2016 WHO Pharmaceuticals
No.6 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 across No country left behind: worldwide pharmacovigilance the world. It also provides signals based on information for safer medicines, safer patients derived from Individual Case Safety Reports (ICSRs)
available in the WHO Global ICSR database, VigiBase®. This newsletter includes two feature articles describing: The aim of the Newsletter is to the 40th meeting of the WHO International Working disseminate information on Group for Drug Statistics Methodology and the 39th the safety and efficacy of pharmaceutical products, Annual Meeting of Representatives of the National based on communications Pharmacovigilance Centres participating in the WHO received from our network of Programme for International Drug Monitoring. national pharmacovigilance centres and other sources such as The Safety and Vigilance team in WHO wishes all its specialized bulletins and journals, as well as partners in WHO. readers across the world a very healthy and prosperous year in 2017.
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, Contents World Health Organization, 1211 Geneva 27, Switzerland, E-mail address: [email protected] Regulatory matters This Newsletter is also available at: http://www.who.int/medicines Safety of medicines
Signal
Feature
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Table of Contents
Regulatory Matters Allopurinol ...... 5 Alogliptin containing products, teneligliptin and linagliptin ...... 5 Daptomycin ...... 5 Direct-acting antivirals for hepatitis C ...... 5 Famciclovir ...... 6 Formalin containing products ...... 6 Golimmab and certolizumab pegol ...... 6 HMG-CoA reductase inhibitors ...... 6 Interferon beta products ...... 7 Levetiracetam and methotrexate ...... 7 Lorazepam injection ...... 7 Nivolumab ...... 8 Olanzapine ...... 8 Peramivir ...... 8 Polaprezinc ...... 8 SGLT2 inhibitors ...... 9 Testosterone and other Anabolic Androgenic Steroids (AAS) ...... 9 Ustekinumab ...... 9 Warfarin and azole antifungal drugs ...... 10 Zoledronic acid ...... 10
Safety of Medicines Brimonidine gel ...... 11 Cervarix® ...... 11 Cobicistat containing products and corticosteroids primarily metabolised by CYP3A ...... 11 Direct-acting antivirals for hepatitis C ...... 12 Etoricoxib ...... 12 Havrix® ...... 12 Incretin-based therapies ...... 13 Levetiracetam ...... 13 Ondansetron ...... 13
WHO Pharmaceuticals Newsletter No. 6, 2016 3
Table of Contents
Signal Denosumab and lichen planus ...... 15 Denosumab and vasculitis ...... 19 Etanercept and injection site ulceration / injection site necrosis – characterization of an ADR ...... 23
Feature The 40th meeting of the WHO International Working Group for Drug Statistics Methodology, Geneva, 27–28 October 2016 ...... 27 The 39th Annual Meeting of Representatives of the National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring ...... 28
WHO Pharmaceuticals Newsletter No. 6, 2016 4
Regulatory Matters
Allopurinol risk of pemphigoid as a Direct-acting antivirals clinically significant adverse Risk of drug-induced reaction. for hepatitis C hypersensitivity syndrome These products are indicated Risk of hepatitis B for type 2 diabetes mellitus. Japan. The Ministry of Health, reactivation Labour and Welfare (MHLW) A total of seven pemphigoid USA. The US Food and Drug and the Pharmaceuticals and cases associated with alogliptin Administration (FDA) has Medical Devices Agency containing products, 14 cases requested that a boxed (PMDA) have announced that with teneligliptin and 15 cases warning about the risk of the package inserts for with linagliptin have been hepatitis B virus (HBV) allopurinol (Zyloric® and reported in Japan. Of these, a reactivation is added to the others) have been updated to causal relationship could not drug labels of direct-acting include the risk of drug- be excluded in two, seven and antivirals for hepatitis C induced hypersensitivity ten cases, respectively. (DDAs). This warning should syndrome (DIHS) as a clinically Reference: also be included in the patient significant adverse reaction. Revision of Precautions, information leaflets or Information on cases of DIHS MHLW/PMDA, 22 November medication guides for these related type 1 diabetes 2016 (www.pmda.go.jp/english/) medicines. mellitus (including fulminant type 1 diabetes mellitus) and DAAs are used to treat chronic ketoacidosis have also been hepatitis C virus (HCV) included. infection. Daptomycin Allopurinol is used for the The FDA identified 24 cases of management of Risk of acute generalized HBV reactivation from reports hyperuricaemia in patients exanthematous pustulosis submitted to the FDA and from with gout or in hypertensive the published literature in patients with hyperuricaemia. Japan. The MHLW and the HCV/HBV co-infected patients treated with DAAs from 22 A total of two cases associated PMDA have announced that the November, 2013 to 18 July, with type 1 diabetes mellitus package insert for daptomycin 2016. Of the cases reported, related to DIHS have been (Cubicin®) has been updated two patients died and one reported in Japan. Of these, a to include the risk of acute required a liver transplant. causal relationship could not generalized exanthematous HBV reactivation was not be excluded in one case. pustulosis as a clinically significant adverse reaction. In reported as an adverse event Reference: addition, the company core in the clinical trials submitted Revision of Precautions, datasheet has been updated. for the DAA approvals because MHLW/PMDA, 22 November patients with HBV co-infection 2016 (www.pmda.go.jp/english/) Daptomycin is an antibiotic were excluded from the trials. used to treat systemic and life- (See WHO Pharmaceuticals Newsletter threatening infections caused Health-care professionals are No.5, 2016: Serious cutaneous adverse by gram-positive organisms. recommended to screen all reactions and the role of genotyping in patients for evidence of current Singapore) A total of two cases associated or prior HBV infection before with acute generalized starting treatment with DAAs, exanthematous pustulosis and to monitor patients using have been reported in Japan. blood tests for HBV flare-ups Alogliptin containing Of these, a causal relationship or reactivation during could not be excluded in one treatment and post-treatment products, teneligliptin case. follow-up. and linagliptin Reference: Reference: Revision of Precautions, Drug Safety Communication, Risk of pemphigoid MHLW/PMDA, 18 October 2016 US FDA, 4 October 2016 (www.pmda.go.jp/english/) (www.fda.gov) Japan. The MHLW and the PMDA have announced that the (See WHO Pharmaceuticals Newsletter package inserts for alogliptin No.3, 2016: Risk of reactivation of hepatitis containing products (Nesina®, B virus in Japan) Liovel® and Inisync®), teneligliptin (Tenelia®) and linagliptin (Tradjenta®) have been updated to include the
WHO Pharmaceuticals Newsletter No. 6, 2016 5
Regulatory Matters
Famciclovir A total of two cases associated certolizumab pegol. These with shock or anaphylaxis have three patients improved when Risk of shock and been reported in Japan. Of they stopped using anaphylaxis these, a causal relationship certolizumab pegol. For the could not be excluded in one remaining two cases, either Japan. The MHLW and the case. there was insufficient information available to PMDA have announced that the Reference: establish a link with package insert for famciclovir Revision of Precautions, certolizumab pegol use or (Famvir®) has been updated MHLW/PMDA, 22 November there were other possible to include the risk of shock and 2016 (www.pmda.go.jp/english/) anaphylaxis as clinically explanations for liver significant adverse reactions. inflammation. Famciclovir is indicated for Health Canada’s review found a possible link between the risk herpes simplex and herpes Golimmab and zoster. of liver inflammation and the certolizumab pegol use of TNF alpha blockers. The A total of three cases Canadian product information associated with shock or Risk of inflammation of the for adalimumab, infliximab and anaphylaxis have been liver etanercept (Enbrel®) already reported in Japan. Of these, a states liver inflammation as a causal relationship could not Canada. Health Canada has very rare event that may lead be excluded in all cases. The updated the Canadian product to liver failure, but not for company core datasheet has information for golimmab golimmab and certolizumab also been revised. In addition, (Simponi®) and certolizumab pegol. cases associated with shock or pegol (Cimzia®) to include Reference: anaphylaxis are also reported information on available Summary Safety Review, in other countries. evidence regarding the risk of Health Canada, 25 October inflammation of the liver. Reference: 2016 (www.hc-sc.gc.ca) Revision of Precautions, Golimmab and certolizumab
MHLW/PMDA, 22 November pegol are Tumour Necrosis 2016 (www.pmda.go.jp/english/) Factor (TNF) alpha blockers used to treat inflammatory diseases such as rheumatoid HMG-CoA reductase arthritis, inflammatory bowel inhibitors Formalin containing disease (e.g. Crohn’s disease or ulcerative colitis) and Risk of immune-mediated products psoriasis. necrotizing myopathy Health Canada has reviewed Risk of shock and Japan. The MHLW and the the link between TNF alpha anaphylaxis PMDA have announced that the blockers and liver inflammation package inserts for HMG-CoA following publication of two Japan. The MHLW and the reductase inhibitors serious cases in the scientific PMDA have announced that the (fluvastatin, pravastatin, literature, in which patients package inserts for formalin simvastatin, atorvastatin, were treated with the TNF containing products used in pitavastatin, rosuvastatin) and alpha blockers, adalimumab dentistry have been updated to their combination preparations (Humira®) and infliximab include the risk of shock and have been updated to include (Remicade®). anaphylaxis as clinically the risk of immune-mediated significant adverse reactions. At the time of this review, five necrotizing myopathy as a The contraindication for serious cases of liver clinically significant adverse patients with a history of inflammation were reported reaction. hypersensitivity to the with certolizumab pegol, of HMG-CoA reductase inhibitors ingredients of these products which one case was reported in are indicated for has also been included. the Canada Vigilance database. hyperlipidaemia and familial There were no cases of liver Formalin containing products hypercholesterolaemia. are used for disinfection of inflammation reported with the infected root canals in use of golimmab. A total of three cases associated with immune- dentistry or sealing, pain relief, Of these five cases reported mediated necrotizing sedation and pulp capping in with certolizumab pegol three myopathy have been reported paediatric dentistry among cases were assessed to be in Japan. Of these, a causal others. potentially linked to relationship could not be WHO Pharmaceuticals Newsletter No. 6, 2016 6
Regulatory Matters excluded in two cases. The limited to make any methotrexate. The review of MHLW/PMDA have stated that conclusions. these reports was limited by cases of immune-mediated many factors such as pre- Health Canada's safety review necrotizing myopathy have existing diseases, other concluded that there was a also been reported overseas. medications taken, and lack of possible link between the use laboratory data (e.g. blood Reference: of interferon beta products for levels of methotrexate). Of Revision of Precautions, multiple sclerosis and the risk these 13 reports, five noted MHLW/PMDA, 18 October 2016 of developing pulmonary that patients who were taking (www.pmda.go.jp/english/) arterial hypertension. both levetiracetam and Reference: methotrexate at the same time Summary Safety Review, had greater amounts of Health Canada, 2 November methotrexate in their blood. 2016 (www.hc-sc.gc.ca) Interferon beta Health Canada's safety review products concluded that there is a potentially greater risk of Risk of pulmonary arterial adverse effects when hypertension Levetiracetam and levetiracetam and methotrexate are taken Canada. Health Canada has methotrexate together. updated the Canadian product Reference: safety information for Drug-drug interaction Summary Safety Review, interferon beta products (type Canada. Health Canada has Health Canada, 24 October 1a (Avonex® and Rebif®) and recommended that the product 2016 (www.hc-sc.gc.ca) type 1b (Betaseron® and information for levetiracetam Extavia®)) to include the risk and methotrexate products is of pulmonary arterial updated to provide information hypertension. about drug-drug interaction, Interferon beta products are which could lead to greater Lorazepam injection used to treat some forms of amounts of methotrexate in Risks of amnesia and multiple sclerosis, a disease of the blood. Product labelling the central nervous system. now recommends that blood apnoea methotrexate and Republic of Korea. The Health Canada reviewed a levetiracetam levels should be Ministry of Food and Drug possible link between the use carefully monitored in patients Safety (MFDS) has announced of interferon beta products for treated with the two drugs at that the package insert for treating multiple sclerosis and the same time. pulmonary arterial lorazepam injection has been hypertension. Levetiracetam is used to help revised to include amnesia and epilepsy treatment be more apnoea as adverse reactions. At the time of the review, effective. Methotrexate is used Lorazepam injection is used as there were two Canadian cases to treat cancer or to treat pre-anaesthetic medication, or of pulmonary arterial arthritis. hypertension that were treatment of anxiety before possibly related to interferon Health Canada carried out a examinations such as beta use, and in both cases, safety review after learning endoscopy, or in other anxiety the patients improved after that the European Medicines disorders which require treating the pulmonary arterial Agency (EMA) was looking into immediate drug action. hypertension and stopping a potential interaction between Through a review of adverse interferon beta use. levetiracetam and events reported in Korea methotrexate. Worldwide, there were 136 Adverse Event Reporting case reports of pulmonary At the time of the review, System (KAERS) from January arterial hypertension in there were no reported cases 1989 to June 2015, the MFDS patients who were using in the Canada Vigilance and the Korea Institute of Drug interferon beta (which includes Database of patients who had Safety and Risk Management the two Canadian cases). In 14 received levetiracetam and (KIDS) have identified a total cases, the pulmonary arterial methotrexate at the same time. of 11 cases associated with hypertension may have been amnesia and three cases The manufacturer of related to interferon beta use. associated with apnoea. levetiracetam provided 13 In the remaining cases, the international reports of a This recommendation information available was too potential interaction between announced by the MFDS was levetiracetam and based on a signal analysis WHO Pharmaceuticals Newsletter No. 6, 2016 7
