2017 WHO Pharmaceuticals
No.3 NEWSLETTER
The WHO Pharmaceuticals Newsletter provides you
with the latest information on the safety of medicines
WHO Vision for Medicines Safety and legal actions taken by regulatory authorities around No country left behind: the world. It also provides signals based on information worldwide pharmacovigilance for safer medicines, safer patients derived from the WHO global database of individual case safety reports, VigiBase.
This newsletter includes two feature articles: Pilot The aim of the Newsletter is to disseminate information on Mobile ‘APP’ for reporting suspected adverse drug the safety and efficacy of reactions launched in Burkina Faso and Zambia, and, pharmaceutical products, Introducing a New Member in the WHO Programme for based on communications received from our network of International Drug Monitoring (WHO PIDM): Paraguay. national pharmacovigilance centres and other sources such as specialized bulletins and journals, as well as partners in WHO.
The information is produced in the form of résumés in English, full texts of which may be obtained on request from:
Safety and Vigilance: Medicines, EMP-HIS, World Health Organization, 1211 Geneva 27, Switzerland, Contents E -mail address: [email protected]
This Newsletter is also available at: Regulatory matters http://www.who.int/medicines Safety of medicines
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Feature
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Table of Contents
Regulatory Matters
Bevacizumab ...... 5 Canagliflozin ...... 5 Caspofungin...... 5 Clopidogrel ...... 5 Codeine and tramadol ...... 6 Denosumab ...... 6 Dipeptidylpeptidase-4 (DPP-4) inhibitors ...... 6 Factor VIII medicines ...... 7 General anaesthetic and sedation drugs ...... 7 Ingenol mebutate ...... 8 Interferon alfa and interferon beta ...... 8 Iodinated contrast medium ...... 8 Pembrolizumab ...... 9 Ticagrelor ...... 9 Valproate ...... 9
Safety of Medicines Crizotinib ...... 10 Direct-acting antivirals (DAAs) ...... 10 Fluconazole ...... 11 Flutamide ...... 11 Multiple sclerosis therapies ...... 12 Ponatinib ...... 12 Testosterone ...... 12 Viekira PAK® and Technivie® (direct-acting antivirals) ...... 12 Ibrutinib and pneumonitis ...... 14
Signal Pregabalin and visual colour distortions ...... 19 SGLT-2 inhibitors and genital pruritus ...... 23
WHO Pharmaceuticals Newsletter No. 3, 2017 3 Table of Contents
Feature Pilot Mobile ‘APP’ for reporting suspected adverse drug reactions launched in Burkina Faso and Zambia ...... 27 Introducing a New Member in the WHO Programme for International Drug Monitoring (WHO PIDM): Paraguay ...... 28
WHO Pharmaceuticals Newsletter No. 3, 2017 4 Regulatory Matters
Bevacizumab bevacizumab and non- Caspofungin mandibular osteonecrosis in Potential risk of non- adult cancer patients. However, Risk of Toxic Epidermal mandibular osteonecrosis in Health Canada has decided to Necrolysis (TEN) and recommend updating the adult cancer patients Stevens-Johnson syndrome product safety information of Canada. Health Canada bevacizumab to include Japan. The Ministry of Health, recommends that the product information on the potential Labour and Welfare (MHLW) safety information for risk. and the Pharmaceuticals and bevacizumab (Avastin®) is Reference: Medical Devices Agency updated to include information Summary Safety Review, (PMDA) have announced that on the potential risk of non- Health Canada, 5 April 2017 the package insert for mandibular osteonecrosis in (www.hc-sc.gc.ca) caspofungin (Cancidas®) has adult cancer patients. been updated to include the risk of Toxic Epidermal Bevacizumab, when used alone, Necrolysis (TEN) and is used for the treatment of oculomucocutaneous syndrome glioblastoma. It can also be Canagliflozin (Stevens-Johnson syndrome) used with other chemotherapy Increased risk of leg and as clinically significant adverse medicines to treat cancers of reactions. the large bowel, lung, female foot amputations reproductive system and the Caspofungin is indicated for USA. The US Food and Drug lining of the abdominal cavity. febrile neutropenia suspected Administration (FDA) has to be caused by a fungal Health Canada initiated a requested that the product infection, and for the treatment review of the risk of non- label for canagliflozin of fungal infections due to mandibular osteonecrosis in (Invokana® and Invokamet®) Candida or Aspergillus. adult cancer patients treated is updated to include the risk of with bevacizumab following the leg and foot amputations. The update followed reports of publication of two reports in TEN and/or Canagliflozin is a sodium- the literature. oculomucocutaneous syndrome glucose cotransporter-2 in patients treated with At the time of the review, (SGLT2) inhibitor and is used caspofungin both in Japan and Health Canada had received with diet and exercise to lower overseas, and following one report of non-mandibular blood sugar in adults with revision of the company core osteonecrosis related to type-2 diabetes. datasheet (CCDS) and package bevacizumab use. There was Final results from two clinical inserts in the United States and insufficient information to trials - the CANVAS Europe. conclude that the use of (Canagliflozin Cardiovascular bevacizumab alone had caused Reference: Assessment Study) and this condition in this report. Revision of Precautions, CANVAS-R (A Study of the MHLW/PMDA, 20 April 2017 Effects of Canagliflozin on Health Canada also looked at (www.pmda.go.jp/english/) Renal Endpoints in Adult information on 67 international reports of non-mandibular Participants with Type-2 osteonecrosis related to the Diabetes Mellitus) - showed use of bevacizumab, including that leg and foot amputations the two cases that triggered occurred twice as often in Clopidogrel the safety review. In 26 of patients treated with Potential risk of spinal these reports, a link between canagliflozin compared to haematoma, cholecystitis bevacizumab and non- patients treated with placebo. mandibular osteonecrosis could and haematemesis Reference: not be ruled out. In the Drug Safety Communication, Republic of Korea. The remaining 41 reports, there US FDA, 16 May 2017 Ministry of Food and Drug were either not enough (www.fda.gov) Safety (MFDS) has announced information to establish a link, that the label for clopidogrel or there were confounding (See WHO Pharmaceuticals Newsletters has been revised to include factors such as the presence of No.2, 2017: Risk of lower limb amputation spinal haematoma, other bone conditions or in Malaysia and Potential risk of toe amputation with SGLT inhibitors in the EU cholecystitis and haematemesis treatments known to cause and No.3, 2016: Risk of leg and foot as adverse reactions. bone damage. amputations: under investigation in the Clopidogrel is a platelet After reviewing available data, USA) aggregation inhibitor and is it was determined that there is indicated for the reduction of not enough information to the rate of cardiovascular establish a definitive link death, myocardial infarction, between the use of
WHO Pharmaceuticals Newsletter No. 3, 2017 5 Regulatory Matters and stroke in patients with 2015 and identified 64 cases of prevent multiple vertebral acute coronary syndrome. serious breathing problems, fractures that can occur due to including 24 deaths, with a temporary increase in bone At the time of review, the codeine-containing medicines resorption. Korea institute of Drug safety in children younger than 18 and Risk Management (KIDS) Denosumab is indicated for years. Nine cases of serious had received three domestic osteoporosis. breathing problems, including reports of spinal haematoma, three deaths, with the use of Off-treatment follow-up results nine domestic and eight tramadol in children younger of overseas clinical studies international reports of than 18 years from January showed a higher incidence of cholecystitis, and six domestic 1969 to March 2016 were also multiple new vertebral and 24 international reports of identified. The majority of fractures in patients who haematemesis with clopidogrel serious adverse effects with discontinued denosumab through Korea Adverse Event both codeine and tramadol compared with those who Reporting System (KAERS) occurred in children younger discontinued placebo which led from 1989 to 2015. Reports for than 12 years, and some cases to the revision of the company clopidogrel and spinal occurred after a single dose of core data sheet (CCDS). In haematoma/cholecystitis/ the medicine. addition, overseas pre-market haematemesis were identified clinical studies showed a to be statistically significant In a review of the medical temporary increase in bone compared to all the other literature the FDA found resorption after discontinuation reports from other drugs. numerous cases of excess of denosumab treatment. The sleepiness and serious This recommendation time to onset of the multiple breathing problems in announced by MFDS was based new vertebral fractures after breastfed infants, including one on signal analysis evaluation discontinuation of denosumab death. A review of the available process in KIDS using adverse treatment found in the studies medical literature for data event reports. was consistent with the time to regarding tramadol use during onset of the temporary Reference: breastfeeding did not reveal increase in bone resorption. Based on the communication any cases of adverse events. Based on these findings, the from MFDS and KIDS, Republic However, tramadol and its MHLW/PMDA concluded that of Korea, April 2017 active form are also present in updating the package insert is breast milk, and tramadol has necessary. the same risks associated with ultra-rapid metabolism as Reference: Codeine and tramadol codeine. Revision of Precautions, MHLW/PMDA, 20 April 2017 Reference: Restriction of use in children (www.pmda.go.jp/english/) Drug Safety Communication, and advice against use in US FDA, 20 April 2017 breastfeeding women (www.fda.gov) USA. The US FDA has changed (See WHO Pharmaceuticals Newsletters Dipeptidylpeptidase-4 the labels of prescription No.2 and No.1, 2017, No.6 and No.1 in 2016, medicines containing codeine No.6, No.5, No.4 and No.3 in 2015, No.5 and (DPP-4) inhibitors No.4 in 2013, and No.5 in 2012 for related and tramadol to inform of the information) Risk of arthralgia restriction of use in children and recommend against the Canada. Health Canada has use of codeine and tramadol updated the product safety medicines in breastfeeding Denosumab information for all mothers due to risk of serious dipeptidylpeptidase-4 (DPP-4) adverse reactions in breastfed Risk of multiple vertebral inhibitors to include infants. These adverse fractures information on the risk of reactions include excess arthralgia (severe joint pain). sleepiness, difficulty Japan. The MHLW and the DPP-4 inhibitors (alogliptin, breastfeeding or serious PMDA have announced that the linagliptin, saxagliptin and breathing problems that could package insert for denosumab sitagliptin) are used to treat result in death. (Pralia®) has been updated to type-2 diabetes in adults. They include the risk of multiple Codeine and tramadol are are used along with an vertebral fractures as a approved to treat pain, and appropriate diet and exercise clinically significant adverse codeine is also approved to to control blood sugar. In some reaction. The MHLW/PMDA treat cough. cases, they are used with have also advised transitioning another anti-diabetic drug. The FDA reviewed adverse to an alternative antiresorptive event reports submitted to the medicine if treatment with Health Canada reviewed the FDA from January 1969 to May denosumab is discontinued, to potential risk of arthralgia with
WHO Pharmaceuticals Newsletter No. 3, 2017 6 Regulatory Matters the use of DPP-4 inhibitors factor VIII medicines should be General anaesthetic following the identification of updated to reflect the reports of adverse effects in conclusion that there is no and sedation drugs the published literature and in clear and consistent evidence the US FDA Adverse Event of a difference in inhibitor Potential risk of effects on Reporting System (FAERS) development between classes development of children’s database. of factor VIII medicines. brains
