WHO Pharmaceuticals Newsletters

2017 WHO Pharmaceuticals

No.6 NEWSLETTER

The WHO Pharmaceuticals Newsletter provides you

with the latest information on the safety of medicines

WHO Vision for Medicines Safety and legal actions taken by regulatory authorities 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 a brief report on the 40th The aim of the Newsletter is to disseminate regulatory Annual Meeting of Representatives of the National information on the safety of Pharmacovigilance Centres participating in the WHO pharmaceutical products, Programme for International Drug Monitoring. based on communications received from our network of national pharmacovigilance centres and other sources such as specialized bulletins and journals, as well as partners in WHO.

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

Safety and Vigilance: Medicines, EMP-HIS, World Health Organization, 1211 Geneva 27, Switzerland, Contents E -mail address: [email protected]

This Newsletter is also available at: Regulatory matters http://www.who.int/medicines Safety of medicines

Signal

Feature

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Table of Contents

Regulatory Matters Amoxicillin containing products ...... 5 Chlorhexidine containing products ...... 5 Clozapine ...... 5 Codeine-containing products ...... 5 Daclizumab ...... 6 DPP-4 inhibitors ...... 6 Fingolimod ...... 6 Fluconazole ...... 7 Fluconazole (non-prescription) ...... 7 Green tea extract-containing natural health products ...... 7 Ibrutinib ...... 8 Levetiracetam ...... 8 Linagliptin ...... 8 Moxifloxacin (oral dosage form) ...... 8 Terbinafine ...... 9

Safety of Medicines Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) ...... 10 Chlorhexidine ...... 10 Clozapine ...... 10 Febuxostat ...... 10 Finasteride ...... 11 Flupirtine-containing medicines ...... 11 Gabapentin ...... 11 Hydroxyethyl-starch containing medicines ...... 12 Intraocular injections of a compounded triamcinolone, moxifloxacin and vancomycin (TMV) formulation ...... 12 Isotretinoin ...... 12

Signal Natalizumab and rapidly evolving central nervous system lymphoma .... 14

WHO Pharmaceuticals Newsletter No. 6, 2017  3 Table of Contents

Feature The 40th Annual Meeting of Representatives of the National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring...... 21 Introducing the WHO Collaborating Centre for Pharmacovigilance in Public Health Programmes and Regulatory Services ...... 24

WHO Pharmaceuticals Newsletter No. 6, 2017  4 Regulatory Matters

Amoxicillin (See page 10 and WHO Pharmaceuticals It should be remembered that Newsletters No.2, 2017: Rare but serious blood and laboratory tests containing products allergic reactions in the USA and No.3, 2016: should be continued in patients Serious allergic reactions in Canada) undergoing treatment and Risk of thrombocytopenia prescription and dispensing Japan. The Ministry of Health, conditions have not been modified. Labour and Welfare (MHLW) Clozapine and the Pharmaceuticals and Reference: Medical Devices Agency Amendments to the patient Información dirigida a (PMDA) have announced that monitoring programme profesionales sanitarios, AEMPS, the package inserts for 4 October 2017, Spain amoxicillin preparations have Spain La Agencia Española de (www.aemps.gob.es) been updated to include the Medicamentos y Productos risk of thrombocytopenia as a (See WHO Pharmaceuticals Newsletter No.5, Sanitarios (AEMPS) has 2015: Modifications for monitoring clinically significant adverse reduced restrictions made in reaction. neutropenia in USA) the patient monitoring Amoxicillin is an antibiotic used programme on clozapine. It is for the treatment of a number no longer a requirement to of bacterial infections. send results of blood and Codeine-containing laboratory tests to the AEMPS products A total of nine cases of when prescribing clozapine. thrombocytopenia associated Contraindication in children with use of amoxicillin have Clozapine is an antipsychotic been reported in Japan. Of used to treat symptoms of and ultra-rapid metabolisers these, a causal relationship schizophrenia and psychotic Australia. The Therapeutic could not be excluded in five disorders associated with Goods Administration (TGA) cases. Parkinson’s disease, when standard treatments are not has updated the product Reference: effective. information documents for all Revision of Precautions, prescription codeine MHLW/PMDA, 17 October 2017 Regular blood and laboratory preparations to include the (www.pmda.go.jp/english/) tests (weekly and monthly restriction of use in children leukocyte counts) have shown and ultra-rapid metabolisers. to be effective in preventing More specifically, codeine the occurrence of products should no longer be Chlorhexidine agranulocytosis and possible used in children under 12 years containing products complications. However, in of age, or in children aged 12- order to reduce the burden 18 years who have recently Risk of anaphylaxis associated with sending blood undergone surgery to remove results, the monitoring their tonsils or adenoids. Japan. The MHLW and the programme has been Codeine should also not be PMDA have announced that the simplified: used by breastfeeding mothers package insert for or in patients known to be It is not mandatory for chlorhexidine containing ultra-rapid metabolisers. products, including over the prescribing doctors to send counter preparations results of blood tests to the Most product information for (Hibitane®, Acesclean®, AEMPS, however this does not over-the-counter codeine preparations now have Despakowa® and others) have exempt them from carrying out warnings to not use them in been updated to include the the tests and keeping records risk of anaphylaxis as a children aged under 12 years. of results in accordance to the clinically significant adverse license authorization From 1 February 2018, all reaction. “Pharmacy Medicine” and conditions. “Pharmacist Only Medicine” Chlorhexidine is generally used  Doctors no longer need to for disinfection. codeine-containing products deliver the patient's chart at will be rescheduled to A total of 12 cases associated the time of prescription and “Prescription Only Medicine”. with shock or anaphylaxis have pharmacies do not need to been reported in Japan. Of request it from the patient Reference: these, a causal relationship in order to dispense. Medicines Safety Update, TGA, could not be excluded in four  Medicines that contain Vol. 8, No. 5, November 2017 (www.tga.gov.au) cases. clozapine continue to be classified as medically (See WHO Pharmaceuticals Newsletters Reference: controlled and, therefore, No.4, No.3, No.2 and No.1, 2017, No.5 and Revision of Precautions, subject to dispensing No.1 in 2016, No.6, No.5, No.4 and No.3 in MHLW/PMDA, 17 October 2017 requirements. 2015 for related information) (www.pmda.go.jp/english/) WHO Pharmaceuticals Newsletter No. 6, 2017  5 Regulatory Matters

