2015 WHO Pharmaceuticals
NEWSLETTER No.6
Prepared in collaboration with the WHO Collaborating Centre for International Drug Monitoring, Uppsala Sweden
The WHO Pharmaceuticals Newsletter provides you The aim of the Newsletter is to with the latest information on the safety of medicines disseminate information on the and legal actions taken by regulatory authorities across safety and efficacy of pharmaceutical products, based on the world. It also includes write-ups on ‘Signals’ from communications received from our Individual Case Safety Reports (ICSRs) available in the network of "drug information WHO Global ICSR database, VigiBase®. officers" and other sources such as specialised bulletins and journals, This newsletter includes three feature articles as well as partners in WHO. describing: the 38th meeting of the WHO International Working Group for Drug Statistics Methodology; Pre- The information is produced in the conference Workshop on WHO ATC/DDD Methodology form of résumés in English, full and Drug Utilization Research; and the 38th Annual texts of which may be obtained on Meeting of Representatives of the National request from: Pharmacovigilance Centres participating in the WHO Safety and Vigilance, Programme for International Drug Monitoring.
EMP-HIS, World Health Organization, 1211 Geneva 27, Switzerland, E-mail address: [email protected]
This Newsletter is also available on our Internet website: http://www.who.int/medicines
Further information on adverse Contents reactions may be obtained from the WHO Collaborating Centre for International Drug Monitoring Box 1051 Regulatory matters 751 40 Uppsala Tel: +46-18-65.60.60 Safety of medicines Fax: +46-18-65.60.80 E-mail: [email protected] Signal Internet: http://www.who-umc.org
Feature
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Table of Contents
Regulatory Matters Aripiprazole ...... 5 Asunaprevir and daclatasvir ...... 5 Azithromycin ...... 5 Ceftriaxone ...... 6 Clopidogrel ...... 6 Codeine ...... 6 Dipeptidyl peptidase-4 (DPP-4) Inhibitors ...... 7 Dutasteride ...... 7 Galantamine ...... 7 Hepatitis C treatments (Viekira Pak® and Technivie®) ...... 7 Iodine-containing contrast agents for medical imaging ...... 8 Magnesium oxide ...... 8 Mirabegron ...... 8 Roxithromycin ...... 9 Sodium glucose co-transporter 2 (SGLT2) inhibitors ...... 9 Strontium ...... 10 Testosterone ...... 10 Ustekinumab ...... 11 Vemurafenib ...... 11
Safety of medicines Crizotinib ...... 12 Entacapone...... 12 Infliximab ...... 12 Newer rotavirus vaccines (Rotarix® and RotaTeq®) ...... 13 Sodium glucose co-transporter 2 (SGLT2) inhibitors ...... 13 Sodium polystyrene sulfonate ...... 14 Tramadol ...... 14 Vemurafenib ...... 14
WHO Pharmaceuticals Newsletter No. 6, 2015 3
Table of Contents
Signal Atomoxetine and neutropenia in paediatric patients ...... 16 Deferasirox and pancreatitis in paediatric patients ...... 20 Desloratadine and aggressive reaction ...... 25
Feature The 38th meeting of the WHO International Working Group for Drug Statistics Methodology, Oslo, 22–23 October 2015 ...... 32 Pre-conference Workshop on WHO ATC/DDD Methodology and Drug Utilization Research, New Delhi, India, 2-3 November 2015...... 33 The 38th Annual Meeting of Representatives of the National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring ...... 34
WHO Pharmaceuticals Newsletter No. 6, 2015 4
Regulatory Matters
Aripiprazole information involving Reference: aripiprazole to investigate Revision of Precautions, Risk of certain impulse potential harms. MHLW/PMDA, 20 October 2015 (www.pmda.go.jp/english/) control behaviours Reference: Summary Safety Review, Canada. Health Canada has Health Canada, 2 November updated the Canadian 2015 (www.hc-sc.gc.ca) prescribing information for Azithromycin aripiprazole (Abilify®) to include a warning statement of Risk of drug reaction risk of pathological gambling Asunaprevir and with eosinophilia and and uncontrollable sexual systemic symptoms behaviours (hypersexuality). daclatasvir (DRESS) Aripiprazole is an oral medication and is used to Risk of interstitial Singapore. The Health treat: pneumonia Sciences Authority (HSA) has manic-depressive illness informed health-care (bipolar I disorder) in adults Japan. The Ministry of Health, professionals of the risk of and adolescents of 13 years Labour and Welfare (MHLW) eosinophilia and systemic and older. This condition is and the Pharmaceuticals and symptoms (DRESS) associated characterised by periods of Medical Devices Agency with the use of azithromycin. elevated moods (mania) (PMDA) have announced the Azithromycin (Zithromax®) is and depression; revision of the package insert a macrolide antibiotic (azalide schizophrenia in adults and for asunaprevir (Sunvepra®) subclass) used to treat upper adolescents of 15 years and and daclatasvir (Daklinza®) to and lower respiratory tract older; include risk of interstitial infections and other infections depression in adults when pneumonia. sensitive to azithromycin. used in combination with Asunaprevir and daclatasvir other drugs. are co-administered for In April 2014, Health Canada updated package inserts (PI) Health Canada conducted a treatment of serogroup 1 of azithromycin-containing safety review following the (genotype 1) chronic hepatitis products to include information European Medicines Agency C or compensated cirrhosis on DRESS. This was based on (EMA)’s warning (product label type C. a report of DRESS suspected update) of the risk of The MHLW/PMDA stated that to be associated with pathological gambling and the cases of interstitial pneumonia azithromycin in Canada, and a inclusion of hypersexuality as have been reported in patients review of published literature. an adverse effect. treated with asunaprevir and To date, the HSA has not At the time of the review, daclatasvir in Japan. received any reports of DRESS Health Canada received five The MHLW/PMDA associated with the use of reports of pathological recommended the addition of azithromycin, but initiated a gambling and/or the following text to the labelling update for hypersexuality, suspected of subsection of the “Clinically azithromycin to warn of being linked with aripiprazole. significant adverse reaction” in reports of DRESS. Upon review of these cases, no the section of the “Adverse conclusions could be made reaction” in the package insert. The HSA has recommended regarding what role, if any, the health-care professionals to be drug may have played due to Interstitial pneumonia: vigilant to the signs and limited information. Interstitial pneumonia may symptoms of DRESS in occur. If cough, dyspnoea, patients who are prescribed Among 14 of the 18 cases of pyrexia, abnormal chest sound azithromycin. These may pathological gambling, and 5 of (crepitations) etc. are include rash, fever, 6 cases of hypersexuality observed, examinations lymphadenopathy, linked to aripiprazole identified including chest X-ray, chest CT haematological abnormalities in the scientific and medical scan, or serum marker test and multi-organ involvement. literature, the behaviours should be performed. If Early and prompt resolved or improved when the interstitial pneumonia is discontinuation of the treatment with aripiprazole suspected, administration of offending drug is important to was stopped or the dosage was this drug should be achieve the best outcome in reduced. discontinued and appropriate patients with DRESS. Health Canada will continue to measures should be adopted. monitor adverse effect WHO Pharmaceuticals Newsletter No. 6, 2015 5
Regulatory Matters
Reference: Clopidogrel aspirin alone. Also, there was Product Safety Alerts, HSA, no apparent increase in the 30 September 2015 Long-term treatment risks of cancer-related deaths (http://www.hsa.gov.sg/) does not change risk of or cancer-related adverse events with long-term (See WHO Pharmaceuticals death Newsletters No.5, 2015: Risk of treatment. drug-induced hypersensitivity USA. A US Food and Drug The FDA has recommended syndrome in Japan and No.6, Administration (FDA) review that health-care professionals 2014: Drug Reaction/Rash with has determined that long-term Eosinophilia and Systemic should consider the benefits Symptoms (DRESS) in Canada) use of the blood-thinning drug and risks of available clopidogrel (Plavix®) does not antiplatelet medicines before increase or decrease overall starting treatment. risk of death in patients with, Reference: Ceftriaxone or at risk of heart disease. The FDA evaluation of the Dual Drug Safety Communication, Antiplatelet Therapy (DAPT) US FDA, 6 November 2015 Risk of acute generalised (www.fda.gov) exanthematous trial and several other clinical trials also does not suggest pustulosis that clopidogrel increases the risk of cancer or death from Japan. The MHLW and the PMDA have announced the cancer. The FDA has been Codeine working with the revision of the package insert manufacturers of clopidogrel to ceftriaxone to include risk of Suspension of use update the label to reflect the acute generalised results of the mortality meta- exanthematous pustulosis. Ethiopia. The Ethiopian Food, analysis. Medicine and Healthcare Ceftriaxone is an antimicrobial Administration and Control Clopidogrel is an antiplatelet used to treat infections such Authority (FMHACA) has medicine used to prevent blood as: sepsis, pharyngitis/ suspended the use of codeine clots in patients who have had laryngitis, tonsillitis, acute for all patients due to the risk a heart attack, stroke, or bronchitis, pneumonia, lung of death and life threatening problems with the circulation in abscess and pyothorax by adverse effects. the arms and legs. It works by several strains. helping to keep the platelets in The suspension is based on the The MHLW/PMDA stated that the blood from sticking US FDA reports of children who cases of acute generalised together and forming clots that developed serious adverse exanthematous pustulosis can occur with certain medical effects after taking codeine for have been reported in patients conditions. pain relief after tonsillectomy treated with ceftriaxone and/or adenoidectomy. These In order to investigate the sodium hydrate in Japan and in children had evidence of an increased risk of death and other countries. In addition, inherited ability to convert cancer-related death reported the company core datasheet codeine into morphine very with clopidogrel in the DAPT (CCDS) has been updated. rapidly. trial, the FDA examined the Based on expert advice and results of the DAPT trial and Codeine is converted to available evidence, the other large, long-term clinical morphine in the cytochrome MHLW/PMDA have trials of clopidogrel with data P450 2D6 (CYP2D6). Some recommended the addition of available on rates of death, people have genetic the “Acute generalised death from cancer, or cancer background that makes this exanthematous pustulosis” to reported as an adverse event. enzyme more active. These the section of the “Clinically “ultra-rapid metabolizers” are The FDA performed meta- significant adverse reaction” in more likely to have higher analyses of other long-term the package insert. blood level of morphine after clinical trials to assess the taking codeine. A study Reference: effects of clopidogrel on death showed that Ethiopians are one Revision of Precautions, rates from all causes. The of “ultra-rapid metabolizers”, MHLW/PMDA, 20 October 2015 results indicate that long-term therefore Ethiopians are more (www.pmda.go.jp/english/) (12 months or longer) dual susceptible for inadvertent antiplatelet therapy with adverse effects of codeine. clopidogrel and aspirin do not appear to change the overall Even though the standard risk of death when compared treatment guideline sets to short-term (6 months or codeine as an alternative less) clopidogrel and aspirin, or medicine for pain management WHO Pharmaceuticals Newsletter No. 6, 2015 6
Regulatory Matters and dry cough, the FMHACA Dutasteride Galantamine is used to has decided to suspend the suppress progression of use of codeine for all patients Risk of hepatic function dementia symptoms in in Ethiopia considering the disorder and jaundice patients with mild to moderate genetic background. Alzheimer’s type dementia. Reference: Japan. The MHLW and the The MHLW/PMDA stated that Communication from FMHACA PMDA have announced the cases of rhabdomyolysis have to WHO, 25 November 2015 revision of the package insert been reported in patients for dutasteride (Avolve® and treated with galantamine (See WHO Pharmaceuticals Zagallo®) to include risk of hydrobromide in Japan. Newsletters No.3 and 4, 2015, hepatic function disorder and No.5 and 4, 2013 and No.5, 2012 jaundice. Based on expert advice and for related information) available evidence, the Dutasteride is used for benign MHLW/PMDA have prostatic hyperplasia and male recommended the addition of Dipeptidyl peptidase- pattern hair loss (androgenetic the following text to the 4 (DPP-4) Inhibitors alopecia). subsection of the “Clinically The MHLW/PMDA stated that significant adverse reaction” in Risk of severe joint pain cases of hepatic function the section of the “Adverse disorder and jaundice have reaction” in the package insert. Egypt. Egyptian been reported in patients Pharmaceutical Vigilance Rhabdomyolysis: treated with dutasteride in Rhabdomyolysis may occur. Center (EPVC) recommends Japan. the addition of a warning label Patients should be carefully to products containing Based on expert advice and monitored. If symptoms dipeptidyl peptidase-4 (DPP-4) available evidence, the including myalgia, feelings of inhibitors, to include Joint Pain MHLW/PMDA have weakness, increased creatine (Arthralgia). recommended the addition of kinase (creatine the following text to the phosphokinase), or increased DPP-4 inhibitors (e.g. subsection of the “Clinically blood and urine myoglobin are sitagliptin, saxagliptin, significant adverse reaction” in observed, administration of linagliptin, and alogliptin) the section of “Adverse this drug should be combined with diet and reaction” in the package insert. discontinued and appropriate exercise are used to lower measures should be adopted. blood sugar in adults with type Hepatic function disorder, 2 diabetes. These medicines jaundice: Reference: are available as single- Hepatic function disorder or Revision of Precautions, ingredient products and in jaundice associated with MHLW/PMDA, 20 October 2015 combination with other increased levels of AST (GOT), (www.pmda.go.jp/english/) diabetes medicines such as ALT (GPT), bilirubin, etc. may metformin. occur. Patients should be carefully monitored. If any This recommendation was abnormalities are observed, Hepatitis C based on the US FDA warning appropriate measures such as of severe and disabling joint discontinuation of treatments (Viekira pain associated with the use of administration should be Pak® and Technivie®) DPP-4 inhibitors. adopted. Reference: Reference: Risk of serious liver Newsletter, EPVC, Volume 6, Revision of Precautions, injury Issue 11, November 2015 MHLW/PMDA, 20 October 2015 USA. The US FDA has issued a (See WHO Pharmaceuticals (www.pmda.go.jp/english/) Newsletter No.5, 2015: DPP-4 warning that hepatitis C inhibitors for Type 2 diabetes may treatments, a fixed-dose cause severe joint pain in the combination of dasabuvir, United States of America) ombitasvir, paritaprevir and Galantamine ritonavir (Viekira Pak®) and a fixed-dose combination of Risk of rhabdomyolysis ombitasvir, paritaprevir and ritonavir (Technivie®) can Japan. The MHLW and the cause serious liver injury in PMDA have announced the patients with underlying revision of the package insert advanced liver disease. for galantamine (Reminyl®) to include risk of rhabdomyolysis. WHO Pharmaceuticals Newsletter No. 6, 2015 7
Regulatory Matters
Cases of hepatic to see blood vessels and “Geriatrics” to the section of decompensation and liver organs in medical images such the “Careful administration” failure in patients with as X-rays or computed and addition of precautions underlying liver cirrhosis were tomography (CT) scans. regarding hypermagnesaemia identified in patients who were to the “Use of geriatrics” In all of the reported cases, taking these medicines. Some section in the package insert. the infants were either of these events resulted in premature or had other serious The MHLW/PMDA also serious outcomes including, underlying medical conditions. recommended the addition of liver transplantation or death, Based on available evidence the following precaution to the mostly in patients taking the FDA believes that this rare section of the “Important Viekira Pak® with evidence of occurrence is usually precaution” in the package advanced cirrhosis even before temporary and resolves insert. starting treatment. without treatment or any Use of the product should At least 26 worldwide cases lasting effects. be kept to a minimum. submitted to FDA Adverse Patients should be The FDA will continue to Event Reporting System were instructed to seek medical evaluate this issue. considered to be possibly or attention if they experience Manufacturers of ICM products probably related to these any symptoms, such as are required to conduct a study medicines. Some of the cases vomiting, bradycardia, to investigate this further. occurred in patients for whom muscular weakness, and these medicines were The FDA has recommended somnolence. contraindicated or not that health-care professionals Reference: recommended. should continue to follow the Revision of Precautions, label recommendations for ICM The FDA requires MHLW/PMDA, 20 October 2015 products and continue to use manufacturers to include (www.pmda.go.jp/english/) clinical judgment to determine information about serious liver if testing for underactive injury adverse events to the thyroid is necessary. Contraindications, Warnings and Precautions, Reference: Postmarketing Experience and Drug Safety Communication, Mirabegron Hepatic Impairment sections of US FDA, 17 November 2015 Risk of severe the Viekira Pak® and (www.fda.gov) Technivie® labels. hypertension, associated cerebrovascular and Reference: cardiac events Drug Safety Communication, US FDA, 22 October 2015 Magnesium oxide The United Kingdom. The (www.fda.gov) Medicines and Healthcare Risk of Products Regulatory Agency hypermagnesaemia (MHRA) has announced that mirabegron is now Japan. The MHLW and the Iodine-containing contraindicated in patients with PMDA have requested the severe uncontrolled contrast agents for revision of the package insert hypertension (systolic blood for magnesium oxide and pressure ≥180 mmHg or medical imaging magnesium oxide-containing diastolic blood pressure ≥110 medicines to include risk of Rare cases of mmHg, or both). The MHRA hypermagnesaemia. recommends blood pressure underactive thyroid in should be measured before Magnesium oxide is used for infants starting treatment, and constipation, prevention of the regularly during treatment, USA. The FDA has approved formation of calcium oxalate especially in patients with changes to the labels of all urinary stone and as an hypertension. iodinated contrast media (ICM) antacid. products to include information Mirabegron (Betmiga®) is a The MHLW/PMDA stated that on cases of underactive thyroid beta 3-adrenoceptor agonist cases of hypermagnesaemia in infants following the use of used in the management of have been reported in patients contrast media containing urinary frequency, urgency, treated with magnesium oxide iodine (contrast dye). and incontinence in overactive in Japan. Based on expert bladder syndrome. Iodinated contrast media advice and available evidence, contain iodine and are given to the MHLW/PMDA have This follows a review of the patients to enhance the ability recommended the addition of latest safety data in the EU.
