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WHO Pharmaceuticals

2021 WHO Pharmaceuticals

No.3 NEWSLETTER

The WHO Pharmaceuticals Newsletter provides you

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

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

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

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

Signal

WHO Pharmaceuticals Newsletter No. 3, 2021

ISBN 978-92-4-003128-9 (electronic version) ISBN 978-92-4-003129-6 (print version)

© World Health Organization 2021

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Table of Contents

Regulatory Matters ...... 4 (genetic recombination) ...... 4 COVID-19 vaccine NRVV Ad (ChAdOx1 nCoV-19) ...... 4 COVID-19 vaccine NRVV Ad26 (JNJ 78436735) ...... 4 Durvalumab (genetic recombination) ...... 5 Iopamidol ...... 5 Levothyroxine () ...... 5 ...... 5 Obeticholic acid ...... 6 Polyethylene glycol (PEG) laxatives and starch-based thickeners ...... 6 Pomalidomide, thalidomide ...... 6 Ritodrine and (co-administration) ...... 7 Shosaikotokakikyosekko ...... 7 Tozinameran ...... 7 Vascular endothelial growth factor (VEGF) inhibitors (systemic use) ...... 7

Safety of medicines ...... 9 Bendamustine ...... 9 ...... 9 Clopidogrel ...... 9 Donepezil ...... 10 Fluoroquinolones ...... 10 Indapamide ...... 10 Lamotrigine ...... 11 Nivolumab ...... 11 Theophylline ...... 11 Tozinameran, COVID-19 vaccine mRNA (mRNA 1273) ...... 11

Signal Levetiracetam and Hypokalaemia ...... 12 Remdesivir and pancreatic toxicity ...... 16 and Pancreatitis ...... 22

WHO Pharmaceuticals Newsletter No. 3, 2021  3 Regulatory Matters

Atezolizumab reported in patients treated (www.ema.europa.eu) with cetuximab in Japan in the (See also WHO Pharmaceuticals Newsletter Risk of severe cutaneous past three years, including No.2, 2021: Possible link to very rare cases adverse reactions (SCAR) three cases for which a causal of unusual blood clots with low blood relationship between the platelet counts in Europe) and event was assessed to be Malaysia. The National Pharmaceutical Regulatory reasonably possible. No patient Agency (NPRA) has announced mortalities have been reported. WHO, Global Advisory Committee on Vaccine Safety that the product information The MHLW and the PMDA (GACVS) review of latest for atezolizumab (Tecentriq®) concluded that the revision of evidence of rare adverse blood has been updated to include the package insert was coagulation events with the risk of severe cutaneous necessary. adverse reactions (SCAR). AstraZeneca COVID-19 Vaccine Reference: (Vaxzevria and Covishield), 16 Atezolizumab is indicated to Revision of Precautions, April 2021. treat non-small cell lung MHLW/PMDA, 30 March 2021 (https://www.who.int/news/item/16- cancer, small cell (www.pmda.go.jp/english/) 04-2021-global-advisory-committee- and triple-negative breast on-vaccine-safety-(gacvs)-review- cancer. SCARs include acute of-latest-evidence-of-rare-adverse- generalized exanthematous blood-coagulation-events-with- pustulosis (AGEP), Stevens- -covid-19-vaccine- Johnson syndrome (JSJ), toxic COVID-19 vaccine (vaxzevria-and-covishield)) epidermal necrolysis (TEN) and drug rash with eosinophilia and NRVV Ad (ChAdOx1 systemic symptoms (DRESS). nCoV-19) Based on analysis from the COVID-19 vaccine company’s global safety data Risk of thrombosis with 99 cases of SCARs have been thrombocytopenia NRVV Ad26 (JNJ syndrome (TTS) identified, of which 36 cases 78436735) were confirmed by Europe. The Committee for histopathology or specialist Risk of thrombosis with diagnosis. Medicinal Products for Human Use (CHMP) has recommended thrombocytopenia Reference: that COVID-19 vaccine NRVV syndrome (TTS) Safety Alerts, NPRA, 22 April Ad (ChAdOx1 nCoV-19) 2021 (www.npra.gov.my/) (Vaxzevria®) must not be Europe. The Pharmacovigilance Risk given to anyone who has had thrombosis with Assessment Committee (PRAC) thrombocytopenia syndrome has recommended that the (TTS). warning of TTS in the product Cetuximab (genetic information for COVID-19 COVID-19 vaccine NRVV Ad vaccine NRVV Ad26 (JNJ recombination) (ChAdOx1 nCoV-19) is a 78436735) (Janssen COVID-19 vaccine for preventing COVID- vaccine®) should be refined to Risk of hypomagnesaemia 19 in people aged 18 years and include advice on investigating older. for signs of thrombosis in Japan. The Ministry of Health, patients presenting with Labour and Welfare (MHLW) As TTS requires specialist thrombocytopenia within three and the Pharmaceuticals and treatment, health-care weeks of vaccination. Medical Devices Agency professionals should consult (PMDA) have announced that applicable guidance and/or COVID-19 vaccine NRVV Ad26 the package insert for specialists to diagnose and (JNJ 78436735) is indicated for cetuximab (genetic treat the condition. preventing COVID-19 in people recombination) (Erbitux®) aged 18 years and older. Also, health-care professionals should be revised to include should check for signs of the risk of hypomagnesaemia Also, TTS will be added as an thrombosis in any person who as an adverse drug reaction. important identified risk in the has thrombocytopenia within risk management plan. Cetuximab is indicated to treat three weeks of vaccination and RAS wild-type, incurable, should advise people to seek The benefits of using the unresectable, urgent medical attention if they vaccine to prevent COVID-19 advance/recurrent colorectal have any symptoms suggesting outweigh the risks of adverse cancer and head and neck thrombosis or effects. cancer. thrombocytopenia. Reference: A total of five cases of Reference: EMA, 7 May 2021 hypomagnesaemia have been EMA, 21 May 2021 (www.ema.europa.eu) WHO Pharmaceuticals Newsletter No. 3, 2021  4 Regulatory Matters

WHO, Statement of the COVID- (AGEP) between different levothyroxine 19 subcommittee of the WHO products according to what is Global Advisory Committee on Japan. The MHLW and the available at their local Vaccine Safety (GACVS) on PMDA have announced that the pharmacies. safety signals related to the package insert for iopamidol From 2015 to 2019, the MHRA Johnson & Johnson/Janssen (Iopamiron®) should be received 335 reports of the COVID-19 vaccine, 19 May revised to include the risk of thyroid condition being 2021. acute generalized (https://www.who.int/news/item/19- exanthematous pustulosis aggravated or ineffectiveness 05-2021-statement-gacvs-safety- (AGEP) as an adverse drug of the levothyroxine product johnson-johnson-janssen-covid-19- reaction. following substitution with vaccine) another. Associated symptoms Iopamidol is used for were mostly consistent with diagnostics such as hypothyroidism or angiocardiography, hyperthyroidism and included aortography and extremity fatigue, headache, malaise, Durvalumab (genetic angiography. , palpitation, nausea myalgia and dizziness. The A total of four cases of AGEP recombination) underlying causes for the have been reported in patients symptoms experienced after treated with iopamidol in Japan Risk of immune switching between products are in the past three years, thrombocytopenic purpura generally unclear. including three cases for which Japan. The MHLW and the a causal relationship between Generic prescribing of PMDA have announced that the the drug and event was levothyroxine remains package insert for durvalumab assessed to be reasonably appropriate for the majority of (genetic recombination) possible. No patient mortalities patients and the licensing of (Imfinzi®) should be revised to have been reported. these generic products is include the risk of immune supported by bioequivalence The MHLW and the PMDA thrombocytopenic purpura as testing. concluded that the revision of an adverse drug reaction. the package insert was If a patient reports persistent Durvalumab is indicated for the necessary. symptoms of their condition treatment of locally-advanced, being aggravated when Reference: unresectable non-small cell switching between different Revision of Precautions, lung cancer and extensive levothyroxine products, health- MHLW/PMDA, 30 March 2021 care professionals should stage small cell lung cancer. (www.pmda.go.jp/english/) consider consistently A total of 15 cases of immune prescribing a specific product thrombocytopenic purpura known to be well tolerated by have been reported in patients the patient. Also, if symptoms treated with durvalumab in Levothyroxine or poor control of thyroid Japan in the past three years, function persist, prescribing an including four cases for which a (tablet) oral solution formulation of causal relationship between the levothyroxine should be drug and event was assessed Risk of related to considered. to be reasonably possible. No aggravating thyroid Reference: patient mortalities have been symptoms when switching reported. Drug Safety Update, MHRA, between different products 19 May 2021 (www.gov.uk/mhra) The MHLW and PMDA concluded that the revision of United Kingdom. The (See also WHO Pharmaceuticals Newsletter the package insert was Medicines and Healthcare No.1, 2020: Potential adverse reactions necessary. Products Regulatory Agency when switching brands in Ireland) (MHRA) has announced that Reference: the product information for Revision of Precautions, levothyroxine is being updated MHLW/PMDA, 30 March 2021 to include the risk of (www.pmda.go.jp/english/) aggravating thyroid symptoms Nivolumab when switching between different levothyroxine Potential risk of certain products (tablets). blood disorders and cytokine release and tumor Iopamidol Levothyroxine is indicated for lysis syndromes the control of hypothyroidism. Risk of acute generalized In the UK, prescribing of Canada. Health Canada has exanthematous pustulosis levothyroxine is usually announced that the product generic, so patients may switch WHO Pharmaceuticals Newsletter No. 3, 2021  5 Regulatory Matters safety information (Canadian patients with cirrhosis. The FDA Adding a PEG-based laxative to Product Monograph, CPM) for believes the benefits of a liquid that has been nivolumab (Opdivo®) has been obeticholic acid outweigh the thickened with a starch-based updated to include a warning of risks for PBC patients who do thickener may counteract the the risk of autoimmune not have advanced cirrhosis. thickening action. hemolytic anemia and it is Health-care professionals Constipation and dysphagia working with the should determine whether a coexist more commonly in the manufacturers to include the patient with PBC has advanced elderly and in those with risks of aplastic anemia, cirrhosis before starting swallowing difficulties. cytokine release syndrome and obeticholic acid. tumor lysis syndrome in CPM. Although the MHRA is not Also, health-care professionals aware of any cases of this Nivolumab is used alone or in should routinely monitor potential interaction in the UK, combination to treat certain patients during the treatment an institute in Canada has type of cancers of the skin, for progression of PBC with issued a safety bulletin head and neck, blood cells, laboratory and clinical discussing a potential harmful lungs and kidneys. assessments to determine interaction between PEG Health Canada reviewed whether to discontinue laxative and starch-based information received from the obeticholic acid. thickeners. manufacturer by searching the Reference: Reference: Canada vigilance database, MedWatch, US FDA, 26 May Drug Safety Update, MHRA, international databases and 2021 (www.fda.gov) 27 April 2021 (www.gov.uk/mhra) published literature. It concluded that there may be a (See also WHO Pharmaceuticals Newsletter link between nivolumab and No.4, 2018: Risk of serious liver injury in the risks of autoimmune Ireland; No.3, 2018: Risk of serious liver hemolytic anemia, aplastic injury in UK; No.5, 2017: Risk of serious liver anemia, cytokine release injury in USA) Pomalidomide, syndrome and tumor lysis thalidomide syndrome. Potential risk of progressive Reference: multifocal Summary Safety Review, Polyethylene glycol Health Canada, 19 May 2021 leukoencephalopathy (PML) (www.hc-sc.gc.ca) (PEG) laxatives and Canada. Health Canada has (See also WHO Pharmaceuticals Newsletter starch-based announced that the product No.4, 2019: Potential risk of thickeners safety information for hemophagocytic lymphohistiocytosis (HLH) pomalidomide (Pomalyst®) has in Canada; No.2, 2019: Risk of serious blood Potential interaction: risk of been updated to include a disorder in Japan) aspiration warning of the risk of progressive multifocal United Kingdom. The leukoencephalopathy (PML).

