WHO Vision for Medicines Safety No country left behind: worldwide pharmacovigilance for safer medicines, safer patients The aim of the Newsletter is to disseminate regulatory information on the safety of pharmaceutical products, based on communications received from our network of national pharmacovigilance centres and other sources such as specialized bulletins and journals, as well as partners in WHO. The information is produced in the form of résumés in English, full texts of which may be obtained on request from: Safety and Vigilance: Medicines, EMP-HIS, World Health Organization, 1211 Geneva 27, Switzerland, E-mail address: pvsupport@who.int This Newsletter is also available at: http://www.who.int/medicines The WHO Pharmaceuticals Newsletter provides you with the latest information on the safety of medicines and legal actions taken by regulatory authorities around the world. It also provides signals based on information derived from the WHO global database of individual case safety reports, VigiBase. This edition of the Newsletter also includes the recommendations from the 42nd Annual Meeting of Representatives of National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring. Given the current interest over the use of chloroquine and hydroxychloroquine in COVID-19, we have also included a summary of case safety reports in Vigibase for these products. Contents Regulatory matters Safety of medicines Signal Feature WHO Pharmaceuticals NEWSLETTER 2020 No.2 ISBN 978-92-4-000568-6 (electronic version) ISBN 978-92-4-000569-3 (print version) © World Health Organization 2020 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). 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WHO Pharmaceuticals Newsletter No. 2, 2020 • 3 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 • 4 Table of Contents National Pharmacovigilance Centres Participating in the WHO Programme for International Drug Monitoring .............................................................................. 32 WHO Pharmaceuticals Newsletter No. 2, 2020 • 5 Regulatory Matters Acitretin Changes to pregnancy prevention requirements New Zealand. Acitretin is used to treat several skin conditions including psoriasis. Acitretin is teratogenic and is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met. Medsafe has announced that the period during which effective contraception must be used has increased from two to three years after the end of treatment with acitretin (Novatretin®). The change was due to the discovery of the formation of etretinate in the presence of alcohol, the half-life of which is 120 days. The package label and foils have been updated to reflect the increased post- treatment contraception requirement from 24 to 36 months. Reference: Prescriber Update, Medsafe, March 2020 (www.medsafe.govt.nz/) Alemtuzumab Updated restrictions and strengthened monitoring United Kingdom. The Medicines and Healthcare Products Regulatory Agency (MHRA) has announced that an EU review recommended a revised indication, additional contraindications and strengthened monitoring for alemtuzumab (Lemtrada®) due to the risk of cardiovascular events, thrombocytopenia and immune-mediated reactions. Alemtuzumab is a monoclonal antibody and is indicated for the treatment of adults with relapsing-remitting multiple sclerosis. The review concluded that serious cardiovascular reactions can rarely occur within one to three days of treatment. However unpredictable and potentially fatal immune-mediated reactions can occur within months and up to at least four years post-treatment. This included Epstein-Barr virus reactivation. Alemtuzumab should only be used as a single disease- modifying therapy in adults with specific conditions. Alemtuzumab is contraindicated in patients with severe active infection until complete resolution, those with a history of stroke and a history of angina. Patients should only be administered alemtuzumab in a hospital with ready access to intensive care facilities and should be monitored closely for cardiovascular reactions and non-immune thrombocytopenia. Reference: Drug Safety Update, MHRA, 12 February 2020 (www.gov.uk/mhra) (See WHO Pharmaceuticals Newsletter No.6, 2019: Risk of cardiovascular disorders and immune-related disorders in EU; No.4, 2019: Risk of serious cardiovascular and immune-mediated adverse reactions in UK; No.3, 2019: Cardiovascular and immune- mediated adverse effects in EU) Allopurinol Risk of aseptic meningitis Japan. The Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) have announced that the package insert for allopurinol (Zyloric®) should be revised to include septic meningitis as an adverse drug reaction. Allopurinol is indicated for management of hyperuricemia in patients with gout or hypertension accompanied by hyperuricemia. Although no cases involving aseptic meningitis have been reported in patients taking allopurinol in Japan during the previous three years, considering that cases were reported overseas the MHLW and PMDA have determined that the revision was necessary. Reference: Revision of Precautions, MHLW/PMDA, 25 February 2020 (www.pmda.go.jp/english/) Aminolevulinic acid Risk of hypotension Japan. The MHLW and the PMDA have announced that the package insert for aminolevulinic acid (Alaglio Divided Granules® and Alabel Oral®) should be revised to include hypotension as an adverse drug reaction. Aminolevulinic acid is indicated for visualization of non-muscle invasive bladder cancer during transurethral resection of the bladder tumour and that of malignant tissue during malignant glioma resection. A total of 26 cases of corresponding adverse events were reported in patients taking aminolevulinic acid in Japan during the previous three years. For 15 of these 26 cases a causal relationship between aminolevulinic acid and the adverse events could not be ruled out. MHLW/PMDA have concluded that revision of the package insert is necessary. Reference: Revision of Precautions, MHLW/PMDA, 25 February 2020 (www.pmda.go.jp/english/) WHO Pharmaceuticals Newsletter No. 2, 2020 • 6 Regulatory Matters Arsenic trioxide Risk of Wernicke’s encephalopathy Japan. The MHLW and the PMDA have announced that the package insert for arsenic trioxide (Trisenox®) should be revised to include Wernicke’s encephalopathy as an adverse drug reaction. Arsenic trioxide is indicated for recurrent or refractory acute promyelocytic leukemia. Although no cases involving Wernicke’s encephalopathy have been reported so far in patients taking arsenic trioxide in Japan, the revision was based on cases overseas. It was determined appropriate as currently there is no evidence on ethnic differences in the safety profile of the drug between patients in Japanese and those overseas. Reference: Revision of Precautions, MHLW/PMDA, 25 February 2020 (www.pmda.go.jp/english/) Cyproterone Risk of meningioma Europe. The European Medicines Agency (EMA) announced that the Pharmacovigilance Risk Assessment Committee (PRAC) has recommended that medicines with daily doses of 10 mg or more of cyproterone should only be used for androgen-dependent conditions such as hirsutism, alopecia, acne and seborrhoea once other treatment options have failed, due to the risk of meningioma. The medicines should only be used for reduction of sex drive in sexual deviations in men when other treatment options are not suitable. There is no change in the use of the medicines in men for prostate cancer. Cyproterone is an antiandrogen medicine acting in the same way as progesterone. It is indicated to treat various androgen-dependent conditions such as hirsutism, alopecia, acne, prostate cancer and reduction of sex drive in sexual deviations in men. Overall, the risk of meningioma risk is rare. Although there is no evidence of a risk for low- dose cyproterone in combination with ethinylestradiol or estradiol, as a precaution, these medicines should not be used in people who have or have had a meningioma. Health-care professionals should monitor patients for clinical signs and symptoms of meningioma. Symptoms include changes in vision, hearing loss, loss of smell, headaches, memory loss, seizures or weakness in extremities. Reference: EMA, 14 February 2020 (www.ema.europa.eu) (See WHO Pharmaceuticals Newsletter No.4, 2019; Risk of meningioma in EU) Direct-acting antivirals (DAAs) 1. Risk of abnormal blood sugar levels (dysglycemia) Canada. Health Canada has announced that it is working with the manufacturers to update product safety information of direct-acting antivirals (DAAs) to include the risk of dysglycemia among diabetic patients. DAAs are indicated for the treatment of chronic hepatitis C virus (HCV) infection. DAAs available in Canada include daclatasvir (Daklinza®), sofosbuvir (Sovaldi®) and the combination of sofosbuvir and ledipasvir (Harvoni®). Health Canada reviewed the potential risk of abnormal blood sugar levels (dysglycemia) with the use of DAAs, including both high blood sugar levels (hyperglycemia) and low blood sugar levels (hypoglycemia). Health Canada reviewed 26 Canadian cases and 10 international cases. It found 735 cases in VigiBase® related to dysglycemia with DAAs, but the data could not be used to confirm or exclude a link between the use of DAAs and the event. Also, Health Canada reviewed 26 published studies in the scientific literature, and identified biological mechanisms to explain how DAAs could lead to hypoglycaemia in diabetic patients. Health Canada’s review has concluded that there is a link between the use of DAAs and the risk of dysglycemia. Reference: Summary Safety Review, Health Canada, 17 February 2020 (www.hc-sc.gc.ca) (See WHO Pharmaceuticals Newsletter No.2, 2018: Possible effects on blood glucose control when used in patients with type 2 diabetes in New Zealand; No.2, 2017: Possible effects on blood glucose control when used in patients with type 2 diabetes: added to the medicine monitoring scheme in New Zealand) 2. Dose adjustment of concomitant drugs required Japan. The MHLW and the PMDA have announced that the package inserts for several DAAs, including Asunaprevir (Sunvepra®), Daclatasvir (Daklinza®) and Sofosbuvir (Sovaldi®), should be revised to include the important precautions that dose adjustment for concomitant drugs may be required. Several studies have reported that dose adjustment may be required for co-administered drugs such as warfarin, tacrolimus and insulin following initiation of DAAs for chronic hepatitis C. In September 2016, the PRAC of EMA recommended that a WHO Pharmaceuticals Newsletter No. 2, 2020 • 7 Regulatory Matters precaution be added to package inserts of DAAs regarding the effects of hepatitis C drugs on the blood coagulability in patients treated with vitamin K antagonists. A study was conducted in Japan with MID-NET® with data from 2010 to 2017. Although the small sample size limits the interpretation of the results, a tendency was observed that was not inconsistent with the preceding studies. Additionally, based on laboratory test results, a possible link between the changes in the patients’ liver function and the changes in warfarin dose-response could not be ruled out. 