2020 WHO Pharmaceuticals

No.4 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.

In addition, this edition of the Newsletter includes The aim of the Newsletter is to disseminate regulatory recommendations from the 42nd Global Advisory information on the safety of Committee on Vaccine Safety (GACVS) meeting. 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

Feature

WHO Pharmaceuticals Newsletter No. 4, 2020

ISBN 978-92-4-001074-1 (electronic version) ISBN 978-92-4-001075-8 (print version)

© World Health Organization 2020

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Table of Contents

Regulatory Matters Apalutamide ...... 4 Bevacizumab ...... 4 Carbimazole ...... 4 Cyproterone ...... 4 Fluoxetine, levothyroxine...... 5 Fulvestrant ...... 5 Ketamine...... 5 Levetiracetam ...... 6 Memantine ...... 6 Nutrition preparations (parenteral) ...... 6 Ondansetron ...... 6 Ruxolitinib, Tofacitinib ...... 7 Testosterone ...... 7 Ticagrelor ...... 7 Tramadol...... 8

Safety of medicines Aminophylline ...... 9 Antipsychotic medicines ...... 9 Direct-acting oral anticoagulants (DOACs) ...... 9 Flucloxacillin ...... 9 Ingenol mebutate ...... 10 Levothyroxine ...... 10 Water (for injection) ...... 10

Signal Aciclovir or valaciclovir - Acute generalised exanthematous pustulosis ...... 11 Alectinib – Rhabdomyolysis ...... 17 Tocilizumab and Cutaneous Vasculitis ...... 23

Feature Recommendations from the 42nd Global Advisory Committee on Vaccine Safety (GACVS) meeting ...... 28

WHO Pharmaceuticals Newsletter No. 4, 2020 • 3 Regulatory Matters

Apalutamide with bevacizumab have been must only be used during reported in Japan during the pregnancy after a strict Risk of toxic epidermal previous three years, including individual benefit/risk necrolysis (TEN) one case for which a causal assessment and only at the relationship between the drug lowest effective dose without Japan. The Ministry of Health, and event was deemed additional administration of Labour and Welfare (MHLW) reasonably possible. Two thyroid hormones. mortalities have been reported and the Pharmaceuticals and Reference: among the seven cases. A Medical Devices Agency Drug Safety Newsletter, HPRA, causal relationship could not be (PMDA) have announced that May 2020 (www.hpra.ie) the package inserts for established for either cases. (See also WHO Pharmaceuticals Newsletter apalutamide (Erleada®) should The MHLW and PMDA have be revised to include toxic No.2, 2019: Increased risk of congenital concluded that revision of the malformations in UK) epidermal necrolysis (TEN) as package insert was necessary. an adverse drug reaction. Reference: Apalutamide is indicated to Revision of Precautions, 2. Risk of acute pancreatitis treat castration-resistant MHLW/PMDA, 16 June 2020 prostate cancer without remote (www.pmda.go.jp/english/) Ireland. The HPRA has metastasis. announced that the product information (SmPC and PL) for A total of two cases involving carbimazole has been updated TEN in patients with to reflect the risk of acute apalutamide have been pancreatitis. reported in Japan during the Carbimazole previous three years, for which Post-marketing reports of 1. Risk of congenital a causal relationship between acute pancreatitis in the drug and event was malformations association with the use of deemed a reasonable carbimazole/thiamazole have Ireland. The Health Products possibility. One of the two been received in EU. Although Regulatory Authority (HPRA) cases led to patient mortality, the mechanism is not fully has announced that the for which a causal relationship understood, decreased time to product information (Summary between the drug and the onset after re-exposure could of Product Characteristics subsequent death was deemed suggest an immunological (SmPC) and Package Leaflet reasonably possible. mechanism. (PL)) for carbimazole has been The MHLW and PMDA have updated to reflect the risk of Immediate discontinuation is concluded that a revision of the congenital malformations. required in patients who package insert was necessary. develop pancreatitis following Carbimazole is a pro-drug that exposure to carbimazole and undergoes rapid metabolism Reference: the patients should be switched into the active metabolite, Revision of Precautions, to alternative treatment. MHLW/PMDA, 19 May 2020 thiamazole. (www.pmda.go.jp/english/) Reference: The Pharmacovigilance Risk Drug Safety Newsletter, HPRA, Assessment Committee (PRAC) May 2020 (www.hpra.ie) completed a review of the

known risk of congenital (See also WHO Pharmaceuticals Newsletter

Bevacizumab malformations associated with No.2, 2019: Risk of acute pancreatitis in UK) carbimazole exposure during Risk of artery dissection pregnancy. Data from epidemiological studies and Japan. The MHLW and the case reports strengthens the Cyproterone PMDA have announced that the evidence that carbimazole/thiamazole package inserts for Restrictions in use due to bevacizumab (Avastin®) exposure during pregnancy is should be revised to include associated with an increased risk of meningioma risk of congenital artery dissection as an adverse 1. Ireland. The HPRA has drug reaction. malformations, especially when administered in the first announced that the SmPC and Bevacizumab is indicated to trimester of pregnancy and at PL for cyproterone containing treat several conditions such as high doses. medicines will be updated to incurable, unresectable include the risk of meningioma advanced/recurrent colorectal Women of childbearing associated with treatment. potential should use effective cancer and malignant glioma. Cyproterone is an antiandrogen contraception during treatment medicine acting in the same A total of seven cases involving with carbimazole. Carbimazole artery dissection in patients way as progesterone. It is WHO Pharmaceuticals Newsletter No. 4, 2020 • 4 Regulatory Matters indicated to treat various meningioma in EU; No.2, 2020: Risk of Fulvestrant androgen-dependent conditions meningioma in EU; No.4, 2019; Risk of meningioma in EU) such as hirsutism, alopecia, Risk of injection site acne, prostate cancer and necrosis and ulcer reduction of sex drive in sexual deviations in men. Japan. The MHLW and the A PRAC review concluded that Fluoxetine, PMDA have announced that the the risk of meningioma package inserts for fulvestrant increases with increasing levothyroxine (Faslodex®) should be revised cumulative doses of to include injection site cyproterone. It also noted that Potential interaction necrosis and ulcer as adverse most cases occur after affecting TSH level drug reactions. prolonged exposure to high New Zealand. Medsafe is Fulvestrant is indicated to treat doses of cyproterone. highlighting a safety concern breast cancer. The PRAC recommended that and encouraging reporting of A total of six cases involving in all indications except cases of potential interaction injection site necrosis and ulcer prostate carcinoma, treatment between fluoxetine (Arrow®, in patients with fulvestrant with higher doses should be Fluox® etc.) and levothyroxine have been reported in Japan restricted to situations where (Eltroxin®, Synthroid® etc.) during the previous three alternative treatments are leading to reduced serum years, including five cases for unavailable and that low doses levels of levothyroxine and which a causal relationship should also be contraindicated increased thyroid-stimulating between the drug and event in patients with a history of hormone (TSH) levels. was deemed reasonably meningioma. Fluoxetine is a selective possible. No patient mortalities Patients should be monitored serotonin reuptake inhibitor have been reported to date. for meningioma in accordance (SSRI) indicated for The MHLW and PMDA have with clinical practice. If a depression, bulimia, obsessive- concluded that revision of the patient taking cyproterone is compulsive disorder and package insert was necessary. diagnosed with meningioma, premenstrual dysphoric treatment must be disorder. Levothyroxine is a Reference: discontinued permanently. synthetic form of the natural Revision of Precautions, hormone thyroxine (T4) MHLW/PMDA, 19 May 2020 Reference: indicated for the treatment of (www.pmda.go.jp/english/) Drug Safety Newsletter, HPRA, hypothyroidism. May 2020 (www.hpra.ie) This investigation was

triggered by a report received 2. United Kingdom. The by the Centre for Adverse Ketamine Medicines and Healthcare Reactions Monitoring (CARM). Products Regulatory Agency There are also some published Potential risk of liver and (MHRA) has announced that a case reports describing reduced bile duct damage European review concluded thyroid function during that treatment with high dose treatment with other SSRIs Canada. Health Canada has cyproterone should be such as escitalopram, announced that it will work restricted to situations where paroxetine and sertraline. with manufacturers to update alternative treatments or the product safety information The mechanism for this interventions are unavailable, of ketamine-containing potential interaction and for all indications except products (Ketalar® and whether this is a class effect of prostate carcinoma. generic) to inform about the SSRIs are not clear. potential risk of liver and bile Up to 12 May 2020, there have The monitoring will continue duct damage. been 10 reports in the UK until November 2020. describing meningioma, which Ketamine is used to make were suspected to be Reference: patients unconscious associated with high dose Safety Communication, (anesthesia) during surgery or cyproterone. There were no Medsafe, 21 May 2020 medical procedures. reports of meningioma with low (www.medsafe.govt.nz/) Health Canada conducted a dose cyproterone. (See also WHO Pharmaceuticals Newsletter review on the risk of liver and Reference: No.6, 2018: Interaction with levothyroxine bile duct damage with the use Drug Safety Update, MHRA, leading to reduced thyroxine levels in UK; of ketamine, following a risk No.1, 2017: Risk of adrenal suppression due 29 June 2020 (www.gov.uk/mhra) communication published by to a pharmacokinetic interaction in UK) the French regulatory agency. (See also WHO Pharmaceuticals Newsletter

No.3, 2020: Restrictions in use due to risk of The assessment reviewed 19

WHO Pharmaceuticals Newsletter No. 4, 2020 • 5 Regulatory Matters international epidemiologic Memantine Parenteral nutrition studies, which could not preparations are widely used to confirm or refute a link Risk of bradyarrhythmia supplement nutrition such as between the liver and/or bile water, electrolyte, amino acid duct damages and the use of Japan. The MHLW and the under malnutrition of ketamine. An additional 22 PMDA have announced that the before/after surgery. individual patient case reports package inserts for memantine The revision is based on a 2020 (one was Canadian) were (Memary®) should be revised investigation by MHLW and reviewed, among which one to include bradyarrhythmia PMDA, on the safety of the was found to be probably such as complete parenteral nutrition linked to the used of ketamine, atrioventricular block and preparations in patients with and 17 possibly linked. Hence, severe sinus bradycardia as an serious renal disorder on Health Canada concluded that adverse drug reaction. dialysis of hemofiltration. there is a potential link between the use of ketamine Memantine is indicated to After reviewing published and damage to the liver and control the progression of scientific journals, overseas bile duct. moderate to severe dementia guidelines and package inserts, of the Alzheimer’s type. the PMDA considered Reference: acceptable to exclude patients Summary Safety Review, A total of four cases involving on dialysis or hemofiltration Health Canada, 10 June 2020 bradyarrhythmia in patients (www.hc-sc.gc.ca) with memantine have been from the contraindication reported in Japan during the section, but emphasized (See also WHO Pharmaceuticals Newsletter previous three years, for two of precautions for administration No.5, 2017: Risk of severe liver injury with which a causal relationship in those patients. This is due to repeated and/or prolonged high-dose use in the abundance of acidic amino France) between the drug and event was deemed reasonably acid in amino acid preparations possible. No patient mortalities for hepatic failure, which may cause acidosis in patients with have been reported to date. renal failure on dialysis. The MHLW and PMDA have Levetiracetam concluded that revision of the Reference: package insert was necessary. Revision of Precautions, Risk of abnormal and MHLW/PMDA, 25 June 2020 aggressive behaviours Reference: (www.pmda.go.jp/english/) Revision of Precautions, Ireland. The HPRA MHLW/PMDA, 16 June 2020 communicated a PRAC (www.pmda.go.jp/english/) recommendation that the product information for Ondansetron levetiracetam (Keppra®, Matever® etc.) should be Potential risk of oral cleft updated to include a warning Nutrition defects on the risk of abnormal and preparations aggressive behaviours. The New Zealand. Medsafe has recommendation resulted from (parenteral) announced that the data sheets a periodic review of safety data of ondansetron-containing in association with Contraindication loosened medicines are being updated levetiracetam. with information on the Japan. The MHLW and the increased risk of oral cleft Levetiracetam is indicated in PMDA have announced that the defects associated with first the treatment of specified package inserts for parenteral trimester use. forms of epilepsy. nutrition preparations was Ondansetron is a selective Patients treated with revised, regarding the use in serotonin receptor antagonist levetiracetam should be patients on dialysis or and is used to manage and monitored for developing hemofiltration, from prevent nausea and vomiting psychiatric signs suggesting contraindications into careful induced by cytotoxic important mood or personality administration. The implicated chemotherapy and changes. If such behaviours products include amino-acid radiotherapy. Ondansetron is are noticed, treatment preparations, peripheral also used off-label during early adaptation or gradual parenteral nutrition pregnancy. In New Zealand, discontinuation should be preparations and total first trimester use of considered. parenteral nutrition preparations (Amizet®, ondansetron is increasing. Reference: Amiparen®, Pareplus®, Two recent epidemiological Drug Safety Newsletter, HPRA, Hicaliq®, Rehabix® etc.). studies investigated the risk of May 2020 (www.hpra.ie) WHO Pharmaceuticals Newsletter No. 4, 2020 • 6 Regulatory Matters orofacial cleft defects and other Health Canada conducted a Cases of venous congenital malformations in safety review and found that thromboembolism have been infants who were exposed to an ongoing safety study for reported in patients with ondansetron in utero, using tofacitinib showed an increased thrombophilia, some of whom data in the United States. The risk of blood clots in the lungs were on anticoagulant result of one study showed and death. A review of an treatment. Continuing statistically significant increase additional 51 cases (eight testosterone treatment in such in oral cleft with the use of Canadian and 43 international) patients requires careful ondansetron, whereas the of thromboembolic events in evaluation after a first result from the other study was people taking tofacitinib thrombotic event. not statistically significant. showed that 38 were possibly Reference: linked to tofacitinib. The Medicines Adverse Drug Safety Newsletter, HPRA, Reactions Committee (MARC) A further assessment of eight May 2020 (www.hpra.ie) noted that although the effect Canadian cases of (See also WHO Pharmaceuticals Newsletter sizes in the studies were small thromboembolic events in No.3, 2017: Risk of arterial and there is some uncertainty patients taking ruxolitinib thromboembolism/venous in the data, the current found that three cases showed thromboembolism in Australia; No.4, 2014: evidence suggests a small a possible link to ruxolitinib. Risk of venous blood clots in the USA) increase in the risk of oral cleft Health Canada concluded that defects associated with the use there is a link between the risk of ondansetron in the first of thromboembolic events and trimester. the use of tofacitinib or Ticagrelor Reference: ruxolitinib. Prescriber Update, Medsafe, Reference: Potential risk of June 2020 bradyarrhythmia (www.medsafe.govt.nz/) Summary Safety Review, Health Canada, 18 June 2020 (See also WHO Pharmaceuticals Newsletter (www.hc-sc.gc.ca) Canada. Health Canada has No.2, 2020: Risk of oral clefts in UK; No.6, announced that it will work 2016: Assessing potential harm to the (See also WHO Pharmaceuticals Newsletter with manufacturers to update No.3, 2020: Risk of venous foetus: insufficient information in Canada) the product safety information thromboembolism and serious and fatal infections in UK; No.6, 2019: Risk of blood of ticagrelor (Brilinta®) to clots in EU; No.5, 2019: Increased risk of inform about the potential risk blood clots and death with higher dose in US of worsening of a slow and and Japan) irregular heartbeat Ruxolitinib, (bradyarrhythmia) and partial

