2020 WHO Pharmaceuticals

No.2 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.

This edition of the Newsletter also includes the The aim of the Newsletter is nd to disseminate regulatory recommendations from the 42 Annual Meeting of information on the safety of Representatives of National Pharmacovigilance pharmaceutical products, Centres participating in the WHO Programme for based on communications received from our network of International Drug Monitoring. Given the current national pharmacovigilance centres interest over the use of chloroquine and

and other sources such as hydroxychloroquine in COVID-19, we have also specialized bulletins and journals, as well as partners in WHO. included a summary of case safety reports in Vigibase for these products.

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

Feature

ISBN 978-92-4-000568-6 (electronic version) ISBN 978-92-4-000569-3 (print version)

© World Health Organization 2020

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Table of Contents

Regulatory Matters Acitretin ...... 5 Alemtuzumab ...... 5 Allopurinol ...... 5 Aminolevulinic acid ...... 5 Arsenic trioxide ...... 6 Cyproterone ...... 6 Direct-acting antivirals (DAAs)...... 6 Fluoroquinolone ...... 7 Fluorouracil, capecitabine, tegafur...... 7 Fosravuconazole ...... 7 Ingenol mebutate (gel) ...... 7 Lorcaserin ...... 8 Montelukast ...... 8 Rotigotine ...... 8 Ulipristal acetate ...... 9

Safety of medicines Clozapine ...... 10 Ferric carboxymaltose ...... 10 Ifosfamide (solution) ...... 10 Mecasermin ...... 10 Nitrofurantoin ...... 11 Ondansetron ...... 11

Information Note Chloroquine and hydroxychloroquine in COVID-19 ...... 12

Signal Agomelatine and Increased Blood Pressure ...... 14 Midostaurin – photosensitivity reaction ...... 19 Tramadol and hyperacusis ...... 24

Feature Recommendations from the 42nd Annual Meeting of Representatives of the

WHO Pharmaceuticals Newsletter No. 2, 2020 • 3 Table of Contents

National Pharmacovigilance Centres Participating in the WHO Programme for International Drug Monitoring ...... 32

WHO Pharmaceuticals Newsletter No. 2, 2020 • 4 Regulatory Matters

Acitretin The review concluded that hypertension accompanied by serious cardiovascular hyperuricemia. reactions can rarely occur Changes to pregnancy Although no cases involving within one to three days of prevention requirements aseptic meningitis have been treatment. However reported in patients taking unpredictable and potentially New Zealand. Acitretin is allopurinol in Japan during the fatal immune-mediated used to treat several skin previous three years, reactions can occur within conditions including psoriasis. considering that cases were months and up to at least four Acitretin is teratogenic and is reported overseas the MHLW years post-treatment. This contraindicated in women of and PMDA have determined included Epstein-Barr virus childbearing potential unless all that the revision was reactivation. of the conditions of the necessary. Pregnancy Prevention Alemtuzumab should only be Reference: Programme are met. used as a single disease- Revision of Precautions, modifying therapy in adults Medsafe has announced that MHLW/PMDA, 25 February with specific conditions. the period during which 2020 (www.pmda.go.jp/english/) effective contraception must be Alemtuzumab is used has increased from two to contraindicated in patients with severe active infection until three years after the end of treatment with acitretin complete resolution, those with (Novatretin®). a history of stroke and a history of angina. Aminolevulinic acid The change was due to the discovery of the formation of Patients should only be Risk of hypotension etretinate in the presence of administered alemtuzumab in a Japan. The MHLW and the alcohol, the half-life of which is hospital with ready access to PMDA have announced that the 120 days. The package label intensive care facilities and package insert for and foils have been updated to should be monitored closely for aminolevulinic acid (Alaglio reflect the increased post- cardiovascular reactions and Divided Granules® and Alabel treatment contraception non-immune Oral®) should be revised to requirement from 24 to 36 thrombocytopenia. include hypotension as an months. Reference: adverse drug reaction. Reference: Drug Safety Update, MHRA, Aminolevulinic acid is indicated Prescriber Update, Medsafe, 12 February 2020 for visualization of non-muscle March 2020 (www.gov.uk/mhra) invasive bladder cancer during (www.medsafe.govt.nz/) (See WHO Pharmaceuticals Newsletter transurethral resection of the No.6, 2019: Risk of cardiovascular disorders

and immune-related disorders in EU; No.4, bladder tumour and that of 2019: Risk of serious cardiovascular and malignant tissue during immune-mediated adverse reactions in UK; malignant glioma resection. Alemtuzumab No.3, 2019: Cardiovascular and immune- mediated adverse effects in EU) A total of 26 cases of corresponding adverse events Updated restrictions and were reported in patients strengthened monitoring taking aminolevulinic acid in

Japan during the previous United Kingdom. The Allopurinol three years. For 15 of these 26 Medicines and Healthcare cases a causal relationship Products Regulatory Agency Risk of aseptic meningitis between aminolevulinic acid (MHRA) has announced that an and the adverse events could EU review recommended a Japan. The Ministry of Health, not be ruled out. revised indication, additional Labour and Welfare (MHLW) contraindications and MHLW/PMDA have concluded and the Pharmaceuticals and strengthened monitoring for that revision of the package Medical Devices Agency alemtuzumab (Lemtrada®) insert is necessary. (PMDA) have announced that due to the risk of the package insert for Reference: cardiovascular events, allopurinol (Zyloric®) should Revision of Precautions, thrombocytopenia and be revised to include septic MHLW/PMDA, 25 February immune-mediated reactions. meningitis as an adverse drug 2020 (www.pmda.go.jp/english/) Alemtuzumab is a monoclonal reaction. antibody and is indicated for Allopurinol is indicated for the treatment of adults with management of hyperuricemia relapsing-remitting multiple in patients with gout or sclerosis.

WHO Pharmaceuticals Newsletter No. 2, 2020 • 5 Regulatory Matters

Arsenic trioxide Cyproterone is an antiandrogen (dysglycemia) with the use of medicine acting in the same DAAs, including both high Risk of Wernicke’s way as progesterone. It is blood sugar levels encephalopathy indicated to treat various (hyperglycemia) and low blood androgen-dependent conditions sugar levels (hypoglycemia). such as hirsutism, alopecia, Japan. The MHLW and the Health Canada reviewed 26 acne, prostate cancer and PMDA have announced that the Canadian cases and 10 reduction of sex drive in sexual package insert for arsenic international cases. It found deviations in men. trioxide (Trisenox®) should be 735 cases in VigiBase® related revised to include Wernicke’s Overall, the risk of meningioma to dysglycemia with DAAs, but encephalopathy as an adverse risk is rare. Although there is the data could not be used to drug reaction. no evidence of a risk for low- confirm or exclude a link Arsenic trioxide is indicated for dose cyproterone in between the use of DAAs and recurrent or refractory acute combination with the event. Also, Health Canada promyelocytic leukemia. ethinylestradiol or estradiol, as reviewed 26 published studies a precaution, these medicines in the scientific literature, and Although no cases involving should not be used in people identified biological Wernicke’s encephalopathy who have or have had a mechanisms to explain how have been reported so far in meningioma. DAAs could lead to patients taking arsenic trioxide hypoglycaemia in diabetic Health-care professionals in Japan, the revision was patients. based on cases overseas. It should monitor patients for was determined appropriate as clinical signs and symptoms of Health Canada’s review has currently there is no evidence meningioma. Symptoms concluded that there is a link on ethnic differences in the include changes in vision, between the use of DAAs and safety profile of the drug hearing loss, loss of smell, the risk of dysglycemia. headaches, memory loss, between patients in Japanese Reference: seizures or weakness in and those overseas. Summary Safety Review, extremities. Reference: Health Canada, 17 February Revision of Precautions, Reference: 2020 (www.hc-sc.gc.ca) EMA, 14 February 2020 MHLW/PMDA, 25 February (See WHO Pharmaceuticals Newsletter (www.ema.europa.eu) 2020 (www.pmda.go.jp/english/) No.2, 2018: Possible effects on blood glucose control when used in patients with (See WHO Pharmaceuticals Newsletter No.4, 2019; Risk of meningioma in EU) type 2 diabetes in New Zealand; No.2, 2017: Possible effects on blood glucose control when used in patients with type 2 diabetes: Cyproterone added to the medicine monitoring scheme in New Zealand) Risk of meningioma Direct-acting antivirals (DAAs) Europe. The European 2. Dose adjustment of Medicines Agency (EMA) concomitant drugs required announced that the 1. Risk of abnormal blood Pharmacovigilance Risk sugar levels (dysglycemia) Japan. The MHLW and the Assessment Committee (PRAC) PMDA have announced that the Canada. Health Canada has has recommended that package inserts for several announced that it is working medicines with daily doses of DAAs, including Asunaprevir with the manufacturers to 10 mg or more of cyproterone (Sunvepra®), Daclatasvir update product safety should only be used for (Daklinza®) and Sofosbuvir information of direct-acting androgen-dependent conditions (Sovaldi®), should be revised antivirals (DAAs) to include the such as hirsutism, alopecia, to include the important risk of dysglycemia among acne and seborrhoea once precautions that dose diabetic patients. other treatment options have adjustment for concomitant failed, due to the risk of DAAs are indicated for the drugs may be required. meningioma. treatment of chronic hepatitis C Several studies have reported virus (HCV) infection. DAAs The medicines should only be that dose adjustment may be available in Canada include used for reduction of sex drive required for co-administered daclatasvir (Daklinza®), in sexual deviations in men drugs such as warfarin, sofosbuvir (Sovaldi®) and the when other treatment options tacrolimus and insulin following combination of sofosbuvir and are not suitable. There is no initiation of DAAs for chronic ledipasvir (Harvoni®). change in the use of the hepatitis C. medicines in men for prostate Health Canada reviewed the In September 2016, the PRAC cancer. potential risk of abnormal of EMA recommended that a blood sugar levels WHO Pharmaceuticals Newsletter No. 2, 2020 • 6 Regulatory Matters precaution be added to dissection associated with adverse drug reactions such as package inserts of DAAs fluoroquinolones. neutropenia, neurotoxicity, regarding the effects of severe diarrhoea and The precaution advises that hepatitis C drugs on the blood stomatitis. fluoroquinolones should only be coagulability in patients treated used after careful benefit-risk Patients with a known complete with vitamin K antagonists. assessment and after DPD deficiency must not be A study was conducted in consideration of other given fluorouracil, capecitabine Japan with MID-NET® with therapeutic options. or tegafur. For patients with a data from 2010 to 2017. partial DPD deficiency, a During the TGA’s investigation, Although the small sample size reduced starting dose of these it was also identified that the limits the interpretation of the medicines should be product information for results, a tendency was considered. fluoroquinolones should be observed that was not updated to include the Reference: inconsistent with the preceding potential adverse events of EMA, 13 March 2020 studies. Additionally, based on dysglycemia and psychiatric (www.ema.europa.eu) laboratory test results, a adverse reactions, including possible link between the toxic psychosis, psychotic changes in the patients’ liver reactions progressing to function and the changes in suicidal ideations, warfarin dose-response could hallucinations or paranoia, as Fosravuconazole not be ruled out. precautions. MHLW/PMDA have concluded Risk of erythema Reference: that the revision of the multiforme Medicines Safety Update, TGA, package insert is necessary. 27 February 2020 Japan. The MHLW and the Reference: (www.tga.gov.au/) PMDA have announced that the Revision of Precautions, (See WHO Pharmaceuticals Newsletter package insert for MHLW/PMDA, 25 February No.6, 2019: Risk of tendon disorders, fosravuconazole (Nailin®) 2020 (www.pmda.go.jp/english/) peripheral neuropathy and psychiatric should be revised to include symptoms in Japan; No.3, 2019: Risk of (See WHO Pharmaceuticals Newsletter erythema multiforme as an musculoskeletal and nervous systems No.5, 2017: Interaction with warfarin in adverse drug reaction. damage in UK; No.1, 2019) New Zealand; No.6, 2016: Interaction Fosravuconazole is indicated potential with warfarin and other vitamin K antagonists: changes to INR in Ireland) for dermatophyte and nail tinea.