WHO Pharmaceuticals Newsletter No. 6, 2015 8
Regulatory Matters
Mirabegron is known to (including torsades de pointes) safety information received increase blood pressure. Cases have been reported in patients from the manufacturer of of severe hypertension have treated with roxithromycin in canagliflozin. Reports of been reported, which include Japan and in other countries. serious acute kidney injury, hypertensive crisis associated In addition, the company core acute renal failure and renal with reports of cerebrovascular datasheet (CCDS) has been failure (severe renal and cardiac events (mainly updated. impairment) were investigated. transient ischaemia attack or These kidney problems occur Based on expert advice and stroke), some with a clear when the kidneys suddenly available evidence, the temporal relation to become unable to filter waste MHLW/PMDA have mirabegron use. products from the blood. recommended the addition of Data are limited regarding use “QT prolongation and At the time of the review, of mirabegron in patients with ventricular tachycardia Health Canada had received stage 2 hypertension (i.e. (including torsades de two reports of acute kidney systolic blood pressure ≥160 pointes)” and injury in canagliflozin users. mm Hg or diastolic blood “Pseudomembranous colitis” to Additional international reports pressure ≥100 mm Hg) and it the section of the “Clinically of kidney injury associated should therefore be used with significant adverse reaction” in with the use of either caution in this group. the package insert. canagliflozin or dapagliflozin Reference: The MHLW/PMDA also were identified. In the review, Drug Safety Update, MHRA, recommended the addition of the evidence indicated a link Volume 9, issue 3: 1, October the “Patients with risk of between events of acute 2015 (www.gov.uk/mhra) prolonged QT” to the section of kidney injury and the use of the “Careful administration” in these SGLT2 inhibitors.
the package insert. A review of the scientific Reference: literature linking canagliflozin Roxithromycin Revision of Precautions, or dapagliflozin to acute kidney MHLW/PMDA, 20 October 2015 injury provided limited Risk of QT prolongation, (www.pmda.go.jp/english/) evidence on this topic, ventricular tachycardia although their renal effects
(including torsades de were noted as a potential pointes) and problem. pseudomembranous Sodium glucose co- In the Health Canada's safety colitis review, it was concluded that transporter 2 (SGLT2) the evidence supported the Japan. MHLW and the PMDA inhibitors existence of a link between the have announced the revision of use of SGLT2 inhibitors and the the package insert for 1. Risk of acute kidney risk of acute kidney injury. roxithromycin (Rulid®) to injury include risk of QT prolongation, (Also see information from TGA on pages 13-14) ventricular tachycardia Canada. Health Canada is (including torsades de pointes) working with manufacturers on Reference: and pseudomembranous updating the Canadian Summary Safety Review, colitis. prescribing information for Health Canada, 16 October 2015 (www.hc-sc.gc.ca) Ceftriaxone is an antimicrobial canagliflozin (Invokana®) and used for treatment of dapagliflozin (Forxiga®) to superficial skin infections, strengthen the warning related deep-seated skin infections, to the risk of kidney injury. 2. Interim update on risk lymphangitis/lymphadenitis, This reflects conclusions drawn of serious ketoacidosis chronic pyoderma by strains of from a safety review conducted genus Staphylococcus, genus by Health Canada. Singapore. The HSA is reviewing the current available Streptococcus, Pneumococcus, Canagliflozin and dapagliflozin information and seeking expert Moraxella (Branhamella) are SGLT2 inhibitors, and can opinion from local clinicians on catarrhalis, Propionibacterium be used as single agents with risk of serious ketoacidosis to acnes, and Mycoplasma diet and exercise or with other determine if there is a need for pneumoniae. products to decrease blood further regulatory action. sugar levels in adults with type The MHLW/PMDA stated that Licence holders have issued 2 diabetes. cases of pseudomembranous ‘Dear Health-Care Professional colitis, QT prolongation and The review was triggered Letters’ (DHCPLs) to warn of ventricular tachycardia following new post market serious and sometimes life- WHO Pharmaceuticals Newsletter No. 6, 2015 9
Regulatory Matters threatening cases of diabetic Strontium is a naturally Testosterone ketoacidosis (DKA) during occurring mineral classified as treatment with SGLT2 a natural health product in Further investigations inhibitors. Canada. It is available in are necessary: risk of different salt forms over the In Singapore, SGLT2 inhibitors, cardiovascular events counter and is used to support namely canagliflozin bone health. (Invokana®), dapagliflozin Singapore. The HSA has (Forxiga®) and empagliflozin Following the precautionary informed health-care (Jardiance®), are indicated as advice by the EMA, for use of professionals of the possible an adjunct to diet and exercise strontium ranelate at the risk of cardiovascular (CV) to improve glycaemic control in prescription dose of 680mg per events associated with use of patients with type 2 diabetes day, Health Canada conducted testosterone-containing mellitus, as monotherapy, add- a safety review. products. The information is on combination therapy with based on changes in product At the time of the review, other glucose-lowering agents labels and safety reviews there were no reports of heart including insulin, and/or initial conducted in Canada, Europe, or circulatory adverse effects combination therapy with New Zealand and the United associated with strontium salts metformin. States. Testosterone is a (citrate, lactate, and steroid hormone involved in In Singapore, the HSA has gluconate). androgenic and anabolic monitored the safety profile of Health Canada's review did not processes. It is mainly the SGLT2 inhibitors following find information available on indicated for replacement their registration. As of August cardiovascular risk with the therapy in males with primary 2015, HSA has received three strontium ranelate form at and secondary hypogonadal local reports of serious DKA doses less than 680 mg/day, disorders. Some of the associated with SGLT2 or with other non-ranelate testosterone-containing inhibitors. forms of strontium at any products are also indicated for HSA will provide an update on dose. Strontium plays an osteoporosis caused by the outcome of its review when active role in the body, and the androgen deficiency, or for completed. salt components (ranelate, masculinisation in female to lactate, citrate, and gluconate) male transsexuals. Reference: help with absorption of the Product Safety Alerts, HSA, The HSA has received one local strontium. There is not enough 30 September 2015 ADR report of myocardial information available to (http://www.hsa.gov.sg/) infarction (MI) associated with compare absorption of the use of testosterone. No (See WHO Pharmaceuticals different strontium salts and/or local ADR reports of venous Newsletters No.5, 2015: Risk of the risk of heart or circulatory thromboembolism associated ketoacidosis and sepsis in Japan adverse effects with low dose with the use of testosterone and No.4, 2015: Risk of diabetic strontium. ketoacidosis in the United have been received. Kingdom) Health Canada will continue to HSA has also consulted local
monitor safety information experts (urologists and involving all salt forms of cardiologists) regarding the strontium and will take potential risk of CV events with Strontium additional actions, if testosterone. Some of the warranted. experts were of the opinion Risk of heart and that methodological limitations circulatory side effects Reference: Summary Safety Review, and biases may have impacted results from the observational Canada. Health Canada Health Canada, 22 October studies conducted. In general, recommends that labels of all 2015 (www.hc-sc.gc.ca) evidence of the risk of CV products containing strontium (See WHO Pharmaceuticals events associated with use of (>4mg elemental/day) should Newsletters No.1, 2 and 4, 2014, testosterone remains weak and be updated to include advice No.3 and 4, 2013 for related further investigations are against the use of strontium information from other countries needed. products in patients who have, and regions) or are at high risk for, heart HSA is working with companies disease, circulatory problems, to ensure that the warnings or blood clots, as a and precautions relating to CV precautionary measure. This events are adequately risk currently remains highlighted across the package uncertain. inserts of testosterone- containing products. WHO Pharmaceuticals Newsletter No. 6, 2015 10
Regulatory Matters
Reference: The TGA's investigation of this Health Canada to list the risk Product Safety Alerts, HSA, safety concern found that of pancreatitis as an adverse 30 September 2015 there was insufficient reaction. This action was based (http://www.hsa.gov.sg/) information at this point in on separate reviews conducted time to establish a definite by the market authorization (See WHO Pharmaceuticals Newsletters No.2, 2015 and No.2, causal relationship between holder and Health Canada. exfoliative dermatitis or 2014 for related information from To date, HSA has not received erythrodermic psoriasis and the United States of America) any adverse reaction reports of treatment with ustekinumab. pancreatitis associated with However, given the vemurafenib. seriousness of these adverse Ustekinumab events and their potential The HSA has advised health- reversibility after cessation of care professionals to remain Risk of serious skin the inciting medicine, the TGA vigilant to the possible signs conditions considered that health-care and symptoms of pancreatitis professionals should be made in patients who are prescribed Australia. The Therapeutic aware of this possible vemurafenib, and to consider Goods Administration (TGA) association. the possibility of pancreatitis in has announced that the the event of unexplained The updated ustekinumab Product Information for abdominal pain. Product Information states that ustekinumab (Stelara®) has patients with plaque psoriasis been updated to include a Reference: may develop erythrodermic precaution regarding serious Product Safety Alerts, HSA, psoriasis, with symptoms that skin conditions. 30 September 2015 may be clinically (http://www.hsa.gov.sg/) Ustekinumab is a human indistinguishable from (See WHO Pharmaceuticals monoclonal antibody that is exfoliative dermatitis, as part Newsletters No.2, 2015: Risk of indicated for the treatment of: of the natural course of their pancreatitis in Canada and No.3, moderate to severe plaque disease. 2014: Association of vemurafenib psoriasis in adult patients Reference: use with drug induced liver injury who are candidates for (DILI) in Canada) Medicines Safety Update, TGA, phototherapy or systemic Vol. 6, No. 5, October 2015 therapy; (www.tga.gov.au) signs and symptoms of active psoriatic arthritis (See WHO Pharmaceuticals (used alone or in Newsletters No.4, 2015: Risk of
combination with rare but serious skin reactions in Singapore, No.2, 2015: Risk of methotrexate) in adults exfoliative dermatitis in the United where response to previous Kingdome and No.1, 2015: Serious non-biological disease- skin disorders (Exfoliative modifying antirheumatic dermatitis and erythrodermic drug therapy has been psoriasis) in Canada) inadequate. This update follows an investigation conducted by the TGA, that examined the Vemurafenib association of serious skin Risk of pancreatitis conditions, namely exfoliative dermatitis (also known as Singapore. The HSA has erythroderma) and updated the local package erythrodermic psoriasis with insert (PI) to include ustekinumab treatment. This information on patient was also investigated by other monitoring and detection of regulators such as the EMA pancreatitis. and Health Canada. Vemurafenib (Zelboraf®) is a Up until 20 May 2015, the TGA low molecular weight inhibitor has received one report of of BRAF serine-threonine erythrodermic psoriasis and no kinase. (BRAF is a human reports of exfoliative dermatitis gene) suspected to be associated to ustekinumab use. This update follows updates to product labels by the EMA and
WHO Pharmaceuticals Newsletter No. 6, 2015 11
Safety of Medicines