At the time of the review, Factor VIII products replace USA. The US FDA has Health Canada received 10 the missing factor VIII in announced that the labels for Canadian reports of severe patients with haemophilia. general anaesthetic and joint pain and 20 international Human plasma-derived factor sedation medicines will be reports from the manufacturers VIII medicines are extracted updated to include information associated with the use of a from blood plasma. on potential effects on brain DPP-4 inhibitor (saxagliptin, Recombinant factor VIII is development in children sitagliptin or linagliptin). produced from DNA technology. younger than three years. The The body may develop Of all the reports, 17 noted updated label changes include: inhibitors as a reaction to these that the patient developed joint A new warning stating that medicines, particularly in pain within the first 30 days of exposure to anaesthetic and patients starting treatment for taking the DPP-4 inhibitor. The sedation medicines for the first time. majority of patients either lengthy periods of time or improved or recovered from The review was started over multiple surgeries or their joint pain after the following a study which procedures may negatively treatment was stopped. concluded that inhibitors affect brain development in develop more frequently in children younger than three Some of the cases have also patients receiving recombinant years. reported medical conditions factor VIII medicines than in Additional information that may have contributed to those receiving plasma-derived describing results of animal the joint pain including gout, factor VIII medicines. studies in pregnancy and pre-existing rheumatoid the young. Exposure to arthritis, Crohn’s disease and The review included relevant general anaesthetic and obesity. studies which differed in their sedative medicines for more design, patient populations and Health Canada’s review of the than three hours can cause findings, and the PRAC available information concluded widespread loss of nerve concluded that they did not there is a potential link cells in the developing provide clear evidence of a between the use of DPP-4 brain, resulting in long-term difference in the risk of inhibitors and the development negative effects on the inhibitor development between of severe joint pain. animal’s behaviour or the two classes of factor VIII learning in young animals. Reference: medicines. Summary Safety Review, Anaesthetic and sedative In addition, due to the different Health Canada, 27 April 2017 medicines are necessary for characteristics of individual (www.hc-sc.gc.ca) infants, children and pregnant products within the two classes, women who require surgery or (See WHO Pharmaceuticals Newsletters the PRAC considered that other painful and stressful No.6, 2015: Risk of severe joint pain in Egypt evaluation of the risk of procedures. In addition, and No.5, 2015: DPP-4 inhibitors for Type 2 inhibitor development should untreated pain can be harmful diabetes may cause severe joint pain in the be at the product level instead USA) to children and their developing of at the class level. The risk nervous systems. for each individual product will continue to be assessed as Reference: more evidence becomes Drug Safety Communication, Factor VIII medicines available. US FDA, 27 April 2017 (www.fda.gov) No clear evidence to Reference: suggest a difference in News and press release, EMA, (See WHO Pharmaceuticals Newsletter No.1, 2017: Potential risk of effects on 5 May 2017 inhibitor development development of children’s brains in the USA) (www.ema.europa.eu) between plasma-derived and recombinant products (See WHO Pharmaceuticals Newsletter No.3, 2013: Review on the benefits and risks in EU. The European Medicines previously untreated patients with Agency (EMA)’s haemophilia A with Kogenate® and Pharmacovigilance Risk Helixate® started in the EU) Assessment Committee (PRAC) has recommended that the prescribing information of
WHO Pharmaceuticals Newsletter No. 3, 2017 7 Regulatory Matters
Ingenol mebutate Ingenol mebutate is indicated For interferon beta, a total of for the cutaneous treatment of 73 ADR reports with 137 1. Risk of hypersensitivity nonkeratotic, non-hypertrophic adverse events were received reactions, herpes zoster and actinic keratosis in adults, and by NPRA between 2002 to is available for topical use in January 2016. Two reports eye injury different strengths. were associated with the SOC Respiratory, Thoracic and Australia. The Therapeutic There have been reports of Mediastinal Disorders, namely Goods Administration (TGA) keratoacanthoma occurring difficulty in breathing and has updated the Product within the area treated with sneezing. Information for ingenol ingenol mebutate, with a time mebutate (Picato gel®) to add to onset ranging from weeks to Whilst there were no reports warnings of hypersensitivity months. specifically on PAH, two cases reactions, herpes zoster and reported patients experiencing The HPRA has advised health- ophthalmic injury as symptoms of PAH namely, care professionals to counsel precautions and adverse chest pain (with use of patients to be vigilant for new effects. peginterferon alfa-2a) as well skin lesions developing within as oedema and abdominal Ingenol mebutate is indicated the area treated with ingenol, distension (with interferon in actinic keratosis. and to immediately consult beta-1b). The TGA investigated safety their doctor should any occur. Reference: concerns relating to ingenol Reference: Reaksi Drug Safety News, mebutate following reports of Drug Safety Newsletter, HPRA, NPRA, No. 34, March 2017 severe allergic reactions, March 2017 herpes zoster, ophthalmic (See WHO Pharmaceuticals Newsletter No.6, injury and local skin reactions 2016: Risk of pulmonary arterial in the United States. Some of hypertension in Canada) these cases were associated Interferon alfa and with the medicine not being used in accordance with its interferon beta directions for use. Iodinated contrast Risk of pulmonary arterial The TGA investigation found hypertension (PAH) medium that the risk of local skin reactions was well- Malaysia. The National Potential risk of communicated in the Product Pharmaceutical Regulatory hypothyroidism Information. However, the Agency (NPRA) has issued Product Information did not instructions to update the Canada. Health Canada has address the potential adverse package inserts for interferon updated the product safety events of alpha and interferon beta information for all iodinated hypersensitivity/anaphylaxis, containing products to include contrast medium (ICM) herpes zoster reactivation or, the potential risk of pulmonary products to include information ophthalmic injury. arterial hypertension (PAH). on potential risk of hypothyroidism in certain Reference: Interferons are a group of patients (mostly infants). In Medicines Safety Update, TGA, glycoproteins that have addition, Health Canada will Vol. 8, No. 2, April-May 2017 immunoregulatory, antiviral publish a Health Product Risk (www.tga.gov.au) and antineoplastic functions. Communication to inform (See WHO Pharmaceuticals Newsletter No.5, Indications include treatment health-care professionals about 2015: Risk of severe allergic reactions and of multiple sclerosis, hepatitis, this safety information and herpes zoster (shingles) in the USA) carcinoma, lymphoma, provide recommendations to leukaemia and myeloma. monitor thyroid function following ICM use in infants. 2. Risk of keratoacanthoma From year 2002 to January 2016, the NPRA has received ICM products are medical Ireland. The Health Products 91 ADR reports with 204 imaging dyes for viewing the Regulatory Authority (HPRA) adverse events associated with insides of different body parts. has stated that the product interferon alfa use. Seven information (Summary of reports were related to the At the time of review, Health Product Characteristics (SmPC) System Organ Class (SOC) Canada had not received any and Package Leaflet (PL)) for Respiratory, Thoracic and Canadian reports of ICM and ingenol mebutate (Picato®) Mediastinal Disorders and hypothyroidism. will be updated to include consisted of cough, difficulty in The safety review examined 23 information on the risk of breathing, bloody sputum, international reports of adverse keratoacanthoma. nasal congestion and epistaxis. effects for hypothyroidism with the use of ICM. Of these, 10
WHO Pharmaceuticals Newsletter No. 3, 2017 8 Regulatory Matters were considered to be related The update was due to cases of (MHRA) has sent a Patient to the use of ICM. In three of myocarditis reported overseas Safety Alert highlighting risks the ten reports, the patients and the revision of the of developmental disorders in recovered and in two reports, company core data sheet unborn children. The alert the patients did not recover. (CCDS). directs organisations to There were no information undertake systematic Reference: provided on recovery of identification of women and Revision of Precautions, patients for the remaining five girls taking valproate and to MHLW/PMDA, 20 April 2017 reports. Thirteen reports did support them to make (www.pmda.go.jp/english/) not contain enough information informed choices. to determine if the ICM product Valproate (Epilim® and played a role in the onset of Depakote®), also known as hypothyroidism. While the valproic acid, is an effective reports represented patients Ticagrelor medication used to treat from all age groups, six of the Potential risk of pulmonary epilepsy and bipolar disorder. 10 reports related to ICM-use haemorrhage involved infants (age less than Evidence suggests around one one year). Republic of Korea. The MFDS in five women taking valproate are not aware of risks in The review of the scientific has announced that the label pregnancy. Evidence from the literature found a link between for ticagrelor has been revised Clinical Practice Research ICM use and the potential risk to include pulmonary Datalink also suggests that the of hypothyroidism. Most of the haemorrhage as an adverse measures put in place to reports involved infants but reaction. increase awareness of risks in adults also experienced this Ticagrelor is used as a platelet pregnancy have not had a adverse effect. aggregation inhibitor. significant effect. Health Canada's review Ticagrelor is administered with In March 2017, the European concluded that there is a rare aspirin and indicated to reduce PRAC initiated a further review potential risk of hypothyroidism the rate of cardiovascular to look at the use of valproate- with the use of ICM in certain death, myocardial infarction, containing medicines in patients, mostly infants. and stroke in patients with acute coronary syndrome. females of childbearing Reference: potential. The committee will Summary Safety Review, At the time of review, the KIDS consider whether these Health Canada, 24 April 2017 had received three domestic medicines require further (www.hc-sc.gc.ca) and six international reports of restrictions of use due to high pulmonary haemorrhage with (See WHO Pharmaceuticals Newsletters risk of developmental disorders ticagrelor through KAERS from No.2, 2017: Possible risk of hypothyroidism and congenital malformations in infants: added to the medicines 1989 to 2015. Reports for in unborn babies, and the monitoring scheme and No.6, 2015: Rare ticagrelor and pulmonary continued use of valproate cases of underactive thyroid in infants in the haemorrhage were identified to during pregnancy. The review USA) be statistically significant will also examine the compared to all the other effectiveness of regulatory reports from other drugs. measures put in place to increase awareness and reduce This recommendation valproate use in patients at risk. Pembrolizumab announced by MFDS was based Risk of myocarditis on a signal analysis evaluation Reference: process in KIDS using adverse Drug Safety Update, MHRA, Japan. The MHLW and the events reports. Volume 10, issue 9:1, April 2017 (www.gov.uk/mhra) PMDA have announced that the Reference: package insert for Based on the communication (See WHO Pharmaceuticals Newsletters pembrolizumab (Keytruda®) from MFDS and KIDS, Republic No.2, 2016, No.2 and No.1, 2015, No.5, has been updated to include of Korea, April 2017 2014, and No.6 and No.3, 2013 for related the risk of myocarditis as a information) clinically significant adverse reaction.