Daclizumab Daclizumab must not be used Reference: in patients with pre-existing Based on the communication Risk of serious liver damage liver disease and should not be from IPC, NCC-PvPI, India, started in new patients with November 2017 (www.ipc.gov.in) over two times the normal Europe. The European (See WHO Pharmaceuticals Newsletters Medicines Agency’s (EMA) has range of liver enzymes. It is No.3, 2017, No.6, 2015 and No.5, 2015 for concluded that further recommended that doctors do related information) restrictions on the use of the not use daclizumab in patients daclizumab (Zinbryta®) are with other autoimmune necessary following a review of conditions. the medicine’s effects on the The PRAC is also Fingolimod liver. recommending that, in addition Contraindicated in patients Daclizumab is a medicine used to the current educational to treat certain patients with materials, patients and health- with underlying cardiac relapsing forms of multiple care professionals in the EU pathology and risks of skin sclerosis. should be given an neoplasms acknowledgment form. The The EMA’s Pharmacovigilance form will be used to confirm Spain After a periodic Risk Assessment Committee that doctors have discussed the evaluation of safety data for (PRAC) review found that risks with their patients and fingolimod (Gilenya®), the unpredictable and potentially that the patients understand AEMPS has recommended that fatal immune-mediated liver the importance of monitoring health-care professionals injury can occur during and checking for signs of liver should not use fingolimod in treatment with daclizumab and damage. patients with underlying for up to six months after cardiac conditions. stopping treatment. Reference: News and press releases, EMA, Gilenya® is the only In order to reduce the risks, 27 October and 10 November medication with fingolimod doctors should now only 2017 (www.ema.europa.eu) currently authorized in Spain. prescribe daclizumab for It is indicated as single disease relapsing forms of multiple (See WHO Pharmaceuticals Newsletter No.4, modifying therapy in highly 2017: Provisional restrictions for use in EU) sclerosis in patients who have active relapsing remitting had an inadequate response to multiple sclerosis (MS)). at least two disease modifying therapies (DMTs) and cannot During a periodic safety be treated with other DMTs. DPP-4 inhibitors evaluation of fingolimod, an outstanding number of cases of In addition, doctors should Risk of arthralgia polymorphic ventricular monitor patients’ liver function arrhythmias were detected (ALT, AST and bilirubin) at India. The Pharmacovigilance after the administration of least once a month as closely Program of India, Indian fingolimod. as possible before each Pharmacopeia Commission treatment and continue (PvPI, IPC) has made Ventricular fibrillation and monitoring them for up to six recommendations to the sudden death were among the months after treatments have Central Drugs Standard Control cases described. In the stopped. Organisation (CDSCO) about deceased patients it was revising the drug safety labels observed that there was a If the patient does not comply for DPP-4 inhibitors to include personal history of cardiac with monitoring requirements arthralgia as a potential pathology. or the response to treatment is adverse drug reaction. inadequate, doctors should Based on the evaluation, a consider stopping treatment. DPP-4 inhibitors are used for number of risk minimization the treatment of type 2 measures have been issued It is recommended that the diabetes mellitus. and this includes doctor should stop treatment if contraindication of use in a patient has liver enzyme Between July 2011 and August patients with underlying levels over three times the 2017, PvPI received 96 reports cardiac conditions. normal limit and refer patients of arthralgia with DPP-4 with signs and symptoms of inhibitors use. The cases were The AEMPS has also liver damage to a liver reviewed by Signal Review recommended that patients specialist. Panel (SRP)-PvPI, IPC who using fingolimod should be concluded that there was a monitored for the appearance Patients who test positive for strong causal relationship of skin lesions. Skin hepatitis B or C infection between DPP-4 inhibitors and evaluations should be carried should also be referred to a arthralgia. out at the beginning of the specialist. treatment and every 6-12 months afterwards. WHO Pharmaceuticals Newsletter No. 6, 2017  6 Regulatory Matters

The AEMPS has stated that Fluconazole (non- taking low dose fluconazole cases of basal cell carcinoma (150 mg or less) or higher as well as other skin neoplasms prescription) doses. Higher dose fluconazole have been reported, including Potential risks to pregnancy products, available by malignant melanoma, outcomes prescription only, are known to squamous cell carcinoma, have pregnancy-related risks Merckel cell carcinoma and Canada. Health Canada has and these are communicated in Kaposi's sarcoma. recommended that the product the product safety information. Reference: safety information for all non- In the pregnancy registry study Información dirigida a prescription fluconazole that suggested a link between profesionales sanitarios, AEMPS, products should be updated to fluconazole use and unwanted 6 November 2017, Spain include the potential risk of effects in pregnancy, there was (www.aemps.gob.es) pregnancy loss and birth not enough information to defects and state that these conclude whether or not the (See WHO Pharmaceuticals Newsletters products are not recommended fluconazole product itself was No.1, 2016: Recommendations to minimise for use by women who are progressive multifocal leukoencephalopathy the cause. trying to become pregnant. (PML) and skin cancer and No.5, 2015: Risk Health Canada's review found of progressive multifocal leukoencephalopathy Non-prescription (oral, 150 that a link between the use of in USA and Japan.) mg) fluconazole products are non-prescription fluconazole authorized to treat vaginal and the risk of unwanted yeast infections. effects in pregnancy cannot be Fluconazole Health Canada reviewed the made at this time based on the potential risk of unwanted currently available information. Risk of hyperpigmentation effects in pregnancy, including The manufacturers have pregnancy loss (i.e., voluntarily updated the product India. The PvPI, IPC has made miscarriage or stillbirth) or safety information in recommendations to the birth defects (i.e., major prescription only products. CDSCO about revising the drug congenital malformations) with Health Canada has safety label for fluconazole, to non-prescription fluconazole recommended that the product include hyperpigmentation as a use, in part because a recently information for all other non- potential adverse drug published study suggested that prescription fluconazole reaction. such a risk may exist. products should be updated in Fluconazole is used for At the time of the review, the same way. treatment of systemic mycosis Health Canada had received Women continue to be advised and for prophylaxis of one Canadian report and three to avoid use of non- cryptococcal meningitis, international reports of prescription fluconazole oesophageal and miscarriages that were possibly products while pregnant. oropharyngeal candidiasis, related to non-prescription vaginal candidiasis and fluconazole use. Five Reference: systemic candidiasis. international cases were Summary Safety Review, identified in the information Health Canada, 9 November Between July 2011 and August received from the 2017 (www.hc-sc.gc.ca) 2017, PvPI received 12 reports manufacturers describing birth of hyperpigmentation with (See WHO Pharmaceuticals Newsletters defects that were possibly fluconazole use. The cases No.3, 2017: Reminder not to use during associated with non- were reviewed by SRP-PvPI, pregnancy in Ireland and Caution in use prescription fluconazole use; during pregnancy in Malaysia and No.3, IPC who concluded that there however there was not enough 2016: Risk of miscarriage in pregnancy: was a strong causal information in any of these under investigation in the USA) relationship between reports to conclude a causal fluconazole and relationship. hyperpigmentation in these cases. A search in the WHO global Green tea extract- database of Individual Case Reference: containing natural Safety Reports (ICSRs), Based on the communication VigiBase, found 360 cases of health products from IPC, NCC-PvPI, India, pregnancy loss or birth defects November 2017 (www.ipc.gov.in) Potential risk of liver injury reported in patients treated with fluconazole. There was not Canada. Health Canada has enough information in these decided to strengthen the reports to conclude that cautionary risk statement in fluconazole caused these the monograph for green tea outcomes or to determine extracts to include the advice whether the women were

WHO Pharmaceuticals Newsletter No. 6, 2017  7 Regulatory Matters on the potential risk of liver trial data, 11 cases of reported in Japan. Of these, a injury. ventricular causal relationship could not be Green tea extract-containing tachycardia/ventricular excluded in two cases. natural health products are fibrillation and six additional Reference: used to help manage weight cases of sudden cardiac death Revision of Precautions, loss (along with diet and in patients exposed to ibrutinib MHLW/PMDA, 17 October 2017 exercise) and as a source of were identified. In 12 of these (www.pmda.go.jp/english/) antioxidants for the 17 cases, the events occurred maintenance of good health. without any evidence of prior cardiac history. Health Canada reviewed the potential risk of liver injury There were 52 cases of associated with green tea ventricular tachyarrhythmias Linagliptin extract because of ongoing reported in post-marketing Risk of interstitial reports of serious liver injuries settings. worldwide, including a recent pneumonia A cumulative review of data report in Canada. from clinical trials and post- Japan. The MHLW and the Health Canada's review marketing cases identified PMDA have announced that the concluded that there may be a eight reports of hepatitis B package insert for linagliptin link between the use of green reactivation in ibrutinib-treated (Trazenta®) has been updated tea extract and the risk of rare patients and causality of to include the risk of interstitial and unpredictable liver injury. ibrutinib was considered to be pneumonia as a clinically While this risk is already probable or possible. significant adverse reaction. identified in Health Canada's Infections (including sepsis, Linagliptin is a medicine used green tea extract’s monograph, neutropenic sepsis, bacterial, for type-2 diabetes mellitus. warnings will be strengthened. viral or fungal infections) have A total of 20 cases associated The safety review also been observed in patients with interstitial pneumonia recommended that green tea treated with ibrutinib. Some of have been reported in Japan. extract products should be these infections resulted in Of these, a causal relationship used by adults only. hospitalisation and, in some could not be excluded in four cases, death. Reference: cases. Summary Safety Review, Ibrutinib continues to have a Reference: Health Canada, 15 November favourable risk-benefit profile Revision of Precautions, 2017 (www.hc-sc.gc.ca) for treating patients with MHLW/PMDA, 17 October 2017 indications specified in the (www.pmda.go.jp/english/) Australian product information.