Regulatory Matters evaluation process using For immune thrombocytopenic between the atypical adverse event reports. Reports purpura, a total of five cases antipsychotic and urinary for lorazepam injections and have been reported in Japan. retention. amnesia/apnoea were Of these, a causal relationship At the time of the review, identified to be statistically could not be excluded in three there were 1254 international significant compared to all the cases. reports of urinary retention other reports from other drugs. A total of six and four cases with the use of any of the Reference: have been reported for atypical antipsychotics. Based on the communication myocarditis and The risk of urinary retention is from MFDS and KIDS, Republic rhabdomyolysis, respectively. mentioned in the product of Korea, November 2016 Of these, a causal relationship safety information for most of could not be excluded in three (See WHO Pharmaceuticals Newsletter for a the atypical antipsychotics. and all cases, respectively. In related case in No.2, 2016: Flunitrazepam - However, the wording used to addition, the company core Precautionary measures for respiratory explain the risk of urinary datasheet has been updated. depression; and risk of apnoea, respiratory retention for the approved depression, and glossoptosis in Japan) Reference: drug olanzapine was not Revision of Precautions, consistent with the evidence MHLW/PMDA, 18 October 2016 reviewed. (www.pmda.go.jp/english/) Reference: Nivolumab Summary Safety Review, Risk of excessive Health Canada, 21 October 2016 (www.hc-sc.gc.ca) immunoreaction after Olanzapine discontinuation of treatment, immune Risk of urinary retention thrombocytopenic purpura, myocarditis and Canada. Health Canada has Peramivir rhabdomyolysis updated safety information for olanzapine to strengthen Risk of acute renal failure Japan. The MHLW and the warnings of the potential risk Japan. The MHLW and the PMDA have announced that the of urinary retention. The PMDA have announced that the package insert for nivolumab update is consistent with the package insert for peramivir (Opdivo®) has been updated safety information provided for (Rapiacta®) has been updated to include the risk of excessive the other atypical antipsychotic to include the risk of acute immunoreaction after products. renal failure as a clinically discontinuation of treatment as Olanzapine is used to treat significant adverse reaction. an important precaution; mental disorders including immune thrombocytopenic schizophrenia, bipolar disorder Peramivir is indicated for purpura, myocarditis and and in some cases, depression. influenza A or B virus infection. rhabdomyolysis as clinically A total of seven cases significant adverse reactions. Health Canada has carried out a safety review investigating associated with acute renal Nivolumab is indicated for: the potential risk of urinary failure have been reported in radically unresectable retention with the use of Japan. Of these, a causal malignant melanoma; atypical antipsychotics. relationship could not be unresectable, advanced, or excluded in two cases. relapsed non-small cell lung At the time of the review, Reference: cancer; and radically Health Canada had received 38 Revision of Precautions, unresectable or metastatic Canadian reports related to MHLW/PMDA, 18 October 2016 renal cell carcinoma. urinary retention and the use (www.pmda.go.jp/english/) of atypical antipsychotics. A total of 50 cases of excessive These reports, together with immunoreaction after information from published discontinuation of treatment literature indicate that most with nivolumab have been patients recovered or were Polaprezinc reported in Japan. Of these, a recovering from the adverse causal relationship could not effect after stopping the Risk of copper deficiency be excluded in 14 cases. The antipsychotic medication. In company core datasheet and some cases, urinary retention Japan. The MHLW and the foreign package inserts include re-occurred after the drug was PMDA have announced that the descriptions about such re-administered, further package inserts for polaprezinc adverse reactions. supporting a potential link (Promac® and others) have WHO Pharmaceuticals Newsletter No. 6, 2016 8
Regulatory Matters been updated to include the and an increased risk of bone association with risk of copper deficiency as a fracture occurring as early as testosterone/anabolic clinically significant adverse 12 weeks of being on androgenic (AAS) abuse. reaction. treatment with canagliflozin, Prescription testosterone but these adverse effects are Polaprezinc is indicated for products are approved as still rare. An increased risk of gastric ulcer. hormone replacement therapy bone fracture associated with for men who have low A total of nine cases associated the use of dapagliflozin was testosterone due to certain with copper deficiency have also noted in patients with medical conditions. been reported in Japan. Of kidney problems (moderate these, a causal relationship renal impairment). No The FDA received cases of could not be excluded in eight evidence of bone-related abuse and dependence with cases, however four of these adverse effects were found to serious outcomes such as: eight cases used the drug for a date with the use of heart attack, heart failure, condition that was outside of empagliflozin. stroke, depression, hostility, the approved indication. aggression, liver toxicity and Health Canada's safety review male infertility. Individuals Reference: concluded that the evidence abusing high doses of Revision of Precautions, supported a link between the testosterone have also MHLW/PMDA, 22 November risks of bone fracture and loss reported withdrawal symptoms 2016 (www.pmda.go.jp/english/) of bone mineral density with such as depression, fatigue, the use of canagliflozin. For irritability, loss of appetite, dapagliflozin, these risks were decreased libido and insomnia. only identified in patients who had kidney problems and this In addition to the new warning, SGLT2 inhibitors is already explained in the information on the importance safety information. No of measuring serum Risk of bone-related side evidence of bone-related testosterone concentration, if effects adverse effects were found to abuse is suspected, has been date with the use of added as a precaution. Canada. Health Canada has empagliflozin. updated the safety information Reference: for canagliflozin to include the Reference: Drug Safety Communication, risk of bone-related adverse Summary Safety Review, US FDA, 25 October 2016 effects. Health Canada, 14 November (www.fda.gov) 2016 (www.hc-sc.gc.ca) Sodium-glucose cotransporter-2 (SGLT2) inhibitors (See WHO Pharmaceuticals Newsletter (canagliflozin (Invokana®), No.5, 2015: Canagliflozin - Increased risk of dapagliflozin (Forxiga®), bone fractures and new information on risk of decreased bone mineral density in US) Ustekinumab empagliflozin (Jardiance®)) are drugs used to treat adults Risk of interstitial with type 2 diabetes. pneumonia Health Canada carried out a Testosterone and Japan. The MHLW and the safety review to evaluate the PMDA have announced that the risk of bone-related adverse other Anabolic package insert for effects with SGLT2 inhibitors. Androgenic Steroids ustekinumab (Stelara®) has The review was triggered been updated to include the following a notice of (AAS) risk of interstitial pneumonia international reports of bone- as a clinically significant related adverse effects Risks associated with abuse adverse reaction. experienced in patients taking and dependence the SGLT2 inhibitor Ustekinumab is indicated for canagliflozin. USA. The US FDA has psoriasis vulgaris and psoriatic approved label changes for all arthritis in patients with an At the time of the review prescription testosterone inadequate response to Health Canada had not products. The labels will conventional therapy. received any Canadian reports include a new warning which of loss of bone mineral density A total of 16 cases associated alerts prescribers to the abuse or broken bones related to the with interstitial pneumonia potential of testosterone and use of SGLT2 inhibitors. have been reported in Japan. the serious adverse outcomes, Of these, a causal relationship Recent medical studies have especially those related to could not be excluded in six found an increased risk of heart and mental health that cases. losing bone mineral density have been reported in WHO Pharmaceuticals Newsletter No. 6, 2016 9
Regulatory Matters
Reference: (INR) have been reported in Revision of Precautions, patients treated with warfarin
MHLW/PMDA, 18 October 2016 and other azole antifungal (www.pmda.go.jp/english/) drugs in Japan. Of these, a causal relationship could not
be excluded in two cases. Thus, MHLW/PMDA considered that caution is also required for Warfarin and azole concomitant administration of antifungal drugs warfarin and other azole antifungal drugs. Risk of bleeding due to Reference: drug-drug interaction Revision of Precautions, MHLW/PMDA, 18 October 2016 Japan. The MHLW and the (www.pmda.go.jp/english/) PMDA have announced that the package inserts for warfarin (See WHO Pharmaceuticals Newsletter and miconazole (Florid®) have No.4, 2016: Miconazole - Potential for been updated to include a serious drug-drug interactions with contraindication of warfarin in the United Kingdom) administering warfarin and miconazole concomitantly due to increased risk of bleeding. The package inserts for other Zoledronic acid antifungal drugs (voriconazole (Vfend® and generics), Risk of Fanconi syndrome itraconazole (Itrizole® and Japan. The MHLW and the generics), fluconazole PMDA have announced that the (Diflucan® and generics) and package inserts for zoledronic fosfluconazole (Prodif®)) have acid (Zometa®, Reclast® and also been updated to include others) have been updated to precautions about concomitant include the risk of Fanconi administration with warfarin. syndrome as a clinically Warfarin is used for treatment significant adverse reaction. and prevention of Zoledronic acid is indicated for thromboembolism. Miconazole, hypercalcaemia of malignancy, voriconazole, itraconazole, bone lesion associated with fluconazole and fosfluconazole multiple myeloma or bone are azole antifungal drugs. metastases from solid tumours A total of 41 cases associated and osteoporosis. with serious bleeding during A total of 11 cases associated concomitant administration or, with Fanconi syndrome have after discontinuation of been reported in Japan. Of concomitant administration of these, a causal relationship miconazole and warfarin have could not be excluded in seven been reported in Japan. Of cases. The company core these, a causal relationship datasheet has also been could not be excluded in 31 updated. cases (two of which occurred after treatment outside the Reference: approved dosage). Revision of Precautions, MHLW/PMDA, 22 November Due to the contraindication of 2016 (www.pmda.go.jp/english/) concomitant administration of miconazole and warfarin, the (See WHO Pharmaceuticals Newsletter use of other azole drugs, No.4, 2015: Risk of acute phase response and renal effects in New Zealand) including those recommended as first-line treatments is expected. A total of five cases of marked increase in prothrombin time (PT) - international normalized ratio WHO Pharmaceuticals Newsletter No. 6, 2016 10