Pembrolizumab is used for Valproate treatment of unresectable malignant melanoma and Risk of developmental unresectable, advanced or disorders recurrent programmed death ligand 1 (PD-L1) positive non- The United Kingdom. The small cell lung cancer. Medicines and Healthcare Products Regulatory Agency
WHO Pharmaceuticals Newsletter No. 3, 2017 9 Safety of Medicines
Crizotinib Direct-acting antivirals cirrhosis, previous history of liver cancer and advanced age. (DAAs) Potential risk of Health Canada’s review gastrointestinal perforation: 1. Potential risk of liver concluded that there was not not enough evidence cancer recurrence: not enough information to establish a link between DAAs and liver enough evidence Canada. Health Canada has cancer recurrence. Health reviewed the potential risk of Canada. Health Canada has Canada has also made a gastrointestinal perforation reviewed the potential risk of request for additional safety with the use of crizotinib liver cancer recurrence with the information from (Xalkori®) following safety use of direct-acting antivirals manufacturers of DAAs reports received by the (DAAs). regarding this risk as it manufacturer. becomes available. DAAs are used for the Crizotinib is authorized to treat treatment of chronic HCV Reference: specific types of advanced lung infection in adult patients, Summary Safety Review, cancers. cirrhosis or liver cancer. Health Canada, 3 May 2017 (www.hc-sc.gc.ca) At the time of the review, At the time of the review, Health Canada did not receive Health Canada had received any Canadian reports for three Canadian reports of liver 2. Potential risk of liver gastrointestinal perforation cancer recurrence with use of failure related to crizotinib use. DAAs (two with Sovaldi® and The safety review evaluated one with Holkira Pak®). All New Zealand. The Medicines and Medical Devices Safety information collected by the three reports were considered Authority (Medsafe) has stated manufacturer and consisted of to be related to the use of Medsafe is continuing to 32 international reports of DAAs. However, other factors monitor reports of adverse gastrointestinal perforation in present in the cases may have the bowel with the use of played a role in liver cancer reactions to DAAs. crizotinib. In general, the recurrence, such as serious The Centre for Adverse reports did not contain enough cirrhosis, previous history of Reactions Monitoring (CARM) information to determine if liver cancer and other has received five case reports crizotinib use caused the treatments known to be of liver failure where the adverse effect. The indication associated with a higher risk of reported suspected medicines itself is also a risk factor. liver cancer recurrence, were included in a DAA including surgery and While some other products in regimen. All five cases were in radiofrequency ablation. the same class as crizotinib patients with cirrhosis using Viekira Pak-RBV®. (e.g. sorafenib, regorafenib The safety review also and axitinib) have been linked examined information from 14 Medsafe advised that patients to gastrointestinal perforation, international reports of liver with cirrhosis who are being Health Canada’s search of the cancer recurrence with the use treated with Viekira Pak® or published literature did not find of DAAs: nine reports involved Viekira Pak-RBV® should: any studies or patient reports Sovaldi®, four reports involved be monitored for clinical of this adverse effect with the Harvoni® and one report signs and symptoms of use of crizotinib. involved Holkira Pak®. All 14 hepatic decompensation reports were considered to be such as ascites, hepatic Health Canada’s review of the related to DAAs use. However, encephalopathy and variceal available information did not other factors associated with a haemorrhage establish a link between the higher risk of liver cancer were use of crizotinib and have hepatic laboratory reported. gastrointestinal perforation. testing before starting A search of the scientific treatment and regularly Reference: during treatment literature identified seven Summary Safety Review, have their treatment relevant studies describing the Health Canada, 4 May 2017 discontinued if they develop recurrence of liver cancer with (www.hc-sc.gc.ca) evidence of hepatic use of DAAs. The role of DAAs
in relation to recurrence of liver decompensation. cancer could not be made Reference: because the length of time the Safety Information, Medsafe, patients were monitored were 12 May 2017 different between studies. The (www.medsafe.govt.nz/) patients in the studies also had a variety of risk factors for liver cancer, including HCV infection,
WHO Pharmaceuticals Newsletter No. 3, 2017 10 Safety of Medicines
Fluconazole The NPRA has provided advice procedentes de las bases de for health-care professionals to datos española (FEDRA), 1. Reminder not to use prescribe oral fluconazole europea (EudraVigilance) y de during pregnancy during pregnancy with caution la OMS (VigiBase), así como los and to consider alternative casos publicados en la Ireland. The HPRA has treatment options, such as literatura científica. clotrimazole for uncomplicated provided the following advice La mayoría de los casos de candidiasis. to health-care professionals: daño hepático asociados a la Fluconazole in standard Reference: administración de flutamida se doses and short-term Reaksi Drug Safety News, describen en pacientes varones treatments should not be NPRA, No. 34, March 2017 con cáncer prostático. Sin used in pregnancy unless embargo se han identificado (See WHO Pharmaceuticals Newsletter No.3, clearly necessary. casos en mujeres a las que se Fluconazole in high doses 2016: Risk of miscarriage in pregnancy: under investigation in the USA) les prescribió flutamida para el and/or in prolonged tratamiento de alguno de los regimens should not be cuadros clínicos citados used during pregnancy anteriormente. except for potentially life- threatening infections. Flutamide Entre las alteraciones hepáticas notificadas en estas mujeres, Fluconazole is used for Severe cases of se encuentran casos muy treatment and prevention of hepatotoxicity with off-label graves que llegaron a requerir specified fungal infections in use trasplante hepático e incluso adults and children. ocasionaron la muerte de la Spain. La Agencia Española de Results of an observational paciente: Medicamentos y Productos study suggests an increased En España se han notificado Sanitarios (AEMPS) recuerda a risk of spontaneous abortion in hasta la fecha un total de los profesionales sanitarios que women taking fluconazole 10 casos de trastornos la única indicación autorizada during the first trimester of hepáticos asociados al uso para flutamida es el carcinoma pregnancy. Previous studies de flutamida en mujeres, de próstata y que no debe have linked high dose and ocho de ellos considerados utilizarse en mujeres para el long-term treatment to birth graves. Las reacciones tratamiento de hirsutismo, defects. adversas notificadas fueron seborrea, acné y alopecia hepatitis, hepatitis Reference: androgenética. colestásica, esteatosis Drug Safety Newsletter, HPRA, Flutamida, antiandrógeno oral hepática y elevación de March 2017 no esteroideo, está autorizado, enzimas hepáticas. La
en combinación con los indicación para la cual se 2. Caution in use during agonistas de la hormona administró flutamida fue hirsutismo, acné y alopecia pregnancy liberadora de hormona luteinizante (LHRH), para el androgenética. Ocho de las Malaysia. The NPRA is tratamiento del carcinoma pacientes se recuperaron mientras que dos reviewing the possible metastásico de próstata. requirieron trasplante association between oral El Comité de Seguridad de hepático. Una de las fluconazole exposure during Medicamentos de Uso Humano pacientes trasplantadas pregnancy and the risk of (CSMH) de la AEMPS ha spontaneous abortion and falleció posteriormente. evaluado recientemente el uso La información de las bases stillbirth. The NPRA advises fuera de indicación de este cautious prescribing of oral de datos EudraVigilance y producto para el tratamiento VigiBase indica que se han fluconazole in pregnancy until de la alopecia androgenética en notificado casos de this review is completed. mujeres. La evaluación se ha características similares Since year 2000 to July 2016, llevado a cabo a raíz de un tanto en países europeos the NPRA has received 149 caso notificado al Sistema como fuera de Europa. safety reports with 236 Español de Farmacovigilancia Diversas publicaciones adverse events associated with de hepatitis con desenlace científicas documentan fluconazole. The highest mortal en una mujer que casos de daño hepático reported adverse events were recibió tratamiento con grave asociado al uso de maculo-papular rash, increased flutamida para esta indicación. flutamida en mujeres fuera hepatic enzymes, and pruritus. En la evaluación se han de las condiciones At the time of this analizado los casos de autorizadas. communication, there were no notificación espontánea de reports related to spontaneous sospechas de reacciones abortion or stillbirth. adversas asociadas a flutamida
WHO Pharmaceuticals Newsletter No. 3, 2017 11 Safety of Medicines
Reference: Ponatinib is used to treat publication of a US FDA safety Información dirigida a adults with chronic myeloid communication in 2014. profesionales sanitarios, AEMPS, leukaemia or Philadelphia- As part of the review, the TGA 27 April 2017, Spain chromosome-positive acute sought advice from the (www.aemps.gob.es) lymphoblastic leukaemia. It is Advisory Committee on the restricted to patients who have Safety of Medicines (ACSOM). limited alternative treatment During the meeting on options with tyrosine kinase 2 September 2016, ACSOM Multiple sclerosis inhibitors. found that there was a weak therapies In November 2014, the MHRA signal of increased informed health-care cardiovascular risks with use of Potential rebound effect professionals of conclusions testosterone medications in after stopping or switching from a European-level review general (but not for specific therapy of the risk of serious vascular events). occlusive events with ponatinib The TGA noted this advice, but The United Kingdom. The and provided advice on given there is only a weak MHRA has reported the minimizing risks. Additional signal, the TGA has decided publication of two articles that long-term follow-up data are that it is not necessary to describe a suspected rebound now available which provide update the Product Information syndrome in patients with further information and support documents for testosterone multiple sclerosis after advice on dose modifications to medicines for the time being. cessation of fingolimod reduce this risk. (Gilenya®) and/or switching to Reference: The available evidence shows alternative treatments. Medicines Safety Update, TGA, that the risk of arterial Vol. 8, No. 2, April-May 2017 In conjunction with other occlusion with ponatinib is (www.tga.gov.au) European national regulatory likely to be dose-dependent authorities and the EMA, the and that dose reduction may (See WHO Pharmaceuticals Newsletter No.4, MHRA is evaluating all available therefore reduce the risk of 2014: Risk of venous blood clots in the USA) evidence on this safety signal. life-threatening vascular events. Further information on the The recommended starting outcome of the review and dose of ponatinib remains at 45 relevant new guidance will be Viekira PAK® and mg once a day for all patients. issued as soon as it is available. Technivie® (direct- Reference: The MHRA reminded health- Drug Safety Update, MHRA, care professionals that they acting antivirals) Volume 10, issue 9:2, April should report any suspected 2017 (www.gov.uk/mhra) Interaction with adverse effects relating to ethinyloestradiol fingolimod or other treatments (See WHO Pharmaceuticals Newsletters for multiple sclerosis, including No.6 and No.1, 2014 and No.6, 2013 for Australia. The TGA has Related information) those that occur after warned that although the discontinuation. Product Information documents Reference: for Viekira PAK® and Viekira Drug Safety Update, MHRA, Testosterone PAK-RBV® state that use with Volume 10, issue 9:3, April ethinyloestradiol-containing 2017 (www.gov.uk/mhra) Risk of arterial medicines is a contraindication due to a potential interaction thromboembolism/venous resulting in elevated alanine thromboembolism transaminase (ALT) blood levels, not all ethinyloestradiol- Ponatinib Australia. The TGA has containing medicines currently reminded health-care provide information and Risk of vascular occlusive professionals that they should precautions regarding this events only prescribe testosterone if interaction. prescribing is in line with the The United Kingdom. The registered indications and Viekira PAK® and Viekira PAK- MHRA has issued advice to Pharmaceutical Benefits RBV® are indicated for the prescribers about considering Scheme restrictions. treatment of genotype 1 dose reduction of ponatinib chronic hepatitis C infection, The TGA has been monitoring (Iclusig®) to 15 mg a day for including patients with testosterone in relation to the patients with chronic phase compensated cirrhosis. risk of arterial chronic myeloid leukaemia (CP- Technivie® is used for thromboembolism/venous CML) who have achieved a treatment of adult patients (in thromboembolism since the major cytogenetic response. combination with ribavirin) with
WHO Pharmaceuticals Newsletter No. 3, 2017 12 Safety of Medicines genotype 4 chronic HCV. Technivie® is not yet marketed in Australia.