Reference: Ibrutinib Medicines Safety Update, TGA, Risk of ventricular Vol. 8, No. 5, November 2017 Moxifloxacin (oral (www.tga.gov.au) tachyarrhythmia, hepatitis B dosage form) reactivation and infection Risk of rhabdomyolysis Australia. The TGA has updated the product Levetiracetam Japan. The MHLW and the information for ibrutinib PMDA have announced that the (Imbruvica®) to include safety Risk of neuroleptic package insert for moxifloxacin information relating to the risks malignant syndrome (Avelox®) has been updated to of ventricular tachyarrhythmia, include the risk of hepatitis B reactivation and Japan. The MHLW and the rhabdomyolysis as a clinically opportunistic infections. PMDA have announced that the significant adverse reaction. package insert for Ibrutinib is used for the Moxifloxacin is an antibiotic levetiracetam (E Keppra®) has treatment of certain types of used for the treatment of a been updated to include the blood cancers, including mantle number of bacterial infections. risk of neuroleptic malignant cell lymphoma and syndrome as a clinically Two cases associated with Waldenstrom's significant adverse reaction. rhabdomyolysis have been macroglobulinaemia chronic reported in Japan, of which lymphocytic leukaemia Levetiracetam is used for the causal relationship could not be (including small lymphocytic treatment of seizures in excluded. lymphoma). epilepsy patients.

In a 2017 study of relevant A total of three cases case reports from post- associated with neuroleptic marketing sources and clinical malignant syndrome have been WHO Pharmaceuticals Newsletter No. 6, 2017  8 Regulatory Matters

Reference: Revision of Precautions,

MHLW/PMDA, 17 October 2017 (www.pmda.go.jp/english/)

Terbinafine Risk of acute generalized exanthematous pustulosis India. The PvPI, IPC has made recommendations to the

CDSCO about revising the drug safety label for terbinafine to include acute generalized exanthematous pustulosis as a potential adverse drug reaction.

Terbinafine is indicated for the treatment of fungal infections. Between July 2011 and August 2017, PvPI received four reports of acute generalized exanthematous pustulosis with terbinafine use. The cases were reviewed by SRP-PvPI, IPC who concluded that there was a strong causal relationship between terbinafine and acute generalized exanthematous pustulosis in these cases.

Reference:

Based on the communication from IPC, NCC-PvPI, India, November 2017 (www.ipc.gov.in)

WHO Pharmaceuticals Newsletter No. 6, 2017  9 Safety of Medicines

Angiotensin Chlorhexidine is a broad- particular care should be taken spectrum antiseptic which is in patients at risk of converting enzyme effective against gram-positive constipation. (ACE) inhibitors and and gram-negative bacteria on Clozapine is an atypical the skin and is widely used to angiotensin II antipsychotic drug. receptor blockers reduce the risk of bacterial infection. In the United Kingdom, there (ARBs) have been 370 reports of This review was conducted gastrointestinal obstruction Avoid during pregnancy following recent international associated with clozapine safety alerts regarding serious between 3 August 1993 and 11 France. L’Agence Nationale de allergic reactions reported with September 2017. In this time Sécurité du Médicament et des antiseptic products containing period, there have also been Produits de Santé (ANSM) has chlorhexidine. reminded health-care 135 reports of faecaloma and professionals that the use of The review concluded that 86 of paralytic ileus. there was no significant angiotensin converting enzyme The risk of gastrointestinal increase in the total number of (ACE) inhibitors and adverse effects is long adverse event reports angiotensin II receptor established with clozapine. associated with chlorhexidine blockers (ARBs) are Warnings are provided in the hypersensitivity received by contraindicated during the Summary of Product the HSA over the past years. second and third trimesters of Characteristics and Patient Fifteen reports of anaphylactic pregnancy and not Information Leaflet and in the reactions related to recommended for use during British National Formulary. chlorhexidine were identified the first trimester. However, in August 2017, a over a span of 36 years (1981 Coroner investigating a death ACE inhibitors and ARBs are to 2017). indicated for the treatment of raised concerns to the MHRA hypertension in adults. Health-care professionals are that health-care professionals advised to inform patients to might have a lack of awareness The ANSM stated that, despite stop using the product and about the risk of pseudo- the recommendation not to use seek immediate medical obstruction or paralytic ileus ACE inhibitors and ARBs during attention if they experience and the fast onset. the first trimester and the symptoms of a serious allergic Patients are advised that if contraindications in the second reaction, such as wheezing, they develop constipation, they and third trimesters, pregnant swelling of the face, or severe should tell their doctor women continue to be exposed rashes. during pregnancy, which may immediately before taking the have serious or even fatal Reference: next dose of clozapine. Product Safety Alerts, HSA, 29 consequences for the fetus or The MHRA stated that it is vital September 2017 new born. that constipation is recognised (http://www.hsa.gov.sg/) Reference: early and actively treated. (See Page 5 and WHO Pharmaceuticals Point d’information, ANSM, 18 Reference: October 2017, France Newsletters No.2, 2017: Rare but serious allergic reactions in the USA and No.3, 2016: Drug Safety Update, MHRA, (www.ansm.sante.fr) Serious allergic reactions in Canada) Volume 11, issue 3: 4, October (See WHO Pharmaceuticals Newsletter No.4, 2017 (www.gov.uk/mhra)

2012: Fetal malformations and candesartan use in pregnancy in Australia) Clozapine Febuxostat Potentially fatal risk of Chlorhexidine intestinal obstruction, faecal Potential risk of heart- impaction, and paralytic related death Risk of serious allergic ileus reactions USA. The US Food and Drug The United Kingdom. The Administration (FDA) has Singapore. The Health Medicines and Healthcare alerted the public that Sciences Authority (HSA) has Products Regulatory Agency preliminary results from a informed health-care (MHRA) has reminded health- safety clinical trial showed an professionals about the care professionals that increased risk of heart-related outcome of its review on the clozapine (Clozaril®, death with febuxostat known risk of allergic reactions, Denzapine®, Zaponex®) is (Uloric®). including anaphylactic contraindicated in patients with reactions, with chlorhexidine- Febuxostat is approved to treat paralytic ileus and when gout in adults. containing products. prescribing clozapine,