Crizotinib Entacapone events with entacapone. The original meta-analysis Risk of cardiac failure No clear evidence: (STRIDE-PD), which was not increased cardiovascular designed to assess cardiovascular risks does not The United Kingdom. The risks MHRA has announced that represent a true increase in severe, sometimes fatal cases USA. The US FDA has found risk due to entacapone and results were likely due to of cardiac failure in patients no clear evidence of an chance. treated with crizotinib increased risk of heart attacks, (Xalkori®) have been stroke, or other cardiovascular Reference: reported. events associated with the use Drug Safety Communication, Crizotinib is licensed to treat of entacapone. As a result, US FDA, 26 October 2015 adults with previously treated information in product labels (www.fda.gov) for entacapone (Comtan®) anaplastic lymphoma kinase (ALK)-positive advanced non- and a combination of small-cell lung cancer. entacapone, carbidopa, and levodopa (Stalevo®) will A review by European remain the same. Infliximab medicines regulators of data from clinical trials and reports Entacapone-containing Limited evidence: risk of from clinical practice has products are used to treat cancer (lymphoma, concluded that this adverse symptoms of Parkinson’s hepatosplenic T-Cell effect is common (i.e. occurs in disease, such as muscle lymphoma, and stiffness, tremors, spasms, and between 1 in 10 and 1 in 100 leukaemia) patients who take crizotinib). poor muscle control. Canada. Health Canada has Up until 25 February 2015 The FDA issued an alert to conducted a safety review to forty cases of cardiac failure patients and health-care evaluate the risk of developing have been reported globally. In professionals warning of a three types of cancers some of these cases, possible increased risk of (lymphoma, hepatosplenic T- symptoms of cardiac failure cardiovascular events and cell lymphoma, and leukaemia) resolved on stopping crizotinib death with entacapone associated with the use of (positive de-challenge), and treatment in August 2010. This infliximab (Remicade®) when symptoms reoccurred when it alert was triggered from used to treat autoimmune was reintroduced (positive re- observations in a clinical trial, diseases of the skin (i.e. challenge). Stalevo Reduction in Dyskinesia Evaluation in psoriasis) in adults. The MHRA has provided the Parkinson’s Disease (STRIDE- Investigators did not find following advice for health-care PD) and in a meta-analysis evidence of an association professionals: that combined the between lymphoma, Monitor all patients for cardiovascular-related findings hepatosplenic T-cell signs and symptoms of from 15 clinical trials lymphoma, or leukaemia, and heart failure (including comparing a combination of the use of infliximab to treat dyspnoea, oedema, or rapid entacapone, carbidopa, and psoriasis. weight gain from fluid levodopa to carbidopa/levodopa. Infliximab is a unique immune retention). The FDA was concerned that system protein (monoclonal Consider reducing the dose, the entacapone was antibody), which works by or interrupting or stopping responsible for these blocking a naturally occurring treatment if symptoms of cardiovascular risks because chemical TNF-α (Tumour heart failure occur. the comparison drugs do not Necrosis Factor-alpha). TNF-α show evidence of an increased Reference: causes inflammation which can risk of cardiovascular events. Drug Safety Update, MHRA, occur due to the body's own Volume 9, issue 4: 1, Manufacturers were requested defence system attacking the November 2015 by the FDA to conduct a study skin, joints, intestines, or (www.gov.uk/mhra) to investigate the potential for stomach (autoimmune disease). (See WHO Pharmaceuticals cardiovascular risk with entacapone use. After Newsletter No.4, 2015: Risk of At the time of the review, the examining results from the cardiac failure in Japan) Canada Vigilance Program requested study and all received 77 reports of available evidence the FDA lymphoma, five reports of a concluded that there is no type of lymphoma (Non- evidence of an increased risk Hodgkin's Lymphoma) that of cardiovascular adverse also included cases of WHO Pharmaceuticals Newsletter No. 6, 2015 12
Safety of Medicines hepatosplenic T-cell professionals to be vigilant to remaining five cases occurred lymphoma, and eight reports symptoms that are indicative beyond the 21-day risk period of leukaemia associated with of intussusception (e.g. identified with rotavirus the use of infliximab to treat vomiting, palpable abdominal vaccination. There were also autoimmune diseases. Health mass, abdominal pain or three reports of Canada's analysis of the diarrhoea) following rotavirus intussusception associated with reports found no association vaccination. The HSA requests RV5, which is less commonly between these cancers with health-care professionals to used in Singapore. All the infliximab use for psoriasis. inform parents or caregivers to patients had either recovered seek treatment early if the or were recovering at the time A review of international data child experiences abdominal of reporting. from the WHO's global pain or bloating, often database retrieved 413 reports Reference: accompanied with persistent or of lymphoma, 73 reports of Product Safety Alerts, HSA, bouts of crying, vomiting, Non-Hodgkin's Lymphoma that 30 September 2015 blood in the stool or change in included cases of hepatosplenic (http://www.hsa.gov.sg/) bowel movements at any time T-cell lymphoma, and 50 after each dose of the vaccine. (See WHO Pharmaceuticals reports of leukaemia Newsletter No.6, 2013: Risk of associated with infliximab Safety concerns of intussusception in Australia) treatment of autoimmune intussusception with rotavirus diseases. Health Canada's immunization were first evaluation of these reports and announced in 1999 with the a review of the scientific and RotaShield® preparation. This Sodium glucose co- medical literature did not led to its withdrawal from the indicate an association market. The risk of transporter 2 (SGLT2) between these cancers and intussusception was estimated inhibitors infliximab treatment at 10-20 cases per 100,000 particularly when used for Rotashield® recipients. Risk of diabetic psoriasis or psoriatic arthritis. Consequently, two newer oral ketoacidosis However, the current safety rotavirus vaccines, the review of reports is limited by monovalent (RV1) Rotarix® Australia. The TGA has several factors, including an and the pentavalent (RV5) announced that serious cases increased risk of cancer in RotaTeq®, underwent large- of diabetic ketoacidosis (DKA) patients having certain scale clinical trials to ensure have been reported in patients underlying diseases or having that there was no elevated risk being treated with inhibitors of taken, or currently taking of intussusception prior to SGLT2. In some of these other medications. market approval in many cases, the presentation of countries (including the United Health Canada will continue to diabetic ketoacidosis was States, Europe and Singapore). monitor side effect information atypical. involving infliximab to identify However, recent post-licensure SGLT2 inhibitors, such as and assess potential harms. studies in some settings, canagliflozin, dapagliflozin and namely Latin America (Mexico Reference: empagliflozin, belong to a class and Brazil), Australia and the Summary Safety Review, of medicine that improves United States, have estimated Health Canada, 29 September glycaemic control in patients the attributable risk of 2015 (www.hc-sc.gc.ca) with type 2 diabetes mellitus. intussusception after rotavirus These medicines have the (See WHO Pharmaceuticals vaccination to be following indications: Newsletter No.5, 2015: Risk of approximately 1.5 to 6 per as an adjunct to diet and non-melanoma skin cancers, 100,000 infants vaccinated. exercise in patients with particularly in psoriasis patients in Australia) A study conducted in Asian type 2 diabetes mellitus for immunized infants with whom metformin is intussusception showed similar contraindicated, or not incidence rates. To date, the tolerated; Newer rotavirus HSA has received 16 reports of as combination therapy in intussusception suspected to patients with type 2 vaccines (Rotarix® be associated with this diabetes with other anti- and RotaTeq®) vaccine, eleven of which hyperglycaemic agents occurred within eight days of including insulin, when Risk of intussusception vaccination. Of these 11 cases, these, together with diet eight cases were reported after and exercise, do not Singapore. The HSA has the first dose and three cases provide adequate glycaemic advised health-care after the second dose. The control.
WHO Pharmaceuticals Newsletter No. 6, 2015 13
Safety of Medicines
This announcement follows a blood is too high. It works by There is a genetic variation in statement published on the binding potassium in the large the metabolism of tramadol, TGA website on 13 August intestine so it can be removed and some individuals convert 2015, with additional from the body. tramadol to the active form of information for health the opioid, called O- To reduce this potential risk, professionals. desmethyltramadol faster than prescribers and patients should usual. This can lead to higher The number of reports of DKA consider separating sodium blood levels, resulting in associated with SGLT2 polystyrene sulfonate dosing breathing difficulties that may inhibitors is low. However, DKA from other medications taken lead to death. is a serious, potentially life- by mouth by at least 6 hours. threatening complication and This includes both prescription The FDA has recommended there is a risk of delay in medications, such as that parents and caregivers of diagnosis and treatment as a antibiotics, blood pressure children taking tramadol who result of its presentation being lowering agents and blood notice any signs of slow or atypical in some cases. thinners, and those purchased shallow breathing, difficult or over-the-counter without a noisy breathing, confusion, or In some of the reported cases, prescription, such as antacids unusual sleepiness should stop just before or at the same time and laxatives. Health-care tramadol and seek medical as the DKA occurred, patients professionals should monitor attention immediately by experienced acute illness (such blood levels or clinical taking their child to the as, urinary tract infection, response to the other emergency room or calling the urosepsis, gastroenteritis, medications when appropriate. ambulance. influenza, trauma or surgery), reduced caloric or fluid intake, If the studies conducted by the The FDA is evaluating all and/or reduced insulin dose. sodium polystyrene sulfonate available information and will manufacturer confirm communicate final conclusions The underlying mechanism for significant interactions with and recommendations to the SGLT2 inhibitor-associated other medications, the FDA will public when the review is DKA has not been established. require all manufacturers of complete. Reference: sodium polystyrene sulfonate Reference: Medicines Safety Update, TGA, products to update product Drug Safety Communication, Vol. 6, No. 5, Ocotber 2015 information labels to include US FDA, 21 September 2015 (www.tga.gov.au) this information. (www.fda.gov) (See WHO Pharmaceuticals Reference: (See WHO Pharmaceuticals Newsletters No.5, 2015: Risk of Drug Safety Communication, Newsletter No.5, 2015: Tramadol ketoacidosis and sepsis in Japan US FDA, 22 October 2015 oral drops not for children under and No.4, 2015: Risk of diabetic (www.fda.gov) the age of 12 years in Australia) ketoacidosis in the United
Kingdom)
Tramadol Vemurafenib Sodium polystyrene Risk of potentiation of sulfonate Risk of slowed or difficult breathing in radiation toxicity Potential risk of drug children The United Kingdom. The interaction MHRA has warned prescribers USA. The US FDA has been of the risk of radiation toxicity investigating the use of USA. The US FDA requests with vemurafenib (Zelboraf®) tramadol in children aged 17 that the manufacturer of when given before, during, or years and younger, for risk of sodium polystyrene sulfonate after radiotherapy. (Kayexalate®) conduct studies slowed or difficult breathing. to investigate its potential to This risk may be increased in Vemurafenib is indicated as bind to other medications children treated with tramadol monotherapy for the treatment administered by mouth. This for pain after surgery to of adults with BRAF V600 could cause drug interactions, remove their tonsils and/or mutation-positive unresectable and decrease the effects of the adenoids. or metastatic melanoma. medication. Tramadol is not approved for A review of global data by EU Sodium polystyrene sulfonate use in children in USA, medicines regulators concluded is used to treat hyperkalaemia, however, data show it is being that vemurafenib can a serious condition in which used “off-label” in the potentiate radiation toxicity. In the amount of potassium in the paediatric population. phase III and phase IV clinical WHO Pharmaceuticals Newsletter No. 6, 2015 14
Safety of Medicines trials, approximately 1 in 20 patients who received vemurafenib had a radiation- related injury, (either radiation recall or radiation sensitisation). These cases occurred in patients who received radiation before, during, or after treatment with vemurafenib. Most cases were confined to the skin, but some involved visceral organs and resulted in a fatal outcome (including one case of radiation necrosis of the liver and two cases of radiation oesophagitis). Most patients had received doses of radiation ≥2 Gy/day. Up until October 2015, the MHRA has received two reports of radiation injury and related events in patients receiving vemurafenib.
The MHRA has advised health- care professionals that vemurafenib should be used with caution when given before, during, or after radiotherapy and prescribers should be aware of the risk of potentiation of radiation toxicity.
Reference:
Drug Safety Update, MHRA, Volume 9, issue 4: 2, November 2015
(www.gov.uk/mhra)
WHO Pharmaceuticals Newsletter No. 6, 2015 15
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 the WHO Global ICSR database, VigiBase®. The database contains over 10 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 31). For information on the UMC Measures of Disproportionate Reporting please refer to WHO Pharmaceuticals Newsletter Issue No. 1, 2012.
UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific research within the field of pharmacovigilance. 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].