The Product Information documents for Viekira PAK® and Viekira PAK-RBV® state that during clinical trials transient, asymptomatic elevations of alanine transaminase (ALT) to greater than five times the upper limit of normal occurred in approximately 1% of all subjects. These ALT elevations were significantly more frequent in female subjects who were using ethinylestradiol-containing medicines. ALT elevations typically occurred during the first four weeks of treatment and declined within approximately two weeks of onset with continued dosing of Viekira PAK® or Viekira PAK- RBV®.
Reference: Medicines Safety Update, TGA, Vol. 8, No. 2, April-May 2017 (www.tga.gov.au)
WHO Pharmaceuticals Newsletter No. 3, 2017 13 Signal
A signal is defined by WHO as reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. A signal is a hypothesis together with data and arguments and it is important to note that a signal is not only uncertain but also preliminary in nature.
The signals in this Newsletter are based on information derived from reports of suspected adverse drug reactions available in the WHO global database of individual case safety reports (ICSRs), VigiBase. The database contains over 15 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. Signals are first communicated to National Pharmacovigilance Centres through SIGNAL (a restricted document from UMC), before being published in this Newsletter. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of Signal (page 26). For information on the UMC Measures of Disproportionate Reporting please refer to WHO Pharmaceuticals Newsletter Issue No. 1, 2012.
UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific research within the field of pharmacovigilance. 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].
Ibrutinib and pneumonitis Dr Birgitta Grundmark, Uppsala Monitoring Centre
Editorial Comment communicating so that relevant stakeholders may act upon it. Since the finalization of the evaluation of the signal pneumonitis in relation to ibrutinib, the closely related term “interstitial lung disease” (ILD) has Introduction been included into the EU SmPC as an acknowledged side effect; hence the signal detected In the regular UMC signal detection screening, by the UMC has been confirmed by regulatory the combination of ibrutinib and pneumonitis bodies and the MAH. Advice on appropriate was detected in the first quarter of 2016 as a monitoring of patients regarding ILD and on the potential signal. clinical handling of patients in whom ILD has occurred has also been added. Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (TK). It belongs to the rapidly growing and evolving class of functionally diverse approved protein kinase Summary inhibiting (PKI) drugs. Ibrutinib is currently the Ibrutinib is an antineoplastic substance belonging to only substance with its particular mechanism the class of protein kinase inhibitors (PKI) where, of action approved for use in humans, although for the majority of other PKI substances, a causal we understand there are others under association between the drugs and pneumonitis or development. Bruton’s TK is a signalling similar respiratory drug reactions, is acknowledged molecule within the B-cell antigen receptor and labelled. (BCR) and cytokine receptor pathways necessary for B-cell trafficking, chemotaxis and In May 2016, 39 cases of pneumonitis in relation to adhesion. The BCR pathway is implicated in ibrutinib use had been reported by the countries several B-cell malignancies, and ibrutinib participating in the WHO Programme for inhibits malignant B-cell proliferation and International Drug Monitoring. An evaluation of the survival.1 The ATC code is L01XE27. reports of pneumonitis in the WHO global database of individual case safety reports, VigiBase, and Numerous approaches to target the inhibition other data has been performed. Based on the of protein kinase (PK) signalling have been available information, the consistent pattern of the explored and developed, e.g. protein and events described in the reports, and our oligonucleotide-based substances targeting background knowledge of the acknowledged growth factor or receptor TK, small-molecule potential of the drug class of PKIs to cause inhibitors targeting unique kinase pneumonitis or interstitial lung disease, our conformational forms and binding sites. Some conclusion is that for ibrutinib a causal association substances have very specific kinase selectivity between the substance and pneumonitis may also profiles whereas others have a broader mode exist. We hence consider this signal worth of action on several PKs.
WHO Pharmaceuticals Newsletter No. 3, 2017 14 Signal
Approvals for ibrutinib show small differences Indication for treatment was reported as CLL in around the world and include indications in mantle 26 cases, MCL in 7 cases and WM, other cell lymphoma (MCL), chronic lymphatic leukaemia specified lymphomas or not given in 4 cases. (CLL) and Waldenström’s macroglobulinaemia (WM) Dosages when reported were usually the with a recommended dose in MCL of 560 mg daily labelled ones, i.e. 420 or 560 mg daily. The and in CLL and WM of 420 mg daily per os. The ibrutinib SmPC gives standardized advice for treatment may continue until disease progression or dose reductions in cases of interaction or until no longer tolerated by the patient. toxicity.1 Dose reductions were reported during Pneumonitis is an inflammation of the lung treatment in a few cases, presumably for interstitium and/or alveoli. Definitions of, and interactions or toxicity reasons prior to, or at borders between pneumonitis and closely related the time of onset or diagnosis of pneumonitis, terms such as interstitial lung disease (ILD), vary although in most reports there is only scant somewhat between authors, languages, and information on the reasons for the dosing medical traditions. This has become apparent while revisions. assessing this signal detected from reports from The recording of any exact time to onset (TTO) different countries. Clinically, pneumonitis is most would not be expected for any case of commonly used to describe an inflammation without pneumonitis due to the natural course of a the presence of an infection, whereas when an disease with an often insidious onset. Data on infection is present it typically is classified as the TTO or time to diagnosis (D) or time to pneumonia. Common symptoms of pneumonitis are hospitalisation (H) is available with varying cough and shortness of breath alongside more degrees of accuracy in most of the reports general symptoms of malaise and fever. Hypoxia (n=32). Where there is uncertainty regarding may or may not be present. A diagnosis of drug the data, the longest period has been assumed induced pneumonitis is usually reached based on and presented. The range of the TTO/D/H is 2 clinical symptoms, X-ray or CT-scan, sometimes weeks to 14.5 months with a median of less biopsy, negative cultures, and the absence and than 6 months. In eight cases the TTO/D/H exclusion of other plausible explanations or a was 2 months or less and in three cases the positive rechallenge. TTO/D/H was 9 months or more. Among several causes of pneumonitis are iatrogenic Only a few reports mention in any detail the exposure including some antibiotics, diagnostic laboratory methods used. Among chemotherapeutics, anti-arrhythmics and radiation methods mentioned are X-ray/CT scan, treatments to the chest. Other causes include bronchoscopy, biopsy, BAL and (negative) exposure to mould, bacterial or animal proteins and cultures. various chemicals and gases. Pneumonitis may also appear as a symptom of other diseases, e.g. In five cases the outcome was fatal, and in connective tissue diseases and lymphoproliferative most of these the cause of death was disorders. Treatment includes, when possible, considered by reporters or concluded from the removal of the underlying cause of the condition, report to be a combination of the reported systemic steroids, and if needed, oxygen and event(s) and the underlying disease, which assisted respiration. would be expected considering the diseases being treated. The pattern of TTO in these In summary, the definitions, aetiology and coding of cases were similar to the cases in general. pneumonitis and similar conditions are diverse. Other contributing causes of death in these cases were described as a history of recurrent pneumonitis, sepsis (n=2), cerebral Reports in VigiBase haemorrhage and a “general infective state”. In May 2016, there were 39 reports of pneumonitis In 16 reports a dechallenge is mentioned in relation to ibrutinib treatment identified in before recovery. Many of the reports mention VigiBase, the WHO international database of treatment with antibiotics apparently under suspected adverse drug reactions. The reported following a primary diagnosis of pneumonia cases originated from and were entered by national with fewer mentioning steroid treatment or a pharmacovigilance centres in four countries: USA need for oxygen treatment for any period of (n=20), Italy (n=14), Germany (n=3) and United time. Among the reports from Italy, a Kingdom (n=2). The gender of the patients in the translation or coding issue cannot be excluded reports mirrors the population studied pre-approval where the coded (English) MedDRA term (as per the EU SmPC) with 27 men and 9 women. pneumonitis in Italian could potentially include In three cases the gender was not reported. In the both pneumonitis and pneumonia 33 reports where age was unambiguously reported, (“polmonite”). When clinically detecting and the age range was 46 to 86 years with a mean age diagnosing pneumonitis, a primary of 69 years and a median of 71 years, also (differential) diagnosis of pneumonia is mirroring the population in the preapproval clinical common and sometimes the two conditions trials. coincide. From the limited data provided, none of the cases could be definitively excluded as
WHO Pharmaceuticals Newsletter No. 3, 2017 15 Signal being cases of pneumonia rather than pneumonitis, EU SmPC states the following regarding side although in some of them this could be suspected. effects of ibrutinib: “The safety profile is based on pooled data Four of the reports include information about a from 555 patients treated with IMBRUVICA in negative rechallenge i.e. where ibrutinib was three phase 2 clinical studies and two reinstated with the same (and in some cases a randomised phase 3 studies and from post- lower) dose without recurrence of the pneumonitis, marketing experience. […] All patients in in some cases with concurrent steroid treatment. clinical studies received IMBRUVICA until In two of the cases the reporter considered that the disease progression or no longer tolerated. underlying disease, rather than ibrutinib, was the The most commonly occurring adverse more probable cause of the event, which would reactions (≥ 20%) were diarrhoea, explain the reaction. In the other two cases, the musculoskeletal pain, upper respiratory tract discovery of pneumonitis appeared to have been a infection, haemorrhage, bruising, rash, and more or less incidental finding, via X-ray and CT nausea. The most common grade 3/4 adverse respectively, and both of these patients also had a reactions (≥ 5%) were anaemia, neutropenia, history of several courses of chemotherapy and pneumonia and thrombocytopenia.” 