Tofacitinib or complete block in the transmission of heart impulses Risk of blood clots in the (second-and third-degree deep veins Testosterone atrioventricular block). Ticagrelor is used to decrease Canada. Health Canada has Caution in patients with thrombophilia or risk factors the risk of having a stroke, announced that it had worked another heart attack or dying for venous with the manufacturer for from heart or blood vessel tofacitinib (Xeljanz®) to thromboembolism disease. update the product safety information to include the Ireland. The HPRA warned Triggered by published serious risk of blood clots in that testosterone-containing international reports of partial the veins and will also work medicinal products should be or complete block in the with the manufacturer for used with caution in patients transmission of heart impulses ruxolitinib (Jakavi®) to update with thrombophilia or risk in patients with ticagrelor, the product safety information factors for venous Health Canada reviewed two to include the risk of thromboembolism, following a potential risks, thromboembolic events. PRAC recommendation to bradyarrhythmia and second- update the product information and third-degree Tofacitinib is used for the (SmPC and PL) for these atrioventricular block. treatment of inflammatory products. diseases such as rheumatoid Of the 18 international cases of arthritis, psoriatic arthritis and Testosterone-containing patients with bradyarrhythmia ulcerative colitis. Ruxolitinib is medicinal products are used as taking ticagrelor assessed, 15 used for the treatment of testosterone replacement were found to be possibly certain rare blood cancers, therapy for male linked to the use of ticagrelor. such as primary myelofibrosis hypogonadism in Ireland. Among the 44 cases (42 and polycythemia vera. international and two

WHO Pharmaceuticals Newsletter No. 4, 2020 • 7 Regulatory Matters

Canadian) assessed regarding frequent ADRs were rash, the risk of second or third- vomiting, and nausea. degree atrioventricular block Serotonin syndrome and related to the use of ticagrelor, convulsions were also reported two reports were found to be in five cases each. probably linked to the use of Reference: ticagrelor, 40 including two Prescriber Update, Medsafe, Canadian cases were possibly June 2020 linked. Of the 9 mortalities (www.medsafe.govt.nz/) among the 44 reports, three were found to be possibly (See also WHO Pharmaceuticals Newsletter linked with the use of No.6, 2015; Risk of slowed or difficult ticagrelor. breathing in children in USA; No.5, 2015: Tramadol oral drops not for children under Health Canada concluded that the age of 12 years in Australia) there may be a link between the use of ticagrelor and the risk of bradyarrhythmia including second- and third- degree atrioventricular block.

Reference: Summary Safety Review, Health Canada, 6 July 2020 (www.hc-sc.gc.ca)

Tramadol

Contraindication in children

New Zealand. Medsafe has informed health-care professionals of updated advice on the use of tramadol in children. Tramadol is centrally-acting synthetic analgesic, used to relieve moderate to severe pain when paracetamol or non- steroidal anti-inflammatory drug (NSAID) is not adequate. Tramadol is metabolized by CYP2D6 to yield principal active metabolite. Patients with a deficiency of CYP2D6 may have reduced benefit from tramadol, whereas patients who are ultra-rapid metabolizers may be more sensitive to adverse drug reactions (ADRs). Following review of their safety data, the companies have now contraindicated the use of tramadol in children aged under 12 years, as well as in children under 18 years for post-operative pain management. The CARM has received 83 ADRs relating to tramadol from 2015 to 2019, where the most

WHO Pharmaceuticals Newsletter No. 4, 2020 • 8 Safety of Medicines

Aminophylline patient suffered a non-fatal thrombin inhibitor dabigatran cardiac arrest shortly after (Pradaxa®). administration of an Risk of urinary retention Use of DOACs increases the antipsychotic. risk of bleeding and can cause Malaysia. The National Antipsychotic medicines are serious bleeds. In the UK, the Pharmaceutical Regulatory generally indicated to treat MHRA continues to receive Agency (NPRA) has reported psychosis such as reports of bleeds, often life- the case of urinary retention in hallucinations, paranoia and threatening or fatal, in a 75-year-old male patient delusions. They may cause QT- association with DOACs in after treatment with prolongation, tachycardia, patients. Thus DOACs should intravenous aminophylline for arrhythmias and changes in be used with caution in acute exacerbation of chronic blood pressure. Clozapine is patients at increased risk of obstructive pulmonary disease also associated with bleeding such as older people (COPD). myocarditis and and patients with low body Aminophylline is a combination cardiomyopathy. weight or renal impairment. of theophylline and In addition to direct effects on Exposure to DOACs is ethylenediamine. Theophylline the cardiovascular system, increased in patients with renal exerts bronchodilatory effect antipsychotic medicines are impairment and it is therefore and is used for the treatment associated with metabolic important that patients receive of COPD. Two products changes such as dyslipidaemia, an appropriate dose depending containing aminophylline are hyperglycaemia and central on renal function. DOACs can registered in Malaysia. obesity. be used in patients with moderate renal impairment but The NPRA has received 46 case Monitoring cardiovascular risk a reduced dose may be reports with 76 adverse events factors in patients taking required. In patients with associated with aminophylline antipsychotic medicines is severe renal impairment use of use, two of which were linked necessary to minimize the risk dabigatran is contraindicated. to urinary retention. On the of serious outcomes. other hand theophylline has Reference: Reference: one report each for urinary Drug Safety Update, MHRA, Prescriber Update, Medsafe, retention and difficulty in 29 June 2020 (www.gov.uk/mhra) urination. As of February 2020, June 2020 WHO’s Vigibase contains 25 (www.medsafe.govt.nz/) (See also WHO Pharmaceuticals Newsletter No.5, 2019: Risk of recurrent thrombotic and 30 reports of urinary retention suspected to be events in Australia and New Zealand; No.4, 2019: Increased risk of recurrent thrombotic cause by aminophylline and events in UK; No.3, 2016: Risk of theophylline respectively. Direct-acting oral thrombocytopenia in Japan) The dosage for aminophylline should be reduced in the anticoagulants elderly population. Patients on (DOACs) aminophylline therapy should Flucloxacillin be monitored for symptoms of Risk of bleeding urinary retention or difficulty Risk of renal toxicity urinating. United Kingdom. The MHRA has advised health-care Reference: New Zealand. Medsafe has professionals to use caution MADRAC Bulletin, NPRA, announced that flucloxacillin when prescribing direct-acting 01/2020 (www.npra.gov.my/) can injure the kidneys as well oral anticoagulants (DOACs) to as the liver. Both interstitial patients at increased risk of nephritis and hepatitis are bleeding, such as older people listed in the flucloxacillin data or people with renal sheets. impairment. Antipsychotic Flucloxacillin is beta-lactam medicines DOACs are used for antibiotic and generally anticoagulation such as indicated to treat infections Risk of cardiovascular prevention of atherothrombotic caused by susceptible Gram- events events and of stroke and positive bacteria. systemic embolism. Available The CARM has received 39 New Zealand. Medsafe has DOACs include the direct factor reports of liver-related reminded prescribers of the Xa inhibitors apixaban reactions and 13 reports of risks of cardiovascular adverse (Eliquis®), edoxaban kidney-related reactions, effects from antipsychotic (Lixiana®), rivaroxaban suggesting that interstitial medicines. The CARM was (Xarelto®) and the direct nephritis may be an under- alerted to a case where a recognized reaction to WHO Pharmaceuticals Newsletter No. 4, 2020 • 9 Safety of Medicines flucloxacillin. Of the 13 reports benefits in EU; No.2, 2020: Risk of skin Water (for injection) of renal reactions, the majority malignancy in UK; No.1, 2020: Use with caution in patients with a history of skin occurred in patients aged over Risk of haemolysis 70 years. cancer in Ireland; Suspension during safety review in EU) Early recognition of Australia. The Therapeutic flucloxacillin-induced interstitial Goods Administration (TGA) nephritis and prompt treatment has reminded health-care reduces the risk of long-term professionals that water for renal impairment. Levothyroxine injection can cause haemolysis resulting in patient harm Reference: Risk of myocardial infarction including death, if large Prescriber Update, Medsafe, quantities are inadvertently June 2020 Malaysia. The NPRA has administered intravenously (www.medsafe.govt.nz/) reported a case of non-ST without being rendered segment elevation myocardial isotonic. infarction (NSTEMI) in an 80- Water for injection is indicated year-old female patient after for dissolving or diluting treatment with levothyroxine injectable therapeutic Ingenol mebutate for subclinical hypothyroidism. substances for parenteral After levothyroxine was administration. Water for Potential risk of skin cancer withdrawn, the reaction injection is hypotonic. It is subsided and patient gradually Canada. Health Canada contraindicated for intravenous recovered. communicated a potential link administration if it is not between ingenol mebutate Levothyroxine is indicated as a adjusted to isotonicity by the (Picato®) and the risk of skin substitution therapy in addition of suitable solutes. cancer. hypothyroidism. Six products The TGA is aware of containing levothyroxine are Ingenol mebutate is applied international reports of mix-ups registered in Malaysia. The risk topically on the skin, in adults, between 1 L bags of water for of developing myocardial to treat actinic keratosis. injection and other 1 L bags infarction following including sodium chloride 0.9% Based on new safety levothyroxine use is and glucose 5%. information from international documented in the product clinical trials, A Health Canada information. All registered injection products review found an increased risk in Australia with a volume of The NPRA has received 223 of skin cancer in patients 100 mL or more are required to local ADR reports with 571 treated with ingenol mebutate. include a statement on the adverse events suspected to be label to indicate if the injection Of the 29 case reports (one related to levothyroxine. There is hypotonic, hypertonic or Canadian) of skin cancer is one report associated with isotonic. reviewed, 26 cases were found NSTEMI, as above-mentioned. to be possibly linked to ingenol The WHO’s Vigibase revealed Health-care professionals mebutate. A further five reports of NSTEMI and 27 should check the label to assessment of 12 scientific reports of acute myocardial ensure there is no confusion literature found 6 studies with infarction suspected to be between water for injection and evidence of the possible link. associated with levothyroxine. other intra venous bags. Thus Health Canada concluded Health-care professionals Reference: that there may be a link should exercise extra caution Medicines Safety Update, TGA, between ingenol mebutate and when initiating levothyroxine in 24 June 2020 (www.tga.gov.au/) the risk of cancer. elderly patients and in patients