MHRA has announced that it Health Canada will also include Obeticholic acid has requested that the this warning in the safety manufacturers of Polyethylene information for thalidomide Risk of serious liver injury glycol (PEG) laxatives to (Thalomid®). update the summary of product Pomalidomide and thalidomide characteristics (SmPC) and the USA. The US Food and Drug are indicated to treat multiple patient information leaflet (PIL) Administration (FDA) has myeloma. announced that it has revised to include information about a the boxed warning for potential interaction with starch Health Canada reviewed the obeticholic acid (Ocaliva®) to based thickeners that can available information by include the risk of serious liver increase the risk of aspiration performing a search in the injury in patients with primary in patients with dysphagia. Canada vigilance database, international database, biliary cholangitis (PBC) and PEG laxative products are used published literature and using advanced cirrhosis of the liver. to treat constipation through information provided by the an osmotic effect. Thickeners Obeticholic acid is indicated to manufacturer. treat PBC. are used to thicken liquids taken by patients with Health Canada’s review The FDA identified 25 cases of dysphagia, including elderly concluded that there is a serious liver injury that led to and those who have trouble possible link between liver decompensation or liver swallowing. There are two main pomalidomide or thalidomide failure associated with the use types of thickening agents: and the risks of PML. of obeticholic acid in PBC starch- and gum-based.

WHO Pharmaceuticals Newsletter No. 3, 2021  6 Regulatory Matters

Reference: Shosaikotokakikyose years of age and older. Summary Safety Review, The PRAC reviewed the Health Canada, 27 May 2021 kko (www.hc-sc.gc.ca) available evidence including Risk of interstitial cases of facial swelling (See also WHO Pharmaceuticals Newsletter pneumonia reported to the European No.2, 2021: Risk of progressive multifocal database for suspected adverse leukoencephalopathy (PML) in Japan) Japan. The MHLW and the effects (EudraVigilance) and PMDA have announced that the scientific literature. A causal association between the package insert for shosaikotokakikyosekko vaccine and the reported cases of facial swelling in people with Ritodrine and (Tsumura Shosaikotokakikyosekko a history of injections with Magnesium sulfate Extract Granules®) should be dermal fillers was considered to be reasonably possible. (co-administration) revised to include the risk of interstitial pneumonia as an Reference: Increased risk of adverse drug reaction. EMA, 7 May 2021 hyperkalaemia Shosaikotokakikyosekko is (www.ema.europa.eu) indicated for relief of tonsillitis Japan. The MHLW and the and peritonsillitis accompanied PMDA have announced that the by painful swollen throat. package inserts for ritodrine (Utemerin®) and magnesium A total of two cases of Vascular endothelial interstitial pneumonia have sulfate (Magsent® and growth factor (VEGF) Magnesol®) should be revised been reported in patients to include the risk of treated with inhibitors (systemic hyperkalaemia in preterm shosaikotokakikyosekko in infants born to mothers who Japan in the past three years, use) including one case for which a were co-administered ritodrine Risk of artery dissections and magnesium sulfate. causal relationship between the drug and event was reasonably and aneurysms Ritodrine is indicated for possible. No patient mortalities Malaysia. The NPRA has threatened abortion/premature have been reported. labor. Magnesium sulfate is issued a directive for all indicated for inhibition of If symptoms such as cough, registration holders of vascular uterine contractions and for dyspnoea, pyrexia and endothelial growth factor prophylaxis and treatment of abnormal chest sounds are (VEGF) inhibitors for systemic eclampsia. observed, administration of the use, requesting that the local shosaikotokakikyosekko should package inserts should be A total of eight cases of be discontinued. updated to include the risk of neonatal hyperkalaemia have artery dissections and Reference: been reported in the newborns aneurysms. of patients treated with Revision of Precautions, ritodrine and magnesium MHLW/PMDA, 13 May 2021 VEGF inhibitors are indicated to sulfate in Japan in the past (www.pmda.go.jp/english/) treat various types of cancers including , three years, including four cases for which a causal thyroid and soft tissue cancers. relationship between the drug There are 21 registered and event was assessed to be products containing VEGF reasonably possible. There has Tozinameran inhibitors for systemic use in been one death reported, but a Malaysia. causal relationship could not be Risk of facial swelling The NPRA has received two established. Europe. The PRAC has reports of aneurysms The MHLW and the PMDA recommended that the SmPC associated with concluded that the revision of and the PIL for tozinameran use in Malaysia. the package insert was (Comirnaty®) should be The mechanism of VEGF necessary. revised to include facial inhibitors causing artery swelling in people with a dissections and aneurysms is Reference: history of injections with unclear but thought to be due Revision of Precautions, dermal fillers as an adverse to the weakening of vascular MHLW/PMDA, 30 March 2021 reaction. (www.pmda.go.jp/english/) wall integrity. Risk factors Tozinameran is indicated for include hypertension or

active immunization to prevent aggravation of pre-existing COVID-19 caused by SARS- hypertension, a previous CoV-2 virus, in individuals 12 history of aneurysm, smoking, WHO Pharmaceuticals Newsletter No. 3, 2021  7 Regulatory Matters diabetes mellitus, coronary, cerebrovascular or peripheral arterial disease. Health-care professionals should carefully consider the risk of artery dissections and aneurysms in patients with risk factors before prescribing VEGF inhibitors for systemic use. Reference: Safety Alerts, NPRA, 20 April 2021 (www.npra.gov.my/) (See also WHO Pharmaceuticals Newsletter No.5, 2020: Risk of aneurysms and artery dissections in New Zealand; No.6, 2020: Risk of aneurysm and artery dissection in Ireland; No.1, 2019: Risk of artery dissections and artery aneurysms in Canada)

WHO Pharmaceuticals Newsletter No. 3, 2021  8 Safety of Medicines

Amitriptyline A recent European review of The risk of poisoning is greater safety data recommends for younger children with low Potential risk of drug periodically monitoring patients bodyweight where the low toxic reaction with eosinophilia taking bendamustine for skin threshold of the drug can be changes and advises patients easily exceeded. Adverse drug and systemic symptoms to contact the doctor if they reactions include coma, Saudi Arabia. The Saudi Food notice worrying skin changes. respiratory depression, bradycardia, hypotension and and Drug Authority (SFDA) has In addition, very rare cases of hypothermia. released a potential safety PML have been reported in signal about drug reaction with patients taking bendamustine. Health-care professionals eosinophilia and systemic If PML is suspected, health- should counsel patients and symptoms (DRESS) associated care professionals should their caregivers about the with the use of Amitriptyline. undertake appropriate importance of following dosing Amitriptyline is a diagnostic evaluations and instructions carefully and with sedative suspend treatment until PML is precisely and ensuring that the properties. excluded. medicines are stored safely and out of reach from children. In 2021, the SFDA reviewed all Reference: the evidence available on the Drug Safety Update, MHRA, Also, off-label prescribing association between 24 March 2021 should only be considered (www.gov.uk/mhra) amitriptyline and DRESS after when other options are unavailable, exhausted, not receiving an individual case safety report (ICSR). tolerated or unsuitable.