Atomoxetine and neutropenia in paediatric patients Dr Ian Boyd, Australia
Summary appears predominantly in the adolescent and paediatric population. Atomoxetine is a relatively potent inhibitor of the presynaptic noradrenaline transporter, a moderate inhibitor of 5HT uptake, and a weak inhibitor of Introduction dopamine uptake with minimal affinity for the other noradrenergic receptors. It is indicated for Atomoxetine is a relatively potent inhibitor of the the treatment of attention deficit hyperactivity presynaptic noradrenaline transporter, a moderate disorder (ADHD) as defined by DSM-IV criteria in inhibitor of 5HT uptake, and a weak inhibitor of children 6 years of age and older, adolescents and dopamine uptake with minimal affinity for the adults. After the elimination of duplicates, there other noradrenergic receptors. Atomoxetine has are currently (4 February 2015) 25 individual case moderate affinity for 5HT2 and GABAA receptors safety reports (ICSRs) in the WHO Global ICSR but poor affinity for most other receptors. It is database, VigiBase® of neutropenia in association indicated for the treatment of attention deficit with atomoxetine in children and adolescents. The hyperactivity disorder (ADHD) as defined by DSM- reports are from Canada, Finland, Germany, IV criteria in children 6 years of age and older, Ireland, Switzerland, the United Kingdom and the adolescents and adults. The most frequent adverse United States. Atomoxetine was the only drug reactions reported during clinical trials of suspected in 20 of the 25 cases. The outcome of atomoxetine in children and adolescents including the neutropenia was indicated in 15 reports. The gastrointestinal reactions, increased blood patients were reported as recovered or recovering pressure and heart rate, decreased appetite, in 10 cases and not recovered in the remaining decreased weight and skin reactions. The product five cases. In the cases where recovery was information does not refer to blood disorders.1 reported, the drug was withdrawn in seven cases, the dose increased in one case and the fate of the Neutropenia is a high level term in WHO-ART with drug was unknown in the remaining two cases. preferred terms consisting of neutropenia, Time to onset showed a clustering around 14-27 granulocytopoenia and leukopenia. days. The preferred term, neutropenia, which is the subject of this signal, is defined as a decrease to Case reports in VigiBase® suggest that there is a 9 possible signal for the association of atomoxetine less than 1.5 x 10 /L of segmented polymorphonuclear and band cells. Neutropenia is and neutropenia. The fact there was a positive 9 2 dechallenge in seven of the 10 reports where considered as ‘‘severe’’ below 0.5 x 10 /L. recovery was documented is suggestive of a drug- induced effect. This is supported by the time to onset of 14-27 days which is consistent with drug- Reports in VigiBase® induced neutropenia. However, the possible As of 4 February 2015, there are a total of 35 association of atomoxetine with neutropenia individual case safety reports (ICSRs) of neutropenia in association with atomoxetine in the WHO Pharmaceuticals Newsletter No. 6, 2015 16
Signal
WHO Global ICSR database, VigiBase®. Out of cases and red cell disorders in three cases. Hepatic these reports, after the elimination of duplicates, reactions were reported in five cases and weight there are 25 cases of neutropenia in children and decrease was reported in four cases. adolescents up to 17 years of age (Table 1). Of the remaining reports, ages range from 22 years to 65 years in seven cases and the remaining case Literature and Labelling has reported age unknown. The reports from children and adolescents were submitted from the The product literature does not refer to neutropenia nor does it mention other blood United Kingdom (9 reports), United States (7), 1 Finland (4), Canada (2), Germany, Ireland and disorders. No reports of neutropenia in Switzerland (1 each). The patients ranged in age association with atomoxetine could be found in the from 6 to 17 years with a median of 12 years. literature. There were 23 males and 2 females. Atomoxetine was the only drug suspected in 20 of Discussion the 25 cases. There were other drugs also suspected in the remaining five cases and they Case reports in VigiBase® suggest that there is a included drugs for treatment of psychotic disorders possible signal for the association of atomoxetine (olanzapine, risperidone) in two cases, an and neutropenia in children and adolescents. antidepressant (fluoxetine) in one case, an Atomoxetine was the only drug suspected in 20 of anticonvulsant (valproic acid) in one case and the 25 cases. In three of the remaining five cases, another drug for the treatment of ADHD there were co-suspected drugs for which (methylphenidate) in the remaining case. Three of neutropenia is labelled. these drugs, olanzapine, risperidone and valproic Time to onset was reported in 11 of the reports acid, refer to neutropenia in their product and ranged from 14 days to 10 months. The information and these drugs may each be a median time was 50 days and there was a possible cause in the three cases where these clustering of five cases between 14 and 27 days. drugs are suspect (Cases 5, 7 and 24). This is consistent with drug- induced neutropenia. Concomitant drugs were reported in 10 of the 25 cases and showed a similar trend to that observed The outcome of the neutropenia was indicated in with the co-suspected drugs with use of 15 reports. The patients were reported as antipsychotic, anticonvulsant, and antidepressant recovered or recovering in 10 cases and not drugs along with the use of other treatments for recovered in the remaining five cases. In the cases ADHD. where recovery was reported, the drug was withdrawn in seven cases, the dose was increased Time to onset was reported in 11 of the reports in one case and the fate of the drug was unknown and ranged from 14 days to 10 months. The in the remaining two cases. In the five cases median time was 50 days and there was a where the patient had not recovered, the drug had clustering of five cases between 14 and 27 days. been discontinued in four cases and the fate of the The outcome of the neutropenia was indicated in drug was unknown in the remaining case. The 15 reports. The patients were reported as seven cases with a positive dechallenge is recovered or recovering in 10 cases and not supportive of a drug-induced effect. The reports recovered in the remaining five cases. In the cases without recovery may simply represent cases that where recovery was reported, the drug was have been reported before the reaction had withdrawn in seven cases, the dose was increased resolved. Drug-induced neutropenia usually 3 in one case and the fate of the drug was unknown resolves after 10 days. in the remaining two cases. In the five cases The possible association of atomoxetine with where the patient had not recovered, the drug had neutropenia appears predominantly in the been discontinued in four cases and the fate of the adolescent and paediatric population. After the drug was unknown in the remaining case. elimination of duplicates, there is a total of 33 The indication for use was stated in 15 reports and reports of neutropenia in association with was ADHD in all 15 cases. Dosage ranged from 18 atomoxetine in the total population. Twenty-five of mg to 100 mg including some cases in which the these reports were reported in the adolescent and dose was escalated. paediatric age groups which represents 75.8% of all the reports. While it may be considered that Other reactions were reported in 19 of the 25 atomoxetine is used preferentially in the younger reports. Other blood disorders were reported in 15 age groups, overall reporting in VigiBase® of these cases and these were mostly other white indicates that of the 16,504 reports submitted, the cell disorders, particularly leucopoenia, in 14 cases age group from 2 to 17 years represents 60% of although thrombocytopenia was reported in five the total reports.
WHO Pharmaceuticals Newsletter No. 6, 2015 17
Signal
Table 1. Case overview of reports from children and adolescents in VigiBase® of neutropenia in association with atomoxetine
Case Age/Sex Other suspected (S) or concomitant (C) Reactions (WHO-ART preferred terms) Outcome drugs
1* 14/M Sertraline (C) Neutropenia, abdominal pain, bone marrow aplasia, fatigue, Recovering hepatitis, thrombocytopenia 2 12/M Pipamperone (C) Neutropenia, anaemia, leukopenia, lymphocytes atypical Unknown 3 12/M Fluoxetine (S) Neutropenia Unknown 4 11/M None Neutropenia, alopecia, weight decrease Recovered 5 14/M Risperidone (S) Neutropenia Unknown 6* 14/F Sertraline (C) Neutropenia, hepatitis cholestatic, hepatic fibrosis, hepatitis Recovered viral, thrombocytopenia, educational problem*** 7 13/M Olanzapine (S) Neutropenia, alkaline phosphatase increased, ALT Unknown Aripiprazole, escitalopram, increased, AST increased, lymphocytosis, monocytosis, guaifenesin (C) blood calcium abnormal#, protein total abnormal*** 8 17/M Valproic acid, sertraline (C) Neutropenia, lymphocytosis Unknown 9 9/M None Neutropenia, abdominal pain, flatulence, gastroenteritis, Recovered haematemesis, hypotension, intestinal obstruction, leukopenia, peripheral ischaemia, systemic inflammatory response syndrome, tachycardia, thrombocytopenia 10 11/M Methylphenidate (S) Neutropenia, leukopenia Unknown 11 16/M None Neutropenia, leukopenia Recovering 12 10/M None Neutropenia, leukopenia, thrombocytopenia Not recovered 13 11/M None Neutropenia, abdominal pain, agitation, anorexia, fatigue, Recovered hallucination, weight decrease 14 12/M Risperidone (C) Neutropenia, leukopenia, weight decrease Not recovered 15 12/F None Neutropenia, leukopenia Recovered 16 11/M None Neutropenia, leukopenia Recovered
17** 11/M Salbutamol (C) Neutropenia Recovering 18 6/M None Neutropenia, leukopenia, rash Recovered 19 7/M Methylphenidate (C) Neutropenia, peripheral ischaemia Unknown 20 10/M None Neutropenia Unknown 21** 11/M Methylphenidate, salbutamol (C) Neutropenia Not recovered 22 11/M None Neutropenia, alkaline phosphatase increased, Recovered hypotension postural, urticaria 23 15/M Methylphenidate (C) Neutropenia Not recovered
24 14/M Valproic acid (S) Neutropenia, bilirubinaemia, epilepsy, lymphopenia, Not recovered Valproic acid (C) thrombocytopenia, weight decrease 25 12/M Melatonin, methylphenidate (C) Neutropenia Not recovered 26 15/M None Neutropenia, leukopenia Unknown 27 10/F None Neutropenia, ALT increased, anaemia, AST increased, Unknown blood disorder, Epstein-Barr virus, hepatic function abnormal, hepatomegaly, monocytopenia, thrombocytopenia
*Cases 1 and 6 are duplicates **Cases 17 and 21 are duplicates ***MedDRA terms
Conclusion suggestive of a drug-induced effect. The clustering of five cases with an onset between 14 and 27 In summary, there are 25 reports from children days is consistent with drug-induced neutropenia. and adolescents associating neutropenia with the However, the possible association of atomoxetine use of atomoxetine. Atomoxetine was the only with neutropenia appears predominantly in the drug suspected in 20 of the 25 cases. The fact adolescent and paediatric population. there was a positive dechallenge in seven of the 10 reports where recovery was documented is WHO Pharmaceuticals Newsletter No. 6, 2015 18
Signal
References and covered the period from 26 November 2002 to 26 November 2005, with a second review 1. Therapeutic Goods Administration. Product completed in 2014. As both reviews revealed Information for Strattera. URL: similar findings and conclusions, we are providing https://www.ebs.tga.gov.au/ebs/picmi/ the high level results of the second review as an picmirepository.nsf/pdf ?OpenAgent&id=CP- illustrative example of the evaluations undertaken. 2010-PI-04269-3. Accessed: 30 January Of note, the results of the last review were 2015. submitted to the EU Regulatory Agencies in 2014 and no further questions were raised or further 2. The Council for International Organizations of actions deemed necessary at that time. Medical Sciences (CIOMS). Reporting Adverse Drug Reactions: Definitions of Terms and In the second assessment, cases reported between Criteria for their Use. CIOMS, Geneva, 1999. 26 May 2008 and 26 May 2013 and coded to the MedDRA preferred term “neutropenia” were URL: http://www.cioms.ch/publications/ reviewed. Time to onset ranged from reporting_adverse_drug.pdf. Accessed: approximately 2 months to 11 months, and did not 30 January 2015. reflect a pattern indicative of a treatment- 3. Longo DL, Fauci AS, Kasper DL, Hauser SL, emergent trend. Thirteen neutropenia cases were Jameson JL, Loscalzo J, eds. Harrison’s identified, but 7 (54%) of those cases either did Principles of Internal Medicine, 18th ed. not provide adequate information to assess the McGraw Hill, New York, 2011. event or presented medical history, historical, or concurrent use of other medication that may provide an alternative explanation for the onset of
neutropenia, for example, medical conditions that reduce cell line counts such as human immunodeficiency virus, a family history of Response from Eli Lilly & Company autoimmune disorders, or use of medications such as risperidone or valproate. Of the remaining 6 cases, which involved adolescent patients, Thank you for the opportunity to provide our 5 described neutropenia and 1 neutropenia/ comments on the possible signal that has been leukopenia. Of the 6 patients, 4 patients generated from the UMC’s VigiBase® safety discontinued atomoxetine treatment while database and the thorough assessment conducted 2 patients continued atomoxetine. Although in 3 of by Dr Boyd. Eli Lilly & Company (Lilly) routinely the 4 patients who discontinued atomoxetine the queries reported adverse events in Lilly’s internal event resolved, these cases did not provide safety database and the FDA Adverse Event sufficient information, for example, medical Reporting System for early signs of potential history, concomitant medication use, and/or the adverse drug reactions in patients treated with patient’s baseline laboratory values to permit Lilly drugs. Lilly recognizes the importance of early adequate medical assessment. Importantly, signal detection and also acknowledges that without baseline measurements, it is impossible to database queries are only one method that can be know whether the condition existed before the employed. Additionally, Lilly’s review of the patients began taking atomoxetine. reported adverse events involves medical assessment of the narratives where information Based on the evaluations summarised above, Lilly provided and not captured in the standard fields has concluded from its previous reviews that there often helps to refine the assessment. is not sufficient evidence to support a causal association or increased risk between atomoxetine Consistent with the UMC, Lilly recognizes that treatment and neutropenia in the treated signals are uncertain and preliminary in nature population. Available information would indicate (UMC, Signals selected by UMC and the clinical that the events reported are either incidental review panel: How the process works). This is findings or may possibly be related to other causes because, for any given adverse event report including pre-existing conditions or concomitant considered in generating a signal, there is no medications, as mentioned above, though more certainty that the adverse event was caused by information in these cases is needed. In addition, the suspected drug. Rather, the adverse event as Dr Boyd mentioned in his article, no reports of could have resulted from the underlying condition neutropenia in association with atomoxetine could being treated, a comorbid condition, a concomitant be found in the literature. Case reports and other medication, or may simply be the result of chance. sources of information that include suspected neutropenia adverse events in atomoxetine- Lilly has completed two reviews of blood treated patients will be reviewed by Lilly and dyscrasias including neutropenia which involved continue to be monitored through routine assessment of individual case narratives, as well pharmacovigilance. as all available information from other data sources. The first review was conducted in 2006
WHO Pharmaceuticals Newsletter No. 6, 2015 19
Signal
Deferasirox and pancreatitis in paediatric patients Dr Ian Boyd, Australia