1 radiation therapy of the chest, which could have influenced the finding. Pneumonitis/ILD are acknowledged and labelled side effects for numerous PKIs Two reports were considered less relevant. They although their detailed mode of action, recorded reactions other than pneumonitis in molecular structure and their approved relation to ibrutinib where the patient rather had a indication differ significantly and hence also history of pneumonitis caused by another drug, their background disease and the spectrum of apparently mistakenly being coded as a “current” complications of the diseases. In VigiBase ADR. Another report has been considered “invalid” there are reports on pneumonitis/ILD for the by the national centre since it only states that the vast majority of PKIs. There appears to be little patient “may” have had an ADR and lacks adequate firm knowledge on the pathophysiology of information. respiratory reactions in relation to PKIs in In 11 of the reports, ibrutinib was the only reported general. drug and in 22 cases it was the only suspected drug. Other notable side effects in several PKIs are In five cases other drugs were reported alongside electrolyte disturbances, hypertension, ibrutinib for which pneumonitis (or ILD) is cardiotoxicity, and hepatotoxicity. mentioned in their respective SmPCs as an acknowledged side effect and which may have Ibrutinib is primarily metabolised by contributed to or caused the event. Rituximab, cytochrome P450 enzyme 3A4 and co- everolimus and/or bendamustine were reported as administration with subsequent interaction with co-suspect drugs, while mesalazine and filgrastim strong or moderate CYP3A4 inhibitors may lead were reported as concomitant drugs.2-6 Details on to higher toxicity and is hence discouraged in when these drugs were started or stopped in the SmPC. However, no such concomitant drug relation to the events were not provided. The or dietary use was noted in any of the reported concomitant use of these drugs does not preclude a cases. causal role for ibrutinib as a sole causal agent or it A publication by Mato et al. recently presents having an interactive or additive effect, but of four cases of ibrutinib-induced pneumonitis in course renders causality assessment from ibrutinib patients with a diagnosis of CLL. The patients, more difficult. aged between 55 and 73 years, one woman Apart from these 39 reported cases of pneumonitis and three men, had been diagnosed with CLL there are also seven cases of the closely related between 3 and 15 years prior to initiation of condition ILD reported for ibrutinib in VigiBase. ibrutinib treatment. They had all had prior These cases are not described in detail in this signal chemotherapy treatment, three of them with review, but do show a similar pattern to the cases several courses. The time to onset of reported with pneumonitis. symptoms or hospitalization was between one and four months. The letter describes the Table 1 presents the cases which provide the best authors’ extensive evaluation, including trans- evidence of a causal relationship between ibrutinib bronchial biopsies and infectious workup. and pneumonitis where investigation results, clinical Examples of biopsy sections are presented. CT course and lack of reference to antibacterial use scans prior, during and after the events are support a diagnosis of non-infective pneumonitis. presented and show clears signs of the condition evolving during treatment. All patients were successfully treated with steroids Literature and Labelling and along with drug discontinuation the Side effects of PKIs in general vary greatly radiographic changes resolved, as did clinical depending on their precise mode of action with few symptoms. In one case a rechallenge was or no side effects being common to them all. The attempted with pneumonitis reoccurring. The authors hypothesize that “inhibiting signal
WHO Pharmaceuticals Newsletter No. 3, 2017 16 Signal
transduction pathways enhances expression of pro- studies have reported an increase in alveolar inflammatory cytokines and the innate immune infiltration of T helper 2 pro-inflammatory system. BTK also appears to serve as a critical cytokines in BTK-deficient mice, resulting in mediator of lipopolysaccharide-induced dendritic cell airway inflammation”.7 maturation and macrophage polarization. Several
Table 1. Characteristics of case reports in VigiBase of pneumonitis in association with ibrutinib Case Age/Sex Other suspected (S) or Ibrutinib Reactions (MedDRA preferred terms) Time to onset Dechallenge, Indication, other relevant information concomitant (C) drugs daily dose rechallenge, outcome 1 55/M Valaciclovir, insulin (both C) - Pneumonitis <7 months Dechallenge positive, CLL, physician report, non-smoker, heavily pre-treated, diagnosis Rechallenge negative confirmed via CT, treatment with steroids, assessed as related
Outcome: recovered 2 73/M Rituximab* (S) 420mg Pneumonitis, diarrhea, anemia, acute 1.5 months Outcome: unknown CLL, clinical trial report, patient presenting after 39 days with fatigue and kidney injury, pyrexia fever, chest x-ray showing pneumonitis; antibiotics started, open biopsy confirmation of pneumonitis with negative cultures, acute respiratory failure with ICU treatment, assessed as related to ibrutinib or possibly to infection but not to rituximab or underlying disease 3 70/M Levothyroxine, pantoprazole, 560mg Pneumonitis, pneumonia, pleural effusion 5 months Dechallenge positive MCL, nurse report, diagnosis confirmed via CT and chest X-ray. treated ezetimibe, rosuvastatin, with decreasing amounts of oxygen after withdrawal amlodipine, acetylsalicylic of drug. acid, metoprolol, Ω-3-acid (all Superimposed pneumonia. C) 4 -/- Rituximab*, bendamustine* 560mg Pneumonitis, ARDS, rhinovirus infection 7 months Fatal Follicular lymphoma, study report ARDS during cycle 8, bronchoscopy (both S) culture positive for rhinovirus, grade 5 rhinovirus infection. Treated with broad spectrum antibiotics and high dose steroids 5 77/M Warfarin, metformin, 420mg Pneumonitis, atrial fibrillation, congestive 3.5 months Dechallenge positive CLL, consumer/physician report, non-smoker, diagnosis of oxycodone, pioglitazione, cardiac failure, swelling pneumonitis confirmed via CT, treated with antibiotics, nifedipine, furosemide (all causality assessed as related, patient restarted on idelalisib and C) rituximab. 6 66/F 10 concomitants none - Pneumonitis, sepsis, death, 1.5 or possibly Fatal CLL, nurse report, ex-smoker, two previous lines of therapy, death due significant for pneumonitis 6 months, to disease progression and reported reactions, sepsis assessed as not (unclear data) related to ibrutinib, no causality assessment for pneumonitis provided 7 78/M 10 concomitants none 420mg Pulmonary fibrosis, pneumonitis, cough, Approx. 3 Dechallenge positive CLL, consumer/physician report, ex-smoker, differing information. significant for pneumonitis 560mg- fatigue, peripheral swelling, muscle months Outcome: recovered History includes GERD, diabetes, arrhythmia, arthritis, heart spasms, arthralgia, myalgia, bone pain, disease, recurrent pneumonia, several previous lines of CLL 280mg- nausea, pyrexia, nasopharyngitis treatment including rituximab, IVIG, cyclophosphamide, fludara. 420mg- After one month of ibrutinib onset of musculoskeletal problems, fatigue. 280mg Dose decreased with positive effect. Dose re-increased with recurring fatigue, shortness of breath, cough and ultimately a pneumonitis diagnosis confirmed via chest X-ray. Dose decreased with some positive effect but ultimately ibrutinib withdrawal. Reinstating ibrutinib was discussed but no definite information. 8 82/M - - Pneumonitis, respiratory failure - Dechallenge positive CLL, literature report (Mahmoudi et al.9) Presented hypoxic but without respiratory complaints after a fall with a scapula fracture. X-ray and CT scan findings suspicion of atypical infection from immunosuppression. Rapid deterioration and ICU treatment w mechanical ventilation. Absence of response to antibiotics, negative cultures, raised CRP, SR and low procalcitonin raises suspicion of inflammatory pneumonitis. Biopsy and BAL consistent w diagnosis. Rapid improvement on steroids after discontinuation of drug. Ibrutinib considered only identifiable agent. 9 57/F - 420mg Pneumonitis 9 months Dechallenge positive, CLL, physician report, treated on a named patient programme continuing 280mg rechallenged at after programme stopped, previous treatment including rituximab and 280mg bendamustine 4 years prior to event, history of bronchial asthma, pneumonitis detected by CT, rechallenge negative with reduced dose (six Outcome: recovered months follow up) 10 69/M Filgrastim*, aciclovir, - Pneumonitis >4 months Dechallenge positive MCL, study report, diagnosis via signs, symptoms and typical X-ray allopurinol, colecalciferol, findings. No data on previous lines of treatment. chloramphenicol, Treated with steroids, cyclophosphamide, oxygen. Recovered. erythropoietin, furosemide, Rechallenge was considered but was not performed as the patient prednisone, tranexamic acid developed AML. Timing of filgrastim not provided in detail. (all C) 11 72/M - 420mg Pneumonitis, sodium decreased 20 days Dechallenge positive CLL, pharmacist report, sparse information, treatment with posaconazole Outcome: recovering 12 72/M Pantoprazole, tamsulosin, 420mg Pneumonitis, pneumonia 2 weeks Dechallenge MCL/CLL (MCL disease progression w leukemic course), physician amlodipine, metoprolol, positive, study report, 2 previous lines of treatment, diagnosis confirmed via CT, enoxaparin, aminophylline/ rechallenge BAL negative, recovered from pneumonia with antibiotics, recovered quinine sulfate (all C) negative (while from pneumonitis with steroids and oxygen, study drug successfully on steroids) rechallenged with concomitant steroid
Outcome: recovering
*Labelled for pneumonitis or related terms (such as interstitial lung disease).
WHO Pharmaceuticals Newsletter No. 3, 2017 17 Signal
A recent review by Shah on the subject of The publication by Mato et al. on four further interstitial lung disease in TKIs provides a thorough thoroughly evaluated and described cases with overview of the disease with a focus on the TKIs for similar histories strongly supports the signal. which this reaction is already labelled. Clinical In summary, with a clinical suspicion and a features and laboratory findings are presented. pattern in a majority of reported cases Incidence data provided is discussed and refers to a consistent with drug induced pneumonitis and large extent to TKIs used for non-small cell lung a recent publication describing a series of cancer and to Japanese patients, with their clinically detailed described cases with a strong apparently different and higher susceptibility for the suspicion of causality, with the vast majority of reaction. Onset of the reaction in TKIs based on drugs in the protein kinase inhibiting class clinical trials and post authorization studies vary having pneumonitis or interstitial lung disease heavily between different TKIs from days to many as an acknowledged side effect in their months (and usually within a year) with more labelling; the signal of pneumonitis induced by severe reactions usually appearing earlier in the ibrutinib merits further investigation to assess course. A discussion of the management of the the need for possible risk minimising activities reaction includes common practices for ILD namely by relevant stakeholders. discontinuation of the culprit, steroids, supportive care and when relevant antibiotics.8 References Discussion and Conclusion 1. European Medicines Agency: Summary of Product Characteristics for ibrutinib There are 21 PKIs for which pneumonitis has been (Imbruvica®). Available from: disproportionately reported in VigiBase. The vast http://www.ema.europa.eu/docs/en_GB/ majority of them have pneumonitis, or less often, document_library/EPAR_-_Product_Information/ ILD present in their labelling. Ibrutinib, with 39 human/003791/WC500177775.pdf. reports on pneumonitis and 7 on ILD in VigiBase is Accessed: September 2016. one of the few exceptions to this. 2. European Medicines Agency: Summary of The 39 cases of pneumonitis reported show a Product Characteristics for rituximab reasonably consistent pattern and history to (MabThera®). Available from: support a causal relationship between ibrutinib and http://www.ema.europa.eu/docs/en_GB/ pneumonitis. The temporal association in the document_library/EPAR_-_Product_Information/ majority of cases supports a causal relationship human/000165/WC500025821.pdf. being similar to the natural history of pneumonitis. Accessed: October 2016. The majority of cases were reported by the 3. European Medicines Agency: Summary of physician diagnosing and treating the event, but the Product Characteristics for everolimus level of detail in the description of diagnostic (Afinitor®). Available from: methods used is not high. A positive dechallenge http://www.ema.europa.eu/docs/en_GB/ and outcome is described in many of the cases, in document_library/EPAR_-_Product_Information/ some also recording steroid treatment. Antibiotic human/001038/WC500022814.pdf. treatment is often mentioned which would be Accessed: October 2016. expected considering that when diagnosing 4. US Food and Drug Administration: Product pneumonitis symptoms of respiratory infections label for bendamustine (Treanda®). overlap with those of pneumonitis and serious Available from: infectious processes always have to be ruled out http://www.accessdata.fda.gov/drugsatfda_ and treated. No case of certain positive rechallenge docs/label/2016/022249s022lbl.pdf. is described in the spontaneously reported cases. Accessed: October 2016. In some cases there are other explanations or 5. Electronic Medicines Compendium: evident confounders present; other suspected or Summary of Product Characteristics for concomitant drugs; in some cases, several previous mesalazine (Asacol®). Available from: lines of treatment for the disease, and in at least https://www.medicines.org.uk/emc/ one case prior radiotherapy to the chest could be medicine/20478. Accessed: October 2016. possible predisposing factors of the pneumonitis. 6. Electronic Medicines Compendium: The underlying disease may have contributed in Summary of Product Characteristics for only few of the cases reported. Likewise, few of the filgrastim (Neupogen®). Available from: reported cases describe previous potentially https://www.medicines.org.uk/emc/ predisposing respiratory disease; one patient did medicine/27485. Accessed: October 2016. have a history of recurrent pneumonitis. In four of the cases a negative rechallenge at the same or 7. Mato AR, Islam P, Daniel C, Strelec L, Kaye lower dose is described. The reports from Italy pose AH, Brooks S, et al. Ibrutinib-induced a specific challenge in that due to translation and pneumonitis in patients with chronic nomenclature issues we cannot rule out the lymphocytic leukemia. Blood, 2016. Feb possibility that among them may be cases of 25;127(8):1064-7. pneumonia rather than pneumonitis.