The SFDA’s investigation Reference: concluded that the current Clonidine Medicines Safety Update, TGA, available evidence from 29 April 2021 (www.tga.gov.au/) assessment of the ICSRs might Risk of overdosing in support a relationship between children amitriptyline and DRESS. This potential signal needs further Australia. The Therapeutic investigation to confirm the Goods Administration (TGA) Clopidogrel risk, and health-care has reminded health-care Potential risk of professionals should be aware professionals that serious of this potential adverse adverse events can occur in hypertension reaction. children who are accidentally overdosed with clonidine Saudi Arabia. The SFDA has Reference: (Catapres® and generic released a potential safety Safety Alerts, SFDA, 2021 brands), and even relatively signal concerning hypertension (www.sfda.gov.sa) minor overdoses can result in associated with the use of clopidogrel. toxicity in young children. Clopidogrel is indicated for use Clonidine is indicated for cardiovascular effects such as in adult patients suffering from Bendamustine high blood pressure, myocardial infarction, and menopausal flushing. ischaemic stroke or Increased risk of non- Clonidine is also prescribed off- established peripheral arterial disease. In 2020, the SFDA melanoma skin cancer and label under careful medical supervision for behavioral reviewed all the evidence progressive multifocal available on the association encephalopathy (PML) disorders in children with attention deficit hyperactivity between clopidogrel and hypertension following an ICSR United Kingdom. The disorder (ADHD), tic disorders sent to the Saudi National MHRA has announced that an and sleep disturbances. Pharmacovigilance Centre. increased risk for non- There have been 43 cases of melanoma skin cancers and adverse drug reactions Causality assessment of this progressive multifocal reported to the TGA that relate case was associated with a encephalopathy (PML) has to overdose, incorrect dose or positive dechallenge and was been observed in patients off-label use of clonidine in considered to be probable. In treated with bendamustine children. Many of the events the WHO global database of (Levact®). required medical intervention ICSRs (VigiBase), 357 ICSRs were found for this Bendamustine is indicated for or hospitalization. The number drug/adverse drug reaction chronic lymphocytic leukaemia, of reports of poisoning has combination as of September. non-Hodgkin’s lymphomas and increased in recent years and 2020. multiple myeloma. similar trends have been observed overseas. The SFDA’s investigation WHO Pharmaceuticals Newsletter No. 3, 2021  9 Safety of Medicines concluded that the current signs or symptoms in treated connective tissue disorders, available evidence from patients. hypertension or rheumatoid assessment of the ICSRs might arthritis. Reference: support a relationship between Safety Alerts, SFDA, 2021 Reference: clopidogrel and hypertension. (www.sfda.gov.sa) Product Safety Alerts, HSA, This signal needs further 12 May 2021 (www.hsa.gov.sg/) investigation to confirm the risk and health-care (See also WHO Pharmaceuticals Newsletter professionals should be aware No.1, 2021: Risk of heart valve regurgitation in UK; No.2, 2020: Risk of aortic aneurysm of this potential adverse Fluoroquinolones reaction. and dissection in Australia; No.6, 2019: Risk of tendon disorders, peripheral neuropathy Reference: Risk of heart valve and psychiatric symptoms in Japan) regurgitation Safety Alerts, SFDA, 2021 (www.sfda.gov.sa) Singapore. The Health Sciences Authority (HSA) has announced that the use of Indapamide systemic fluoroquinolones are Donepezil associated with a small Potential risk of increased risk of heart valve Rhabdomyolysis Potential risk of QT regurgitation. prolongation Saudi Arabia. The SFDA has Fluoroquinolones are indicated released a potential safety to treat infections such as Saudi Arabia. The SFDA has signal of rhabdomyolysis acute sinusitis and acute released a potential safety associated with the use of bronchitis. There are seven signal concerning QT indapamide. systemic fluoroquinolones used prolongation associated with in Singapore: ciprofloxacin, Indapamide is a thiazide-like the use of donepezil. ofloxacin, norfloxacin, diuretic medication generally Donepezil is indicated for lomefloxacin, levofloxacin, used in the treatment of symptomatic treatment of mild moxifloxacin and pefloxacin. hypertension. to moderately severe Fluoroquinolones are known to SFDA has reviewed the local Alzheimer’s dementia. increase the risk of collagen- and WHO global databases to related disorders such as The SFDA has comprehensively find and assess related case tendonitis, tendon rupture, and reviewed all relevant data and reports of indapamide aortic aneurysm and evidence to evaluate this risk, associated rhabdomyolysis. dissection. which includes case-report The search resulted in 33 case- analysis, data mining of the In September 2020, the EMA reports. Casualty assessments WHO global database of ICSRs, concluded that fluoroquinolone were made on a selection of and relevant evidence from the use may increase the risk of good quality reports. literature. A total of 132 ICSRs heart valve regurgitation, and Seven cases of rhabdomyolysis were found globally in the WHO as a result the EMA with indapamide reported a database of ICSRs in December recommended that the existing positive dechallenge, four were 2020. Casualty assessments warning on aortic aneurysm assessed to be probable, five were made on a selection of and dissection in the package possible and one unassessable. good quality reports. inserts of systemic and inhaled fluoroquinolone-containing Additionally, The More than half of the selected products should be expanded disproportionality of the ICSRs were assessed to have a to include heart valve observed and the expected supportive association (seven regurgitation. reporting rate for this probable and 14 possible). drug/adverse drug reaction Statistical data mining of The HSA has not received any pair was supportive for an reports in VigiBase showed that local reports of heart valve- association. the number of observed cases related disorders associated were more than expected. with fluoroquinolone. In conclusion, the weighted cumulative evidence identified Multiple articles in the Health-care professionals are from causality assessment of literature supported this advised to take into the reported cases and data association, and included consideration the risk when mining are sufficient to support evidence of a class effect and a prescribing systemic a potential association between published case-report for fluoroquinolones and the indapamide and the risk of donepezil. availability of other therapeutic rhabdomyolysis. Health-care options for patients with pre- Health-care professionals professionals should be aware existing risk factors such as should be aware of this of this potential risk and heart valve diseases, potential risk and monitor any monitor any signs or symptoms WHO Pharmaceuticals Newsletter No. 3, 2021  10 Safety of Medicines in treated patients. In 2021, the SFDA reviewed all (mRNA 1273) the evidence available on the Reference: association between nivolumab Safety Alerts, SFDA, 2021 Risk of myocarditis and hypoparathyroidism (www.sfda.gov.sa) following an ICSR sent to the Europe. The PRAC has Saudi National requested more detailed Pharmacovigilance Centre. information on myocarditis and The SFDA’s investigation pericarditis from the marketing Lamotrigine concluded that this needs authorization holder of further investigation to confirm tozinameran. This should be Potential risk of arrhythmia the risk and health-care included in the next pandemic professionals should be aware summary safety report before USA. The US FDA has of this potential adverse considering if any other announced that study findings reaction. regulatory action is needed. showed a potential risk of Additionally, the PRAC has arrhythmias in patients with Reference: requested the marketing heart disease who are taking Safety Alerts, SFDA, 2021 authorization holder for COVID- lamotrigine (Lamictal®). (www.sfda.gov.sa) 19 vaccine mRNA (mRNA Lamotrigine is indicated to 1273) (COVID-19 vaccine treat seizures and bipolar Moderna®) to also monitor for disorder. cases of myocarditis and pericarditis and to the provide Laboratory tests performed at Theophylline a detailed analysis. therapeutically relevant concentrations have shown Potential risk of Reference: that lamotrigine can increase encephalopathy EMA, 7 May 2021 the risk of serious arrhythmias, (www.ema.europa.eu) Saudi Arabia. The SFDA has which can be life-threatening in released a potential safety patients with important signal concerning structural or functional heart WHO, COVID-19 subcommittee encephalopathy associated with disorders. of the WHO Global Advisory the use of theophylline. Committee on Vaccine Safety The risk of arrhythmias may Theophylline is indicated for (GACVS) reviews cases of mild increase further if used in the treatment of the symptoms myocarditis reported with combination with other and reversible airflow COVID-19 mRNA vaccines, 26 medicines that block sodium obstruction associated with May 2021. channels in the heart. chronic asthma and other (https://www.who.int/news/item/26- Health-care professionals chronic lung diseases. 05-2021-gacvs-myocarditis- should assess whether the reported-with-covid-19-mrna- In 2021, the SFDA reviewed all potential benefits of vaccines) the evidence available on the lamotrigine outweigh the association between potential risk of arrhythmias theophylline and for each patient. encephalopathy following an Reference: ICSR sent to the Saudi National MedWatch, US FDA, 31 May Pharmacovigilance Centre. 2021 (www.fda.gov) The SFDA’s investigation concluded that further investigation to confirm this

risk is needed, and health-care Nivolumab professionals should be aware of this potential adverse Potential risk of reaction. hypoparathyroidism Reference: Safety Alerts, SFDA, 2021 Saudi Arabia. The SFDA has (www.sfda.gov.sa) released a potential safety signal of hypoparathyroidism associated with the use of nivolumab. Nivolumab is indicated for the Tozinameran, COVID- treatment of unresectable 19 vaccine mRNA malignant melanoma.

WHO Pharmaceuticals Newsletter No. 3, 2021  11 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 26 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 28). 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.

Levetiracetam and Hypokalaemia Mónica Tarapués, Ecuador

Summary September 2000. Around 2005, oral tablets and solutions were approved for children, and in 2006, Levetiracetam is considered a remarkable it began to be used for the treatment of status antiepileptic drug due to its mechanism of action, epilepticus. At the time of writing, levetiracetam is which is unrelated to the Na+ channels or to indicated for the treatment of epilepsy in adults, GABAergic transmission. Few interactions are adolescents, children, and infants. It is a described for this drug due to its minimal hepatic pyrrolidone derivative (S-enantiomer of α-ethyl-2- metabolism; however, sixty-six percent of its oxo-1-pyrrolidine acetamide), chemically unrelated elimination depends on the renal function. Drug- to existing antiepileptic active substances. induced hypokalaemia is a hazardous reaction that Regarding its mechanism of action, it is well known could lead, in the worst cases, to death. A screening that the interaction is between levetiracetam and of VigiBase, the WHO global database of individual the synaptic vesicle protein 2A. In this way, it does case safety reports, identified disproportionate not exhibit the classical action of other antiepileptic reporting of the MedDRA Preferred Term (PT) because there is no effect on voltage- “Hypokalaemia” with levetiracetam. A selection of dependent Na+ channels or GABAergic the cases with a completeness score above 0.60 transmission. (1) was made to analyse drug–reaction association patterns. A consistent time to onset and a biological Hypokalaemia is a common and sometimes serious plausibility support this signal. Through this electrolyte imbalance. Its presence can aggravate analysis, it seems reasonable to consider the the baseline clinical conditions of patients. The association between hypokalaemia and hypokalaemia categories are well known: mild with levetiracetam use. Currently, only the product plasma levels of >3.0–3.5 mmol/L generally information from Canada warns of hypokalaemia as asymptomatic; moderate 2.5–3.0 mmol/L its an adverse reaction to levetiracetam, but all symptoms are cramping, malaise, myalgia, clinicians should be aware of this adverse event. weakness; and severe < 2.5 mmol/L associated with electrocardiogram changes (including ST-

segment depression, U-wave elevation, T-wave Introduction inversion), arrhythmias and paralysis. Drug-induced hypokalaemia could be associated with a decrease In December 1999, levetiracetam was approved in in potassium intake, or with increased potassium the United States (US) as an antiepileptic drug for shifting (transcellular shifts). This electrolyte the treatment of adults with partial seizures, and disbalance is commonly associated with diuretics, approval by the European Union (EU) followed in

WHO Pharmaceuticals Newsletter No. 3, 2021  12 Signal

β2- agonists drugs, corticosteroids, some being oral route (ten reports), followed by antimicrobials, or high doses of insulin (2). intravenous (nine) and transplacental (one). In the case of the transplacental route, it seems according

to the narrative text that exposure of the new-born Reports in VigiBase was during the pregnancy span. Regarding the concomitant medicines, hydrocortisone was During 2017, the MedDRA Preferred Term reported as a co-suspected drug in two cases, “hypokalaemia” was highlighted for the drug however, in one report, the starting date was given levetiracetam in VigiBase, the WHO global database in the same timeframe as levetiracetam. of individual case safety reports. This combination Lacosamide was also mentioned as co-suspected in was kept under review in order to gather more two other cases, within the same timeframe as cases. As of 15 September 2019, in an updated and levetiracetam. In four reports the use of proton extended search in the database, there were 74 pump inhibitors such as esomeprazole (one as co- reports of this drug–adverse drug reaction (ADR). suspected and another one as concomitant) and Seventeen cases were suspected as duplicates; (two cases as concomitant) was therefore, 57 were considered. Due to the high mentioned. number of cases, an analysis of the reports with a completeness score over 0.6 was undertaken. In Hypokalaemia was described as the single ADR in the present case series, 23 cases were evaluated. eleven cases. Hypomagnesemia was reported in four cases as a co-reported reaction, and in two of The reports came from eight countries. Eleven these cases, the starting dates mentioned were the patients were female, the other eleven were male, same as hypokalaemia. Likewise, three reports and gender was not specified in one report. The mentioned diarrhoea, two during the same time age was recorded in twenty-one patients. Ten out of period as hypokalaemia. The plasmatic level of twenty-one were adults, nine were elderly, one was potassium concentrations was registered in fourteen aged 5, and one a new-born. More than half of the cases, with a range of 2.2 – 3.3 mmol/L, in all cases were submitted by physicians (sixteen cases the levels being reported after the reports). In fourteen cases the ADR was considered levetiracetam was started. as serious, mainly because of prolonged hospitalization (eight cases), or concomitant Levetiracetam was withdrawn from three patients medically important conditions (five cases). One and the dose reduced in another one, all these case was reported as serious because the patient being reported as recovered. In ten patients the died. The summary of case characteristics is set out dose was not changed, and of these, four were in Table 1. described as recovered, another four as recovering, one as not recovered, and for the last one the Levetiracetam was the unique suspected drug in 14 outcome was unknown. Sixteen cases had a reports, the therapeutic indication being epilepsy narrative; in seven of these a supplement of (focal seizures, convulsions, partial seizures with potassium was mentioned. One patient died; this secondary generalization). The time to onset was was an elderly person (aged 83), with co-reported mentioned in eighteen reports, in seventeen cases a ADRs pneumonia, atrial fibrillation, tachycardia, range from the same day up to two months was hypoproteinaemia, hypoalbuminemia, and blood given. In one case the patient experienced the ADR lactate dehydrogenase increased, but there was no after two years of treatment. Half of the patients narrative. It is difficult to attribute the fatal had a time to onset around ten days after starting outcome to the hypokalaemia. levetiracetam. The route of administration was mentioned in twenty reports, the more frequent

Table 1. Summary characteristics of 57 case reports in VigiBase of hypokalaemia in association with Levetiracetam in VigiBase Characteristic 23 cases with high completeness score 34 cases with low completeness score (above 0.6) (less than 0.59) Age (median / range) 57 years / 0* - 90 years 45 years / 5 – 87 years Patient sex distribution 11 female / 11 male / 1 unknown 21 female / 13 male Geographical spread India (n=7), Germany (n= 4), Italy (n=3), US (n=17), Germany (n=6), United Kingdom Japan (n=3), Greece (n=2), France (n=2), US n=2 and Italy, Korea, Japan, Turkey, Denmark, and Ireland (n=1 each) France, Hungary, Belgium , Ireland (n= 1 each) Reporter types 16 physicians; 4 pharmacists; 3 other health 17 physicians; 3 pharmacists; 9 other health professionals professionals; 2 consumers; 3 unknown Single suspect drug 14 reports 9 reports Single reported drug 7 reports 4 reports