Summary were reported in about 2% of patients. Serious acute pancreatitis may potentially occur as a Deferasirox is an orally active chelator that is complication of gallstones (and related biliary highly selective for iron (III). Deferasirox disorders).1 promotes excretion of iron, primarily in the faeces. It is indicated for the treatment of chronic iron Acute pancreatitis is an inflammatory disease of overload due to frequent blood transfusions in the pancreas, characterized by abdominal pain, patients with beta thalassaemia major aged 6 frequently severe and of sudden onset, and almost years and older and for the treatment of chronic always accompanied by increased pancreatic iron overload due to blood transfusions when enzymes in the blood and urine. Although in about deferoxamine therapy is contraindicated or 80% of cases the disease is mild, severe attacks inadequate. There are currently (March 2015) 14 may lead to shock with renal and pulmonary individual case safety reports (ICSRs) in the WHO insufficiency, which may prove fatal. In non-fatal Global ICSR Database, VigiBase® of pancreatitis in cases, clinical, morphological and functional children and adolescents in association with recovery usually occurs. Drug-induced pancreatitis deferasirox. The reports are from France, is usually an acute condition. The clinically Germany, South Africa, the United Kingdom and suspected diagnosis of acute pancreatitis should the United States. Deferasirox was the only drug always be confirmed by biochemical investigations. suspected in 11 of the 14 cases. The outcome of Chronic pancreatitis is in most cases characterized the pancreatitis was indicated in 10 reports. The by recurrent or persisting abdominal pain. The patients were reported as recovered or recovering diagnosis cannot be satisfactorily established in nine cases and the outcome was fatal in the unless there is evidence of persistent remaining case. In the cases where recovery was morphological change or pancreatic insufficiency, reported, the drug was withdrawn in six cases and manifested by, for example, steatorrhoea or continued in the other three cases. diabetes mellitus. Pancreatic enzymes in blood or urine are usually increased during attacks of acute Case reports in VigiBase® suggest that there is a pain, but usually to a less extent than in acute signal for the association of deferasirox and pancreatitis.2 pancreatitis. Time to onset is consistent with a drug-induced effect and although it does appear to Gallstones are the leading cause of acute be longer than usual in some cases, this is pancreatitis (30-60% in most series). Alcohol is consistent with other reports of drug-induced the second most common cause, responsible for pancreatitis. The response to dechallenge is 15-30% cases in the United States. Other more supportive of a drug-induced effect. However, the common causes include endoscopic retrograde possible association of deferasirox with choliangiopancreatography, hypertriglyceridaemia, pancreatitis appears predominantly in the trauma, surgery and drugs.3 Approximately 0.1- paediatric population. 2% of cases of acute pancreatitis are drug- related.4 Responsible drugs include azathioprine,
6-mercaptopurine, oestrogens, tetracycline, Introduction valproic acid, sulindac, ACE inhibitors, HMG-CoA reductase inhibitors, isoniazid and anti-HIV Deferasirox is an orally active chelator that is medications.3,4 highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, Reports in VigiBase® primarily in the faeces. It is indicated for the treatment of chronic iron overload due to frequent As of March 2015, after the elimination of blood transfusions in patients with beta duplicates, there are a total of 14 individual case thalassaemia major aged 6 years and older and for safety reports (ICSRs) of pancreatitis in the treatment of chronic iron overload due to association with deferasirox in children and blood trans- fusions when deferoxamine therapy is adolescents in the WHO Global ICSR Database, contraindicated or inadequate. The most frequent VigiBase® (see Table 1). The reports describe reactions reported during chronic treatment with pancreatitis in 10 female and 4 male subjects aged deferasirox in adult and paediatric patients include from 4 to 16 (median: 12) years old. The reports gastrointestinal disturbances in about 26% of were submitted from the United Kingdom (6 patients (mainly nausea, vomiting, diarrhoea or reports), France (4), South Africa (2), Germany abdominal pain), skin rash in about 7% of patients and the United States (1 each). and increases in serum creatinine in about 36% of patients. Gallstones and related biliary disorders
WHO Pharmaceuticals Newsletter No. 6, 2015 20
Signal
Deferasirox was the only drug suspected in 11 of reported, the drug was withdrawn in six cases and the 14 cases. There were other drugs also continued in the other three cases. In the case suspected in the remaining three cases and they where the patient died, the drug was withdrawn. included azithromycin, ceftriaxone and The indication for use was stated in 11 reports and hydroxycarbamide in one case, amoxicillin, indicated iron overload in four cases, sickle cell clarithromycin and omeprazole in another case, disease in four cases, thalassaemia major in two and deferoxamine in the remaining case. cases and diamond-blackfan anaemia in the Concomitant drugs were reported in four cases remaining case. Dosage was stated in 12 reports and included folic acid (3 cases) and antibiotics and ranged from 250 mg daily to 2000 mg daily (3). (median: 813 mg). Time to onset was reported in nine of the reports Other reactions were reported in seven reports and ranged from 17 days to over five years and included hepatic reactions in six reports and (median: 11 months). The outcome of the abdominal pain in five reports. Renal complications pancreatitis was indicated in 10 reports. The were reported in four cases, vomiting was patients were reported as recovered or recovering reported in three cases with fever and increased in nine cases and the outcome was fatal in the amylase was present in two cases. remaining case. In the cases where recovery was
Table 1. Case overview of reports in VigiBase® of pancreatitis in association with deferasirox
Case Age/Sex Other suspected (S) or concomitant (C) Reactions (WHO-ART preferred terms) Outcome drugs 1 4/F None Pancreatitis Died 2 8/F None Pancreatitis Recovering 3 5/M None Pancreatitis Unknown 4 16/F Azithromycin, ceftriaxone, hydroxycarbamide Pancreatitis, fever, hepatitis cholestatic, hepatocellular Recovered (all S) damage, hepatomegaly 5 16/F Benzoyl peroxide, benzoyl peroxide/ Pancreatitis, abdominal pain, azotaemia, coagulation time Recovered clindamycin phosphate, folic acid, increased, diabetes mellitus, disseminated intravascular hydrocortisone, hydroxycarbamide, coagulation, fluid overload, hepatic function abnormal, INR tetracycline (all C) increased, renal failure acute, respiratory insufficiency
6 12/F None Pancreatitis Unknown 7 16/M None Pancreatitis, abdominal pain, back pain, jaundice, hepatitis Recovered 8 12/M Amoxicillin, clarithromycin, omeprazole (all S) Pancreatitis, abdominal pain, amylase increased, Recovered fever, vomiting 9 16/M Ascorbic acid, copper (both C) Pancreatitis, abdominal pain, coagulation disorder, gastritis, Unknown hepatic function abnormal, hepatocellular damage, nephropathy toxic, vomiting
10 12/F Codeine, diclofenac, folic acid, paracetamol, Pancreatitis Recovered phenoxymethylpenicillin (all C)
11 12/F None Pancreatitis Unknown 12 12/F Folic acid, phenoxymethylpenicillin (both C) Pancreatitis Recovering 13* 14/F Deferoxamine (S) Pancreatitis, abdominal pain, ALT increased, amylase Recovering increased, anaemia, ascites, azotaemia, bilirubinaemia, C-reactive protein increased, hepatic enzymes increased, hepatitis, hypoproteinaemia, iron metabolism disorder, leukocytosis, lymphopenia, splenomegaly, urticaria, vomiting, blood creatinine decreased**
14* 14/F Deferoxamine (C) Pancreatitis, abdominal pain, ALT increased, amylase Recovering increased, anaemia, ascites, azotaemia, bilirubinaemia, C-reactive protein increased, hepatic enzymes increased, iron metabolism disorder, leukocytosis, lymphopenia, splenomegaly, urticaria, vomiting, blood creatinine decreased**, ultrasound abdomen abnormal**
15 7/F None Pancreatitis, acidosis, hepatocellular damage, renal Recovered failure acute
*Cases 13 and 14 are duplicates **MedDRA terms
WHO Pharmaceuticals Newsletter No. 6, 2015 21
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Literature and Labelling as deferasirox and was continued along with deferasirox and would seem to be a possible The product literature does not refer to cause. In case 8, pancreatitis occurred eight days pancreatitis although it does indicate that after omeprazole was commenced and at the end gallstones and related biliary disorders were of a seven day course of clarithromycin and reported in about 2% of patients and that serious amoxicillin while deferasirox had been taken for up acute pancreatitis may potentially occur as a to three years. Recovery occurred after the complication of gallstones (and related biliary withdrawal of deferasirox while omeprazole was disorders).1 continued. In case 13, deferoxamine, although a In the literature, Galanello and co-workers suspected drug, had been withdrawn 18 days reported on a Phase II clinical trial on the safety before onset and appears an unlikely cause as it and tolerability of deferasirox in paediatric patients was only after it was replaced by deferasirox that with transfusion-dependent beta thalassaemia pancreatitis occurred. major. Of the 39 patients studied, one developed Time to onset was reported in nine of the reports pancreatitis but this was considered by the authors and ranged from 17 days to over five years to be either a typical complication of thalassaemia (median: 11 months). This is reasonably or an incidental medical problem. It was not consistent with a drug-induced effect although considered to be treatment-related and did not onset in some cases appears to be rather longer lead to discontinuation.5 than anticipated. However, Tatley noted that time Chang and colleagues reported on a study which to onset may be six (or even nine) months after evaluated whether twice daily deferasirox commencement of the suspected causative treatment showed increased efficacy or tolerability medicine.12 Moreover, Balani and Grendell also in unresponsive or intolerant patients. Seven of observed that onset can be delayed. Pancreatitis in the 25 patients received twice-daily deferasirox association with HMG-CoA reductase inhibitors because of intolerance to the once-daily dose. One rarely occurs early, onset of pancreatitis in of these patients had developed pancreatitis in association with ACE inhibitors ranges from five which only elevated amylase levels were noted.6 weeks to a year, onset of pancreatitis with valproic acid ranges from three to 17 months and onset of Vichinsky et al. evaluated the long-term safety and pancreatitis with oestrogen and sulindac ranges efficacy of deferasirox in patients with sickle cell from a few weeks to five years.4 disease (SCD) who first completed a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled The outcome of the pancreatitis was indicated in study and then entered a 4-year extension, 10 reports. The patients were reported as continuing to receive deferasirox, or switching recovered or recovering in nine cases and the from DFO to deferasirox. Of the 185 patients outcome was fatal in the remaining case. In the assessed, one withdrew from the study due to cases where recovery was reported, the drug was pancreatitis which had a suspected relationship to withdrawn in six cases and continued in the other deferasirox treatment. Another patient developed three cases. This is reasonably supportive of a increased blood amylase also suspected to be drug-induced reaction. In case 5, however, both related to deferasirox treatment.7 folic acid and tetracycline were withdrawn on the same date as deferasirox. Although neither were suspected, pancreatitis is listed in the product Discussion information for tetracycline and is a possible cause.13 Case reports in VigiBase® suggest that there is a signal for the association of deferasirox and The product literature does not refer to pancreatitis in paediatric patients. Deferasirox was pancreatitis although it does indicate that the only drug suspected in 11 of the 14 cases. gallstones and related biliary disorders were There were other drugs also suspected in the reported in about 2% of patients and that serious remaining three cases and they included acute pancreatitis may potentially occur as a azithromycin, ceftriaxone and hydroxycarbamide complication of gallstones (and related biliary 1 in one case, amoxicillin, clarithromycin and disorders). None of the patients reported in this omeprazole in another case and deferoxamine in series, however, appeared to have gallstones. the remaining case. Azithromycin, ceftriaxone, There are three reports in the literature in which hydroxycarbamide and clarithromycin have a isolated patients in clinical trials of deferasirox reference to the possibility of pancreatitis as a developed pancreatitis. One of these was a 5 possible adverse reaction in their product paediatric patient. In the other reports, the age of information.8,9,10,11 In case 4, ceftriaxone was used the patients developing pancreatitis was not stated for only two days and ceased five days before but 7 of the 11 patients included in the efficacy onset and azithromycin was also only used for two analysis reported by Chang et al. were aged from days and ceased one day before onset. These 12 to 20 years while 48.6% of the patients would appear to be unlikely causes. reported by Vichinsky et al. were aged 16 years or 6,7 Hydroxycarbamide was initiated at the same time less.
WHO Pharmaceuticals Newsletter No. 6, 2015 22
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The possible association of pancreatitis with 5. Galanello R, Piga A, Forni GL, Bertrand Y, deferasirox appears predominantly in the Foschini ML, Bordone E et al. Phase II clinical adolescent and paediatric population. There is a evaluation of deferasirox, a once-daily oral total of 62 reports of pancreatitis in association chelating agent, in pediatric patients with b- with deferasirox in the total population. The age is thalassemia major. Haematologica reported in 28 of them. The fact that 14 of these reports were reported in the adolescent and 2006;91:1343-51. paediatric age groups represents 50% of these 6. Chang H-H, Lu M-Y, Liao Y-M, Lin P-C, Yang reactions in this age group. While it is possible Y-L, Lin D-T et al. Improved efficacy and that deferasirox is used preferentially in the tolerability of oral deferasirox by twice-daily younger age groups, overall reporting in dosing for patients with transfusion- VigiBase® indicates that of the 7,148 deferasirox dependent b-thalassemia. Pediatr Blood reports submitted where the age was known, the age group from 2 to 17 years represents only Cancer. 2011;56:420-4. 16.8% of the total reports. 7. Vichinsky E, Bernaudin F, Forni GL, Gardner R, Hassell K, Heeney MM et al. Long-term
safety and efficacy of deferasirox (Exjade) for Conclusion up to 5 years in transfusional iron-overloaded In summary, there are 14 cases associating patients with sickle cell disease. Br J pancreatitis with the use of deferasirox in Haematol. 2011;154:387-97. paediatric and adolescent patients. Deferasirox 8. Electronic Medicines Compendium. Summary was the only drug suspected in 11 of the 14 cases. of Product Characteristics for Zithromax. URL: Time to onset is consistent with a drug-induced http://www.medicines.org.uk/emc/medicine/ effect and although it does appear to be longer 1477. Accessed: 22 April 2015. than usual in some cases, this is consistent with other reports of drug-induced pancreatitis. The 9. Electronic Medicines Compendium. Summary response to dechallenge is supportive of a drug- of Product Characteristics for Rocephin. URL: induced effect. There is some support in the http://www. medicines.org.uk/emc/medicine/ literature for the association with three reports in 1729. Accessed: 22 April 2015. which isolated patients in clinical trials of 10. Electronic Medicines Compendium. Summary deferasirox developed pancreatitis. However, the of Product Characteristics for Hydrea. URL: possible association of deferasirox with http://www. medicines.org.uk/emc/medicine/ pancreatitis appears predominantly in the paediatric population. 19081. Accessed: 22 April 2015. 11. Electronic Medicines Compendium. Summary
of Product Characteristics for Clarithromycin. References URL: http:// www.medicines.org.uk/emc/ 1. European Medicines Agency. Summary of medicine/22754. Accessed: 22 April 2015. Product Characteristics for Product 12. Tatley M. Drug-induced pancreatitis: an Information for Exjade. URL: unlucky DIP. Prescriber Update 2005;26:32-3. http://www.ema.europa.eu/docs/en_GB/ 13. Electronic Medicines Compendium. Summary document_library/EPAR_-_Product_ of Product Characteristics for Tetracycline Information/ human/000670/WC500033925. Tablets. URL: http://www.medicines.org.uk/ pdf. Accessed: 21 April 2015. emc/medicine/24185. Accessed: 13 May 2. The Council for International Organizations of 2015. Medical Sciences (CIOMS). Reporting adverse
drug reactions: Definitions of terms and criteria for their use. CIOMS, Geneva, 1999. URL: http://www.cioms.ch/publications/ Response from Novartis reporting_adverse_drug.pdf. Accessed: 14 April 2015. 3. Longo DL, Fauci AS, Kasper DL, Hauser SL, In response to a WHO signal evaluation on the Jameson JL, Loscalzo J, eds. Harrison’s association of deferasirox and pancreatitis in Principles of Internal Medicine, 18th ed. paediatric patients, Novartis presents the McGraw Hill, New York, 2011. Company analysis of this signal. To date, the patient exposure of deferasirox (Exjade) is 4. Balani AR, Grendell, JH. Drug-induced estimated to be over 245,000 patient-treated- pancreatitis: incidence, management and years including > 7,200 in clinical trials. Novartis prevention. Drug Saf. 2008;31:823-37. has reviewed 38 cases of pancreatitis in paediatric patients in the Novartis safety database WHO Pharmaceuticals Newsletter No. 6, 2015 23