Health Canada will ask for with underlying cardiovascular additional information from the disease. In those, the lowest manufacturer to determine if possible dose should be the benefits of the use of initiated followed by gradual ingenol mebutate continue to increase. outweigh its risks as a Reference: treatment option for actinic MADRAC Bulletin, NPRA, keratosis. 01/2020 (www.npra.gov.my/) Reference: Summary Safety Review, Health Canada, 2 July 2020 (www.hc-sc.gc.ca) (See also WHO Pharmaceuticals Newsletter No.3, 2020: Risks of skin cancer outweigh

WHO Pharmaceuticals Newsletter No. 4, 2020 • 10 Signal

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

The signals in this Newsletter are based on information derived from reports of suspected adverse drug reactions available in the WHO global database of individual case safety reports (ICSRs), VigiBase. The database contains over 22 million reports of suspected adverse drug reactions, submitted by National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring. VigiBase is, on behalf of the WHO, maintained by the Uppsala Monitoring Centre (UMC) and periodic analysis of VigiBase data is performed in accordance with UMC’s current routine signal detection process. International pharmaceutical companies, when identified as uniquely responsible for the drug concerned, are invited to comment on the signal text. Signals are thereafter communicated to National Pharmacovigilance Centres, before being published in this Newsletter. Signal texts from UMC might be edited to some extent by WHO and may differ from the original version. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of Signal (page 27). For information on the UMC Measures of Disproportionate reporting please refer to WHO Pharmaceuticals Newsletter Issue No. 1, 2012.

UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific research within the field of pharmacovigilance. For more information, on the UMC Measures of Disproportionate Reporting etc., visit www.who-umc.org. To leave a comment regarding the signals in this Newsletter, please contact: the Uppsala Monitoring Centre, Box 1051, SE-751 40 Uppsala, Sweden. E-mail: [email protected].

Aciclovir or valaciclovir - Acute generalised exanthematous pustulosis

Camilla Westerberg, Uppsala Monitoring Centre

Summary was confirmed by patch tests. In addition, since AGEP can be confused with a herpes eruption, it The combination of aciclovir and acute generalised seems important to warn that aciclovir and exanthematous pustulosis (AGEP) was found in a valaciclovir can potentially cause AGEP. routine signal detection screening of VigiBase, the WHO global database of individual case safety reports, performed in December 2018, and Introduction valaciclovir was later added to the assessment. Based on the overall reporting of adverse reactions Aciclovir is an antiviral drug used to treat herpes for aciclovir or valaciclovir and the adverse reaction simplex and zoster infections. The antiviral effect is AGEP in VigiBase, the expected value for the due to inhibition of the herpes virus DNA number of reports for the combinations was five polymerase enzyme, thereby inhibiting viral DNA and three respectively, while the observed numbers synthesis and replication. When taken orally, were 10 and 14. The combinations were highlighted aciclovir is slowly and poorly absorbed. Aciclovir is as disproportionately reported by IC analysis. Age widely distributed in tissues and body fluids, range, time-to-onset (TTO) and drug withdrawal including brain, kidney, lung, liver, muscle, spleen, were similarly described in the case series and uterus, vaginal mucosa, vaginal secretions, corresponded with the clinical picture of AGEP in cerebrospinal fluid, and herpetic vesicular fluid. most reports. However, the valaciclovir case series Valaciclovir is the L-valine ester of aciclovir and is had few narratives, and a number of co-suspected almost completely converted to aciclovir and valine drugs known to cause skin eruptions, making the in the body.1,2 assessment difficult. In many of the reports in both case series, co-reported drugs included labelled Acute generalised exanthematous pustulosis (AGEP) causes of AGEP or other severe cutaneous adverse is a severe skin reaction, characterized by an acute reactions (SCARs) such as Stevens-Johnson onset (less than 10 days and typically within 48 3,4 Syndrome (SJS) and Toxic Epidermal Necrolysis hours) of mainly small non-follicular pustules on (TEN). Though inconsistently, SJS and TEN are an erythematous base. Systemic involvement labelled for some aciclovir products. It is possible sometimes occurs, but only in about one fifth of that initial presentations of these SCARs could be cases. The reaction is usually drug-related, with confused with AGEP. more than 90% of AGEP cases provoked by medications. Most often these are beta-lactam In these two case series, despite the limitations, antibiotics (penicillins, cephalosporins, quinolones). there are several reports indicating that Other medicines that have been implicated include aciclovir/valaciclovir can be strongly suspected to pristinamycin, tetracyclines, sulphonamides, oral have been the cause of the drug induced skin antifungals, diltiazem, hydroxychloroquine, reaction, and in two published case reports, this WHO Pharmaceuticals Newsletter No. 4, 2020 • 11 Signal

4,5 carbamazepine, and paracetamol. However, AGEP reported, by IC analysis (IC025 = 0.8). After is not listed in the product labelling for all of these excluding suspected duplicates, 10 cases remained medicines. Treatment consists of the removal of the in the series. Age ranged between 20 and 96 years, drug causing the reaction and use of potent topical with a median of 65 years, and there was an equal or systemic steroids, plus symptom management distribution of men and women. Valaciclovir was and infection prevention. Spontaneous resolution added to the assessment at a later stage. As of 1 usually occurs within two weeks after December 2019, there were 14 cases of valaciclovir discontinuation of the causative drug.4,5,6 and AGEP found in VigiBase (de-duplicated data). Age ranged between 33 years and 86 years (two AGEP is classified among the severe cutaneous unknown), with a median of 66 years and, as with adverse reactions (SCARs), which are very rare but aciclovir, half of the reports concerned women, and potentially life-threatening reactions of delayed half men. The expected number of cases was three hypersensitivity. SCARs include AGEP, drug and the IC value for valaciclovir and AGEP was reactions with eosinophilia and systemic symptoms 025 1.2. (DRESS), and the most severe form of SCARs: the Stevens–Johnson syndrome/toxic epidermal All but two aciclovir reports, where the reporter was necrolysis (SJS/TEN) spectrum. unknown, were submitted by a healthcare professional. For eight patients, the drug was The mechanism and classification of SCARs are stopped, and the reaction was reported to have described by Bellón as “delayed T-cell-mediated abated in six cases. An outcome ‘recovering’ or type IV hypersensitivity reactions in the Gell and ‘recovered’ was reported for eight of the aciclovir Coombs classification in which drug-specific T cells cases. Six of these eight patients had stopped the can be identified in the peripheral blood or skin drug; it was not stated what action was taken in the infiltrates. The variation in clinical conditions has other two reports. resulted in type IV reactions being further sub- classified according to different cytokine production In 10 of the 14 valaciclovir reports, the patient had patterns by T cell subsets and to the contribution of recovered or was recovering after stopping the certain subpopulations of leukocytes to the drug, and for one patient the outcome after inflammation and tissue damage. Traditionally, stopping valaciclovir was stated as unknown. In DRESS is considered a type IVb Th2-driven three reports however, the patients had not reaction, SJS/TEN a type IVc cytotoxic reaction, and improved or recovered despite a documented AGEP a type IVd reaction”. 7 withdrawal of valaciclovir in one of these. For aciclovir, the time-to-onset (TTO) ranged between

one and 21 days, and for valaciclovir, between one Reports in VigiBase day and six months. The combination of aciclovir and AGEP was found in Countries represented in the combined case series a routine signal detection screening of VigiBase, the were Australia, China, Czech Republic, France, WHO global database of individual case safety India, Italy, Japan, Malaysia, Portugal, Switzerland, reports, performed in December 2018. As of 6 Thailand and the United States of America (US). October 2019, there were 16 cases reporting the The characteristics of the case series are set out in combination. The expected value for the number of Table 1 for the aciclovir cases, and in Table 2 for reports on the combination was five, and the valaciclovir. association was highlighted as disproportionally

Table 1. Characteristics of case reports in VigiBase of AGEP in association with aciclovir Case Age/ Suspected (S) or concomitant Reactions Biopsy or TTO Action Outcome Comment Sex (C) drugs (MedDRA patch test taken with PT) result drug 1 75/M Aciclovir*, Solifenacin* (S) AGEP, Skin biopsy - Drug Unknown Published case report describes Concomitant lisinopril, Erythema, proved drug withdrawn/ aciclovir as treatment for the nitrendipine, solifenacin; Swelling induced unknown reaction and points to solifenacin tamsulosin mentioned in the reaction outcome as prime suspect published case report 2 68/F Aciclovir* (S) Alprazolam, AGEP - 1 days - Recovering TTO seems to have been 2 days. Budesonide;Formoterol, No dates reported for Lercanidipine, Metformin, concomitant drugs Simvastatin, Venlafaxine* (C) 3 70/M Aciclovir*, Benzylpenicillin, AGEP - 3 days - Recovering Both benzylpenicillin and Gabapentin*, Olanzapine (S) gabapentin were started after aciclovir (TTO 1 and 0 days). 4 26/F Aciclovir* (S), AGEP - 11 days Drug Recovering TTO probably shorter since Dexamethasone (C) withdrawn/ narrative states that eruptions Reaction appeared before admission to abated ICU and reaction start date

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Case Age/ Suspected (S) or concomitant Reactions Biopsy or TTO Action Outcome Comment Sex (C) drugs (MedDRA patch test taken with PT) result drug Concomitant ranitidine and reported to be day after calcium mentioned in admission. narrative 5 73/F Aciclovir*, Cefotaxime*, AGEP - 4 days Drug Recovered Cefotaxime and dexamethasone Dexamethasone (S) withdrawn/ were started 11 days before Duloxetine*, Ofloxacin**, Reaction (TTO=15 days) but discontinued Omeprazole*, Perindopril*, abated together with aciclovir according Pregabalin*, Valproic acid* to narrative (C) 6 61/F Aciclovir*, AGEP Biopsy 4 days Drug Recovered According to narrative, the Cilastatin;Imipenem*, indicated withdrawn/ patients journal vaguely states Ciprofloxacin*, AGEP Reaction macular eruptions 3-4 months Vancomycin** (S) Cytarabine, abated prior to reported event. Daunorubicin, Gemtuzumab TTO=22 days for co-suspected (C) Rechallenge drugs. /No recurrence 7 20/F Acetylcysteine;Benzalkonium; AGEP, - 3 days Drug - Antibiotic was discontinued but Tuaminoheptane***, Rash withdrawn/ aciclovir was continued, together Aciclovir*, Amoxicillin**, unknown with a topical corticosteroid. The Biclotymol (S) outcome day after, the reaction was aggravated 8 50/M Aciclovir* (S) Drug name/s AGEP - - Drug Recovered Treatment duration = 2 days. under assessment for who-dd withdrawn/ However, not much information (herbal remedy) (C) Reaction in report abated 9 53/M Aciclovir* (S) AGEP Biopsy 21 days Drug Recovered Published case report. Methylprednisolone (C) confirmed withdrawn/ AGEP. Reaction Positive abated patch test for aciclovir Rechallenge /Reaction recurred 10 96/M Aciclovir* (S) AGEP - 3 days Drug Recovered Antibiotics started and stopped Piperacillin;Tazobactam** (S) withdrawn/ on the same day as the reaction Reaction occurred. Aciclovir continued abated for an additional 6 days. * SJS, TEN, or Erythema multiforme (EM) labelled in an SmPC from the Electronic Medicines Compendium https://www.medicines.org.uk/emc ** AGEP + SJS, TEN or EM labelled in an SmPC from the Electronic Medicines Compendium https://www.medicines.org.uk/emc *** SJS, TEN or EM reported but only with other drugs

Case 2 in Table 1 has venlafaxine as a co-reported all over the body. The patient was admitted to the drug, however, the narrative describes the start of intensive care unit (ICU). The reporter assesses the aciclovir treatment for submammary erythema and causality as probable. The narrative of case 7 the eruption of AGEP after two days. Case 4 was indicates that an antibiotic taken concomitantly was from a dermatologist who described how the patient discontinued but oral aciclovir was continued, after took aciclovir and shortly after developed eruptions which the reaction was aggravated.