WHO Pharmaceuticals Newsletter No. 3, 2021  13 Signal

Category of 3 reported as mild, 7 reported as moderate, 4 5 reported as mild, 1 reported as severe, 28 hypokalaemia reported as severe, 9 reports unknown reports unknown Time-to-onset Mentioned in 18 reports with a median of 10 Mentioned in 2 reports days 30 and 60 days 12 reports after 1 to 10 days, 3 reports after 11 to 20 days, 2 report after 60 days, 1 report after 2 years Withdrawn/recovered 1 report with dose reduced, 3 reports with drug 1 report with drug withdrawn and the reaction withdrawn and all with reaction abated abated 8 reports with dose not changed and reaction abated or in recovering

Literature and Labelling magnesium 1.35 mg/dL. Despite the potassium supplement at the hospital, the patients did not The literature suggests that levetiracetam is widely fully recover, and consequently levetiracetam was used due to high tolerability comparing favourably withdrawn.(10) In 2018, another case from Turkey with other antiepileptic drugs used in epilepsy, and described a 34 year-old woman who was admitted because it can be used when other drugs are to hospital after attempting to commit suicide. In contraindicated or patients have a refractory the laboratory test hypokalaemia (3.1 mEq/lt) and condition to other antiepileptics. (1) hypomagnesemia (1.2 mg/dl) were observed; the Sixty-six percent (66%) of levetiracetam is excreted patient was taking 2500 mg/day levetiracetam for unchanged by glomerular filtration in the kidney, epilepsy although the duration of treatment was not with subsequent tubular reabsorption, as well as its described.(11) These publications suggest that the primary metabolite (ucb L057). The plasma half-life hypokalaemia observed could be due to a of levetiracetam across studies is 6 to 8 hours, transcellular shift mechanism, an unknown side however the labelling mentions it could be greater effect of the levetiracetam, given that they ruled- in subjects with renal impairment and in the elderly, out other potential causes such as metabolic primarily due to impaired renal clearance. In alkalosis or gastrointestinal losses. (9–11) patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50% reduction of the daily Discussion and Conclusion maintenance dose is recommended when the In this case series, it is difficult to rule out other creatinine clearance is <60 mL/min/1.73m2.(3,4) potential causes as there is a lack of information The Summary of Product Characteristics (SPC) of regarding the baseline condition of the patients. levetiracetam in the US and Europe does not list However, the association should be considered, hypokalaemia as an ADR. However, the SPC in given the high suspicion of the reporters and the Canada mentions hypokalaemia as an ADR fourteen reports where levetiracetam was the only observed in the post-marketing surveillance. (5–8) drug mentioned. On the other hand, diarrhoea – another potential cause – was only mentioned in In the literature, a case report published in 2014 two cases. It is worth noting that the time to onset from Turkey described a 23-year-old man where in most cases (twelve patients out of twenty-three) hypokalaemia was found during routine blood tests was within ten days after starting levetiracetam. six weeks after taking 500 mg levetiracetam twice daily. After the nephrology consultation, his Regarding other drugs that can be associated with hypokalaemia (3.1 mmol/L; normal: 3.5–5.5 hypokalaemia, corticosteroids, and methylxanthines mmol/L) and hypomagnesaemia (0.56 mmol/L; are strongly associated with drug-induced normal: 0.75–1.30 mmol/L)) were considered to be hypokalaemia and other electrolyte imbalances.(2) associated with levetiracetam; it was withdrawn and In one patient, hydrocortisone and theophylline the electrolytes returned to normal after two were reported as co-suspected drugs. However, weeks.(9) In 2015 a publication from Greece levetiracetam was used in the same temporal described hypokalaemia and hypomagnesemia sequence of these drugs, and for that reason it is associated with levetiracetam in two patients. A 90 not possible to rule out their potential association year-old female patient had received levetiracetam with hypokalaemia. 500 mg twice daily intravenously; two days later a Magnesium deficiency exacerbates potassium low plasma level of potassium and magnesium were wasting by increasing distal potassium secretion. identified (2.4 mmol/L, and 0.58 mmol/L, However, hypomagnesemia alone does not respectively). The other patient was a 79 year-old necessarily cause hypokalaemia.(12) In this case female who had been administrated levetiracetam series, four patients had hypomagnesemia, but in at 1 gr twice daily intravenously, and three days two cases the starting dates were unknown and in later the level of potassium was 2.4 mmol/L and WHO Pharmaceuticals Newsletter No. 3, 2021  14 Signal the other two cases, they had the same starting the available evidence based on the date as hypokalaemia, making the analysis of the pharmacokinetics of the drug, suggest a potential potential causal relationship between causal relationship between levetiracetam and hypomagnesaemia and hypokalaemia difficult. Then hypokalaemia. Current product information for again, there are several reports regarding the levetiracetam does not sufficiently inform physicians association of proton pump inhibitors and about electrolyte imbalance, and the product hypomagnesemia.(13,14) Esomeprazole was labelling may need to be revised worldwide since mentioned as a co-suspected drug for hypokalaemia the Canadian SPC already includes hypokalaemia as and hypomagnesemia in one patient. This potential an ADR identified in post-marketing (6). interaction needs further analysis in large studies.

In a prospective study of 32 children in Greece (18 References females, 14 males, mean age 5.94 ± 4.1 years, range 1- 15 years) being treated with levetiracetam 1. Deshpande LS, DeLorenzo RJ. Mechanisms of for the onset of epilepsy, no statistical differences Levetiracetam in the Control of Status were observed in the alteration of serum sodium, Epilepticus and Epilepsy. Front Neurol. 2014 potassium, and magnesium from two to six months Jan 31;5:11. with the use of levetiracetam.(15) However, the authors point to the small number of patients 2. Veltri KT, Mason C. Medication-induced studied as a major limitation of their study, and hypokalemia. Vol. 40, P and T. Medi Media USA suggest that the young age of patients may have Inc; 2015. p. 185–90. played a protective role in the prevention of 3. Wright C, Downing J, Mungall D, Khan O, electrolyte imbalance. Following clinical trials made Williams A, Fonkem E, et al. Clinical in this age group, levetiracetam has been Pharmacology and Pharmacokinetics of authorized for use in children, and is therefore Levetiracetam. Front Neurol. 2013 Dec considered a safe therapeutic option for this group 4;4:192. of patients.(16) However, our sample has two patients under 18 years old, even one case of a 4. Jarvie D, Mahmoud SH. Therapeutic drug new-born patient with hypokalaemia. monitoring of levetiracetam in select populations. J Pharm Pharm Sci. In the twenty-three patients, only four had their 2018;21(1S):149s-176s. dose of levetiracetam reduced or withdrawn, and these patients were reported as recovered. 5. Food and Drug Administration. HIGHLIGHTS However, some patients started with the potassium OF PRESCRIBING INFORMATION. KEPPRA® supplement, such as in three cases reported as [Internet]. [cited 2020 May 1]. Available from: recovered, despite no change in the dose of https://www.accessdata.fda.gov/drugsatfda_d levetiracetam, nor withdrawal. In the same way, in ocs/label/2019/021035s102,021505s042lbl.pdf two other patients in whom the action with 6. Health Canada. KEPPRA. Levetiracetam levetiracetam was reported as unknown, the Product information [Internet]. 2019 [cited outcome was reported as recovered. It is important 2020 May 7]. Available from: https://health- to consider the treatment received for this ADR, and products.canada.ca/dpd- whether patients would have an asymptomatic bdpp/info.do?lang=en&code=71262 hypokalaemia; the dechallenge as an outpatient could be difficult to identify and report, because the 7. Mbizvo GK, Dixon P, Hutton JL, Marson AG. levels of potassium could return to normal two to The adverse effects profile of levetiracetam in four weeks after withdrawal, and the reporter might epilepsy: A more detailed look. Vol. 124, not have had this information at the time that they International Journal of Neuroscience. Informa sent the report. Healthcare; 2014. p. 627–34. The biological plausibility comes through a 8. Keppra 500 mg film-coated tablets - Summary transcellular shift imbalance of potassium, as of Product Characteristics (SmPC) - (emc) discussed in the case reports.(9–11) This [Internet]. [cited 2020 May 9]. Available from: hypothesis goes in tandem with the alterations of https://www.medicines.org.uk/emc/product/22 the potassium homeostasis described as a cause of 93/smpc drug-induced hypokalaemia.(17,18) A previous 9. Aksoy D, Cevik B, Kurt S, Pekdas E, Solmaz V. signal regarding acute renal failure associated with Hypokalemia and hypomagnesaemia related to levetiracetam was published in 2016 by Uppsala levetiracetam use. J Clin Neurosci. Monitoring Centre; this ADR is already mentioned in 2014;21(11):1989–90. the US SPC as an ADR identified in post-marketing surveillance, and in the EU SPC as having a rare 10. Vallianou NG, Geladari E, Chroni P, Kokkinakis frequency.(19) The occurrence of renal adverse E. Levetiracetam-associated Hypokalemia and effects seems reasonable, based on to Hypomagnesaemia among Two Patients levetiracetam pharmacokinetics. Treated for Seizures. CNS Neurosci Ther. 2015;21(6):539–539. In conclusion, patients being treated with levetiracetam should be closely monitored for 11. Key A, Sch T, Case JM, Demir M, Canpolat O, changes in their potassium levels. Our analysis, and Yigit IP, et al. Levetiracetam-Induced WHO Pharmaceuticals Newsletter No. 3, 2021  15 Signal

Hypokalemia and Hypomagnesemia. Sch J Med Neurosci Ther. 2018;24(9):846–7. Case Reports ( SJMCR ). 2018;6559:36–7. 16. Eriksson K, Kälviäinen R. Pharmacologic 12. Huang CL, Kuo E. Mechanism of hypokalemia management of convulsive status epilepticus in in magnesium deficiency. Vol. 18, Journal of childhood. Vol. 5, Expert Review of the American Society of Nephrology. American Neurotherapeutics. Expert Rev Neurother; Society of Nephrology; 2007. p. 2649–52. 2005. p. 777–83. 13. Famularo G. A Relationship Between Proton 17. Buckley MS, Leblanc JM, Cawley MJ. Electrolyte Pump Inhibitors and Hypomagnesemia? Vol. disturbances associated with commonly 93, Mayo Clinic Proceedings. Elsevier Ltd; prescribed medications in the intensive care 2018. p. 1530. unit. Crit Care Med. 2010;38(6 SUPPL.). 14. Perazella MA. Proton pump inhibitors and 18. Palmer BF, Clegg DJ. Physiology and hypomagnesemia: A rare but serious pathophysiology of potassium homeostasis. complication. Vol. 83, Kidney International. Adv Physiol Educ. 2016 Dec;40(4):480–90. Nature Publishing Group; 2013. p. 553–6. 19. Choonara I, Star K. Levetiracetam and 15. Attilakos A, Garoufi A, Paschalidou M, Tsirouda impaired renal function. WHO Pharm Newsl. M, Siafakas N, Dinopoulos A. Serum sodium, 2016;(2):18–23. potassium, and magnesium in children with epilepsy treated with levetiracetam monotherapy: A prospective study. CNS