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(spontaneous, clinical trial, and literature reports). Patients with transfusional iron overload resulting In 3 cases there were no identifiable confounders from haemolytic conditions (including thalassaemia to exclude a possible causal relationship; therefore and sickle cell disease [SCD]) have an increased Novartis cannot exclude an association between risk of biliary-mediated pancreatitis with rates events of acute pancreatitis in paediatric patients reaching 20-40% (Silva 2015, Cosentini 2005). and treatment with Exjade. Patients with SCD have an increased risk of cholelithiasis from bilirubin stones that result from
increased haemolysis and serum bilirubin Background concentration (Amoako 2013). Pancreatitis has several causes and symptoms. As stated in the current label, cholelithiasis has Acute Pancreatitis (AP) is defined by the presence been uncommonly reported in clinical trial patients of 2 of the 3 following criteria (Harrison’s Principles treated with Exjade, and there have been post- of Internal Medicine, 18th Edition): marketing reports of serious acute pancreatitis • Abdominal pain characteristic of AP; which occurred as a complication of gallstones • Serum amylase and/or lipase >3 times the (and related biliary disorders). Both cholelithiasis upper limit of normal (ULN); and and biliary-mediated pancreatitis are documented • Characteristic findings of AP on cross- as adverse events in the product information. sectional abdominal imaging (preferably by
computed tomography (CT) scan). Preclinical data The prevalence of acute pancreatitis in adults ranges between 6 and 45/100,000 person-years in Inflammatory and degenerative changes in the various populations and ages, with lesser rates gallbladder and bile ducts were seen in marmosets reported in younger patients. In children, the at high doses of deferasirox that generally resulted estimated incidence of pancreatitis ranges in morbidity/mortality. Similar findings were between 3.6 and 13.2/100,000 children (Morinville observed in the intra-hepatic bile ducts in 2012). The etiologies of pancreatitis are quite transgenic mice at 100 mg/kg (standard diet) after varied in childhood, and differ from those seen in 4 and 26 weeks of treatment. adults. In pre-clinical toxicity testing, the pancreas was In a review by Latif, the most common etiologies not identified as a target organ. of AP in children were biliary (32.6%), medication toxicity (25.6%), and idiopathic (22.3%) (Latif 2008). Inflammatory bowel disease presenting as Individual case safety reports from Novartis acute pancreatitis was more frequent among the safety database. paediatric population (Broide, 2011). Hereditary pancreatitis is the second most common congenital Due to the unavailability of exposure data by age pancreatic disorder following cystic fibrosis in group, an estimated reporting rate in the children (Dayal, 2013). paediatric population (age below 18 years) cannot be calculated. Three possible etiological factors for pancreatitis in the population treated with Exjade include biliary As of 4 June 2015, there are 38 cases of Exjade- sludge formation, haem-induced inflammatory pancreatitis drug-event combinations in paediatric cytokines, and hypoxia. patients in the Novartis safety database (spontaneous, clinical trial, literature reports). In Biliary sludge may be an antecedent of gallstones eleven cases, there was limited information, and also lead to pancreatitis even in the absence questionable diagnosis, or negative rechallenge for of gallstones (Lee 1988). Infections are frequent in Exjade. In 13 cases, there was evidence of biliary patients with thalassemia or SCD, requiring the tract etiology for pancreatitis. Three cases were frequent use of antibiotics, including ceftriaxone, temporarily associated with other medication which seems to promote sludge formation. known to induce pancreatitis. One had a prior history of chronic pancreatitis. Seven patients Haem released from hame proteins has been developed pancreatitis in the setting of concurrent shown to promote a systemic inflammatory acute illness associated with pancreatitis (sickle response and organ failure. The important role of cell crisis – 2; acute renal failure – 1; new onset inflammatory cytokines in the pathogenesis of Crohn’s disease – 1; acute systemic infection – 3) acute pancreatitis is well known (Saruc 2003). In the remaining three cases with sufficient Reduced perfusion of the pancreas leading to information for assessment (two with underlying hypoxia and ischemia is a well-described beta-thalassaemia, and one with SCD), no mechanism causing or worsening pancreatitis. The confounding factor could be identified, and a pathological oxygen saturation of haemoglobin in causal association with Exjade could not be thalassaemia has been described (Löhr 2014). AP excluded. has been depicted as a rare manifestation of vaso- occlusive painful crisis in SCD (Ahmed S 2003). WHO Pharmaceuticals Newsletter No. 6, 2015 24
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Conclusions 5. Dayal A and Prasad VSV. (2013) Acute While the majority of sufficiently documented pancreatitis in children. Recent advances in cases included alternative explanations and/or pediatrics. Pediatric Gastroenterology, were confounded, three cases contained no Hepatology and Nutrition. Special volume 23. identifiable confounder; a causal relationship could Chapter 22:330-337. therefore not be excluded between acute 6. Harrison’s Principles of Internal Medicine, 18th pancreatitis and deferasirox treatment in the Edition. Greenberger NJ; Conwell DL; Wu BU, paediatric population. Banks PA. “Chapter 313. Acute and Chronic Although it is recognized that the underlying Pancreatitis.” Harrison’s Principles of Internal disease in Exjade-treated patients could present a Medicine, 18e. Eds. Longo DL, Fauci AS, contributing factor to the etiology of pancreatitis, Kasper DL et al. New York, NY: McGraw-Hill, via haemolysis- induced biliary complications, 2012. AccessMedicine. Web. 08Jun 2015 possible hame-induced inflammatory mediators, or ischemia-mediated effects (particularly in sickle 7. Latif SU, Park A, Shah AU, et al (2008) cell crises), Novartis considers it pertinent to add Pediatric pancreatitis: Epidemiology, “Acute pancreatitis” to the label as an adverse etiologies, and recurrence, a retrospective drug reaction derived from post-marketing reports study. Gastroenterology;134(4, Suppl. 1): with an unknown frequency due to the severity A141. and specificity of the event. 8. Lee SP, Maher K, Nicholls JF. (1988) Origin and fate of biliary sludge. Gastroenterology; References 94(1):170-6. 9. Löhr JM, Haas S. (2014) Can a polymorphism 1. Ahmed S, Siddiqui AK, Siddiqui RK, et al in the thalassemia gene and a heterozygote (2003) Acute pancreatitis during sickle cell CFTR mutation cause acute pancreatitis? vaso-occlusive painful crisis. Am J World J Clin Cases ;2(3): 62-66. Hematol;73(3):190-3. 10. Morinville VD, Husain SZ, Bai H, et al (2012) 2. Amoako MO, Casella JF, Strouse JJ. (2013) Definitions of pediatric pancreatitis and survey High rates of recurrent biliary tract of present clinical practices. J Pediatr obstruction in children with sickle cell disease. Gastroenterol Nutr;55(3):261-5. Pediatr Blood Cancer;60(4):650-2. 11. Saruc M, Yuceyar H, Turkel N, et al (2003) An 3. Broide E, Dotan I; Weiss B, et al (2011) experimental model of hemolysis-induced Idiopathic pancreatitis preceding the diagnosis acute pancreatitis. Braz J Med Biol Res. of inflammatory bowel disease is more 36(7):879-86. frequent in pediatric patients. J Pediatr 12. Silva IV, Reis AF, Palaré MJ, et al (2015) Gastroenterol Nutr;52(6) :714-7. Sickle cell disease in children: chronic 4. Cosentini A, Stranieri G, Capillo S,et al (2005) complications and search of predictive factors Acute pancreatitis in the paediatric age group: for adverse outcomes. Eur J a personal experience. Eur Rev Med Haematol;94(2):157-61. Pharmacol Sci; 9(1): 33-40.
Desloratadine and aggressive reaction Ms Lovisa Sandberg, Uppsala Monitoring Centre
Summary supportive temporal relationship and positive dechallenge, and of those, two reported a As of March 2015, the WHO Global Individual Case subsequent positive rechallenge. The adult reports Safety Report (ICSR) database, VigiBase®, were less convincing in supporting a signal, but included 17 ICSRs of aggressive reaction one of the cases represented a rapid onset, associated with desloratadine. Desloratadine is a positive dechallenge as well as positive selective peripheral histamine (H1) receptor rechallenge, and thus this signal is not limited to antagonist, indicated for the relief of symptoms children. Central nervous system (CNS) adverse associated with allergic rhinitis and urticaria in reactions have previously been reported for children and adults. Ten of the VigiBase® reports desloratadine, hence penetration into the brain involved children, of which six presented with a and the possibility of other clinically relevant CNS WHO Pharmaceuticals Newsletter No. 6, 2015 25
Signal effects cannot be ruled out. Additional loratadine Reports in VigiBase® reports in VigiBase® and the fact that aggression As of March 2015 the WHO Global Individual Case is a known adverse reaction for cetirizine, another Safety Report (ICSR) database, VigiBase®, second-generation antihistamine, contribute to included 17 ICSRs of the WHO-ART preferred term suspicions of a possible class effect. ‘aggressive reaction’ associated with desloratadine. The first report entered VigiBase® in 2002 and reports have continuously been Introduction submitted to VigiBase® up to 2014. The majority Desloratadine is a non-sedative, selective of the reports (12) originate from Europe (Austria, peripheral histamine (H1) receptor antagonist, Croatia, France, Greece, Germany, the indicated for the relief of symptoms associated Netherlands, Norway, and Sweden), three reports with allergic rhinitis and urticaria.1 This second- are from the United States, and two from Canada. generation antihistamine was authorized The cases represent 6 females and 11 males and throughout the European Union and the United patient ages range from 1 to 79 years (median States in 2001 and is currently available in large age 12 years). The majority of the cases are parts of the world, including Latin America, Africa reported by physicians (7 reports), pharmacists and Asia.1,2,3 Desloratadine is the primary active (4), or consumers/non-health professionals (3). metabolite of loratadine, a widely used Paediatric reports antihistamine which was introduced in 1993 and is Ten of the reports involve children, all but two of now available over the counter.4,5 Desloratadine is 1,2 them being 8 years of age or younger. The still subject to medical prescription. characteristics of these cases are presented in In the European Union desloratadine is approved Table 1. All paediatric reports are from 2006 or for use in adults, adolescents and children over more recent. Three of the reports were classified the age of 1 year.1 In the United States the drug is as serious by the reporter. 2 approved for patients of 6 months and older. The Six of the reports describe that the patient had recommended daily dose for adults and recovered or was recovering from the reaction at adolescents (12 years of age and over) is 5 mg, the time of reporting, all of them upon withdrawal for children from 6 to 11 years 2.5 mg, from 1 to 5 1,2 of the drug. Two of the cases describing a positive years 1.25 mg and from 6 to 11 months 1 mg. dechallenge also report a positive rechallenge and Desloratadine reaches maximum plasma one of those describes a repeated positive concentration after approximately three hours, rechallenge. In the remaining four cases, and the half-life is about 27 hours. The enzyme desloratadine was withdrawn but the patients had responsible for the metabolism is still unknown, so not recovered at the time of reporting (3 reports) interactions with other medicinal products cannot or the outcome was unknown (1). be excluded.1 Time to onset varies from one or a few days up to The most common adverse reactions reported in seven months. One report does not provide clinical trials were fatigue, dry mouth and precise time to onset information but the duration headache (frequency ≥ 1/100 to < 1/10). of desloratadine use is about one year. For the six Additional psychiatric and nervous system adverse reports with positive dechallenge, time to onset is reactions reported during the post-marketing “during administration” (1 report), one to two days period include hallucinations, dizziness, (2), three days (2) and a few weeks (1). somnolence, insomnia, psychomotor hyperactivity 1 Desloratadine is the sole suspect drug in all of and seizures (frequency < 1/10,000). Aggressive these six cases; however two of them report reaction is not listed as an adverse reaction, 1,2,4,5 concomitant medication previously associated with neither for desloratadine nor loratadine. aggressive behaviour (budesonide) or mood 5,9 Aggression is a wide term and is not a diagnosis in changes (cyamemazine). In the latter case, itself. It may instead be a symptom of or related cyamemazine had been used for one year together to many different conditions, such as attention- with risperidone for autism; after adding deficit hyperactivity disorder (ADHD) or dementia, desloratadine the reaction was experienced two and it may overlap with other terms, such as days later. Only one of the remaining four cases irritability and emotional lability.6,7 Aggressive reports co-suspected drugs: montelukast, for behaviour can manifest throughout life and may which aggressive reaction is a labelled adverse be part of the natural development process in reaction, and chlarithromycin, which has been 5 children. For toddlers and pre-school children associated with irritability. Chlarithromycin aggression generally peaks at 18 to 24 months treatment was however stopped about two weeks and slowly decreases by the age of 5.7 The nature before reaction onset. Fluticasone, for which of aggressive behaviour is complex and involves aggressive reaction is labelled, is concomitantly genetic and environmental factors, different neural used in one case and pseudoephedrine, for which circuits, and several neurotransmitters, including irritability is mentioned as a symptom of serotonin (5-HT), dopamine, and GABA.8 overdosage, is concomitantly used in another case.5 WHO Pharmaceuticals Newsletter No. 6, 2015 26