WHO Pharmaceuticals Newsletter No. 6, 2017  10 Safety of Medicines

The product information for hair loss with finasteride 1 mg. flupirtine-containing medicines febuxostat already carries a The risk of depression is also for pain relief. warning about cardiovascular associated with finasteride 5 Flupirtine is an analgesic used events, based on information mg treatment for benign to treat acute pain in patients from clinical trials that showed prostatic hypertrophy. who cannot use other pain a higher rate of heart-related Finasteride at a dose of 1mg medicines such as opioids or problems in patients treated (Propecia® and generics) is nonsteroidal anti-inflammatory with febuxostat compared to indicated for the treatment of medicines (NSAIDs). an alternative treatment, androgenic alopecia and, at a allopurinol. These problems The review was requested by dose of 5mg (Chibro-Proscar® included heart attacks, strokes the German medicines and generics), is indicated to and heart-related deaths. As a authority and follows a treat and control benign result, the FDA required an previous EMA review in 2013 prostatic hyperplasia. additional post market safety which introduced measures to clinical trial to increase Since the commercialization of restrict the use of these understanding of these Propecia®, psychiatric adverse medicines due to concerns of differences. effects have been reported, serious liver problems. suggesting a possible link The safety trial was conducted Risk minimization measures between finasteride and in over 6,000 patients with included limiting the use of depression or suicidal thoughts. gout, treated with either flupirtine to no more than two The risk of depression is also febuxostat or allopurinol. The weeks and introducing liver mentioned in the Summary of preliminary results show that function tests before and Product Characteristics (SmPC) overall, febuxostat did not during treatment. The EMA also and package leaflet of Chibro- increase the risk of combined requested that studies were Proccar®. cardiac events compared to conducted to show if these allopurinol. However, when Following the latest European restrictions were effective in cardiac outcomes were safety report on these reducing the risks. Results evaluated separately, medicines, the EMA has suggest that despite a febuxostat showed an requested an amendment to reduction in the overall use of increased risk of heart-related the information documents for flupirtine, it is still being used deaths and death from all all 1 mg and 5 mg medicinal outside the restrictions causes. products to warn health introduced in 2013. professionals and patients Furthermore, cases of serious Reference: about the risk of mood changes, liver damage associated with Drug Safety Communication, suicidal ideation and this medicine have continued US FDA, 11 November 2017 (www.fda.gov) depression. Finasteride to be reported. treatment should be EMA’s PRAC has therefore (See WHO Pharmaceuticals Newsletter No.3, discontinued in the presence of begun a further review to re- 2016: Risk of heart failure in Canada) any psychiatric symptoms. evaluate the benefits and risks The ANSM also reminds health for these medicines and decide care professionals that adverse whether additional regulatory drug reactions related to actions should be taken. Finasteride decrease in libido, erectile Reference: dysfunction and ejaculation News and press releases, EMA, Risk of depression and disorders can persist after 27 October 2017 suicidal thoughts stopping the drug. (www.ema.europa.eu) Reference: France. L’ANSM has informed patients and health-care Point d’information, ANSM, 26 professionals of the risk of October 2017, France (www.ansm.sante.fr) depression and suicidal Gabapentin thoughts with the use of finasteride. Risk of severe respiratory L’ANSM recommends treatment depression interruption and additional Flupirtine-containing monitoring should be medicines The United Kingdom. The considered if patients MHRA has stated that experience a change in mood Review of benefit risk gabapentin (Neurontin®) has during treatment with balance been associated with a rare finasteride. Cases of risk of severe respiratory depression and, more rarely, Europe. The EMA has initiated depression even without use of suicidal ideation have been a safety review of the benefits concomitant opioid medicines. observed in men treated for and risks related to the use of

WHO Pharmaceuticals Newsletter No. 6, 2017  11 Safety of Medicines

Gabapentin is an anti-epileptic infusion into a vein and are Intraocular vancomycin is used drug indicated for: used as blood volume by many ophthalmologists  partial seizures with and expanders to prevent shock during cataract surgery with without secondary following acute bleeding. the intent of preventing generalisation postoperative endophthalmitis. The review was after utilization  peripheral neuropathic pain There is no FDA-approved studies indicated that HES- such as painful diabetic vancomycin formulation for containing medicines were neuropathy and post- intraocular injection. The being used outside their herpetic neuralgia in adults. formulation is usually prepared authorised uses, including in at the surgical site or obtained In the United Kingdom, there critically ill patients and those in advance of surgery from a have been 50 reports of with sepsis and kidney injury, compounding pharmacy. respiratory depression or despite restrictions introduced dyspnoea associated with in 2013 to reduce the risks of The FDA received a report in gabapentin between 19 February kidney problems and deaths. August 2017 of bilateral HORV 1996 and 1 September 2017. in a patient following injections The drug utilization studies had Of these cases, 17 report of a compounded TMV been requested by EMA’s PRAC opioids as co-suspect or formulation in each eye after in 2013 in order to verify concomitant medications. cataract surgery procedures adherence to restrictions. that were done two weeks The MHRA has advised health- The PRAC will review the apart. care professionals to be aware results of these studies and all of the risk of central nervous No cases of HORV were other available data, and system (CNS) depression, reported in a retrospective assess the impact on the including severe respiratory analysis of medical records of benefit-risk balance of HES- depression, with gabapentin 922 patients (1541 eyes) who containing medicines for and to consider whether dose underwent cataract surgeries infusion, and issue a adjustments might be with intravitreal injections of recommendation on whether necessary in patients at higher compounded TMV formulations marketing authorizations risk of respiratory depression, from November 2013 to should be maintained, varied, including elderly people, December 2015. The adverse suspended or withdrawn across patients with compromised event being reported here the EU. respiratory function, serves as a reminder that respiratory or neurological Reference: intraocular administration of disease, or renal impairment, News and press releases, EMA, vancomycin, including when and patients taking other CNS 27 October 2017 the vancomycin is one of depressants. (www.ema.europa.eu) multiple active ingredients in a compounded drug, can result in Reference: HORV. Drug Safety Update, MHRA, Volume 11, issue 3: 2, October Reference: 2017 (www.gov.uk/mhra) Intraocular injections Drug Safety Communication, of a compounded US FDA, 3 October 2017 (www.fda.gov) triamcinolone, moxifloxacin and Hydroxyethyl-starch vancomycin (TMV) containing medicines formulation Isotretinoin New review of benefit-risk Not recommended for use balance Rare reports of erectile during cataract surgery dysfunction and decreased Europe. The EMA has initiated libido a safety review of benefits and USA. The US FDA has stated that the prophylactic use of risks of medicines containing The United Kingdom. The intraocular vancomycin, alone hydroxyethyl-starch (HES). MHRA has stated that cases of or in a compounded drug sexual dysfunction, HES containing products are combining multiple active predominantly involving used for the management of ingredients such as erectile dysfunction and hypovolaemia (low blood triamcinolone, moxifloxacin, decreased libido, have been volume) caused by acute and vancomycin (TMV) reported rarely in patients (sudden) blood loss, where formulation, is generally not taking oral isotretinoin treatment with alternative recommended for use during (Roaccutane®) for severe acne. infusion solutions known as cataract surgery because of the ‘crystalloids’ alone is not risk of haemorrhagic occlusive In the United Kingdom, the considered to be sufficient. retinal vasculitis (HORV). MHRA have received 14 Yellow HES medicines are given by Card reports of sexual

WHO Pharmaceuticals Newsletter No. 6, 2017  12 Safety of Medicines dysfunction associated with isotretinoin between the 1985 and 7 September 2017. In the same time period, there have been 49 reports of erectile or ejaculation dysfunction, and 23 reports of decreased or loss of libido associated with isotretinoin. The MHRA has advised health- care professionals to be aware of reports of sexual adverse effects, including erectile dysfunction and decreased libido, in patients taking oral isotretinoin, indicated for severe acne. The exact incidence of these adverse reactions is unknown but is considered to be rare.