Safety of Medicines
Brimonidine gel Cervarix® Cobicistat containing Risk of exacerbation of Potential risk of Guillain- products and rosacea Barré Syndrome: increased corticosteroids risk not identified The United Kingdom. The primarily metabolised Medicines and Healthcare Canada. Health Canada has by CYP3A Products Regulatory Agency reviewed the potential link (MHRA) has provided advice to between Cervarix® and Potential drug interaction: health-care professionals and Guillain-Barré Syndrome (GBS). increased risk of systemic patients on the application of corticosteroid effects brimonidine gel to decrease Cervarix® is a vaccine used to protect against infection by the the risk of exacerbation of Ireland. The Health Products rosacea. human papillomavirus (HPV) types 16 and 18 that cause Regulatory Authority (HPRA) Brimonidine is a topical gel cervical and anal cancer. has identified a potential indicated for the symptomatic interaction between cobicistat treatment of facial erythema of At the time of the review, containing products and rosacea in adults. there were no Canadian cases corticosteroids primarily of GBS reported following metabolised by CYP3A, which Brimonidine gel treatment vaccination with Cervarix®. could lead to an increase in should be started with a small systemic corticosteroid effects. amount of gel (less than the No cases of GBS were reported maximum dose) for at least in clinical trials prior to Cobicistat is a pharmacokinetic one week and the dose should marketing Cervarix®. After enhancer used as part of be increased gradually, based marketing, the manufacturer antiretroviral combination on tolerability and response to received 45 reports worldwide therapy in human treatment. of GBS from May 2007 until immunodeficiency virus-1 November 2015. Only 10 of (HIV-1) infected adults. Symptom exacerbation is these reports had signs and Cobicistat is a selective commonly reported in patients symptoms of GBS. However, it mechanism-based inhibitor of treated with brimonidine gel, was not possible to determine the cytochrome P450 enzyme and includes cases of rebound if there was a link between subfamily, CYP3A. Inhibition of effect after the therapeutic Cervarix® and GBS in these CYP3A-mediated metabolism effect wears off (approximately cases because not enough by cobicistat enhances the 8–12 hours after application). information was available for systemic exposure of CYP3A Cases in which exacerbation of assessment, or there were substrates. symptoms (particularly other possible causes of GBS. erythema and flushing) has The EMA’s Pharmacovigilance occurred during treatment The review did find that the Risk Assessment Committee soon after it was applied have number of cases of GBS (PRAC) has recently reviewed been reported. Across all reported following vaccination cases of adrenal suppression clinical studies, 16% of with Cervarix® is much lower and Cushing’s syndrome linked patients who were receiving than the number expected in with an interaction between brimonidine gel had symptom the general population. cobicistat containing products and corticosteroids that are exacerbation. Most patients Health Canada's review of all metabolised by CYP3A. recovered after stopping available information did not treatment. find an increased risk of GBS The HPRA has stated that co- Reference: following vaccination with administration of CYP3A Drug Safety Update, MHRA, Cervarix®. Health Canada will metabolised corticosteroids Volume 10, issue 4:1, continue to monitor the with cobicistat is not November 2016 adverse effect information recommended unless the (www.gov.uk/mhra) involving Cervarix® to identify potential benefit to the patient and assess potential harms. outweighs the risk, in which case patients should be
monitored for systemic Reference: corticosteroid effects. Summary Safety Review, Alternative corticosteroids Health Canada, 27 October which are less dependent on 2016 (www.hc-sc.gc.ca) CYP3A metabolism, e.g. beclomethasone for intranasal (See WHO Pharmaceuticals Newsletter No.6, 2012: Safety review shows balance of or inhalational use should be risks and benefits remains clearly positive in considered, particularly for the United Kingdom) long term use. WHO Pharmaceuticals Newsletter No. 6, 2016 11
Safety of Medicines
Reference: Etoricoxib Havrix® Drug Safety Newsletter, HPRA, October 2016 Reduced initial dose Potential risk of recommendation for thrombocytopenia: No risk rheumatoid arthritis and identified in review ankylosing spondylitis Direct-acting antivirals Canada. Health Canada has The United Kingdom. The reviewed a potential link for hepatitis C MHRA has recommended that between vaccination with the starting dose for treatment Havrix® and the development Interaction potential with of rheumatoid arthritis or of thrombocytopenia after warfarin and other vitamin ankylosing spondylitis with receiving a report of a patient K antagonists: changes to etoricoxib is reduced to 60 mg developing a low platelet count INR once daily, with the option to following vaccination with increase to a maximum of Havrix®. Ireland. The HPRA has issued 90 mg once daily if necessary. advice to health-care Havrix® is a vaccine used to professionals on monitoring Etoricoxib is indicated for the protect against hepatitis A the international normalised symptomatic relief of virus infection in people at risk ratio (INR) more closely in osteoarthritis, rheumatoid of coming into contact with the patients concurrently treated arthritis, ankylosing spondylitis, virus. and the pain and signs of with vitamin K antagonists. At the time of the review, one inflammation associated with case of thrombocytopenia Direct-acting antivirals for acute gouty arthritis. following vaccination with hepatitis C are used to treat Etoricoxib is also indicated for Havrix® had been reported to chronic hepatitis C virus (HCV) the short-term treatment of the Canada Vigilance Program infection. moderate pain associated with and three cases were also dental surgery. A signal of a potential drug reported to the Canadian interaction leading to a Following an EU-wide review in Adverse Events Following reduced INR has recently been 2008 of the benefits and risks Immunization Surveillance identified with co- of etoricoxib, the marketing System (CAEFISS). administration of direct-acting authorisation holder was No confirmed cases of antivirals and vitamin K required to conduct clinical thrombocytopenia were antagonists. The case reports trials to assess the efficacy and reported in clinical trials prior on which the signal was based safety of etoricoxib 60 mg to marketing of Havrix®. From were reviewed by the EMA’s once daily for the treatment of 1992 until 2015, the PRAC. The PRAC has rheumatoid arthritis and manufacturer received 99 recommended that the product ankylosing spondylitis international reports of information of direct-acting including comparison with thrombocytopenia. It was not antivirals should be updated to etoricoxib 90 mg. include a recommendation for possible to determine if there close monitoring of INR in From these trials, there is was a link between Havrix® patients treated with vitamin K evidence that the 60-mg dose and thrombocytopenia for antagonists, as liver function is effective in rheumatoid either the Canadian or may change during treatment arthritis and ankylosing international cases because: with direct-acting antivirals. spondylitis. However, for some the cases were either not patients, the 90-mg dose will confirmed as While no change in the be more efficacious, although thrombocytopenia; there were pharmacokinetics of warfarin is it is not possible to predict other possible causes of expected, close monitoring of which patients might benefit thrombocytopenia; or there INR is recommended with all from the higher dose. was not enough information vitamin K antagonists. provided for assessment. Reference: Reference: Drug Safety Update, MHRA, The number of cases of Drug Safety Newsletter, HPRA, Volume 10, issue 3:1, October thrombocytopenia following October 2016 2016 (www.gov.uk/mhra) vaccination with Havrix® reported internationally and in Canada is much lower than the number expected in the general population.
No association between the hepatitis A vaccine and
WHO Pharmaceuticals Newsletter No. 6, 2016 12
Safety of Medicines thrombocytopenia has been models have suggested that 10 ml syringe was used reported in the literature. the use of incretin-based instead of a 1 ml one, leading therapies may be linked to an to a 10-fold overdose), or Health Canada’s review did not increased risk of pancreatic because of a misunderstanding identify a link between cancer, results from clinical by the caregiver about how to vaccination with Havrix® and trials and many studies looking properly measure the dose. thrombocytopenia following a at the patterns, causes, and Levetiracetam overdose often review of the available data. effects of health and disease has no symptoms, but it may Health Canada will continue to conditions in people, do not cause sleepiness, agitation, monitor the adverse effect support this link. difficulty breathing and coma. information involving Havrix® to identify and assess potential Reference: Reference: harms. Summary Safety Review, Press release, EMA, 14 October Health Canada, 21 October 2016 (www.ema.europa.eu) Reference: 2016 (www.hc-sc.gc.ca) Summary Safety Review, Health Canada, 27 October (See WHO Pharmaceuticals Newsletters 2016 (www.hc-sc.gc.ca) No.3, 2013: Investigating findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes in EU and No.2, 2013: Ondansetron Reports of possible increased risk of pancreatitis and pre-cancerous findings of Assessing potential harm to the foetus: insufficient Incretin-based the pancreas in US) information therapies Canada. Health Canada is Risk of pancreatic cancer: working with the Drug Safety Not enough evidence Levetiracetam and Effectiveness Network to further investigate the extent Canada. Health Canada has Only to be used with dosing of ondansetron (Zofran®) use concluded in a review that syringe provided with during pregnancy and the risk there is not enough evidence package to avoid accidental to the foetus. Health Canada to confirm a link between overdose has requested that incretin-based therapies and manufacturers submit pancreatic cancer. EU. The EMA has information they may have recommended measures to regarding birth defects and use Incretin-based therapies ensure safe use of of ondansetron during (sitagliptin, saxagliptin, levetiracetam (Keppra® and pregnancy. linagliptin, alogliptin) are used generics) oral solution to avoid with or without other anti- medication errors and the risk Ondansetron is indicated for diabetic drugs along with diet of overdose. nausea and vomiting and exercise to improve blood associated with cancer sugar levels in adult patients Parents and carers should only treatment or surgery. It is not with type 2 diabetes. use the syringe provided with authorized in Canada to treat the package to measure the nausea and vomiting with During the last few years, a dose of levetiracetam. The ondansetron during pregnancy. small number of studies have packages and labels will be found a possible link between colour-coded to indicate the Health Canada carried out a the use of incretin-based volume of the bottle, the safety review to assess the risk therapies and an increased risk volume of the dosing syringe, of birth defects with the use of of pancreatic cancer. and the age range of the ondansetron. Worldwide, the number of case patient that the medicine At the time of the review, reports of pancreatic cancer should be used for. Health Canada had received 14 potentially linked to the use of reports of birth defects in the incretin-based therapies have Levetiracetam is a medicine for newborn babies of mothers been increasing steadily. This the treatment of epilepsy. treated with ondansetron. In led Health Canada to conduct a Cases of accidental overdose four of these reports, there review. At the time of the have been reported with was insufficient information on review, 15 cases of pancreatic levetiracetam oral solution; the the time of exposure of cancer that may have been majority of cases occurred in ondansetron during pregnancy. linked to the use of incretin- children aged between 6 In two other reports, based therapies had been months and 11 years. Most of ondansetron was given after reported to Health Canada. the cases occurred when the the organs of the fetus were Although some non-clinical medicine was used with an already developed. In the studies using animal or human incorrect dosing syringe (e.g. a remaining eight reports,
WHO Pharmaceuticals Newsletter No. 6, 2016 13
Safety of Medicines ondansetron was given to the mother at the stage the organs were developing. In these eight reports, a link between birth defects and ondansetron could not be ruled out. Information about the medical history of the mother, including additional medications she may have been taking, and exposure time were lacking. There were no patterns of birth defects. Findings from published scientific studies were inconsistent and inconclusive. There were concerns with study design, and the majority had a number of limitations such as use of concomitant medications.