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/) (See WHO Pharmaceuticals Newsletter No.5, 2017: Interaction with warfarin in New Zealand; No.6, 2016: Interaction potential with warfarin and other vitamin K antagonists: changes to INR in Ireland) Fluoroquinolone Risk of aortic aneurysm and dissection Australia. The Therapeutic Goods Administration (TGA) has announced that the product information for fluoroquinolone antibiotics has been updated to include the risk of aortic aneurysm and dissection. Fluoroquinolones are broad- spectrum antibiotics that are active against both Gram- negative and Gram-positive bacteria. Fluoroquinolone antibiotics marketed in Australia include ciprofloxacin, norfloxacin and moxifloxacin. The TGA investigated a safety signal relating to the rare but serious potential adverse event of aortic aneurysm and dissection associated with fluoroquinolones. The precaution advises that fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options. During the TGA’s investigation, it was also identified that the product information for fluoroquinolones should be updated to include the potential adverse events of dysglycemia and psychiatric adverse reactions, including toxic psychosis, psychotic reactions progressing to suicidal ideations, hallucinations or paranoia, as precautions. Reference: Medicines Safety Update, TGA, 27 February 2020 (www.tga.gov.au/) (See WHO Pharmaceuticals Newsletter No.6, 2019: Risk of tendon disorders, peripheral neuropathy and psychiatric symptoms in Japan; No.3, 2019: Risk of musculoskeletal and nervous systems damage in UK; No.1, 2019) Fluorouracil, capecitabine, tegafur Pre-treatment testing recommended for cancer Europe. The EMA’s PRAC has recommended that patients should be tested for the lack of dihydropyrimidine dehydrogenase (DPD), an enzyme needed to break down fluorouracil, before cancer treatment with fluorouracil and prodrugs (capecitabine and tegafur) via injection or infusion. No pre-treatment testing is needed for topical treatment with fluorouracil. Fluorouracil is indicated to treat various cancers. Also, it is applied to the skin for actinic keratosis and dermal warts. Lack of DPD enzyme causes fluorouracil to build up in the blood, which may lead to severe and life-threatening adverse drug reactions such as neutropenia, neurotoxicity, severe diarrhoea and stomatitis. Patients with a known complete DPD deficiency must not be given fluorouracil, capecitabine or tegafur. For patients with a partial DPD deficiency, a reduced starting dose of these medicines should be considered. Reference: EMA, 13 March 2020 (www.ema.europa.eu) Fosravuconazole Risk of erythema multiforme Japan. The MHLW and the PMDA have announced that the package insert for fosravuconazole (Nailin®) should be revised to include erythema multiforme as an adverse drug reaction. Fosravuconazole is indicated for dermatophyte and nail tinea. A total of eight cases have been reported in patients taking fosravuconazole in Japan during the previous three years. For five of the eight cases, a causal relationship between fosravuconazole and the events could not be ruled out. No patient mortalities have been reported to date. MHLW/PMDA have concluded that revision of the package insert is necessary. Reference: Revision of Precautions, MHLW/PMDA, 25 February 2020 (www.pmda.go.jp/english/) Ingenol mebutate (gel) Risk of skin malignancy WHO Pharmaceuticals Newsletter No. 2, 2020 • 8 Regulatory Matters United Kingdom. The MHRA has announced that the licence of ingenol mebutate gel (Picato®) has been suspended as a precautionary measure while the EMA continues to investigate an increased incidence of benign and malignant skin tumours in several clinical studies. Ingenol mebutate gel is indicated for the treatment of actinic keratosis in adults when the outer layer of the skin affected is not thickened or raised. Several studies have found a higher incidence of skin tumours in the treatment area in patients who had used ingenol mebutate or a related ester. Post-marketing reports of skin tumours in patients treated with ingenol mebutate gel have also been received. Although the number of uncertainties remain and the data are still being reviewed, given the concerns regarding the possible risk of skin malignancy, the EMA has recommended a precautionary EU-wide suspension of ingenol mebutate gel. Reference: Drug Safety Update, MHRA, 12 February 2020 (www.gov.uk/mhra) (See WHO Pharmaceuticals Newsletter No.1, 2020: Use with caution in patients with a history of skin cancer in Ireland; No.1, 2020: Suspension during safety review in EU; No.6, 2019: Increased incidence of skin tumours in UK; No.5, 2019: Potential risk of skin cancer in EU) Lorcaserin Withdrawal due to the risk of cancer USA. The US Food and Drug Administration (FDA) has requested the manufacturer to voluntarily withdraw lorcaserin (Belviq®, Belviq XR®) from the US market due to an increased risk of cancer. Lorcaserin is used in combination with a reduced- calorie diet and increased physical activity to help weight loss in adults who are obese or overweight and have weight- related medical problems. It works by increasing feelings of fullness. When FDA approved lorcaserin in 2012, the manufacturer was required to conduct a clinical trial to evaluate the risk of cardiovascular problems. The lorcaserin group reported higher frequency of several different types of cancers. Health-care professionals should stop prescribing lorcaserin; they should contact patients currently taking lorcaserin, inform them of the increased occurrence of cancer, and ask them to stop taking lorcaserin. Additionally, health- care professionals should discuss alternative weight-loss medicines or strategies with the patients. Reference: MedWatch, US FDA, 13 February 2020 (www.fda.gov) (See WHO Pharmaceuticals Newsletter No.1, 2020: Potential risk of cancer in USA) Montelukast Boxed warning strengthened for serious behaviour and mood-related changes USA. The FDA has announced that it is strengthening existing warnings about serious behaviour and mood-related changes with montelukast (Singulair® and generics). Montelukast is a prescription medicine indicated to prevent asthma attacks and for the long-term treatment of asthma. It is also approved to control the symptoms of allergic rhinitis, also known as hay fever, such as sneezing and runny nose. Montelukast prescribing information already includes warnings about mental health adverse drug reactions, including suicidal thoughts or actions. However, many health-care professionals and patients are not aware of the risk. FDA decided a stronger warning is needed after conducting an extensive review of available information. Health-care professionals should ask patients about any history of psychiatric illness prior to initiating treatment, and consider the risks and benefits of montelukast when deciding to prescribe or continue patients on the medicine. Also, they should advice patients of the risk of neuropsychiatric events when prescribing montelukast, and monitor those treated with montelukast for neuropsychiatric symptoms. Reference: MedWatch, US FDA, 4 March 2020 (www.fda.gov) (See WHO Pharmaceuticals Newsletter No.6, 2019: Risk of neuropsychiatric reactions in UK; No.3, 2013: Neuropsychiatric risks in Australia) Rotigotine Risk of rhabdomyolysis Japan. The MHLW and the PMDA have announced that the package insert for rotigotine (Neupro patch®) should be revised to include rhabdomyolysis as an adverse drug reaction. Rotigotine is indicated for the treatment of Parkinson’s disease and moderate to severe idiopathic restless legs syndrome. A total of four cases of rhabdomyolysis have been reported in patients treated with rotigotine in Japan during the previous three years. For three out of the four cases, a causal relationship between rotigotine and the events could not be excluded. No patient mortalities have been reported to date. WHO Pharmaceuticals Newsletter No. 2, 2020 • 9 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 • 10 Safety of Medicines Clozapine Risk of serious bowel complications USA. The FDA has strengthened the existing warning that constipation caused by clozapine (Clozaril®, Fazaclo ODT® and Versacloz®) can progress to serious bowel complications. Clozapine is indicated for schizophrenia. Clozapine affects how the intestines function in the majority of patients. The serious bowel complications can lead to hospitalization or even death if constipation is not diagnosed and treated quickly. Patients should contact a health-care professional if they have symptoms that can be associated with serious bowel problems such as nausea, vomiting or stomach pain. Health-care professionals should avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility; advise patients frequently of the significant risk of constipation and life- threatening bowel issues and the need to stay hydrated to prevent constipation; and monitor patients for symptoms of potential complications associated with gastrointestinal hypomotility such as nausea, abdominal distension and vomiting. Reference: Safety Alerts for Human Medical Products, US FDA, 28 January 2020 (www.fda.gov) (See WHO Pharmaceuticals Newsletter No.3, 2019: Risk of intestinal ulcer and intestinal perforation in Japan; No.4, 2018: Gastrointestinal effects in Australia) Ferric carboxymaltose Risk of hypophosphataemia Australia. The TGA has announced that symptomatic hypophosphataemia is a known risk associated with the use of ferric carboxymaltose (Ferinject®) and it is recommended that health-care providers should routinely evaluate a patient’s risk factors before commencing ferric carboxymaltose and follow up at-risk patients. Ferric carboxymaltose is administered intravenously for treatment of iron deficiency when oral iron preparations are ineffective or cannot be used. Ferric carboxymaltose is known to cause mild, usually asymptomatic hypophosphataemia, but may present with pain, nausea and asthenia. Severe hypophosphataemia may be associated with symptomatic physiological dysfunction. Hypophosphataemia can be the cause of asthenia, fatigue, muscular weakness, breathlessness, tachycardia and headaches. The TGA adverse events database has 15 reports of hypophosphataemia with ferric carboxymaltose. Severe hypophosphataemia was reported in four cases. Reference: Medicines Safety Update, TGA, 27 February 2020 (www.tga.gov.au/) Ifosfamide (solution) Risk of encephalopathy Europe. The EMA has started a review of ifosfamide (solution) to examine the risk of encephalopathy. Ifosfamide is indicated to treat several cancers including solid tumours and lymphomas. It is available as a ready-made solution, a concentrate for solution and a powder for solution. An investigation in 2016 suggested that the incidence of encephalopathy was higher with the ready-made solution than with the powder. It was concluded that the risk may be linked to the degradation of the active substance and impurities developing over time in the solution. As a result, the solution’s shelf-life was reduced. Since then other studies suggested that the risk still remains higher. Hence a more thorough review is needed. EMA will now assess the available data on the risk of encephalopathy with ifosfamide ready-made solution or concentrate for solution. Reference: EMA, 13 March 2020 (www.ema.europa.eu) Mecasermin Risk of benign and malignant neoplasia United Kingdom. The MHRA has announced that cases of benign and malignant neoplasms have been observed among children and adolescents who received mecasermin (Increlex®). Mecasermin is a recombinant human insulin-like growth factor 1. It is indicated for the treatment of growth failure in children and adolescents with confirmed severe primary insulin-like growth factor 1 deficiency. It is already contraindicated in patients with active or suspected neoplasia. An EU review identified an increased incidence of benign and malignant tumours in patients treated with mecasermin. Most cases occurred in patients treated outside the authorized indication or exceeding the maximum dose. WHO Pharmaceuticals Newsletter No. 2, 2020 • 11 Safety of Medicines Following the review, the contraindication will be expanded to children or adolescents with any condition of medical history that increases the risk of benign or malignant neoplasia. Reference: Drug Safety Update, MHRA, 27 January 2020 (www.gov.uk/mhra) (See WHO Pharmaceuticals Newsletter No.1, 2020: Potential risk of benign or malignant tumours in Japan) Nitrofurantoin Risk of pulmonary and hepatic impairment and peripheral neuropathy New Zealand. Medsafe has announced that the use of nitrofurantoin in patients with significant renal impairment can cause pulmonary or hepatic impairment or peripheral neuropathy. Nitrofurantoin is a bactericidal antibiotic with activity exclusively in the urine. It is indicated for the treatment and prophylaxis of urinary tract infections. Significant renal impairment is a contraindication to nitrofurantoin. Aadequate glomerular filtration and renal tubular secretion is needed to achieve an effective therapeutic concentration in the urine. While therapeutic doses of nitrofurantoin are rapidly excreted into the urine in patients with normal renal function, in patients with impaired renal function the plasma concentration increases and there is a higher risk of nitrofurantoin toxicity. The Medicines Adverse Reactions Committee reviewed the evidence for safe use of nitrofurantoin in patients with a greater degree of renal impairment. During the 10- year period to 2019, the Centre for Adverse Reactions Monitoring (CARM) received 150 adverse reaction reports in which nitrofurantoin was a suspect medicine. Of the reports, 46 were on interstitial lung disease, 17 were on hepatic reactions including hepatic cirrhosis and pneumonitis and 3 were on peripheral neuropathy. Reference: Prescriber Update, Medsafe, March 2020 (www.medsafe.govt.nz/) Ondansetron Risk of oral clefts United