Table 2. Characteristics of case reports in VigiBase of AGEP in association with valaciclovir Case Age/ Suspected (S) or Reactions Biopsy or TTO Action Outcome Comment Sex concomitant (C) (MedDRA patch test taken with drugs PT) result drug 1 33/F Amoxicillin;Cla- AGEP Skin biopsy - Drug Recovered Published case report. Valacoclovir vulanic acid**, confirmation. withdrawn/ used as treatment for eruptions Ampicillin;Sulbac- Positive patch Reaction tam, Co- test for abated trimoxazole*, amoxicillin; Valaciclovir, clavulanic acid Vancomycin** (S)

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Case Age/ Suspected (S) or Reactions Biopsy or TTO Action Outcome Comment Sex concomitant (C) (MedDRA patch test taken with drugs PT) result drug 2 52/ Paracetamol, AGEP - 5 days Drug Recovered Negative rechallenge reported for M Valaciclovir (S) withdrawn/ Paracetamol. No dates reported for Ceftriaxone**, Reaction ceftriaxone or minocycline. Minocycline* (C) abated Ceftriaxone was also withdrawn

Rechallenge /unknown outcome 3 -/M Doxorubicin, AGEP - 2 days Drug Recovered All drugs (except metoclopramide) Folinic acid, withdrawn/ started on the same day and were Gemcitabine*, Reaction withdrawn. Dose reportedly not Metoclopramide, abated changed for metoclopramide Ondansetron, Sulfamethoxazole; Trimethoprim*, Valaciclovir, Vinorelbine (S) 4 -/F Ceftriaxone**, AGEP - 2 days Drug Recovered TTO for ceftriaxone: 5 days Valaciclovir (S) withdrawn/ Reaction abated 5 43/F Valaciclovir (S) AGEP - - Drug Unknown Reporter: Other Health Professional, withdrawn/ Consumer/Non-Health Professional unknown outcome 6 86/ Valaciclovir (S) AGEP, - 1 days - Not Treatment continued 5 days after M Syncope recovered onset of AGEP. Syncope outcome also reported as not recovered 7 76/F Naproxen*, AGEP, Acute - 2 days Drug Recovered TTO = 2 days for naproxen, Valaciclovir (S) kidney injury withdrawn/ mecobalamin, teprenone and Amlodipine;Ator- Reaction phenol;zinc. vastatin*, abated Amlodipine;atorvastatin treatment Mecobalamin, ongoing since several years Phenol;Zinc, Teprenone (C) 8 75/ Dexamethasone, AGEP Patch test 5 days Drug Recovered All drugs started and stopped on the M Lenalidomide*, positive for withdrawn/ same day. Phenoxymethylpenicillin Phenoxymethyl- amoxicillin Reaction was the only drug the patient had not penicillin, abated taken before Sulfamethoxazole; Trimethoprim*, Valaciclovir (S) 9 68/F Cefpodoxime, AGEP, Biopsy AGEP was 2 days Drug Not According to the narrative, Piperacillin;Tazob skin abnormal, biopsy withdrawn/ recovered cefpodoxime was primary suspect actam**, C-reactive confirmed on No effect drug, but valaciclovir or an Valaciclovir (S) protein two occasions observed infectious cause were not excluded Glimepiride, increased, as alternative explanations. Metformin, Leukocytosis, Piperacillin;tazobactam was Pioglitazone, Lymphopenia, administered about 20 days after Torasemide* (C) Neutrophilia, first onset of AGEP, and this Pyrexia, Skin resulted in new eruptions, exfoliation erythroderma and circulatory collapse requiring intensive care. 10 62/ Amoxicillin**, AGEP - 14 days Drug Recovered Reported drug start date for M Carbamazepine**, withdrawn/ amoxicillin is after reported reaction Valaciclovir (S) Reaction start. However, it is included in the abated “dose regimen” described in the narrative and the nature of the date Rechallenge could suggest an error in reporting /unknown outcome 11 81/ Influenza vaccine AGEP The biopsy was 6 Dose not Not TTO vaccine: 9 days M (Vaxigrip), in favour of a months changed/No recovered Eruptions are reported to have Sulfamethoxazole; post-viral or effect started “at the same time as a medically observed pharyngitis”.

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Case Age/ Suspected (S) or Reactions Biopsy or TTO Action Outcome Comment Sex concomitant (C) (MedDRA patch test taken with drugs PT) result drug Trimethoprim*, induced Valaciclovir (S) reaction. Rechallenge /unknown outcome 12 81/F Valaciclovir (S), AGEP Two biopsies, 3 days Drug Recovering Narrative mentions Ebastine, taken on thigh withdrawn/ codeine;paracetamol taken during Monotildiem, Co and arm, Reaction three days about 8 days before Aprovel, Elisor, indicated a drug abated eruption of temporal lesions which Inexium are induced SCAR- in turn was treated with valaciclovir mentioned as type reaction since herpes zoster was suspected. ongoing treatment Patient had taken topical aciclovir in narrative before without any problem. 13 50/ Valaciclovir (S) AGEP Biopsy indicate 2 days Drug Recovered Patient experienced pustular M drug induced withdrawn/ eruptions twice before current event. reaction Reaction Allergologic work up then positive abated for amoxicillin and Introna® (Interferon alfa-2b). No work up performed for valaciclovir after most recent event. 14 64/F Amlodipine*, AGEP, Rash Biopsy showed 12 days Drug Recovered TTO urticaria/AGEP suspicion: Bortezomib*, pustular, leukocytoclastic withdrawn/ Thalidomide: 7/11 days Dexamethasone, Urticaria vasculitis with Reaction Amlodipine: 19/24 days Enoxaparin, secondary abated Valaciclovir: 8/12 days Thalidomide*, epidermal Bortezomib: 7/11 days Valaciclovir (S) lesions Dexamethasone: -1/3 days Enoxaparin: -4/0 days

Reporter mentions low extrinsic imputability for valaciclovir * SJS, TEN, or EM labelled in an SmPC from the Electronic Medicines Compendium https://www.medicines.org.uk/emc ** AGEP + SJS, TEN or EM labelled in an SmPC from the Electronic Medicines Compendium https://www.medicines.org.uk/emc

Narratives of valaciclovir cases 12 and 13 describe not a SCAR but it is important to note as it is often clinical scenarios where the patient took valaciclovir caused by herpes simplex virus, and may not be and developed pustular eruptions shortly after. The clearly distinguishable from AGEP in its early stage.5 patient in case 12 was treated for herpes zoster Two of the cases in the series for aciclovir have with “bétadine” and valaciclovir. After three days, been published in the literature. The first concerns about five days after stopping case 1 in Table 1 where solifenacin is suspected to codeine+paracetamol, taken for post-surgical pain, be the causative drug.14 The second corresponds pruritic lesions appeared. The patient in case 13 with case 9, and describes in detail the diagnosis had experienced pustular eruptions twice before. where a biopsy revealed typical characteristics of The first time, valaciclovir was one of four drugs AGEP. Aciclovir was suspected and replaced, and taken, but no allergy tests were made. The second the reaction abated. Two months later, the time, amoxicillin and interferon were deemed exclusion of other potential causative agents than causative after positive allergy tests. The third time, aciclovir was made, using patch tests.15 valaciclovir was introduced and the eruptions appeared within two days. An additional published case report from Finland, not corresponding to any in the case series,

describes a 44-year-old woman developing pustules Literature and labelling after treatment with aciclovir against labial herpes. The diagnosis of AGEP secondary to aciclovir AGEP is not labelled for either aciclovir or therapy was confirmed by positive patch testing.16 valaciclovir. Erythema multiforme (EM) and SJS/TEN are labelled with the frequency “Not Case 1 in Table 2 is described in the literature, known” for aciclovir 200 mg tablets from Wockhardt mentioning acute localised exanthematous UK Ltd, and “Rare” for aciclovir 800 mg tablets from pustulosis (ALEP) as the reaction, though the term Accord.1,8 However, in labels for other formulations, reported to VigiBase was AGEP. The case report no mention is made of severe skin reactions.9,10 The presents an antibiotic as the cause of the reaction valaciclovir labels in the UK do not mention SCARs.2 and valaciclovir as a treatment of an assumed diagnosis of shingles.17 In aciclovir labels from the US, EM, SJS and TEN are mentioned frequently.11,12 However, the reaction is typically not mentioned in topical formulations. In labels for valaciclovir, only EM is mentioned.13 EM is WHO Pharmaceuticals Newsletter No. 4, 2020 • 15 Signal

Discussion mentions a “low extrinsic imputability” of valaciclovir. Aciclovir case reports that strongly implicate aciclovir as the cause of AGEP, include two The fact that there are few reports where one or published cases where the causative drug was more co-reported drugs do not have a SCAR in the confirmed by patch test, and two unconfounded label, usually SJS/TEN but sometimes AGEP, as reports with good narratives (cases 2 and 4). Case found in trials or as post-marketing experience, is 7, describing an aggravated skin reaction after the most important possible confounder for both discontinuation of confounding drugs also indicates case series. Overlap between SJS/TEN and AGEP aciclovir as the causative drug. does occur but this is rare,18 so it is not clear if this would increase the possibility of aciclovir or Most aciclovir reports (n=7) have a time to onset of valaciclovir causing AGEP, despite related between one and four days, consistent with the mechanisms. expected onset time for the reaction, and two reports have 11 and 21 days between drug intake However, diagnostic confusion between SCARs can and reaction onset. However, the report where it occur in the early stages18 and also between severe took 21 days to develop the reaction is the AGEP, especially with mucous membrane published case with patch test confirmation (case involvement and SJS/TEN.4 The latter might not 9). It seems that there are circumstances where the have greatly impacted the case series as it is more reaction is delayed, and in this particular case, the likely that AGEP would be diagnosed as SJS/TEN concomitant administration of a corticosteroid is than the reverse because of the characteristic mentioned as one suspected cause of the delay, pustules. However, a limitation of the case series is together with the absence of prior exposure to the absence of histopathology which clearly aciclovir and the “low sensitizing potential of the distinguishes between the SCARs. drug”. Interestingly, in the aciclovir case where Finally, it is important to note that AGEP might be time to onset was reported as 11 days, an oral confused with a herpes eruption, and two reports corticosteroid is reported to have been taken mention that aciclovir/valaciclovir was used as concomitantly. For valaciclovir, TTO ranged between treatment for the eruptions (case 1 in Tables 1 and one day and six months. However, the latter case is 2). In addition, a literature report not in the series unusual, and if excluding it as an outlier, the described a case where AGEP was confused with a longest TTO in the case series was 14 days. herpes eruption.19 Case reports that strongly implicate valaciclovir as the cause of AGEP include cases 12 and 13 where the narratives describe clinical scenarios where the Conclusion patient took valaciclovir and developed pustular eruptions shortly after. The patient in case 12 was In these case series, there are several cases where treated with codeine+paracetamol before the aciclovir and, though to a lesser extent, valaciclovir, eruption of a temporal lesion, and paracetamol has can be strongly suspected to have been the cause been implicated as a cause of AGEP. However, the of AGEP, and in two literature reports, this was treatment only continued for three days, which confirmed by patch tests. Since the condition can be means that it was stopped well before the temporal confused with a herpes eruption, it seems important lesion emerged some days later. The lesion was to warn that also aciclovir could potentially cause suspected to be herpes zoster and treated with the skin reaction. “bétadine” and valaciclovir, and after three more days, pruritic lesions appeared. The patient in case 13 had experienced pustular eruptions twice before. References The third time, valaciclovir was introduced and the 1. Electronic Medicines Compendium: Summary of eruptions appeared within two days. Product Characteristics for aciclovir (Wockhardt Most valaciclovir cases are co-reported with one or UK Ltd). Available from: more antibiotics labelled to cause AGEP or a https://www.medicines.org.uk/emc/product/23 different SCAR, and in some of the reports, it seems 51/smpc. Accessed 2019-10-25. more likely that a different drug was the cause of 2. Electronic Medicines Compendium: Summary of the reaction. In three cases (1, 8 and 9), an Product Characteristics for valaciclovir antibiotic is confirmed or strongly suspected as the (Valtrex®). Available from: cause, and in one case (11), it is more likely that https://www.medicines.org.uk/emc/product/54 the causative drug was the vaccine which was 67/smpc. Accessed: 2019-12-15. administered nine days before onset, alternatively an ongoing infection, while valaciclovir had been 3. Botelho, Luciane & Picosse, F.R. & Padilha, M.H. taken for six months. In case 14, the eruptions & Michalany, Nilceo & Góis, Aécio & Porro, appeared some time into the treatment for Adriana. (2010). Acute Generalized leukaemia the patient was undergoing. All drugs Exanthematous Pustulosis Induced by were withdrawn, however bortezomib was re- Cefepime: A Case Report. Case reports in introduced without the eruptions reappearing. dermatology. 2. 82-87. 10.1159/000314474. Therefore, thalidomide, valaciclovir and amlodipine 4. Szatkowski J, Schwartz RA, Acute generalized were still all suspects, although the reporter WHO Pharmaceuticals Newsletter No. 4, 2020 • 16 Signal