The findings from animal studies have not established that ondansetron can cause birth defects. Available information were not sufficient to establish a link between the use of ondansetron during pregnancy and the risk of birth defects. Health Canada will continue to monitor safety information involving the use of ondansetron.
Reference: Summary Safety Review, Health Canada, 16 November
2016 (www.hc-sc.gc.ca)
WHO Pharmaceuticals Newsletter No. 6, 2016 14
Signal
A signal is defined by WHO as reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. A signal is a hypothesis together with data and arguments and it is important to note that a signal is not only uncertain but also preliminary in nature.
The signals in this Newsletter are based on information derived from individual case safety reports (ICSRs) available in VigiBase®, the WHO international database of suspected adverse drug reactions. The database contains over 14 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. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of Signal (page 26). 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. UMC’s vision is to improve worldwide patient safety and welfare by reducing the risk of medicines. For more information, 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].
Denosumab and lichen planus Dr Ian Boyd, Australia
Summary months, the concept of drug withdrawal is not meaningful. There appears to be a positive Denosumab is a human monoclonal antibody rechallenge in one case. It is possible that (IgG2) that targets and binds with high affinity denosumab may cause LP using a similar and specificity to the receptor activator of nuclear mechanism to that of TNF-α inhibitors. factor kappa-B ligand (RANKL), preventing activation of its receptor, RANK, on the surface of osteoclast precursors and osteoclasts. Prevention Introduction of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby Denosumab is a human monoclonal antibody decreasing bone resorption in cortical and (IgG2) that targets and binds with high affinity trabecular bone. Denosumab is indicated for the and specificity to the receptor activator of nuclear treatment of osteoporosis in postmenopausal factor kappa-B ligand (RANKL), preventing women and in men at increased risk of fractures, activation of its receptor, RANK, on the surface of and treatment of bone loss associated with osteoclast precursors and osteoclasts. Prevention hormone ablation in men with prostate cancer at of the RANKL/RANK interaction inhibits osteoclast increased risk of fractures. After the elimination of formation, function and survival, thereby suspected duplicates there are (as of 1 January decreasing bone resorption in cortical and 2016) 14 individual case safety reports in the trabecular bone. Denosumab is indicated for the WHO Global ICSR database, VigiBase®, of lichen treatment of osteoporosis in postmenopausal planus (LP) in association with denosumab. The women and in men at increased risk of fractures, reports are from Canada, Denmark, Greece, the and treatment of bone loss associated with Netherlands, Serbia, Switzerland, and the United hormone ablation in men with prostate cancer at States. Denosumab was the only drug suspected increased risk of fractures. The most common side in 12 of the 14 cases. The outcome of the LP was effects with denosumab (seen in more than one stated in six of the 14 reports. All six patients patient in ten) are musculoskeletal pain and pain were reported as recovered or recovering. In these in the extremity. Uncommon cases of cellulitis; patients, the drug was reported as withdrawn in rare cases of hypocalcaemia, hypersensitivity, four cases while the outcome of the drug was osteonecrosis of the jaw and atypical femoral unknown in the remaining two cases. fractures have been observed in patients taking denosumab.1 Case reports in VigiBase® suggest that there is a possible signal for the association of denosumab Lichen planus (LP) is a chronic mucocutaneous and LP. Time to onset is consistent with a drug disease that affects the skin, tongue, and oral induced effect. Dechallenge is generally supportive mucosa. The disease presents itself in the form of of a drug association but for a drug such as papules, lesions or rashes. The commonly affected denosumab, which is administered every six sites are near the wrist and the ankle. The cause WHO Pharmaceuticals Newsletter No. 6, 2016 15
Signal of LP is not known. While there are many theories antibiotics, arsenic, iodides, chloroquine, to explain LP, it is believed it can be classified as quinidine, phenothiazines, and diuretics.3,4 an autoimmune disease.2,3 Some LP-type rashes
(often referred to as lichenoid reactions) occur as adverse reactions to a variety of drugs including Reports in VigiBase® nonsteroidal anti-inflammatory drugs, anti- hypertensives such as angiotensin converting As of 1 January 2016 there are 18 individual case enzyme inhibitors and beta-blockers, tetracyclines, safety reports of LP in association with denosumab sulfonamides, penicillamine, allopurinol, gold, in the WHO Global ICSR database, VigiBase® (Table 1).
Table 1. Case overview of reports in VigiBase® of lichen planus in association with denosumab
Case Age/Sex Other suspected (S) or concomitant (C) drugs Reactions (WHO-ART preferred terms) Outcome 1 74/F Calcium, colecalciferol, lornoxicam, pantoprazole, panadol extra* (all C) Lichen planus, stomatitis aphthous, gastrointestinal Unknown disorder, oral pain 2 68/F Ascorbic acid/pyridoxine hydrochloride/biotin/tocopheryl acetate/folic acid/ Lichen planus, arthralgia, myalgia, rash Unknown cyanocobalamin/retinol/pantothenic acid/riboflavin/phytomenadione/ nicotinamide/ferrous fumarate/thiamine mononitrate/magnesium oxide/zinc oxide/cupric oxide/calcium/potassium chloride, calcium, ergocalciferol, fish oil (all C)
3 -/- None Lichen planus Unknown 4 64/F Alprazolam, amitriptyline, calcium, calcium carbonate, calcium citrate/ Lichen planus, anxiety, coughing, dysuria, headache, Unknown magnesium, fish oil, fluoxetine, guaifenesin, iron, levothyroxine, macrogol infection localised, insomnia, pain, pruritus, pruritus ani, rash, 3350, mometasone, sumatriptan, probiotic* (all C) macular rash, sinusitis, vaginal disorder, vaginal haemorrhage, vulvovaginal rash**
5 66/F None Lichen planus Unknown 6*** 78/F Adalimumab (S) Lichen planus aggravated, acanthosis, dermatitis, Recovering Acetylsalicylic acid, alfacalcidol, atorvastatin, calcium eczema, hyperkeratosis, keratosis, osteoporosis, rash carbonate/calcium lactate gluconate, cyanocobalamin (all C) psoriaform
7 66/F Rituximab (S) Lichen planus, anus discomfort, pruritus ani, vulva disorder Unknown 8 72/F Pantoprazole, propranolol, levothyroxine (all C) Lichen planus Recovered 9 71/F Amlodipine, atorvastatin, clopidogrel, diazepam, meclozine, Lichen planus, eczema, goitre, macule, rash pruritic, skin Unknown omeprazole, quinapril (all C) swelling, skin hyperpigmentation 10 85/F Lansoprazole (C) Lichen planus, abdominal pain, abscess genital female, abscess, Recovering alopecia, appetite lost, back pain, blisters, burning sensation, cystitis, depressed mood, dermatitis lichenoid, discomfort bodily, eye inflamed, erythema, heartburn, hiatus hernia, itching, nausea, oral pain, pain, popular rash, pruritus, rash, skin atrophy, skin exfoliation, skin nodule, urinary tract infection, vaginitis, vaginal itching, vulvovaginal discomfort, weight decrease, body height decreased**, oral disorder**
11*** -/F Adalimumab (S) Lichen planus, rash psoriaform, pruritus, urticaria Recovering Acetylsalicylic acid, alfacalcidol, atorvastatin, calcium, cyanocobalamin, etanercept, levothyroxine, perindopril (all C)
12 69/F Calcium carbonate, ergocalciferol (both C) Lichen planus, drug eruption Unknown 13*** 77/F Adalimumab (S) Lichen planus aggravated, itching, psoriasis, urticaria Recovering Acetylsalicylic acid, alfacalcidol, atorvastatin, calcium, cyanocobalamin, etanercept, levothyroxine, perindopril (all C)
14 65/F Calcium, ergocalciferol, levothyroxine, lorazepam, omeprazole (all C) Lichen planus, gum pain, skin reaction localised Recovering 15*** 78/F Adalimumab (S) Lichen planus aggravated, acanthosis, dermatitis, Recovering Acetylsalicylic acid, alfacalcidol, atorvastatin, calcium eczema, hyperkeratosis, keratosis, osteoporosis, rash carbonate/calcium lactate gluconate, cyanocobalamin (all C) psoriaform
16*** 78/F Adalimumab (S) Lichen planus aggravated, psoriasis Recovering Acetylsalicylic acid, alfacalcidol, atorvastatin, calcium carbonate/calcium lactate gluconate, cyanocobalamin (all C)
17 59/F None Lichen planus Recovering 18 86/F None Lichen planus Recovered
* Reported drug ** MedDRA term *** Cases 11, 13, 15 and 16 are suspected duplicates of case 6
WHO Pharmaceuticals Newsletter No. 6, 2016 16
Signal
After the elimination of four suspected duplicates, were co-suspected in the two remaining cases. the remaining 14 reports were submitted from the The product literature for these two drugs also do United States (8 reports), Canada, Denmark, not refer to LP.5,6 There is, however, a report in Greece, the Netherlands, Serbia and Switzerland the literature of two cases of LP-like eruptions (1 report each). The patients ranged in age from after infliximab and adalimumab therapy for 59 to 86 years with a median of 69 years in the 13 psoriasis. The authors noted that in addition, at reports which provided this information. There that time (2009), 11 cases of LP or lichenoid drug were 13 females and the gender was not stated in eruptions have been previously reported in the remaining report. patients taking tumour necrosis factor (TNF)-α inhibitors, in addition to several cases of Denosumab was the only drug suspected in 12 of psoriasiform eruptions with a lichenoid histology.7 the 14 cases. Adalimumab was an additional In a more recent report, a case of toxic epidermal suspected drug in one case and rituximab was an necrolysis treated with infliximab, which additional suspected drug in another case. subsequently triggered erosive LP involving the Concomitant drugs were reported in 10 of the 14 mouth and vulva was described. The authors cases and indicated a patient population with a noted that LP and lichenoid eruptions are an number of concomitant conditions indicated by the emerging side effect of TNF-α antagonists, with 14 use of calcium (6 patients), drugs for the cases reported to date. Seven cases were treatment of stomach acidity (5), vitamin D (4), associated with infliximab, with the others other vitamins and/or minerals (3), and drugs for attributed to etanercept, adalimumab and treatment of each of hypothyroidism and anxiety lenercept.8 There have been no reports in (3). Denosumab was reported to have been association with rituximab. administered subcutaneously, as expected, in all seven cases which provided the information. The Time to onset was reported in seven of the reports indication for use was stated in 11 reports and was and ranged from a few days to seven months after osteoporosis or postmenopausal osteoporosis in all the drug was administered with a median of about cases. Dosage was reported in seven cases and 3-4 weeks. This would appear consistent with a was 60 mg per six months in three reports, 60 mg drug induced effect. without the frequency mentioned in four reports, The outcome of the LP was stated in six of the 14 and two other reports specified one dosage form reports. All six patients were reported as per six months. recovered or recovering. In these patients, the Time to onset was reported in seven of the reports drug was reported as withdrawn in four cases and ranged from a few days to seven months after while the outcome of the drug was unknown in the the drug was administered with a median of about remaining two cases. For a drug that is injected 3-4 weeks. periodically, mostly every six months for denosumab, the effect of drug withdrawal or The outcome of the LP was stated in six of the 14 dechallenge is not meaningful. In one report (case reports. All six patients were reported as 6), the patient had pre-existing LP which was recovered or recovering. In these patients, the apparently aggravated by denosumab. In another drug was reported as withdrawn in four cases report (case 8), it is unclear whether the patient while the outcome of the drug was unknown in the had pre-existing LP but it was reported that LP remaining two cases. worsened after the first administration of Other reactions were reported in nine of the 14 denosumab, then recovered and then worsened cases. These included rashes in five cases, again after the second administration. This dermatitis, eczema or another skin condition in appears to be a positive rechallenge. four cases and pruritus in three cases. As indicated above, the cause of LP is not known and it is difficult to identify any patients in this case series who may be predisposed to LP. Literature and Labelling Lichenoid reactions, however, are known to occur The product literature does not refer to LP but it as adverse reactions to drugs and this appears notes that the skin reactions rash and eczema are likely in these cases. As noted above, TNF-α common and that cases of cellulitis have been inhibitors have been implicated in the induction of reported uncommonly.1 There are also no reports lichenoid reactions but because TNF-α has been of LP in association with denosumab in the medical implicated in the pathogenesis of LP, such literature. induction is somewhat unexpected. It has been suggested that TNF-α inhibition may precipitate lichenoid reactions through disruption of a delicate Discussion balance between TNF-α and interferon-α in susceptible patients.7 Another suggested Case reports in VigiBase® suggest that there is a hypothesis is that the inhibition of TNF-α allows possible signal for the association of denosumab upregulation of other precursor pro-inflammatory and LP. Denosumab was the only drug suspected cytokines, such as interferon-α, which causes in 12 of the 14 cases. Adalimumab and rituximab WHO Pharmaceuticals Newsletter No. 6, 2016 17