Reference:

Drug Safety Update, MHRA, Volume 11, issue 3: 3, October 2017 (www.gov.uk/mhra)

(See WHO Pharmaceuticals Newsletter No.1, 2017: Potential risk of impotence (erectile dysfunction) in Canada)

WHO Pharmaceuticals Newsletter No. 6, 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 16 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. Signal texts from UMC might be edited to some extent by WHO and may differ from the original version. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of Signal (page 20). 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].

Natalizumab and rapidly evolving central nervous system lymphoma Mr Daniele Sartori and Dr Birgitta Grundmark, Uppsala Monitoring Centre

Summary incidence age ranges and altered immunosurveillance in the CNS mediated by Natalizumab is an 4b1-integrin inhibitor which natalizumab in immunocompetent patients limits lymphocyte passage through the blood–brain suggest that natalizumab potentially has a role barrier. With its immunomodulation properties it is in a rapid progression of CNSL. approved and mainly used for the treatment of multiple sclerosis (MS). In the United States it is approved also for Crohn’s disease. Introduction As of May 2015 there were 16 cases of central Natalizumab is a recombinant humanized nervous system lymphoma (CNSL) in association antibody that prevents lymphocytes from with natalizumab reported to VigiBase, the WHO entering the central nervous system (CNS) and global database of individual case safety reports, the small intestine.1 Natalizumab selectively originating from five countries. The combination binds to the 4 subunit of the 4b1 integrin was highlighted in VigiBase with an IC value of 3.12 complex (Very Late Antigen, VLA4) inhibiting in the third quarter of 2013. A literature review has its interaction with vascular cell adhesion brought forward five cases, four of which are molecule 1 (VCAM-1), thus interfering with the included in the VigiBase case series here presented. extravasation of lymphocytes. It thereby After the elimination of duplicates and the gathering reduces inflammatory activity in the brain, for of literature cases, 12 cases have been considered instance in multiple sclerosis (MS). Treatment for discussion. The age of the patients ranges from is administered through intravenous infusions 28 to 59 years, with a median of 44 years. None of of 300 mg once per month.2 Natalizumab’s the patients was reported to be approved indications are relapsing remitting immunocompromised. Patients were diagnosed with MS, and in the United States also Crohn’s CNSL after the third dose in six cases, after the disease. It is mainly used for the treatment of seventh in two, while in three patients a biopsy was MS which is mirrored in that in over 90% of performed before the third. Only one case reflected the total number of case reports for a longer treatment of 21 cycles before the onset of natalizumab in VigiBase (121,115 reports as of CNSL. Q3 2016) MS is stated as the indication for Differential diagnosis between CNSL and MS may be treatment. difficult, which has to be taken into account when MS is an autoimmune chronic inflammatory assessing the signal. A consistent pattern of very condition, the pathogenesis of which is still to short duration of treatment before diagnosis, be fully characterized, but it is accompanied by apparent abrupt and rapid development of disease, a dysregulation of the blood-brain barrier a median age of reported cases outside high- leading to an increased permeability and

WHO Pharmaceuticals Newsletter No. 6, 2017  14 Signal trafficking of lymphocytes. Natalizumab has positive progressive lymphoma disease) and 26 with effects in MS, thanks to its VLA4-VCAM-1 complex immunostimulants. As of Q3 2016, the inhibiting action. In healthy individuals, the vascular combination natalizumab-central nervous parenchyma of the blood–brain barrier restricts the system lymphoma has an IC of 3.18. access to the CNS, making it an immunoprivileged In the case series considered, eight patients site. VCAM-1 is minimally expressed on endothelial were female and four were males. Their blood brain barrier cells, but pro-inflammatory average and median age were 46 and 44 years stimuli (such as tumour necrosis factors or respectively, age ranging from 28 to 59 years. interleukins) and chronic inflammatory conditions Natalizumab was the only suspected drug in 11 (such as MS) trigger its upregulation, facilitating reports and in the remaining one lymphocyte entry into the CNS.3 methylprednisolone, azathioprine, interferon Primary central nervous system lymphoma (CNSL) beta-1a, methotrexate and cytarabine were co- is mainly of the diffuse large B-cell type.4 It is a suspects (although the last two were given as rare disease with incidence rates higher in males CNSL therapy). The duration of natalizumab than females (0.8 vs 0.5 per 100,000 person- treatment before diagnosis ranged from 1 to years)5 and the median age of diagnosis is 65 years. 21 cycles, with a median of 3. CNSL cases The incidence rate in the age range between 55 and reported with natalizumab are summarized in 64 year-olds is 0.85 (0.83-0.93, 95% CI) per Table 1. 100,000, in the age range 45 to 54 years it is 0.45

(0.42-0.48, 95% CI) per 100,000, the rate from ages 35 to 44 is 0.27 per 100,000 (0.25-0.30, 95% Literature and Labelling CI), and between 20 and 34 years the rate is 0.11 (0.10-0.12, 95% CI).6 The EU SmPC for natalizumab states the following regarding malignancies: “No The most prominent risk factor for primary CNSL is differences in incidence rates or the nature of immunosuppression, e.g. AIDS-related.7 Epstein- malignancies between natalizumab- and Barr virus (EBV) has been consistently found in placebo-treated patients were observed over immunosuppressed primary CNSL patients, two years of treatment. However, observation although immunosuppression may also promote over longer treatment periods is required CNSL in EBV-negative patients.8 EBV positive before any effect of natalizumab on lymphomas in the central nervous system of malignancies can be excluded”. The summary immunocompetent individuals are rare and usually safety profile further states: “in placebo- secondary to lymphomas originating elsewhere.9,10 controlled trials in 1,617 MS patients treated Diagnostic imaging of CNSL and MS can overlap and with natalizumab for up to two years (placebo: one may be misinterpreted for the other. Both 1,135)”.2 Known active malignancies are, as conditions initially respond well to high doses of per the EU SmPC, listed as contraindications steroids. Brain biopsy can rule out MS if a present while the US FDA label lists lymphoma as a lymphoma has not been significantly affected by contraindication to treatment.15 steroid treatment.11 Development of malignancies in MS has been linked to immunosuppressive A literature review revealed five case reports therapies, but not significantly associated with documenting CNSL in association with immunomodulators.12 MS patients were in the past natalizumab. Four of them have been identified considered to be at a lower risk of malignancies13, as cases already present in VigiBase (see though recently an increase in breast cancer risk “Literature Reference” column in Table 1), has been pointed out.14 based on patient demographics, concomitant drugs, reported events and case narratives. An abstract reports two cases (not included in the case series) with sparse information, one of Reports in VigiBase which concerned a 38-year-old woman As of May 2015, there were a total of 16 cases of diagnosed with primary CNSL 22 months after natalizumab in association with the MedDRA starting natalizumab, which concludes that preferred term “Central nervous system lymphoma” CNSL should be carefully considered in patients in VigiBase, the WHO global database of individual suspected of having MS, and that biopsies case safety reports; after removal of duplicates 12 should be considered in patients with unusual cases remained. All cases were serious, save one, lesions. It also adds that natalizumab should the seriousness of which was not reported. The be used with care if CNSL is suspected as it countries of origin were: United States (n=5), decreases immunosurveillance and allows United Kingdom (n=3), Germany (n=2), Australia lesions to expand rapidly.16 and France (1 each).