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One report (case 2) describes an 8 year-old female loratadine and cetirizine without experiencing this who experienced aggression and irritability reaction. following administration of desloratadine for allergic rhinitis, with a latency of one to two days after start of treatment. Desloratadine was Literature and labelling withdrawn after six days and the patient recovered within one day. Concomitant medication was not Psychiatric and nervous system disorder reactions, reported and the patient had no known medical including hallucinations, dizziness, somnolence, history. The past drug therapy indicated that the insomnia, psychomotor hyperactivity and seizures, patient had experienced aggression after a have been reported in association with desloratadine as adverse reactions during the previous intake of a cetirizine tablet and a 1 loratadine tablet on different occasions. The case post-marketing period. In three placebo- was reported by a specialist physician and the controlled clinical trials, desloratadine was reaction was assessed as probably related to administered for 15 days to a total of 246 children desloratadine. aged 6 months to 11 years. In infants and toddlers aged 12 months to 23 months emotional lability Another report (case 4) concerns a 20 month-old was reported at a frequency greater than with female and is reported by the patient’s mother. placebo (3.1%, 0%), as was irritability in infants The child was given desloratadine several times in aged 6 to 11 months (12.1%, 11.3%).2 Nothing is periods of five to seven days for about 1.5 years, mentioned in the British National Formulary for mainly for allergic reactions to insect bites. No Children about the use of desloratadine and other medication was reported. The mother adverse events related to aggression.10 Aggression described that the child was always rather irritable has been reported as an adverse event in the and aggressive when taking the drug, and at night post-marketing period for cetirizine, another she seemed to go through something like a second-generation antihistamine indicated for nightmare. The sender of the report assessed the allergic rhinitis and chronic idiopathic urticaria.11,12 reaction as certainly related to desloratadine, because of positive rechallenge. First-generation antihistamines have more pronounced sedative properties than second- Adult reports generation antihistamines, but have also been Seven of the reports concern adults. Two of these associated with agitation and irritability.5,13 These present with multiple possible confounders or compounds, as compared to second-generation other more likely reasons for the reaction. For antihistamines, have less H1 receptor selectivity another three adult cases the reported information and more easily enter the central nervous system is sparse, and thus the prerequisites to make (CNS).13 It is inconclusive whether the limited proper assessments of these cases are limited. penetration of second-generation antihistamines One of them however reports a time to onset of into CNS is determined by active efflux from the one month. brain via P-glycoprotein (P-gp) or a restricted 13,14,15 One case, reported by a specialist doctor, indicates penetration through the blood-brain barrier. a possible interaction effect from concomitant use Cerminara et al. described seizures induced by of desloratadine and risperidone. The case desloratadine in four children. They speculated describes a 38 year-old male who had used that susceptible patients might have a mutation in desloratadine for years when adding risperidone the gene coding for P-gp, causing an abnormal for autistic disorder. A few hours after the first variant of P-gp, and thus limiting the efflux of dose of risperidone the patient experienced violent desloratadine from the CNS.16 thoughts, difficulty in standing, dystonia, sedation, trismus and salivation. After withdrawal of Animal studies have indicated that inactivating the risperidone the reactions abated. The patient had histaminergic (H1) system may reduce aggression previously experienced violent thoughts while on in rodents, suggestively through decreased 17,18 another antipsychotic drug. The reactions may be serotonin (5-HT) activity. However, variations explained by risperidone alone in this case, in the histaminergic system and the nature of however in the light of the paediatric case 1, which aggression among species, as well as limitations to 8,19 also has risperidone co-reported, the interaction animal models raise uncertainty to whether hypothesis may also be worth consideration. these results could be fully applied to humans. The remaining report describes a 32 year-old male presenting with aggressiveness 1-1.5 hours after desloratadine intake. The patient had taken several doses and the reaction is reported to have occurred after each intake. This case also describes a positive dechallenge, with a recovery within 36 hours after drug withdrawal, as well as a positive rechallenge. No concomitant medication was reported. The patient had previously used WHO Pharmaceuticals Newsletter No. 6, 2015 27
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Table 1. Characteristics of paediatric reports of aggressive reaction in association with desloratadine in VigiBase® Case Age/ Suspected (S) or Reactions* Time to Dechallenge/ Outcome at Comment Sex concomitant (C) drugs onset Rechallenge time of report 1 15/M Desloratadine (S) Aggressiveness, 2 days Positive dechallenge Recovering Daily dose: 1 mg behaviour disorder, (symptoms began to Risperidone, excitability, titubation decline 7 days after Medical history: cyamemazine (both C) withdrawal, however still Autism after 14 days not fully Use of concomitant recovered) medication for one year 2 8/F Desloratadine (S) Aggression, irritability 1-2 days Positive dechallenge (drug Recovered Daily dose: 2.5 mg withdrawn after six days, patient recovered within one day) 3 5/M Desloratadine (S) Aggression 2 days Drug withdrawn – outcome Unknown Daily dose: 2.5 mg unknown Brompheniramine Aggressive behaviour maleate/ after taking amoxicillin pseudoephedrine hydrochloride (C) 4 1/F Desloratadine (S) Aggressiveness, “During Positive dechallenge Recovered Desloratadine taken irritability, nightmare, admini- several times in peri- drug effect lack of stration” Positive rechallenge ods of 5-7 days for (repeatedly) about 1.5 years 5 4/M Desloratadine (S) Aggression, 3 days Positive dechallenge Recovered Daily dose: 2.5 mg sleepiness One hour time to onset for sleepiness 6 4/M Desloratadine, Aggressive behaviour, 7 months Negative dechallenge Not recovered Daily dose: 2.5 mg clarithromycin, stress, fever, petit mal montelukast** (all S) Chlarithromycin treatment stopped two weeks before aggressive behaviour onset 7 12/F Desloratadine (S) Aggressive reaction, 5 days Drug withdrawn and Not recovered Daily dose: 5 mg delirium, psychotic treatment with haloperidol, reaction nos, child’s condition has hallucination auditory improved 8 8/F Desloratadine (S) Aggressive reaction "A few Positive dechallenge Recovered Daily dose: 5 mg Daily weeks" aggressiveness Budesonide**, Positive rechallenge olopatadine (both C) (reintroduced with 2.5 mg) 9 4/M Desloratadine (S) Aggressiveness 3 days Positive dechallenge (patient Recovered Daily dose: 2.5 mg recovered within a week after withdrawal) 10 8/M Desloratadine (S) Aggressive behaviour, - Negative dechallenge Not recovered Daily dose: 2.5-5 mg psychic disturbance, Fluticasone**, insomnia Duration of deslo- salbutamol (both C) ratadine use approxi- mately one year
*Reactions are shown as reported. Due to differences in reporting terminology some terms in the table represent WHO-ART and some MedDRA. **Associated with aggressive behaviour.5
Discussion concomitant use over a period of one year of antipsychotic drugs indicated for autism. VigiBase® paediatric reports on aggressive reaction and desloratadine represent six cases Two additional paediatric cases reported a time to with a supportive temporal relationship and onset consistent with the other cases, but negative positive dechallenge, and of these, two reported a or unknown outcome of dechallenge. One of these subsequent positive rechallenge. Four of these cases however reported that the patient was cases had no other medication reported while one improving upon withdrawal of the drug together case reported concomitant use of another with treatment of haloperidol. This case described antihistamine (eye drops) and a corticosteroid other reactions, including psychotic reaction and (nasal spray) previously associated with hallucinations, the latter a known adverse reaction aggression, and another case reported WHO Pharmaceuticals Newsletter No. 6, 2015 28
Signal for desloratadine and which may lead to of an aggressive reaction associated with aggression. loratadine, entered between 1992 and 2015 and originating from 13 different countries. This, The remaining two cases involving children were together with the fact that aggression is described less convincing with long or missing time to onset, as an adverse reaction for cetirizine11,12, another negative dechallenge and co-reported drugs second-generation antihistamine, points to a previously associated with aggression. possible class effect. The medical histories of the patients were seldom reported and identified possible confounders were few in relation to the number of paediatric reports. Conclusion The neurological and behavioural development of Reports in VigiBase® primarily, but not children may be seen as a confounding factor and exclusively, support a signal on aggressive differentia- ting coincidental aggressiveness as a reaction associated with desloratadine use in natural course of development, from a true causal children. The paediatric reports represent a association is difficult. However, a possible causal plausible temporal relationship, positive de- and relationship is supported by a plausible temporal rechallenges and only a few identified possible relationship, positive de- and rechallenge, and confounders. Psychiatric and neurologic adverse complementary adult cases. reactions have been reported for the drug and The adult reports were less convincing in thus penetration into the brain and the possibility supporting a signal. However, one of the adult of other clinically relevant CNS effects cannot be cases presented no obvious confounders, a rapid excluded. Additional loratadine reports in onset of the reaction, positive dechallenge as well VigiBase® and the fact that aggression is a known as positive rechallenge, and thus this signal is not adverse reaction for cetirizine, contribute to limited to children. suspicions of a possible class effect. The main proportion of the cases did not indicate a Thank you to the national pharmacovigilance serious reaction; however, aggression may have centres contributing additional case information severe implications. As aggressive behaviour upon request. sometimes involves violence, both the patient him/herself and his/her surroundings may be at risk of being physically injured, and aggressive References behaviour, even if only verbal, may have consequences on social interactions and the 1. European public assessment report (EPAR) for quality of life. Another implication is the legal desloratadine (Aerius®). URL: http://www. aspect, in which it may be important to find ema.europa.eu/ema/. Accessed: November explanations for aggressive action. 2014. Although desloratadine is said not to readily cross 2. US FDA product label for desloratadine the blood-brain barrier, this cannot be completely (Clarinex®). URL: http://www.accessdata. excluded and there have been reports of CNS fda.gov/scripts/cder/drugsatfda/. Accessed: 1,2,16 adverse reactions from this drug. One November 2014. example is emotional lability, which may in a wider 3. Sweetman SC (ed), Martindale: The Complete sense include the term discussed in this signal, Drug Reference. [online] London: found to be reported at greater frequency for Pharmaceutical Press. URL: http://www. desloratadine than for placebo in infants and toddlers.2 The neurobiology of aggression is medicinescomplete.com. Accessed: November complex and is supposed to involve many different 2014. neural circuits and neurotransmitters and a 4. US FDA approved drugs information. URL: mechanism can only be speculated. However, http://www.accessdata.fda.gov. Accessed penetration into the brain and the possibility of March 2015. triggering clinically relevant CNS adverse effects in 5. UK EMC Summaries of product characteristics susceptible patients, cannot be ruled out. Worth noting is that half of the paediatric cases had a (SPCs). URL: http://www.medicines.org.uk/. higher than recommended daily dose, indicating a Accessed: February 2015. possible dose-relationship. Two of these cases also 6. Medscape. URL: reported concomitant use of another http://emedicine.medscape.com/article/ antihistamine, which may suggest a possible 288689-overview. Accessed: March 2015. additive effect. 7. Liu J, Lewis G, Evans L. Understanding The range of countries reporting this association aggressive behavior across the life span. J strengthens the signal in the sense of being Psychiatr Ment Health Nurs. 2013 broadly observed. Also important to highlight, Mar;20(2):156-68. when this combination was assessed, VigiBase® contained in addition 108 reports (45 paediatric) WHO Pharmaceuticals Newsletter No. 6, 2015 29
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8. Nelson RJ, Trainor BC. Neural mechanisms of aggression. Nat Rev Neurosci. 2007 Jul;8(7):536-46. 9. Vidal France product information for cyamemazine (Tercian®). URL: http://www.vidal.fr/substances/1136/
cyamemazine/. Accessed: March 2015. 10. British Medical Association and the Royal Pharmaceutical Society of Great Britain. British National Formulary for children 2013-
2014. UK: BMJ Publishing Group. 2013. 11. US FDA product label for cetirizine (Zyrtec®). URL: http://www.accessdata.fda.gov/scripts/ cder/drugsatfda/. Accessed: November 2014. 12. UK EMC Summary of product characteristics (SPC) for cetirizine (Piriteze®). URL: http://www.medicines.org. uk/emc/. Accessed: November 2014. 13. Yanai K, Rogala B, Chugh K, Paraskakis E, Pampura AN, Boev R. Safety considerations in the management of allergic diseases: focus on antihistamines. Curr Med Res Opin. 2012 Apr;28(4):623-42. 14. Uesawa Y, Hishinuma S, Shoji M. Molecular determinants responsible for sedative and non-sedative properties of histamine H1- receptor antagonists. J Pharmacol Sci. 2014;124(2):160-8. 15. Conen S, Theunissen EL, Vermeeren A, van Ruitenbeek P, Stiers P, Mehta MA, et al. The role of P-glycoprotein in CNS antihistamine effects. Psychopharmacology (Berl). 2013 Sep;229(1):9-19. 16. Cerminara C, El-Malhany N, Roberto D, Lo Castro A, Curatolo P. Seizures induced by desloratadine, A second-generation antihistamine: clinical observations. Neuropediatrics. 2013;44:222-4. 17. Noguchi S, Inukai T, Kuno T, Tanaka C. The suppression of olfactory bulbectomy-induced muricide by antidepressants and antihistamines via histamine H1 receptor blocking. Physiol Behav. 1992 Jun;51(6):1123-7. 18. Yanai K, Son LZ, Endou M, Sakurai E, Nakagawasai O, Tadano T, et al. Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience. 1998 Nov;87(2):479-87. 19. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008 Jul;88(3):1183-241.
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CAVEAT DOCUMENT
Accompanying statement to data released from the Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring
Uppsala Monitoring Centre (UMC) in its role as the WHO Confidential data Collaborating Centre for International Drug Monitoring According to WHO policy and UMC Guidelines, ICSRs receives reports of suspected adverse reactions to 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, considered sensitive due to the nature of the data. the WHO Programme for International Drug Monitoring. Limited details about each suspected adverse reaction When receiving and using adverse reaction data are received by the UMC. The information is stored in (“Data”), the user agrees and acknowledges that it will the WHO Global Individual Case Safety Report be the controller of any such Data. Accordingly, the database, VigiBase®. It is important to understand the user shall adhere to all applicable legislation such as, limitations and qualifications that apply to this but not limited to, EU and national legislation regarding information and its use. protection of personal data (e.g. the Data Protection Directive 95/46/EC and Regulation (EC) No 45/2001, as The reports submitted to UMC generally describe no applicable). As the controller of the Data, the user shall more than suspicions which have arisen from be liable for any and all processing of the Data and observation of an unexpected or unwanted event. In shall indemnify and hold the UMC harmless against any most instances it cannot be proven that a specific claim from a data subject or any other person or entity medicinal product (rather than, for example, underlying due to a breach of any legislation or other regulation illness or other concomitant medication) is the cause of regarding the processing of the Data. an event. Non-permitted use of VigiBase® Data includes, but is Reports submitted to National Centres come from both not limited to: regulated and voluntary sources. Some National patient identification or patient targeting Centres accept reports only from medical practitioners; identification, profiling or targeting of general other National Centres accept reports from a broader practitioners or practice range of reporters, including patients. Some National Centres include reports from pharmaceutical companies Some National Centres strongly recommend that in the information submitted to UMC; other National anyone who intends to use their information should Centres do not. contact them for interpretation.
The volume of reports for a particular medicinal product Any publication, in whole or in part, of information may be influenced by the extent of use of the product, obtained from UMC must include a statement: publicity, the nature of the reactions and other factors. No information is provided on the number of patients (i) regarding the source of the information, exposed to the product. (ii) that the information comes from a variety of
sources, and the likelihood that the suspected Some National Centres that contribute information to adverse reaction is drug-related is not the same VigiBase® make an assessment of the likelihood that a in all cases, medicinal product caused the suspected reaction, while (iii) that the information does not represent the others do not. opinion of the World Health Organization.
Time from receipt of a report by a National Centre until UMC may, in its sole discretion, provide further submission to UMC varies from country to country. instructions to the user, responsible person and/or Information obtained from UMC may therefore differ from organization in addition to those specified in this those obtained directly from National Centres. statement and the user, responsible person and/or organization undertakes to comply with all such For the above reasons interpretations of adverse instructions. reaction data, and particularly those based on comparisons between medicinal products, may be misleading. The supplied data come from a variety of sources. The likelihood of a causal relationship is not Omission of this statement may exclude the the same in all reports. Any use of this information responsible person or organization from receiving must take these factors into account. further information from VigiBase®.