WHO Pharmaceuticals Newsletter No. 3, 2017 18 Signal
8. Shah RR. Tyrosine Kinase Inhibitor-Induced 9. Mahmoudi M, Murthy V, Suh J, Bradshaw A, Interstitial Lung Disease: Clinical Features, Sloance M. Ibrutinib-Induced Rapidly Diagnostic Challenges, and Therapeutic Progressive Inflammatory Pneumonitis. Dilemmas. Drug Saf. 2016 Aug 17. [Epub ahead American Thoracic Society International of print]. Conference Abstract, 2015.
Pregabalin and visual colour distortions Dr Linda Härmark, the Netherlands Pharmacovigilance Centre Lareb
Summary commonly, people with poor colour vision cannot distinguish between shades of blue and Twenty-five reports in the WHO global database of yellow. Poor colour vision can be inherited individual case safety reports, VigiBase, describe a (most common) or be acquired. Poor colour relationship between the drug pregabalin and vision can be caused by diseases such as sickle changes in colour vision. Based on these reports, it cell anaemia, diabetes, macular degeneration, is recommended to add changes in colour vision to Alzheimer’s disease, glaucoma, Parkinson’s the product information leaflet of pregabalin. disease, chronic alcoholism and leukaemia. Poor or deficient colour vision, often referred to as Certain medications such as antibiotics, colour blindness, is an inability to distinguish barbiturates, anti-tuberculosis drugs, high between certain colours, while still seeing colour. blood pressure medications and several Colour blindness can be inherited (most common) medications to treat nervous disorders may or it can be caused by diseases or drugs. Pregabalin also cause colour blindness. For people without (Lyrica®) is a drug that can be used for the poor or deficient colour vision, the ability to treatment of pain due to nerve injury, fibromyalgia, see colours deteriorates slowly with age.4,5 epilepsy and anxiety disorders. Chromatopsia is a visual defect in which On the basis of the 25 reports in VigiBase that were coloured objects appear unnaturally coloured, highlighted in the joint UMC/Lareb signal detection and colourless objects appear tinged with sprint that took place in October 2016, it seems colour. Chromatopsia may be caused by drugs, that the time to onset is quick, the changes in disturbance of the optic centres, cataract colour vision seem to occur within hours to days extraction or dazzling light.6 after starting the drug. This adverse reaction also Pregabalin is associated with a number of seems to be reversible; in seven cases the patients adverse drug reactions (ADRs) affecting the regained normal colour vision after stopping eye, such as blurred vision, diplopia, peripheral pregabalin. vision loss, visual disturbance, eye swelling, Although changes in colour vision can have other visual field defect, reduced visual acuity, eye causes, the relationship with pregabalin is pain, asthenopia, photopsia, dry eyes, strengthened by the fact that changes in colour increased lacrimation, eye irritation, vision loss, vision is a known adverse reaction of other drugs keratitis, oscillopsia, altered visual depth (vigabatrin and tiagabine) which exert their effects perception, mydriasis, strabismus and visual in a similar way as pregabalin. brightness.1 However, visual colour distortions such as colour blindness and chromatopsia, have not been described. Introduction Pregabalin has been approved for the European Reports in VigiBase Union (EU) and United States (US) markets since 2004. It is indicated for the treatment of This drug-ADR combination was identified in a neuropathic pain, postherapeutic neuralgia, diabetic signal detection screening with focus on peripheral neuropathy, fibromyalgia, epilepsy and patient reports in VigiBase, the WHO global for generalised anxiety disorder.1,2 Pregabalin is a database of individual case safety reports. In γ-aminobutyric acid (GABA) analogue and exerts its total, eight reports were identified using the effects by binding to the α2 – δ subunit of voltage MedDRA preferred term (PT) ‘colour blindness’, gated calcium channels, leading to a decreased and 13 reports using the MedDRA PT synaptic release of neurotransmitters.3 ‘chromatopsia’. The reports are presented in Table 1. The presentation of reported ADRs in Poor or deficient colour vision, often referred to as the table has been restricted to those colour blindness, is an inability to see the difference concerning the eye, and other ADRs that were between certain colours, while still seeing colour. reported have been omitted. Most people with this condition cannot distinguish between certain shades of red and green. Less
WHO Pharmaceuticals Newsletter No. 3, 2017 19 Signal
Table 1. Characteristics of case reports in VigiBase of colour blindness and chromatopsia in association with pregabalin. ADRs are restricted to those related to the eyes.
Case Reporter Sex/ Suspected (S), Indication Daily dose Reactions Time to onset Action taken with the Age Interacting (I) or (MedDRA drug, Outcome concomitant (C) preferred drugs terms related to the eye) 1 Consumer F/ Pregabalin, Neuralgia 75 mg once daily Eyes swollen, Within a day to Drug withdrawn Adult methylprednisolone, flashing vision, 3 days Recovered paracetamol/tramadol burning sensation (all S) in face, vision abnormal, colour blindness,
2 Consumer F/ Pregabalin (S) Fibromyalgia 75 mg twice daily Cataract, blindness, - Dose not changed 59 Morphine, paracetamol/ impaired driving Cataract, blindness, colour ocycodone (both C) ability, visual blindness - recovered impairment, foreign body in eye, colour Impaired driving ability, foreign blindness, visual body in eye, back pain - outcome acuity reduced not applicable Visual impairment and visual acuity - outcome unknown
3 Consumer M/- Prednisone, paracetamol Nerve injury, limb - Astigmatism, - Drug withdrawn (Both S) injury transient blindness, Astigmatism, colour blindness Pregabalin, amitriptyline colour blindness, and visual impairment, not (both I) eye disorder, eye recovered irritation, vision blurred, visual Outcome unknown for all other impairment events
4 Physician F/- Pregabalin (S), Fibromyalgia - Colour blindness, - Dose reduced Hydrocodone, folic acid, scotoma, vison Recovered from vision blurred blurred alprazolam, modafinil, Outcome unknown for the other paracetamol/hydrocodone events bitartrate (all C)
5* Consumer F/- Pregabalin, varenicline Fibromyalgia 50 mg three times Colour blindness, - Dose not changed (both S) daily diplopia, impaired Outcome unknown or not Sodium chloride, driving ability, applicable for all events duloxetine, opthalmological benzonatate, tramadol, examination methylphenidate, abnormal diazepam, salbutamol, fluticasone/salmeterol (all C)
6 Unknown F/44 Pregabalin (S) Nervousness, 50 mg three times Colour blindness, - Action taken with the drug is not pain daily eye pain, reported intraocular pressure Outcome unknown increased, visual disturbance, visual field defect
7 Physician F/37 Pregabalin (S) Generalized 50 mg once daily Vision blurred, 1 hour Dose not changed Lorazepam, anxiety disorder tunnel vision, Not recovered esomeprazole, defective colour levothyroxine (all C) vision
8 Physician M/63 Pregabalin (S) Polyneuropathy - Peripheral vision “Days” Drug withdrawn Ramipril, tramadol defective, blurred Recovered (both C) vision, defective colour vision Rechallenge was performed - no recurrence of events 9 Consumer F/59 Pregabalin (S) - 75 mg three times Diplopia, - Action taken with the drug is not Paracetamol/oxycodon, daily vision blurred, reported prednisone, ibuprofen chromatopsia Outcome unknown (all C)
10 Consumer F/31 Pregabalin (S) Fibromyalgia 150-200 mg twice Visual impairment, - Dose reduced Patient used 30 daily ocular discomfort, Outcome unknown concomitant drugs migraine, photophobia, face injury, impaired driving ability, activities of daily living impaired, vision blurred,
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Case Reporter Sex/ Suspected (S) or Indication Daily dose Reactions Time to onset Action taken with the Age concomitant (C) (MedDRA drug, Outcome drugs preferred terms related to the eye)
11 Pharmacist M/78 Pregabalin (S) Post herpetic 75 mg twice daily Vision colour tinged, Within a day Drug withdrawn Recovered Acetylsalicylic acid, neuralgia sleepy atenolol, cetirizine, clopidogrel, isosorbide, lansoprazole, nicorandil, perindopril, simvastatin (all C)
12 Consumer F/65 Pregabalin (S) Neuralgia 50 mg three times daily Chromatopsia, - Action taken with the drug is Baclofen, tizanidine, dizziness, not reported celecoxib (all C) somnolence, vision Outcome unknown blurred, fatigue
13 Other HCP F/- Pregabalin (S) Fibromyalgia 100 mg three times Impaired driving - Dose reduced Not Morphine, levothyroxine, daily ability, recovered hydrochlorothiazide, chromatopsia, visual vitamin D, sertraline, acuity reduced, tocopherol, zolendronic vision blurred acid, cyanocobalamin, calcium (all C)
14 Other HCP M/- Pregabalin (S) - - Chromatopsia, - Action taken with the drug is visual acuity not reported reduced, visual impairment Outcome unknown
15 Physician M/75 Pregabalin (S), Pain NOS 75 mg twice daily Vision abnormal, For vision Drug withdrawn Recovered Telmisartan, tamsulosin, eye pain, abnormal a day, omeprazole, chromatopsia for the other acetylsalicylic acid, events a few days torasemide (all C)
16 Other HCP F/- Pregabalin (S), Not reported 75 mg three times daily Activities of daily Unknown, for Drug withdrawn Chromatopsia Ibandroninic acid, living impaired, visual impairment recovered methylprogesterone chromatopsia, visual 7 months Outcome of Activities of daily acetate/conjugated acuity reduced, living impaired - unknown visual field defect, estrogens, oxycodone, Visual acuity reduced, visual visual impairment levothyroxine, retinol, field defect and visual calcium, paracetamol/ impairment - not recovered hydrocodone (all C)
17 Pharmacist F/44 Pregabalin (S) Diabetic - Chromatopsia, - Drug withdrawn Recovered neuropathy photophobia, tunnel vision
18 Consumer M/- Pregabalin (S) Back injury 50 mg three times daily Astenophia, 2 months Drug withdrawn Hydrocodone, oxycodone, chromatopsia, vision Not recovered olmesartan, diltiazem, blurred fluticasone/salmeterol, tiotropium (all C)
19** Other HCP M/59 Pregabalin (S), modafinil, Diabetic - Chromatopsia - Drug withdrawn Recovered metformin, glimepiride (all nephropathy C)
20 Physician F/- Pregabalin (S) Ill-defined - Chromatopsia - Drug withdrawn Outcome disorder unknown Rechallenge was performed - outcome unknown
21 Unknown M/51 Pregabalin (S), Neck pain - Chromatopsia - Drug withdrawn Outcome Paracetamol/hydrocodone, unknown carisoprodol, zolpidem Rechallenge was performed - (all C) outcome unknown
NOS= Not otherwise specified. *Case 5; In this case CT abnormal, convulsion, EEG abnormal, loss of consciousness, pineal neoplasm and pituitary tumour were also reported. It is more likely that the reported symptoms concerning the eye were caused by the tumour rather than by pregabalin. **Case 19, the author of this signal suspected that the indication for use should be diabetic neuropathy.