Kingdom. The MHRA has announced that exposure to ondansetron (Zofran®) during the first trimester of pregnancy is suggested to be associated with a small increased risk of the baby having a cleft lip and/or cleft palate. Ondansetron, a 5-HT3 receptor antagonist, is indicated for the management, prevention or treatment of nausea and vomiting. Recent epidemiological studies reported a small increased risk of orofacial malformations in babies born to women who used ondansetron in early pregnancy. Key evidence was an observational study of 1.8 million pregnancies in the US. The data were recently reviewed within Europe and considered to be robust. The decision to use ondansetron during pregnancy should be based on professional judgement, and in consultation with the woman who is informed of the potential benefits and risks of use, both to her and to her unborn baby. Reference: Drug Safety Update, MHRA, 27 January 2020 (www.gov.uk/mhra) (See WHO Pharmaceuticals Newsletter No.6, 2016: Assessing potential harm to the foetus: insufficient information in Canada) WHO Pharmaceuticals Newsletter No. 2, 2020 • 12 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 the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus due to its immunomodulatory activity [1]. Chloroquine has a wide range of antiviral effects, including effects on coronavirus [2]. In a recent in vitro study the new antiviral drug remdesivir [3] as well as chloroquine were found to be effective in preventing replication of SARS-CoV-2 [2]. On 18 February 2020 an expert consensus guideline in China recommended chloroquine in mild to severe cases of COVID-19, as it was considered to improve the success rate of treatment, shorten hospital stay, and improve patient outcomes [4]. Although chloroquine is a widely used drug which has been on the market for a very long time, the efficacy and safety profile has not been thoroughly studied in the SARS-CoV-2 infected patients. Hydroxychloroquine has similar therapeutic effects as chloroquine, but fewer adverse effects, and is more readily available in some countries. Like chloroquine, hydroxychloroquine also has in vitro activity against SARS-CoV-2, with relatively higher potency against SARS-CoV-2 than chloroquine. Both drugs are being trialled in patients with mild to severe COVID-19 in clinical studies [5]. On March 28, 2020, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to allow hydroxychloroquine sulphate and chloroquine phosphate products to be used for certain hospitalized patients with COVID- 19. This was based on the totality of scientific evidence available to FDA, that considers it reasonable to believe that chloroquine phosphate and hydroxychloroquine sulphate may be effective in treating COVID-19, and that, when used under the conditions described in this authorization, the known and potential benefits of chloroquine phosphate and hydroxychloroquine sulphate when used to treat COVID-19 outweigh the known and potential risks of such products. [6] On the 1st of April, the European Medicines Agency communicated that chloroquine and hydroxychloroquine should only be used within the context of clinical trials or national emergency use programmes.[7] Current evidence of effectiveness of chloroquine and hydroxychloroquine in COVID-19 has also been evaluated by the Oxford COVID-19 Evidence Service Team [8]. It was concluded that at present, there is insufficient in vivo evidence to recommend their use for the current pandemic outside of clinical trials. High-quality studies are urgently needed to provide guidance to clinicians and policy-makers. More recently, the pharmacology and clinical pharmacology of chloroquine and hydroxychloroquine have been reviewed and relevant discussions are ongoing in the context of COVID-19 prevention and treatment, in particular, about the dosing considerations [9]. In VigiBase, the WHO global database of individual case safety reports, managed by Uppsala Monitoring Centre (UMC), since 1968 and up to 23 February 2020 there were 5,741 unique cases from 80 countries reporting adverse events associated with chloroquine: the top three organ systems involved were skin and subcutaneous tissue disorders (31%, 1,804 cases), gastrointestinal disorders (25%, 1,421 cases) and nervous system disorders (22%, 1,233 cases). Cardiac disorders (5.8%, 331 cases) ranked ninth. There were 122 fatal cases, accounting for 2.1% of the total reported cases. Among them, cardiac disorders (37%, 45 cases) ranked first place. Cardiac toxicity was the primary cause of chloroquine fatal adverse events. A single large dose (mostly accidental or intentional overdose) of chloroquine related mainly to arrhythmia; and cardiomyopathy was the main manifestation of chronic exposure. It is well known that chloroquine can cause QT interval prolongation in some patients, and in patients with risk factors for QT prolongation (including hypokalaemia and drugs that also prolong QT interval) chloroquine should be used with caution. Although the case reports with chloroquine (that did not mention COVID-19) were accumulated as stated above, as of 2 April 2020, there were no individual case safety reports in VigiBase that could be linked to the use of chloroquine in COVID-19. There are a handful of reports for hydroxychloroquine that mention COVID-19 as the indication or where this may possibly be the indication. Reported events in these very few WHO Pharmaceuticals Newsletter No. 2, 2020 • 13 Information Note reports have not so far given rise to any safety signal. References 1. Datapharm Limited. Electronic Medicines Compendium (EMC): Summary of Product Characteristics for chloroquine (Avloclor®). Available at: https://www.medicines.org.uk/emc/product/549 0/smpc#COMPOSITION. Accessed 28 Feb 2020. 2. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro[J]. Cell Res, 2020,DOI: 10.1038/s41422- 020-0282-0. 3. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. Coronavirus susceptibility to the antiviral remdesivir (GS- 5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio 2018;9 pii: e0 0221-18. doi: 10.1128/mBio.0 0221-18. 4. Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):185-8. 5. BMJ Best Practice https://bestpractice.bmj.com/topics/en- gb/3000168 6. https://www.fda.gov/news-events/press- announcements/coronavirus-covid-19-update- daily-roundup-march-30-2020 7. https://www.ema.europa.eu/en/news/covid-19- chloroquine-hydroxychloroquine-only-be-used- clinical-trials-emergency-use-programmes 8. https://www.cebm.net/covid-19/chloroquine- and-hydroxychloroquine-current-evidence-for- their-effectiveness-in-treating-covid-19/ By Oxford COVID-19 Evidence Service Team 9. White NJ and Tarning J. Chloroquine and hydroxychloroquine pharmacology. Available at: https://www.recoverytrial.net/files/recovery- intervention-sheet-hydroxychloroquine-v2-0.pdf Accessed 10 April 2020. WHO Pharmaceuticals Newsletter No. 2, 2020 • 14 Signal A signal is defined by WHO as reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. A signal is a hypothesis together with data and arguments and it is important to note that a signal is not only uncertain but also preliminary in nature. The signals in this Newsletter are based on information derived from 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: signals@who-umc.org. Agomelatine and Increased Blood Pressure Dr. Tamás Paál, Hungary Summary Agomelatine is a non-selective melatonin receptor MT1 and MT2 agonist plus a neutral serotonergic 5- HT2C antagonist indicated for the treatment of major depressive episodes. Of the 24 reports from eight countries on increased blood pressure and agomelatine in the WHO global database of individual case safety reports (VigiBase), twelve were eligible for assessment. Of these, six revealed a consistent pattern of a short time to onset and nine reported recovery on dechallenge, with a positive rechallenge in two of them. Although data on the mechanism of action of agomelatine, as well as a former signal, suggest a mild hypo- rather than hypertensive action, it is also true that melatonin, which is structurally closely related to agomelatine, has hypertension as a labelled adverse effect. Thus, despite the presence of additional risk factors for hypertension in a considerable proportion of these cases, a contributory role of agomelatine to the events cannot be excluded. Introduction Agomelatine has been authorised in the European Union and other countries for the treatment of major depressive episodes. It has not been authorised in the USA. Agomelatine is a potent, non-selective melatonin receptor MT1 and MT2 agonist plus a neutral serotonergic 5-HT2C antagonist. Synergy between the two types of receptors has been hypothesized as accounting for its mode of action. Inhibition of the 5-HT2C receptor is held responsible for the direct antidepressant effect. Unlike other antidepressants that often trigger sleep disorders the advantage of agomelatine is that it has a beneficial effect on sleep.1-3 Agomelatine is indicated for adults (over 18 years) because of the lack of data in paediatric populations. The recommended dose is 25 to 50 mg daily taken orally at bedtime. Its safety profile requires regular monitoring of liver function in all patients before and during treatment. Agomelatine is metabolised mainly by CYP1A2 (90%) and CYP2C9/19 (10%). Consequently, drugs that interact with these isoenzymes may interact with agomelatine.4 Normal blood pressure (BP) varies with age and is influenced by various factors such as cardiac output, vascular resistance and venous return and pressure; any change in these variables can lead to fluctuations in BP. Thus, there is no absolute 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 normal”, then higher values as different stages of hypertension. However, these values vary with age (e.g. the normal values are 117/77 and 134/87 mmHg between 14 to 19, and 60 to 64 years, respectively).5 Twenty-four reports have been observed in the WHO global database of individual case safety reports (ICSRs), VigiBase, for blood pressure increased (BPI) under agomelatine treatment. WHO Pharmaceuticals Newsletter No. 2, 2020 • 15 Signal Reports in VigiBase On 14 April 2019, 24 reports were retrieved from VigiBase for BPI following agomelatine administration (Table 1). The adverse events occurred between December 2012 and November 2017. The ICSRs originated from eight countries: Germany (15 cases), Austria (2), Switzerland (2), and Australia, the Czech Republic, Portugal, South Africa, and Turkey (one each). They were spontaneous reports except cases 2 and 21 which came from clinical studies. The reporters were physicians with the exception of cases 1 and 16 (non-health-care professionals), 12 (pharmacist), as well as 10 and 20 (other health-care professionals), while in case 11 the reporter was unknown. In cases 3, 7 and 14 the outcome was not reported, otherwise, except in cases 11 and 16, the patients recovered. In the reports agomelatine was the only suspected drug, except case 9 where all those administered except esomeprazole were reported as suspected. In 14 cases where the increased blood pressure values were also reported, they varied considerably. The cases in Table 1 were analysed first to exclude those where the concomitant medication could cause BPI/hypertension. The European product information of the concomitant drugs (European Medicines Agency webpage or the MRI product index6) revealed that, in addition to typical antidepressants (trazodone, paroxetine, venlafaxine, sertraline and clomipramine), pregabalin (used, among others, in cases of generalised anxiety) and ezetimibe (primary hypercholesterinaemia) have hypertension labelled as an adverse effect. Thus, cases 3, 4, 9 and 13 were not used for the initial review. (In cases 8, 21 and 23, paroxetine or clomipramine were indicated as concomitant drugs, however, their administration was discontinued before agomelatine was started, and the BPI occurred days later, so these cases were included.) During the next “filtering”, the following cases were excluded: cases 2, 5 and 8 (one and a half months, two years and nine months agomelatine treatment before the onset of BPI, respectively), case 7 (poor reporting), case 10 (according to its narrative, the agomelatine treatment was maintained, but the patient’s BP improved), case 14 (onset of BPI reported on the day of the agomelatine administration, then the treatment was continued with no further data), case 15 (it was a suicide attempt, taking among others, 1050 mg agomelatine with no BPI first then 150/90 mmHg