Fluorouracil, A total of eight cases have been reported in patients capecitabine, tegafur taking fosravuconazole in Fluoroquinolone Japan during the previous Pre-treatment testing three years. For five of the Risk of aortic aneurysm and recommended for cancer eight cases, a causal dissection relationship between Europe. The EMA’s PRAC has fosravuconazole and the events Australia. The Therapeutic recommended that patients could not be ruled out. No Goods Administration (TGA) should be tested for the lack of patient mortalities have been has announced that the dihydropyrimidine reported to date. product information for dehydrogenase (DPD), an fluoroquinolone antibiotics has enzyme needed to break down MHLW/PMDA have concluded been updated to include the fluorouracil, before cancer that revision of the package risk of aortic aneurysm and treatment with fluorouracil and insert is necessary. dissection. prodrugs (capecitabine and Reference: Fluoroquinolones are broad- tegafur) via injection or Revision of Precautions, spectrum antibiotics that are infusion. No pre-treatment MHLW/PMDA, 25 February active against both Gram- testing is needed for topical 2020 (www.pmda.go.jp/english/) negative and Gram-positive treatment with fluorouracil. bacteria. Fluoroquinolone Fluorouracil is indicated to treat antibiotics marketed in various cancers. Also, it is Australia include ciprofloxacin, applied to the skin for actinic norfloxacin and moxifloxacin. keratosis and dermal warts. Ingenol mebutate The TGA investigated a safety Lack of DPD enzyme causes (gel) signal relating to the rare but fluorouracil to build up in the serious potential adverse event blood, which may lead to Risk of skin malignancy of aortic aneurysm and severe and life-threatening WHO Pharmaceuticals Newsletter No. 2, 2020 • 7 Regulatory Matters

United Kingdom. The combination with a reduced- adverse drug reactions, MHRA has announced that the calorie diet and increased including suicidal thoughts or licence of ingenol mebutate gel physical activity to help weight actions. However, many (Picato®) has been suspended loss in adults who are obese or health-care professionals and as a precautionary measure overweight and have weight- patients are not aware of the while the EMA continues to related medical problems. It risk. FDA decided a stronger investigate an increased works by increasing feelings of warning is needed after incidence of benign and fullness. conducting an extensive review malignant skin tumours in of available information. When FDA approved lorcaserin several clinical studies. in 2012, the manufacturer was Health-care professionals Ingenol mebutate gel is required to conduct a clinical should ask patients about any indicated for the treatment of trial to evaluate the risk of history of psychiatric illness actinic keratosis in adults when cardiovascular problems. The prior to initiating treatment, the outer layer of the skin lorcaserin group reported and consider the risks and affected is not thickened or higher frequency of several benefits of montelukast when raised. different types of cancers. deciding to prescribe or continue patients on the Several studies have found a Health-care professionals medicine. Also, they should higher incidence of skin should stop prescribing advice patients of the risk of tumours in the treatment area lorcaserin; they should contact neuropsychiatric events when in patients who had used patients currently taking prescribing montelukast, and ingenol mebutate or a related lorcaserin, inform them of the monitor those treated with ester. Post-marketing reports increased occurrence of cancer, montelukast for of skin tumours in patients and ask them to stop taking neuropsychiatric symptoms. treated with ingenol mebutate lorcaserin. Additionally, health- gel have also been received. care professionals should Reference: discuss alternative weight-loss MedWatch, US FDA, 4 March Although the number of medicines or strategies with 2020 (www.fda.gov) uncertainties remain and the the patients. data are still being reviewed, (See WHO Pharmaceuticals Newsletter given the concerns regarding Reference: No.6, 2019: Risk of neuropsychiatric the possible risk of skin MedWatch, US FDA, 13 reactions in UK; No.3, 2013: malignancy, the EMA has February 2020 (www.fda.gov) Neuropsychiatric risks in Australia) recommended a precautionary (See WHO Pharmaceuticals Newsletter EU-wide suspension of ingenol No.1, 2020: Potential risk of cancer in USA) mebutate gel.

Reference: Rotigotine Drug Safety Update, MHRA, 12 February 2020 Risk of rhabdomyolysis (www.gov.uk/mhra) Montelukast Japan. The MHLW and the (See WHO Pharmaceuticals Newsletter Boxed warning PMDA have announced that the No.1, 2020: Use with caution in patients strengthened for serious package insert for rotigotine with a history of skin cancer in Ireland; No.1, (Neupro patch®) should be 2020: Suspension during safety review in behaviour and mood-related EU; No.6, 2019: Increased incidence of skin changes revised to include tumours in UK; No.5, 2019: Potential risk of rhabdomyolysis as an adverse skin cancer in EU) USA. The FDA has announced drug reaction. that it is strengthening existing Rotigotine is indicated for the warnings about serious treatment of Parkinson’s behaviour and mood-related disease and moderate to changes with montelukast severe idiopathic restless legs (Singulair® and generics). Lorcaserin syndrome. Montelukast is a prescription Withdrawal due to the risk A total of four cases of medicine indicated to prevent rhabdomyolysis have been of cancer asthma attacks and for the reported in patients treated long-term treatment of USA. The US Food and Drug with rotigotine in Japan during asthma. It is also approved to Administration (FDA) has the previous three years. For control the symptoms of requested the manufacturer to three out of the four cases, a allergic rhinitis, also known as voluntarily withdraw lorcaserin causal relationship between hay fever, such as sneezing (Belviq®, Belviq XR®) from rotigotine and the events could and runny nose. the US market due to an not be excluded. No patient increased risk of cancer. Montelukast prescribing mortalities have been reported information already includes to date. Lorcaserin is used in warnings about mental health

WHO Pharmaceuticals Newsletter No. 2, 2020 • 8 Regulatory Matters

MHLW/PMDA have concluded that the revision of the package insert is necessary. Reference: Revision of Precautions, MHLW/PMDA, 25 February 2020 (www.pmda.go.jp/english/)

Ulipristal acetate

Risk of hepatic injury

Europe. The EMA’s PRAC has recommended that women stop taking ulipristal acetate (Esmya®) for uterine fibroids while a safety review on the risk of liver injury is ongoing. Meanwhile, no new patients should start treatment with the medicine. Ulipristal acetate is indicated to treat moderate to severe symptoms of uterine fibroids in women who have not reached menopause. A 2018 EMA review concluded that there is a risk of rare but serious liver injury with ulipristal acetate for the treatment of uterine fibroids, risk minimisation measures were subsequently implemented. The EMA is starting a new review following a recent case of liver injury that led to liver transplantation. Health-care professionals should immediately advise patients being treated with ulipristal acetate for uterine fibroids to stop the treatment, and to report signs and symptoms of liver injury such as nausea, vomiting, right hypochondrial pain, anorexia and jaundice. Also, liver function testing should be conducted two to four weeks after treatment is stopped. Reference: EMA, 13 March 2020 (www.ema.europa.eu) (See WHO Pharmaceuticals Newsletter No.5, 2018: New measures to minimize risk of liver injury in EU and Canada; No.4, 2018: New measures to minimise the risk of liver injury in EU; No.2, 2018: Potential risk of liver injury in EU) WHO Pharmaceuticals Newsletter No. 2, 2020 • 9 Safety of Medicines

Clozapine Ferric solution, a concentrate for solution and a powder for Risk of serious bowel carboxymaltose solution. complications Risk of hypophosphataemia An investigation in 2016 suggested that the incidence of USA. The FDA has Australia. The TGA has encephalopathy was higher strengthened the existing announced that symptomatic with the ready-made solution warning that constipation hypophosphataemia is a known than with the powder. It was caused by clozapine (Clozaril®, risk associated with the use of concluded that the risk may be Fazaclo ODT® and Versacloz®) ferric carboxymaltose linked to the degradation of the can progress to serious bowel (Ferinject®) and it is active substance and impurities complications. recommended that health-care developing over time in the Clozapine is indicated for providers should routinely solution. As a result, the schizophrenia. Clozapine evaluate a patient’s risk factors solution’s shelf-life was affects how the intestines before commencing ferric reduced. Since then other function in the majority of carboxymaltose and follow up studies suggested that the risk patients. at-risk patients. still remains higher. Hence a more thorough review is The serious bowel Ferric carboxymaltose is needed. complications can lead to administered intravenously for hospitalization or even death if treatment of iron deficiency EMA will now assess the constipation is not diagnosed when oral iron preparations are available data on the risk of and treated quickly. ineffective or cannot be used. encephalopathy with ifosfamide ready-made solution or Patients should contact a Ferric carboxymaltose is known concentrate for solution. health-care professional if they to cause mild, usually have symptoms that can be asymptomatic Reference: associated with serious bowel hypophosphataemia, but may EMA, 13 March 2020 problems such as nausea, present with pain, nausea and (www.ema.europa.eu) vomiting or stomach pain. asthenia. Severe hypophosphataemia may be Health-care professionals associated with symptomatic should avoid co-prescribing physiological dysfunction. clozapine with other Hypophosphataemia can be the Mecasermin anticholinergic medicines that cause of asthenia, fatigue, can cause gastrointestinal muscular weakness, Risk of benign and hypomotility; advise patients breathlessness, tachycardia malignant neoplasia frequently of the significant risk and headaches. of constipation and life- United Kingdom. The threatening bowel issues and The TGA adverse events MHRA has announced that the need to stay hydrated to database has 15 reports of cases of benign and malignant prevent constipation; and hypophosphataemia with ferric neoplasms have been observed monitor patients for symptoms carboxymaltose. Severe among children and of potential complications hypophosphataemia was adolescents who received associated with gastrointestinal reported in four cases. mecasermin (Increlex®). hypomotility such as nausea, Reference: abdominal distension and Mecasermin is a recombinant Medicines Safety Update, TGA, vomiting. human insulin-like growth 27 February 2020 factor 1. It is indicated for the Reference: (www.tga.gov.au/) treatment of growth failure in Safety Alerts for Human children and adolescents with Medical Products, US FDA, confirmed severe primary 28 January 2020 (www.fda.gov) insulin-like growth factor 1 deficiency. It is already (See WHO Pharmaceuticals Newsletter Ifosfamide (solution) No.3, 2019: Risk of intestinal ulcer and contraindicated in patients with intestinal perforation in Japan; No.4, 2018: active or suspected neoplasia. Gastrointestinal effects in Australia) Risk of encephalopathy An EU review identified an Europe. The EMA has started a increased incidence of benign and malignant tumours in review of ifosfamide (solution) to examine the risk of patients treated with encephalopathy. mecasermin. Most cases occurred in patients treated Ifosfamide is indicated to treat outside the authorized several cancers including solid indication or exceeding the tumours and lymphomas. It is maximum dose. available as a ready-made WHO Pharmaceuticals Newsletter No. 2, 2020 • 10 Safety of Medicines

Following the review, the 150 adverse reaction reports in contraindication will be which nitrofurantoin was a expanded to children or suspect medicine. Of the adolescents with any condition reports, 46 were on interstitial of medical history that lung disease, 17 were on increases the risk of benign or hepatic reactions including malignant neoplasia. hepatic cirrhosis and pneumonitis and 3 were on Reference: peripheral neuropathy. Drug Safety Update, MHRA, 27 January 2020 Reference: (www.gov.uk/mhra) Prescriber Update, Medsafe, March 2020 (See WHO Pharmaceuticals Newsletter No.1, 2020: Potential risk of benign or (www.medsafe.govt.nz/) malignant tumours in Japan)

Ondansetron Nitrofurantoin Risk of oral clefts Risk of pulmonary and United Kingdom. The hepatic impairment and MHRA has announced that peripheral neuropathy exposure to ondansetron (Zofran®) during the first New Zealand. Medsafe has trimester of pregnancy is announced that the use of suggested to be associated nitrofurantoin in patients with with a small increased risk of significant renal impairment the baby having a cleft lip can cause pulmonary or and/or cleft palate. hepatic impairment or peripheral neuropathy. Ondansetron, a 5-HT3 receptor antagonist, is indicated for the Nitrofurantoin is a bactericidal management, prevention or antibiotic with activity treatment of nausea and exclusively in the urine. It is vomiting. indicated for the treatment and prophylaxis of urinary tract Recent epidemiological studies infections. Significant renal reported a small increased risk impairment is a of orofacial malformations in contraindication to babies born to women who nitrofurantoin. used ondansetron in early pregnancy. Key evidence was Aadequate glomerular filtration an observational study of 1.8 and renal tubular secretion is million pregnancies in the US. needed to achieve an effective The data were recently therapeutic concentration in reviewed within Europe and the urine. While therapeutic considered to be robust. doses of nitrofurantoin are rapidly excreted into the urine The decision to use in patients with normal renal ondansetron during pregnancy function, in patients with should be based on impaired renal function the professional judgement, and in plasma concentration increases consultation with the woman and there is a higher risk of who is informed of the nitrofurantoin toxicity. potential benefits and risks of use, both to her and to her The Medicines Adverse unborn baby. Reactions Committee reviewed the evidence for safe use of Reference: nitrofurantoin in patients with a Drug Safety Update, MHRA, greater degree of renal 27 January 2020 impairment. During the 10- (www.gov.uk/mhra) year period to 2019, the Centre (See WHO Pharmaceuticals Newsletter for Adverse Reactions No.6, 2016: Assessing potential harm to the Monitoring (CARM) received foetus: insufficient information in Canada)

WHO Pharmaceuticals Newsletter No. 2, 2020 • 11 Information Note

Chloroquine and hydroxychloroquine in COVID-19

Qingxia Zhang, Xuan Wu Hospital, Capital Medical University, Beijing, China and Qun-Ying Yue, Uppsala Monitoring Centre

Chloroquine and hydroxychloroquine have been in use for many years, in the treatment of malaria, amoebic liver abscess and several rheumatological conditions. More recently these (and other medicines) are also being investigated for their possible use in COVID-19. While we await more conclusive evidence from various ongoing investigations, it is important to remain alert to potential adverse events and manage known adverse reactions with these products.