Signal activation of both T cells and dendritic cells.8 Since 8. Worsnop F, Wee J, Natkunarajah J, Moosa Y, RANKL is a member of the TNF superfamily, it is Marsden R. Reaction to biological drugs: possible that denosumab may cause LP through a infliximab for the treatment of toxic epidermal similar mechanism.9 necrolysis subsequently triggering erosive lichen planus. Clin Exp Dermatol. 2012
Dec;37(8):879-81. Conclusion 9. Gaur U, Aggarwal BB. Regulation of In summary, there are 14 reports associating LP proliferation, survival and apoptosis by with the use of denosumab. Denosumab was the members of the TNF superfamily. Biochem only drug suspected in 12 of the 14 reports. Time Pharmacol. 2003;66:1403-8. to onset is consistent with a drug induced effect. Dechallenge is generally supportive of a drug association but for a drug such as denosumab, which is administered every six months, the concept of drug withdrawal is not meaningful. Response from Amgen There appears to be a positive rechallenge in one Amgen acknowledges that cases of lichen planus case. It is possible that denosumab may cause LP have been reported. As part of ongoing using a similar mechanism to that of TNF-α inhibitors. pharmacovigilance activities, Amgen has previously conducted a comprehensive safety assessment to evaluate the risk of lichen planus References with the use of denosumab and reported the results in Periodic Benefit-Risk Evaluation 1. European Medicines Agency. Summary of Report/Periodic Safety Update Report Number 8. product characteristics for Prolia. Available For evaluation of this safety signal, Amgen from: http://www.ema.europa.eu/docs/ utilized a cumulative review of all study and non- en_GB/document_library/EPAR_-_Product_ study adverse event reports with denosumab as Information/human/001120/WC500093526.pdf. well as a review of the epidemiology data with Accessed: 3 February 2016. lichen planus, nonclinical data and controlled 2. American Academy of Dermatology. Lichen clinical trial data. Biological plausibility was also planus. Available from: http://www.aad.org/ assessed. Based upon the comprehensive review, public/diseases/ rashes/lichen-planus. no new safety risk was identified for lichen planus Accessed: 19 February 2016. with the use of denosumab. The Amgen 3. Medline Plus. Lichen planus. Available from: conclusion to close the signal lichen planus was http://www.nlm.nih.gov/medlineplus/ency/ endorsed by the Pharmacovigilance Risk article/000867.htm. Accessed: 19 February Assessment Committee (dated 10 April 2015). 2016. The benefit:risk profile of denosumab remains 4. Sugerman PB, Savage NW. Oral lichen favourable in the current approved indications planus: causes diagnosis and management. and the product label adequately reflects the Aust Dental J 2002;47:290-7. safety profile of Prolia. Amgen will continue to 5. Electronic Medicines Compendium. Summary monitor events of lichen planus through ongoing of Product Characteristics for Humira. routine pharmacovigilance activities. Available from: http://www.medicines.org.uk/ emc/medicine/21201. Accessed: 31 March 2016.
6. Electronic Medicines Compendium. Summary of Product Characteristics for Mabthera. Available from: http://www.medicines.org.uk/ emc/medicine/2570. Accessed: 31 March 2016. 7. Asarch A, Gottlieb AB, Lee J, Masterpol KS, Scheinman PL, Stadecker MJ, Massarotti EM, Bush ML. Lichen planus-like eruptions: an emerging side effect of tumor necrosis factor- α antagonists. JAAD 2009;61:104-11.
WHO Pharmaceuticals Newsletter No. 6, 2016 18
Signal
Denosumab and vasculitis Dr Ian Boyd, Australia
Summary treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures, Denosumab is a human monoclonal antibody and treatment of bone loss associated with (IgG2) that targets and binds with high affinity hormone ablation in men with prostate cancer at and specifi- city to the receptor activator of increased risk of fractures. The most common side nuclear factor kappa-B ligand (RANKL), preventing effects with denosumab (seen in more than one activation of its receptor, RANK, on the surface of patient in ten) are musculoskeletal pain and pain osteoclast precursors and osteoclasts. Prevention in the extremity. Uncommon cases of cellulitis; of the RANKL/RANK interaction inhibits osteoclast rare cases of hypocalcaemia, hypersensitivity, formation, function and survival, thereby osteonecrosis of the jaw and atypical femoral decreasing bone resorption in cortical and fractures have been observed in patients taking trabecular bone. Denosumab is indicated for the denosumab.1 treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures, Vasculitis comprises a heterogeneous group of and treatment of bone loss associated with inflammatory vascular lesions that can involve any hormone ablation in men with prostate cancer at kind of blood vessel, irrespective of its lumen or increased risk of fractures. After the elimination of location. Vasculitis gives rise to such conditions as duplicates there are (as of 1 January 2016) 30 ischaemia or thrombosis, which may cause serious individual case safety reports of vasculitis in organ damage and be life-threatening. Vasculitis is association with denosumab in VigiBase®, the a necrotizing inflammatory lesion of blood vessels, WHO Global ICSR database. The reports are from leading to their occlusion or disruption, with Argentina, Australia, France, Germany, Greece, clinical sequelae. The clinicopathological diagnosis Ireland, the Netherlands, Spain, Switzerland, the of vasculitis is supported by the demonstration of United Kingdom and the United States. elevated levels of acute-phase reactants Denosumab was the only drug suspected in 29 of (demonstrated by, for example, erythrocyte the 30 cases. The outcome of the vasculitis was sedimentation rate, differential blood count stated in 16 cases and the patients were reported showing thrombocytosis and leukocytosis, and C- as recovered or recovering in 10 cases, not reactiveprotein), high levels of rheumatoid factors recovered in five cases and in the remaining case, and cryoglobulins, hypocomplementaemia, the patient died unrelated to the adverse reaction. antinuclear antibodies (ANA), and anti-neutrophil cytoplasmic antibodies (ANCA) especially those Case reports in VigiBase® suggest that there is a ANCAs directed against proteinase 3 or possible signal for the association of denosumab myeloperoxidase.2 Hypersensitivity vasculitis is an and vasculitis. Time to onset is consistent with a acute form of this condition that is marked by drug induced effect. Dechallenge is not particularly inflammation or redness of the skin that occurs supportive of a drug association but for a drug when contact is made with an irritating substance. such as denosumab, which is administered every It is characterized by the appearance of red spots six months, the concept of drug withdrawal is not on the skin – most commonly, palpable purpura. meaningful. Although the patients in this case Palpable purpura are raised spots that are usually series had a number of concomitant conditions, red in color but may darken to a purple color. there is little in the reports to indicate any other However, there are many other types of rashes possible cause for vasculitis, other than the use of that can occur. Substances that can cause skin denosumab. It is possible that denosumab may inflammation include medications, infections or cause vasculitis using a similar mechanism to that any other foreign object which may induce an of TNF-α inhibitors. allergic reaction.3 Hypersensitivity vasculitis is usually represented histopathologically as leukocytoclastic vasculitis (LCV) which is a term Introduction commonly used to denote a small vessel vasculitis. Denosumab is a human monoclonal antibody Hypersensitivity vasculitis is thought to be (IgG2) that targets and binds with high affinity mediated by immune complex deposition. In this and specificity to the receptor activator of nuclear form of vasculitis, circulating antigens in the body factor kappa-B ligand (RANKL), preventing (produced by factors such as medications, activation of its receptor, RANK, on the surface of infections, and neoplasms) induce antibody osteoclast precursors and osteoclasts. Prevention formation. These antibodies bind to the circulating of the RANKL/RANK interaction inhibits osteoclast antigen and create immune complexes, which then formation, function and survival, thereby deposit within vessels, activating complement and decreasing bone resorption in cortical and inducing inflammatory mediators. Inflammatory trabecular bone. Denosumab is indicated for the mediators, adhesion molecules, and local factors may affect the endothelial cells and may play a WHO Pharmaceuticals Newsletter No. 6, 2016 19
Signal role in the manifestations of this disease.4 Time to onset was reported in only 11 of the Vasculitis and its consequences may be the reports and ranged from three days to nine primary or sole manifestation of a disease or months after the drug was administered with a alternatively, it may be a secondary component of median of about two months. Two cases reported another primary disease. Vasculitis may be onset after receiving the second dose – after one confined to a single organ, such as the skin, or it week and three months respectively. may simultaneously involve several organ The outcome of the vasculitis was stated in 16 of systems.5 the 30 reports. Ten of the patients were reported It should be noted that in WHO-ART, vasculitis is a as recovered or recovering, five were reported as preferred term with many included terms. not recovered and the remaining patient died, Vasculitis is also a high level term which apart unrelated to the reaction. In the 10 reports with from vasculitis includes the related preferred recovery, the drug was reported as withdrawn in terms arteritis, Churg Strauss syndrome, five cases, dose not changed in one case while the polyarteritis nodosa, Takayasu’s arteritis, and action taken with the drug was unknown in the Wegener’s granulomatosis. MedDRA is more remaining four cases. In the five reports without specific with vasculitis as a preferred term and recovery, the drug was reported as withdrawn in many of the terms which are included terms in two cases while the action taken with the drug was WHO-ART are preferred terms in the same high unknown in the remaining three cases. level term. Other reactions were reported in 20 of the 30 cases. These included skin reactions in 15 cases including rashes in seven cases. These are Reports in VigiBase® probably related to vasculitis. A variety of other As of 1 January 2016 there are 32 individual case reactions were reported including arthralgia or safety reports (ICSRs) of vasculitis in association similar reactions in four cases, malaise in four with denosumab in VigiBase®, the WHO Global cases and gait abnormal in three cases. ICSR database (Table 1). After the elimination of two suspected duplicates, the reports were submitted from the United States (16 reports), Literature and Labelling Australia, Germany, Switzerland and the United The product literature does not refer to vasculitis Kingdom (2 reports each), and Argentina, France, nor does it refer to any other vascular reactions. It Greece, Ireland, the Netherlands and Spain (1 notes that the skin reactions rash and eczema are report each). The patients ranged in age from 36 common and that cases of cellulitis have been to 93 years with a median of 74 years in the 26 reported uncommonly.1 There are also no reports reports which provided this information. There of vasculitis in association with denosumab in the were 28 females and two males. medical literature. Denosumab was the only drug suspected in all of the 30 cases except one. In this case, lercanidipine and sevelamer were also suspected. Concomitant Discussion drugs were reported in only 12 of the 30 cases and indicated a patient population with a number Case reports in VigiBase® suggest that there is a of concomitant conditions indicated by the use of possible signal for the association of denosumab vitamin D (7 patients), drugs for the treatment of and vasculitis. Denosumab was the only drug hypertension (5), stomach acidity (5) and calcium suspected in 29 of the 30 cases. Lercanidipine and (5), pain management (4), and drugs for sevelamer were co-suspected in the remaining case. The product literature for these two drugs do treatment of hypothyroidism, lipid management 6,7 and sleep disorders (2). Denosumab was reported not refer to vasculitis. to have been administered subcutaneously, as Time to onset was reported in only 10 of the expected, in all 11 cases which provided the reports and ranged from three days to nine information. The indication for use was stated in months after the drug was administered with a 24 reports and included osteoporosis or median of about two months. This would appear postmenopausal osteoporosis in 22 reports, consistent with a drug induced effect since drug- spondyloarthritis in one report and bone induced vasculitis is an immune mediated reaction metastases in one report. Dosage was reported in which would be expected to take weeks or months 16 cases and was 60 mg per six months in eight to develop. Indeed, one report in the literature has reports, 60 mg without the frequency mentioned noted that vasculitis in association with antithyroid in four reports, 60 mg per one month in one drugs had a time to onset with a range of 1 to 372 report, one dosage form per six months in two months (median: 42 months).8 reports and lastly 120 mg per four weeks in the case where bone metastases was the indication.