value later, but the patient had a mild hypertension), and case 22 as the patient had an underlying hypertension and, according to the narrative, a reduction of the antihypertensive treatment was made at the time of agomelatine initiation. Thus, only 12 ICSRs (cases 1, 6, 11, 12, 16-21, 23 and 24) remained for detailed analysis. Well-controlled arterial hypertension/hypertension as one of the patients’ underlying diseases was reported in cases 17-20 and 24. The reported time to onset of the increased blood pressure was a few hours in case 17, three days in case 23, about seven days in cases 12 and 21, while general statements (such as ”after introduction” or “initiation”, ”since she took it”) indicated that the time to onset seemed to be short (in cases 1, 16, 20, 24). In case 18 the BPI happened “after the dose was increased from 25 mg to 50 mg”. In nine cases (1, 6, 12, 17, 19, 20, 21, 23 and 24) positive dechallenge (plus in case 18 reaction abated for dose reduction) while in two cases (1, 12) positive rechallenge were reported. It should also be stressed that labelled adverse effects of agomelatine (e.g. migraine, nausea, sweats, anxiety, restlessness, insomnia, dizziness and blurred vision), if they occurred in the analysed cases, also abated at the same time as BPI did (cases 19-21 in Table 1). In case 12 increased heart rate abated together with BPI while the outcome of other events labelled for agomelatine (tiredness, somnolence and headache) was not reported. It should be noted that 17 reports for hypertension following agomelatine administration were also found in VigiBase (13 October 2019). In six of them no concomitant medication was reported and in six other cases, although there was concomitant medication, agomelatine was reported as the only suspect drug. (Only two of these latter six cases also reported concomitant medications which have hypertension as a labelled ADR, i.e. allopurinol and sertraline.) In four cases positive dechallenge also occurred. The time to onset, when it could be identified from the reports, varied from “same day” (three cases) to two days (two cases), and around two weeks (two cases) up to one month or longer (seven cases). Labelled adverse effects of agomelatine occurred and abated together with the hypertension in ten cases. Although these “agomelatine and hypertension” reports were not combined with the “agomelatine and BPI” ones, they seem to be in line with the latter and strengthen the results of this analysis. Literature and labelling Hypertension/BPI is not listed in the European Summary of Product Characteristics of agomelatine. Furthermore, it states that “agomelatine had neutral effect on heart rate and blood pressure in clinical trials”.4 (There were clinical trials where hypertension was reported in the agomelatine arm. Its frequency was found to be 1.2%7 but because of the limited number of the subjects involved and the lack of a placebo arm in this trial, the causality could not be established.) It is also well-known that people suffering from depression are more likely than the others to develop hypertension.8 Experiments have suggested that agomelatine prevents rather than causes hypertension.9 Moreover, in 2014, the Uppsala Monitoring Centre WHO Pharmaceuticals Newsletter No. 2, 2020 • 16 Signal published a signal on hypotension occurring under agomelatine treatment. In response to the signal the marketing authorisation holder accepted that 5- HT2C/5-HT2B antagonists could induce an antihypertensive effect in animals and/or humans with hypertension, while it did not endorse it as a clinically relevant safety concern.10 Melatonin, structurally closely related to agomelatine but binding to the MT receptors exclusively is used for sleep disorders such as short-term primary insomnia or to decrease jet- lag.11 It is interesting that clinical studies revealed that its use at night an hour before sleep appeared to lower BP. (There is some debate about its mechanism: is it based on serotonin antagonism by melatonin or is it because the subjects had fuller, better quality sleep?)11, 12 On the other hand, melatonin has hypertension as a labelled adverse effect13, 14 with a frequency of “uncommon” (that means 0.1 to 1.0%).13 It is also well-known that some medicines that usually lower blood pressure may paradoxically increase blood pressure.14 There are drugs (such as pregabalin, indicated, among others, to generalised anxiety disorders) that have labelled adverse reactions both hypo- and hypertension with the same frequency.15 Discussion and conclusion Based on the overall reporting of adverse reactions for agomelatine and of the adverse reaction BPI in VigiBase as a whole, the expected value for the number of reports of the combination is 16 and the IC025 is negative (as of 27 June 2019). However, agomelatine is not used in the USA where BPI is more commonly reported overall, and in a disproportionality analysis adjusted for region of origin, the expected value is around 10, rendering a stronger statistical association which would be highlighted as disproportionally reported by IC analysis. This means that if its calculation is restricted to the rest of the world (non-US reports), the IC025 is positive. Moreover, taking the high number of positive dechallenges in the analysed ICSRs into account (where labelled adverse effects of agomelatine abated together with the BPI) and the positive (in one case double) rechallenges, they strongly suggest a positive causal relationship. The BPI action of agomelatine might be dose- dependent (it occurred only at higher doses in one case and the patient who experienced repeated rechallenges was a slow CYP metaboliser). Moreover, the fact that the individual variability of the absolute bioavailability of agomelatine is substantial4 might explain its rare and sporadic occurrence. Considering also the mild hypotensive action of agomelatine and the preceding signal on agomelatine – hypotension,10 where the number of positive dechallenges were also high with one positive rechallenge, the former statement may be extended to agomelatine – change in BP (both hypo- and hypertension). The paradoxical action of certain antihypertensives causing BPI may be explained by an impaired BP regulation system that “over-reacts” to the stimulus. Indeed, five patients of the analysed 12 ICSRs (in cases 17-20 and 24) had reported “well-controlled” hypertension (i.e. an underlying disease where the BP regulation was impaired). The marketing authorisation holder’s statements in certain ICSR narratives that the cases do not trigger any changes in the core data sheet are fully agreed upon, the reaction is far from being proven and can be extremely rare. However, a signal only means information on a possible causal relationship between an adverse event and a drug. Considering the above-mentioned aspects, in conclusion, agomelatine and BPI (perhaps also more widely: agomelatine and change in BP) is considered a signal. References 1. Guardiola-Lemaitre B. De Bodinat C. Delagrange P. Millan MJ. Munoz C. Mocaër E. Agomelatine: mechanism of action and pharmacological profile in relation to antidepressant profile. Br J Pharmacol. 2014:171:3604-19. 2. Munoz C. Valdoxan: antidepressant efficacy at all time phases of treatment. Medicographia. 2010:32(2):171-6. Available from: https://www.medicographia.com/2010/10/valdo xan-antidepressant-efficacy-at-all-time-phases- of-treatment/. Accessed: 26 April 2019. 3. Emet M. Ozcan H. Ozel I. Yajla M. Halici Z. Hacimuftuoglu A. A Review of Melatonin, Its Receptors and Drugs. Eurasian J Med. 2016:48(2):135-41. 4. European Medicines Agency: Summary of Product Characteristics for agomelatine (Valdoxan). Available from: https://www.ema.europa.eu/en/documents/pro duct-information/valdoxan-epar-product- information_en.pdf. Accessed: 29 May 2019. 5. Idealbloodpressureinfo.com. Blood Pressure Chart By Age: Check Out What Should Your BP Be. Available from: https://www.idealbloodpressureinfo.com/blood- pressure-chart-by-age/. Accessed: 10 June 2019. 6. Heads of Medicines Agency. MRI Product Index. http://mri.cts-mrp.eu/Human/ 7. Corruble E. de Bodinat C. Belaïdi C. Goodwin GM. agomelatine study group. Efficacy of agomelatine and escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24- wk randomized, controlled, double-blind trial. WHO Pharmaceuticals Newsletter No. 2, 2020 • 17 Signal Int J Neuropsychopharmacol., 2013:16(10):2219-34. 8. Woolston C. Depression and High Blood Pressure. Available from: https://consumer.healthday.com/encyclopedia/ depression-12/depression-news- 176/depression-and-high-blood-pressure- 644943.html. Accessed: 26 April 2019. 9. Tain YL. Lin YJ. Chan JYH. Lee CT. Hsu CN. Maternal melatonin and agomelatine therapy prevents programmed hypertension in male offspring of mother exposed to continuous light. Biol Reproduction 2017:97(4):636-43. 10. Uppsala Monitoring Centre. Agomelatine and Hypertension. WHO Pharm. Newsletter 2014(4): 13-17. 11. Cook M. Serotonin, Melatonin, and Blood Pressure. Available from: https://www,dailymedicaldiscoveries.com/serot onin-melatonin-blood-pressure/. Accessed: 26 April 2019. 12. Cure HBP. Melatonin and High Blood Pressure – Is There a Connection? Available from: https://www.naturaltreatmentforhypertension.c om/blog/melatonin-and-high-blood-pressure-is- there-a-conncetion. Accessed: 20 May 2019. 13. European Medicines Agency: Summary of Product Characteristics for melatonin (Circadin prolonged-release tablets). Available from: https://www.ema.europa.eu/en/documents/pro duct-information/circadin-epar-product- information_en.pdf. Accessed: 12 June 2019. 14. Grossman E. Messer FH. Drug-induced Hypertension: An Unappreciated Cause of Secondary Hypertension. Am J Med. 2012:125(1):14-22. 15. Electronic Medicines Compendium: Summary of Product Characteristics for pregabalin (Lyrica capsules.) Available from: https://www.medicines.org.uk/emc/medicine/1 4651. Accessed: 26 April 2019. Table 1. Overview of reports in VigiBase of blood pressure increased in association with agomelatine Case Sex, age Underlying disease Agomelatine dose, treatment duration Concomitant drugs Reported reactions De/Rechallenge 1 M, 74 coronary by-pass, insomnia 25 mg/d, not specified (within 1 month) nebivolol, lercanidipine, tamsulosin, finasteride, diazepam BPI, tachycardia, muscle cramps Positive dechallenge, positive rechallenge 2 F, 72 hypertension, depression, obesity 25 mg/d, 1.5 m BPI, nausea 3 F, 58 depression, hypertension, sleep disorder 25 mg/d, 18 d lorazepam, trazodone BPI, dizziness, heart rate increased, Nausea 4 M, 72 depression, BPH, glaucoma, hyper- cholesteremia. arterial hypertension, insomnia, obesity, sleep apnoea syndrome, gonarthrosis 50 mg/d, 2 m telmisartan, ezetimibe, dorzolamide, simvastatin BPI, alanine aminotransferase, aspartate aminotransferase and gamma-glutamiltransferase increased positive dechallenge (all events) 5 F, 63 depression, arterial hypertension, obesity 25 mg, 2 y losartan BPI, sinus tachycardia 6 M, 52 depression, somatization disorder 25 mg BPI positive dechallenge 7 BPI 8 M, 31 depression (cousin psychiatric) 25 mg/d, 9 m hyoscine, medazepam, paroxetine BPI, suicidal and homicidal ideation, nervousness, anger, aggression, impaired driving ability positive dechallenge (all events unspecified) 9 M, 53 recurrent depression, generalised anxiety disorders bisoprolol, clonazepam, pregabalin, venlafaxine, mirtazapine (all also suspected drugs), esomeprazole BPI, vertigo, aggression aggravated, fall, gait instability, tension WHO Pharmaceuticals Newsletter No. 2, 2020 • 18 Signal Case Sex, age Underlying disease Agomelatine dose, treatment duration Concomitant drugs Reported reactions De/Rechallenge 10 F, 61 sleep disturbance, pain in spine, bronchitis, prolapsed disc nos 25 mg/d, (onset 14 d) trolnitrate, valsartan, budesonide/formoterol, levothyroxine, lidocaine, zolpidem BPI, transient ischemic attack, paraesthesia, muscle tension, insomnia Agomelatine maintained, BPI recovered 11 F, 59 7 d flecainide, warfarin, atorvastatin BPI, drug interaction 12 F, cca 30 Depression 25 mg/d cca 1w escitalopram, ethyl loflazepate, alprazolam, salbutamol BPI, increased heart rate, tiredness, somnolence, headache positive dechallenge, 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 hypertension, chronic alcohol abuse, suicide attempt 1050 mg (suicidal intention), 1 d mirtazapine, lercanidipine BPI, increased alkaline phosphatase, AST and bilirubin and blood glucose and C- 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, Hashimoto’s disease, hypometabolism (CYP2 d6 and c19 slow metaboliser) 25 mg/d, 1 m 6.25 mg/d, 17 d 12.5 mg/d, 4 m the drug was withdrawn for a period of time between the different dosage regimens. BPI occurred after reintroducing it at dose 12.5 mg levothyroxine BPI, anxiety, insomnia, hot flushes facial, migraine, nausea, sweats, generalised hot feeling, blue-red colouration of the skin 17 M, 74 depression, coronary heart disease, arterial hypertension, diabetes mellitus type 2 25 mg/d, 1 d trimipramine, glyceryl trinitrate amlodipine, metoprolol, HCT, captopril/HCT BPI, restlessness, nocturnal awakening positive dechallenge 18 F, 54 depression, hypertension 50 mg/d 25 mg/d Patient started on 25 mg, the dose was then increased to 50 mg and the patient experienced BPI antihypertensives BPI, red face dose reduced to 25 mg/d and BPI recovered 19 ?, ? sleep disorder, hypertension, reflux esophagitis, left bundle branch block 25 mg/d, 11 d lercanidipine (1 y), esomeprazole BPI, new left bundle branch block, chest pain, dizziness, blurred vision positive dechallenge (all) 20 F, over 70 depression, GI inflammation viral, hypertension, irritable bowel, panic attacks, sleep disorder, bowel cancer removed, cerebral disorder, anxiety disorder 50 mg/d, around 1 m (onset: “since she took agomelatine”) ciprofloxacin, HCT/olmesartan BPI, blurred vision, head pressure, noises in head, stiff neck, anxiety aggravated, contraindicated drug administered positive dechallenge (all) WHO Pharmaceuticals Newsletter No. 2, 2020 • 19 Signal Case Sex, age Underlying disease Agomelatine dose, treatment duration Concomitant drugs Reported reactions De/Rechallenge 21 F, 39 recurrent depressive disorder 25 mg/d, 18 d opipramol, paroxetine BPI, aggressive behaviour, dizziness, excitement, mood swings, suicidal ideation, unrest positive dechallenge (all) 22 M, 45 insomnia, hypertension 25 mg/d, 4 d, then 50 mg/d, about 2 w bisoprolol BPI, shaking of hands, feeling irritated, panic attacks, nausea, dizziness, sweating BPI abated when amlodipine was taken 23 M, 71 depression, Parkinson’s disease 25 mg/d, 7 d benserazide, levodopa, clomipramine BPI positive dechallenge 24 F, 44 anxiodepressive syndrome, hypertension, post-concussion syndrome 25 mg/d, 10 d escitalopram, pantoprazole, ramipril BPI, headache positive dechallenge 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 Midostaurin is a protein kinase inhibitor indicated as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis, systemic mastocytosis with associated haematological neoplasm or mast cell leukaemia. Reports in the French pharmacovigilance database, the Base Nationale de Pharmacovigilance (BNPV) as well as in VigiBase, the WHO global database of individual case safety reports (ICSRs), indicate that midostaurin can cause photosensitivity reactions while interacting with sunlight in certain patients. All cases found were marked as serious and the treatment in most cases continued, in some with recorded advice of sun protection. In one case the drug was permanently withdrawn, and the treating physician issued a contraindication for the drug for the patient following a photosensitivity test with a very strong reaction to the drug. There is no mention of photosensitivity in the product labels for midostaurin, but in a French compassionate use programme involving 28 patients, 25% of the patients reported an occurrence of photosensitivity reactions following treatment with midostaurin, strengthening the suspicion based on the reports found in BNPV and VigiBase. Introduction Midostaurin is a protein kinase inhibitor indicated as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN), or mast cell leukaemia (MCL). It is also used in combination with daunorubicin and cytarabine and high-dose cytarabine consolidation chemotherapy, as well as for patients in complete response, followed by midostaurin as monotherapy for adult patients newly diagnosed with acute myeloid leukaemia (AML) positive for the tyrosine kinase protein ‘fms- like tyrosine kinase 3’ (FLT3) mutation.1 Midostaurin inhibits several receptor tyrosine kinases, including FLT3 and tyrosine-protein kinase KIT (also called CD117). It also inhibits FLT3 receptor signalling and induces cell cycle arrest and apoptosis in leukemic cells over-expressing FLT3 wild-type receptors, or expressing an FLT3 mutation called internal tandem duplication (ITD), or tyrosine kinase domain (TKD) mutant receptors. Midostaurin additionally inhibits several other receptor tyrosine kinases such as platelet-derived growth factor receptor (PDGFR), or vascular endothelial growth factor receptor 2 (VEGFR2), and members of the serine/threonine kinase family protein kinase 3 (PKC). It causes growth arrest while binding to the catalytic domain of these kinases where it inhibits the mitogenic signalling of the respective growth factors in cells.1 Sun sensitivity occurs in people of all ages, for both sexes and with different skin types. However, people with low levels of melanin, who have very WHO Pharmaceuticals Newsletter No. 2, 2020 • 20 Signal white skin and rarely tan, are often considered more photosensitive, relative to people with darker skin types who tan more easily.2 Drug-induced photosensitivity reactions occur as a result of the combined effects of a drug and sunlight in susceptible patients and has the potential to increase the incidence of skin cancer. Exposure to either the drug or the sunlight alone is not enough to cause a reaction. Photoactivation of chemicals leads to the occurrence of one or more sun sensitivity reactions, such as rash and burns. Adverse photosensitivity responses to drugs predominantly occur as phototoxic reactions, more immediate than photo allergy, and reversible by withdrawal or substitution of the drug. There is a problem of inaccuracy in the reporting of these adverse drug reactions because of the difficulty in distinguishing between regular sunburn and mild drug photosensitivity reactions, as well as the patient being able to control the incidence by taking protective action. Some examples of drug classes known for a high level of adverse photosensitivity are diuretics, antibacterials and nonsteroidal anti- inflammatory drugs (NSAIDs).3 Reports in the Base Nationale de Pharmacovigilance (BNPV) and VigiBase Reports of midostaurin causing severe photosensitivity reactions were first identified at the regional pharmacovigilance centre of Toulouse, France, following one index case reported in 2019. The case concerned a patient who had been treated with midostaurin for over 2 months when, after having taken a walk outside in sunny spring weather, experienced a severe photosensitivity reaction. This led to withdrawal of the drug after having had a photosensitivity test performed in hospital where a minimal dose of the drug was given, and UVA-light was applied. A very strong reaction followed, the drug was permanently withdrawn, and the treating physician issued a contraindication for the drug for this patient. When checking in the French database of adverse drug reaction reports, the Base Nationale de Pharmacovigilance (BNPV) at this time, seven additional reports with the same kind of reaction were found. When replicating the search in VigiBase®, the WHO global database of individual case safety reports (ICSRs), two additional reports were retrieved, from Germany and the United States. The case from Toulouse was subsequently entered into both BNPV and VigiBase. The time to onset of the reaction varied between the patients for which this information was recorded, from 10 days up to one year. After the onset of the reaction, several patients continued taking the drug, with a mention of recurring sun sensitivity at repeated exposure made in two cases (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 protection and for one of these, extensive protective measures are mentioned with hat, long gloves, sunscreen of 50+ strength, as well as a booked appointment for sun protection education. One case was received from a dermatologist who judged the patient’s exanthema, or alternatively a phototoxic reaction, as probably related to midostaurin, despite the patient’s intake of a confounding drug, valsartan, known to be able to 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 concomitant (C) drugs Daily dose Reactions (MedDRA preferred terms) - Outcome Time to onset De-challenge/ Re-challenge Database of origin 1 M/57 Midostaurin (S) NA Toxic skin eruption - recovered Photosensitivity reaction - Not recovered 10 days NA/Y BNPV 2 M/75 Midostaurin (S) NA Toxic skin eruption - unknown Photosensitivity reaction- Not recovered 86 days NA/Y BNPV 3 F/67 Midostaurin (S) NA Photosensitivity reaction -not recovered Basal cell carcinoma - recovered with sequalae Actinic keratosis - not recovered Toxic skin eruption -recovered 30 days NA/NA BNPV 4 M/69 Midostaurin (S) NA Erythrosis - not recovered Photosensitivity reaction - not recovered 1 year NA/NA BNPV 5 M/29 Midostaurin (S) NA Photosensitivity reaction - recovered with sequelae 2 months NA/NA BNPV 6* M/68 Midostaurin (S) Ketotifen (S) Desloratadine (C) Montelukast (C) 200 mg/day Photosensitivity reaction - recovering 8 months NA/NA BNPV (also present in VigiBase) WHO Pharmaceuticals Newsletter No. 2, 2020 • 21 Signal Case Age/Sex Suspected (S) or concomitant (C) drugs Daily dose Reactions (MedDRA preferred terms) - Outcome Time to onset De-challenge/ Re-challenge Database 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 Photosensitivity reaction** - N/A 308 days NA/NA BNPV 8 F/78 Midostaurin (S) 50 mg/day Photosensitivity reaction - recovering Photosensitivity reaction - recovering 58 days Y/NA BNPV (also present in VigiBase) 9 F/66 Midostaurin (S) 100 mg/ 2 per day Swelling face - N/A Eyelid oedema - N/A Photosensitivity reaction - N/A NA NA/NA VigiBase 10 M/- Midostaurin (S) Valsartan (C) Atorvastatin (C) 25 mg/- Rash - N/A Photosensitivity reaction - N/A 4 months NA/NA VigiBase *Case 6 is also published as a case report in the literature[ref 9] **Term identified in the narrative Literature and Labelling In the centrally authorized European product characteristics for midostaurin there is no mention of photosensitivity reactions. Dermatitis exfoliative and hyperhidrosis are given as very common skin reactions while dry skin and keratitis are marked as common skin reactions.1 In addition, the European periodic assessment report from 2017 states that the phototoxic potential was evaluated in albino hairless mice with only mild skin reactions occurring after oral administration of midostaurin and UV-A or UV-A and UV-B irradiation.4 A cumulative search made in the safety database of market authorisation holder Novartis, during the same year, revealed 11 cases of “photosensitivity or photo dermatosis conditions”. The cases had multiple co-suspected drugs known to cause photosensitivity and had an unreasonable time to onset or had a prior history of photosensitivity which, according to Novartis, made a causal relationship unlikely.4 The US Daily Med product information for midostaurin does not mention a potential for photosensitivity reactions.5 However, for another protein kinase inhibitor, namely imatinib, the following is set out in the UK product labelling; “Phototoxicity: Exposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associated with imatinib treatment”.6 For another protein kinase inhibitor, gefitinib, it is stated that “the results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicity potential”. 