exanthematous pustulosis (AGEP): A review and 12. US Food and Drug Administration: Product label update. J Am Acad Dermatol 2015;73:843-8. for ACYCLOVIR capsule (Boscogen, Inc.). Available from: 5. DermNet NZ, Acute generalised exanthematous https://dailymed.nlm.nih.gov/dailymed/drugInf pustulosis. Available from: o.cfm?setid=f5174611-2734-4610-b12f- https://dermnetnz.org/topics/acute- eb5a7f39d7b6. Accessed 2019-12-18. generalised-exanthematous-pustulosis/ Accessed: 2020-01-20. 13. US Food and Drug Administration: Product label for VALTREX- valacyclovir hydrochloride tablet, 6. Feldmeyer L, Heidemeyer K, Yawalkar N. Acute film coated (GlaxoSmithKline LLC). Available generalized exanthematous pustulosis from: pathogenesis genetic background clinical https://dailymed.nlm.nih.gov/dailymed/drugInf variants and therapy. Int J Mol Sci. 2016 Jul o.cfm?setid=f8e0d8f8-cb73-4206-a484- 27;17(8). 88f5c4fbd719. Accessed 2019-12-18. 7. Bellón, T. Mechanisms of Severe Cutaneous 14. Stumpfová, A. Akutní generalizovaná Adverse Reactions: Recent Advances. Drug Saf. exantematózní pustulóza. Dermatol. praxi (2019) 42:973–992. 2018; 12(1): 40–42. 8. Electronic Medicines Compendium: Summary of 15. Serra D, Ramos L, Brinca A, Gonçalo M. Acute Product Characteristics for aciclovir 250mg generalized exanthematous pustulosis Powder for Solution for Infusion (Wockhardt UK associated with acyclovir, confirmed by patch Ltd). Available from: testing. Dermatitis. 2012 Mar-Apr;23(2):99- https://www.medicines.org.uk/emc/product/56 100. 96/smpc. Accessed 2019-12-18. 16. Kubin, ME, Jackson, P, Riekki, R. Acute 9. Electronic Medicines Compendium: Summary of Generalized Exanthematous Pustulosis Product Characteristics for Aciclovir Tablets BP Secondary to Acyclovir Confirmed by Positive 800mg (Accord-UK Ltd). Available from: Patch Testing. Acta Derm Venereol 2016; 96: https://www.medicines.org.uk/emc/product/61 860–861. 75/smpc. Accessed 2019-12-18. 17. Dhital, R, Mir, I, Basnet, S, Poudel, D, Patel, N. 10. Electronic Medicines Compendium: Summary of Acute localized exanthematous pustulosis: a Product Characteristics for aciclovir 400 mg rare cutaneous drug eruption. Ann Allerg Tablets (Ranbaxy). Available from: Asthma Im. 2018 Nov;121(5);64-5. https://www.medicines.org.uk/emc/product/43 35/smpc. Accessed 2019-12-18. 18. Bouvresse S. et al. Toxic epidermal necrolysis, DRESS, AGEP: do overlap cases exist? Orphanet 11. US Food and Drug Administration: Product label J Rare Dis. 2012 Sep 25;7:72. for ACYCLOVIR- acyclovir sodium injection, solution (Fresenius Kabi USA, LLC). Available 19. Blake, T, Scuderi, S. A Case of Acute from: Generalised Exanthematous Pustulosis after https://dailymed.nlm.nih.gov/dailymed/drugInf Unprotected Sexual Intercourse on Holidays in o.cfm?setid=badf347b-eeee-4239-9c74- Bali. Case Rep Dermatol. 2014 Jan-Apr; 6(1): 966f262925aa. Accessed 2019-12-18. 29–33.

Alectinib – Rhabdomyolysis

Mariano Madurga Sanz, Spain

Summary treated with crizotinib. The EU Summary of Product Characteristics (SmPC) lists myalgia or Alectinib is a highly selective and potent ALK musculoskeletal pain and raised creatine (anaplastic lymphoma kinase) and RET (“rearranged phosphokinase (CPK) as reported in patients in during transfection”) tyrosine kinase inhibitor. pivotal trials with alectinib, including grade 3 Alectinib (Alecensa® in the EU, US; Alecensaro® in events. The median time to increased grade 3 CPK Canada) is indicated as first-line monotherapy for was 14 days across clinical trials. Myalgia and adults with ALK-positive advanced non-small-cell increased blood CPK are labelled for alectinib in the lung cancer (NSCLC). As monotherapy it is also EU and the US product labels. However, it is not indicated for the treatment of adults with ALK- labelled for rhabdomyolysis. positive advanced NSCLC who have been previously

WHO Pharmaceuticals Newsletter No. 4, 2020 • 17 Signal

As of 19 May 2019, there were eight reports in Alectinib was granted an accelerated approval by VigiBase, the WHO global database of individual the US Food and Drug Administration (FDA) in case safety reports, for alectinib and the adverse December 2015 to treat patients with ALK-positive drug reaction (ADR), rhabdomyolysis. The reports advanced NSCLC whose disease worsened after, or support a relationship between alectinib and who could not tolerate, treatment with crizotinib; rhabdomyolysis, with six cases giving alectinib as this was converted into full approval in November the only suspected drug, and six cases reporting a 2017. It had conditional approval from the positive dechallenge, of which two also had a European Medicines Agency (EMA) in February 2017 positive rechallenge. In addition, the time-to-onset for the same indication, which was extended in is consistent in the cases where this information is October 2017 with the indication to first-line available (12-14 days). treatment of adult patients with ALK-positive advanced NSCLC.11 Current product information for alectinib does not contain sufficient precautions and warnings to Currently alectinib as monotherapy is indicated for inform healthcare professionals and patients about the first-line treatment of adult patients with ALK- the potential of rhabdomyolysis as an adverse positive advanced NSCLC; and as monotherapy for effect. the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib.1

Alectinib is available as capsules (150 mg). The Introduction recommended dose is four capsules taken twice a day with food (a total of 1,200 mg daily). For Tyrosine kinases such as anaplastic lymphoma patients with severe hepatic impairment the kinase (ALK) are becoming major areas of interest recommended dose is three capsules twice a day for the development of new chemotherapy agents. with food (900 mg). The doctor may reduce the ALK plays an important role in the development of dose or stop treatment temporarily if side effects the brain; it also drives the progression of several occur. In certain cases, treatment should be cancers, including anaplastic large-cell lymphoma, permanently stopped.1 Most adverse effects due to neuroblastoma, and non-small-cell lung cancer ALK inhibitors can be managed efficiently via dose (NSCLC). Alectinib is a highly selective and potent modifications or interruptions.12-14 ALK and RET (“rearranged during transfection") tyrosine kinase inhibitor. In preclinical studies, Medicines-related myotoxicities such as inhibition of ALK tyrosine kinase activity led to rhabdomyolysis or myoglobinuria are the most blockage of downstream signalling pathways serious medical emergencies. Rhabdomyolysis is an including STAT 3 (“signal transducer and activator acute and fulminant necrotizing myopathy that can of transcription 3”) and PI3K/AKT cause severe myalgia, muscle swelling and (“phosphoinositide 3-kinase”/”protein kinase B”, weakness, and increased serum CPK as high as also called AKT) and induction of tumour cell death 2,000 times upper limit of normal (ULN). It is (apoptosis).1,2 Alectinib demonstrated in vitro and in associated with myoglobinuria (urine that appears vivo activity against mutant forms of the ALK dark brown or pink due to the presence of enzyme, including mutations responsible for pigmented myoglobin), which can cause acute renal resistance to crizotinib. The major metabolite of failure and death. If the offending agent is removed alectinib (M4), metabolised by CYP3A4, has shown and patients are aggressively treated, the muscle similar in vitro potency and activity.1,2 typically heals well.15 Activating mutations or translocations in the gene encoding ALK have been identified in different Reports in VigiBase tumours, including NSCLC, where it is present in about 2 to 5% of cases and in 3 to 7% of The combination alectinib–rhabdomyolysis was first adenocarcinomas.3-5 ALK is a receptor tyrosine identified in 2016 in a screening of VigiBase, the kinase that shows striking homology with members WHO global database of individual case safety of the insulin receptor family, whose physiological reports (ICSRs), focussing on new drugs and function is still unclear.6 The translocation of ALK serious adverse drug reactions (ADRs). Alectinib is determines the expression of the resulting fusion labelled for myalgia and increased blood CPK in protein and the consequent aberrant signalling of both the EU and the US product labels. However, it ALK in the NSCLC. The identification of ALK as a is not labelled for rhabdomyolysis.1,2 potential therapeutic target in the treatment of As of May 2019, out of over 20 million ICSRs in NSCLC has led to the development of drugs aimed VigiBase, there were 1,993 ICSRs with alectinib as at inhibiting its activity. The first two with this a suspected medicine. A total of eight ICSRs (0.4% mechanism of action to be authorized were of the alectinib reports), with the combination crizotinib (Xalkori®), and subsequently ceritinib alectinib and rhabdomyolysis were retrieved from (Zykadia®), both for patients not previously treated VigiBase on 19 May 2019 and reviewed case by and for those who have already received treatment case. The number expected was three; the IC for the disease.7-10 Other tyrosine kinase inhibitors 0.25 was -0.1; the most recent report was 19 May 2019; (with stem –tinib) that are used in NSCLC include the number of reports where it was the single alectinib, brigatinib and lorlatinib. suspected drug was six; the number of positive dechallenges was six; the number of positive WHO Pharmaceuticals Newsletter No. 4, 2020 • 18 Signal rechallenges two. There were eight ICSRs classified Germany (two reports), Portugal (two), Austria, as ‘serious’. Canada, USA, and Australia (one each). Details of case reports are set out in Table 1. The reports were submitted from six countries:

Table 1: Characteristics of case reports in VigiBase of rhabdomyolysis in association with alectinib Case Age/ Suspected (S) or concomitant Daily Reactions Time- Dechallenge/ Outcome Sex (C) drugs dose to-onset Rechallenge (TTO) 1* 57/m Alectinib (S), pantoprazole 1,200 mg Rhabdomyolysis 14 days Positive/Not First doses (C), levetiracetam (C) applicable, were negative due to withdrawn reduced dosage after TTO, (450 mg twice recovered in 5 daily) days, two days later new dose reduced to 900mg/day 2 53/m Alectinib (S), tinzaparin unknown Rhabdomyolysis, CPK increased 14 days Positive/Positive sodium(C) at lower dose 3 64/f Alectinib (S), enoxaparin (C), 1,200 mg Decreased appetite, blood CPK 12 days Unknown / Recovered dexamethasone (C), increased, pyrexia; gastritis; nausea; Unknown with with some nadroparin (C), mirtazapine arthralgia; pelvic pain; large intestine reduced dosage sequelae (C), pantoprazole (C), perforation: peritonitis; pyelonephritis; (450 mg twice zopiclone (C), naloxone (C), rhabdomyolysis; sepsis; transaminases daily, and 300 mg oxycodone (C), torasemide increased; pelvic hematoma; general twice daily) (C), calcium carbonate + physical health deterioration; colecalciferol (C) retroperitoneal hematoma; retroperitoneal hemorrhage; diverticulitis 4 49/m Alectinib (S), dexamethasone 1,200 mg Rhabdomyolysis, edema lower limb, 13 days Positive/Positive Recovering (C) myalgia, blood CPK increased, asthenia, grip strength decreased 5 ?/m Alectinib (S), dexamethasone 1,200 mg Rhabdomyolysis, hepatic function No data Positive/Negative Recovered; (C), furosemide (C) abnormal, edema lower limb but hepatic function abnormal - Not recovered 6 64/f Alectinib (S), rosuvastatin --- Rhabdomyolysis (CPK >10,000) No data Positive/No data Recovering/re- calcium (S) solving 7 -/m Alectinib (S), tamsulosin (C), 1,200 mg Rhabdomyolysis No data Unknown/No Unknown finasteride (C), bisoprolol (C), data pantoprazole (C), linagliptin (C), rosuvastatin calcium (C), folic acid (C), crizotinib (C), apixaban (C), simvastatin (C), 8 58/m Alectinib (S), pirfenidone (S) 1,200 mg Rhabdomyolysis, blood CPK No data Positive/No data Recovered increased, myalgia, swelling, peripheral swelling, wrong patient received product *Index case