Remdesivir and pancreatic toxicity Elena Rocca, Uppsala Monitoring Centre

Summary pancreatitis, the series offers evidence for a drug- induced, COVID-19-independent onset of pancreatic Remdesivir is a novel antiviral which, during the symptoms. The summary of product characteristics 2020 COVID-19 pandemic, gained emergency does not contain any information about remdesivir- approval in several countries for use in hospitalized induced pancreatic effects. Other approved COVID-19 patients. The knowledge of remdesivir’s antivirals of the nucleoside analogue class are safety profile is therefore still limited. On a thought to cause pancreatitis, and their mechanism molecular level remdesivir is an adenosine analogue of toxicity is defined in the literature. The that competes with endogenous adenosine temporality and the positive dechallenge in several triphosphate (ATP) resulting in abnormal replication of the cases, together with biological plausibility, of viral RNA with loss of further replication. A recent and analogy with other antiviral drugs, and the analysis by the UMC, focusing on ICSRs from uncertainties in relation to COVID-19, support our COVID-19 treatments, found that as of December claim that the hypothesis of a causal relationship 2020 there were 13 relevant reports with between remdesivir treatment and pancreatic remdesivir and the MedDRA High Level Term (HLT) toxicity needs to be further monitored. ‘Acute and Chronic Pancreatitis’, or with related investigations, in VigiBase, the WHO global database of ICSRs. The reports were from five Introduction countries in the European and American (Region of the Americas) WHO regions. Remdesivir was the Remdesivir is an antiviral drug indicated for the single suspected drug in nine cases of which five treatment of coronavirus disease 2019 (COVID-19) mentioned positive dechallenge. In eight of the in hospitalized patients and/or in hospitalized cases, pancreatic symptoms were the only ones COVID-19 patients in need of supplemental reported. The time to onset ranged from one to oxygen1. The drug is approved for intravenous nine days (median four). One patient died of administration under the supervision of a health COVID-19 infection nine days after positive professional. Remdesivir is an adenosine analogue dechallenge and after recovery from pancreatic prodrug which is metabolized within host cells to symptoms. In two cases, the patients presented form the pharmacologically active nucleoside with pancreatic symptoms after recovery from analogue triphosphate metabolite. The COVID-19. Although the cases of positive phosphoramidate prodrug allows a faster cell dechallenge are confounded by concomitant drugs, uptake of remdesivir, compared to the non- some of which have been rarely associated with phosphoramidated active metabolite (designated as

WHO Pharmaceuticals Newsletter No. 3, 2021  16 Signal

GS-441524)1. Remdesivir competes with the natural focus of this analysis. As of 8th December 2020, adenosine substrate for incorporation into RNA there were 12 unique individual case safety reports chains being formed by the SARS-CoV-2 RNA- (ICSRs) for remdesivir with the MedDRA High Level dependent RNA polymerase, resulting in abnormal Term (HLT) ‘Acute and Chronic Pancreatitis’ in replication of the viral RNA2. Preliminary VigiBase: six contained the PT ‘Pancreatitis’, four pharmacokinetic data indicates that remdesivir is ‘Pancreatitis acute’, and two ‘Oedematous extensively metabolized by cytochrome P450 pancreatitis’. A search with HLT ‘Digestive ’ enzymes CYP2C8, CYP2D6 and CYP3A4. Remdesivir (SOC investigations) gave nine additional ICSRs and metabolites are predominantly excreted in (three with PT ‘Pancreatic enzymes increased’, two urine and the terminal half- life is approximately 24 with ‘Lipase increased’, one with ‘Lipase urine’, two hours3. According to this, complete excretion of the with ‘Amylase increased’, and one with metabolite GS-441524 takes about five days from ‘Hyperamylasemia’). Of these, three ICSRs are the last administration of remdesivir. included in this case series as informative (one with PT ‘Hyperamylasemia’, one with PT ‘Amylase The most common aetiological factors for Increased’, and one with the PTs ‘Lipase increased’ pancreatitis are gallstones and alcohol consumption, and ‘Amylase increased’), while the others were with severe hypertriglyceridaemia, infective agents, excluded because of numerous co-reported and drug adverse reactions also among described symptoms, which make the association with causes for pancreatic inflammation4. A possible pancreatitis more uncertain. In two of the reports causal association between COVID-19 and acute temporality was incompatible with causation, pancreatitis has been reported5,6. Genetic factors, leaving 13 relevant reports from five countries in obesity and diabetes are predisposing conditions. the European and American WHO regions. The Drug-induced pancreatitis is thought to account for details of these reports are shown in Table 1. The about 5% of acute pancreatitis cases4 and there is a patient’s age ranged from 38 to 79 years (median substantial list of drugs that have been associated 55), with nine males and four females. Nine cases with the condition, primarily based on case reports were reported as serious and ten as recovered or containing rechallenge information7. However, recovering. Remdesivir was the single suspected possible mechanisms and times to onset are drug reported in nine cases and there were five with variable which makes drug-induced pancreatitis a positive dechallenge. In eight of the cases, difficult adverse effect to evaluate. Dysfunction of pancreatic symptoms were the only ones reported. the sphincter of Oddi, which regulates the flow of The time to onset ranged from 1 to 9 days (median pancreatic secretions into the intestine, is 4). In two cases the time to onset was five days suggested as one possible mechanism underlying after the last dose. acute pancreatitis, and this may be drug-induced in patients with a history of cholecystectomy8. Diagnostic criteria, where reported, were based on abdominal pain in association with increased levels

of biomarkers such as serum amylase and lipase. Reports in VigiBase Imaging was used in three cases (2, 5, 7 in Table 1). Five cases (3, 6, 11, 12, 13), described A recent analysis of VigiBase by the UMC focused on increased biomarkers without clinical symptoms, ICSRs related to drugs used in COVID-19 patients. giving a weaker basis for a diagnosis of pancreatitis. Remdesivir related ICSRs were therefore within the

Table 1. Characteristics of the ICSRs of remdesivir and pancreatic PTs in VigiBase. Known risk factors for pancreatitis are highlighted in bold. Case Age/S Co-reported suspected Reported MedDRA Time to Action taken/ Other information ex (S) or concomitant Preferred Terms onset outcome drugs (days) 1 52/M Dexamethasone Pancreatitis acute 2 Dechallenge/ Treatment duration: 2 days. Ascorbic acid Therapy interrupted recovering No previous history suggesting Ergocalciferol predisposition to pancreatitis. Rivaroxaban Symptoms and biomarkers level (lipase) compatible with pancreatitis. Ondansetron Dexamethasone administered and Paracetamol interrupted at nearly overlapping dates. 2 53/M Dexamethasone Pancreatitis acute 8 (5 Not applicable/ Treatment duration: 3 days. after last recovering No previous history suggesting dose) predisposition to pancreatitis. Biomarkers (lipase, amylase) and symptoms compatible with acute pancreatitis. Choledocholithiasis or cholecystitis were ruled out sonographically.

WHO Pharmaceuticals Newsletter No. 3, 2021  17 Signal

Case Age/S Co-reported suspected Reported MedDRA Time to Action taken/ Other information ex (S) or concomitant Preferred Terms onset outcome drugs (days) Symptoms of acute pancreatitis appear after the patient has recovered from COVID-19. Patient is re-hospitalized for acute pancreatitis. Dexamethasone administered at nearly overlapping dates. 3 64/F Dexamethasone (S) Pancreatitis acute 3 Dechallenge/ Treatment duration: 5 days. Tocilizumab recovering Obesity. Previous surgeries: cholecystectomy Azithromycin Biomarkers compatible with pancreatitis Bemiparin (peak pancreatic amylase of 500 U/L). Ceftriaxone Otherwise asymptomatic. Case narrative do not indicate pancreatitis as a motivation of Enoxaparin therapy cessation. Oxygen Dexamethasone: TTO 5 days, treatment Acetylsalicylic acid duration 11 days, withdrawn. Chlorthalidone Tocilizumab: one single dose, TTO: 6 days. Finasteride Levosulpiride

4 52/F None reported Pancreatitis acute Not Not reported Not reported Cholelithiasis reported 5 38/M Tocilizumab (S) Pancreatitis 2 None/ Treatment duration: 10 days. Lopinavir;ritonavir Pyrexia recovering Concomitant condition: class 1 obesity. Dyspnoea 'Five months later, a CT scan showed improvement of the pancreatic injury'. Tocilizumab: treatment duration 1 day, TTO 2 days. 6 69/F None reported Pancreatitis 5 None/ Treatment duration: 5 days. Covid-19 Pneumonia not reported 90,4 kg. 'On day 5, patient's lipase was elevated to 1056, consistent with pancreatitis'. 7 42/F Escitalopram Pancreatitis 9 (5 Not applicable/ Treatment duration: 4 days. Enoxaparin after last recovering Previous history: diabetes, obesity, dose) Dexamethasone depression. Famotidine Reported symptoms and biomarkers (lipase elevated to 262 U/L) compatible with mild Insulin pancreatitis. Ultrasound imaging excluded gallstones Pantoprazole Symptoms appeared after recovery from Gabapentin COVID-19 symptoms, although CT scan of the lungs shows signs of multifocal Oxygen pneumonia. 8 79/M Tocilizumab (S) Pancreatitis 4 Not reported Not reported 9 70/M Furosemide (S) Pancreatitis 7 Dechallenge/ Treatment duration: 6 days. Paracetamol recovered Died of COVID-19 infection nine days after pancreatic symptoms resolved. Amiodarone Furosemide: treatment duration 2 days, TTO Warfarin 3 days, withdrawn. Acetylsalicylic acid Diagnostic criteria not provided. Tazobactam Ramipril Piperacillin Prednisolone Ciprofloxacin Spiramycin

WHO Pharmaceuticals Newsletter No. 3, 2021  18 Signal

Case Age/S Co-reported suspected Reported MedDRA Time to Action taken/ Other information ex (S) or concomitant Preferred Terms onset outcome drugs (days) Heparin Cefotaxime 10 42/M Ceftriaxone Oedematous 6 Not applicable/ Treatment duration: unclear. Heparin pancreatitis recovering Concomitant condition: abdominal pain Hepatitis (since 14 days before pancreatitis). Azithromycin Hepatitis: TTO 4 days. No diagnostic criteria are provided for oedematous pancreatitis. 11 59/M Amylase increased 1 Not withdrawn/ Reported symptom: increased amylase to not recovered 243U/L one day after treatment initiation (but amylase and 469U/L six days after initiation. levels are Amylase increase has a registered peak decreasing after (841U/L) nine days after initiation and start therapy decreasing again (512U/L) 13 days after conclusion) initiation (3 days after therapy completion). No medical history pointing to predisposition to pancreatitis. 12 55/M Methylprednisolone Hyperamylasaemia 1 Dechallenge/ Treatment duration: 4 days. Furosemide recovering From the start of treatment with remdesivir, serum amylase progressively increased to 4500 U/L (upper limit normal 136 U/L) and began to decrease after the last dose was omitted. 13 74/M Venlafaxine Amylase increased 4 Dechallenge/ Not reported Hydroxycarbamide Lipase increased recovering TTO = Time to onset