7 Other protein kinase inhibitors have the potential for phototoxicity, either noted in vitro or as an adverse drug reaction, in their respective product labels (among others: erlotinib, nilotinib, pazopanib, vandetanib, afatinib and vemurafenib).8 A class effect of certain protein kinase inhibitors cannot be ruled out. A class effect including midostaurin is also suggested by Alsulaili et al., who described one of the patients included in this signal (no. 6) as a case report submitted to the journal Annales de Dermatologie et de Vénéréologie in 2017. Alsulaili and colleagues hypothesise that the phototoxic effect could be favoured by the inhibition of the ABCG2 drug transporter.9 Photosensitivity related to midostaurin was also noted in a prospective survey performed by the French National Reference Centre for Mastocytosis (CEREMAST) on patients with mastocytosis who were treated with midostaurin under a transitory-use authorization programme. Between 2012 and 2015, 28 patients received midostaurin at a dose of 100 mg twice daily. One out of four patients in this survey reported an occurrence of photosensitivity reactions following treatment.10 Discussion and Conclusion All cases found in BNPV and VigiBase were marked as serious, and yet, probably due to lack of treatment options and the gravity of the disease, the treatment in most cases continued, in some with recorded advice of sun protection. In one case the sun sensitivity was confirmed by a photosensitivity test performed with UVA-light which resulted in a strong reaction despite a minimum dose administered for midostaurin. Two other cases described reoccurring photosensitivity reactions while continuing to take the drug. Although the time to onset of the reactions varied among the patients included in this signal, this is probably of less relevance given that the reaction is linked to the exposure to sunlight. Also, as photosensitivity reactions can occur in varying degrees, lighter reactions might have occurred in other patients but not have been recognized as such. Several other protein kinase inhibitors include information about sun sensitivity in their product labels,8 and although the mechanisms for these WHO Pharmaceuticals Newsletter No. 2, 2020 • 22 Signal drugs are not fully understood, a class effect causing sun sensitivity is possible and has previously been proposed.9 Photosensitivity related to midostaurin has previously been noted in a prospective survey where as many as one out of four patients reported occurrence of photosensitivity.10 Sun sensitivity reactions increase the risk of aggravating existing skin conditions, can worsen diverse autoimmune disorders, and can also eventually lead to skin cancer. Photosensitivity reactions are preventable and might not be recognized as such if they are not mentioned in the product labels. Patients should be informed about these adverse drug reactions so that they are able to take drugs of this profile without being exposed to unnecessary harm. References 1. EU summary of product characteristics (EU SPC) for Midostaurin (Rydapt). URL: https://www.ema.europa.eu/en/documents/pro duct-information/rydapt-epar-product- information_en.pdf. Accessed: 17/05/2019 2. DermNet NZ. URL: https://www.dermnetnz.org/topics/photosensiti vity/. Accessed: 19/10/25 3. Moore D.E. Drug-Induced Cutaneous Photosensitivity. Drug Saf. 2002:25(5)345-372. 4. European assessment Report for Midostaurin (Rydapt). URL: https://www.ema.europa.eu/en/documents/ass essment-report/rydapt-epar-public-assessment- report_en.pdf. Accessed: 19/06/2019 5. US Daily Med summary of product characteristics for Midostaurin (Rydapt). URL:https://dailymed.nlm.nih.gov/dailymed/dru gInfo.cfm?setid=11fa3fc9-6776-49a6-b1c1- 653f627c3e58&audience=consumer. Accessed: 19/06/2019 6. UK summary of product characteristics (UKeMC) for Imatinib (Glivec). URL: https://www.medicines.org.uk/emc/product/77 79/smpc. Accessed: 05/06/2019 7. UK summary of product characteristics (UKeMC) for Gefitinib (Iressa). URL: URL: https://www.medicines.org.uk/emc/product/66 02 . Accessed: 05/06/2019 8. UK summary of product characteristics (UKeMC) for different protein kinase inhibitors (ATC group L01XE). URL: https://www.medicines.org.uk/emc/. Accessed: 05/06/2019 9. Alsulaili M., Marguery M.C, Tournier E. et al. Éruption photodistribuée sous midostaurine. Annales de Dermatologie et de Vénéréologie. 2017: 144(12) :337. 10. Chandesris M.O, Damaj G., Canioni D. et al. Midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016: 374(26)2605-7. Response from Novartis 1 Introduction The UMC-WHO collaborating Centre for International Drug Monitoring invited Novartis to comment on a draft signal document concerning midostaurin and photosensitivity before distribution to the national pharmacovigilance centers in the member countries of the WHO Programme for International Drug Monitoring. 2 Novartis Response Novartis acknowledges UMC-WHO signal assessment on midostaurin and photosensitivity. As requested by UMC-WHO, Novartis has performed a detailed analysis of this safety topic including data from all available data sources, as presented below. 2.1 Preclinical toxicology data Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro assays have demonstrated that midostaurin absorbs light in the relevant spectrums of UVB and UVA range. However, animal studies did not provide a conclusive evidence of a photosensitive potential of midostaurin. 2.2 Data from midostaurin clinical trials Review of data from midostaurin clinical trials in AML indication did not reveal any imbalance of photosensitivity reaction in the active arm, as compared to the placebo arm. Although in the advanced systemic mastocytosis pool the incidence of events pertaining to photosensitivity reaction was relatively higher as compared to the AML indications (2.8% vs. 0.9%), these incidence rates were based on a very limited absolute number of events (n=4) for making a meaningful causality assessment. Of note, cutaneous manifestations are frequent in patients with mastocytosis as part of the natural history of the disease itself and hence, a causal role of midostaurin based on these limited numbers of events in a single arm study in the mastocytosis setting is difficult to ascertain. WHO Pharmaceuticals Newsletter No. 2, 2020 • 23 Signal 2.3 Data from Novartis Global Safety Database A cumulative search using the Preferred Terms (PT): Application site photosensitivity reaction, Chronic actinic dermatitis, Implant site photosensitivity, Infusion site photosensitivity reaction, Injection site photosensitivity reaction, Juvenile spring eruption, Photodermatosis, Photoonycholysis, Photosensitivity reaction, Polymorphic light eruption, Pseudoporphyria, Retinal phototoxicity, Solar dermatitis, Solar urticaria, and Sunburn with MedDRA v22.1 was performed in the Novartis Global Safety Database (until 15-Jan-2020). This search retrieved 10 cases [Managed Access Program (MAP), n=9 and Spontaneous Report (SR), n=1] disclosing 11 events of interest. Seven of the nine MAP cases were reported from France, while single cases were reported from Germany and United States, respectively. The reported PTs in these 10 cases were ‘Photosensitivity reaction’ n=9, ‘Pseudoporphyria’ and ‘Sunburn’ n=1 each. The reported indications for midostaurin were systemic mastocytosis n=8, and mastocytosis n=1, while the indication was not reported in one case. One of the 10 cases reporting possible sunburn, the event occurred during sun-exposure while working with plastics (potential for allergic reaction); the event was confounded by the concomitant use of valaciclovir. In seven other cases, limited information was reported regarding the concomitant medications, medical history (including history of dermatological conditions), time to onset of the event, and clinical course of the event. The remaining two cases are discussed below. One case refers to a 68-year-old male subject who experienced photosensitivity reaction (erythematous lesions in the photo-exposed areas associated with bullae on both dorsal aspects of hands and the face) while taking midostaurin for more than seven months for systemic mastocytosis. The event happened when he went on his first beach-side holidays after eight years. Relevant concomitant medications included desloratadine, perindopril, and rosuvastatin. Skin biopsy showed eczema along with necrotic keratinocytes and discreet lymphocytic infiltrates. Blood and urinary porphyrins as well as photobiological testing were normal, the polychromatic minimal erythema dose was 1883 mJ/cm2 (normal range was greater than 400), and phototest UVA 13 J/cm2 was negative at 24 hours with normal pigmentation. The subject improved with the appropriate protective measures. Midostaurin was continued unchanged, but the photosensitivity reaction did not recur. Novartis Comment: In this case, the reported photosensitivity reaction could be a normal physiological response to prolonged sunlight exposure in mastocytosis indication. In addition, the concomitant administration of desloratadine, perindopril, and rosuvastatin were strong confounding factors for the event. Midostaurin was continued, but the photosensitivity reaction did not recur. Hence, a causal role of midostaurin is unlikely for the event of photosensitivity reaction. In the second case, a 78-year-old female subject had been taking midostaurin for around two months for the treatment of mastocytosis, and experienced photosensitivity reaction (erythema and facial edema, photodistributed erythematopapular lesions). The subject’s medical history was not reported, and the relevant concomitant medications included mirtazapine, cetirizine and pantoprazole. Photo-tests demonstrated a decrease in the minimum erythematous dose (DEM) of 0.5 J with UVA for midostaurin. Midostaurin was stopped, and the subject recovered after treatment with corticosteroids, photo-protection measures and hydrochloroquine. Novartis Comment: Though photo-test was positive for midostaurin, the concomitant administration of pantoprazole, mirtazapine, and cetirizine were strong risk-factors. Considering the strong confounders, causal role of midostaurin for the photosensitivity reaction could not be conclusively established. 3 Literature Two articles (Chandesris et al 2016, Chandesris et al 2017) mention the incidence (25%) of photosensitivity reaction in a French MAP in 28 mastocytosis subjects without further stating further details about the reported photosensitivity reactions. Of note, the seven case reports from the French MAP are databased in Novartis Global Safety Database and were commented above. Siiskonen et al 2017 highlighted the involvement of mast cells in the pathophysiology of polymorphic light eruptions and sunburns. 4 Conclusion A comprehensive review of data from all available sources did not reveal any new or changing safety signal related to the use of midostaurin and photosensitivity reaction. Based on the limited reports of photosensitivity reaction reported only in the mastocytosis indications, a causal relationship with midostaurin cannot be established because cutaneous manifestations are frequent in all mastocytosis patients. Further, the release of mast cell mediators and mast cell degranulation in mastocytosis patients may be precipitated by a variety of stimuli including extremes of temperatures or sudden temperature changes. In the absence of conclusive evidence of a causal association between midostaurin use and photosensitivity reaction, Novartis is of the opinion that no change to the label is warranted at this point in time. Novartis will continue monitoring this safety topic applying routine pharmacovigilance measures and will notify the Authorities should further data indicate causality. WHO Pharmaceuticals Newsletter No. 2, 2020 • 24 Signal 5 References Chandesris, MO, Damaj, G, Canioni, D, et al. (2016) Midostaurin in advanced systemic mastocytosis. New England Journal of Medicine; 374 (26):2605-7. Chandesris, MO, Damaj, G, Lortholary, O, et al. (2017) Clinical potential of midostaurin in advanced systemic mastocytosis. Blood and Lymphatic Cancer: Targets and Therapy; 7: 25-35. Siiskonen H, Smorodchenko A, Krause K, et al. (2017) Ultraviolet radiation and skin mast cells: Effects, mechanisms and relevance for skin diseases. Experimental Dermatology: 27 (1): 3-8. Tramadol and hyperacusis Marian Attalla, Uppsala Monitoring Centre Summary Tramadol and hyperacusis was identified as a potential signal in a screening of VigiBase, the WHO global database of individual case safety reports, focusing on patient reports. As of June 2019, there were 20 reports for the combination. Overall, they support an association between tramadol and hyperacusis with all cases reporting tramadol as the only suspect drug, and with a consistent time-to- onset of up to two days among all cases that provided it. In addition, six cases reported a positive dechallenge and two a positive rechallenge. κ-opioid receptor-mediated facilitation of NMDA receptor sensitivity to glutamate has been suggested as a mechanism for hyperacusis in rodents. Hyperacusis is not listed as an adverse reaction in the label for tramadol, and while changes in sensorial capacity is, this might not be specific enough for the patients, who would benefit from more precise labelling. Introduction Tramadol is indicated for the treatment of moderate to severe pain. It’s an opioid agonist acting on μ-, δ- and κ-opioid receptors, with a higher affinity for the μ receptor.1 The analgesic effect is also achieved by inhibiting neuronal reuptake of noradrenaline and by enhancing serotonin release. Peak plasma concentration is