WHO Pharmaceuticals Newsletter No. 3, 2017 21 Signal
In case 1, the patient had previously used controlled design. All subjects underwent pregabalin at high doses to treat her trigeminal colour visual evoked potential tests and colour neuralgia and experienced dizziness, somnolence perimetry at baseline and after receiving and intense lethargy which were resolved after placebo, VGB (2000 mg) or CBZ (400 mg). discontinuation of pregabalin. No allergy was Whereas CBZ induced a mild overall experienced at that time. The symptoms started impairment of the chromatic and achromatic with a burning face, and the morning after she had systems, VGB induced a selective blue a tendency to vomit, facial rash and swelling of the impairment. The differential changes the two eyes. Paracetamol/tramadol was withdrawn, since antiepileptic drugs induced in visual tests this was the drug she had not previously used. The presumably depended on their different next day the rash had expanded and she mechanisms of action. The selective blue experienced pruritus, she had flashes in her eyes, impairment in colour visual tests in VGB- and intense lights and she could not distinguish treated healthy subjects is consistent with items (also reporting that everything looked square). gamma-aminobutyric acid GABA-ergic In addition, at an unspecified date the patient could inhibition also at retinal level.9 not recognize colours. A further study investigated colour vision in In case 7, one hour after the first dose the patient patients treated with VGB or CBZ monotherapy. developed tunnel vision, impaired colour vision, There were 32 epilepsy patients treated with blurred vision and difficulties in reading. The patient VGB monotherapy, 18 patients treated with had no medical history of retinal degradation, CBZ monotherapy, and 47 age- matched ophthalmological or neurological diseases and no healthy controls examined. Abnormal colour history of eye diseases. perception was found in 32% of the epilepsy patients treated with VGB monotherapy and In case 8, the patient noticed a gradually worsening 28% of the epilepsy patients treated with CBZ visual disorder with blurred vision over a few days, monotherapy.10 peripheral vision impairment, and loss of perception of colour after the dose was increased from 25 mg In another study, the effects of the GABA-ergic twice daily (treatment duration unknown) to 75 mg antiepileptic drug (AED), tiagabine, on colour twice daily. Pregabalin was discontinued and the vision and contrast sensitivity was investigated. patient recovered. The patient’s medical history Twenty newly-diagnosed patients with partial included diabetes mellitus, hypertension, peripheral epilepsy (aged 19-72 years), receiving arterial occlusive disease, strabismus and alcohol tiagabine as their initial monotherapy for 5-41 use. months were examined. Three patients were excluded from the colour vision evaluation for In three cases (3, 13 and 18) the patient had not congenital red-green colour vision defects. recovered at the time of reporting, even though the Seven out of 17 patients (41%) had acquired drug had been withdrawn or the dose had been colour vision deficit. This study suggests that reduced. It is possible that the report was AED therapy with tiagabine, as with other submitted before the patient had the opportunity to established and newer AEDs may interfere with recover. Other explanations might be that in some colour perception.11 cases the colour vision distortion is not reversible or that the colour vision distortion in these patients In the studies described above, it seems that were not caused by pregabalin and therefor did not the GABA-ergic properties of VGB and improve when withdrawing or reducing the dose of tiagabine contribute to the colour vision the drug. deficiency. VGB is an irreversible inhibitor of GABA-transaminase (GABA-T), the enzyme
responsible for the metabolism of the inhibitory Literature and Labelling neurotransmitter GABA. This inhibition causes increased levels of GABA in the central nervous Colour vision distortions such as colour blindness system. Tiagabine is thought to inhibit GABA and chromatopsia are not labelled in the EU 1,2 uptake into presynaptic neurons, thereby summary of product characteristics or Drugs.com. providing more GABA available for binding to These ADRs are also not mentioned in the 7,8 receptors on postsynaptic cells. This enhances literature and a PubMed search using the terms the activity of GABA, the major inhibitory “Colour Vision Defects”[Mesh]) AND neurotransmitter in the central nervous system. “Pregabalin”[Mesh] returned no hits. However, It is possible that the colour vision distortion colour vision disturbances have been documented seen in patients using pregabalin can be with anti-epileptic drugs; primarily, but not explained by the same mechanism. Pregabalin exclusively, in anti-epileptic drugs that enhance is a GABA analogue and thereby enhancing GABA transmission. GABA activity just as VGB and tiagabine.12 In a study, the effects of a single oral dose of vigabatrin (VGB) and carbamazepine (CBZ) on visual function in normal healthy volunteers was investigated. Volunteers were randomly assigned to three groups according to a single-blind, placebo-
WHO Pharmaceuticals Newsletter No. 3, 2017 22 Signal
Discussion and Conclusion 3. Taylor CP, Angelotti T, Fauman E. This signal presents a case series of 25 reports Pharmacology and mechanism of action of concerning pregabalin and colour vision distortions. pregabalin: the calcium channel alpha2- When information about the latency period is delta (alpha2-delta) subunit as a target for present, it seems that the symptoms develop quite antiepileptic drug discovery. Epilepsy Res. quickly within hours to days after the start of the 2007 Feb;73(2):137-50. drug. In seven cases there is a positive dechallenge, 4. Mayo Clinic Poor Colour Vision. Available indicating that this adverse drug reaction is from: http://www.mayoclinic.org/diseases- reversible when the drug is withdrawn. Colour vision distortions can also have other causes, such conditions/poor-color-vision/symptoms- as sickle cell anaemia, diabetes, macular causes/dxc-20263383. Accessed 6 degeneration, Alzheimer’s disease, glaucoma, December 2016. Parkinson’s disease, chronic alcoholism and 5. Colour blind awareness. Available from: leukaemia. Pregabalin is indicated for use in http://www.colourblindawareness.org. diabetic pheripheral neuropathy, and in such cases Accessed 6 December 2016 it is possible that the diabetes could be the cause of 6. NDI Foundation. Available from: the colour vision distortion. However, in the case series only one case explicitly states that the http://www.ndif.org/ terms/4617-chromatopsia indication was diabetic peripheral neuropathy, and Accessed 6 December 2016. in this case the patient recovered after withdrawal 7. Aronson JK, editor. Meyler’s Side Effects of of the drug, hence eliminating confounding by Drugs. 15th ed. Elsevier; Amsterdam, the indication. In case 5, it is more likely that the Netherlands; 2006. patient’s tumour was the cause of the colour vision 8. Fraunfelder FT, Fraunfelder FW, Chambers distortion than the drug. WA, editors. Drug Induced Ocular Side In the literature, colour vision distortions have been Effects. 7th ed. Elsevier; 2015. described with the use of VGB and tiagabine. It is 9. Mecarelli O, Rinalduzzi S, Accornero N. believed that this effect is mediated by the GABA- Changes in color vision after a single dose ergic effects of these drugs on the retina. Pregabalin, which is a GABA analogue, could of vigabatrin or carbamazepine in healthy probably cause colour vision distortions through the volunteers. Clin Neuropharmacol. 2001 same mechanisms. With this case series and a Jan;24(1):23-6. mechanism which can explain how pregabalin can 10. Nousiainen I, Kalviainen R, Mantyjarvi M. cause colour vision distortion, we believe that this Color vision in epilepsy patients treated with association is a signal and that the term colour vigabatrin or carbamazepine monotherapy. vision should be included in the label. Ophthalmology 2000 May;107(5):884-8. 11. Sorri I, Kalviainen R, Mantyjarvi M. Color References vision and contrast sensitivity in epilepsy patients treated with initial tiagabine 1. European Medicines Agency: Summary of monotherapy. Epilepsy Res. 2005 Product Characteristics for pregabalin (Lyrica®). Dec;67(3):101-7. Available from: www.emea.europa.eu. Accessed: 12. Micromedex® Healthcare Series. Available 6 December 2016 from: www. micromedexsolutions.com. 2. Approval history for pregabalin. Available from: Accessed: 6 December 2016. https://www.drugs.com/mtm/pregabalin.html# drug-info-approval. Accessed 6 December 2016.
SGLT-2 inhibitors and genital pruritus A non-serious event with the potential for noncompliance and/or discontinuation Dr Rebecca E Chandler, Uppsala Monitoring Centre
Summary reaction for these types of drugs which was known at the time of approval. A joint Sodium glucose cotransporter-2 inhibitors (SGLT- UMC/Lareb signal detection sprint performed in 2i) are members of a relatively new class of oral October 2016, highlighted reports from antidiabetic agents which are used in the treatment patients that were retrieved from VigiBase, the of type 2 diabetes mellitus as monotherapy or in WHO global database of individual case safety combination with other agents. Itching in the reports, which revealed that often patients genital area is a common non-serious adverse
WHO Pharmaceuticals Newsletter No. 3, 2017 23 Signal stop taking these medications because of this Reports in VigiBase adverse event. During a joint UMC/Lareb signal detection A 71 year old female with a history of type 2 sprint with a focus on patient reports, a total of diabetes and hypertension was initiated on 99 individual case safety reports which empagliflozin. The patient was treated for cystitis included the MedDRA preferred term (PT) approximately one month after starting therapy. 'pruritus genital' for dapagliflozin, canagliflozin Also, the patient experienced non-serious events of and empagliflozin were identified in VigiBase, thrush, burning in the urogenital area, redness in the WHO global database of individual case the urogenital area, blistering in the urogenital area safety reports as of 6 November 2016. and hypoglycaemia. In the course of five days the Forty-eight reports of pruritus genital (48.5%) itching increased up to intolerability. Therapy for have been received for dapagliflozin, 31 the event of cystitis was antibiotics and antifungal (31.3%) for canagliflozin and 20 (20.2%) for cream; therapy of the symptoms in the urogenital empagliflozin. area included unspecified ointments without success and a mild-cortisone containing ointment which 67.7% of the reports have been described helped slightly. Empagliflozin was discontinued. events in females, 28.3% of the reports for males. A 60 year old female experienced severe itching, soreness, and reddening of the genital area and an 40.4% of the reports originated from the inability to sit while on therapy with dapagliflozin. Americas, 36.4% from Europe, and 23.2% The patient was diagnosed with candidal mycosis from Asia. and treated with antifungal cream. The cream did not bring improvement and the patient discontinued The most commonly co-reported MedDRA PT dapagliflozin “on her own” in response to the events. were genital burning sensation (9.1%), pollakiuria (7.1%) and dysuria (5.1%).