Chloroquine is an antimalarial drug, also used in Current evidence of effectiveness of chloroquine the treatment of autoimmune diseases such as and hydroxychloroquine in COVID-19 has also rheumatoid arthritis and systemic lupus been evaluated by the Oxford COVID-19 Evidence erythematosus due to its immunomodulatory Service Team [8]. It was concluded that at activity [1]. present, there is insufficient in vivo evidence to recommend their use for the current pandemic Chloroquine has a wide range of antiviral effects, outside of clinical trials. High-quality studies are including effects on coronavirus [2]. In a recent in urgently needed to provide guidance to clinicians vitro study the new antiviral drug remdesivir [3] as and policy-makers. well as chloroquine were found to be effective in preventing replication of SARS-CoV-2 [2]. More recently, the pharmacology and clinical pharmacology of chloroquine and On 18 February 2020 an expert consensus hydroxychloroquine have been reviewed and guideline in China recommended chloroquine in relevant discussions are ongoing in the context of mild to severe cases of COVID-19, as it was COVID-19 prevention and treatment, in particular, considered to improve the success rate of about the dosing considerations [9]. treatment, shorten hospital stay, and improve patient outcomes [4]. In VigiBase, the WHO global database of individual case safety reports, managed by Uppsala Although chloroquine is a widely used drug which Monitoring Centre (UMC), since 1968 and up to 23 has been on the market for a very long time, the February 2020 there were 5,741 unique cases from efficacy and safety profile has not been thoroughly 80 countries reporting adverse events associated studied in the SARS-CoV-2 infected patients. with chloroquine: the top three organ systems Hydroxychloroquine has similar therapeutic effects involved were skin and subcutaneous tissue as chloroquine, but fewer adverse effects, and is disorders (31%, 1,804 cases), gastrointestinal more readily available in some countries. Like disorders (25%, 1,421 cases) and nervous system chloroquine, hydroxychloroquine also has in vitro disorders (22%, 1,233 cases). Cardiac disorders activity against SARS-CoV-2, with relatively higher (5.8%, 331 cases) ranked ninth. There were 122 potency against SARS-CoV-2 than chloroquine. fatal cases, accounting for 2.1% of the total Both drugs are being trialled in patients with mild reported cases. Among them, cardiac disorders to severe COVID-19 in clinical studies [5]. (37%, 45 cases) ranked first place. On March 28, 2020, the US Food and Drug Cardiac toxicity was the primary cause of Administration (FDA) issued an Emergency Use chloroquine fatal adverse events. A single large Authorization (EUA) to allow hydroxychloroquine dose (mostly accidental or intentional overdose) of sulphate and chloroquine phosphate products to be chloroquine related mainly to arrhythmia; and used for certain hospitalized patients with COVID- cardiomyopathy was the main manifestation of 19. This was based on the totality of scientific chronic exposure. It is well known that chloroquine evidence available to FDA, that considers it can cause QT interval prolongation in some reasonable to believe that chloroquine phosphate patients, and in patients with risk factors for QT and hydroxychloroquine sulphate may be effective prolongation (including hypokalaemia and drugs in treating COVID-19, and that, when used under that also prolong QT interval) chloroquine should the conditions described in this authorization, the be used with caution. known and potential benefits of chloroquine phosphate and hydroxychloroquine sulphate when Although the case reports with chloroquine (that used to treat COVID-19 outweigh the known and did not mention COVID-19) were accumulated as potential risks of such products. [6] stated above, as of 2 April 2020, there were no individual case safety reports in VigiBase that could On the 1st of April, the European Medicines Agency be linked to the use of chloroquine in COVID-19. communicated that chloroquine and There are a handful of reports for hydroxychloroquine should only be used within the hydroxychloroquine that mention COVID-19 as the context of clinical trials or national emergency use indication or where this may possibly be the programmes.[7] indication. Reported events in these very few

WHO Pharmaceuticals Newsletter No. 2, 2020 • 12 Information Note reports have not so far given rise to any safety for chloroquine in the treatment of novel signal. coronavirus pneumonia. Expert consensus on chloroquine phosphate for the treatment of

novel coronavirus pneumonia [in Chinese]. References Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):185-8. 1. Datapharm Limited. Electronic Medicines Compendium (EMC): Summary of Product 5. BMJ Best Practice Characteristics for chloroquine (Avloclor®). https://bestpractice.bmj.com/topics/en- Available at: gb/3000168 https://www.medicines.org.uk/emc/product/549 6. https://www.fda.gov/news-events/press- 0/smpc#COMPOSITION. Accessed 28 Feb 2020. announcements/coronavirus-covid-19-update- 2. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, daily-roundup-march-30-2020 Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and 7. https://www.ema.europa.eu/en/news/covid-19- chloroquine effectively inhibit the recently chloroquine-hydroxychloroquine-only-be-used- emerged novel coronavirus (2019-nCoV) in clinical-trials-emergency-use-programmes vitro[J]. Cell Res, 2020,DOI: 10.1038/s41422- 020-0282-0. 8. https://www.cebm.net/covid-19/chloroquine- and-hydroxychloroquine-current-evidence-for- 3. Agostini ML, Andres EL, Sims AC, Graham RL, their-effectiveness-in-treating-covid-19/ By Sheahan TP, Lu X, et al. Coronavirus Oxford COVID-19 Evidence Service Team susceptibility to the antiviral remdesivir (GS- 5734) is mediated by the viral polymerase and 9. White NJ and Tarning J. Chloroquine and the proofreading exoribonuclease. mBio 2018;9 hydroxychloroquine pharmacology. Available at: pii: e0 0221-18. doi: 10.1128/mBio.0 0221-18. https://www.recoverytrial.net/files/recovery- intervention-sheet-hydroxychloroquine-v2-0.pdf 4. Multicenter collaboration group of Department of Accessed 10 April 2020. Science and Technology of Guangdong Province and Health Commission of Guangdong Province

WHO Pharmaceuticals Newsletter No. 2, 2020 • 13 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 22 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 31). 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].

Agomelatine and Increased Blood Pressure

Dr. Tamás Paál, Hungary

Summary is held responsible for the direct antidepressant effect. Unlike other antidepressants that often Agomelatine is a non-selective melatonin receptor trigger sleep disorders the advantage of MT1 and MT2 agonist plus a neutral serotonergic 5- agomelatine is that it has a beneficial effect on HT antagonist indicated for the treatment of major 2C sleep.1-3 depressive episodes. Of the 24 reports from eight countries on increased blood pressure and Agomelatine is indicated for adults (over 18 years) agomelatine in the WHO global database of because of the lack of data in paediatric individual case safety reports (VigiBase), twelve populations. The recommended dose is 25 to 50 mg were eligible for assessment. Of these, six revealed daily taken orally at bedtime. Its safety profile a consistent pattern of a short time to onset and requires regular monitoring of liver function in all nine reported recovery on dechallenge, with a patients before and during treatment. Agomelatine positive rechallenge in two of them. Although data is metabolised mainly by CYP1A2 (90%) and on the mechanism of action of agomelatine, as well CYP2C9/19 (10%). Consequently, drugs that as a former signal, suggest a mild hypo- rather than interact with these isoenzymes may interact with hypertensive action, it is also true that melatonin, agomelatine.4 which is structurally closely related to agomelatine, Normal blood pressure (BP) varies with age and is has hypertension as a labelled adverse effect. Thus, influenced by various factors such as cardiac despite the presence of additional risk factors for output, vascular resistance and venous return and hypertension in a considerable proportion of these pressure; any change in these variables can lead to cases, a contributory role of agomelatine to the fluctuations in BP. Thus, there is no absolute events cannot be excluded. threshold to define “normal BP”. In general, patients are taught that 120/80 (systolic/diastolic in mmHg) is taken as “normal”, 130/85 as “high Introduction normal”, then higher values as different stages of Agomelatine has been authorised in the European hypertension. However, these values vary with age Union and other countries for the treatment of (e.g. the normal values are 117/77 and 134/87 major depressive episodes. It has not been mmHg between 14 to 19, and 60 to 64 years, authorised in the USA. Agomelatine is a potent, respectively).5 non-selective melatonin receptor MT1 and MT2 Twenty-four reports have been observed in the agonist plus a neutral serotonergic 5-HT 2C WHO global database of individual case safety antagonist. Synergy between the two types of reports (ICSRs), VigiBase, for blood pressure receptors has been hypothesized as accounting for increased (BPI) under agomelatine treatment. its mode of action. Inhibition of the 5-HT2C receptor

WHO Pharmaceuticals Newsletter No. 2, 2020 • 14 Signal

Reports in VigiBase as one of the patients’ underlying diseases was reported in cases 17-20 and 24. The reported time On 14 April 2019, 24 reports were retrieved from to onset of the increased blood pressure was a few VigiBase for BPI following agomelatine hours in case 17, three days in case 23, about administration (Table 1). The adverse events seven days in cases 12 and 21, while general occurred between December 2012 and November statements (such as ”after introduction” or 2017. The ICSRs originated from eight countries: “initiation”, ”since she took it”) indicated that the Germany (15 cases), Austria (2), Switzerland (2), time to onset seemed to be short (in cases 1, 16, and Australia, the Czech Republic, Portugal, South 20, 24). In case 18 the BPI happened “after the Africa, and Turkey (one each). They were dose was increased from 25 mg to 50 mg”. In nine spontaneous reports except cases 2 and 21 which cases (1, 6, 12, 17, 19, 20, 21, 23 and 24) positive came from clinical studies. The reporters were dechallenge (plus in case 18 reaction abated for physicians with the exception of cases 1 and 16 dose reduction) while in two cases (1, 12) positive (non-health-care professionals), 12 (pharmacist), rechallenge were reported. It should also be as well as 10 and 20 (other health-care stressed that labelled adverse effects of professionals), while in case 11 the reporter was agomelatine (e.g. migraine, nausea, sweats, unknown. In cases 3, 7 and 14 the outcome was anxiety, restlessness, insomnia, dizziness and not reported, otherwise, except in cases 11 and 16, blurred vision), if they occurred in the analysed the patients recovered. In the reports agomelatine cases, also abated at the same time as BPI did was the only suspected drug, except case 9 where (cases 19-21 in Table 1). In case 12 increased heart all those administered except esomeprazole were rate abated together with BPI while the outcome of reported as suspected. In 14 cases where the other events labelled for agomelatine (tiredness, increased blood pressure values were also reported, somnolence and headache) was not reported. they varied considerably. It should be noted that 17 reports for hypertension The cases in Table 1 were analysed first to exclude following agomelatine administration were also those where the concomitant medication could found in VigiBase (13 October 2019). In six of them cause BPI/hypertension. The European product no concomitant medication was reported and in six information of the concomitant drugs (European other cases, although there was concomitant Medicines Agency webpage or the MRI product medication, agomelatine was reported as the only index6) revealed that, in addition to typical suspect drug. (Only two of these latter six cases antidepressants (trazodone, paroxetine, also reported concomitant medications which have venlafaxine, sertraline and clomipramine), hypertension as a labelled ADR, i.e. allopurinol and pregabalin (used, among others, in cases of sertraline.) In four cases positive dechallenge also generalised anxiety) and ezetimibe (primary occurred. The time to onset, when it could be hypercholesterinaemia) have hypertension labelled identified from the reports, varied from “same day” as an adverse effect. Thus, cases 3, 4, 9 and 13 (three cases) to two days (two cases), and around were not used for the initial review. (In cases 8, 21 two weeks (two cases) up to one month or longer and 23, paroxetine or clomipramine were indicated (seven cases). Labelled adverse effects of as concomitant drugs, however, their administration agomelatine occurred and abated together with the was discontinued before agomelatine was started, hypertension in ten cases. Although these and the BPI occurred days later, so these cases “agomelatine and hypertension” reports were not were included.) combined with the “agomelatine and BPI” ones, During the next “filtering”, the following cases were they seem to be in line with the latter and excluded: cases 2, 5 and 8 (one and a half months, strengthen the results of this analysis. two years and nine months agomelatine treatment before the onset of BPI, respectively), case 7 (poor reporting), case 10 (according to its narrative, the Literature and labelling agomelatine treatment was maintained, but the Hypertension/BPI is not listed in the European patient’s BP improved), case 14 (onset of BPI Summary of Product Characteristics of agomelatine. reported on the day of the agomelatine Furthermore, it states that “agomelatine had administration, then the treatment was continued neutral effect on heart rate and blood pressure in with no further data), case 15 (it was a suicide clinical trials”.4 (There were clinical trials where attempt, taking among others, 1050 mg hypertension was reported in the agomelatine arm. agomelatine with no BPI first then 150/90 mmHg Its frequency was found to be 1.2%7 but because of value later, but the patient had a mild the limited number of the subjects involved and the hypertension), and case 22 as the patient had an lack of a placebo arm in this trial, the causality underlying hypertension and, according to the could not be established.) narrative, a reduction of the antihypertensive treatment was made at the time of agomelatine It is also well-known that people suffering from initiation. depression are more likely than the others to develop hypertension.8 Thus, only 12 ICSRs (cases 1, 6, 11, 12, 16-21, 23 and 24) remained for detailed analysis. Experiments have suggested that agomelatine prevents rather than causes hypertension.9 Well-controlled arterial hypertension/hypertension Moreover, in 2014, the Uppsala Monitoring Centre WHO Pharmaceuticals Newsletter No. 2, 2020 • 15 Signal published a signal on hypotension occurring under extended to agomelatine – change in BP (both agomelatine treatment. In response to the signal hypo- and hypertension). The paradoxical action of the marketing authorisation holder accepted that 5- certain antihypertensives causing BPI may be HT2C/5-HT2B antagonists could induce an explained by an impaired BP regulation system that antihypertensive effect in animals and/or humans “over-reacts” to the stimulus. Indeed, five patients with hypertension, while it did not endorse it as a of the analysed 12 ICSRs (in cases 17-20 and 24) clinically relevant safety concern.10 had reported “well-controlled” hypertension (i.e. an underlying disease where the BP regulation was Melatonin, structurally closely related to impaired). agomelatine but binding to the MT receptors exclusively is used for sleep disorders such as The marketing authorisation holder’s statements in short-term primary insomnia or to decrease jet- certain ICSR narratives that the cases do not trigger lag.11 It is interesting that clinical studies revealed any changes in the core data sheet are fully agreed that its use at night an hour before sleep appeared upon, the reaction is far from being proven and can to lower BP. (There is some debate about its be extremely rare. However, a signal only means mechanism: is it based on serotonin antagonism by information on a possible causal relationship melatonin or is it because the subjects had fuller, between an adverse event and a drug. Considering better quality sleep?)11, 12 On the other hand, the above-mentioned aspects, in conclusion, melatonin has hypertension as a labelled adverse agomelatine and BPI (perhaps also more widely: effect13, 14 with a frequency of “uncommon” (that agomelatine and change in BP) is considered a means 0.1 to 1.0%).13 signal. It is also well-known that some medicines that usually lower blood pressure may paradoxically References increase blood pressure.14 There are drugs (such as pregabalin, indicated, among others, to generalised 1. Guardiola-Lemaitre B. De Bodinat C. anxiety disorders) that have labelled adverse Delagrange P. Millan MJ. Munoz C. Mocaër E. reactions both hypo- and hypertension with the Agomelatine: mechanism of action and same frequency.15 pharmacological profile in relation to antidepressant profile. Br J Pharmacol.