reached after 4.9 hours and the half-life is six hours.1 The analgesic effect occurs within 30-60 minutes after intake.2,3 Hyperacusis can be described as experiencing “sounds of everyday life as intrusively loud, uncomfortable, and sometimes painful”.4 It can either develop suddenly or over time. To avoid noise, some people may withdraw from normal daily activities and may therefore become isolated. School and work may also be compromised.4,5 The causes of hyperacusis are unknown but it has been linked with a number of conditions including tinnitus, damage to the inner ear or brain, migraines, depression and post-traumatic stress disorder, Bell’s palsy and Ménière’s disease. Exposure to sudden loud noise or a negative life event can also trigger hyperacusis. However, for many people with hyperacusis there is no clear cause.4,6 Tramadol and hyperacusis was first identified as a potential signal in a screening of VigiBase focusing on patient reports, in April 2018. The aim of this assessment is to investigate if there is a causal relationship between tramadol and hyperacusis. Reports in VigiBase As of June 2019, there were 20 reports of tramadol and hyperacusis (see Table 1). The combination was not disproportionately over-reported, with the expected number of reports being 21 (26 June 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 in 18 cases) ranged from 17 to 62 years, with a median of 38 years. Eleven reports were from consumers, four from pharmacists, four from physicians and the reporter type was unknown for the remaining. In two cases, hyperacusis seemed to have occurred after tramadol withdrawal. In one case (5), the patient experienced hyperacusis, flu symptoms, tiredness, light sensitivity, poor sleep and formication after tramadol was stopped and the reporter attributed these to withdrawal symptoms. The other case of hyperacusis after withdrawal (8) describes a patient who was on tramadol treatment for five years for back pain (50 mg/d). The narrative revealed that six months after tramadol had been withdrawn the patient started treatment with sertraline and experienced extreme sound and light sensitivity, sexual dysfunction, extreme irritation/anger, suicidal thoughts, fatigue, and auditory hallucinations. WHO Pharmaceuticals Newsletter No. 2, 2020 • 25 Signal In all the remaining 18 cases, tramadol was the only drug reported as suspected. Concomitant drugs were reported in 10 cases, none of which are labelled for hyperacusis. Two cases (3, 17) reported the use of sumatriptan, which is used for migraines, and another case (4) reported the use of venlafaxine, which is usually used to treat depression. Both conditions have been linked with hyperacusis. Three cases (11, 18, 20) reported the use of other opioids in addition to tramadol. Time-to-onset was provided in 14 cases and it was reported to be one day or less in 13; in the remaining case it was two days. The action taken with tramadol was unknown in six cases, dose not changed in four, dose reduced in one (case 11) and drug withdrawn in seven cases (cases 1, 2, 9, 12, 15, 17, 20). Of the eight cases where the drug was withdrawn or the dose was reduced, six reported a recovery. In case 15, concomitant drugs were also withdrawn at the same time as tramadol and the patient recovered. An additional four patients recovered but the action taken with the drug was either unknown or the dose was not changed. Two cases (1, 18) reported a positive rechallenge. Case 18, reported by a physician, describes a 32- year-old patient who experienced hyperacusis (no other events reported) on the same day that treatment with tramadol was started. The case reported a positive rechallenge but there was no detailed information about the event, and it did not state whether the drug was withdrawn, prior to rechallenge. Case 1 describes a patient who experienced hyperacusis 15-25 minutes after starting on tramadol for postoperative pain. No other concomitant drugs and no other adverse events were reported. Both a positive dechallenge and a positive rechallenge were reported (without much information about the event). A few cases illustrate how hyperacusis affected the patient’s life. For example, case 3 describes a 32- year-old female who experienced increased sound sensitivity only when taking tramadol, which went away once the dose wore off. The patient also took desogestrel/ethinylestradiol, levothyroxine and sumatriptan: “Sounds become louder, more penetrating and grating. For example, when someone is talking or cutlery on a plate. Almost like sound is more in your face. It becomes difficult to be around other people or in noisy places.” Twelve cases co-reported other reactions. The top co-reported terms were headache (6 cases), nausea (5), dizziness (4), photophobia (4), somnolence (4), vomiting (4), fatigue (3), hyperhidrosis (3), insomnia (3) and irritability (3). All of these are labelled in the tramadol Summary of Product Characteristics (SmPC) except for photophobia and irritability.1 Labelling and literature Hyperacusis is not labelled for tramadol in either the UK or the US.1,7 However, tinnitus is described as a symptom of withdrawal in the UK SmPC,1 along with psychiatric adverse reactions, including changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase), and changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders). In the US label, tinnitus and deafness are listed under “other adverse experiences, causal relationship unknown”.7 Hyperacusis is not given on the Patient Information Leaflet (PIL) either. However some PILs for different tramadol products state that psychological reactions may appear, such as “a change in mood (mostly high spirits, occasionally irritated mood), changes in activity (slowing down but sometimes an increase in activity), and decreased cognitive and sensory perception (being less aware and less able to make decisions, which may lead to errors in judgement)”.8,9 The PIL for another product lists “changes in senses and recognition” as an adverse reaction.10 The SmPCs for the opioid oxycodone, list hyperacusis as an adverse reaction.11,12 Some brands list it under the group “ear and labyrinth disorders”, while others list it under “psychiatric disorders”. In the PIL, "abnormally acute sense of hearing (hyperacusis)" is described.13 However, the labels for other opioids such as morphine, codeine, tapentadol, hydromorphone, hydrocodone, fentanyl, buprenorphine, oxymorphone, meperidine, methadone, pentazocine, and butorphanol do not list hyperacusis, while labels for buprenorphine, butorphanol and fentanyl list tinnitus.14-16 Discussion It has been suggested that opioids can affect hearing. There have been reports of hearing loss associated with chronic opioid use or with opioid overdose.17,18 Also, as mentioned above, tinnitus (even deafness) is listed in the labels of some opioids including tramadol.1,7,14-16 Often, tinnitus and hyperacusis co-exist. In patients with a primary complaint of hyperacusis, the prevalence of tinnitus has been reported to be 86%. For patients with a primary complaint of tinnitus, the prevalence of hyperacusis has been reported to be 40%. As such it has been suggested that hyperacusis and tinnitus could have common mechanisms.19 Both hyperacusis and tinnitus can be worsened by fatigue and stress. In their work, Sahley et al. proposed that in response to stress, endogenous dynorphins are released that act on κ-opioid receptors in cochlea.20,21 This in turn might facilitate NMDA receptor sensitivity to glutamate, possibly leading to increased auditory sensitivity. Indeed in one of their studies, κ-opioid receptor agonists ((-)pentazocine and U-50488H) were administered across the cochlear round window membrane in chinchillas.20 The amplitude changes observed WHO Pharmaceuticals Newsletter No. 2, 2020 • 26 Signal amounted to increases in sensitivity of between 4 to 8 decibels. So a suggested mechanism for hyperacusis is through κ-opioid receptor-mediated facilitation of NMDA receptor sensitivity to glutamate, that may occur under stressful conditions.21 As previously mentioned, oxycodone is labelled for hyperacusis.11,12 A study found that oxycodone acts as a κ2b-opioid agonist with relatively low affinity for the μ receptor.22 This could strengthen the hypothesis that hyperacusis could be mediated by κ-opioid receptor activation. On the other hand, tramadol has the highest affinity for the μ receptor.1,23 However, it still acts on κ receptors and could in theory also cause hyperacusis through them, but perhaps to a lesser extent. Considering the extensive use of tramadol globally, the number of reports in VigiBase is low. The association is not disproportionally over-reported, with the number of observed reports being 20 and the expected number 21. However, the available cases do support a relationship between tramadol intake and hyperacusis. Specifically, all cases reported tramadol as the only suspect drug and the time-to-onset was two days or less among the 14 cases that provided it. Also, in the eight cases where tramadol was withdrawn or its dose reduced, six reported a positive dechallenge and two a positive rechallenge. A few cases mentioned other conditions linked with hyperacusis. Two (3, 17) reported concomitant treatment with sumatriptan, which is used for migraines. But in both of these, hyperacusis occurred on the same day as tramadol was started. Also, in case 17, the patient had been on sumatriptan for 12 years before tramadol introduction, so the patient’s history of migraines seems unlikely to be related to the event. The start date of sumatriptan in case 3 was unknown. Another case (4) reported treatment with venlafaxine for an “ill-defined disorder”. The drug is usually used to treat depression, also a condition to which hyperacusis has been linked. However, the start date of both venlafaxine and tramadol was not given and thus the time relationship to the event is unknown. Moreover, three cases reported the use of another opioid in addition to tramadol. Cases 11 and 18 report codeine/paracetamol with unknown start date, but in both cases hyperacusis occurred within one day after the start of tramadol. Case 20 mentions concomitant treatment with pentazocine which has agonist action at κ-opioid receptors and antagonist action at µ receptors.24 Pentazocine was started a week before and stopped a day before tramadol was introduced and hyperacusis occurred. One could argue that the adverse reaction “changes in sensorial capacity” or “changes in senses and recognition” described in tramadol labels1,10 could be interpreted as encompassing changes in hearing capacity, e.g. hyperacusis, since hearing is one of the five basic senses in humans (sight, hearing, taste, smell, touch). However, patients might not realise that hyperacusis could be part of this and the majority of these reports come from consumers. Conclusion Hyperacusis following the intake of tramadol has been found in VigiBase from a number of countries. The association is not disproportionally over- reported. However, the following point towards a causal relationship: - Tramadol is the only suspected drug in all cases. - There is a close temporal relationship (two days or less) when the information on time- to-onset is available. - Six cases report a positive dechallenge and two also report a positive rechallenge although details in some reports were missing. - κ-opioid receptor-mediated facilitation of NMDA receptor sensitivity to glutamate has been suggested as a mechanism for hyperacusis. - The opioid oxycodone is labelled for hyperacusis. The label for tramadol already lists changes in sensorial capacity as an adverse reaction. However, patients may not realise that hyperacusis could be part of this and may not appreciate the possible impact it could have on the quality of life. Since the majority of these reports come from consumers, they could benefit from clearer labels. References 1. Electronic Medicines Compendium: Summary of Product Characteristics for tramadol (Brimisol®). Available from: https://www.medicines.org.uk/emc/product/85 50/smpc. Accessed: 15 June 2019. 2. Tramadol: strong painkiller to treat severe pain. nhs.uk. 2018. Available from: https://www.nhs.uk/medicines/tramadol/. Accessed: 5 Dec 2019. 3. Tramadol Hydrochloride Monograph for Professionals - Drugs.com. Available from: https://www.drugs.com/monograph/tramadol- hydrochloride.html. Accessed: 5 Dec 2019. 4. Hyperacusis. British Tinnitus Association. Available from: https://www.tinnitus.org.uk/hyperacusis. Accessed: 5 Dec 2019. 