Literature and labelling between the use of remdesivir and development of pancreatitis, a confounding factor is that Publicly available information on remdesivir’s safety pancreatitis might be a clinical manifestation of profile, though still limited, includes COVID-19 itself. Although still uncertain, such a hypersensitivity, infusion-related and anaphylactic clinical feature of COVID-19 is indicated by the reactions (rare), transaminase elevation (very pancreatic expression of SARS-CoV-2 molecular common), nausea (common), headache (common), target ACE-211, by case reports,5,6 and by the fact rash (common), and renal impairment (precaution). that the infection was associated with increased Interactions including risk of decreased antiviral biomarkers of pancreatic injury12 (which, however, activity when co-administrated with and taken alone should not necessarily be interpreted as hydroxychloroquine have also been signalled1. The pancreatic dysfunction13). Reports that can help summary of product characteristics does not discern confounding with underlying COVID-19 contain any information about remdesivir-induced disease are therefore of particular interest. pancreatic effects. This series contains three cases that are interesting Antivirals of the nucleoside analogue class, such as in that they point to a COVID-19 independent onset those used to treat HIV, have been causally of the pancreatic symptoms (cases 2, 7 and 9 in associated with pancreatitis, with inhibition of Table 1). Cases 2 and 7 describe symptoms of mitochondrial DNA synthesis as the underlying pancreatic injury appearing after recovery from the mechanism9. Given that remdesivir is also a COVID-19 infection, both on day 5 after the last nucleoside analogue, based on the criteria of dose of remdesivir. Bearing in mind the available plausibility and analogy, it seems sensible to pharmacokinetic data3 these timeframes may be monitor pancreatic reactions reported in connection considered clinically reasonable, if we accept the with remdesivir. Despite scarce data, the theoretical possibility that the process of injury commenced possibility of a similar mechanism for remdesivir, before the symptoms appeared. In both cases together with the need for monitoring, has been remdesivir is the only suspected drug, although pointed out10. dexamethasone, which has on rare occasions been associated with pancreatitis14, is reported as concomitant in both. The cases thus provide some Discussion and conclusion indication of a COVID-19 independent pancreatic When evaluating the plausibility of a causal relation injury. Since in both cases alternative causes were excluded by imaging, and since the patient in case WHO Pharmaceuticals Newsletter No. 3, 2021  19 Signal

2 is described as healthy before contracting COVID- pancreatic reactions. Limited remdesivir 19, and the patient in case 7 has no described characterisation, incomplete knowledge about relevant co-morbidity except for obesity, they speak COVID-19 pathophysiology, and the substantial in favour of drug-induced pancreatitis, with both number of concomitant medications used to treat remdesivir and dexamethasone suspect. Evidence in COVID-19, make causality assessment and clinical the same direction is provided by case 9, reporting analyses of ICSRs particularly challenging. a positive dechallenge with improvement of In this situation, we argue that the criteria of pancreatitis while the patient was still severely analogy with similar drugs and biological plausibility unwell from COVID-19. Here, furosemide, for which could be used for support. Remdesivir shares the pancreatitis is a known rare reaction, is reported as mechanism of action with other approved co-suspected with a short treatment duration (two nucleoside analogues, including those used to treat days) and a time to onset of three days. Death from HIV, which are thought to cause pancreatitis, most COVID-19 occurred nine days after recovery from commonly through mitochondrial toxicity. Although pancreatitis, although detailed diagnostic criteria for there is no evidence for the pancreatic toxicity of pancreatitis (and recovery) are not provided in the remdesivir, it has been pointed out that there is a report. theoretical possibility for a common mechanism of In two of the cases remdesivir is the only reported action between remdesivir and similar antiviral drug, however these are not very informative. In drugs10. one of them (case 6) elevated lipase is reported on The case series here presented offers some the fifth and last day of remdesivir treatment. evidence of COVID-19 independent, drug-induced Most cases in the series are confounded by pancreatic symptoms in COVID-19 patients. The concomitant or co-suspected drugs that might temporality and the positive dechallenge in several contribute to, or cause, the pancreatic symptoms. of the cases supports the hypothesis that Dexamethasone, associated on rare occasions to remdesivir, together with other COVID-19 pancreatitis14, is reported as concomitant or co- treatments, may have caused or contributed to the suspected, and administered at almost overlapping onset of symptoms compatible with pancreas injury. days with remdesivir in four cases. One case of Taking into account the particular uncertainties in increased serum amylase (case 12, Table 1) also relation to the disease treated, and the possible role mentioned the concomitant use of furosemide, for of concomitant treatments, although not a strong which pancreatitis is a known reaction, however the signal, there is reason to further monitor the rise in serum amylase was noted after the hypothesis of a causal relationship between beginning of remdesivir therapy, increased as remdesivir treatment and pancreatic toxicity. therapy continued, and normalised after discontinuation. Tocilizumab, also linked to pancreatitis in three case studies and one FDA case report15, is co-suspected and concomitant in two of References the cases here analysed. Tocilizumab has also been 1. European Medicines Agency. Summary of signalled as being causally related to pancreatitis product characteristics for Veklury. Available following the COVID-19 focused analysis at UMC. from: For tocilizumab, the causality assessment is aided https://www.ema.europa.eu/en/documents/oth by the fact that the drug has a longer history of use er/veklury-product-information-approved- and almost 200 ICSRs could be identified regardless chmp-25-june-2020-pending-endorsement- of the indication. With a novel medication such a european-commission_en.pdf. Accessed: remdesivir, exclusively indicated for COVID-19, September 21, 2020. evidence is still sparse. 2. Warren TK, Jordan R, Lo MK, Ray AS, Mackman One case (case 3, Table 1) describes a COVID-19 RL, Soloveva V, et al. Therapeutic efficacy of patient with a history of cholecystectomy who the small molecule GS-5734 against Ebola virus presented with increased serum amylase after three in rhesus monkeys. Nature. days of therapy with remdesivir and 2016;531(7594):381-5. dexamethasone. In rare cases, recent cholecystectomy predisposes to acute pancreatitis, 3. Eastman RT, Roth JS, Brimacombe KR, et al. but the details do not provide the date of surgery, Remdesivir: A Review of Its Discovery and making it difficult to evaluate the predisposition of Development Leading to Emergency Use this patient8. Remdesivir and dexamethasone may Authorization for Treatment of COVID-19. ACS have increased the risk for developing pancreatitis Cent Sci. 2020;6(5):672-683. in a patient with prior cholecystectomy. 4. Forsmark CE, Vege SS, Wilcox CM. Acute In summary, at the time of writing, remdesivir has Pancreatitis. N Engl J Med. 2016;375(20):1972- recently received emergency approval, with scarce 81. pre-approval experimental use for this indication. 5. Aloysius MM, Thatti A, Gupta A, Sharma N, The first reports of clinical experiences with Bansal P, Goyal H. COVID-19 presenting as remdesivir for COVID-19 treatment have started to acute pancreatitis. Pancreatology. appear in the literature but are still sparse; to our 2020;20(5):1026-1027. knowledge, none present safety concerns regarding WHO Pharmaceuticals Newsletter No. 3, 2021  20 Signal

6. Kumaran NK, Karmakar BK, Taylor OM. Drug Ther. 2020;40(7):659-671. Coronavirus disease-19 (COVID-19) associated 11. Dioscoridi L. Pancreas and coronavirus disease- with acute necrotising pancreatitis (ANP). BMJ 2019. Pancreas Open J. 2020;4(1):1-2.12. Case Rep CP. 2020;13(9):e237903. 12. Wang F, Wang H, Fan J, Zhang Y, Wang H, 7. Badalov N, Baradarian R, Iswara K, Li J, Zhao Q. Pancreatic Injury Patterns in Patients Steinberg W, Tenner S. Drug-Induced Acute With Coronavirus Disease 19 Pneumonia. Pancreatitis: An Evidence-Based Review. Clin Gastroenterology. 2020;159(1):367-370. Gastroenterol Hepatol. 2007;5(6):648-661.e3. doi:10.1016/j.cgh.2006.11.023 13. de-Madaria E, Siau K, Cárdenas-Jaén K. Increased amylase and lipase in patients with 8. Vaghlkar, K., Pawanarkar, A., Vagholkar S., COVID-19 pneumonia: don´t blame the Pathan S., Desai R. Post cholecystectomy pancreas just yet! Gastroenterology.2020 2020. pancreatitis: a misleading entity. International doi:10.1053/j.gastro.2020.04.044 Surgery Journal. 2016; 3(2): 941-3 14. Ataallah B, Abdulrahman M, Al-Zakhari R, 9. Oliveira NM, Ferreira FAY, Yonamine RY, Buttar BS, Nabeel S. Steroid-Induced Chehter EZ. Antiretroviral drugs and acute Pancreatitis: A Challenging Diagnosis. Cureus. pancreatitis in HIV/AIDS patients: is there any 2020;12(7). association? A literature review. Einstein. 2014;12(1):112-119. 15. Flaig T, Douros A, Bronder E, Klimpel A, Kreutz R, Garbe E.. Tocilizumab-induced pancreatitis: 10. Jorgensen SCJ, Kebriaei R, Dresser LD. case report and review of data from the FDA Remdesivir: Review of Pharmacology, Pre- Adverse Event Reporting System. Journal of clinical Data, and Emerging Clinical Experience clinical pharmacy and therapeutics. 2016; for COVID-19. Pharmacother J Hum Pharmacol 41(6):718-721.

Response from Gilead

For the response to the WHO-UMC regarding were complications of concurrent bacterial infection pancreatic toxicity and RDV: or malignancy, in 17% the pancreatitis symptoms predated the exposure to remdesivir, 24% First, we would like to thank you for the opportunity contained insufficient information , and 45% to review the draft signal report prepared by the included drugs known to induce pancreatitis, with Uppsala Monitoring Center (UMC) in which a some cases also involving contribution of risk potential association between remdesivir and factors for pancreatitis and/or severe complications pancreatic toxicity is discussed. Gilead has been of COVID-19 infection and its treatment (including and is continuously monitoring events reported as the Khadka report). In summary, consistent with pancreatic toxicity as part of its standard signal the findings of UMC, uncertainties in relation to the detection process. In fact, a signal of acute role of COVID-19 disease, severity of the patient’s pancreatitis was identified by Gilead in March 2021 illness and the possible role of concomitant based on a literature case report where acute treatments provided alternative etiologies for the pancreatitis was deemed possibly associated with events of pancreatitis. remdesivir by the author (Khadka 2021). A total of 29 potential pancreatitis cases were identified for Gilead will continue to monitor events of review in the context of over 1 million patients pancreatitis through routine pharmacovigilance. treated with remdesivir. Review of the cases Safety information received from all sources is reported to Gilead did not provide sufficient carefully evaluated on an ongoing basis for any new evidence of a causal association with acute safety signals and the prescribing information is pancreatitis and remdesivir (i.e., the signal was not updated promptly as new adverse drug reactions validated). Of the cases reviewed, 14% were are identified. inconsistent with a diagnosis of acute pancreatitis or