Twenty-three of the reports were received Introduction from consumers or non-health professionals (eight of which were classified as “serious”) Sodium glucose cotransporter-2 inhibitors (SGLT-2i) and 25 were received from physicians (none of are members of a relatively new class of oral which were classified as “serious”). antidiabetic agents. Three medicines in this class, Furthermore, fifty-four (54.5%) of the reports dapagliflozin, canagliflozin and empagliflozin, are documented that the drug was discontinued currently marketed for use in the treatment of type secondary to the reported adverse drug 2 diabetes mellitus as monotherapy or in reactions. combination with other agents.
SLGT-2i work by inhibiting glucose reabsorption in the kidney and thereby promoting urinary excretion Literature and Labelling of glucose. Studies have revealed that SGLT-2i have beneficial effects on blood glucose levels, but also The summary of product characteristics for they reduce blood pressure and induce weight loss. each of these products notes that most genital Given that the action of these agents is independent infections were mild to moderate and only of both insulin secretion and insulin action, another rarely resulted in discontinuation. The patient benefit of these agents is a lower risk of information leaflet notes only that genital hypoglycaemia.1 infections are common to very common and manifest with irritation, itching, unusual Given their mechanism of action, one of the major discharge or odour. There is no information safety concerns for the SLGT-2i is an increased risk provided to the patient to seek medical of genital infections caused by high levels of glucose consultation for treatment of these infections. in the urine. This safety concern is common enough that it was observed in clinical trials and has been fairly well characterised. Genital infections are Discussion and Conclusion largely fungal in nature, manifesting as mycotic vulvovaginitis in females and mycotic balanitis in The aim of communication is to highlight that males. Such infections have been estimated to some events can be characterised as non- affect 5-10% of patients using SGLT-2i and are serious in the clinical trial setting but may more common in premenopausal women, patients manifest in the post marketing period as with a history of genital infections, and obese severe events which have a large enough patients. There was no evidence of a relationship impact on the quality of life for the patient that between the incidence of genital infections and the discontinuing the medication is necessary. amount of glycosuria observed in the clinical trials. Additionally, more guidance by drug Furthermore, rates of infections are highest in the developers or regulators on how to manage 2-4 first few months of treatment. these effects may be necessary to ensure that patients who receive benefit from taking the medications are able to remain compliant with them.
WHO Pharmaceuticals Newsletter No. 3, 2017 24 Signal
References 3. European Medicines Agency: Summary of 1. Ferrannini E, Solini A. SGLT2 inhibition in Product Characteristics for canagliflozin diabetes mellitus: rationale and clinical (Ivokana®). Available from: prospects. Nat Rev Endocrinol. 2012;8:495- http://www.ema.europa.eu/docs/en_GB/ 502. document_library/EPAR_-_Product_Information/ 2. European Medicines Agency: Summary of human/002649/WC500156456.pdf Product Characteristics for dapagliflozin. Accessed February 2017. (Forxiga®). Available from: 4. European Medicines Agency: Summary of Product Characteristics for empagliflozin. http://www.ema.europa.eu/docs/en_GB/ (Jardiance®). Available from: document_library/EPAR_-_Product_Information/ http://www.ema.europa.eu/docs/en_GB/ human/002322/WC500136026.pdf. Accessed: document_library/EPAR_-_Product_Information/ February 2017. human/002677/WC500168592.pdf. Accessed: February 2017.
WHO Pharmaceuticals Newsletter No. 3, 2017 25 Signal
CAVEAT DOCUMENT
Accompanying statement to data released from VigiBase®, the WHO international database of suspected adverse drug reactions
Uppsala Monitoring Centre (UMC) in its role as the World Confidential data Health Organization (WHO) Collaborating Centre for According to WHO policy and UMC Guidelines, ADR International Drug Monitoring receives reports of reports sent from the WHO PIDM member countries suspected adverse reactions to medicinal products from to VigiBase® are anonymized, but they are still to be National Centres in countries participating in the WHO considered sensitive due to the nature of the data. pharmacovigilance network, the WHO Programme for When receiving and using adverse reaction data International Drug Monitoring (PIDM). The information is (“Data”), the user agrees and acknowledges that it stored in VigiBase®, the WHO international database of will be the controller of any such Data. Accordingly, suspected adverse drug reactions (ADRs). It is important the user shall adhere to all applicable legislation such to understand the limitations and qualifications that apply as, but not limited to, EU and national legislation to this information and its use. regarding protection of personal data (e.g. the Data The reports submitted to UMC generally describe no more Protection Directive 95/46/EC and Regulation (EC) than suspicions which have arisen from observation of an No 45/2001, as applicable). Transfer of sensitive unexpected or unwanted event. In most instances it data to a third party is generally prohibited subject cannot be proven that a specific medicinal product (rather to limited exceptions explicitly stated in applicable than, for example, underlying illness or other concomitant legislation. medication) is the cause of an event. As the controller of the Data, the user shall be liable Reports submitted to National Centres come from both for any and all processing of the Data and shall regulated and voluntary sources. Some National Centres indemnify and hold the UMC harmless against any accept reports only from medical practitioners; other claim from a data subject or any other person or National Centres accept reports from a broader range of entity due to a breach of any legislation or other reporters, including patients. Some National Centres regulation regarding the processing of the Data. include reports from pharmaceutical companies in the Non-permitted use of VigiBase® Data includes, but information submitted to UMC; other National Centres do is not limited to: not. patient identification or patient targeting The volume of reports for a particular medicinal product identification, profiling or targeting of general may be influenced by the extent of use of the product, practitioners or practice publicity, the nature of the reactions and other factors. No Any publication, in whole or in part, of information information is provided on the number of patients exposed obtained from UMC must include a statement: to the product. (i) regarding the source of the information Some National Centres that contribute information to (ii) that the information comes from a variety of VigiBase® make an assessment of the likelihood that a sources, and the likelihood that the suspected medicinal product caused the suspected reaction, while adverse reaction is drug-related is not the same others do not. Time from receipt of a report by a National in all cases, Centre until submission to UMC varies from country to (iii) that the information does not represent the country. Information obtained from UMC may therefore opinion of the World Health Organization. differ from those obtained directly from National Centres. Omission of this statement may exclude the If in doubt or in need of help for interpretation of country responsible person or organization from specific data, UMC recommends to contact the concerned receiving further information from VigiBase®. NC before using the data. UMC may, in its sole discretion, provide further For the above reasons interpretations of adverse instructions to the user, responsible person and/or reaction data, and particularly those based on organization in addition to those specified in this comparisons between medicinal products, may be statement and the user, responsible person and/or misleading. The supplied data come from a variety organization undertakes to comply with all such of sources. The likelihood of a causal relationship is instructions. not the same in all reports. Any use of this Uppsala Monitoring Centre (UMC) Box 1051, SE-751 40 Uppsala, Sweden information must take these factors into account. Tel: +46-18-65 60 60, E-mail: [email protected] www.who-umc.org
WHO Pharmaceuticals Newsletter No. 3, 2017 26 Feature
Pilot Mobile ‘APP’ for reporting suspected adverse drug reactions launched in Burkina Faso and Zambia
As we are evolving towards a paperless world, it is not a surprise that there is an increase in demand for electronic adverse drug reaction (ADR) reporting options. Many countries are utilising electronic reporting forms via a web-link that can be obtained on a computer screen. The link is often located on the website of the national pharmacovigilance centre and requires internet access in order to report an ADR. Although the use of electronic reporting via a website is thought to increase the frequency and timeliness of reporting, the requirement of a computer and internet access may limit its use, particularly in countries and areas where there is poor or intermittent internet access. Recent technological advances have led to the development of mobile apps for reporting ADRs, many of which allow reports to be made offline with the possibility of sending the report later when the user is online and internet access is available. Croatia, the Netherlands and UK have rolled out a mobile ‘app’ that was developed as part of the “Web-Recognising Adverse Drug Reactions (WEB-RADR)” project. This project is supported by the European Commission’s Innovative Medicines Initiative, and explores the volume, breadth and quality of social media data, and consequently, where they may add value from a pharmacovigilance perspective. One of the work packages of this initiative is dedicated to developing a mobile app for reporting ADRs. The app is the same in all three countries, except that it is translated and branded for different national settings. An additional feature of this app is that it promotes two-way communication by providing feedback to the reporter after a report has been submitted. Such feedback can range from a confirmation that the report was received, to an overview of how often a type of ADR has been reported and what has been done with the report that was submitted. The concept of a WHO “white app” was announced at the 39th Annual Meeting of Representatives of the National Pharmacovigilance Centres Participating in the WHO Programme for International Drug Monitoring (PIDM), in Muscat Oman, November 2016 (1). The notion of the ‘white app’ envisages making the WEB-RADR app available to other non EU countries in the WHO PIDM. It is non-branded and can be built-upon by the country interested in using the app and adapted to the national context. Drug lists and MedDRA* terms can be incorporated as drop down lists, in addition to free text. The app will be made available to other countries through a stepwise approach starting with a pilot phase in one French and one English speaking country. The WEB-RADR team in collaboration with WHO worked with representatives from Burkina Faso and Zambia to nationalise the app in both countries. After preliminary testing, the app went live on 8 May 2017. Both countries are planning a widespread awareness campaign, involving leaflets, interviews on the radio, television and an official launch ceremony. WHO plans to use the experiences from the pilot countries to draw lessons learnt as part of the initial steps towards making the app available for all.
1. World Health Organization. The 39th Annual Meeting of Representatives of the National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring. The WHO Pharmaceuticals Newsletter. 2016(6):26-7.
* Medical Dictionary for Regulatory Activities, developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) to provide single standardised international medical terminology to be used for regulatory communication and evaluation of data pertaining to medicinal products for human use.
WHO Pharmaceuticals Newsletter No. 3, 2017 27 Feature
Introducing a New Member in the WHO Programme for International Drug Monitoring (WHO PIDM): Paraguay
El Dpto. de Farmacovigilancia fue creado e incorporado al organigrama de la Dirección Nacional de Vigilancia Sanitaria dependiente del Ministerio de Salud Pública y Bienestar Social mediante Resolución Ministerial S.G. N° 314 en el año 2013. A la fecha este Departamento se encuentra enmarcado dentro del proceso de fortalecimiento institucional e interactuando con otras dependencias del Ministerio de Salud, especialmente con los programas de lucha contra el SIDA (PRONASIDA) y la Tuberculosis (PNCT). En el último año se han incorporado nuevos elementos al marco regulatorio especialmente con miras a la implementación de las Buenas Prácticas de Farmacovigilancia y actualmente se encuentra abocado a la creación de una red de hospitales centinela. ----- The Department of Pharmacovigilance was established under the National Agency of Health Surveillance, Ministry of Public Health and Social Welfare after the Ministerial Resolution S.G. No. 314 was issued in 2013. To date, this Department is involved in strengthening pharmacovigilance practices and regularly interacts with other units of the Ministry of Health, in particular HIV (PRONOSIDA) and TB (PNCT) public health programmes. Since last year, new components have been added to the regulatory framework, and there is a focus on implementing Good Pharmacovigilance Practices, and forming a pharmacovigilance network in sentinel hospitals.
WHO Pharmaceuticals Newsletter No. 3, 2017 28