5. What Causes This? | Hyperacusis. Available from: http://www.hyperacusis.net/what-is- it/what-causes-this/. Accessed: 5 Dec 2019. WHO Pharmaceuticals Newsletter No. 2, 2020 • 27 Signal 6. What Is Sound Sensitivity (Hyperacusis)? WebMD. Available from: https://www.webmd.com/brain/sound- sensitivity-hyperacusis. Accessed: 5 Dec 2019. 7. US Food and Drug Administration: Product label for tramadol. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInf o.cfm?setid=ae7c54b1-b440-4cca-97e8- e5b825413d32&audience=consumer. Accessed: 6 Sep 2019. 8. Electronic Medicines Compendium: Patient Information Leaflet for tramadol (Maxitram SR®). Available from: https://www.medicines.org.uk/emc/product/69 89/pil. Accessed: 9 Oct 2019. 9. Electronic Medicines Compendium: Patient Information Leaflet for tramadol (Maneo®). Available from: https://www.medicines.org.uk/emc/product/84 75/pil. Accessed: 4 Nov 2019. 10. Electronic Medicines Compendium: Patient Information Leaflet for tramadol. Available from: https://www.medicines.org.uk/emc/product/46 48/pil. Accessed: 4 Nov 2019. 11. Electronic Medicines Compendium: Summary of Product Characteristics for oxycodone (Carexil®). Available from: https://www.medicines.org.uk/emc/product/20 68/smpc. Accessed: 9 Oct 2019. 12. Electronic Medicines Compendium: Summary of Product Characteristics for oxycodone (Lynlor®). Available from: https://www.medicines.org.uk/emc/product/11 97/smpc. Accessed: 31 Oct 2019. 13. Electronic Medicines Compendium: Patient Information Leaflet for oxycodone (Lynlor®). Available from: https://www.medicines.org.uk/emc/product/11 97/pil. Accessed: 31 Oct 2019. 14. Electronic Medicines Compendium: Summary of Product Characteristics for buprenorphine (Bunov®). Available from: https://www.medicines.org.uk/emc/product/97 98/smpc. Accessed: 22 Jul 2019. 15. US Food and Drug Administration: Product label for butorphanol. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInf o.cfm?setid=b8e48063-0b40-ee43-85c1- 4ef2de80c404&audience=consumer. Accessed: 22 Jul 2019. 16. Electronic Medicines Compendium: Summary of Product Characteristics for fentanyl. Available from: https://www.medicines.org.uk/emc/product/54 00/smpc. 22 Jul 2019. 17. Oroei M, Peyvandi AA, Mokhtarinejad F. Opioid Drugs and Sensorineural Hearing Loss. Addict Health. 2018 Jan;10(1):64–6. 18. Kopec KT, Nelson LS. Opioid-Induced Hearing Loss. Emergency Medicine. 2012 Nov;44(11):4– 6. 19. Baguley DM. Hyperacusis. J R Soc Med. 2003 Dec;96(12):582–5. 20. Sahley TL, Anderson DJ, Chernicky CL. Bi- phasic intensity-dependent opioid-mediated neural amplitude changes in the chinchilla cochlea: partial blockade by an N-Methyl-D- Aspartate (NMDA)-receptor antagonist. Eur J Pharmacol. 2008 Feb 2;580(1–2):100–15. 21. Sahley TL, Hammonds MD, Musiek FE. Endogenous dynorphins, glutamate and N- methyl-d-aspartate (NMDA) receptors may participate in a stress-mediated Type-I auditory neural exacerbation of tinnitus. Brain Res. 2013 Mar 7;1499:80–108. 22. Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain. 2007 Dec 5;132(3):289–300. 23. Raffa B, Vaught L, Shank P, Codd E. Opioid and Nonopioid Components Independently Contribute to the Mechanism of Action of Tramadol, an ‘Atypical’ Opioid Analgesic. 1992;260:11. 24. Electronic Medicines Compendium: Summary of Product Characteristics for pentazocine. Available from: https://www.medicines.org.uk/emc/product/88 33/smpc. Accessed. 11 Nov 2019. Table 1. Characteristics of case reports in VigiBase of hyperacusis in association with tramadol. Case number Age/ Sex Suspected (S), interacting (I) or concomitant (C) drugs Reactions (MedDRA PT) Time-to-onset (TTO) Action taken with drug (dechallenge/rechallenge, - for unknown) Outcome 1 -/F Tramadol (S) Hyperacusis 15-25 minutes Drug withdrawn/Reaction abated Rechallenge/Reaction recurred Recovered WHO Pharmaceuticals Newsletter No. 2, 2020 • 28 Signal Case number Age/ Sex Suspected (S), interacting (I) or concomitant (C) drugs Reactions (MedDRA PT) Time-to-onset (TTO) Action taken with drug (dechallenge/rechallenge, - for unknown) Outcome Note: no details around rechallenge – only reported in structured field 2 38/F Tramadol (S) Acetylsalicylic acid, Gabapentin, Macrogol 3350, Senna (C) Dyspnoea, Flushing, Hyperacusis, Hypopnoea, Somnolence - Note: TTO not reported but narrative reveals that events occurred after tramadol intake and the duration of tramadol use was 1 day. Drug withdrawn/- Unknown 3 32/F Tramadol (S) Desogestrel/ ethinylestradiol, Levothyroxine, Sumatriptan (C) Hyperacusis 0 days Dose not changed/- Unknown 4 -/F Tramadol (S), Venlafaxine (C) Asthenia, Decreased appetite, Fatigue, Hyperacusis, Irritability, Malaise, Tinnitus - Dose not changed/No effect observed Not recovered 5 54/F Tramadol (S) Fatigue, Formication, Hyperacusis, Influenza, Photophobia, Poor quality sleep, Withdrawal syndrome - Note: Patient had been on tramadol for years and experienced ADRs in response to drug withdrawal. -/Reaction abated Recovering 6 21/ M Tramadol (S) Note: follow-up information also reveals treatment with “THC” Abdominal pain upper, Aggression, Anxiety, Appetite disorder, Bone pain, Burning sensation, Confusional state, Constipation, Coordination abnormal, Decreased immune responsiveness, 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 0 days - Not recovered 7 41/F Tramadol (S) Hyperacusis, Insomnia, Pruritus 0 days -/Reaction abated Recovered 8 40/ M Tramadol (S) Anxiety, Cognitive disorder, Derealisation, Fatigue, General physical health deterioration, Hyperacusis, Impaired work ability, Memory impairment, Nervous - Note: Patient had used -/Reaction abated Recovered WHO Pharmaceuticals Newsletter No. 2, 2020 • 29 Signal Case number Age/ Sex Suspected (S), interacting (I) or concomitant (C) drugs Reactions (MedDRA PT) Time-to-onset (TTO) Action taken with drug (dechallenge/rechallenge, - for unknown) Outcome system disorder, Photophobia, Psychotic disorder tramadol for 5 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 abated Recovered 10 20/F Tramadol (S) Hyperacusis 30 minutes Dose not changed/Reaction abated Recovered 11 28/F Tramadol (S) Codeine/paracetamol (C) Aggression, Amnesia, Anger, Anxiety, Confusional state, Delusion, Depressed mood, Emotional disorder, Feeling abnormal, Hallucination, Headache, Hyperacusis, Irritability, Pain, Photophobia, Somnolence, Tremor 1 day (within) Dose reduced/No effect observed Not recovered 12 57/F Tramadol (S) Dizziness, Feeling abnormal, Headache, Hyperacusis, Photophobia, Somnolence - Note: TTO not reported but tramadol was stopped the same day it was started. Drug withdrawn/Reaction abated - 13 17/F Tramadol (S), Paracetamol (C) Hyperacusis 2 days Dose not changed/- Unknown 14 47/F Tramadol (S) Asthenia, Feeling cold, Headache, Hyperacusis, Hyperhidrosis, Syncope, Tremor - - - 15 38/F Tramadol (S), Diclofenac, Tolperisone (C) Hyperacusis, Nausea, Rash, Vomiting 0 days Drug withdrawn/Reaction abated Note: concomitant drugs also reported to be withdrawn on same day as tramadol Recovered 16 62/ M Tramadol (S), Atenolol, Ibuprofen (C) Disturbance in attention, Dysarthria, Hyperacusis, Nausea, Panic attack, Urinary retention, Vomiting 2 hours Note: ibuprofen was introduced at the same time as tramadol. Drug withdrawn/- - 17 39/ M Tramadol (S), Paracetamol, Sumatriptan, Testosterone (C) Note: concomitant drugs had been taken Anorgasmia, Constipation, Dizziness, Dry mouth, Fatigue, Headache, Hyperacusis, Hyperhidrosis, Insomnia, Logorrhoea, Nausea, Pruritus, Respiratory rate decreased, Tremor 1 hour Drug withdrawn/Reaction abated Recovered WHO Pharmaceuticals Newsletter No. 2, 2020 • 30 Signal Case number Age/ Sex Suspected (S), interacting (I) or concomitant (C) drugs Reactions (MedDRA PT) Time-to-onset (TTO) Action taken with drug (dechallenge/rechallenge, - for unknown) Outcome for 12-23 years before tramadol introduction. 18 32/F Tramadol (S) Bupivacaine/glucose, Codeine/paracetamol, Diclofenac, Paracetamol, Rubella vaccine (C) Hyperacusis 0 days - Rechallenge/Reaction recurred Note: withdrawal information lacking although a positive rechallenge is reported Recovered 19 51/F Tramadol (S) Balance disorder, Headache, Hyperacusis, Photophobia, Vomiting 1 day - Recovered 20 36/ M Tramadol (S) Bendroflumethiazide/ propranolol, Diazepam, Pentazocine (C) Decreased appetite, Dizziness, Hyperacusis, Nausea, Stomatitis 0 days Drug withdrawn 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. Recovering WHO Pharmaceuticals Newsletter No. 2, 2020 • 31 Signal CAVEAT DOCUMENT Statement of reservations, limitations and conditions relating to data released from VigiBase, the WHO global database of individual case safety reports (ICSRs). Understanding and accepting the content of this document are formal conditions for the use of VigiBase data. Uppsala Monitoring Centre (UMC) in its role as the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring receives reports of suspected adverse reactions to medicinal products from National Centres in countries participating in the WHO Programme for International Drug Monitoring. The information is stored in VigiBase, the WHO global database of individual case safety reports (ICSRs). It is important to understand the limitations and qualifications that apply to this information and its use. Tentative and variable nature of the data Uncertainty: The reports submitted to UMC generally describe no more than suspicions which have arisen from observation of an unexpected or unwanted event. In most instances it cannot be proven that a specific medicinal product is the cause of an event, rather than, for example, underlying illness or other concomitant medication. Variability of source: Reports submitted to national centres come from both regulated and voluntary sources. Practice varies: some national centres accept reports only from medical practitioners; others from a broader range of reporters, including patients, some include reports from pharmaceutical companies. Contingent influences: The volume of reports for a particular medicinal product may be influenced by the extent of use of the product, publicity, the nature of the adverse effects and other factors. No prevalence data: No information is provided on the number of patients exposed to the product, and only a small part of the reactions occurring are reported. Time to VigiBase: Some national centres make an assessment of the likelihood that a medicinal product caused the suspected reaction, while others do not. Time from receipt of an ICSR by a national centre until submission to UMC varies from country to country. Information obtained from UMC may therefore differ from that obtained directly from national centres. For these reasons, interpretations of adverse effect data, and particularly those based on comparisons between medicinal products, may be misleading. The data comes from a variety of sources and the likelihood of a causal relationship varies across reports. Any use of VigiBase data must take these significant variables into account. Prohibited use of VigiBase Data includes, but is not limited to: • patient identification or patient targeting • identification, profiling or targeting of general practitioners or practice Any publication, in whole or in part, of information obtained from VigiBase must include a statement: (i) recording ‘VigiBase, the WHO global database of individual case safety reports (ICSRs)’ as the source of the information (ii) explaining that the information comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases (iii) affirming that the information does not represent the opinion of the UMC or the World Health Organization. Omission of this statement may exclude the responsible person or organization from receiving further information from VigiBase. UMC may, in its sole discretion, provide further instructions to the user, responsible person and/or organization in addition to those specified in this statement and the user, responsible person and/or organization undertakes to comply with all such instructions. Uppsala Monitoring Centre (UMC) Box 1051, SE-751 40 Uppsala, Sweden Tel: +46-18-65 60 60, E-mail: info@who-umc.org www.who-umc.org WHO Pharmaceuticals Newsletter No. 2, 2020 • 32 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 • 33 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 WHO Pharmaceuticals Newsletter No. 2, 2020 • 34 Feature • 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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WHO pharmaceuticals newsletter: 2020, No. 2
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