018]. Available at: warnings and precautions in the national drug fact https://www.accessdata.fda.gov/drugsatfda_do sheet, and we would like to inform the global cs/label/2015/021759s019lbledt.pdf network for consideration at national level. 10. Agencia Española de Medicamentos y Productos The analysis and writing of the signal were Sanitarios-AEMPS [Internet]. FOLINATO performed with kind peer review by colleagues from CÁLCICO NORMON 50 mg Polvo y disolvente the Uppsala Monitoring Centre who participated in para solución inyectable EFG / FOLINATO the workshop mentioned in the text; Birgitta CÁLCICO NORMON 350 mg Polvo para solución Grundmark, Lovisa Sandberg, and Elki Sollenbring. inyectable EFG. Available at: https://cima.aemps.es/cima/dochtml/ft/70340/

FT_70340.html References: 11. Food and Drug Adminsitration-FDA [internet]. 1. MedlinePlus [Internet]. U.S. National Library of LevoLeucovorin injection. [updated November Medicine. [updated 30 December 2019]. 2013]. Available at: Fluorouracil Injection. Available at: https://www.accessdata.fda.gov/drugsatfda_do https://medlineplus.gov/druginfo/meds/a68270 cs/label/2015/203563Orig1s000lbl.pdf 8.html 12. Health Canada [Internet]. Product monograph: 2. Dailymed [Internet]. U.S. National Library of PRODUCT MONOGRAPH LEUCOVORIN CALCIUM Medicine. [updated 23 February 2017]. Label: INJECTION 10 mg/mL USP. [updated August Fluorouracil injection, solution. Available at: 2018]. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInf https://pdf.hres.ca/dpd_pm/00046849.PDF o.cfm?setid=66d451fe-2436-494c-80c5- 13. Agencia Española de Medicamentos y Productos 4528c8e34369#L8a71c005-1a49-46d2-a01a- Sanitarios-AEMPS [Internet]. Docetaxel Hospira 0786b921dc76 10 mg/ml concentrado para solución para 3. Medicines & Healthcare products Regulatory perfusión. [updated September 2018]. Agency – MHRA [Internet]. SUMMARY OF Disponible en: PRODUCT CHARACTERISTICS- Fluorouracil 25 https://cima.aemps.es/cima/dochtml/ft/71799/ mg/ml Injection. [updated 12 April 2019]. FT_71799.html Available at: 14. Food and Drug Administration – FDA [Internet]. http://www.mhra.gov.uk/home/groups/spcpil/d DOCETAXEL INJECTION, for intravenous use. ocuments/spcpil/con1555647114072.pdf [updated September 2018]. Available at: 4. UpToDate [Internet]. Sinus bradycardia. [23 https://www.accessdata.fda.gov/drugsatfda_do January 2019]. Available at: cs/label/2018/022234s011,202356s003lbl.pdf https://www.uptodate.com/contents/sinus- 15. Health Canada [Internet]. Product monograph: bradycardia PrDOCETAXEL INJECTION USP 10 mg/mL 5. Agencia Española de Medicamentos y Productos Sterile Solution. [updated June 2019]. Available Sanitarios-AEMPS [Internet]. Fluorouracilo at: https://pdf.hres.ca/dpd_pm/00045702.PDF Accord 50 mg/ml solución inyectable o para 16. Health Canada [Internet]. Product monograph: WHO Pharmaceuticals Newsletter No. 5, 2020 • 22 Signal