WHO Pharmaceuticals Newsletter No. 3, 2021  21 Signal

Tocilizumab and Pancreatitis Dr. Ian Boyd, Australia

Summary frequently severe and of sudden onset, and is almost always accompanied by increased pancreatic Tocilizumab (TCZ) is a humanised monoclonal enzymes in the blood and urine. Although in about antibody against -6 (IL-6) and is 80% of cases the disease is mild to moderate, indicated in the treatment of rheumatoid arthritis severe pancreatitis has a mortality rate of 20%. (RA) as well as some other forms of arthritis. TCZ Drug-induced pancreatitis is usually an acute has also been approved for chimeric antigen condition.2,3 receptor T-cell therapy induced cytokine release syndrome and has been used recently in the Gallstones are the leading cause of acute treatment of patients with severe COVID-19 pancreatitis (21-33%) with alcohol as the next most infection. A recent analysis by the UMC of the WHO common cause (16-27%). Other common causes global database of ICSRs, VigiBase, focused on include hypertriglyceridaemia, hypercalcemia, drugs used in COVID-19 patients. As of 29 familial (hereditary) pancreatitis, and viral November 2020, the UMC analysis identified five infections.4 Approximately 0.1-5% of cases of acute individual case safety reports (ICSRs) in VigiBase pancreatitis are drug-related.2,4 More than 500 which reported pancreatitis or pancreatitis acute medications have been implicated as a cause of with the use of TCZ for COVID-19. There are 202 acute pancreatitis and many of them have been reports (189 de-duplicated) for the combination, shown to have a definite association.4 Responsible regardless of indication, and in respect of the 189 drugs include , 6-mercaptopurine, de-duplicated cases the IC is 0.6 and the IC025 is oestrogens, tetracycline, valproic acid, sulindac, 0.4, which indicates a disproportionate association. ACE inhibitors, HMG-CoA reductase inhibitors An analysis of the 189 cases was considered (statins), isoniazid and anti-HIV medications.3,4 impractical so it was restricted to those 41 cases with more complete information. These reports were from Belgium, Croatia, Denmark, France, Reports in VigiBase Germany, Greece, Japan, Spain, and the United Kingdom. A recent analysis by the UMC focused on drugs used in COVID-19 patients. It has been suggested that TCZ appears to be a likely cause as it was the only severe COVID-19 infection is associated with a suspected drug in 31 of the 41 reports. With 25 cytokine storm and pulmonary inflammation cases which occurred from one week to ten months, secondary to a dysregulated host immune response. the time to onset is consistent with other well As TCZ is indicated for clinical management of recognised drug causes of pancreatitis. Patients cytokine release syndrome, it may be useful to were reported as recovered or recovering in 32 of ameliorate the intense inflammatory manifestations the 41 cases, not recovered in eight cases, and associated with severe COVID-19 infection. There there was a fatal outcome in the remaining case. In were many publications in 2020 which described the 32 cases where recovery was reported, TCZ was studies on the use of TCZ in COVID-19 patients, withdrawn in 25 cases. Recovery after withdrawal is and although the results have been mixed, a recent consistent with an effect of the drug. There are also publication has demonstrated that TCZ reduced the reports of the association in the literature. likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not

improve survival.5 As of 29 November 2020, the Introduction UMC analysis identified five individual case safety reports (ICSRs) which reported pancreatitis or Tocilizumab (TCZ) is a humanised monoclonal pancreatitis acute with TCZ for the indications antibody against interleukin-6 (IL-6) and is ‘COVID-19’ or ‘Corona virus infection’ in the WHO indicated for the treatment of rheumatoid arthritis global database of ICSRs, VigiBase. There are 202 (RA) as well as some other forms of arthritis.1 TCZ reports (189 de-duplicated) for the combination has also been approved for chimeric antigen regardless of indication. receptor T-cell therapy induced cytokine release syndrome and has been used recently in the With respect to the 189 de-duplicated cases treatment of patients with severe COVID-19 regardless of indication, the Information Component infection. The most reported adverse reactions (IC) is 0.6 (189 observed, 125 expected) and the include upper respiratory tract infections, IC025 is 0.4 which indicates a disproportionate nasopharyngitis, headache, hypertension, and association. In 148 of these cases, TCZ is the only increased liver function tests. More serious adverse suspected drug. An analysis of the 189 cases was reactions include serious infections, complications of considered impractical so it was restricted to those diverticulitis, and hypersensitivity reactions. cases with more complete information and only those cases with age and gender, start date and Acute pancreatitis is an inflammatory disease of the action taken with TCZ, date of onset and recovery pancreas, characterized by abdominal pain,

WHO Pharmaceuticals Newsletter No. 3, 2021  22 Signal information were considered. These cases are cases. In the remaining four cases, there were shown in Table 1. other drugs which were withdrawn but in three of these cases, they are not known to be associated There were 41 such cases submitted by France (18 with pancreatitis. In one case (Case 1), a medicine cases), Spain and the United Kingdom (both 5), containing both an ACE inhibitor and a statin (which Japan (4), Germany (3), Croatia and Greece (both are possible causes of pancreatitis) was also 2), and Belgium and Denmark (both 1). There was withdrawn. Patients were reported as not recovered one additional case from Switzerland involving a in eight cases. In these cases, TCZ was withdrawn 30-year-old male which met the criteria, but use of in four cases, continued in three cases and the TCZ occurred after onset of the reaction and it was action with the drug was reported as “not not considered. A majority of the patients were applicable” in the remaining case. The other case female (26), which is not surprising as the most had a fatal outcome. common indication was RA, a disease which has a predominance of female patients. Ages ranged from Pancreatitis or acute pancreatitis was the only 5 to 83 years, with a median age of 54.5 years reaction reported in 28 of the 41 reports. In another which is relatively young. four cases, there were additional reactions that related to pancreatitis such as abdominal pain (4 TCZ was the only suspected drug in 31 of the 41 cases), amylase increased (2), and diarrhoea (2). cases. In the remaining ten, there were multiple In the remaining nine cases, there was a variety of suspected drugs, but the only other drugs other reactions but no obvious pattern to these suspected more than once were the closely related reactions apart from some known to be associated corticosteroids, prednisone, prednisolone, and with TCZ use, such as hypertriglyceridaemia (3 methylprednisolone (in 4 cases), and cases) and abnormal liver functions tests (3). hydroxychloroquine (in 2 cases). Other commonly occurring concomitant drugs included corticosteroids (13 cases), drugs for the treatment Labelling and literature of hypertension (11 cases), proton pump inhibitors and other drugs for the treatment of the The product literature does not refer to gastrointestinal tract (9), (8), drugs pancreatitis.1 It does, however, indicate that for the treatment of pain (7), statins (6), and drugs hypertriglyceridaemia is an uncommon reaction. As for the treatment of diabetes (4) and osteoporosis noted above, hypertriglyceridaemia is a possible (4). Corticosteroids and methotrexate are cause of pancreatitis and three of the cases in this commonly used in association with TCZ and the series refer to hypertriglyceridaemia as an other concomitant drugs were generally reflective of additional adverse reaction. other underlying conditions which accompany the condition for which TCZ was prescribed, particularly There have, however, been several cases of RA. In fact, RA was the indication in 28 of the 41 pancreatitis in association with TCZ reported in the reports. There were a variety of indications in the literature. Flaig and co-workers described a 40- other 13 reports with Horton’s disease, Takayasu’s year-old male who developed pancreatitis about two disease, polymyalgia rheumatica, and COVID-19 all weeks after the second dose of TCZ for treatment of 6 being implicated in two reports. Dosages varied RA. The authors ruled out other causes of greatly depending on the indication and the pancreatitis, TCZ was withdrawn and the patient condition of the patient. The most common dosage recovered. The authors also noted that there had (10 patients) was 162-167 mg per week; 400-720 been three previous reports of this association. mg per month was reported in seven patients, and Parekh and colleagues described a patient receiving 560-800 mg over an unknown period was reported TCZ for RA who developed acute necrotising in seven patients. pancreatitis, and in a paper on the REACTION study, Takeuchi and colleagues reported acute Time to onset varied significantly from one day to pancreatitis as an adverse event in one patient.7,8 eight years, with a median of five months. Nine In the other case, a 60-year-old man with RA cases occurred within a month and nine cases developed severe hepatitis after the use of TCZ for occurred from two to eight years, while almost half three months. At the same time, he was noted to the cases (18) had an onset from one to eight have developed mild pancreatitis, characterised by months. elevated lipase levels.9 Flaig and colleagues also reviewed the FAERS database in the United States Patients were reported as recovered or recovering and noted 74 pancreatic adverse events in in 32 of the 41 cases, not recovered in eight cases, association with TCZ including 52 cases of acute and there was a fatal outcome in the remaining pancreatitis.6 More recently, in response to the case. Two of those patients who recovered were increased use of TCZ in COVID-19, the FAERS reported as recovered with sequelae but there was database was investigated for the occurrence of no information on the nature of these sequelae. In statistically significant reporting odds ratios (RORs) the 32 cases where recovery was reported, TCZ was for hepatic reactions in association with TCZ.10 withdrawn in 25 cases, continued in three cases, Statistically significant RORs were found for the 61 and reported as “not applicable” in the remaining cases of acute pancreatitis (ROR: 1.99, 95% CI four cases. In the 25 cases in which TCZ was 1.55-2.56) and for the 151 cases of pancreatitis withdrawn, it was the only drug reported in five (ROR: 1.65, 95% CI 1.41-1.94). In another recent cases, and the only drug reported withdrawn in 16 WHO Pharmaceuticals Newsletter No. 3, 2021  23 Signal review of TCZ in COVID-19, Morrison and coworkers case. In the 32 cases where recovery was reported, reported two cases of acute hypertriglyceridaemia TCZ was withdrawn in 25 cases, continued in three in association with TCZ, one of which had elevated cases, and reported as “not applicable” in the levels of serum amylase.11 remaining four cases. Recovery after withdrawal is consistent with an effect of the drug. When drugs