WHO Pharmaceuticals Newsletter No. 6, 2016 20
Signal
Table 1. Case overview of reports in VigiBase® of vasculitis in association with denosumab
Case Age/Sex Other suspected (S) or concomitant (C) drugs Reactions (WHO-ART preferred terms) Time to Outcome onset 1 36/M Calcium carbonate, vitamin D NOS, warfarin (all C) Vasculitis, medication error (off label use) - Unknown 2 78/F None Vasculitis, purpura, serum sickness, vomiting 6 months Recovered 3 77/F None Vasculitis 3 days Unknown 4 74/F Bisoprolol, colecalciferol, hydrochlorothiazide, Vasculitis 1.5-2.5 Not recovered levothyroxine, losartan, calcio* (all C) months 5 73/F None Vasculitis, eczema 3 months Recovered 6 78/F None Vasculitis, rash - Unknown 7 81/M None Vasculitis, cellulitis, rash pustular 3-4 months Recovered 8 -/F None Vasculitis - Not recovered 9 83/F Enalapril maleate/lercanidipine hydrochloride, Vasculitis, bullous eruption, rash pustular - Not recovered omeprazole, alfacalcidol* (all C) 10 93/F None Vasculitis, asthenia, cheilitis, choking, face oedema, malaise, - Unknown pruritus, somnolence, transient ischaemic attack 11 71/F Bromazepam, clopidogrel, fentanyl, levothyroxine, Vasculitis 9 months Not recovered morphine, nicorandil, pantoprazole, paracetamol, phloroglucinol/trimethylphloroglucinol, pregabalin, propofol, propranolol (all C) 12 69/F None Vasculitis, skeletal pain - Unknown 13 -/F None Vasculitis - Unknown 14 -/F None Vasculitis, auto-antibody response, pulmonary disorder, renal - Unknown failure acute 15 69/F None Vasculitis, malaise, oedema, paraesthesia, rash, adverse drug - Unknown reaction** 16*** 79/F Lercanidipine, sevelamer (both S) Vasculitis, alopecia, cardiac arrest, condition aggravated, 3 days Died – unrelated to Ace inhibitors, allopurinol, atenolol, colecalciferol, hyperparathyroidism, hypocalcaemia, hypophosphataemia, reaction gemfibrozil, nicorandil, omeprazole, perhexiline (all C) pruritus, skin exfoliation 17 81/F Colecalciferol/calcium carbonate, hydrochlorothiazide/ Vasculitis, allergy, diverticulitis, purpura, skin discolouration - Unknown amiloride hydrochloride, omeprazole, plantago ovata, ranelic acid, tramadol, zoledronic acid, calcio* (all C) 18 55/F Capecitabine, megestrol, morphine, paracetamol (all Vasculitis, gait abnormal, hypokinesia - Recovering C) 19 64/F None Vasculitis, arthralgia, pain - Unknown 20 71/F None Vasculitis, allergy, confusion, malaise, skin nodule - Recovered 21 81/F None Vasculitis, abdominal pain, faeces discoloured, faecal Within 2 Recovered incontinence, gait abnormal, hyperpyrexia, inflammation weeks localized, limb pain, lymphangitis, musculoskeletal disorder, oedema, rash erythematous, urinary incontinence, vascular disorder, vision abnormal 22 -/F None Vasculitis 10 days Recovering 23 88/F Gabapentin (C) Vasculitis, micturition frequency, neuralgia, oedema peripheral, skin - Unknown disorder, sleep disorder, cerumen impaction** 24 74/F Atorvastatin, calcium, cetirizine, dexlansoprazole, Vasculitis, anaemia, hypocalcaemia, immune system disorder, 15 weeks Not recovered ergocalciferol, hydrochlorothiazide/valsartan, ranitidine, infection bacterial, infection viral, neutropenia, pulmonary oedema vitamins NOS, zolpidem (all C) and 33 other reactions 25 68/F Sulindac (C) Vasculitis - Unknown 26 88/F Metoprolol, tramadol, zolpidem (all C) Vasculitis 1 month Recovered 27 73/F Ergocalciferol, hydrochlorothiazide (both C) Vasculitis, angina pectoris, arthralgia, avascular necrosis bone, - Recovered cystitis, gait abnormal, oedema peripheral, pharyngitis, pneumonia, rash, skeletal pain, upper respiratory tract infection, weight increase, bed rest**, wheelchair user** 28 67/F None Vasculitis, abdominal pain, chest pain, dyspnoea, rash - Unknown 29 76/F None Vasculitis, malaise, muscle injury - Unknown 30 61/F None Vasculitis - Recovering 31*** 79/F Sevelamer (S) Vasculitis, alopecia, cellulitis, hyperparathyroidism, - Died – unrelated to Allopurinol, atenolol, colecalciferol, gemfibrozil, hypocalcaemia, hypophosphataemia, oedema peripheral, ulcer** reaction lercanidipine, nicorandil, omeprazole (all C) 32*** 79/F None Vasculitis, alopecia, haemorrhage NOS, oedema, rash - Unknown erythematous, skin exfoliation, ulcer**, secretion discharge**
NOS = Not otherwise specified * Reported drug ** MedDRA term *** Cases 16, 31 and 32 are suspected duplicates
WHO Pharmaceuticals Newsletter No. 6, 2016 21
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In this case series, the underlying time to onset References may be 3 to 6 months and those patients who 1. European Medicines Agency. Summary of experienced a quick reaction have possibly product characteristics for Prolia. Available received the drug or a similar one before and from: http://www. ema.europa.eu/docs/ those patients who reacted after the second dose en_GB/document_library/EPAR_-_Product_ are following a similar pattern. Information/human/001120/WC500093526.pdf. The outcome of the vasculitis was stated in 16 Accessed: 3 February 2016. reports. In the 10 cases with recovery, the drug 2. The Council for International Organizations of was reported as withdrawn in five cases and in the Medical Sciences (CIOMS). Reporting Adverse six cases without recovery, the drug was reported Drug Reactions: Definitions of Terms and as withdrawn in two cases. For a drug that is Criteria for their Use. CIOMS, Geneva, 1999. injected periodically though, mostly every six Available from: http://www.cioms.ch/ months for denosumab, the effect of drug publications/reporting_adverse_drug.pdf. withdrawal or dechallenge is not meaningful. Accessed: 3 February 2016. Major causes of vasculitis include infections such 3. Wint C, Spriggs BB. Healthline: hypersensitivity as hepatitis B and hepatitis C, blood cancers, vasculitis. Available from: http://www. immune system diseases such as rheumatoid healthline.com/health/allergic-vasculitis#Overview1. arthritis, lupus and scleroderma and reactions to Accessed: 3 February 2016. 9 drugs. Although the patients in this case series 4. Patel M, Callen JP, Vleugels RA, Wells MJ, Miller had a number of concomitant conditions only one JJ, James WD. Medscape: hypersensitivity patient was reported with one of these conditions, vasculitis. Available from: http://emedicine. rheumatoid arthritis in case 25. Vasculitis can be medscape.com/article/1083719-overview#a5. confirmed by biopsy. Only two of the cases Accessed: 3 February 2016. reported biopsy-proven vasculitis while in two 5. Longo DL, Fauci AS, Kasper DL, Hauser SL, cases, biopsies appeared to be negative. In two Jameson JL, Loscalzo J, eds. Harrison’s other cases, there was evidence for a different Principles of Internal Medicine, 18th ed. diagnosis so it is possible that not all 30 cases McGraw Hill, New York, 2011. describe vasculitis. 6. Electronic Medicines Compendium. Summary of There have been reports of vasculitis in association Product Characteristics for Zanidip. Available 10,11 with tumour necrosis factor (TNF)-α inhibitors. from: http://www.medicines.org.uk/emc/ In one of these reports, the authors suggested a medicine/17624. Accessed: 15 February 2016. relationship between the introduction of therapy 7. Electronic Medicines Compendium. Summary of with TNF-α inhibitors and anti-drug antibody Product Characteristics for Renvela. Available production. The resulting immune complexes and from: http://www.medicines.org.uk/emc/ recruitment of inflammatory mediators may lead medicine/22781. Accessed: 15 February 2016. to cutaneous vasculitis.10 In another report, the authors documented 8. Noh JH, Yasuda S, Sato S, Matsumoto M, Kunii Y, Noguchi Y et al. Clinical characteristics of 233 cases of autoimmune disease associated with myeloperoxidase antineutrophil cytoplasmic 11 TNF-α inhibitors including 113 cases of vasculitis. antibody-associated vasculitis caused by Since RANKL is a member of the TNF superfamily, antithyroid drugs. J Clin Endocrinol Metab. it is possible that denosumab may cause vasculitis 2009;94:2806-11. through a similar mechanism.12 9. Mayo Clinic. Vasculitis. Available from: http://www.mayoclinic.org/diseases-conditions/ vasculitis/basics/causes/con-20026049. Conclusion Accessed: 3 February 2016. In summary, there are 30 reports associating 10. McCain ME, Quinet RJ, Davis WE. Etanercept vasculitis with the use of denosumab. Denosumab and infliximab associated with cutaneous was the only drug suspected in 29 of the 30 vasculitis. Rheumatology 2002;41:116-7. reports. Time to onset is consistent with a drug 11. Ramos-Casals M, Brito-Zeron P, Munoz S, Soria induced effect. Dechallenge is not particularly N, Galiana D, Bertolaccini L, Cuadrado M-J, supportive of a drug association but for a drug Khamashta MA. Autoimmune diseases induced such as denosumab which is administered every by TNF targeted therapies. Medicine six months, the concept of drug withdrawal is not 2007;86:242-51. meaningful. Although the patients in this case series had considerable morbidity, there is little in 12. Gaur U, Aggarwal BB. Regulation of the reports to indicate any other possible cause for proliferation, survival and apoptosis by vasculitis. It is possible that denosumab may members of the TNF superfamily. Biochem cause vasculitis using a similar mechanism to that Pharmacol. 2003;66:1403-8. of TNF-α inhibitors.