The combination had been highlighted in Q3 2013 with an IC of 3.12. As a comparison, as of June 2016, there were 247 reports of CNSL in VigiBase, 141 reported in relation with immunosuppressants, 84 with anti-neoplastics (mainly reporting

WHO Pharmaceuticals Newsletter No. 6, 2017  15 Signal

Table 1. Overview of case reports of central nervous system lymphoma in association with natalizumab in VigiBase

Other suspected (S) or Duration of Reported reactions Literature Case Age/Sex Comments concomitant (C) drugs treatment (MedDRA preferred terms) reference 1 40/M Antidepressants (C) 21 cycles B-cell lymphoma, Non- EBV negative Schweikert et 17 Hodgkin’s lymphoma, HIV negative al. cerebral lymphoma, central nervous system lymphoma Azathioprine one month washout before natalizumab treatment 2 40/M - 7 cycles Cerebral lymphoma Treated with interferon beta 1b, later - with beta 1a and steroids for flare ups. Discontinuation of previous treatments in favor of natalizumab Lymphoma confirmed by biopsy

3 28/M - 7 cycles Cerebral lymphoma Three years before diagnosis 4 doses of Na et al.25 mitoxantrone received. Six months before diagnosis, patient MRI did not show lymphoma. EBV IgG present EBV IgM absent HIV negative

4 40/F Azathioprine, 3 cycles Death, diffuse large B-cell Diagnosis confirmed through Matzke et al.26 or 44/F methylprednisolone (both lymphoma biopsy JC negative S) EBV negative Interferon beta 1a (C) Cumulative dose of 12 g of azathioprine, stopped four years before natalizumab first dose

5 55/F - 3 cycles Central nervous system Age at higher risk for CNSL Sharaf et al.27 lymphoma 6 58/F - 3 cycles Central nervous system Age at higher risk for - lymphoma, acute confusion CNSL Biopsy state, brain lesion, bladder confirmed CNSL infection JC negative ruled out suspicion of PML 7 -/F - 3 cycles Central nervous system Initially diagnosed with MS, treated with - lymphoma, medication error natalizumab. Drug was stopped when MS was “later discovered” to be CNSL

8 45/M Sertraline, pantoprazole, 3 cycles Central nervous system Initially diagnosed with MS, - baclofen, paracetamol (all lymphoma, diffuse large B- treated with natalizumab. Suspect C) cell lymphoma, enterococcal of misdiagnosis bacteraemia, urinary tract Treatment interrupted after MRI and infection pseudomonal biopsy confirmed CNSL. Causality unrelated.

9 39/F Tramadol, hydrocortisone, 3 cycles Central nervous system Diagnosis confirmed through biopsy - methylprednisolone, lymphoma, convulsion, Attention deficit disorder levetiracetam, amitriptyline, bradyarrhythmia, multiple Familial history of epilepsy 16 year lorazepam, tocopherol, sclerosis history of MS ethinylestradiol/ Status epilepticus triggered drospirenone, clonazepam, ondansetron, colecalciferol, hospitalization and diagnosis of lymphoma amphetamine/ dextromethamphetamine, Causality was reported as unrelated esomeprazole, oxycodone, prednisone, phenytoin, zolpidem (all C)

10 41/F - 2 cycles Central nervous system Diagnosis confirmed through biopsy - lymphoma Lesion detected by MRI which grew “rapidly” after therapy with natalizumab Causality according to reporter: unrelated despite reporter noted deterioration of condition 11 56/F Modafinil, prednisone, 1 cycle Central nervous system Age at higher risk for CNSL Sjögren’s - cyclophosphamide, lymphoma, post lumbar syndrome as added risk fluoxetine (all C) puncture syndrome, multiple Time of diagnosis: approximately 2 weeks sclerosis relapse, pneumonia, infection 12 59/F Omeprazole, 1 cycle Central nervous system Age at higher risk for CNSL - hydrochlorothiazide/ lymphoma, acute respiratory Limited number of cycles strongly argue olmesartan, medoxomil/ failure against a role of natalizumab amlodipine besilate, temazepam, pravastatin, risedronic acid (all C)

WHO Pharmaceuticals Newsletter No. 6, 2017  16 Signal

The index case, brought forward by Schweikert et al, A clinical finding reported to be indicative of an concerns a 40-year-old male who developed CNSL immunosuppression-related lymphoma is the after 21 doses of natalizumab. The patient was presence of EBV: two cases (cases 1 and 4) initially diagnosed with MS through MRI and CSF were found to be EBV negative and another analysis at the age of 37 and responded well to one (case 3) did not have an active EBV methylprednisolone. He underwent treatment with infection. Epstein-Barr virus can be identified in interferon beta-1a after a year and was later almost every (99%) patient affected by MS.21 diagnosed with remitting relapsing MS after an MRI Given that profound immunosuppression can showed new white matter lesions. A brain biopsy induce CNSL and that MS patients are treated was performed, which was consistent with MS. with immunosuppressive agents, it should also Treatment with interferon was suspended and be noted that previous treatments such as azathioprine was started. The worsening of his azathioprine may have oncogenic effects.22 condition prompted new methylprednisolone pulses Nevertheless, natalizumab is not known to and after a one-month washout period from induce strong immunosuppression, moreover azathioprine the patient was started on natalizumab. in the patient who had been treated with Roughly two years later, a new brain biopsy showed azathioprine the cumulative dosage was low a diagnosis of CNSL, and natalizumab was (12 grams). discontinued. PCR for EBV was negative, as well as Cases 7 and 8 both report the events as HIV tests, suggesting immunocompetence and patients being misdiagnosed with MS, later arguing against an immunosuppression-related changed to CNSL. These findings highlight the lymphoma.17 necessity of thorough differential diagnostic An additional case was presented by Phan-Ba et al: investigations. a 40-year-old male, complaining of blurred vision, It is worth noting that in most cases the headaches and attention disorder and with a 20- patients have been diagnosed with MS several year history of MS was treated with two courses of years before the initiation of natalizumab or natalizumab after two high steroid pulses. An EBV the occurrence of CNSL. This may either point negative CNSL was diagnosed and treated with in the direction of a causal role of the drug or polychemotherapy, leading to reduction of tumour in a confounding by indication; the reason for mass. The authors suggested a natalizumab- the initiation of a new drug being an as yet dependent lymphomagenesis to be unlikely, instead undetected or misdiagnosed CNSL. The reason discussing its potential to speed up lymphoma for changing to, or initiation of natalizumab is progression.18 not clearly stated in any of the reports, however, the approved indication for natalizumab is second-line treatment for Discussion and Conclusion patients in whom first-line treatments have CNSL has so far not been noted as an issue in long- failed and for patients with rapidly evolving term study results on the safety of natalizumab.19,20 severe relapsing remitting MS. However, in This is not to be expected in smaller studies some of the cases (cases 1 and 3), there is considering the rarity of the disease per se. The documentation of a thorough investigation cases in VigiBase, which complement the ones before the initiation of the drug (e.g. MRI, found in the reviewed literature, may still support a biopsy) without any indication of an existing potential association between the medicinal product CNSL before start of treatment with the drug. and the events. In light of this, a hypothesis could be that The occurrence of 12 cases of uncommon natalizumab may play a role in the rapid malignancy in temporal relation to treatment with progression of a pre-existing cerebral natalizumab raises questions on the possibility of lymphoma. This could be supported by the causality. Six of the cases (cases 1, 2, 3, 4, 8, 9) mechanism through which natalizumab exerts occurred in patients far below the median age of therapeutic action, which might also make it a CNSL diagnosis, five of which showed a consistent promoter of malignant cell growth by reducing time to diagnosis pattern with a median of three CNS immunosurveillance. Within the case administrations and hence only three months prior series, the original extract of case 10 reports a to the diagnosis. These six patients were not rapid growth of a previously identified lesion reported to be immunocompromised. The reporters after two infusions of natalizumab, compatible of three cases (cases 8, 9, 10) considered the CNSL with the history of the case presented by Phan to be unrelated to natalizumab. Ba et al. Two cases (cases 11 and 12) were identified only In conclusion, despite uncertainties regarding a after one dose of treatment making a role of causal role of natalizumab in the rapid natalizumab less plausible. In addition, a patient’s progression of central nervous system age could increase the risk of independent lymphoma23, 24, the addition of VigiBase data development of CNSL, which should also be to existing literature case reports may add accounted for in cases 5 and 6 (albeit these two sufficient evidence to discuss the need for an were diagnosed within median range of treatment update of the safety profile of natalizumab. duration). The presented case series includes CNSL WHO Pharmaceuticals Newsletter No. 6, 2017  17 Signal