2014:171:3604-19. Discussion and conclusion 2. Munoz C. Valdoxan: antidepressant efficacy at Based on the overall reporting of adverse reactions all time phases of treatment. Medicographia. for agomelatine and of the adverse reaction BPI in 2010:32(2):171-6. Available from: VigiBase as a whole, the expected value for the https://www.medicographia.com/2010/10/valdo number of reports of the combination is 16 and the xan-antidepressant-efficacy-at-all-time-phases- IC025 is negative (as of 27 June 2019). However, of-treatment/. Accessed: 26 April 2019. agomelatine is not used in the USA where BPI is 3. Emet M. Ozcan H. Ozel I. Yajla M. Halici Z. more commonly reported overall, and in a Hacimuftuoglu A. A Review of Melatonin, Its disproportionality analysis adjusted for region of Receptors and Drugs. Eurasian J Med. origin, the expected value is around 10, rendering a 2016:48(2):135-41. stronger statistical association which would be highlighted as disproportionally reported by IC 4. European Medicines Agency: Summary of analysis. This means that if its calculation is Product Characteristics for agomelatine restricted to the rest of the world (non-US reports), (Valdoxan). Available from: the IC025 is positive. Moreover, taking the high https://www.ema.europa.eu/en/documents/pro number of positive dechallenges in the analysed duct-information/valdoxan-epar-product- ICSRs into account (where labelled adverse effects information_en.pdf. Accessed: 29 May 2019. of agomelatine abated together with the BPI) and the positive (in one case double) rechallenges, they 5. Idealbloodpressureinfo.com. Blood Pressure strongly suggest a positive causal relationship. Chart By Age: Check Out What Should Your BP Be. Available from: The BPI action of agomelatine might be dose- https://www.idealbloodpressureinfo.com/blood- dependent (it occurred only at higher doses in one pressure-chart-by-age/. Accessed: 10 June case and the patient who experienced repeated 2019. rechallenges was a slow CYP metaboliser). Moreover, the fact that the individual variability of 6. Heads of Medicines Agency. MRI Product Index. the absolute bioavailability of agomelatine is http://mri.cts-mrp.eu/Human/ substantial4 might explain its rare and sporadic 7. Corruble E. de Bodinat C. Belaïdi C. Goodwin occurrence. GM. agomelatine study group. Efficacy of Considering also the mild hypotensive action of agomelatine and escitalopram on depression, agomelatine and the preceding signal on subjective sleep and emotional experiences in agomelatine – hypotension,10 where the number of patients with major depressive disorder: a 24- positive dechallenges were also high with one wk randomized, controlled, double-blind trial. positive rechallenge, the former statement may be

WHO Pharmaceuticals Newsletter No. 2, 2020 • 16 Signal

Int J Neuropsychopharmacol., 12. Cure HBP. Melatonin and High Blood Pressure – 2013:16(10):2219-34. Is There a Connection? Available from: https://www.naturaltreatmentforhypertension.c 8. Woolston C. Depression and High Blood om/blog/melatonin-and-high-blood-pressure-is- Pressure. Available from: there-a-conncetion. Accessed: 20 May 2019. https://consumer.healthday.com/encyclopedia/ depression-12/depression-news- 13. European Medicines Agency: Summary of 176/depression-and-high-blood-pressure- Product Characteristics for melatonin (Circadin 644943.html. Accessed: 26 April 2019. prolonged-release tablets). Available from: https://www.ema.europa.eu/en/documents/pro 9. Tain YL. Lin YJ. Chan JYH. Lee CT. Hsu CN. duct-information/circadin-epar-product- Maternal melatonin and agomelatine therapy information_en.pdf. Accessed: 12 June 2019. prevents programmed hypertension in male offspring of mother exposed to continuous light. 14. Grossman E. Messer FH. Drug-induced Biol Reproduction 2017:97(4):636-43. Hypertension: An Unappreciated Cause of Secondary Hypertension. Am J Med. 10. Uppsala Monitoring Centre. Agomelatine and 2012:125(1):14-22. Hypertension. WHO Pharm. Newsletter 2014(4): 13-17. 15. Electronic Medicines Compendium: Summary of Product Characteristics for pregabalin (Lyrica 11. Cook M. Serotonin, Melatonin, and Blood capsules.) Available from: Pressure. Available from: https://www.medicines.org.uk/emc/medicine/1 https://www,dailymedicaldiscoveries.com/serot 4651. Accessed: 26 April 2019. onin-melatonin-blood-pressure/. Accessed: 26 April 2019.

Table 1. Overview of reports in VigiBase of blood pressure increased in association with agomelatine Case Sex, Underlying disease Agomelatine dose, Concomitant drugs Reported reactions De/Rechallenge age treatment duration 1 M, 74 coronary by-pass, 25 mg/d, not specified nebivolol, BPI, tachycardia, muscle Positive insomnia (within 1 month) lercanidipine, cramps dechallenge, tamsulosin, finasteride, positive diazepam rechallenge 2 F, 72 hypertension, 25 mg/d, 1.5 m BPI, nausea depression, obesity 3 F, 58 depression, 25 mg/d, 18 d lorazepam, trazodone BPI, dizziness, heart rate hypertension, sleep increased, Nausea disorder 4 M, 72 depression, BPH, 50 mg/d, 2 m telmisartan, ezetimibe, BPI, alanine aminotransferase, positive glaucoma, hyper- dorzolamide, aspartate aminotransferase and dechallenge (all cholesteremia. arterial simvastatin gamma-glutamiltransferase events) hypertension, increased insomnia, obesity, sleep apnoea syndrome, gonarthrosis 5 F, 63 depression, arterial 25 mg, 2 y losartan BPI, sinus tachycardia hypertension, obesity 6 M, 52 depression, 25 mg BPI positive somatization disorder dechallenge 7 BPI 8 M, 31 depression (cousin 25 mg/d, 9 m hyoscine, medazepam, BPI, suicidal and homicidal positive psychiatric) paroxetine ideation, nervousness, anger, dechallenge (all aggression, impaired driving events ability unspecified) 9 M, 53 recurrent depression, bisoprolol, clonazepam, BPI, vertigo, aggression generalised anxiety pregabalin, venlafaxine, aggravated, fall, gait disorders mirtazapine (all also instability, tension suspected drugs), esomeprazole

WHO Pharmaceuticals Newsletter No. 2, 2020 • 17 Signal

Case Sex, Underlying disease Agomelatine dose, Concomitant drugs Reported reactions De/Rechallenge age treatment duration 10 F, 61 sleep disturbance, pain 25 mg/d, (onset 14 d) trolnitrate, valsartan, BPI, transient ischemic attack, Agomelatine in spine, bronchitis, budesonide/formoterol, paraesthesia, muscle tension, maintained, BPI prolapsed disc nos levothyroxine, insomnia recovered lidocaine, zolpidem 11 F, 59 7 d flecainide, warfarin, BPI, drug interaction atorvastatin 12 F, cca Depression 25 mg/d escitalopram, ethyl BPI, increased heart rate, positive 30 cca 1w loflazepate, alprazolam, tiredness, somnolence, dechallenge, salbutamol headache positive rechallenge (BPI and heart rate) 13 M, 61 depression, insomnia 25 mg/d sertraline BPI, tachycardia, palpitations positive dechallenge, positive rechallenge 14 M, 18 Depression 25 mg/d, 0 d 15 F, 63 depression, arterial 1050 mg (suicidal mirtazapine, BPI, increased alkaline hypertension, chronic intention), 1 d lercanidipine phosphatase, AST and bilirubin alcohol abuse, suicide and blood glucose and C- attempt reactive protein and creatinine and LDH and GGT, aspiration, high creatine kinase and uric acid, febrile reaction, hypokalaemia, nervousness, tachycardia, unrest 16 F, 54 depression, 25 mg/d, 1 m levothyroxine BPI, anxiety, insomnia, hot Hashimoto’s disease, 6.25 mg/d, 17 d flushes facial, migraine, hypometabolism 12.5 mg/d, 4 m nausea, sweats, generalised hot (CYP2 d6 and c19 slow the drug was feeling, blue-red colouration of metaboliser) withdrawn for a the skin period of time between the different dosage regimens. BPI occurred after reintroducing it at dose 12.5 mg 17 M, 74 depression, coronary 25 mg/d, 1 d trimipramine, glyceryl BPI, restlessness, nocturnal positive heart disease, arterial trinitrate amlodipine, awakening dechallenge hypertension, diabetes metoprolol, HCT, mellitus type 2 captopril/HCT 18 F, 54 depression, 50 mg/d antihypertensives BPI, red face dose reduced to hypertension 25 mg/d 25 mg/d and Patient started on 25 BPI recovered mg, the dose was then increased to 50 mg and the patient experienced BPI 19 ?, ? sleep disorder, 25 mg/d, 11 d lercanidipine (1 y), BPI, new left bundle branch positive hypertension, reflux esomeprazole block, chest pain, dizziness, dechallenge (all) esophagitis, left bundle blurred vision branch block 20 F, depression, GI 50 mg/d, around 1 m ciprofloxacin, BPI, blurred vision, head positive over inflammation viral, (onset: “since she took HCT/olmesartan pressure, noises in head, stiff dechallenge (all) 70 hypertension, irritable agomelatine”) neck, anxiety aggravated, bowel, panic attacks, contraindicated drug sleep disorder, bowel administered cancer removed, cerebral disorder, anxiety disorder