Illustrative case reports 420 U/L (normal range 39-190); one day later, the patient started oral alectinib, 600 mg twice daily for Three of the eight ICSRs can illustrate important NSCLC, ALK positive; on 13 November, CPK was details: one index case, the first documented ICSR 1,615 U/L and the patient was diagnosed with in the onset of this signal (alectinib and rhabdomyolysis (severity not reported). The patient rhabdomyolysis) with positive dechallenge; one had muscle pain, but no increase in creatinine level case with clear temporal sequence and rechallenge; was noted for the time of the event. No further and a third with pharmacological interactions for investigations were performed to confirm the rhabdomyolysis syndrome: diagnosis, as the combination of clinical condition Case 1: is the index case, from an oncologist, and the laboratory tests appeared to be sufficient. concerning a 57-year-old male patient. On 29 Therapy with alectinib was interrupted on the same October laboratory tests showed blood CPK to be day. No treatment was reported for the event. On WHO Pharmaceuticals Newsletter No. 4, 2020 • 19 Signal

17 November CPK was 705 U/L, and according to Literature and labelling the reporter, the rhabdomyolysis had resolved, as As of 25 June 2019, no published cases of he described in the suspected ADR report. On 19 rhabdomyolysis associated with alectinib (or other November, it was decided to restart therapy with ALK inhibitors such as ceritinib, crizotinib, oral alectinib at a reduced dose of 450 mg twice brigatinib, lorlatinib) could be found in the daily, with close monitoring. On 24 November CPK literature. A recent alectinib review12 found the was 380 U/L. same results. Also, two systematic reviews13,14, the Case 4: a 49-year-old adult male, who had first with 15 trials (2,005 patients), the second with increased CPK and rhabdomyolysis, associated with 14 studies (2,793 patients) found no the use of alectinib, for ALK-positive lung cancer, rhabdomyolysis cases were associated with alectinib started oral alectinib on 28 June, 600 mg twice (or other ALK inhibitors). daily for NSCLC. He was also taking dexamethasone Among the ALK inhibitors, alectinib is considered for an unknown indication. The ADR occurred 13 well tolerated. Compared to crizotinib, alectinib is days after the start of the administration of the associated with lower rates of vision disorder (10%) suspected drug. The reporter noted that the and gastrointestinal ADRs, but higher rates of medication was halted on 12 July due to symptoms serious hepatic or musculoskeletal ADRs.12 of rhabdomyolysis, and that it was restarted with the same dose when CPK had decreased The EMA Committee for Medicinal Products for sufficiently. The reporter noted in his ADR report, Human Use (CHMP) European Public Assessment “treatment resumed on 20 July maintaining an Report11 already indicates that the only signal of effective treatment”. He did not mention if there increased toxicity related to alectinib was was a dose reduction. With reintroduction, myalgia/CPK increase. The most common side rhabdomyolysis reoccurred and the patient again effects of alectinib in the EU SmPC1 and US FDA experienced myalgia, asthenia and oedema of the product label2 include: tiredness; constipation; lower limbs; but only a moderate to light increase swelling in hands, feet, ankles, face and eyelids; of the CPK. anaemia; muscle pain, tenderness and weakness (myalgia). Myalgia or musculoskeletal pain occurred Case 7: an elderly male patient with type 2 in 26% of patients in pivotal clinical studies diabetes, started therapy on 11 May with oral NP28761, NP28673 and BO28984=ALEX. Raised alectinib, 600 mg twice daily for NSCLC. CPK occurred in 41% of 347 patients, with CPK Concomitant medication included tamsulosin, laboratory data available in pivotal clinical studies finasteride, bisoprolol, pantoprazole, linagliptin, NP28761, NP28673 and ALEX. rosuvastatin calcium, folic acid, vitamin D, crizotinib, apixaban, magnesium and simvastatin. The EU SmPC1 published by EMA in 2017 mentions On an unknown date, he had rhabdomyolysis and safety data collected during drug development: was admitted to hospital. Therapy with alectinib was interrupted; the outcome of the Severe myalgia and creatine phosphokinase rhabdomyolysis was reported as unknown. (CPK) elevation: cases of myalgia (28%) Simultaneous treatment with two statins including myalgia events (22%) and (rosuvastatin calcium and simvastatin), known musculoskeletal pain (7.4%) have been potential causes of myopathy and rhabdomyolysis, reported in patients treated with alectinib was present in this ICSR, but the reporter did not across pivotal clinical trials (NP28761, consider statins as suspected for the ADR. By NP28673, BO28984=ALEX). contrast, in Case 6 in Table 1 the reporter also There is similar information on the US FDA and included rosuvastatin calcium as a suspected drug, Canada product labels:2,16 as well as alectinib. In conclusion, in this case, there could also have been a pharmacological Elevations of CPK occurred in 41% of 347 interaction due to a synergistic effect. patients with CPK laboratory data available across pivotal clinical trials (NP28761, A screening of VigiBase on 25 June 2019 using the NP28673, BO28984=ALEX) with alectinib. The MedDRA SMQ “Rhabdomyolysis/Myopathy - Narrow” incidence of grade 3 elevations of CPK was with alectinib found 13 ICSRs, of which eight were 4%. Median time to grade 3 CPK elevation those with rhabdomyolysis previously described was 14 days (interquartile range 13-28 days). (Table 1), and five other cases with MedDRA Dose modifications for elevation of CPK preferred terms (PTs) such as “myopathy” (four occurred in 3.2% of patients. cases) and “myoglobin blood increased” (one), plus several co-reported preferred terms, such as There is a warning about severe myalgia and “myalgia”, “blood CPK increased”, “asthenia”, increases in CPK: patients should be advised to “oedema peripheral”, “blood creatinine increased”, report any unexplained muscle pain, or muscle pain and so on. A search with the SMQ that does not go away, muscle tenderness or “Rhabdomyolysis/Myopathy - Broad” with alectinib weakness, as mentioned in the EU SmPC, US FDA 1, 2, 16 resulted in 258 ICSRs, with more PT related: and Canada product labels. CPK levels should myalgia, myositis, CPK increased, muscular be assessed every two weeks (14 days) for the first weakness, etc. month of treatment, and as clinically indicated in patients reporting symptoms. Based on the degree

WHO Pharmaceuticals Newsletter No. 4, 2020 • 20 Signal of the CPK increase, alectinib should be withheld, Mutation incidence and coincidence in non- then resumed or have the dose reduced. In the EU, small-cell lung cancer: meta-analyses by US, Canada product labelling, details are given on ethnicity and histology (mutMap). Ann Oncol. how to modify and reduce the dose according to 2013;24(9):2371-6. CPK elevations, and other serious ADRs (ALT/AST or 4. Gerber DE, Gandhi L, Costa DB. Management bilirubin elevations, bradycardia, renal impairment and future directions in non-small cell lung among other ADRs).1,2,16 cancer with known activating mutations. Am In the EU, US and Canada product labelling, there is Soc Clin Oncol Educ Book. 2014:e353-65. no information on pharmacological interactions with 5. Iacono D, Chiari R, Metro G, Bennati C, Bellezza medicines that could increase blood CPK or induce G, Cenci M, et al. Future options for ALK- rhabdomyolysis, such as statins.1,2,16 positive non-small cell lung cancer. Lung Cancer. 2015;87(3):211-9. Discussion and conclusion 6. Gómez JJ, de Castro J, Concha A, Felip E, Isla D, Lopez-Rioz F, et al. Recomendaciones para la Besides hepatotoxicity, myalgia and CPK increase determinación de biomarcadores en el are the next category of ADRs to be watchful for. carcinoma de pulmón no microcítico avanzado. Among available ALK inhibitors, this is unique to Consenso Nacional de la Sociedad Española de alectinib, and brigatinib to a lesser extent (43% Anatomía Patológica y de la Sociedad Española versus 30% respectively for CPK elevation of any de Oncología Médica. Rev Esp Patol. grade).12 As myalgia and CPK increase is not well 2012;45(1):14-28. recognized for patients, prior to treatment initiation, they need to be informed of potential symptoms 7. European Medicines Agency (EMA). Summary of such as muscle pain or weakness. As with hepatic Product Characteristics for crizotinib (Xalkori®). ADRs, CPK increase also has an early onset, with Available from: mean time to grade 3 increase (>5 × ULN) https://www.ema.europa.eu/en/documents/pro occurring at approximately day 14, so CPK levels duct-information/xalkori-epar-product- need to be monitored every two weeks for the first information_en.pdf. Accessed: 2019-06-25. month and then as often as clinically indicated. If 8. European Medicines Agency (EMA). Summary of severe myalgia or an increase in CPK occurs, it is Product Characteristics for ceritinib (Zykadia®). reasonable to withhold alectinib until it resolves to Available from: at least grade 1 in severity. https://www.ema.europa.eu/en/documents/pro Currently rhabdomyolysis is not described in the duct-information/zykadia-epar-product- labels for alectinib; only myalgia and increased CPK information_en.pdf. Accessed: 2019-06-25. are.1,2,16 However, the cases in VigiBase support an 9. US Food & Drug Administration. Xalkori®. association between alectinib and rhabdomyolysis, Prescribing Information. Revised: 03/2016. with six cases reporting alectinib as the only Available from: suspected drug, and with six cases reporting a https://www.accessdata.fda.gov/drugsatfda_do positive dechallenge, of which two also report a cs/label/2016/202570s016lbl.pdf. Accessed: positive rechallenge. In addition, the time-to-onset 2019-06-25. is consistent in the cases where this was provided (12-14 days). Current product information for 10. US Food & Drug Administration. Zykadia®. alectinib does not inform patients and health care Prescribing Information. Revised: 05/2017. providers about the potential interactions with Available from: statins and their synergistic effect on https://www.accessdata.fda.gov/drugsatfda_do rhabdomyolysis. cs/label/2017/205755s009lbl.pdf. Accessed: 2019-06-25.

11. CHMP European Public Assessment Report. References Alecensa®. 12 October 2017. 1. European Medicines Agency (EMA): Summary of EMA/CHMP/833519/2017. Available in: Product Characteristics for alectinib https://www.ema.europa.eu/en/documents/vari (Alecensa®). Available from: ation-report/alecensa-h-c-4164-ii-0001-epar- https://www.ema.europa.eu/en/documents/pro assessment-report_en.pdf. Accessed: 2019-06- duct-information/alecensa-epar-product- 25. information_en.pdf. Accessed: 2019-06-25. 12. Zhu V, Ou SH. Safety of alectinib for the 2. US Food & Drug Administration. Alecensa®. treatment of metastatic ALK-rearranged non- Prescribing Information. Revised: 06/2018. small cell lung cancer. Expert Opin Drug Saf. Available from: 2017;16(4):509-14. https://www.accessdata.fda.gov/drugsatfda_do 13. Costa RB, Costa RLB, Talamantes SM, Kaplan cs/label/2018/208434s004lbl.pdf. Accessed: JB, Bhave MA, Rademaker A, et al. Systematic 2019-06-25. review and meta-analysis of selected toxicities 3. Dearden S, Stevens J, Wu YL, Blowers D. of approved ALK inhibitors in metastatic non-

WHO Pharmaceuticals Newsletter No. 4, 2020 • 21 Signal

small cell lung cancer. Oncotarget. 2018 Apr aware. Curr Rheumatol Rep. 2010 24;9(31):22137-46. Jun;12(3):213–20. 14. Kassem L, Shohdy KS, Lasheen S, Abdel- 16. Canada Health. Alecensaro. Product Rahman O, Ali A, Abdel-Malek RR. Safety issues Monography. Revised: September 25, 2018. with the ALK inhibitors in the treatment of Available from: NSCLC: A systematic review. Crit Rev Oncol https://www.rochecanada.com/PMs/Alecensaro/ Hematol. 2019;134:56-64. Alecensaro_PM_E.pdf. Accessed: 2019-06-25. 15. Valiyil R, Christopher-Stine L. Drug-related myopathies of which the clinician should be