WHO Collaborating Centre for International Drug Monitoring, Box 1051, SE-751 40 Uppsala, Sweden Tel: +46-18-65 60 60, Fax: +46-18-65 60 88, E-mail: [email protected]
WHO Pharmaceuticals Newsletter No. 6, 2015 31
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The 38th meeting of the WHO International Working Group for Drug Statistics Methodology, Oslo, 22–23 October 2015
Medicines can provide substantial benefits, however, at the same time they have the potential to harm patients. This can result in significant costs to both high and low/middle income countries. The proportion of expenditure on medicines varies between countries and it is important to understand the patterns of use (for example, the types of medicines and their quantity). Drug Utilization Studies are essential for monitoring these patterns and trends, and understanding their impact on the efficiency with which health outcomes are gained. The Anatomical Therapeutic Chemical (ATC) classification system and the Defined Daily Dose (DDD) serve as a tool 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 geographical and professional backgrounds, including clinical pharmacology, clinical medicine, international public health, drug utilization and drug regulation. The members of the International Working Group represent different users of the ATC/DDD system and different nationalities as they represent the six WHO global regions. The Working Group provides scientific expert advice to WHO and the WHO Collaborating Centre for Drug Statistic Methodology (WHOCC Oslo), to discuss and approve all new ATC codes, DDD assignments and alterations to existing ATC codes and DDDs. The Working Group also supports the further development of the ATC/DDD system and methods, manuals and guidelines for the practical application and appropriate use of the ATC/DDD system in drug utilization studies in a variety of settings, particularly those applicable to low and middle income countries.
The 38th meeting of the WHO International Working Group for Drug Statistics Methodology was held at the Norwegian Institute of Public Health in Oslo, Norway. The meeting started with an Open Session which provided an opportunity for anyone, including industry, to present additional information on ATC/DDD to the experts to assist them in their decision-making at the subsequent closed session. During the Closed session, WHOCC Oslo reported on its recent activities. The Working Group intensively discussed the ATC classification and DDD items for several medicinal products, reviewed classifications, the objections and alterations of existing ATC classifications and future challenges. The Working Group discussed new DDDs for several drugs based on the available information including indications and doses used in various countries, and reviewed objections to the assigned DDDs to alter the DDDs. The Working Group also discussed the ATC/DDD Toolkit, which is in the process of development. The purpose of the toolkit is to raise awareness and to provide guidance on how to set up and use the international ATC/DDD methodology. The ATC/DDD Toolkit will be a comprehensive online resource for anyone interested in undertaking drug utilization studies. Decisions made during discussions by the Working Group on ATC classification or DDD assignment will be published on the website of the WHOCC Oslo and in the publication, WHO Drug Information. Decisions on a new or revised ATC classification or DDD assignment are published at first as a temporary list. Any interested party wishing to dispute this decision has the opportunity to comment within a specified period after its publication. For more information, please see WHOCC Oslo website: http://www.whocc.no/
WHO Pharmaceuticals Newsletter No. 6, 2015 32
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Pre-conference Workshop on WHO ATC/DDD Methodology and Drug Utilization Research, New Delhi, India, 2-3 November 2015.
A pre-conference workshop on WHO ATC/DDD methodology and drug utilization research was held on 2-3 November 2015 in New Delhi, India, preceding the 38th Annual Meeting of Representatives of National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring. This 2-day workshop on the WHO ATC/DDD methodology and drug utilization studies consisted of lectures, hands-on exercises and group discussions. The experts from the WHO Collaborating Centre for Drug Statistic Methodology (WHOCC Oslo), the Indian Council of Medical Research and the National Coordinating Centre for Pharmacovigilance Programme of India provided lectures on historical background, need for drug utilization studies, basics of the WHO Classification (ATC/DDD) system, procedures for ATC/DDD assignment, its applications, data sources, methods used for drug utilization research, current status and future prospects, in particular for low and middle income settings. About 50 participants joined this session and actively participated in discussions with great enthusiasm. Several questions were raised both during and after the sessions. The workshop received positive feedback from participants. Comments from the participants include; “Excellent organization, excellent learning”, “Course was excellent and the case studies for the working groups were superb”, “Very useful sharing of the rationale behind the ATC classification and the DDD”, “The working group was excellent. Please add more of that in coming courses”, “More frequent courses needed.” Based on the positive feedback and given the need to promote and support the use of this tool, WHO will continue to organise Workshops on ATC/DDD in collaboration with WHOCC Oslo.
WHO Collaborating Centre for Drug Statistics Methodology
WHO Pharmaceuticals Newsletter No. 6, 2015 33
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The 38th Annual Meeting of Representatives of the National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring
Indian Pharmacopoeia Commission hosts the annual meeting of representatives of the National Pharmacovigilance Centres in New Delhi, India
Minister of Health and Family Welfare, Over 150 representatives from 44 countries J P Nadda inaugurates the WHO meeting travelled to India to attend the three-day meeting from 4 to 6 November 2015. The commitment of the Indian government to the cause of pharmacovigilance (PV) and medicines safety was marked by the presence of the Minister of Health and Family Welfare, Minister J P Nadda at the inauguration ceremony of the 38th Annual Meeting of Representatives of the National
Pharmacovigilance Centres (NPCs) participating in the WHO Programme for International Drug Monitoring (PIDM).
Opening ceremony
In Minister Nadda’s opening address, he emphasized the importance of PV, and declared
that “Given the critical role that it plays in ensuring safety of medical products, it is imperative that pharmacovigilance is developed as an effective instrument for Representatives from National PV Centres around the understanding and prevention of the world travelled to attend adverse effects and any other drug related problems.” The annual meeting of representatives of the NPCs is a platform for representatives from around the world to meet and discuss PV issues. Each year an NPC hosts the meeting, and this year the Indian
Pharmacopoeia Commission (IPC) welcomed delegates to the hotel Grand New Delhi, India.
WHO Pharmaceuticals Newsletter No. 6, 2015 34
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Meeting structure Success story: database linking and At the end of the 37th annual meeting of transition to E2B in Chile representatives of the NPCs participating in WHO
PIDM in China 2014, participants were invited to suggest topics for the 2015 agenda by completing the questionnaire provided at the end of the meeting. The list of topics were sent electronically to all NPCs in early 2015 in the form of a second questionnaire, which requested topics to be prioritized. This set the agenda for 2015, reflecting the needs of Member States.
The meeting sessions consisted of plenaries, Chile is a South American country occupying a long narrow strip updates, working groups and problems of current of land bordering the South Pacific Ocean. It is estimated that interest. Each plenary was chaired by a panel, and there are currently over 17 million inhabitants in Chile. The NPC in Chile was initially formed in 1995 and joined the WHO PIDM in delegates participated in discussions following 1996. presentations. Topics covered in the plenary sessions included, the importance of storytelling in The NPC is situated in the National Drugs Regulatory Authority. Currently, Individual Case Safety Reports (ICSRs) are compiled pharmacovigilance, success stories in Oman and in an excel spreadsheet database. Initially reports were received Chile, building a global safety culture, PV in a as an email or as paper form and were manually imputed into small country (strategies, challenges, the database. This process is very time consuming, however was opportunities and inspirations), signal detection, manageable with relatively small number of reports. However the PV programme in India: current status, reporting rates increased substantially (~ 10000 reports /year) after it became mandatory for health-care professionals and the integration with public health programmes, and pharmaceutical industry to report adverse drug reactions in the role of adverse drug reaction (ADR) monitoring 2010. Hence, processing reports into the database was no longer centres. During the update sessions, presentations timely. In addition to this, three separate parallel reporting were made on: adverse events reporting during syste ms existed: 1) the initial excel database held at the NPC; 2) mass drug administration, patient reporting, using an online database for adverse events following immunization (AEFIs): 3) an online database for reporting suspected adverse PV indicators in routine PV practice, and the WHO- effects (created by the institution’s Information Technology unit). UMC algorithm to detect Substandard/spurious/ The use of three databases made analysis of ICSRs difficult. In falsely-labelled/falsified/counterfeit medical 2013, the NPC took steps to consolidate data from the three products (SSFFCs). databases and transfer data to the WHO global database of ICSRs, VigiBase using the internationally recommended format, ICH- E2B. E2B is a standardized format for transferring data between databases of different structure. It works by defining the type of information as well as the format of the information (using XML document Extendable Markup Language) to be transferred. Chile initially transferred data to VigiBase® using the INTDIS format in excel.
The NPC in Chile plan to approach this by identifying and implementing changes in the database needed to comply with E2B standards, developing data bridges to transmit information between the three databases to form a single pool of data, and to develop tools to transmit data to VigiBase (under E2B standards).
Measures taken to consolidate data included developing a computer programme in Excel to facilitate data entry. This used O Abiri from Sierra Leone presenting standardized terminology and made data entry of reports during the update session partially automatic. Secondly, custom filters were added to the Excel database to help with data analysis. The transition is still in process, and the next step is to ensure all AFEI reports received The session on problems of current interest online are transferred to the Excel database. Tools are being consisted of short presentations based on pre- developed for this. In the meantime the International Vaccine Institute in South Korea is working with the NPC to implement a selected abstracts that were submitted prior to the tool to generate E2B messages from vaccine reports in the Excel meeting. There was a range of topics, some database. The national immunization programme is adapting focused on particular ADRs of concern, for their system in terms of coding and data fields to become example dimethyl fumarate and progressive compatible with the NPC database, this is expected to be ready multifocal leukoencephalopathy. Others discussed in January 2016. PV systems and country experiences, for example Finally, the WHO Collaborating Centre (CC) for International strengthening PV systems in South Africa. Drug Monitoring in Uppsala will support Chile to make the E2B Delegates were given the opportunity to share message in a format that can be imported to VigiBase® by email initially, with the plan to switch data transfer from NPC computer their experiences, interact and help find solutions. to VigiBase® directly (server to server).
Summary of presentation by J R Saelzer from Chile
WHO Pharmaceuticals Newsletter No. 6, 2015 35
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Adverse event reporting during mass drug administration and reducing the spread of Ebola in Sierra Leone
Sierra Leone is situated in west coast of Africa and has a population of about 9 to 10 million people. The country is comprised of four geopolitical regions and 12 districts. In May 2014, health officials confirmed the presence of a case of Ebola in the eastern part of Sierra Leone. By August 2014, the disease spread to all but one district in the country. Ebola, formally known as Ebola haemorrhagic fever is a virus disease that can be transmitted to people from wild animals and spreads in the human population through human to human transmission. Mortality rate is high and up until November 1st, there have been over 3500 deaths related to Ebola in Sierra Leone. Ebola is characterized by fever, diarrhoea, headache, vomiting muscular pain, and in some instances bleeding. Most of these symptoms occur in other common health conditions, such as malaria and typhoid. The signs and symptoms usually manifest between 2- 21 days after contact with the virus. The risk of the virus spreading was increased in Sierra Leone due to many factors, such as: poor socioeconomic status, weak health-care infrastructures, limited knowledge of the disease, lack of manpower, delay in effective coordinated response mechanisms to outbreaks (nationally and internationally), traditional and cultural practices, (e.g. washing of dead bodies, caring for the sick at home, hand shaking, and hugging). Of particular risk, was the potential confusion between symptoms of Ebola and malaria. As symptoms are similar, people with malaria often presented themselves at Ebola treatment centres, hence non- infected persons were at risk of exposure. Mass drug administration (MDA) of malaria chemoprevention was introduced as an intervention to reduce the spread of Ebola. Hence, a combination of amodiaquine and artesunate (AS-AQ) was distributed and administered to communities with the aim of controlling malaria. By reducing the number of febrile cases due to malaria in the community, the number of suspected Ebola episodes that would otherwise require screening and isolation in Ebola treatment centres would be reduced, reducing the risk of Ebola transmission among malaria patients. During the MDA campaign it was imperative to monitor for suspected ADRs, to ensure that the drug combination is safe when administrating on a large scale, and to learn more about the drug safety profile when used in this population. The PV objectives were: to quantify previously recognized ADRs, identify unknown ADRs, evaluate effectiveness, and to decrease mortality and morbidity related to adverse events. In addition, the PV initiative built the trust of the community. For example, the misconception that the anti-malaria tablets caused Ebola was managed through effective advocacy and communication. Prior to MDA, the community and health workers were sensitized on the need for the MDA, monitoring the safety of medicines and report ing ADRs. This involved TV and radio programmes, media, social media and pre-conferences/meetings. Both active and passive PV methods were employed during the MDA. For active surveillance, monitoring was managed at four levels: community, health facility, district and national levels. A total of 33 PV monitors and supervisors were assigned at national and district levels, and over 8000 drug distributers were involved. Independent monitors in the community were also employed. Community monitors visited communal areas, health facilities and made door to door visits. In addition a 24 hour toll-free call centre was set up to answer queries during the campaign. Reports of ADRs were received at all levels. The district PV supervisors would check for completeness before forwarding reports to the NPC. At the NPC ICSRs were collated, assessed for completeness, assigned severity grading, screened for unknown events and subjected to causality assessments. Reports were evaluated to identify unknown ADRs, and the range of ADRs to expect, so that health workers can counsel patients and health facilities can know what to monitor. In addition, parameters of non-compliance could be identified. It was found that some patients were not fully compliant, and may have not completed the full three day course or split the doses (e.g. take one tablet twice a day instead of two together). In some circumstances it may have been beneficial to provide incentives, for example, food and water with doses to reduce adverse events. On reflection, it was highlighted that there needs to be better provision of rescue medications. During this campaign the NPC successfully managed information by being available in person at the distribution sites during mass administration, where they built trust and awareness resulting in acceptance of the programme amongst the community. Summary of presentation by O Abiri from Sierra Leone
Eight working groups took place over the first two Future meeting
days of the meeting. Delegates had the th opportunity to select and attend two. During the The Sultanate of Oman has offered to host the 39 working groups participants took part in annual meeting of representatives of the NPCs discussions and worked together to formulate participating in the WHO PIDM, from 14 to 17 recommendations for NPCs, WHO and WHO CCs. November 2016. The recommendations were presented to all participants on day 3 of the meeting. The recommendations will be published in the WHO Pharmaceuticals Newsletter No.1, 2016.
M Juma from the Sultanate of Oman presenting in the updates session
Working Group on PV in Pregnancy
WHO Pharmaceuticals Newsletter No. 6, 2015 36