WHO Pharmaceuticals Newsletter No. 2, 2020 • 18 Signal

Case Sex, Underlying disease Agomelatine dose, Concomitant drugs Reported reactions De/Rechallenge age treatment duration 21 F, 39 recurrent depressive 25 mg/d, 18 d opipramol, paroxetine BPI, aggressive behaviour, positive disorder dizziness, excitement, mood dechallenge (all) swings, suicidal ideation, unrest 22 M, 45 insomnia, hypertension 25 mg/d, 4 d, then 50 bisoprolol BPI, shaking of hands, feeling BPI abated mg/d, about 2 w irritated, panic attacks, nausea, when dizziness, sweating amlodipine was taken 23 M, 71 depression, Parkinson’s 25 mg/d, 7 d benserazide, levodopa, BPI positive disease clomipramine dechallenge 24 F, 44 anxiodepressive 25 mg/d, 10 d escitalopram, BPI, headache positive syndrome, pantoprazole, dechallenge hypertension, ramipril post-concussion syndrome BPI = blood pressure increased, d = day, w = week, y = year, BPH = benign prostatic hyperplasia, HCT = hydrochlorothiazide

Midostaurin – photosensitivity reaction

Sarah Watson, Uppsala Monitoring Centre and Dr. Geneviève Durrieu, Centre Régional de Pharmacovigilance, Toulouse, France

Summary with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated Midostaurin is a protein kinase inhibitor indicated as haematological neoplasm (SM-AHN), or mast cell monotherapy for the treatment of adult patients leukaemia (MCL). It is also used in combination with aggressive systemic mastocytosis, systemic with daunorubicin and cytarabine and high-dose mastocytosis with associated haematological cytarabine consolidation chemotherapy, as well as neoplasm or mast cell leukaemia. Reports in the for patients in complete response, followed by French pharmacovigilance database, the Base midostaurin as monotherapy for adult patients Nationale de Pharmacovigilance (BNPV) as well as newly diagnosed with acute myeloid leukaemia in VigiBase, the WHO global database of individual (AML) positive for the tyrosine kinase protein ‘fms- case safety reports (ICSRs), indicate that like tyrosine kinase 3’ (FLT3) mutation.1 midostaurin can cause photosensitivity reactions while interacting with sunlight in certain patients. Midostaurin inhibits several receptor tyrosine All cases found were marked as serious and the kinases, including FLT3 and tyrosine-protein kinase treatment in most cases continued, in some with KIT (also called CD117). It also inhibits FLT3 recorded advice of sun protection. In one case the receptor signalling and induces cell cycle arrest and drug was permanently withdrawn, and the treating apoptosis in leukemic cells over-expressing FLT3 physician issued a contraindication for the drug for wild-type receptors, or expressing an FLT3 mutation the patient following a photosensitivity test with a called internal tandem duplication (ITD), or tyrosine very strong reaction to the drug. There is no kinase domain (TKD) mutant receptors. Midostaurin mention of photosensitivity in the product labels for additionally inhibits several other receptor tyrosine midostaurin, but in a French compassionate use kinases such as platelet-derived growth factor programme involving 28 patients, 25% of the receptor (PDGFR), or vascular endothelial growth patients reported an occurrence of photosensitivity factor receptor 2 (VEGFR2), and members of the reactions following treatment with midostaurin, serine/threonine kinase family protein kinase 3 strengthening the suspicion based on the reports (PKC). It causes growth arrest while binding to the found in BNPV and VigiBase. catalytic domain of these kinases where it inhibits the mitogenic signalling of the respective growth

factors in cells.1 Introduction Sun sensitivity occurs in people of all ages, for both Midostaurin is a protein kinase inhibitor indicated as sexes and with different skin types. However, monotherapy for the treatment of adult patients people with low levels of melanin, who have very

WHO Pharmaceuticals Newsletter No. 2, 2020 • 19 Signal white skin and rarely tan, are often considered reaction. This led to withdrawal of the drug after more photosensitive, relative to people with darker having had a photosensitivity test performed in skin types who tan more easily.2 hospital where a minimal dose of the drug was given, and UVA-light was applied. A very strong Drug-induced photosensitivity reactions occur as a reaction followed, the drug was permanently result of the combined effects of a drug and withdrawn, and the treating physician issued a sunlight in susceptible patients and has the contraindication for the drug for this patient. potential to increase the incidence of skin cancer. Exposure to either the drug or the sunlight alone is When checking in the French database of adverse not enough to cause a reaction. Photoactivation of drug reaction reports, the Base Nationale de chemicals leads to the occurrence of one or more Pharmacovigilance (BNPV) at this time, seven sun sensitivity reactions, such as rash and burns. additional reports with the same kind of reaction Adverse photosensitivity responses to drugs were found. When replicating the search in predominantly occur as phototoxic reactions, more VigiBase®, the WHO global database of individual immediate than photo allergy, and reversible by case safety reports (ICSRs), two additional reports withdrawal or substitution of the drug. There is a were retrieved, from Germany and the United problem of inaccuracy in the reporting of these States. The case from Toulouse was subsequently adverse drug reactions because of the difficulty in entered into both BNPV and VigiBase. distinguishing between regular sunburn and mild The time to onset of the reaction varied between drug photosensitivity reactions, as well as the the patients for which this information was patient being able to control the incidence by taking recorded, from 10 days up to one year. After the protective action. Some examples of drug classes onset of the reaction, several patients continued known for a high level of adverse photosensitivity taking the drug, with a mention of recurring sun are diuretics, antibacterials and nonsteroidal anti- sensitivity at repeated exposure made in two cases inflammatory drugs (NSAIDs).3 (cases 1 and 2). In one case there is a positive dechallenge. In three cases it is documented that the patients had been recommended extensive sun Reports in the Base Nationale de protection and for one of these, extensive Pharmacovigilance (BNPV) and VigiBase protective measures are mentioned with hat, long Reports of midostaurin causing severe gloves, sunscreen of 50+ strength, as well as a photosensitivity reactions were first identified at the booked appointment for sun protection education. regional pharmacovigilance centre of Toulouse, One case was received from a dermatologist who France, following one index case reported in 2019. judged the patient’s exanthema, or alternatively a The case concerned a patient who had been treated phototoxic reaction, as probably related to with midostaurin for over 2 months when, after midostaurin, despite the patient’s intake of a having taken a walk outside in sunny spring confounding drug, valsartan, known to be able to weather, experienced a severe photosensitivity cause photosensitivity.

Table 1. Characteristics of case reports in VigiBase® and BNPV of photosensitivity reaction in association with midostaurin Case Age/Sex Suspected (S) or Daily dose Reactions (MedDRA preferred terms) - Time to De-challenge/ Database concomitant (C) drugs Outcome onset Re-challenge of origin 1 M/57 Midostaurin (S) NA Toxic skin eruption - recovered 10 days NA/Y BNPV Photosensitivity reaction - Not recovered 2 M/75 Midostaurin (S) NA Toxic skin eruption - unknown 86 days NA/Y BNPV Photosensitivity reaction- Not recovered 3 F/67 Midostaurin (S) NA Photosensitivity reaction -not recovered 30 days NA/NA BNPV Basal cell carcinoma - recovered with sequalae Actinic keratosis - not recovered Toxic skin eruption -recovered 4 M/69 Midostaurin (S) NA Erythrosis - not recovered 1 year NA/NA BNPV Photosensitivity reaction - not recovered 5 M/29 Midostaurin (S) NA Photosensitivity reaction - recovered with 2 months NA/NA BNPV sequelae 6* M/68 Midostaurin (S) 200 mg/day Photosensitivity reaction - recovering 8 months NA/NA BNPV Ketotifen (S) (also Desloratadine (C) present in Montelukast (C) VigiBase)

WHO Pharmaceuticals Newsletter No. 2, 2020 • 20 Signal

Case Age/Sex Suspected (S) or Daily dose Reactions (MedDRA preferred terms) - Time to De-challenge/ Database concomitant (C) drugs Outcome onset Re-challenge of origin Ropinirole (C) Esomeprazole (C) Rivaroxaban (C) Rosuvastatin (C) Verapamil (C) Perindopril (C) 7 M/74 Midostaurin (S) NA Basal cell carcinoma - N/A 308 days NA/NA BNPV Photosensitivity reaction** - N/A 8 F/78 Midostaurin (S) 50 mg/day Photosensitivity reaction - recovering 58 days Y/NA BNPV Photosensitivity reaction - recovering (also present in VigiBase) 9 F/66 Midostaurin (S) 100 mg/ 2 Swelling face - N/A NA NA/NA VigiBase per day Eyelid oedema - N/A Photosensitivity reaction - N/A 10 M/- Midostaurin (S) 25 mg/- Rash - N/A 4 months NA/NA VigiBase Valsartan (C) Photosensitivity reaction - N/A Atorvastatin (C) *Case 6 is also published as a case report in the literature[ref 9] **Term identified in the narrative

Literature and Labelling this signal (no. 6) as a case report submitted to the journal Annales de Dermatologie et de Vénéréologie In the centrally authorized European product in 2017. Alsulaili and colleagues hypothesise that characteristics for midostaurin there is no mention the phototoxic effect could be favoured by the of photosensitivity reactions. Dermatitis exfoliative inhibition of the ABCG2 drug transporter.9 and hyperhidrosis are given as very common skin reactions while dry skin and keratitis are marked as Photosensitivity related to midostaurin was also common skin reactions.1 In addition, the European noted in a prospective survey performed by the periodic assessment report from 2017 states that French National Reference Centre for Mastocytosis the phototoxic potential was evaluated in albino (CEREMAST) on patients with mastocytosis who were hairless mice with only mild skin reactions occurring treated with midostaurin under a transitory-use after oral administration of midostaurin and UV-A or authorization programme. Between 2012 and 2015, UV-A and UV-B irradiation.4 A cumulative search 28 patients received midostaurin at a dose of 100 mg made in the safety database of market twice daily. One out of four patients in this survey authorisation holder Novartis, during the same reported an occurrence of photosensitivity reactions year, revealed 11 cases of “photosensitivity or following treatment.10 photo dermatosis conditions”. The cases had multiple co-suspected drugs known to cause photosensitivity and had an unreasonable time to Discussion and Conclusion onset or had a prior history of photosensitivity which, according to Novartis, made a causal All cases found in BNPV and VigiBase were marked relationship unlikely.4 The US Daily Med product as serious, and yet, probably due to lack of information for midostaurin does not mention a treatment options and the gravity of the disease, potential for photosensitivity reactions.5 However, the treatment in most cases continued, in some for another protein kinase inhibitor, namely with recorded advice of sun protection. In one case imatinib, the following is set out in the UK product the sun sensitivity was confirmed by a labelling; “Phototoxicity: Exposure to direct sunlight photosensitivity test performed with UVA-light should be avoided or minimised due to the risk of which resulted in a strong reaction despite a phototoxicity associated with imatinib treatment”.6 minimum dose administered for midostaurin. Two For another protein kinase inhibitor, gefitinib, it is other cases described reoccurring photosensitivity stated that “the results of an in vitro phototoxicity reactions while continuing to take the drug. study demonstrated that gefitinib may have Although the time to onset of the reactions varied phototoxicity potential”. 7 Other protein kinase among the patients included in this signal, this is inhibitors have the potential for phototoxicity, either probably of less relevance given that the reaction is noted in vitro or as an adverse drug reaction, in linked to the exposure to sunlight. Also, as their respective product labels (among others: photosensitivity reactions can occur in varying erlotinib, nilotinib, pazopanib, vandetanib, afatinib degrees, lighter reactions might have occurred in and vemurafenib).8 A class effect of certain protein other patients but not have been recognized as kinase inhibitors cannot be ruled out. A class effect such. Several other protein kinase inhibitors include including midostaurin is also suggested by Alsulaili information about sun sensitivity in their product 8 et al., who described one of the patients included in labels, and although the mechanisms for these

WHO Pharmaceuticals Newsletter No. 2, 2020 • 21 Signal drugs are not fully understood, a class effect https://www.ema.europa.eu/en/documents/ass causing sun sensitivity is possible and has essment-report/rydapt-epar-public-assessment- previously been proposed.9 Photosensitivity related report_en.pdf. Accessed: 19/06/2019 to midostaurin has previously been noted in a 5. US Daily Med summary of product prospective survey where as many as one out of characteristics for Midostaurin (Rydapt). four patients reported occurrence of URL:https://dailymed.nlm.nih.gov/dailymed/dru photosensitivity.10 gInfo.cfm?setid=11fa3fc9-6776-49a6-b1c1- Sun sensitivity reactions increase the risk of 653f627c3e58&audience=consumer. Accessed: aggravating existing skin conditions, can worsen 19/06/2019 diverse autoimmune disorders, and can also 6. UK summary of product characteristics (UKeMC) eventually lead to skin cancer. Photosensitivity for Imatinib (Glivec). URL: reactions are preventable and might not be https://www.medicines.org.uk/emc/product/77 recognized as such if they are not mentioned in the 79/smpc. Accessed: 05/06/2019 product labels. Patients should be informed about these adverse drug reactions so that they are able 7. UK summary of product characteristics (UKeMC) to take drugs of this profile without being exposed for Gefitinib (Iressa). URL: URL: to unnecessary harm. https://www.medicines.org.uk/emc/product/66 02 . Accessed: 05/06/2019