WHO Pharmaceuticals Newsletter No. 6, 2016 22
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Response from Amgen and controlled clinical trial data with denosumab. Biological plausibility was also assessed. Based on Amgen acknowledges that cases of vasculitis have this comprehensive review, no new safety risk was been reported. Based on a request from the identified for vasculitis in association with the use Pharmacovigilance Risk Assessment Committee of denosumab. The Amgen conclusions to close (PRAC), Amgen has performed a comprehensive the signal vasculitis was endorsed by the PRAC safety assessment to evaluate the risk of vasculitis with no additional analyses required (dated 10 events with the use of denosumab and reported in April 2014). The benefit:risk profile of denosumab Periodic Benefit-Risk Evaluation Report/Periodic remains favourable in the current approved Safety Update Report 7. For evaluation of this indications and the product label adequately safety signal, Amgen utilized a cumulative review reflects the safety profile of Prolia. Amgen will of all study and non-study adverse event reports continue to monitor events of vasculitis with with denosumab as well as a review of the denosumab through ongoing routine epidemiology data of vasculitis, nonclinical data pharmacovigilance activities.
Etanercept and injection site ulceration / injection site necrosis – characterization of an ADR Ms Marilina Castellano, Uppsala Monitoring Centre
The combination of injection site ulceration and for the PT injection site vesicles. The 31 reports etanercept was highlighted in VigiBase®, the WHO originate from the United States, the United international database of suspected adverse drug Kingdom and Colombia. The majority of these reactions. This analysis focused on the WHO-ART patients were receiving treatment for rheumatoid preferred term (PT) ‘injection site ulceration’ and arthritis; psoriatic arthropathy and psoriasis were was then extended to the adjacent PT ‘injection other reported indications. Among the co-reported site necrosis’, as they are a related phenomenon. terms were rash and pain. Seven cases described Etanercept is a recombinant receptor inhibitor for systemic symptoms such as oedema generalized, the Tumour Necrosis Factor and it is indicated as influenza like symptoms or nausea. Two cases co- an immunomodulator for the treatment of both reported injection technique errors and two primary and secondary arthritis in adults.1 injection site infections. One third of the cases Etanercept injection site reactions are well provided additional details where the reaction was documented and characterised2; they are usually described as manifesting with nodules, welts or mild, including bleeding, bruising, erythema, vesicles. In particular, one patient developed itching, pain or swelling, and injection site extensive erythema covered in small open sores ulcerations are not mentioned; these reactions and another experienced multiple ulcers that usually occur within one month but recall injection developed between calves and ankles at both legs. site reactions can also occur at the most recent Reactions manifested from one week to five years site of injection. In addition, serious skin reactions after therapy was started where this information such as cutaneous vasculitis are also mentioned in was provided, occurring within one month in the the product information.1 In general, injection site majority of cases. In six of these cases, the event ulcerations can be due to either an improper occurred shortly or within two days after the injection technique that may result in infection and injection was given, with one patient experiencing consequently to ulceration or to the drug itself via the event after each injection. Etanercept was the different mechanisms. As an example, only suspected drug in all cases save one where immunomodulators injected intramuscularly have infliximab was also suspected. Two cases are been reported as causing necrotizing vasculitis.3 unlikely to be related to etanercept, as in one the Serious skin reactions at the injection site reaction occurred at a shingle vaccine injection represent a complication that may lead to therapy site, and in the other the reaction occurred before discontinuation: this notice aims to report cases of the therapy was started. injection site ulceration and to characterize more In the light of the ability of this medication to accurately etanercept-induced injection site cause vasculitis1, together with the predisposition reactions. of the underlying disease4, detailed information As of January 2016, there are 29 reports for the provided by the original reports for this PT injection site ulceration in VigiBase® and two combination are consistent with manifestations of more reports for the PT injection site necrosis. A cutaneous vasculitis.5 These findings would widened search in VigiBase® revealed 444 reports therefore strengthen the hypothesis that
WHO Pharmaceuticals Newsletter No. 6, 2016 23
Signal etanercept induced injection site reactions are 0.02% of events of ISRs reported from clinical immune-mediated.2 On the other hand, for the trials are considered to be serious adverse events. cases where either a wrong injection technique or A cumulative search of Pfizer’s safety database up local infection were reported, the likely explanation to 18 April 2016 for the Medical Dictionary for is that poor technique could have led first to Regulatory Activities (MedDRA) Preferred Terms infection and then to ulceration. As these patients (PTs) Injection site ulcer and Injection site are all adults, they are likely to self-inject the necrosis identified 39 and 7 cases, respectively. drug; more efforts should be put into providing These 46 cases represent less than 0.04% of all patients with training. cases of ISRs reported to Pfizer. Of these, 13 cases were reported as serious, representing less than 0.15% of all reported serious cases of ISRs. References Pfizer expects, but cannot confirm, that there is 1. Electronic Medicines Compendium. Summary of significant overlap with the 31 cases retrieved for Product Characteristics for etanercept the search of the same PTs performed by the UMC (Enbrel®). Available from: https://www. in VigiBase® (WHO Global ICSR database). The medicines.org.uk/emc/medicine/19162. majority of cases in Pfizer’s safety database were Accessed: 13 January 2016. reported from the United States, with 1 case from 2. Batycka-Baran A, Flaig M, Molin S, Ruzicka T, the United Kingdom, and no cases reported from Prinz JC. Etanercept-induced injection site Colombia. Additional countries reporting cases to reactions: potential pathomechanisms and Pfizer include Argentina, Brazil, France, Japan, the clinical assessment. Expert Opin Drug Saf. Netherlands, Spain, and Switzerland. A review of 2012 Nov;11(6):911-21. these cases showed minimal relevant information including lack of information on diagnosis, 3. Shai A, Maibach HI. Wound healing and ulcers treatment, concomitant medications, and of the skin diagnosis and therapy: The practical descriptive information regarding the approach. Berlin, Heidelberg: Springer-Verlag manifestations of the ISRs. The review did not Berlin Heidelberg; 2005. Available from: reveal any cases which described suspected or http://public.eblib.com/choice/ confirmed cutaneous vasculitis. publicfullrecord.aspx?p=30914. Accessed: 13 January 2016. Pfizer is of the view that the causes of serious 4. Xue Y, Cohen JM, Wright NA, Merola JF. Skin ISRs are likely multifactorial. Hypersensitivity, signs of rheumatoid arthritis and its therapy- infection due to improper injection technique or induced cutaneous side effects. Am J Clin device failure, and cutaneous vasculitis have been Dermatol. 2016 Apr;17(2):147-62. described as potential causes. A small study that assessed biopsy data from etanercept-associated 5. Panuncialman J, Falanga V. Unusual causes of ISRs suggested T-lymphocyte mediated delayed cutaneous ulceration. Surg Clin North Am. 2010 type hypersensitivity reactions, with eventual Dec;90(6):1161-80 induction of tolerance, as a possible mechanism of action.2 While cutaneous vasculitis is listed as a rare (≥ 1/10,000 to < 1/1,000) adverse reaction
for etanercept,1 the currently available evidence in Pfizer’s safety database does not suggest that events reported as injection site ulceration or Response from Pfizer injection site necrosis are due to cutaneous The Uppsala Monitoring Centre (UMC) invited vasculitis. Pfizer, as the Marketing Authorization Holder Pfizer strongly agrees that patient training in the (MAH) for etanercept (Enbrel®) in Europe, to use of proper injection technique to prevent comment on a proposed communication from the infections that could lead to serious ISRs is very UMC regarding a signal of injection site ulceration/ important. To this end, Pfizer maintains extensive injection site necrosis in patients treated with region-specific educational programs, which differ etanercept. according to individual market requirements. Pfizer agrees with the UMC that injection site These programs for patients and health-care reactions (ISRs) are well characterised and providers support the use of proper injection reported as very common adverse reactions technique and include visual teaching guides, associated with etanercept therapy, occurring at a demonstration devices, and instructional materials frequency of ≥ 1/10.1 The local symptoms of ISRs in both print and video format. They also include a are usually mild, including bleeding at the toll free number and website for patient assistance puncture site, bruising, erythema, itching, pain or and questions in many regions. swelling, and are generally transient and do not Pfizer continues regular pharmacovigilance 1 recur with treatment. In fact, less than 1.5% of surveillance monitoring of the important risk of ISR events reported to Pfizer as postmarketing ISRs through review of postmarketing data, cases are classified as serious, and less than clinical trial data, and published literature. Pfizer WHO Pharmaceuticals Newsletter No. 6, 2016 24
Signal acknowledges UMC’s additional characterisation of ISRs and seeks further clarification through ongoing surveillance with a particular focus on identifying any causes for which the risk can be mitigated through increased awareness and patient and physician education.
References 1. Enbrel (etanercept) Summary of Product Characteristics applicable to EU/EEA Member States. Available from: http://www.ema. europa.eu/ema/index.jsp?curl=pages/medicine s/human/medicines/000262/human_med_ 000764.jsp&mid=WC0b01ac058001d124
2. Zeltser R, Valle L, Tanck C, et al. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept. Arch Dermatol. 2001;137(7):893-9.