Response from Roche

First, we would like to thank you for the opportunity elevation at the time of the event. to review the signal report prepared by the Uppsala Concomitant medications include levetiracetam Monitoring Center (UMC) in which an association for which rhabdomyolysis, muscular weakness between alectinib and rhabdomyolysis is postulated. and CPK elevations are labeled events. Hence, there were elements lacking to confirm the Roche has been and is continuously monitoring diagnosis of rhabdomyolysis and an alternative events reported as rhabdomyolysis as part of its explanation available. standard signal detection process. To date, this monitoring has not rendered evidence that the Case 2 [Roche ID 1596813]: In this case the cases reported with the Preferred Term of patient reported muscle pain, a CPK increase ‘rhabdomyolysis’ are confirmed cases of drug- up to 16.42 µmol/L, that is 5.2 the ULN induced rhabdomyolysis which could be attributed (ULN<3.17 µmol/L), and creatinine increased to alectinib. at 132 µmol/L (ULN=106 µmol/L) at the time when the highest CPK level was reported, and As noted in the signal report prepared by the UMC, up to 152 µmol/L one month later, when CPK rhabdomyolysis is a serious medical emergency levels were back to normal. Serum myoglobin which can be life-threatening. Upon the review of was also increased at 127 µg/L. The reported the cases reported during clinical trials and from the events do not match the definition of post-marketing experience with alectinib, Roche has rhabdomyolysis as the maximum CPK increase observed cases of myalgia and of creatine reported remained below 10 time the ULN. In phosphokinase (CPK) increase but none with a addition, there was an alternative explanation degree of severity and elements required to confirm provided by the reporter since the patient did the diagnosis of rhabdomyolysis. For the strenuous physical exercise followed by pain assessment of the cases reporting the verbatim (he had cut a 50 meter long and 3 m high “rhabdomyolysis” in this comment document, a hedgerow by hand). case definition described by Holbrook et al (2011) was used. This considers the following 3 main Case 3 [Roche ID 1603916]: In this case the criteria to establish a case of rhabdomyolysis: patient reported many events among which CPK increase above 1500 UI/L, that is over 10 - Muscle symptoms (such as unexplained times the ULN (ULN=140), and elevated myalgia or muscle weakness) creatinine to a maximum of 1.9 mg/dL - Increase of CPK above 10000 U/L or above 10 (ULN=0.9). Myalgia or muscular weakness are times the upper limit of normal (ULN) [for the not described explicitly, but she reportedly had Health Canada definition; above 50 times ULN pain in the pelvis. These results could confirm for the US MedWatch definition] the diagnosis of rhabdomyolysis. However the - and renal involvement such as: rhabdomyolysis occurred in a context of life o serum creatinine elevation temporally threatening retroperitoneal bleeding and linked to CPK elevation impaired medical condition including brain o and/or myoglobinemia metastasis and cachexia. Concomitant o and/or myoglobinuria medications included mirtazapine for which o and/or brown urine rhabdomyolysis is a labeled event. Therefore, a o or renal compromise. causal role of alectinib is not confirmed in the presence of strong alternative explanations The eight cases retrieved and described by the UMC from the patient concurrent conditions and have been reviewed by Roche and assessments for concomitant medication. these cases are proposed in the paragraph below. Case 4 [Roche ID 2175246]: In this case the Case 1 [Roche ID 1492032]: In this case the patient reported myalgia, muscle weakness patient reported muscle pain and a CPK (‘grip strength decreased’) and CPK increase increase up to 1615 U/L, corresponding 8.5 without reported values. There was no renal time the ULN (ULN=190). There were no renal signs or symptoms and no creatinine elevation. signs or symptoms and there was no creatinine The reported elements are insufficient to

WHO Pharmaceuticals Newsletter No. 4, 2020 • 22 Signal

confirm a diagnosis of rhabdomyolysis. rhabdomyolysis is not confirmed. Case 5 [Roche ID 2252786]: In this case the Roche found that one (Case 3) of the eight cases patient reported none of the elements identified by the UMC matches the criteria for the pertaining to the rhabdomyolysis definition, diagnosis of rhabdomyolysis proposed by Holbrook therefore it is not possible to confirm the et al. with CPK increase above 10 times the ULN diagnosis due to insufficient information. and renal involvement. However, alternative explanations for the event were present in this Case 6 [Case not identified in Roche Safety case, therefore a causal relationship between the database]: As this case was not identified in rhabdomyolysis and alectinib is deemed to be not Roche safety database, an evaluation is not confirmed. While the criteria for the diagnosis of possible due to insufficient information; rhabdomyolysis are not met in the remaining however it is noted that a statin is reported as evaluable cases, the reported events of myalgia and a co-suspect medication and rhabdomyolysis is CPK elevation are adequately reflected as adverse a known adverse reaction with statins. drug reaction in the alectinib product labels, Case 7 [Roche ID 2171117]: In this case the including corresponding warning and precautionary patient reported extreme muscle weakness information, monitoring of CPK levels as well as and pleural effusion leading to hospitalization. dose interruption/reduction guidelines in case of Rhabdomyolysis is reported but without CPK CPK elevations > 5 times the ULN. values, and no renal involvement is reported.

In addition, and as noted by the UMC, a statin is reported as a concomitant medication. References Case 8 [Roche ID 2178566]: In this case the Holbrook A, Wright M, Sung M, Ribic C, Baker S. patient reported muscle pain and CPK increase Statin-associated rhabdomyolysis: is there a dose- at 3000 UI/L (no ULN reported). There was no response relationship? Canadian Journal of renal involvement reported, so a diagnosis of Cardiology. 2011 Mar 1;27(2):146-51.

Tocilizumab and Cutaneous Vasculitis

Prof Richard Day, Australia

Summary cutaneous vasculitis, although the standard of the 16 reports were generally poor. This potential Tocilizumab is a biological agent that inhibits adverse drug reaction, however, is not listed in the interleukin-6 that is indicated in rheumatoid drug label approved by FDA. arthritis, and recently, polymyalgia rheumatica and giant cell arteritis. Administration intravenously or subcutaneously leads to a rapid decline in C- Introduction reactive protein. The medicine is corticosteroid- sparing in polymyalgia and giant cell arteritis. Tocilizumab is one of an important group of Sixteen reports from VigiBase of cutaneous biological agents that have revolutionized the vasculitis, an inflammation of small blood vessels, treatment of rheumatoid arthritis. It is a fully the majority labelled as serious, occurred after a human monoclonal antibody that inhibits the median of 60 days treatment but with a wide range inflammatory cytokine, interleukin-6 (IL-6). IL-6 for time to onset. Reports were entered in VigiBase synthesis is driven by interleukin-1(IL-1) and from June 2012 until April 2019. Reactions were tumour necrosis factor-alpha, up-stream cytokines more prevalent in men and with higher dose rates that are also targets for inhibitory therapies, of 8 mg/kg monthly intravenously. Fifteen of these including IL-1 receptor antagonist (anakinra) and a cases were in patients with rheumatoid arthritis. A number of tumour necrosis factor inhibitor number of medicines taken in addition to recombinant proteins, including etanercept, tocilizumab were listed as ‘suspected’ contributors adalimumab, infliximab and golimumab. to the cutaneous vasculitis reaction, including other Tocilizumab also has an indication for juvenile biological medicines, namely tumour necrosis factor idiopathic arthritis, and more recently, polymyalgia inhibitors, abatacept, anakinra and leflunomide, all rheumatica (PMR)(1), and giant cell arteritis.(2) these in one case. Dechallenge was successful in six cases and rechallenge led to recurrence in the one Tocilizumab therapy is administered parenterally, subject re-exposed providing reasonable evidence either intravenously or subcutaneously (SC), and for an association between tocilizumab and results in rapid reduction of C-reactive protein

WHO Pharmaceuticals Newsletter No. 4, 2020 • 23 Signal

(CRP) concentrations, the preferred biomarker for patient would need to weigh 100 kg for a dose of at systemic inflammation. IL-6 promotes the least 400 mg if the dose rate was 4 mg/kg. In six production of CRP from the liver. Optimally, the subjects, the dose was not reported. Therefore, for drug is given with concomitant methotrexate in the 8 cases of 11 where the drug was delivered patients with rheumatoid arthritis (RA) or juvenile intravenously and the dose reported, seven of the idiopathic arthritis (JIA), since the combination is eight were given 8 mg/kg. There is divergence in more effective at slowing disease progression as the ‘label’ regarding the recommended dose of RA. manifest by joint bone erosions. In PMR, In some jurisdictions e.g. USA it is 4 mg/kg every 4 tocilizumab is corticosteroid-sparing, beneficial in weeks (or 162 mg SC every 2 weeks)(5) and in reducing the dose and duration related adverse others it is 8 mg/kg every 4 weeks (or 162 mg SC effects of corticosteroids, notably osteoporosis, type every week). The one case dosed with 4 mg/kg 2 diabetes mellitus, weight gain, muscle loss and came from the USA. sleep disturbance. Data on duration of therapy with tocilizumab until A number of cases of cutaneous vasculitis the onset of the vasculitis from the VigiBase reports associated with tocilizumab have now been is limited (6 of 16 case reports) and some reports reported, including reports submitted to only note ‘start’ and ‘stop’ months, not the day of VigiBase.(3) Cutaneous vasculitis is inflammation of the month, the reaction commenced. Median small blood vessels and is confined to the skin. duration of therapy was 161 days however in the Typically, it presents with palpable purpura and/or few cases (6) where ‘time to onset’ of reaction was petechiae, essentially small haemorrhages that recorded, the median was 60 days, but the range have formed small blood clots. However, it is also a was from 2 to 540 days. recognised manifestation of rheumatoid arthritis. Regarding medications preceding and/or during and/or immediately following the period of exposure to tocilizumab, some were suspected as Reports in VigiBase contributing to the vasculitis. There were three Sixteen cases of apparent cutaneous vasculitis have cases prescribed methotrexate, which was been reported in association with tocilizumab from suspected as contributing in one of these. In one the middle of June 2012 up until April 2019. The case rituximab, and in another, certolizumab, was cases were from nine countries (UK 4, USA 3, suspected, along with tocilizumab, as contributing. France 2, Japan 2 and one each from Germany, One patient had been taking sulfasalazine and Belgium, Slovakia, Hungary and Canada). Fifteen bucillamine but these were not suspected cases had a diagnosis of RA and there was one contributors to the vasculitis. One patient was person with JIA. There were 11 men and 5 women described as having ‘RA aggravated’ and ‘condition affected, an unexpected distribution given RA is aggravated’. This patient was treated (in order of more prevalent in women at around 75%.(4) administration) with etanercept, then adalimumab, Patients were aged 16 to 78 (median 63; n = 13). then abatacept, then tocilizumab, then anakinra, There were 13 of the 16 cases that were labelled then leflunomide and finally, tofacitinib. It is serious. Four were associated with prolonged uncertain if this patient’s cutaneous vasculitis hospitalization with one of these described as a life- occurred in relation to tocilizumab, as all of the threatening condition. One case was described as aforementioned drugs including leflunomide were disabling/incapacitating. Eight individual’s reactions recorded as suspected contributors. were labelled as ‘other’. Only two subjects were Glucocorticosteroids were noted as concomitant participants in clinical trials. One patient was medications for three patients, one given 1000 mg rechallenged with tocilizumab and the vasculitis methylprednisolone possibly for their cutaneous recurred. This person had also been exposed to vasculitis, another person, doses of oral prednisone rituximab, but ultimately this was not considered as ranging from 15 to 45 mg/day for the six months related to the vasculitis, an opinion in keeping with following cessation of tocilizumab, suggesting the result of the rechallenge. treatment for the cutaneous vasculitis and one a therapeutic dose for RA of prednisone 5 mg/day. A The quality of the reports as assessed by patient who had JIA and suspected tocilizumab ‘completeness scores’ were poor, range 0.2 to 0.9. caused vasculitis was taking cortisone that was Fourteen of the reports were submitted by listed as ‘suspected’ as a cause of the vasculitis. physicians. There were patchy reports of reactions, features or The drug was administered as an intravenous investigations accompanying the cutaneous infusion monthly or, with a more recent vasculitis. Complement C4 was noted as decreased formulation, via weekly or second weekly SC. Only in two patients and one of these also had reduced two of the reports indicated administration via the C3, thus suggesting immune complex aetiology. SC, the dose being 162 mg and these cases were The person with JIA exhibited splenomegaly, fever, reported recently (2017 and 2018). The reported Sweet’s syndrome (acute febrile neutrophilic doses of tocilizumab were 8 mg/kg (2 cases), 4 dermatosis) and Stevens-Johnson syndrome. In this mg/kg (1 case) and actual doses of 480 mg person, cutaneous vasculitis occurred while taking (female), 560 mg (male), 440 mg (female), 400 mg methotrexate and about 6 months later, tocilizumab (male) and 580 mg (male), these latter five likely to was commenced, and a rash was reported. Both be equivalent to 8mg/kg given that an individual WHO Pharmaceuticals Newsletter No. 4, 2020 • 24 Signal drugs were continued for about nine months. The ceased. Therefore, there is significant doubt that diagnoses of Sweet’s syndrome and Stevens- the presumed vasculitis was caused by tocilizumab Johnson syndrome occurred together, about the in this case. time both methotrexate and tocilizumab were