8. UK summary of product characteristics (UKeMC) References for different protein kinase inhibitors (ATC 1. EU summary of product characteristics (EU SPC) group L01XE). URL: for Midostaurin (Rydapt). URL: https://www.medicines.org.uk/emc/. Accessed: https://www.ema.europa.eu/en/documents/pro 05/06/2019 duct-information/rydapt-epar-product- 9. Alsulaili M., Marguery M.C, Tournier E. et al. information_en.pdf. Accessed: 17/05/2019 Éruption photodistribuée sous midostaurine. 2. DermNet NZ. URL: Annales de Dermatologie et de Vénéréologie. https://www.dermnetnz.org/topics/photosensiti 2017: 144(12) :337. vity/. Accessed: 19/10/25 10. Chandesris M.O, Damaj G., Canioni D. et al. 3. Moore D.E. Drug-Induced Cutaneous Midostaurin in advanced systemic mastocytosis. Photosensitivity. Drug Saf. 2002:25(5)345-372. N Engl J Med. 2016: 374(26)2605-7. 4. European assessment Report for Midostaurin (Rydapt). URL:

Response from Novartis

1 Introduction However, animal studies did not provide a The UMC-WHO collaborating Centre for conclusive evidence of a photosensitive potential of International Drug Monitoring invited Novartis to midostaurin. comment on a draft signal document concerning midostaurin and photosensitivity before distribution 2.2 Data from midostaurin clinical trials to the national pharmacovigilance centers in the Review of data from midostaurin clinical trials in member countries of the WHO Programme for AML indication did not reveal any imbalance of International Drug Monitoring. photosensitivity reaction in the active arm, as

compared to the placebo arm. Although in the 2 Novartis Response advanced systemic mastocytosis pool the incidence Novartis acknowledges UMC-WHO signal of events pertaining to photosensitivity reaction was assessment on midostaurin and photosensitivity. As relatively higher as compared to the AML indications requested by UMC-WHO, Novartis has performed a (2.8% vs. 0.9%), these incidence rates were based detailed analysis of this safety topic including data on a very limited absolute number of events (n=4) from all available data sources, as presented below. for making a meaningful causality assessment. Of note, cutaneous manifestations are frequent in patients with mastocytosis as part of the natural 2.1 Preclinical toxicology data history of the disease itself and hence, a causal role Midostaurin is a small molecule that inhibits of midostaurin based on these limited numbers of multiple receptor tyrosine kinases. In vitro assays events in a single arm study in the mastocytosis have demonstrated that midostaurin absorbs light setting is difficult to ascertain. in the relevant spectrums of UVB and UVA range. WHO Pharmaceuticals Newsletter No. 2, 2020 • 22 Signal

2.3 Data from Novartis Global Safety reaction did not recur. Hence, a causal role of Database midostaurin is unlikely for the event of A cumulative search using the Preferred Terms photosensitivity reaction. (PT): Application site photosensitivity reaction, Chronic actinic dermatitis, Implant site In the second case, a 78-year-old female subject photosensitivity, Infusion site photosensitivity had been taking midostaurin for around two months reaction, Injection site photosensitivity reaction, for the treatment of mastocytosis, and experienced Juvenile spring eruption, Photodermatosis, photosensitivity reaction (erythema and facial Photoonycholysis, Photosensitivity reaction, edema, photodistributed erythematopapular Polymorphic light eruption, Pseudoporphyria, lesions). The subject’s medical history was not Retinal phototoxicity, Solar dermatitis, Solar reported, and the relevant concomitant medications urticaria, and Sunburn with MedDRA v22.1 was included mirtazapine, cetirizine and pantoprazole. performed in the Novartis Global Safety Database Photo-tests demonstrated a decrease in the (until 15-Jan-2020). This search retrieved 10 cases minimum erythematous dose (DEM) of 0.5 J with [Managed Access Program (MAP), n=9 and UVA for midostaurin. Midostaurin was stopped, and Spontaneous Report (SR), n=1] disclosing 11 the subject recovered after treatment with events of interest. Seven of the nine MAP cases corticosteroids, photo-protection measures and were reported from France, while single cases were hydrochloroquine. reported from Germany and United States, respectively. The reported PTs in these 10 cases Novartis Comment: Though photo-test was positive were ‘Photosensitivity reaction’ n=9, for midostaurin, the concomitant administration of ‘Pseudoporphyria’ and ‘Sunburn’ n=1 each. The pantoprazole, mirtazapine, and cetirizine were reported indications for midostaurin were systemic strong risk-factors. Considering the strong mastocytosis n=8, and mastocytosis n=1, while the confounders, causal role of midostaurin for the indication was not reported in one case. photosensitivity reaction could not be conclusively established. One of the 10 cases reporting possible sunburn, the event occurred during sun-exposure while working with plastics (potential for allergic reaction); the 3 Literature event was confounded by the concomitant use of Two articles (Chandesris et al 2016, Chandesris et valaciclovir. In seven other cases, limited al 2017) mention the incidence (25%) of information was reported regarding the concomitant photosensitivity reaction in a French MAP in 28 medications, medical history (including history of mastocytosis subjects without further stating dermatological conditions), time to onset of the further details about the reported photosensitivity event, and clinical course of the event. The reactions. Of note, the seven case reports from the remaining two cases are discussed below. French MAP are databased in Novartis Global Safety Database and were commented above. Siiskonen et One case refers to a 68-year-old male subject who al 2017 highlighted the involvement of mast cells in experienced photosensitivity reaction the pathophysiology of polymorphic light eruptions (erythematous lesions in the photo-exposed areas and sunburns. associated with bullae on both dorsal aspects of hands and the face) while taking midostaurin for more than seven months for systemic mastocytosis. 4 Conclusion The event happened when he went on his first A comprehensive review of data from all available beach-side holidays after eight years. Relevant sources did not reveal any new or changing safety concomitant medications included desloratadine, signal related to the use of midostaurin and perindopril, and rosuvastatin. Skin biopsy showed photosensitivity reaction. Based on the limited eczema along with necrotic keratinocytes and reports of photosensitivity reaction reported only in discreet lymphocytic infiltrates. Blood and urinary the mastocytosis indications, a causal relationship porphyrins as well as photobiological testing were with midostaurin cannot be established because normal, the polychromatic minimal erythema dose cutaneous manifestations are frequent in all was 1883 mJ/cm2 (normal range was greater than mastocytosis patients. Further, the release of mast

400), and phototest UVA 13 J/cm2 was negative at cell mediators and mast cell degranulation in 24 hours with normal pigmentation. The subject mastocytosis patients may be precipitated by a improved with the appropriate protective measures. variety of stimuli including extremes of Midostaurin was continued unchanged, but the temperatures or sudden temperature changes. In photosensitivity reaction did not recur. the absence of conclusive evidence of a causal association between midostaurin use and Novartis Comment: In this case, the reported photosensitivity reaction, Novartis is of the opinion photosensitivity reaction could be a normal that no change to the label is warranted at this physiological response to prolonged sunlight point in time. Novartis will continue monitoring this exposure in mastocytosis indication. safety topic applying routine pharmacovigilance In addition, the concomitant administration of measures and will notify the Authorities should desloratadine, perindopril, and rosuvastatin were further data indicate causality. strong confounding factors for the event. Midostaurin was continued, but the photosensitivity WHO Pharmaceuticals Newsletter No. 2, 2020 • 23 Signal

5 References Cancer: Targets and Therapy; 7: 25-35. Chandesris, MO, Damaj, G, Canioni, D, et al. (2016) Siiskonen H, Smorodchenko A, Krause K, et al. Midostaurin in advanced systemic mastocytosis. (2017) Ultraviolet radiation and skin mast cells: New England Journal of Medicine; 374 (26):2605-7. Effects, mechanisms and relevance for skin Chandesris, MO, Damaj, G, Lortholary, O, et al. diseases. Experimental Dermatology: 27 (1): 3-8. (2017) Clinical potential of midostaurin in advanced systemic mastocytosis. Blood and Lymphatic

Tramadol and hyperacusis Marian Attalla, Uppsala Monitoring Centre

Summary migraines, depression and post-traumatic stress disorder, Bell’s palsy and Ménière’s disease. Tramadol and hyperacusis was identified as a Exposure to sudden loud noise or a negative life potential signal in a screening of VigiBase, the WHO event can also trigger hyperacusis. However, for global database of individual case safety reports, many people with hyperacusis there is no clear focusing on patient reports. As of June 2019, there cause.4,6 were 20 reports for the combination. Overall, they support an association between tramadol and Tramadol and hyperacusis was first identified as a hyperacusis with all cases reporting tramadol as the potential signal in a screening of VigiBase focusing only suspect drug, and with a consistent time-to- on patient reports, in April 2018. The aim of this onset of up to two days among all cases that assessment is to investigate if there is a causal provided it. In addition, six cases reported a relationship between tramadol and hyperacusis. positive dechallenge and two a positive rechallenge.

κ-opioid receptor-mediated facilitation of NMDA receptor sensitivity to glutamate has been Reports in VigiBase suggested as a mechanism for hyperacusis in rodents. Hyperacusis is not listed as an adverse As of June 2019, there were 20 reports of tramadol reaction in the label for tramadol, and while and hyperacusis (see Table 1). The combination changes in sensorial capacity is, this might not be was not disproportionately over-reported, with the specific enough for the patients, who would benefit expected number of reports being 21 (26 June from more precise labelling. 2019). There were 15 cases for females and five for males. The reports came from Denmark (4), UK (4), Netherlands (4), Australia (2), US (2) and Canada, France, Norway, and Thailand (1 each). Age (given Introduction in 18 cases) ranged from 17 to 62 years, with a Tramadol is indicated for the treatment of moderate median of 38 years. Eleven reports were from to severe pain. It’s an opioid agonist acting on μ-, consumers, four from pharmacists, four from δ- and κ-opioid receptors, with a higher affinity for physicians and the reporter type was unknown for the μ receptor.1 The analgesic effect is also the remaining. achieved by inhibiting neuronal reuptake of In two cases, hyperacusis seemed to have occurred noradrenaline and by enhancing serotonin release. after tramadol withdrawal. In one case (5), the Peak plasma concentration is reached after 4.9 patient experienced hyperacusis, flu symptoms, hours and the half-life is six hours.1 The analgesic tiredness, light sensitivity, poor sleep and effect occurs within 30-60 minutes after intake.2,3 formication after tramadol was stopped and the Hyperacusis can be described as experiencing reporter attributed these to withdrawal symptoms. “sounds of everyday life as intrusively loud, The other case of hyperacusis after withdrawal (8) uncomfortable, and sometimes painful”.4 It can describes a patient who was on tramadol treatment either develop suddenly or over time. To avoid for five years for back pain (50 mg/d). The noise, some people may withdraw from normal daily narrative revealed that six months after tramadol activities and may therefore become isolated. had been withdrawn the patient started treatment School and work may also be compromised.4,5 with sertraline and experienced extreme sound and light sensitivity, sexual dysfunction, extreme The causes of hyperacusis are unknown but it has irritation/anger, suicidal thoughts, fatigue, and been linked with a number of conditions including auditory hallucinations. tinnitus, damage to the inner ear or brain, WHO Pharmaceuticals Newsletter No. 2, 2020 • 24 Signal