such as TCZ are used periodically, the nature of Discussion and Conclusion drug withdrawal may not be straightforward and the reporting of “not applicable” for the action taken A UMC analysis has identified 189 de-duplicated with the drug may reflect such difficulties in cases of pancreatitis or pancreatitis acute with TCZ interpretation. In two of these four cases, the regardless of indication, with an IC of 0.6 and an reaction appeared a few days after the completion IC025 of 0.4 which indicates a disproportionate of a course of TCZ, so the result is the same as if association. An analysis of the 189 cases was the drug was deliberately withdrawn. In another considered impractical so it was restricted to those case, the reaction appeared and resolved in the cases with more complete information. period between two doses one month apart. The TCZ appears to be a likely cause as it was the only remaining case was difficult to interpret. suspected drug in 31 of the 41 reports. In the In the eight cases where patients were reported as remaining ten reports, there were multiple not recovered, TCZ was withdrawn in four cases, suspected drugs, but the only other drugs continued in three cases and the action with the suspected more than once were the closely related drug was given as “not applicable” in the remaining corticosteroids, prednisone, prednisolone, and case. In one of the four cases in which TCZ was methylprednisolone (in four cases) and withdrawn, this was only done after a final dose was hydroxychloroquine (in two cases). given a day after onset of pancreatitis so Time to onset varied significantly, from one day to interpretation in this case is difficult. In another eight years, with a median of five months. Nine case, TCZ was continued on a weekly basis for cases occurred within a month and another nine another three months after the onset of pancreatitis occurred from two to eight years, while almost half and then for a further three months after a four- the cases (18) had an onset of one to eight months. month period of no treatment. The remaining two With 25 cases which occurred from one week to ten cases describe a lack of recovery despite drug months, the time to onset is consistent with other withdrawal. The remaining case where the action well recognised drug causes of pancreatitis. A case with the drug was “not applicable”, was difficult to control study with ACE inhibitors has shown that the interpret. highest risk was during the first six months of The lack of recovery in the three cases in which the therapy while the time to onset with enalapril has drug was continued is consistent with an effect of 4 been reported to be from five weeks to one year. the drug. In one of the cases, however, the patient Two cases of rechallenge with angiotensin receptor died five days after onset of pancreatitis. The cause antagonists occurred, initially from four days to of death appeared to be complications of COVID-19 three months, while pancreatitis rarely occurs disease. The remaining case also had a fatal within the first three months of treatment with outcome. The patient developed acute, necrotising 4 statins. Two cases of rechallenge with tetracycline pancreatitis three months after commencing TCZ occurred initially within four days to three months, and four weeks after it was withdrawn. The patient while time to onset with isoniazid occurred between died three weeks later. The cause of death was not 4 11 and 21 days. Onset with azathioprine and stated but necrotising pancreatitis has a relatively mercaptopurine occurred within the first few high rate of mortality and may have been the cause 4 weeks. It was interesting that the two cases in of death. which TCZ was used for treatment of COVID-19, the time to onset was short at one and eight days, The product literature does not refer to pancreatitis respectively. The time to onset in those other cases but there have been several cases of pancreatitis in (with a lower level of information) in which TCZ was association with TCZ reported in the literature. The used to treat COVID-19, although unknown, must case report by Flaig and coworkers is well have also been relatively short due to the short documented, with other causes of pancreatitis ruled time period from the date TCZ was first used for out, recovery after TCZ withdrawal, and strongly that indication to the date the most recent cases suggests that TCZ is the cause of the pancreatitis.6 have been submitted. On the other hand, those Although not as well documented, the other four cases with a longer time to onset would not have publications which describe pancreatitis or yet occurred so it is not possible to draw any increased serum amylase levels in association with conclusions on this point. There have also been TCZ strengthen the proposition that TCZ is a case reports of acute pancreatitis in association with possible cause of pancreatitis. This possibility is COVID-19, although strong evidence of causality is further strengthened by the disproportionate ROR of lacking. If both COVID-19 and TCZ were possible the association in the FDA database.10 causes, the time to onset may be shortened.12,13,14 In summary, there is a signal for the association of Patients were reported as recovered or recovering pancreatitis and acute pancreatitis in association in 32 of the 41 cases, not recovered in eight cases with TCZ. There are a significant number of reports and there was a fatal outcome in the remaining in VigiBase and those which are well documented WHO Pharmaceuticals Newsletter No. 3, 2021  24 Signal have TCZ as the only suspected drug in 76% of the Rep J 2013;1:40-3. cases. Time to onset supports an association as 8. Takeuchi T, Tanaka Y, Amano K, Hoshi D, does recovery after withdrawal. There are reports in Nawata M, Nagasawa H, et al. Clinical, the literature and both VigiBase and FAERS show a radiographic and functional effectiveness of disproportionation in favour of the association. tocilizumab for rheumatoid arthritis patients - REACTION 52-week study. Rheumatology 2011;50:1908-15. References 9. Alfreijat M, Habibi M, Bhatia P, Bhatia A. Severe 1. Electronic Medicines Compendium: Summary of hepatitis associated with tocilizumab in a Product Characteristics for tocilizumab patient with rheumatoid arthritis. Rheumatology (RoActemra). Available from: RoActemra 2013;52:1340-1. 20mg/ml Concentrate for Solution for Infusion - Summary of Product Characteristics (SmPC) - 10. Gatti M, Fusaroli M, Caraceni P, Poluzzi E, De (emc) (medicines.org.uk). Accessed: 17 Ponti F, Raschi E. Serious adverse events with December 2020. tocilizumab: pharmacovigilance as an aid to prioritize monitoring in COVID-19. Br J Clin 2. Longo DL, Fauci AS, Kasper DL, Hauser SL, Pharmacol 2020; Epub ahead of print 8 July Jameson JL, Loscalzo J, editors. Harrison’s 2020. DOI: 10.1111/bcp.14459. Principles of Internal Medicine. 18th ed. McGraw Hill: New York; 2011. 11. Morrison AR, Johnson JM, Ramesh M, Bradley P, Jennings J, Smith ZR. Acute 3. Mederos MA, Reber HA, Girgis MD. Acute hypertriglyceridaemia in patients with COVID- pancreatitis: a review. JAMA 2021;325:382-90. 19 receiving tocilizumab. J Med Virol 4. Balani AR, Grendell, JH. Drug-induced 2020;92:1791-2. pancreatitis: incidence, management and 12. Kumaran NK, Karmakar BK, Taylor OM. prevention. Drug Saf. 2008;31:823-37. Coronavirus disease-19 (COVID-19) associated 5. Salama C, Han J, Yau L, Reiss WG, Kramer B, with acute necrotising pancreatitis (ANP). BMJ Neidhart JD, et al. Tocilizumab in patients Case Rep CP. 2020;13(9):e237903. hospitalized with Covid-19 pneumonia. N Engl J doi:10.1136/bcr-2020-237903. Med 2021;384:20-39. 13. Aloysius MM, Thatti A, Gupta A, Sharma N, 6. Flaig T, Douros A, Bronder E, Klimpel A, Kreutz Bansal P, Goyal H. COVID-19 presenting as R, Garbe E. Tocilizumab-induced pancreatitis: acute pancreatitis. Pancreatology. case review and report of data from the FDA 2020;20(5):1026-1027. Adverse Event Reporting System. J Clin Pharm doi:10.1016/j.pan.2020.05.003 Ther. 2016;41:718-21. 14. De-Madaria E, Capurso G. COVID-19 and acute 7. Parekh PJ, Howerton D, Johnson DA. Not your pancreatitis: examining the evidence. Nat Rev everyday case of acute pancreatitis: a rare Gastroenterol Hepatol 2021,18:3-4. complication of a common diagnosis. ACG Case https://doi.org/10.1038/s41575-020-00389-y

Table 1. Characteristics of selected reports in VigiBase of pancreatitis in association tocilizumab Case Age/ Other suspected (S) or concomitant Reactions (MedDRA preferred terms) Outcome Action taken Time to Gender (C) drugs with drug onset 1 50/M /acetylsalicylic acid/ramipril Pancreatitis Recovered Withdrawn 7 m (S), methotrexate (C) 2 57/F None Pancreatitis acute Recovered Continued 8 y 3 57/F Rosuvastatin, sitagliptin (both S), Pancreatitis acute, asthenia, abdominal Recovered Not 8 y metformin, glimepiride (both C) pain upper applicable 4 39/M Prednisone, atorvastatin, Pancreatitis acute Recovering Withdrawn 5 m hydrochlorothiazide (all S), clopidogrel, bisoprolol, acetylsalicylic acid, amlodipine/perindopril, lansoprazole, spironolactone (all C) 5 69/F None Pancreatitis acute Recovered Withdrawn 2 d 6 58/M* Hydroxychloroquine, ceftriaxone, Pancreatitis acute, hypertriglyceridaemia Recovered Withdrawn 7 d azithromycin, methylprednisolone, lopinavir/ritonavir (all S) 7 21/F* Hydroxychloroquine, linezolid, Pancreatitis acute, acute kidney injury, Not Continued 1 d amphotericin b (all S) hepatitis, hypocoagulable state recovered

WHO Pharmaceuticals Newsletter No. 3, 2021  25 Signal

Case Age/ Other suspected (S) or concomitant Reactions (MedDRA preferred terms) Outcome Action taken Time to Gender (C) drugs with drug onset 8 59/F Methotrexate (C) Pancreatitis Recovered Withdrawn 9 m with sequelae 9 53/F None Pancreatitis acute Recovering Withdrawn 2 m 10 79/F Colecalciferol, tramadol, bisoprolol, Pancreatitis acute Recovered Withdrawn 2 y trimebutine, atorvastatin, ramipril, paracetamol, acetylsalicylic acid (all C) 11 83/F None Pancreatitis Not Withdrawn 18 d recovered 12 73/F Prednisone (S) Pancreatitis acute Recovering Not 2 m applicable 13 66/F Calcium/colecalciferol, potassium, Pancreatitis, abdominal pain, amylase Not Withdrawn 5 m teriparatide, paracetamol, morphine, increased, diarrhoea, weight decreased recovered metoprolol, , vancomycin, multivitamins, , prednisolone, minerals (all C) 14 43/F Methotrexate, , etoricoxib, Pancreatitis acute, cholelithiasis, Not Withdrawn 6 w prednisone (all C) hypercholesterolaemia, recovered hypertriglyceridaemia, pneumonia 15 47/F Alprazolam, atorvastatin, bisoprolol, Pancreatitis acute Recovering Withdrawn 3 y clopidogrel, pancreatin, valproic acid (all C) 16 49/F Methotrexate, leflunomide, insulin (all Pancreatitis, organising pneumonia Recovered Withdrawn 2 m C) 17 75/M None Pancreatitis, transaminases increased Recovered Withdrawn 2 m 18 44/F Methotrexate, tacrolimus (both S) Pancreatitis acute Recovering Continued 16 d 19 37/M None Pancreatitis Not Continued 3 m recovered 20 61/F Acetylsalicylic acid, allopurinol, Pancreatitis, arthralgia, biliary Not Withdrawn 16 m cortisone, insulin, insulin glargine, obstruction, chills, back pain, drug recovered insulin lispro, methotrexate, omeprazole, ineffective, blood disorder, fatigue, torasemide (all C) intervertebral disc protrusion, liver function test abnormal, liver function test increased, musculoskeletal discomfort, pancreatic cyst, spondylolisthesis, stenosis, tendon rupture, white blood cell count increased 21 5/M Inotuzumab, tisagenlecleucel-T (both S) Pancreatitis, acute lymphocytic Not Not 8 m leukaemia, blood bilirubin increased, recovered applicable blood fibrinogen decreased, lipase increased, lymphocyte count decreased, neutrophil count decreased, platelet count decreased, white blood cell count decreased 22 66/M Indapamide, lansoprazole, Pancreatitis acute Recovering Not 5 m (all C) applicable 23 47/M Prednisone (C) Pancreatitis acute Recovered Withdrawn 4 y 24 59/F Levothyroxine (C) Pancreatitis, abdominal discomfort, Recovered Withdrawn 6 m diarrhoea, pustule 25 56/M Prednisolone (S), acetylsalicylic acid, Pancreatitis acute Recovered Withdrawn 16 d altizide/spironolactone, anagrelide, levothyroxine, potassium, (all C) 26 41/M Methotrexate (C) Pancreatitis, hypertriglyceridaemia Recovering Withdrawn 3 w 27 28/F Clopidogrel, lansoprazole, prednisone, Pancreatitis Recovered Not 4 m rosuvastatin (all C) applicable 28 46/M Brinzolamide, bisoprolol, latanoprost, Pancreatitis acute Not Continued 4 y prednisone (all C) recovered 29 53/M Leflunomide (S) Pancreatitis acute Recovered Withdrawn 2 y

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Case Age/ Other suspected (S) or concomitant Reactions (MedDRA preferred terms) Outcome Action taken Time to Gender (C) drugs with drug onset 30 35/F Folic acid, loxoprofen, methotrexate (all Pancreatitis acute Recovering Withdrawn 17 m C) 31 49/F None Pancreatitis acute Recovered Withdrawn 13 m 32 67/F None Pancreatitis Recovered Withdrawn 5 w 33 35/F Prednisolone (C) Pancreatitis acute Recovered Continued 6 y 34 81/F Amlodipine/atorvastatin, bucillamine, Pancreatitis acute Recovering Withdrawn 3 y eldecalcitol, lansoprazole, minodronic acid, pilocarpine, prednisolone, sulfasalazine, tacrolimus (all C) 35 35/M Azathioprine (C) Pancreatitis acute, acute abdomen, Recovered Withdrawn 3 m amylase increased 36 71/F Omeprazole, prednisolone, risedronic Pancreatitis acute Recovering Withdrawn 11 m acid (all C) 37 28/M Azathioprine, prednisolone (both C) Pancreatitis, abdominal distension, Recovered Withdrawn 11 d abdominal pain, abdominal sepsis, with abdominal tenderness, back pain, blood sequelae pressure decreased, body temperature increased, condition aggravated, heart rate increased, immunosuppression, oxygen saturation decreased, respiratory rate increased, splenic infarction, Takayasu's arteritis 38 57/F Deflazacort, oxandrolone (both C) Pancreatitis Recovered Withdrawn 1 m 39 40/M Metamizole, prednisolone, ramipril, Pancreatitis acute Recovering Withdrawn 6 w calcium/colecalciferol, omeprazole (all C) 40 73/F Blinded methotrexate (S), alfacalcidol, Pancreatitis acute Recovered Withdrawn 14 m amlodipine, clopidogrel, folic acid, hydroxychloroquine, ibandronic acid, metformin, sitagliptin, simvastatin, valsartan (all C) 41 62/F Amlodipine, citalopram, iron, lisinopril, Pancreatitis acute, pancreatitis Died Withdrawn 3 m , omeprazole, simvastatin, necrotising tramadol (all C) *COVID-19 cases

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CAVEAT DOCUMENT

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

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

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