Table 1. Cases of cutaneous vasculitis associated with tocilizumab in VigiBase Case Age/ Seriousness Other suspected (S) or concomitant (C) drugs Time to Action drug Outcome Sex criteria* onset 1 70/M - Tocilizumab (S) - - Not recovered 2 67/M - Tocilizumab, rituximab (S) - Drug withdrawn/Reaction Recovered abated Rechallenge/Reaction recurred 3 -/F - Tocilizumab (S) - - Unknown 4 48/M Other Tocilizumab (S) 7 days Drug withdrawn/Reaction Recovering Folic acid, methotrexate, metoclopramide, naproxen, abated omeprazole, sildenafil, tramadol (C) 5 55/M Prolonged Tocilizumab (S) 18 months Drug withdrawn/Reaction Recovering hospitalization abated 6 63/F Other Tocilizumab, etanercept, adalimumab, abatacept, Drug withdrawn Unknown anakinra, leflunomide (S) Tofacitinib (C) 7 55/M Other Tocilizumab (S) - - Recovering 8 -/F Life threatening, Tocilizumab (S) - - Unknown prolonged Methylpresdnisolone (C) hospitalization 9 78/M Other Tocilizumab, certolizumab pegol (S) 2 days Drug withdrawn/Reaction Recovered abated 3.5 months after cessation of drug 10 16/F Prolonged Tocilizumab, methotrexate, cortisone (S) 10 months Drug withdrawn Unknown hospitalization 11 65/M Other Tocilizumab (S) 2 months Drug withdrawn/Reaction Recovering Sulfasalazine, bucillamine, isoniazid, prednisolone, abated omeprazole, celecoxib, nateglinide, alfacalcidol (C) 12 74/M Disabling, Tocilizumab (S) 2 months Drug withdrawn/Reaction Recovered incapacitating Methotrexate, folic acid, prednisolone, lansoprazole, abated metformin, acetylsalicylic acid, simvastatin, senna, furosemide, ramipril, doxazosin, bisoprolol, isosorbide monohydrate (C) 13 54/M Prolonged Tocilizumab (S) Drug withdrawn Unknown hospitalization Dihydrocodeine, paracetamol, omeprazole, nitrazepam, folic acid, diazepam (C) 14 67/M Other Tocilizumab (S) - - Recovering 15 52/F Other Tocilizumab (S) - - Recovered 16 -/M Other Tocilizumab (S) - - Recovered *Seriousness is classified in accordance with the criteria defined in the ICH E2A guideline

Literature and Labelling laboratory findings apart from an elevated CRP. The prednisone dose was increased and abatacept Sakaue et al reported the first case of commenced with good effect. There was no leukocytoclastic vasculitis in 2014.(3) There do not recurrence and no rechallenge with tocilizumab. appear to be further publications in the literature. Sakaue et al noted that the vasculitis in association The case described by Sakaue and colleagues was a with TNFI occurs on average around 30 weeks (210 Japanese woman aged 62 years with RA for 25 days) compared to the median of 8 weeks (60 years. Treatment with infliximab for five years was days) in the VigiBase cases. However, in Sakaue et followed with etanercept but control was not al’s case it was over five years and there were two achieved, and tocilizumab was commenced. The VigiBase cases occurring after one year’s initial dose was 8 mg/kg for one month, then 4 tocilizumab therapy. mg/kg along with prednisone 3 mg/day, and good control of her RA was achieved for five years. An The FDA label notes that serious hypersensitivity inflammatory disease flare along with palpable reactions, including anaphylaxis, have occurred with purpura on limbs and buttocks led to a skin biopsy tocilizumab but without further information. that showed leukocytoclastic vasculitis without IgA Cutaneous vasculitis is not listed as an adverse drug deposition, and not fulfilling criteria for Henoch- reaction.(5) Schönlein purpura. There were no other relevant

WHO Pharmaceuticals Newsletter No. 4, 2020 • 25 Signal

Discussion and Conclusion recommended range. Given the new indications of PMR and giant cell arteritis, prevalent and important Tocilizumab has been generally well tolerated. As conditions, in the light of these reports, vigilance is with other biologic medicines there is a risk of recommended. serious infections including reactivation of tuberculosis (TB), hepatitis B and C, and In summary, the review of the 16 cases reported in opportunistic infections including disseminated VigiBase provides good evidence that tocilizumab, fungal infections. Testing for latent TB and hepatitis like TNF inhibitor biological agents, is associated infection prior to commencement is mandatory. The with cutaneous vasculitis. The possible risk factors drug is associated with elevations of serum for the association are possibly male sex, duration cholesterol in adults. The label indicates that of exposure of many months and higher dose rates elevations of hepatic enzymes can occur, and namely 8 mg/kg monthly intravenously. The case recently a warning regarding liver failure, for a causal relationship between the drug and transplantation and deaths has been published by vasculitis is quite strong with six of 16 responding Canadian and US regulatory agencies, and other to ‘dechallenge’ and one patient subject to a agencies are considering their own responses. rechallenge manifesting the vasculitis again. Sakaue et al (2014) note that biologic agents used for inflammatory rheumatic conditions such as RA, References psoriasis and psoriatic arthritis have been associated with autoimmune adverse events, 1. Toussirot É, Martin A, Soubrier M, Redeker S, especially the tumour necrosis factor inhibitor Régent A. Rapid and Sustained Response to (TNFI) group of biologics. The most frequent Tocilizumab in Patients with Polymyalgia conditions reported have been SLE but vasculitis Rheumatica Resistant or Intolerant to and skin involvement in these conditions is Glucocorticoids: A Multicenter Open-label Study. common. The Journal of Rheumatology. 2016;43(1):249- 51. This series from VigiBase of 16 cases of associations between tocilizumab therapy, mainly for RA, and 2. Stone JH, Tuckwell K, Dimonaco S, Klearman M, cutaneous vasculitis add to only one in the Aringer M, Blockmans D, et al. Trial of literature. There is an unusual proportion of males Tocilizumab in Giant-Cell Arteritis. N Engl J Med. with RA in these cases. Regarding the strength of 2017;377(4):317-28. the association and possible causation, there is only one report with a rechallenge. In this case the 3. Sakaue S, Sumitomo S, Kubo K, Fujio K, vasculitis recurred, providing strong evidence of Yamamoto K. Tocilizumab-induced causality. Also, six of the cases responded positively leucocytoclastic vasculitis in a patient with to dechallenge, adding further strength to the case rheumatoid arthritis. Rheumatology (Oxford). for an association. The stated treatment duration 2014;53(8):1529-30. with tocilizumab had a median of 161 days, and 4. Rudan I, Sidhu S, Papana A, Meng S-J, Xin-Wei median time to onset of reaction in six of the cases Y, Wang W, et al. Prevalence of rheumatoid of 60 days, but both medians have a very wide arthritis in low- and middle-income countries: A range. This is quite long for drug-induced cutaneous systematic review and analysis. Journal of vasculitis that is often in the order of 7-14 days Global Health. 2015;5(1):010409-. until onset.(6) However, vasculitis induced by anti- TNF agents has been noted to occur after 30 weeks 5. US Food and Drug Administration: Product label exposure.(7) It has been suggested that the for tocilizumab (Actemra®). Available from: immunogenic stimulus for autoimmune reactions https://www.accessdata.fda.gov/drugsatfda_do such as vasculitis may be less for tocilizumab cs/label/2010/125276lbl.pdf. Accessed: 20 compared to TNF inhibitors.(3) January 2020. The doses of tocilizumab noted most commonly 6. Martinez-Taboada VM, Blanco R, Garcia-Fuentes were high, at 8 mg/kg. Some guidelines groups and M, Rodriguez-Valverde V. Clinical features and regulatory labels recommend 4 mg/kg monthly outcome of 95 patients with hypersensitivity (162 mg SC second weekly), stating that the lower vasculitis. Am J Med. 1997;102(2):186-91. dose rate is better tolerated without substantial 7. Ramos-Casals M, Roberto Perez A, Diaz-Lagares reduction in efficacy. C, Cuadrado MJ, Khamashta MA, Group BS. Unfortunately, there are no biopsy reports for any Autoimmune diseases induced by biological of the VigiBase cases. Although there are very few agents: a double-edged sword? Autoimmunity cases, there may be a predilection for males, the Reviews. 2010;9(3):188-93. elderly and dosing at the higher end of the

WHO Pharmaceuticals Newsletter No. 4, 2020 • 26 Signal

CAVEAT DOCUMENT

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

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

WHO Pharmaceuticals Newsletter No. 4, 2020 • 27 Feature

Recommendations from the 42nd Global Advisory Committee on Vaccine Safety (GACVS) meeting

The Global Advisory Committee on Vaccine Safety (GACVS) was established in 1999 to provide independent, authoritative, scientific advice to WHO on vaccine safety issues of global or regional concern. In view of the COVID 19 pandemic, the 42nd GACVS meeting was an extraordinary meeting that took place virtually on 27 to 28 May 2020 aimed at providing guidance to countries in preparation for the potential introduction of COVID- 19 vaccines. The objectives of the meeting were • to identify challenges that are specific to vaccine safety monitoring, particularly in low- and middle- income countries (LMICs); • to determine systems and capacity that would be required, particularly in LMICs, • to monitor, assess and manage known and unknown adverse events following immunization (AEFI) in the context of COVID-19 vaccines; • to review and provide recommendations on the elements of a pharmacovigilance (PV) preparedness workplan for LMICs ahead of COVID-19 vaccine roll-out; and • to review and provide recommendations on the proposed approach and roadmap for COVID-19 vaccine risk/benefit communication. GACVS discussed the COVID-19 vaccines in the pipeline and current lead candidates under consideration, potential adverse events of special interest (AESI) after COVID-19 vaccines, regulatory perspectives and approaches to prepare countries for AEFIs and AESI in the context of COVID-19 vaccine introduction. Also discussed were the application of standardized templates for risk/benefit assessment of vaccines, COVID-19 vaccine risk/benefit communication and infodemic management during COVID-19 response. Following the GACVS deliberations, following recommendations were made.1

Key recommendations • COVID-19 vaccine safety surveillance infrastructure and capacity should ideally be in place; existing infrastructures should be reactivated and actively engaged prior to vaccine introduction in all countries. • A working group of experts should be established to provide guidance to countries and regions on prerequisites for vaccine introduction. • Creation of a basic adverse events of special interest (AESI) list should be considered. Prioritization of AESI may be based on those identified in the COVID-19 clinical trials. • Available and newly generated Brighton Collaboration case definitions for AESI and tools to assess certainty of cases should be shared widely for countries to use and to be aligned. • A working group should be established to incorporate specific case definitions when Brighton Collaboration definitions do not exist for the prioritized AESI in the list; and that minimum institutional capacity is put in place in countries for their identification. • Countries should consider using a Delphi method in instances where case definitions are not available from the Brighton Collaboration. • WHO should work with national teams of Expanded Programme on Immunization in order to strengthen routine vaccine safety monitoring alongside COVID-19-related activities. • National regulators should review risk management plans obtained from vaccine developers and share with immunization programmes and other stakeholders in countries and incorporate them into their vaccine safety preparedness strategies at the time of vaccine introduction. • Developers should share available regional and international safety data including safety summaries with the reviewing regulatory authority. • Any review of the safety of new vaccines should be based on the appropriate Brighton Collaboration standardized templates for risk/benefit assessment of vaccines.

1 The full report is available in the Weekly Epidemiological Record (WER): https://apps.who.int/iris/bitstream/handle/10665/333136/WER9528-eng-fre.pdf?ua=1 WHO Pharmaceuticals Newsletter No. 4, 2020 • 28 Feature

• An ambitious, proactive plan for communicating vaccine safety is needed to assist Members States and relevant stakeholders before, during and after the COVID-19 vaccine’s introduction. It was observed that while social media comments are highly visible and may influence political decision-making, they do not necessarily influence individual behaviour. • The Communication approaches should clearly explain the difference between AESI and AEFI to relevant stakeholders.

WHO Pharmaceuticals Newsletter No. 4, 2020 • 29