patients well below the median age of diagnosis, 8. Bashir RM, Hochberg FH, Harris NL, Purtilo not reported to have been immunocompromised at D. Variable expression of Epstein-Barr virus the time of investigations and with consistent time genome as demonstrated by in situ to diagnosis. Moreover, a natalizumab-induced hybridization in central nervous system reduction in CNS immunosurveillance is proposed as lymphomas in immunocompromised a plausible biological mechanism for the evolution or potentiation of CNSL. Confounding due to missed patients. Mod Pathol. 1990;3(4):429-34. CNSL diagnosis and attribution of symptoms to MS 9. Commins DL. Pathology of primary central progression as opposed to CNSL growth/progression nervous system lymphoma. Neurosurgical should be accounted for. At the same time there focus. 2006;21(5):E2. appears to be a need for thorough diagnostic 10. Krogh-Jensen M, Johansen P, D’Amore F. investigations before initiating natalizumab as a Primary central nervous system lymphomas second or later line of treatment in MS, given the overlapping symptoms and imaging of the two in immunocompetent individuals: histology, conditions, the apparent improvement of CNSL Epstein-Barr virus genome, Ki-67 lesions after steroid treatment and the possibility proliferation index, p53 and bcl-2 gene that natalizumab may have a role in rapid expression. Leuk Lymphoma. 1998;30(1- progression of CNSLs. 2):131-42. 11. Hunt MA, Jahnke K, Murillo TP, Neuwelt EA. Distinguishing primary central nervous References system lymphoma from other central 1. Ransohoff RM. Natalizumab for Multiple Sclerosis. nervous system diseases: a neurosurgical N Engl J Med. 2007;356(25):2622-9. perspective on diagnostic dilemmas and 2. Electronic Medicines Compendium: Summary of approaches. Neurosurgical focus. Product characteristics for natalizumab 2006;21(5):E3. (Tysabri®). Available from: https://www. 12. Lebrun C, Vermersch P, Brassat D, Defer G, medicines.org.uk/emc/medicine/18447. Rumbach L, Clavelou P, et al. Cancer and Accessed: 2016-10-19. multiple sclerosis in the era of disease- 3. Steffen BJ, Butcher EC, Engelhardt B. Evidence modifying treatments. J Neurol. for involvement of ICAM-1 and VCAM-1 in 2011;258(7):1304-11. lymphocyte interaction with endothelium in 13. Kingwell E, Bajdik C, Phillips N, Zhu F, Oger experimental autoimmune encephalomyelitis in J, Hashimoto S, et al. Cancer risk in the central nervous system in the SJL/J mouse. multiple sclerosis: findings from British Am J Pathol. 1994;145(1):189-201. Columbia, Canada. Brain 2012 4. Hattab EM, Martin SE, Al-Khatib SM, Kupsky WJ, Oct;135(10):2973-9. Vance GH, Stohler RA, et al. Most primary 14. Sun LM, Lin CL, Chung CJ, Liang JA, Sung central nervous system diffuse large B-cell FC, Kao CH. Increased breast cancer risk for lymphomas occurring in immunocompetent patients with multiple sclerosis: a individuals belong to the nongerminal center nationwide population-based cohort study. subtype: a retrospective analysis of 31 cases. Eur J Neurol. 2014 Feb;21(2):238-44. Mod Pathol. 2010;23(2):235-43. 15. US Food and Drug Administration: Product 5. O’Neill BP, Decker PA, Tieu C, Cerhan JR. The label for natalizumab (Tysabri®). Available changing incidence of primary central nervous from: http://www.accessdata. system lymphoma is driven primarily by the fda.gov/drugsatfda_docs/label/2016/12510 changing incidence in young and middle-aged 4s953s955lbl.pdf. Accessed: 19 October men and differs from time trends in systemic 2016. diffuse large B-cell non-Hodgkin’s lymphoma. 16. Longbrake E, Schmidt R, Cross A, Alvarez E. Am J Hematol. 2013;88(12):997-1000. Primary Central Nervous System Lymphoma 6. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Mimicking Multiple Sclerosis With Y, Dowling J, et al. CBTRUS statistical report: Spontaneously Remitting Lesions. primary brain and central nervous system Neurology 2014 April;82(10) Suppl. P5.172. tumors diagnosed in the United States in 2007- 17. Schweikert A, Kremer M, Ringel F, Liebig T, 2011. Neuro-oncology. 2014;16 Suppl 4:iv1- 63. Duyster J, Stüve O, et al. Primary central 7. Villano JL, Koshy M, Shaikh H, Dolecek TA, nervous system lymphoma in a patient McCarthy BJ. Age, gender, and racial differences treated with natalizumab. Ann Neurol. 2009 in incidence and survival in primary CNS Sep;66(3):403-6. lymphoma. Br J Cancer. 2011;105(9):1414-8.

WHO Pharmaceuticals Newsletter No. 6, 2017  18 Signal

18. Phan-Ba R, Bisig B, Deprez M, De Prijck B, 23. Ransohoff RM. Natalizumab, multiple Delrue G, Herens C, et al. Primary central sclerosis, and primary central nervous nervous system lymphoma in a patient treated system lymphoma: enigma, wrapped in with natalizumab. Ann Neurol. 2011;69(6):1060- mystery, enclosed in conundrum. Ann 1. Neurol. 2009;66(3):259-61. 19. Butzkueven H, Kappos L, Pellegrini F, Trojano M, 24. Bozic C, LaGuette J, Panzara MA, Sandrock Wiendl H, Patel RN, et al. Efficacy and safety of AW. Natalizumab and central nervous natalizumab in multiple sclerosis: interim system lymphoma: no clear association. observational programme results. J Neurol Ann Neurol. 2009;66(3):261-2. Neurosurg Psychiatry. 2014;85(11):1190-7. 25. Na A, Hall N, Kavar B, King J. Central 20. Planas R, Martin R, Sospedra M. Long-term nervous system lymphoma associated with safety and efficacy of natalizumab in relapsing- natalizumab. J Clin Neurosci. 2014 remitting multiple sclerosis: impact on quality of Jun;21(6):1068-70. life. Patient related outcome measures. 26. Matzke M, Schreiber S, Elolf E, Metz I, 2014;5:25-33. Mawrin C, Heinze HJ, et al. Natalizumab- 21. Sumaya CV, Myers LW, Ellison GW. Epstein-Barr associated central nervous system virus anti-bodies in multiple sclerosis. Arch lymphoma?--another patient. Mult Scler. Neurol. 1980;37(2):94-6. 2012;18(11):1653-4. 22. Kandiel A, Fraser AG, Korelitz BI, Brensinger C, 27. Sharaf N, Shaunak S. Patient developed Lewis JD. Increased risk of lymphoma among primary CNS lymphoma after three courses inflammatory bowel disease patients treated of natalizumab. J Neurol Neurosurg with azathioprine and 6-mercaptopurine. Gut. Psychiatry. 2012;83(Suppl 2):A20. 2005;54(8):1121-5.