In all the remaining 18 cases, tramadol was the Hyperacusis is not labelled for tramadol in either only drug reported as suspected. Concomitant the UK or the US.1,7 However, tinnitus is described drugs were reported in 10 cases, none of which are as a symptom of withdrawal in the UK SmPC,1 along labelled for hyperacusis. Two cases (3, 17) reported with psychiatric adverse reactions, including the use of sumatriptan, which is used for migraines, changes in mood (usually elation, occasionally and another case (4) reported the use of dysphoria), changes in activity (usually venlafaxine, which is usually used to treat suppression, occasionally increase), and changes in depression. Both conditions have been linked with cognitive and sensorial capacity (e.g. decision hyperacusis. Three cases (11, 18, 20) reported the behaviour, perception disorders). In the US label, use of other opioids in addition to tramadol. tinnitus and deafness are listed under “other adverse experiences, causal relationship Time-to-onset was provided in 14 cases and it was unknown”.7 reported to be one day or less in 13; in the remaining case it was two days. The action taken Hyperacusis is not given on the Patient Information with tramadol was unknown in six cases, dose not Leaflet (PIL) either. However some PILs for different changed in four, dose reduced in one (case 11) and tramadol products state that psychological reactions drug withdrawn in seven cases (cases 1, 2, 9, 12, may appear, such as “a change in mood (mostly 15, 17, 20). Of the eight cases where the drug was high spirits, occasionally irritated mood), changes in withdrawn or the dose was reduced, six reported a activity (slowing down but sometimes an increase in recovery. In case 15, concomitant drugs were also activity), and decreased cognitive and sensory withdrawn at the same time as tramadol and the perception (being less aware and less able to make patient recovered. An additional four patients decisions, which may lead to errors in recovered but the action taken with the drug was judgement)”.8,9 The PIL for another product lists either unknown or the dose was not changed. “changes in senses and recognition” as an adverse reaction.10 Two cases (1, 18) reported a positive rechallenge. Case 18, reported by a physician, describes a 32- The SmPCs for the opioid oxycodone, list year-old patient who experienced hyperacusis (no hyperacusis as an adverse reaction.11,12 Some other events reported) on the same day that brands list it under the group “ear and labyrinth treatment with tramadol was started. The case disorders”, while others list it under “psychiatric reported a positive rechallenge but there was no disorders”. In the PIL, "abnormally acute sense of detailed information about the event, and it did not hearing (hyperacusis)" is described.13 However, the state whether the drug was withdrawn, prior to labels for other opioids such as morphine, codeine, rechallenge. Case 1 describes a patient who tapentadol, hydromorphone, hydrocodone, fentanyl, experienced hyperacusis 15-25 minutes after buprenorphine, oxymorphone, meperidine, starting on tramadol for postoperative pain. No methadone, pentazocine, and butorphanol do not other concomitant drugs and no other adverse list hyperacusis, while labels for buprenorphine, events were reported. Both a positive dechallenge butorphanol and fentanyl list tinnitus.14-16 and a positive rechallenge were reported (without much information about the event). Discussion A few cases illustrate how hyperacusis affected the patient’s life. For example, case 3 describes a 32- It has been suggested that opioids can affect year-old female who experienced increased sound hearing. There have been reports of hearing loss sensitivity only when taking tramadol, which went associated with chronic opioid use or with opioid away once the dose wore off. The patient also took overdose.17,18 Also, as mentioned above, tinnitus desogestrel/ethinylestradiol, levothyroxine and (even deafness) is listed in the labels of some sumatriptan: opioids including tramadol.1,7,14-16 Often, tinnitus and hyperacusis co-exist. In patients with a primary “Sounds become louder, more penetrating and complaint of hyperacusis, the prevalence of tinnitus grating. For example, when someone is talking has been reported to be 86%. For patients with a or cutlery on a plate. Almost like sound is more primary complaint of tinnitus, the prevalence of in your face. It becomes difficult to be around hyperacusis has been reported to be 40%. As such other people or in noisy places.” it has been suggested that hyperacusis and tinnitus Twelve cases co-reported other reactions. The top could have common mechanisms.19 co-reported terms were headache (6 cases), nausea Both hyperacusis and tinnitus can be worsened by (5), dizziness (4), photophobia (4), somnolence (4), fatigue and stress. In their work, Sahley et al. vomiting (4), fatigue (3), hyperhidrosis (3), proposed that in response to stress, endogenous insomnia (3) and irritability (3). All of these are dynorphins are released that act on κ-opioid labelled in the tramadol Summary of Product receptors in cochlea.20,21 This in turn might facilitate Characteristics (SmPC) except for photophobia and NMDA receptor sensitivity to glutamate, possibly irritability.1 leading to increased auditory sensitivity. Indeed in one of their studies, κ-opioid receptor agonists ((-)pentazocine and U-50488H) were administered Labelling and literature across the cochlear round window membrane in chinchillas.20 The amplitude changes observed WHO Pharmaceuticals Newsletter No. 2, 2020 • 25 Signal amounted to increases in sensitivity of between 4 to taste, smell, touch). However, patients might not 8 decibels. So a suggested mechanism for realise that hyperacusis could be part of this and hyperacusis is through κ-opioid receptor-mediated the majority of these reports come from consumers. facilitation of NMDA receptor sensitivity to glutamate, that may occur under stressful conditions.21 Conclusion As previously mentioned, oxycodone is labelled for Hyperacusis following the intake of tramadol has hyperacusis.11,12 A study found that oxycodone acts been found in VigiBase from a number of countries. as a κ2b-opioid agonist with relatively low affinity for The association is not disproportionally over- the μ receptor.22 This could strengthen the reported. However, the following point towards a hypothesis that hyperacusis could be mediated by causal relationship: κ-opioid receptor activation. On the other hand, tramadol has the highest affinity for the μ - Tramadol is the only suspected drug in all receptor.1,23 However, it still acts on κ receptors cases. and could in theory also cause hyperacusis through - There is a close temporal relationship (two them, but perhaps to a lesser extent. days or less) when the information on time- Considering the extensive use of tramadol globally, to-onset is available. the number of reports in VigiBase is low. The - Six cases report a positive dechallenge and association is not disproportionally over-reported, two also report a positive rechallenge with the number of observed reports being 20 and although details in some reports were the expected number 21. However, the available missing. cases do support a relationship between tramadol intake and hyperacusis. Specifically, all cases - κ-opioid receptor-mediated facilitation of reported tramadol as the only suspect drug and the NMDA receptor sensitivity to glutamate has time-to-onset was two days or less among the 14 been suggested as a mechanism for cases that provided it. Also, in the eight cases hyperacusis. where tramadol was withdrawn or its dose reduced, - The opioid oxycodone is labelled for six reported a positive dechallenge and two a hyperacusis. positive rechallenge. The label for tramadol already lists changes in A few cases mentioned other conditions linked with sensorial capacity as an adverse reaction. However, hyperacusis. Two (3, 17) reported concomitant patients may not realise that hyperacusis could be treatment with sumatriptan, which is used for part of this and may not appreciate the possible migraines. But in both of these, hyperacusis impact it could have on the quality of life. Since the occurred on the same day as tramadol was started. majority of these reports come from consumers, Also, in case 17, the patient had been on they could benefit from clearer labels. sumatriptan for 12 years before tramadol introduction, so the patient’s history of migraines seems unlikely to be related to the event. The start References date of sumatriptan in case 3 was unknown. Another case (4) reported treatment with 1. Electronic Medicines Compendium: Summary of venlafaxine for an “ill-defined disorder”. The drug is Product Characteristics for tramadol usually used to treat depression, also a condition to (Brimisol®). Available from: which hyperacusis has been linked. However, the https://www.medicines.org.uk/emc/product/85 start date of both venlafaxine and tramadol was not 50/smpc. Accessed: 15 June 2019. given and thus the time relationship to the event is 2. Tramadol: strong painkiller to treat severe pain. unknown. nhs.uk. 2018. Available from: Moreover, three cases reported the use of another https://www.nhs.uk/medicines/tramadol/. opioid in addition to tramadol. Cases 11 and 18 Accessed: 5 Dec 2019. report codeine/paracetamol with unknown start 3. Tramadol Hydrochloride Monograph for date, but in both cases hyperacusis occurred within Professionals - Drugs.com. Available from: one day after the start of tramadol. Case 20 https://www.drugs.com/monograph/tramadol- mentions concomitant treatment with pentazocine hydrochloride.html. Accessed: 5 Dec 2019. which has agonist action at κ-opioid receptors and antagonist action at µ receptors.24 Pentazocine was 4. Hyperacusis. British Tinnitus Association. started a week before and stopped a day before Available from: tramadol was introduced and hyperacusis occurred. https://www.tinnitus.org.uk/hyperacusis. Accessed: 5 Dec 2019. One could argue that the adverse reaction “changes in sensorial capacity” or “changes in senses and 5. What Causes This? | Hyperacusis. Available recognition” described in tramadol labels1,10 could from: http://www.hyperacusis.net/what-is- be interpreted as encompassing changes in hearing it/what-causes-this/. Accessed: 5 Dec 2019. capacity, e.g. hyperacusis, since hearing is one of the five basic senses in humans (sight, hearing,

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6. What Is Sound Sensitivity (Hyperacusis)? https://dailymed.nlm.nih.gov/dailymed/drugInf WebMD. Available from: o.cfm?setid=b8e48063-0b40-ee43-85c1- https://www.webmd.com/brain/sound- 4ef2de80c404&audience=consumer. Accessed: sensitivity-hyperacusis. Accessed: 5 Dec 2019. 22 Jul 2019. 7. US Food and Drug Administration: Product label 16. Electronic Medicines Compendium: Summary of for tramadol. Available from: Product Characteristics for fentanyl. Available https://dailymed.nlm.nih.gov/dailymed/drugInf from: o.cfm?setid=ae7c54b1-b440-4cca-97e8- https://www.medicines.org.uk/emc/product/54 e5b825413d32&audience=consumer. Accessed: 00/smpc. 22 Jul 2019. 6 Sep 2019. 17. Oroei M, Peyvandi AA, Mokhtarinejad F. Opioid 8. Electronic Medicines Compendium: Patient Drugs and Sensorineural Hearing Loss. Addict Information Leaflet for tramadol (Maxitram Health. 2018 Jan;10(1):64–6. SR®). Available from: 18. Kopec KT, Nelson LS. Opioid-Induced Hearing https://www.medicines.org.uk/emc/product/69 Loss. Emergency Medicine. 2012 Nov;44(11):4– 89/pil. Accessed: 9 Oct 2019. 6. 9. Electronic Medicines Compendium: Patient 19. Baguley DM. Hyperacusis. J R Soc Med. 2003 Information Leaflet for tramadol (Maneo®). Dec;96(12):582–5. Available from: https://www.medicines.org.uk/emc/product/84 20. Sahley TL, Anderson DJ, Chernicky CL. Bi- 75/pil. Accessed: 4 Nov 2019. phasic intensity-dependent opioid-mediated neural amplitude changes in the chinchilla 10. Electronic Medicines Compendium: Patient cochlea: partial blockade by an N-Methyl-D- Information Leaflet for tramadol. Available Aspartate (NMDA)-receptor antagonist. Eur J from: Pharmacol. 2008 Feb 2;580(1–2):100–15. https://www.medicines.org.uk/emc/product/46 48/pil. Accessed: 4 Nov 2019. 21. Sahley TL, Hammonds MD, Musiek FE. Endogenous dynorphins, glutamate and N- 11. Electronic Medicines Compendium: Summary of methyl-d-aspartate (NMDA) receptors may Product Characteristics for oxycodone participate in a stress-mediated Type-I auditory (Carexil®). Available from: neural exacerbation of tinnitus. Brain Res. 2013 https://www.medicines.org.uk/emc/product/20 Mar 7;1499:80–108. 68/smpc. Accessed: 9 Oct 2019. 22. Nielsen CK, Ross FB, Lotfipour S, Saini KS, 12. Electronic Medicines Compendium: Summary of Edwards SR, Smith MT. Oxycodone and Product Characteristics for oxycodone morphine have distinctly different (Lynlor®). Available from: pharmacological profiles: radioligand binding https://www.medicines.org.uk/emc/product/11 and behavioural studies in two rat models of 97/smpc. Accessed: 31 Oct 2019. neuropathic pain. Pain. 2007 Dec 13. Electronic Medicines Compendium: Patient 5;132(3):289–300. Information Leaflet for oxycodone (Lynlor®). 23. Raffa B, Vaught L, Shank P, Codd E. Opioid and Available from: Nonopioid Components Independently https://www.medicines.org.uk/emc/product/11 Contribute to the Mechanism of Action of 97/pil. Accessed: 31 Oct 2019. Tramadol, an ‘Atypical’ Opioid Analgesic. 14. Electronic Medicines Compendium: Summary of 1992;260:11. Product Characteristics for buprenorphine 24. Electronic Medicines Compendium: Summary of (Bunov®). Available from: Product Characteristics for pentazocine. https://www.medicines.org.uk/emc/product/97 Available from: 98/smpc. Accessed: 22 Jul 2019. https://www.medicines.org.uk/emc/product/88 15. US Food and Drug Administration: Product label 33/smpc. Accessed. 11 Nov 2019. for butorphanol. Available from:

Table 1. Characteristics of case reports in VigiBase of hyperacusis in association with tramadol. Case Age/ Suspected (S), Reactions (MedDRA PT) Time-to-onset Action taken with drug Outcome number Sex interacting (I) or (TTO) (dechallenge/rechallenge, concomitant (C) drugs - for unknown) 1 -/F Tramadol (S) Hyperacusis 15-25 minutes Drug withdrawn/Reaction Recovered abated Rechallenge/Reaction recurred

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Case Age/ Suspected (S), Reactions (MedDRA PT) Time-to-onset Action taken with drug Outcome number Sex interacting (I) or (TTO) (dechallenge/rechallenge, concomitant (C) drugs - for unknown)