WHO Pharmaceuticals Newsletter No. 6, 2016 25
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CAVEAT DOCUMENT
Accompanying statement to data released from VigiBase®, the WHO international database of suspected adverse drug reactions
Uppsala Monitoring Centre (UMC) in its role as the World Health Confidential data Organization (WHO) Collaborating Centre for International Drug According to WHO policy and UMC Guidelines, ADR Monitoring receives reports of suspected adverse reactions to reports sent from the WHO PIDM member countries to medicinal products from National Centres in countries VigiBase® are anonymized, but they are still to be participating in the WHO pharmacovigilance network, the WHO considered sensitive due to the nature of the data. Programme for International Drug Monitoring (PIDM). The When receiving and using adverse reaction data information is stored in VigiBase®, the WHO international (“Data”), the user agrees and acknowledges that it will database of suspected adverse drug reactions (ADRs). It is be the controller of any such Data. Accordingly, the user important to understand the limitations and qualifications that shall adhere to all applicable legislation such as, but not apply to this information and its use. limited to, EU and national legislation regarding The reports submitted to UMC generally describe no more than protection of personal data (e.g. the Data Protection suspicions which have arisen from observation of an Directive 95/46/EC and Regulation (EC) No 45/2001, as unexpected or unwanted event. In most instances it cannot be applicable). Transfer of sensitive data to a third party is proven that a specific medicinal product (rather than, for generally prohibited subject to limited exceptions example, underlying illness or other concomitant medication) is explicitly stated in applicable legislation. the cause of an event. As the controller of the Data, the user shall be liable for Reports submitted to National Centres come from both any and all processing of the Data and shall indemnify regulated and voluntary sources. Some National Centres accept and hold the UMC harmless against any claim from a reports only from medical practitioners; other National Centres data subject or any other person or entity due to a accept reports from a broader range of reporters, including breach of any legislation or other regulation regarding patients. Some National Centres include reports from the processing of the Data. pharmaceutical companies in the information submitted to Non-permitted use of VigiBase® Data includes, but is not UMC; other National Centres do not. limited to: The volume of reports for a particular medicinal product may be patient identification or patient targeting influenced by the extent of use of the product, publicity, the identification, profiling or targeting of general nature of the reactions and other factors. No information is practitioners or practice provided on the number of patients exposed to the product. Any publication, in whole or in part, of information Some National Centres that contribute information to obtained from UMC must include a statement: VigiBase® make an assessment of the likelihood that a (i) regarding the source of the information medicinal product caused the suspected reaction, while others (ii) that the information comes from a variety of sources, do not. Time from receipt of a report by a National Centre until and the likelihood that the suspected adverse submission to UMC varies from country to country. Information reaction is drug-related is not the same in all cases, obtained from UMC may therefore differ from those obtained (iii) that the information does not represent the opinion directly from National Centres. of the World Health Organization. If in doubt or in need of help for interpretation of country Omission of this statement may exclude the specific data, UMC recommends to contact the concerned NC responsible person or organization from receiving before using the data. further information from VigiBase®. For the above reasons interpretations of adverse UMC may, in its sole discretion, provide further reaction data, and particularly those based on instructions to the user, responsible person and/or comparisons between medicinal products, may be organization in addition to those specified in this misleading. The supplied data come from a variety of statement and the user, responsible person and/or sources. The likelihood of a causal relationship is not the organization undertakes to comply with all such same in all reports. Any use of this information must instructions. take these factors into account.
Uppsala Monitoring Centre (UMC) Box 1051, SE-751 40 Uppsala, Sweden
Tel: +46-18-65 60 60, E-mail: [email protected] www.who-umc.org
WHO Pharmaceuticals Newsletter No. 6, 2016 26
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The 40th meeting of the WHO International Working Group for Drug Statistics Methodology, Geneva, 27–28 October 2016
The Anatomical Therapeutic Chemical (ATC) classification system and the Defined Daily Dose (DDD) serve as tools for Drug Utilization Research (DUR). DUR is undertaken to improve quality of drug use in health-care settings. DUR can also be used to compare drug consumption at international levels. The WHO International Working Group for Drug Statistics Methodology consists of 12 members representing a wide range of professional backgrounds including: clinical pharmacology, clinical medicine, international public health, drug utilization and drug regulation. The members of the International Working Group originate from six WHO global regions and represent different types of users of the ATC/DDD system. The 40th meeting of the WHO International Working Group for Drug Statistics Methodology was held at Pavillon Albert Gallatin, Chateau de Penthes, Geneva, Switzerland. In the Open Session, industry representatives presented additional information to the experts to support their application for ATC codes and/or DDDs. The meeting was chaired by Prof Morten Anderson and Dr Shanthi Pal who welcomed the participants, in particular, two new experts from American region and Western Pacific region. The WHO Collaborating Centre (CC) for drug statistics methodology in Oslo reported on its recent activities: the workshop in New Delhi in November 2015 on the margins of annual meeting of National Pharmacovigilance Centres; ATC/DDD training courses in Oslo and Burkina Faso; and the workshop integrating ATC/DDD system in pharmacovigilance and drug utilization research in Rabat, Morocco, which aimed to promote the quality of use of medicines, participation at the ATC/DDD related meetings and publication of the Drug Utilization Research handbook. The WHOCC Oslo also presented future activities such as development of accessible 40th WHO IWG for Drug Statistics Methodology, ATC/DDD Open Data, ATC/DDD Webinar and Geneva, October, 2016 ATC/DDD Toolkit. The Working Group discussed the ATC classification and DDD items for several medicinal products, the objections and alterations of existing ATC classifications and future challenges. The Working Group also discussed new DDDs for 18 drugs based on the available information including indications and doses used in various countries. In addition objections to the assigned DDDs and alterations of the DDDs were also discussed. On the second day, Dr Suzanne Hill, Director of the Department of Essential Medicines and Health Products in WHO Headquarters, joined the meeting to speak about WHO’s activities on antimicrobial resistance (AMR) and the importance of the ATC/DDD system for measuring antibiotic consumption. Decisions made through discussions by the Working Group on ATC classification or DDD assignment will be published on the website of the WHOCC in Oslo and in the publication, WHO Drug Information. Decisions on a new or revised ATC classification or DDD assignment are published initially in a temporary list. Any interested party wishing to dispute this decision has the opportunity to comment within a specified period after its publication. The WHOCC Oslo publishes the complete ATC Index with DDDs and guidelines for ATC classification and DDD assignment annually. For more information, please see WHOCC Oslo website: http://www.whocc.no/
WHO Pharmaceuticals Newsletter No. 6, 2016 27
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The 39th Annual Meeting of Representatives of the National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring
The National Pharmacovigilance Centre in Oman hosts the annual meeting of National Pharmacovigilance Centres, in Muscat, Oman The annual meeting of National Pharmacovigilance Centres (NPCs) is a platform for representatives from around the world to meet and discuss pharmacovigilance issues. Each year an NPC hosts the meeting, and this year the NPC in Oman welcomed delegates to the Grand Millennium Hotel in Muscat, Sultanate of Oman. Nearly 200 representatives from around 50 countries travelled to the Sultanate of Oman to attend the four- day meeting from 14 to 17 November 2016.
Minister of Health attends the opening ceremony for the WHO meeting. The 39th meeting was inaugurated by the Minister of Health, Dr Ahmed Mohamed Obaid Al-Saidi and the Regional director of the WHO Eastern Mediterranean office, Dr Ala Alwan.
Participants presented their posters to the Minister of Hussein Al Ramimmy presented on the pharmacovigilance Health Dr Ahmed Mohamed Obaid Al-Saidi and the programme in Oman during the opening ceremony. Regional director of the WHO Eastern Mediterranean Regional Office, Dr Ala Alwan.
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Meeting Structure and content At the end of the 38th annual meeting of NPCs in India in 2015, participants were invited to suggest topics for the 39th annual meeting. This set the agenda for 2016, reflecting the needs of Member States. The meeting sessions consisted of plenaries, updates, working groups, problems of current interest and for the first time, tutorials. Plenary included regional challenges on pharmacovigilance (PV); the SCOPE1 project and value added to the WHO PIDM; mobile app for adverse drug reaction (ADR) reporting; countries in conflict and impact on pharmacovigilance; adverse events identification through social media; safety monitoring in seasonal malaria chemoprevention, and pregnancy and PV. Mohamed Ahmed from Libya engaging in discussions.
Mick Foy from Medicines and Healthcare Products Regulatory Hadir Rostom from Egyptian Pharmaceutical Vigilance Agency (MHRA) in the UK presented an update on two work Centre (EPVC) presenting an account of the challenges that packages from the SCOPE project. One work package of the EPVC faced during a time of political and economic project consisted of the development of a mobile app for instability in Egypt. reporting. The app has been launched in the UK, Croatia and the Netherlands. The app is not only a reporting tool but also serves as an information provider to reporters. The app will be piloted outside Europe in Burkina Faso and Zambia. There are plans to scale up the accessibility of the app to other countries following lessons learnt from the pilot.
Updates: Included presentations on: ADR reporting and global statistics; and harmonizing multiple vigilance systems were given by WHO Collaborating Centres (WHO CC) for International Drug Monitoring, and WHO CC for Strengthening Pharmacovigilance Practices respectively. Working Groups: Eight working groups were run over a period of two days. Prior to the workshop, delegates were provided with a list of objectives and outcomes and had the opportunity to attend two workshops of preference. During each workshop, moderated discussions were held and attendees formulated and agreed on a list of recommendations that were specifically targeted at WHO, WHO CCs and / or the NPCs. A delegated rapporteur amongst the workshop participants presented to the whole delegation during the plenary session on the last day of the meeting. Danny Kofi-Armah from WHO CC for Advocacy and training in PV reporting back recommendations made in one of the working groups.
1 Strengthening Collaborations for Operating Pharmacovigilance in Europe WHO Pharmaceuticals Newsletter No. 6, 2016 29
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Working group topics consisted of: 1) Defining the pharmacovigilance research question for countries: how do we go about it; 2) Pharmacovigilance communication campaigns: how to measure impact; 3) What people want from pharmacovigilance: What is your big question; 4) Solutions to improve approaches to, and enhance consumer reporting; 5) What to teach pharmacovigilance beginners; 6) Why and when do we undertake cohort event monitoring?; 7) Herbal-drug interactions; 8) Statistical methods in pharmacovigilance. The finalized and confirmed version of the recommendations will be available in the next issue of the WHO Pharmaceuticals Newsletter. Problems of Current Interest: The session on problems of current interest consisted of short presentations based on abstracts that were submitted prior to the meeting. There were a range of topics, some focused on particular ADRs of concern, for example tenofovir and renal impairment. Others discussed initiatives to improve reporting, quality of reports and information sharing. Tutorial by Ruth Savage from WHO CC for Tutorial by Linda Harmark on case by case Delegates were given the International Drug Monitoring on what signal detection. opportunity to share their happens to potential signals. experiences, interact and help find solutions. Tutorials: This year was the first to introduce tutorial sessions within the meeting. There were six different tutorial sessions that ran parallel to each other for three of the four days of the meeting. The tutorials sessions were: case by case signal detection (French and English), Vigilyze, what happens to potential signals, Vigiflow, Tutorial by Rachida Soulyamani on case by Tutorial by Alexander Dodoo on interacting interacting with the media. case signal detection in French. with the media.
Future meeting Uganda has offered to host the 40th annual meeting of representatives of the NPCs participating in the WHO PIDM, from 7 to 10 November 2017.
Helen Ndagije from Uganda inviting participants to the 40th annual meeting of representatives of the NPCs participating in the WHO PIDM.
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