WHO Pharmaceuticals Newsletter No. 6, 2017  19 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 is information submitted to UMC; other National Centres do 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. 6, 2017  20 Feature

The 40th Annual Meeting of Representatives of the National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring

The WHO annual meeting of National Pharmacovigilance Centres (NPCs) is a platform for countries from around the world to meet and discuss pharmacovigilance issues. Each year an NPC participating in the WHO Programme for International Drug Monitoring hosts the meeting, and this year the National Drug Authority in Uganda welcomed delegates to the Speke Resort, Muyonyo in Kampala. More than 150 representatives from over 50 countries travelled to the resort to attend the four-day meeting from 7 to 10 November 2017. The meeting was opened by Dr Morries Seru, the commissioner of Health Services, Ministry of Health, Uganda. An enchanting ambience was created by Public Health Ambassadors Uganda, who performed a skit. The skit touched upon numerous important issues related to reporting of adverse effects, and was successful in communicating the importance of pharmacovigilance (PV) in a creative manor.

Preconference workshop On 6 of November a preconference workshop on Medical Dictionary for Regulatory Activities (MedDRA) in Pharmacovigilance was organized. MedDRA is a rich and highly specific standardised medical terminology to facilitate sharing of regulatory information internationally for medical products used by humans. MedDRA was developed in the early 1990s, and was based on terminology belonging to the Medicines and Healthcare products Regulatory Agency (MHRA). It was developed using the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) process by ICH partners.

WHO Pharmaceuticals Newsletter No. 6, 2017  21 Feature

The aim was to standardize international medical terminology for regulatory communication. In order to maintain the terminology and add terms, as medical knowledge grows, the ICH MedDRA Maintenance and Support Services Organization, MSSO has developed a maintenance process to ensure that MedDRA maintains a logical structure and consistency. VigiFlow, developed by the Uppsala Monitoring Centre and is a web-based individual case safety report management system, is available for use by National Pharmacovigilance Centres of the WHO PIDM. In the past it contained integrated international terminologies such as the WHO-Adverse Reaction Terminology (WHO-ART) dictionary as well as MedDRA. Many countries using VigiFlow enter data using WHO-ART, however the system will be using only MedDRA in the future, hence the need to support countries to switch from WHO-ART terminology to MedDRA was identified, and a training workshop was organized. Over 100 participants from over 30 countries arrived early in Kampala, to attend the MedDRA pre-course. Presentations on making the transition from WHO-ART to MedDRA and an introduction to MedDRA were made. Participants were then split into working groups and completed exercises together.

Meeting Structure and content This year, the meeting consisted of closed and open sessions. The closed session was by invitation only, and only nominees selected by PV focal points from NPCs were invited. In the open session, non-state actors such as the Bill and Melinda Gates Foundation (BMGF), International Society of Pharmacovigilance (ISOP), Council for International Organizations of Medical Sciences (CIOMS), and representatives from pharmaceutical industry (International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)) were invited.

Closed session At the end of each annual meeting of NPCs, participants are invited to suggest topics for the forthcoming annual meeting. This sets the agenda of the next meeting so that it reflects the needs of Member States. The theme of the 2017 meeting was “Smart-Safety Surveillance: When resources are limited”. The meeting sessions consisted of plenaries, updates, working groups, problems of current interest and tutorials. In the first plenary, Dr Shanthi Pal from WHO reported back on progress and achievements that WHO and WHO Collaborating Centres have made on the recommendations of the previous Annual Meeting in Oman Muscat 2016. Following this, an overview of the concept and progress of the Smart Safety Surveillance initiative was presented. An example of implementing a regional mechanism to strengthen PV capacity in the Caribbean was described. The second plenary on day-2 of the meeting consisted of success stories from Croatia, Democratic Republic of Congo, Japan and Uganda.

WHO Pharmaceuticals Newsletter No. 6, 2017  22 Feature

Updates Updates were given on ongoing PV studies in India and research on patient reporting and risk sprints; reporting mobile phone technology for ADR reporting in Burkina Faso and Zambia; and development of the PV undergraduate curriculum.

Signals of Current interest This session consisted of short presentations based on abstracts that were submitted prior to the meeting. Approximately 15 participants had the opportunity to present and discuss PV issues. A range of topics were presented which ranged from antibacterial resistance, signals identified with HIV, malaria and TB medicines, signals with reproductive health products and other particular ADRs of concern.

Tutorials Six different tutorials ran parallel to each other on each day and participants had the opportunity to choose three tutorials in total. The tutorial sessions included topics such as VigiFlow, active surveillance and developing a PV bulletin.

Working Groups Eight working groups were offered over a period of two days. Prior to the workshop, delegates were provided with a list of objectives and outcomes and had the opportunity to attend two workshops of preference. During each workshop, moderated discussions were held and attendees formulated and agreed on a list of recommendations that were specifically targeted at WHO, WHO CCs and/or the NPCs. A delegated rapporteur amongst the workshop participants presented to the whole delegation during the plenary session on the last day of the meeting. Working groups consisted of: 1) PV inspections: Needs, Capacity, Cooperation; 2) Risk Management Plans (RMPs) for teratogenic drugs; 3) Scope of Pharmacovigilance; 4) Risk Minimization Measures: Implementation & Responsibilities; 5) How do we measure impact of PV; 6) Role of Pharmacovigilance Centres in promoting quality use of medicines; 7) Communication of Pharmacovigilance actions; 8) Benefit-Risk Assessment: approaches. The recommendations from the working groups will be available in the next issue of the WHO Pharmaceuticals Newsletter.

WHO Pharmaceuticals Newsletter No. 6, 2017  23 Feature

Introducing the WHO Collaborating Centre for Pharmacovigilance in Public Health Programmes and Regulatory Services

We are pleased to announce that the Pharmacovigilance Programme of India (PvPI), Indian Pharmacopeia Commission (IPC), in Ghaziabad has been designated as the WHO Collaborating Centre for Pharmacovigilance in Public Health Programmes and Regulatory Services. WHO works with a network of more than 700 Collaborating Centres in 80 countries to support the implementation of mandated work. PvPI will support the WHO Programme for International Drug Monitoring to deliver WHO strategies and operational plans in pharmacovigilance. A work plan and terms of reference have been jointly agreed to include the following:  Support WHO to develop relevant tools and guidelines for enhancing Pharmacovigilance (PV) practice in low and middle income countries (LMIC) in Asia and beyond.  Contribute to capacity building of WHO Member States to establish high quality pharmacovigilance systems for medical products.  Scientific support to countries for pharmacovigilance in public health programmes (e.g. Tuberculosis, Neglected Tropical Diseases, Vector Borne Diseases, HIV-AIDS, Immunization Programmes) and regulatory issues.  Work-sharing and joint activities in regulatory pharmacovigilance

More information about the WHO Collaborating Centre for Pharmacovigilance in Public Health Programmes and Regulatory Services can be found on the WHO Medicines Safety website: http://www.who.int/medicines/regulation/medicines-safety/about/collab-centres-india/en/

WHO Pharmaceuticals Newsletter No. 6, 2017  24