Note: no details around rechallenge – only reported in structured field 2 38/F Tramadol (S) Dyspnoea, Flushing, Hyperacusis, - Drug withdrawn/- Unknown Acetylsalicylic acid, Hypopnoea, Somnolence Gabapentin, Macrogol 3350, Senna (C) Note: TTO not reported but narrative reveals that events occurred after tramadol intake and the duration of tramadol use was 1 day. 3 32/F Tramadol (S) Hyperacusis 0 days Dose not changed/- Unknown Desogestrel/ ethinylestradiol, Levothyroxine, Sumatriptan (C) 4 -/F Tramadol (S), Asthenia, Decreased appetite, Fatigue, - Dose not changed/No Not Venlafaxine (C) Hyperacusis, Irritability, Malaise, Tinnitus effect observed recovered 5 54/F Tramadol (S) Fatigue, Formication, Hyperacusis, - -/Reaction abated Recovering Influenza, Photophobia, Poor quality sleep, Withdrawal syndrome Note: Patient had been on tramadol for years and experienced ADRs in response to drug withdrawal. 6 21/ Tramadol (S) Abdominal pain upper, Aggression, 0 days - Not M Anxiety, Appetite disorder, Bone pain, recovered Burning sensation, Confusional state, Note: follow-up Constipation, Coordination abnormal, information also reveals Decreased immune responsiveness, treatment with “THC” Dependence, Depression, Disturbance in attention, Dizziness, Dry mouth, Dysgeusia, Erectile dysfunction, Euphoric mood, Fatigue, Feeling hot, Gastric ulcer, Headache, Heart rate decreased, Hyperacusis, Hyperaesthesia, Hyperhidrosis, Hypoglycaemia, Influenza like illness, Insomnia, Irritability, Memory impairment, Mental impairment, Muscle spasms, Muscle twitching, Nausea, Neuralgia, Orthostatic hypotension, Paraesthesia, Parosmia, Periodontitis, Photophobia, Pyrexia, Shock, Somnolence, Syncope, Throat tightness, Vision blurred, Vomiting, Weight fluctuation, Withdrawal syndrome 7 41/F Tramadol (S) Hyperacusis, Insomnia, Pruritus 0 days -/Reaction abated Recovered 8 40/ Tramadol (S) Anxiety, Cognitive disorder, Derealisation, - -/Reaction abated Recovered M Fatigue, General physical health deterioration, Hyperacusis, Impaired work ability, Memory impairment, Nervous Note: Patient had used WHO Pharmaceuticals Newsletter No. 2, 2020 • 28 Signal

Case Age/ Suspected (S), Reactions (MedDRA PT) Time-to-onset Action taken with drug Outcome number Sex interacting (I) or (TTO) (dechallenge/rechallenge, concomitant (C) drugs - for unknown) system disorder, Photophobia, Psychotic tramadol for 5 disorder years. 6 months after stopping treatment with tramadol patient was treated with sertraline to which he experienced sound sensitivity among other reactions 9 20/F Tramadol (S) Hyperacusis 4 hours Drug withdrawn/Reaction Recovered abated 10 20/F Tramadol (S) Hyperacusis 30 minutes Dose not Recovered changed/Reaction abated 11 28/F Tramadol (S) Aggression, Amnesia, Anger, Anxiety, 1 day (within) Dose reduced/No effect Not Codeine/paracetamol Confusional state, Delusion, Depressed observed recovered (C) mood, Emotional disorder, Feeling abnormal, Hallucination, Headache, Hyperacusis, Irritability, Pain, Photophobia, Somnolence, Tremor 12 57/F Tramadol (S) Dizziness, Feeling abnormal, Headache, - Drug withdrawn/Reaction - Hyperacusis, Photophobia, Somnolence abated Note: TTO not reported but tramadol was stopped the same day it was started. 13 17/F Tramadol (S), Hyperacusis 2 days Dose not changed/- Unknown Paracetamol (C) 14 47/F Tramadol (S) Asthenia, Feeling cold, Headache, - - - Hyperacusis, Hyperhidrosis, Syncope, Tremor 15 38/F Tramadol (S), Hyperacusis, Nausea, Rash, Vomiting 0 days Drug withdrawn/Reaction Recovered Diclofenac, Tolperisone abated (C) Note: concomitant drugs also reported to be withdrawn on same day as tramadol 16 62/ Tramadol (S), Atenolol, Disturbance in attention, Dysarthria, 2 hours Drug withdrawn/- - M Ibuprofen (C) Hyperacusis, Nausea, Panic attack, Urinary retention, Vomiting Note: ibuprofen was introduced at the same time as tramadol. 17 39/ Tramadol (S), Anorgasmia, Constipation, Dizziness, Dry 1 hour Drug withdrawn/Reaction Recovered M Paracetamol, mouth, Fatigue, Headache, Hyperacusis, abated Sumatriptan, Hyperhidrosis, Insomnia, Logorrhoea, Testosterone (C) Nausea, Pruritus, Respiratory rate decreased, Tremor Note: concomitant drugs had been taken

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Case Age/ Suspected (S), Reactions (MedDRA PT) Time-to-onset Action taken with drug Outcome number Sex interacting (I) or (TTO) (dechallenge/rechallenge, concomitant (C) drugs - for unknown) for 12-23 years before tramadol introduction. 18 32/F Tramadol (S) Hyperacusis 0 days - Recovered Bupivacaine/glucose, Rechallenge/Reaction Codeine/paracetamol, recurred Diclofenac, Paracetamol, Rubella vaccine (C) Note: withdrawal information lacking although a positive rechallenge is reported 19 51/F Tramadol (S) Balance disorder, Headache, Hyperacusis, 1 day - Recovered Photophobia, Vomiting 20 36/ Tramadol (S) Decreased appetite, Dizziness, 0 days Drug withdrawn Recovering M Bendroflumethiazide/ Hyperacusis, Nausea, Stomatitis propranolol, Diazepam, Pentazocine (C) Note: pentazocine, another opioid with agonist action at kappa receptors, was started a week before and stopped a day before tramadol was started and subsequent onset of ADR. Tramadol was withdrawn a day after reaction occurred. It is possible that pentazocine could be related to event.

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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. 2, 2020 • 31 Feature

Recommendations from the 42nd Annual Meeting of Representatives of the National Pharmacovigilance Centres Participating in the WHO Programme for International Drug Monitoring

The annual meeting of National Pharmacovigilance Centres (NPCs) participating in the WHO Programme for International Drug Monitoring (PIDM) provides a platform for representatives from around the world to meet and discuss pharmacovigilance (PV) issues. Representatives of Member States have the opportunity to interact with each other, WHO, and WHO Collaborating Centres (WHO CCs) face to face, exchange information on country needs, and propose how WHO and WHO CCs can support them. One of the most important outcomes from this meeting is the formation of recommendations which shape the future of PV. Recommendations are made by delegates through group work. The forty second annual meeting of representatives of NPCs participating in the WHO PIDM was held from 30 October to 1 November 2019, in Bogotá, Colombia. The meeting included four working groups that discussed various issues in PV. The summary of discussions and the recommendations are described in this article.

Working Group 1: Making adverse drug reaction (ADR) reporting ‘easy like Sunday morning’ This working group aimed to examine factors affecting global ADR reporting rates and quality of reporting, as well as how measures implemented to improve the number and quality of ADR reports can be translated into better regulatory action and/or clinical practice. Methods to measure the impact of these factors were explored.

The following recommendations were proposed by Representatives, which can be adopted by NPCs, WHO, and WHO CCs, where appropriate. Training • Offer twinning programmes to share experiences at local, regional and global level • Deliver training for different target groups, such as regulators, TOT (train the trainers) and facilitators, health-care professionals, patients and patient groups Establish PV focal points • Identify and establish PV focal points in local health-care systems • Engage with local focal points to facilitate quality ADR reporting • Train/re-train the focal points on reporting requirements, processes, and tools Align • Integrate PV systems into national health-care system (hospital, primary care, pharmacy etc.) with the right integration in patient management • Link PV system with public health programmes • Link ADR reporting with electronic health records (EHR) where available • Collaborate with health-care professional associations and patient associations Others • Make reporting rates available to national and regional PV centres • Use the number of ADRs reported to the national/regional centres as an indicator • Establish national and international PV day • Develop user-friendly and cheaper apps for reporting • Provide different forms for different purposes (quality defects, substandard and falsified drugs) that are accessible through e-reporting and apps • Offer additional options for patient reporting such as: free call line, text messages, WhatsApp, etc. • Deliver unified systems

During the discussion, delegates underscored the importance of PV professionals working collaboratively with other health-care and public health partners, such as hospitals, drug information centres, and multi-drug

WHO Pharmaceuticals Newsletter No. 2, 2020 • 32 Feature

resistance programmes. It was also suggested that a core reporting form, adaptable for various reporting needs, could be beneficial in improving quantity and quality of ADR reporting.

Working Group 2: Smart Safety Surveillance (3S): What does it mean, how do we implement it? The objective of this working group was to discuss the concept of Smart Safety Surveillance (3S) and share related experiences and ongoing 3S initiatives. The 3S approach aims to strengthen pharmacovigilance capacity in the long-term by establishing end-to-end safety surveillance of products from their clinical development to the post-market stages. It was agreed that the 3S is an approach and not a method. The goal of 3S is to effectively allocate limited resources to monitor the safety of health products. Its application can be country-specific and approaches can be tailored to unique risks identified. It involves identifying investments with best value for expenditure, assessment of gaps and introducing 3S in the PV institutional development plan (IDP), and then reassessment of the IDP. The criteria for identifying “products” that fit the 3S approach was reviewed and the improvements/recommendations on the 3S approach using experiences from Thailand, were proposed.

Recommendations for NPCs • Incorporate 3S into the WHO Global Benchmarking Tool (GBT), since both employ the same approach for gap identification and the development of mitigation strategies, as part of the IDP • Adopt a country- and region-specific approach to 3S; the tailored approach will best respond to their unique risks, competing priorities and available resources

Recommendations for WHO, WHO CCs and NPCs • Explore the implementation of 3S for studying population-specific aspects, e.g. pregnant women taking medications

Working Group 3: Signal detection and methodology This working group discussed general methods of signal detection, appropriate choice of signal detection methods, their advantages and limitations, and the use of different data sources.

Recommendations for NPCs • Identify areas for improving quality of ADR reporting (for example using live-chat with reporters) • Improve access to internet and scientific literature • Develop tools for sharing information at national level with health-care professionals • Increase human resources for PV (for example, hiring volunteers from academia and medical school) • Develop clear Standard Operating Procedures and work flow for signal detection • Convene a technical committee, which includes a focal point of contact, for consultation on each signal • Provide adequate training, with assessment, to health-care professionals on ADR reporting • Create regional country networks to share information • Leverage Vigilyze, to monitor data and signals, and to follow-up quantitative analysis with qualitative ones

Recommendations for WHO and WHO CCs • Share safety signal investigations and information from other authorities • Create a live-chat feature on VigiLyze to facilitate communication among regulators with common problems of interest • Support signal detection capacity building with the use of tools such as VigiLyze • Promote harmonization of signal detection for Member States • Develop signal detection methodologies for countries with small databases • Establish recommendations for prioritization, especially in regulatory authorities that receive a high volume of low-quality reports

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• Promote inter-country networking for experience sharing

With regard to limited PV resources facing some countries as a barrier to signal detection, it was shared as an example that the African Medicines Regulatory Harmonization (AMRH) Programme supports countries for capacity building. The Programme was established in 2012. Although its current scope focuses primarily on registration and inspection, it does expand into regulatory functions such as pharmacovigilance. It demonstrates how capacity building can be more realistic at regional levels rather than national levels.

Working group 4: Using the WHO Global Benchmarking Tool (GBT) for improving national PV systems The aim of this working group was to understand the structure and purpose of the WHO GBT and the concept of Institutional Development Plans (IDPs). Experiences of the WHO GBT in Chile, Eritrea, El Salvador and Uganda were shared. Opportunities to integrate PV within a regulatory IDP for incremental, measurable and sustainable growth of the NPC were discussed.

Recommendations for NPCs • Make PV an integral part of the regulatory system to support appropriate regulatory decisions and actions on the safe use of medical products • Encourage self-assessment using WHO GBT to identify areas for improvement and help prepare for formal benchmarking by WHO. A PV system assessment will raise the level of the national regulatory authority (NRA) being benchmarked. • Develop PV action plan as part of regulatory IDP with the aim of an integrated PV system to promote consistency, efficiency and effectiveness, while taking 3S principles into consideration • To have a global overview to facilitate coordinated efforts • To avoid duplication of work by sharing tools, resources, and common tasks • To integrate medicines and vaccines PV at all stage of the PV process

Recommendations for WHO, WHO CCs and NPCs • Human resources are the key component for any performing PV system, and a PV system needs sufficient human resources, trained on methods, tools and techniques • Adopt a more effective and sustainable approach to capacity building, based on IDPs and defined competencies, that includes: • A train-the-trainers approach • A mix of virtual and in-class training • Mentorship • Collaboration with centres of training excellence

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