PrJAMP-ONDANSETRON ONDANSETRON Sakti Chakrabarti , Joerg Herrmann , Amir INJECTION, USP 2 mg/mL ondansetron (as Lerman y Axel Grothey. 5-fluorouracil and ondansetron hydrochloride dihydrate). [updated cardiotoxicity: a review. Ther Adv Med Oncol. 17 March 2015]. Available at: 2018 June, Vol 10: 1 - 18. https://pdf.hres.ca/dpd_pm/00029958.PDF 24. Eskilsson J1, Albertsson M, Mercke C. Adverse 17. Agencia Española de Medicamentos y Productos cardiac effects during induction chemotherapy Sanitarios-AEMPS [Internet]. Ondansetrón treatment with cis-platin and 5-fluorouracil. Accord 2 mg/ml solución inyectable EFG. Radiother Oncol. 1988 Sep;13(1):41-6. [updated February 2018]. Available at: 25. Instituto Nacional de Enfermedades Neoplásicas https://cima.aemps.es/cima/dochtml/ft/72117/ – INEN. Guía de Práctica Clínica de Cáncer de FT_72117.html Colon. Lima – Perú 2013. Available at: 18. Food and Drug Adminsitration – FDA [Internet]. http://www.inen.sld.pe/portal/documentos/pdf/ CISPLATIN for injection, for intravenous use. normas_tecnicas/2013/08072014_GU%C3%8D [updated February 2019. Available at: AS_DE_PR%C3%81CTICA_CL%C3%8DNICA_D https://www.accessdata.fda.gov/drugsatfda_do E_C%C3%81NCER_DE_COLON.pdf cs/label/2019/018057s089lbl.pdf 26. Dailymed [Internet]. LABEL: CAPECITABINE 19. Health Canada [Internet]. Product monograph: 150MG- capecitabine tablet, film coated. PrIRINOTECAN irinotecan hydrochloride [updated 22 February 2019]. Available at: trihydrate for injection 20 mg/mL. [updated 06 https://dailymed.nlm.nih.gov/dailymed/drugInf March 2019]. Available at: o.cfm?setid=7f555b6b-60db-45e2-a61e- https://pdf.hres.ca/dpd_pm/00049996.PDF 537e57f43fdc 20. Talapatra K, Rajesh I, Rajesh B, Selvamani B, 27. Food and Drug Administration – FDA [Internet]. Subhashini J. Transient asymptomatic Highlights of prescribing information XELODA bradycardia in patients on infusional 5- (capecitabine) tablets, for oral use. [updated fluorouracil. J Can Res Ther 2007; 3:169-71 February 2019]. Available at: https://www.accessdata.fda.gov/drugsatfda_do 21. Nakajima T, Kawamori H, Ohno M, Kusunoki N, cs/label/2019/020896s042lbl.pdf Yamazaki Y, Takase S. A Case of Severe Bradycardia Induced by Combination 28. Agencia Española de Medicamentos y Productos Chemotherapy with Cisplatin and 5-Fluorouracil Sanitarios – AEMPS [Internet]. Anexo I: Ficha [Abstract]. Gan To Kagaku Ryoho. 2015 técnica o resumen de las características del Nov;42(11):1415-8. producto. Capecitabina Accord. [updated 09 January 2017]. Available at: 22. Khan MA, Masood N, Husain N, Ahmad B, Aziz https://cima.aemps.es/cima/pdfs/ft/112762023 T, Naeem A. A retrospective study of /FT_112762023.pdf cardiotoxicities induced by 5-fluorouracil (5-FU) and 5-FU based chemotherapy regimens in 29. European Medicines Agency – EMA. EPAR Pakistani adult cancer patients at Shaukat summary for the public – Xeloda Khanum Memorial Cancer Hospital & Research (Capecitabina). [updated April 2019]. Available Center. 2012 May, Volume 62, Issue 5: 430-4. at: https://www.ema.europa.eu/en/documents/ove 23. Jaskanwal D. Sara, Jasvinder Kaur , Ryan rview/xeloda-epar-summary-public_es.pdf Khodadadi , Muneeb Rehman , Ronstan Lobo ,

WHO Pharmaceuticals Newsletter No. 5, 2020 • 23 Signal

CAVEAT DOCUMENT

Statement of reservations, limitations and conditions relating to data released from VigiBase, the WHO global database of individual case safety reports (ICSRs). Understanding and accepting the content of this document are formal conditions for the use of VigiBase data.

Uppsala Monitoring Centre (UMC) in its role as the World For these reasons, interpretations of adverse effect Health Organization (WHO) Collaborating Centre for data, and particularly those based on comparisons International Drug Monitoring receives reports of between medicinal products, may be misleading. suspected adverse reactions to medicinal products from The data comes from a variety of sources and the National Centres in countries participating in the WHO likelihood of a causal relationship varies across Programme for International Drug Monitoring. The reports. Any use of VigiBase data must take these information is stored in VigiBase, the WHO global significant variables into account. database of individual case safety reports (ICSRs). It is Prohibited use of VigiBase Data includes, but is not important to understand the limitations and qualifications limited to: that apply to this information and its use. • patient identification or patient targeting Tentative and variable nature of the data • identification, profiling or targeting of general Uncertainty: The reports submitted to UMC generally practitioners or practice describe no more than suspicions which have arisen from observation of an unexpected or unwanted event. In most Any publication, in whole or in part, of information instances it cannot be proven that a specific medicinal obtained from VigiBase must include a statement: product is the cause of an event, rather than, for example, (i) recording ‘VigiBase, the WHO global database of underlying illness or other concomitant medication. individual case safety reports (ICSRs)’ as the source Variability of source: Reports submitted to national of the information centres come from both regulated and voluntary sources. (ii) explaining that the information comes from a variety Practice varies: some national centres accept reports only of sources, and the probability that the suspected from medical practitioners; others from a broader range of adverse effect is drug-related is not the same in all reporters, including patients, some include reports from cases pharmaceutical companies. (iii) affirming that the information does not represent the Contingent influences: The volume of reports for a opinion of the UMC or the World Health Organization. particular medicinal product may be influenced by the extent of use of the product, publicity, the nature of the Omission of this statement may exclude the adverse effects and other factors. responsible person or organization from receiving further information from VigiBase. No prevalence data: No information is provided on the UMC may, in its sole discretion, provide further number of patients exposed to the product, and only a instructions to the user, responsible person and/or small part of the reactions occurring are reported. organization in addition to those specified in this Time to VigiBase: Some national centres make an statement and the user, responsible person and/or assessment of the likelihood that a medicinal product organization undertakes to comply with all such caused the suspected reaction, while others do not. Time instructions. from receipt of an ICSR by a national centre until submission to UMC varies from country to country. Uppsala Monitoring Centre (UMC) Information obtained from UMC may therefore differ from Box 1051, SE-751 40 Uppsala, Sweden that obtained directly from national centres. Tel: +46-18-65 60 60, E-mail: [email protected] www.who-umc.org

WHO Pharmaceuticals Newsletter No. 5, 2020 • 24